Registered Members Login:
   
Forgotten Your Details? Click Here To Recover +
Welcome To The ShareCafe Community - Talk Shares And Take Stock With Smart Investors - New Here? Click To Register >

3 Pages (Click to Jump) V   1 2 3 >

PunkassDerm
Posted on: Feb 20 2019, 09:47 AM


Group: Member
Posts: 418

Last drop I believe was for the long delay and uncertainty. This time we have July 8 FDA decision date on the books. ASX 200 would be a nice prelude, early catalyst.

I get to to smirk as I drive off in a big smokey GT3 burnout, at the bozos who laughed at my 15 years sacrificed and invested.

Next to my smart smiling friends in their respective supercars!
  Forum: By Share Code

PunkassDerm
Posted on: Feb 19 2019, 06:51 AM


Group: Member
Posts: 418

If you shuffle the letters of Giles Delaney...does it spell Lord Voldemort?
  Forum: By Share Code

PunkassDerm
Posted on: Feb 16 2019, 01:43 PM


Group: Member
Posts: 418

Maybe announcement 1 week before inclusion? Its darn close either way! Like dividend record vs payment date.

....and you said that!
  Forum: By Share Code

PunkassDerm
Posted on: Feb 16 2019, 01:25 PM


Group: Member
Posts: 418

Last year March 18...it's the 8th this year?

EDIT:

https://www.marketindex.com.au/asx200

Could it be March 15? see link

Attached Image

  Forum: By Share Code

PunkassDerm
Posted on: Feb 13 2019, 08:39 PM


Group: Member
Posts: 418

Nostalgic for a naturally aspirated combustion engine and manual transmission. I suppose I'll have to invest in algae biofuel next to stave off electric cars. Carbon sequestration in process, cleaner than batteries in the long run. Kinda carbon neutral.

If I must go electric (hybrid) I'd suffer with a 918 Spyder.
  Forum: By Share Code

PunkassDerm
Posted on: Feb 13 2019, 02:22 PM


Group: Member
Posts: 418

Who knows what tomorrow brings...and I have 200k+ shares to play with. Don't wanna be Smaug.
Grateful for an extremely long, finally rewarding run. Toys.
  Forum: By Share Code

PunkassDerm
Posted on: Feb 13 2019, 02:12 PM


Group: Member
Posts: 418

I'd say stem cell injections plus Scenesse or new topical formulation, there might be something there.
  Forum: By Share Code

PunkassDerm
Posted on: Feb 13 2019, 02:01 PM


Group: Member
Posts: 418

Little diversion:


I sold my first 5K shares today (CLVLY), right at opening for 16.50. First purchase in 2004, time to take some profit and have a little fun.
I hope everyone with skin in the game has a little guilty pleasure coming, especially those who have endured and sacrificed. Mine arrived on Saturday and oh she purrs. Wish I could post a video of the exhaust note.

Cheers,

PAD

PS And she's a 3 pedal, the only way to go!



Attached Image


Attached Image


Attached Image

  Forum: By Share Code

PunkassDerm
Posted on: Feb 11 2019, 10:16 PM


Group: Member
Posts: 418

I dunno...maybe attempts to manipulate on message boards because lack of communication from corporate?

My guess still undervalued. What is the most recent research (reliable) target price? Makes me feel another breakout imminent.
Again, I am not a sophisticated investor but sounds like shorter speak?
  Forum: By Share Code

PunkassDerm
Posted on: Feb 4 2019, 01:59 PM


Group: Member
Posts: 418

Not sure if there was any more than a pilot study for acne, 3 patients. Acne Rosacea is a variant of acne. As an anti-inflammatory should help. But there are so many effective treatments out there. Isotretinoin can be curative in a 6 month course. There is no superior treatment for hidradenitis suppurativa (HS) though, maybe a more severe under-treated disease to focus on.

https://www.ncbi.nlm.nih.gov/pubmed/22845050

Beneficial effects of the melanocortin analogue Nle4-D-Phe7-α-MSH in acne vulgaris.
J Eur Acad Dermatol Venereol. 2014 Jan;28(1):108-11. doi: 10.1111/j.1468-3083.2012.04658.x. Epub 2012 Jul 27.


Böhm M1, Ehrchen J, Luger TA.

Abstract

BACKGROUND:
α-Melanocyte-stimulating hormone (α-MSH) is a melanocortin peptide that increases skin pigmentation during ultraviolet light-mediated tanning. As α-MSH has been shown to possess anti-inflammatory effects, we assessed the clinical potential of a superpotent α-MSH analogue, afamelanotide (Nle(4)-D-Phe(7)-α-MSH), in patients with acne vulgaris, the most common inflammatory skin disorder.

METHODS:
Afamelanotide (16 mg) was given in a phase II open-label pilot study subcutaneously as a sustained-release resorbable implant formulation to 3 patients with mild-to-moderate facial acne vulgaris. Evaluation included lesion count, adverse effects and patient-reported outcome. Monitoring of laboratory parameters included differential blood counts, electrolytes, urine analysis, and liver and kidney function tests. Skin melanin density was measured by reflectance spectrophotometry.

RESULTS:
The total number as well as the number of inflammatory acne lesions declined in all patients 56 days after the first injection of afamelanotide. Life quality as measured by Dermatology Life Quality Index likewise improved in all 3 patients 56 days after the first injection of afamelanotide. There were no adverse effects except mild and short-term fatigue in one patient. All patients experienced increased pigmentation especially on the face. Clinically relevant changes in laboratory parameters were not detected.

CONCLUSIONS:
Afamelanotide appears to have anti-inflammatory effects in patients with mild-to-moderate acne vulgaris. Future trials are needed to confirm the anti-inflammatory action of this melanocortin analogue in patients with acne vulgaris.
  Forum: By Share Code

PunkassDerm
Posted on: Feb 2 2019, 05:26 AM


Group: Member
Posts: 418

Just added some shares of PTN for shits n giggles, in case there is some major blockbuster there. I think i just started my own melanocortin SPDR/Hedge.
  Forum: By Share Code

PunkassDerm
Posted on: Feb 1 2019, 03:40 AM


Group: Member
Posts: 418

bremelanotide gets a focus page (5), afamelanotide gets another footnote.


https://www1.magellanrx.com/media/839400/mr...rx1119_0119.pdf


afamelanotide Clinuvel Erythropoietic porphyria Intradermal Submitted - NDA;
Fast Track; Orphan
Drug; Priority
Review
07/08/2019


bremelanotide AMAG Hypoactive sexual desire
disorder (premenopausal
women)
SC Submitted - NDA 06/21/2019




Women's Health
bremelanotide SC
AMAG


PROPOSED INDICATIONS
Hypoactive sexual desire disorder (HSDD) in premenopausal women

CLINICAL OVERVIEW
Bremelanotide is a melanocortin 4 receptor agonist that acts on the MC1 and MC4 receptors, which regulate
sexual behavior. Its proposed mechanism of action balances inhibitory and excitatory neural pathways in the
brain to restore sexual desire. Bremelanotide is intended to be used in anticipation of a sexual encounter.
Two pivotal, randomized, double-blind, placebo-controlled RECONNECT trials enrolled a total of 1,202
premenopausal women (≥ 18 years old; mean age 39 years) with HSDD and no psychological, gynecological,
or urological conditions suspected to contribute to the sexual dysfunction. In both trials, after 24 weeks of
treatment, bremelanotide demonstrated statistically significant improvement in desire, as measured by the
Female Sexual Function Index – Desire (FSFI-D) domain, and decrease in associated distress, as measured
by the Female Sexual Distress Scale – Desire/Arousal/Orgasm (FSDS-DAO) Desire score. While many
secondary endpoints were met and both studies reported improvement in the number of satisfying sexual
events (SSEs), the difference between bremelanotide and placebo in number of SSEs was not statistically
significant (64.4% versus 50.9% in Study 301 and 64.8% versus 47.3% in Study 302, respectively). The
most common adverse effects were transient mild nausea, flushing, and headache.
Bremelanotide was studied at a dose of 1.75 mg taken as-desired prior to a sexual encounter; no more
than 1 dose was taken every 24 hours. Bremelanotide was self-administered SC via an auto-injector.

PLACE IN THERAPY
HSDD is one facet of female sexual disorder. It occurs in approximately 5% to 13% of women, with a
peak incidence at around 40 to 60 years of age. In younger women, HSDD is frequently associated with
patient factors, such as dysfunctional relationships, chronic disease, depression, gynecologic disorders,
and use of certain medications (e.g., SSRIs). Diagnosis is usually made when symptoms cause distress or
negatively impact relationships.
Treatment of female sexual dysfunction should be individualized to address underlying physical,
psychological, and relational factors. It can include psychotherapy and pharmacotherapy (estrogen, shortterm testosterone, antidepressants [e.g., bupropion, SSRI]). However, currently available pharmacologic
therapies for female sexual dysfunction have limited efficacy and are associated with side effects and
potential risks. The only FDA-approved medication for HSDD in premenopausal women is the oral oncedaily serotonin agonist/antagonist, flibanserin (Addyi®). Flibanserin is taken at bedtime due to its sedative
affects and carries boxed warnings for alcohol consumption, hypotension, and syncope.
If approved, bremelanotide, a first-in-class melanocortin agonist, will provide a new mechanism and route
of administration to treat HSDD in premenopausal women. Unlike flibanserin, it is administered on an asdesired basis and can be safely used concurrently with alcohol.

FDA APPROVAL TIMELINE
June 21, 2019
  Forum: By Share Code

PunkassDerm
Posted on: Jan 28 2019, 10:35 AM


Group: Member
Posts: 418

I guess it can...and Scenesse can provide sufferers the independence to stay off of disability benefits (be productive members of society, dignity).

https://www.disabilitybenefitshome.com/disa...ility-benefits/


Winning SSDI or SSI for Porphyrias

Regardless of your health condition, the SSA will first determine whether a claimant meets the nonmedical requirements of SSI or SSDI. For SSDI this means the claimant will need to have sufficient work credits to be considered insured, and their condition must be expected to last for 12 continuous months. For SSI the claimant must be aged, blind or disabled and not be able to work for at least 12 continuous months. Additionally, they must meet the income and resource limitations of the SSI program.

Determining disability status for SSDI and SSI for Porphyrias

The Social Security Administration has two methods of determining whether a claimant is disabled: is there condition and corresponding symptoms listed in the SSA Listing of Impairments (or does it “meet or exceed” a listing) or do they have the residual capacity to work (this consideration is made through a medical vocational allowance).

There are several listings for porphyrias, and the listing which is used to evaluate your condition will depend on the type of porphyria. For instance, familial porphyria or erythropoietic protoporphyria are considered photosensitive disorders and can be evaluated under 8.0 Skin Disorders, Section 8.07 Genetic Photosensitive Disorders.

Under this listing the SSA will determine if your condition has caused “extensive skin lesions that have lasted or can be expected to last for a continuous period of at least 12 months or you do not have the ability to function outside of a “highly protective environment for a continuous period of at least 12 months.”

Other acute porphyrias which cause seizures or paralysis can be evaluated under separate listings which correspond to your symptoms. For instance, if you are experiencing seizures you may meet or exceed a listing under 11.00 Neurological.

Winning SSDI or SSI through a medical vocational allowance

If your condition does not meet or exceed a listing you will need sufficient evidence to prove you do not have the residual capacity to work. Through the medical vocational allowance process, the SSA will review your medical records and work history and determine whether you can continue to work your current job, previous job or retrain for new work given your age, education, work history, and health condition.
  Forum: By Share Code

PunkassDerm
Posted on: Jan 20 2019, 01:32 PM


Group: Member
Posts: 418

Maybe transition to cosmetics / regenerative medicine. Stem cells and MSH.

Cure HPV (warts), non-melanoma skin cancer and acne....we would be twiddling thumbs in derm.
  Forum: By Share Code

PunkassDerm
Posted on: Jan 20 2019, 12:38 PM


Group: Member
Posts: 418

Still in infancy, how many GI absorption peptides are currently on market? How far off?

I'm still waiting for my safe tan anti-inflammatory drug.

Totally ready to retire at 200/share. But I'll take 300.
  Forum: By Share Code

PunkassDerm
Posted on: Jan 20 2019, 11:23 AM


Group: Member
Posts: 418

Seems purposefully vague. The intention to monopolize an entire class without actually have a drug? Would this sort of patent have any teeth legally? I nothing of drug patents.

Claiming a patent for every variant of a structure.
  Forum: By Share Code

PunkassDerm
Posted on: Jan 20 2019, 07:54 AM


Group: Member
Posts: 418

That's why I saw a study co-administered with a PPI. Already an issue. Thanks! Gotta take a second med just for absorption?

Oh wait...they could use cimetidine.
  Forum: By Share Code

PunkassDerm
Posted on: Jan 20 2019, 05:47 AM


Group: Member
Posts: 418

See disclosures at the end...This is race, and they better speed it up.


https://www.medpagetoday.com/dermatology/ge...rmatology/52419


Novel Drug Works for Photosensitivity
Side effect profile acceptable


by Kay Jackson, Contributing Writer, MedPage Today
July 02, 2015

Action Points
The alpha-melanocyte-stimulating hormone analogue, afamelanotide, appears to be safe and efficacious in the treatment of erythropoietic protoporphyria -- the rare condition whose sufferers become people of the night.
Afamelanotide had an acceptable side-effect and adverse-event profile and improved the quality of life for patients with this severe photodermatitis, allowing them to tolerate more sun exposure without pain due to phototoxicity, Robert J. Desnick, PhD, MD, of the department of genetics and genomic sciences, Icahn School of Medicine at Mount Sinai, New York, NY, and colleagues reported in two studies published in the New England Journal of Medicine. "The main results, which were concordant and consistent across the two trials, indicated that afamelanotide was safe and effective," said the researchers.

Prior to this, there was no effective treatment for erythropoietic protoporphyria, noted Desnick. "Although several treatments, including beta carotene, N-acetyl-L-cysteine, and vitamin C, have been described in the literature, a systematic review of more than 20 studies showed little to no benefit," he said.
"For the first time, there is a treatment (afamelanotide) that results in improvement of quality of life of patients with erythropoietic protoporphyria," Henry W. Lim, MD, Chairman, department of dermatology at Henry Ford Hospital, Detroit, MI, told MedPage Today. Lim was also a co-investigator in the study.


The study was funded by Clinuvel Pharmaceuticals; ClinicalTrials.gov numbers, NCT01605136 and NCT00979745, a grant from the National Institutes of Health (NIH) (R15 HL 117199), and an NIH Career Development Award (K23 DK095946).

Desnick reported consulting fees from Alnylam and Recordati Rare Diseases and grant support and stock options from Alnylam and a pending patent related to the treatment of acute hepatic porphyrias (13/835,613).

Lim has received consulting fees from Ferndale Laboratories, Uriage, Sanofi, and Johnson & Johnson, and grant support from Ferndale Laboratories and Estee Lauder.

Co-investigators also reported relationships with Mitsubishi Tanabe, Allergan, Orphan Europe and Orion Pharma.
  Forum: By Share Code

PunkassDerm
Posted on: Jan 20 2019, 05:42 AM


Group: Member
Posts: 418

Was going to say same thing. Like insulin, a peptide cannot be delivered PO (per os) or by oral route.

1. Peptides are fragile, need to be injectable or transdermal, also good call.
2. I think it's now well known side effects profile better with the tapered intermittent dose, depo. SAFETY!!!
3. See above, plus ensures patient compliance to regimen.
4. In office administration, measure of control and compliance. Ensures all metric monitored to receive dose.
5. There are many injected drugs:
insulin
all biologics by nature are monoclonal antibodies and are injected
birth control
oncology, nearly all new immunotherapies are injectables or infusions (PO peptides it appears will be far off and not available for every sequence)
6. MT-7117 still makes you tan, and efficacy is unknown
7. Higher potential for cosmetic "abuse" with a self administered pill.


I cannot find information on pharmacokinetics or mechanism of action (or even confirm a melanocortin), but Mitsubishi has had its fingers in Clinuvel trials through investigators.
Also not against oral medications, but it seems FDA liked the idea of control by SQ administration.


Lastly I would not feed the animals (or Iggiots). Keloids from large bore needle? Infection? Unless Iggy was personally administering the drug I would not worry.
  Forum: By Share Code

PunkassDerm
Posted on: Jan 17 2019, 09:27 AM


Group: Member
Posts: 418

First step to auto-photoprotection and DNA repair...

What happens if Key West bans some sunscreens? Depends on where you stand
BY GWEN FILOSA
JANUARY 14, 2019 12:47 PM

https://www.miamiherald.com/news/local/comm...e224135955.html


Key West city leaders on Tuesday will consider a proposal to ban the sale of certain sunscreens that contain two ingredients some scientists and activists say are harming the coral reef.

But the sunscreen industry and some doctors are fighting back, saying those two ingredients at issue, oxybenzone and octinoxate, prevent skin cancer and that without them skin cancer rates will rise dramatically. Banning them won’t save the reef, they say.

“Coral reefs have been disappearing for 50 years; these sunscreens have been around 25 years,” said Dr. Andy Weinstein, president of the Florida Society of Dermatology and Dermatologic Surgeons.

Weinstein, who sees about 8,000 cases of skin cancer at his small office in Boynton Beach, notes that those two ingredients are what make it possible to produce sunscreens with SPF percentages of 40 to 60.


“There’s no question that the skin cancer rates would increase in those who don’t have access to these sunscreens,” Weinstein said. “There will be fewer people using sunscreen in Key West. You’re going to have some finite increase in the rate of skin cancer.”

The Key West City Commission will take a first look and vote on the issue Tuesday during its 6 p.m. meeting at City Hall. A second vote at a future meeting is required to make it a law, punishable by a $100 fine.

If approved, the law wouldn’t go into effect for a year, giving retailers time to phase out the targeted sunscreens. After that, it will cost them $100 a sale if they deviate from the ordinance.


The issue could turn into an emotional fight Tuesday evening.

Reef Relief, a Keys environmental protection nonprofit group, has been rallying local people to show up in support of the sunscreen ban.

They believe Craig Downs, a scientist whose peer-reviewed study published in 2015 in the Archives of Environmental Contamination and Toxicology, showed oxybenzone was harmful to the reef. He helped inspire a similar ban by Hawaii, passed earlier this year.

Downs told the City Commission during a first discussion last month, “We’re not seeing new coral. Ninety-nine percent of Florida Keys coral coverage has disappeared in the last 50 years. You lose that last one percent, you’ve got nothing.”

One Florida dermatologist, who is also a Ph.D scientist, says he supports the ban on sunscreen containing the two ingredients. He said that sunscreen is only one layer of protection from the sun, along with clothing and sun shades.

“This proposed ordinance will not prevent people from being able to protect themselves,” said Dr. John Strasswimmer, a research professor of biochemistry and a clinical professor of dermatology at Florida Atlantic University in Boca Raton. “If the ordinance goes into effect, people will still have a very good choice of environmentally friendly sunscreen available.”

Strasswimmer believes the chemical-based sunscreens with oxybenzone are harmful to the reef. As a scuba diver, he is concerned about the effects of sunscreen chemicals on the reef.

He prefers a mineral-based sunscreen, ones with zinc or titanium. The problem is, he sometimes travels to places where he doesn’t have an option.

“I always reach for a mineral sunscreen, that’s my personal preference,” Strasswimmer said. But often, when he takes flights, he can’t bring his own and sometimes has to settle for chemical-based sunscreens. “I use that when need be,” he said.

The pro-ban science is like going out on a limb, Weinstein said.


“Other researchers aren’t necessarily aligned with his perspective,” Weinstein said. “The last thing we want is a public health crisis being caused by bad environmental research. “
  Forum: By Share Code

PunkassDerm
Posted on: Jan 16 2019, 09:51 AM


Group: Member
Posts: 418

I think the cost per implant will prevent off label use, unless good research supports otherwise (and insurance allows). Like HHD, XP other porphyrias. Maybe vitiligo ahead of approval.
Other question...will the instos jump back in until next plateau?
  Forum: By Share Code

PunkassDerm
Posted on: Jan 10 2019, 10:51 AM


Group: Member
Posts: 418

Thank God, I'm ready to take some profit no matter what.

I caved and bought my GT3 this week, get busy living or get busy dying Andy Dufresne.
Nice metal roof for the house forever in renovation.

And some relief for the shadow jumpers.
  Forum: By Share Code

PunkassDerm
Posted on: Jan 2 2019, 10:07 AM


Group: Member
Posts: 418

Unless that's a puka shell necklace and not a vitiligo patch. Hard to tell, quite linear.
  Forum: By Share Code

PunkassDerm
Posted on: Jan 2 2019, 08:35 AM


Group: Member
Posts: 418

Face responds best to treatment, that may be why.
  Forum: By Share Code

PunkassDerm
Posted on: Dec 20 2018, 03:30 AM


Group: Member
Posts: 418

https://seekingalpha.com/news/3418194-clinu...arkening-effect


Clinuvel Pharma's afamelanotide shows positive effect in vitiligo study but skin darkening effect dampens recruitment
Dec. 19, 2018 10:42 AM ET|


A Phase 2 clinical trial evaluating Aussie drugmaker Clinuvel Pharmaceuticals' (OTCPK:CLVLY) SCENESSE (afamelanotide) plus ultraviolet B therapy in Asian patients with a skin discoloration disorder called vitiligo showed a positive effect in restoring pigmentation.

Skin darkening during treatment prompted the withdrawal of three participants (out of 21) and has hampered recruitment since this population considers it undesirable.

The company is assessing its options for future labeling, possibly refining suitable patients to those with a loss of pigmentation of at least 10% of their body surface area. Patients with more modest disease, less than 2% of their body surface area, may prefer topical therapy.

Clinical trials in North America are being planned.
  Forum: By Share Code

PunkassDerm
Posted on: Dec 3 2018, 01:26 AM


Group: Member
Posts: 418

Boards tomorrow and taking a break from cramming, thinking of Parkinson's, a horrible disease for the individual and family. No good treatment, hopes to slow with dopamine agonists and control symptoms. The dopamine centers in the substantial nigra are subject to degradation in this disease, dark structures pigment originally termed neuromelanin (by appearance) but turns out structurally composed of true melanin compounds. Just look at the loss of pigment in the substantial nigra below, that occurs with the progression of PD. THEN the link between PD and Melanoma. MSH may again serve as a free radial scavenger to protect these dopamine producing cells, protecting from degradation. This blows my mind.

I am increasingly frustrated with Clinuvel, but hope to bloody hell there is a larger plan to explore/treat/capitalize on these neurodegenerative diseases. Give me something, do your #^%#$% jobs.



Attached Image




Substantia nigra neuromelanin: structure, synthesis, and molecular behaviour
L Zecca, D Tampellini, M Gerlach, P Riederer, R G Fariello, and D Sulzer
Mol Pathol. 2001 Dec; 54(6): 414–418.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1187132/


Abstract

The pigmented neurones of the substantia nigra are typically lost in Parkinson's disease; however, the possible relation between neuronal vulnerability and the presence of neuromelanin has not been elucidated. Early histological studies revealed the presence of increasing amounts of neuromelanin in the substantia nigra with aging in higher mammals, showed that the neuromelanin granules are surrounded by a membrane, and comparatively evaluated the pigmentation of the substantia nigra in different animal species. Histochemical studies showed the association of neuromelanin with lipofuscins. However, systematic investigations of the structure, synthesis, and molecular interactions of neuromelanin have been undertaken only during the past decade. In these later studies, neuromelanin was identified as a genuine melanin with a strong chelating ability for iron and an affinity for compounds such as lipids, pesticides, and MPP+. The affinity of neuromelanin for a variety of inorganic and organic toxins is consistent with a postulated protective function for neuromelanin. Moreover, the neuronal accumulation of neuromelanin during aging and the link between its synthesis and a high cytosolic concentration of catechols suggest a protective role. However, its putative neuroprotective effects could be quenched in conditions of toxin overload.
  Forum: By Share Code

PunkassDerm
Posted on: Dec 3 2018, 12:51 AM


Group: Member
Posts: 418

The melanoma‐linked “redhead” MC1R influences dopaminergic neuron survival

Xiqun Chen MD, PhD Hongxiang Chen MD, PhD Waijiao Cai MD, PhD Michael Maguire MS Bailiu Ya MD, PhD Fuxing Zuo MD, PhD Robert Logan MS Hui Li MD, PhD Katey Robinson PhD Charles R. Vanderburg PhD Yang Yu PhD Yinsheng Wang PhD David E. Fisher MD, PhD Michael A. Schwarzschild MD, PhD
First published: 26 December 2016 https://doi.org/10.1002/ana.24852


https://onlinelibrary.wiley.com/doi/full/10.1002/ana.24852


Abstract

Objective

Individuals with Parkinson disease are more likely to develop melanoma, and melanoma patients are reciprocally at higher risk of developing Parkinson disease. Melanoma is strongly tied to red hair/fair skin, a phenotype of loss‐of‐function polymorphisms in the MC1R (melanocortin 1 receptor) gene. Loss‐of‐function variants of MC1R have also been linked to increased risk of Parkinson disease. The present study is to investigate the role of MC1R in dopaminergic neurons in vivo.

Methods

Genetic and pharmacological approaches were employed to manipulate MC1R, and nigrostriatal dopaminergic integrity was determined by comprehensive behavioral, neurochemical, and neuropathological measures.

Results

MC1Re/e mice, which carry an inactivating mutation of MC1R and mimic the human redhead phenotype, have compromised nigrostriatal dopaminergic neuronal integrity, and they are more susceptible to dopaminergic neuron toxins 6‐hydroxydopamine and 1‐methyl‐4‐phenyl‐1,2,3,6‐tetrahydropyridine (MPTP). Furthermore, a selective MC1R agonist protects against MPTP‐induced dopaminergic neurotoxicity.

Interpretation

Our findings reveal a protective role of MC1R in the nigrostriatal dopaminergic system, and they provide a rationale for MC1R as a potential therapeutic target for Parkinson disease. Together with its established role in melanoma, MC1R may represent a common pathogenic pathway for melanoma and Parkinson disease. Ann Neurol 2017;81:395–406
  Forum: By Share Code

PunkassDerm
Posted on: Dec 3 2018, 12:48 AM


Group: Member
Posts: 418

Parkinson’s Disease and Melanoma: Co-Occurrence and Mechanisms
Journal of Parkinson's Disease, vol. 8, no. 3, pp. 385-398, 2018
Authors: Bose, Aninditaa; * | Petsko, Gregory A.a | Eliezer, Davidb


https://content.iospress.com/articles/journ...sease/jpd171263

Abstract

Parkinson’s disease (PD) is a neurodegenerative disorder that is characterized by loss of dopaminergic neurons in the substantia nigra pars compacta, depletion of dopamine in the striatum and the presence of Lewy bodies. Cancer is uncontrolled growth of cells in the body and migration of these cells from their site of origin to other parts of the body. PD and cancer are two opposite diseases, one arising from cell proliferation and the other from cell degeneration. This fundamental difference is consistent with inverse comorbidity between most cancers and neurodegenerative diseases. However, a positive association of PD and melanoma has been reported which has recently become of significant interest. A link between PD and cancer has been supported by many epidemiological studies, most of which show that PD patients have a lower risk of developing most cancers than the general population. However, the mechanisms underlying this epidemiological observation are not known. In this review we focus on epidemiological studies correlating PD and melanoma and the possible mechanisms underlying the co-occurrence of the two diseases. We explore possible explanations for the important observations that more PD patients develop melanoma that would otherwise be expected and vice-versa.
  Forum: By Share Code

PunkassDerm
Posted on: Oct 31 2018, 05:22 AM


Group: Member
Posts: 418

Or convert shares at a premium fee.
  Forum: By Share Code

PunkassDerm
Posted on: Oct 30 2018, 10:44 PM


Group: Member
Posts: 418

Could you get in with 1 share? International platform like Scottrade, purchase 1 CUV? For them to exclude shows devious intent.
  Forum: By Share Code

PunkassDerm
Posted on: Oct 30 2018, 06:51 AM


Group: Member
Posts: 418

Needs a 😂 button!
  Forum: By Share Code

PunkassDerm
Posted on: Oct 30 2018, 03:49 AM


Group: Member
Posts: 418

1. Donate to APF, check.

2. Write to my congressman/women, now check.
Just made request for civil discourse and bipartisan cooperation. That healthcare is difficult mostly to providers.
And to look into FDA obfuscation/obstruction of the afamelanotide application.

US holders may request the same of their representatives.
  Forum: By Share Code

PunkassDerm
Posted on: Oct 30 2018, 12:13 AM


Group: Member
Posts: 418

Where is FDA status update? Even a definite delay would go further to stop the bleeding than nothing. Or this BS lab expansion.

Also very comical Lachlan Hay email is listed. Does anyone receive a reply from Clinuvel?
  Forum: By Share Code

PunkassDerm
Posted on: Oct 29 2018, 10:17 AM


Group: Member
Posts: 418

What makes me upset is the reality...

delay delay delay, no news and delay some more. Wolgen pays himself. Rinse and repeat.

Is that announcement actual news?
Whats happening with FDA application?
Cosmetic line?
How about Vitiligo results/direction?
New indication identified?

Equally as fatigued after almost a decade and a half. I said before SP heals all wounds, well direct relationship up and down.
  Forum: By Share Code

PunkassDerm
Posted on: Oct 28 2018, 08:15 AM


Group: Member
Posts: 418

Reading for my recertification exam and came across ACTH as a treatment for gout.
Along with RA and PsA, melanocortin class as tx for inflammatory arthritis is solid.
It appears they are the keys to the cytokines, master-regulators up and down.


Now who is blocking the first FDA approval of a Melanocortin? Or who is pulling the marionette strings of FDA bozos?
Or inept Wolgen?

Just wanted to break the deafening silence.
Watch Haunting of Hill house. Ghosts come in many forms.



https://www.ncbi.nlm.nih.gov/m/pubmed/19814819/

Melanocortin peptides inhibit urate crystal-induced activation of phagocytic cells.

Abstract

INTRODUCTION: The melanocortin peptides have marked anti-inflammatory potential, primarily through inhibition of proinflammatory cytokine production and action on phagocytic cell functions. Gout is an acute form of arthritis caused by the deposition of urate crystals, in which phagocytic cells and cytokines play a major pathogenic role. We examined whether alpha-melanocyte-stimulating hormone (alpha-MSH) and its synthetic derivative (CKPV)2 influence urate crystal-induced monocyte (Mo) activation and neutrophil responses in vitro.

METHODS: Purified Mos were stimulated with monosodium urate (MSU) crystals in the presence or absence of melanocortin peptides. The supernatants were tested for their ability to induce neutrophil activation in terms of chemotaxis, production of reactive oxygen intermediates (ROIs), and membrane expression of CD11b, Toll-like receptor-2 (TLR2) and TLR4. The proinflammatory cytokines interleukin (IL)-1beta, IL-8, and tumor necrosis factor-alpha (TNF-alpha) and caspase-1 were determined in the cell-free supernatants. In parallel experiments, purified neutrophils were preincubated overnight with or without melanocortin peptides before the functional assays.

RESULTS: The supernatants from MSU crystal-stimulated Mos exerted chemoattractant and priming activity on neutrophils, estimated as ROI production and CD11b membrane expression. The supernatants of Mos stimulated with MSU in the presence of melanocortin peptides had less chemoattractant activity for neutrophils and less ability to prime neutrophils for CD11b membrane expression and oxidative burst. MSU crystal-stimulated Mos produced significant levels of IL-1beta, IL-8, TNF-alpha, and caspase-1. The concentrations of proinflammatory cytokines, but not of caspase-1, were reduced in the supernatants from Mos stimulated by MSU crystals in the presence of melanocortin peptides. Overnight incubation of neutrophils with the peptides significantly inhibited their ability to migrate toward chemotactic supernatants and their capacity to be primed in terms of ROI production.

CONCLUSIONS: Alpha-MSH and (CKPV)2 have a dual effect on MSU crystal-induced inflammation, inhibiting the Mos' ability to produce neutrophil chemoattractants and activating compounds and preventing the neutrophil responses to these proinflammatory substances. These findings reinforce previous observations on the potential role of alpha-MSH and related peptides as a new class of drugs for treatment of inflammatory arthritis.

  Forum: By Share Code

PunkassDerm
Posted on: Oct 22 2018, 01:07 AM


Group: Member
Posts: 418

OUTRAGE or JUST PLAIN RAGE
...Wolgen, Desiree and everyone involved should be breaking down the doors of the FDA. How is this balanced?
This is big pharma lobby at it pinnacle, corruption


https://www.rollingstone.com/culture/cultur...-opioid-744475/


FDA Could Approve Opioid 10 Times Stronger Than Fentanyl

This week, an FDA panel voted 10-3 to recommend approval for a new fast-acting form of an opioid drug that’s 10 times more potent than fentanyl.
Opioid overdose is the leading cause of death for Americans under the age of 50, with the sharpest increase in overdose deaths in 2017 connected to fentanyl and other synthetic opioids. Fentanyl — a highly regulated prescription drug that has been extensively counterfeited in recent years — is extremely dangerous because it’s much stronger than heroin, so drug users who either don’t realize the substance they’re using is cut with fentanyl, or don’t anticipate such a strong effect, can easily overdose.
  Forum: By Share Code

PunkassDerm
Posted on: Oct 20 2018, 08:29 AM


Group: Member
Posts: 418

Not quite...

But I do have the farm bet on it, also “all in” club. Adding since April 2004.

Id like my own Wolgen Tan someday, with a slight green glow
  Forum: By Share Code

PunkassDerm
Posted on: Oct 20 2018, 07:58 AM


Group: Member
Posts: 418

I've also seen in practice, 5-10 cases of both Darier's and HHD. Never XP. Japan is that market no?
  Forum: By Share Code

PunkassDerm
Posted on: Oct 20 2018, 07:52 AM


Group: Member
Posts: 418

CLVLY dividend breakdown... 0.01412/share with fees and taxes withheld


Attached Image

  Forum: By Share Code

PunkassDerm
Posted on: Oct 20 2018, 07:42 AM


Group: Member
Posts: 418

Novel idea to pursue simultaneously...walk AND chew gum

...instead of a .02 dividend
  Forum: By Share Code

PunkassDerm
Posted on: Oct 20 2018, 07:40 AM


Group: Member
Posts: 418

After a couple of indications, hopefully will simply be approved by insurances off indication with some good study evidence. No need to gain approval over and over?

or label extension/new indication to be much faster with safety data established?


https://www.sciencedirect.com/science/artic...149291813001768


Conclusions

Development of and regulatory approval for new uses of already-approved drugs and biologics is an important source of innovation by biopharmaceutical firms. Despite rising development costs, the output of new-use approvals has remained stable in recent years, driven largely by the pursuit of new pediatric indications. FDA approval-phase times have generally declined substantially for all types of applications since the mid-1990s following legislation that provided a new source of income for the agency. However, while the resources needed to review supplemental applications are likely lower in general than for original-use approvals, the approval-phase times for important new uses are no lower than for important original-use applications.
  Forum: By Share Code

PunkassDerm
Posted on: Oct 20 2018, 03:38 AM


Group: Member
Posts: 418

Isn’t HHD already in phase II, with known excellent response? I’d love to see both, but HHD seems further along.

Everything with Clinuvel is conjecture, maybe strategically important in this case to keep quiet until well underway.
We are the ginger bastard stepchildren of Dr Wolgen. IMHO BTW, who is either on Senesse himself or is not working hard enough to have a tan like his. What bets you say he is also a client/patient?
  Forum: By Share Code

PunkassDerm
Posted on: Oct 20 2018, 02:11 AM


Group: Member
Posts: 418

I’m hoping HHD, appears to control an uncontrollable disease. Genetic condition. Money on dat


http://www.orphan-drugs.org/2014/02/10/pha...ease-commences/

Hailey-Hailey Disease

Hailey-Hailey Disease (HHD, also known as familial benign chronic pemphigus) is a rare, lifelong, inherited disorder where epidermal skin cells (keratinocytes) cannot properly adhere. This causes periodic eruption of plaque-like lesions, blisters and ulcerations on areas where skin folds (flexural), often on the neck, armpits or groin. Most patients have permanent lesions. HHD usually appears in the third or fourth decade of life.

HHD is passed on as a dominant trait (autosomal dominant). In approximately 70% of all patients a positive family history can be traced. Mutations in the ATP2C1 gene (localised on chromosome 3q21-q24), encoding the Golgi secretory pathway calcium pump (Ca2+-dependent ATPase), impair epidermal keratinocyte adhesion.

....In 2012, the first proof of concept open-label pilot study of afamelanotide in HHD was carried out in two female patients (age 53 and 61). At the time of the start of the study, the patients both had existing skin lesions and ulcerations which had been present since their adolescent years.

Following afamelanotide treatment, the lesions began to visibly decrease in size and totally disappeared by day 60. The clinical remission was also reflected by an improved QOL measured by the Medical Outcome Survey Short-Form 36 (SF-36). No adverse reactions were reported. Both patients experienced moderate skin tanning, as expected on the basis of the secondary pharmacology of SCENESSE®. Disease recurrence was only seen in the patients eight months after completion of the treatment (Biolcati et al., 2013). By comparison, only few complete or partial remissions are reported in the literature.

  Forum: By Share Code

PunkassDerm
Posted on: Oct 16 2018, 02:40 AM


Group: Member
Posts: 418

Personal note from Desiree and from her staff. If you want know what she thinks about afamelanotide, please donate yourself.
She is amazing and such an advocate, works so hard for EPP.
When we hit it big time, I pledge to increase that donation. Selfish feel good.

I think she is by far, a stronger influence on FDA than Wolgen could ever be.
...altruistically and in practice
  Forum: By Share Code

PunkassDerm
Posted on: Oct 14 2018, 03:39 AM


Group: Member
Posts: 418

C/O ShareScene PAD

Attached Image
  Forum: By Share Code

PunkassDerm
Posted on: Oct 14 2018, 03:19 AM


Group: Member
Posts: 418

totally odd. has exchange rate changed drastically?
Mine was on TD Ameritrade, my broker. Seems like a heavy hit for a fee.
Fixed at record date or fluid until payout?

Still pennies, I'm waiting for SP30USD
  Forum: By Share Code

PunkassDerm
Posted on: Oct 14 2018, 03:07 AM


Group: Member
Posts: 418

Looks same to me: 0.0141
simple exchange

Attached Image

Attached Image

  Forum: By Share Code

PunkassDerm
Posted on: Oct 10 2018, 01:24 PM


Group: Member
Posts: 418

Dramatic

The other cream is Efudex-Carac-5FU or 5-fluorouracil.

It works great and its cheap.
You can titrate dosing and use in smaller quadrants to control downtime.
You can dilute with moisturizer.
See below, lower micronized version with less irritation.
You can take off the panties and take your medicine. Jest of course.

BTW, I've seen the worst inflammatory responses with imiquimod (Aldara/Zyclara) resulting in scarring hypopigmentation.
It's all about using with common sense. Which also means a few extra minutes counseling patients, and showing them the raw hamburger picks so they don't go there.


There are bigger fish to fry, 5FU is an effective treatment for AK, doubtful will ever get the indication. Plus AKs are acquired, you earned them!
Same with PMLE, wasted resources exploring.

In all seriousness Efudex works awesome, I put that shit on everything.


I also truly believe in cost/efficacy. If there is something effective and cheap, I prefer it. EPP, Vitiligo, HHD are all needy indications and worthy of afamelanotide.
Photoprotection some day...when the price goes down. That will be golden.


Cutis. 2002 Aug;70(2 Suppl):22-9.
Effective treatment of actinic keratosis with 0.5% fluorouracil cream for 1, 2, or 4 weeks.

Weiss J1, Menter A, Hevia O, Jones T, Ling M, Rist T, Roberts J, Shavin JS, Sklar J, Webster G, Connolly M, Furst K, Levy S.

Abstract
New therapeutic options would benefit patients with actinic keratosis (AK), a precancerous condition that is a significant health concern. The efficacy and safety of a microsphere-based formulation of 0.5% fluorouracil cream were evaluated in a randomized, double-blind, multicenter, parallel-group study. Patients (N= 177) were randomized to receive 0.5% fluorouracil or vehicle once daily for 1, 2, or 4 weeks. Efficacy was assessed by lesion counts and clearance. Safety was evaluated by monitoring adverse events, including facial irritation. Significant improvements were seen from baseline to posttreatment follow-up in all efficacy variables for all fluorouracil regimens compared with vehicle. Patients treated for one week experienced significant improvements compared with vehicle, although efficacy increased with increasing treatment duration. Most patients experienced mild to moderate facial irritation of predictable onset and duration. Once-daily administration of 0.5% fluorouracil cream for 1, 2, or 4 weeks is safe and effective for the treatment of AKs.
  Forum: By Share Code

PunkassDerm
Posted on: Oct 9 2018, 01:17 AM


Group: Member
Posts: 418

CLVLY holders:

Ex-dividend date - September 20, 2018
Amount - $0.0143
Record date - September 21, 2018
Pay date - October 18, 2018

I forgot about the exchange rate, my enthusiasm wanes.
Above from my on-line broker account.
  Forum: By Share Code

PunkassDerm
Posted on: Oct 8 2018, 11:48 PM


Group: Member
Posts: 418

I bet its multifactorial:

FDA dragging feet
Worried about tan as side effect, agree duh its a benefit
Lobby from large pharma, money corrupts the poor regulators
Clinuvel mis-management. Though they may have a great big picture, it is a company learning on the fly. Ego-driven CEO
See above, study design and inability the multitask FDA/EMA/marketing/roll-out

Recruit good help to navigate
Or Partner with big Pharma
Or be acquired by Allergan



  Forum: By Share Code

PunkassDerm
Posted on: Oct 8 2018, 11:41 PM


Group: Member
Posts: 418

I also think ambulance chasing lawyers jump on every freaking medication/implant/procedure. Sick of the commercials for EVERYTHING MEDICAL.

Every medication has side effects, finasteride clearly lists impotence as a side effect. BPH itself can cause ED.

I was also on Finasteride for both BPH and to help maintain an early receding hairline. I took 1.25mg every other day for 2 years. Didn't seem to help my GU symptoms too much and I stopped. Mostly noticed an increase in energy within 2-3 weeks, so it was bogging me down. I think slamming finasteride is a bit much though, works for many although not me. Karma is a bitch, the lawyers and greedy people looking for a payday will go after every medication. People choose to take these meds and side effects are inevitable, as long as they are disclosed it is the choice of the patient and provider to make together.

Safety profile for afamelanotide appears stellar, I would stick to that instead. Life is a series of choices. Patients should also take some responsibility for outcomes.


Soft finasteride suffers should pop a little blue pill and move on. General health and lifestyle isn't figured into these things either.
  Forum: By Share Code

PunkassDerm
Posted on: Oct 8 2018, 10:31 PM


Group: Member
Posts: 418

Before male pattern alopecia, finasteride approved for BPH (swelling of prostate).


Hopefully we follow suit:


MEDICINES EVOLVED TO MAKE YOU BEAUTIFUL, LABEL EXTENSIONS/NEW INDICATIONS

Minoxidil: Hypertension > Pattern Alopecia (Rogaine)

Botox: Blepharospasm > rhytides, migraines, bladder spasticity, hyperhidrosi, upper and lower limb spasticity

Bimatoprost (latisse): Glaucoma > Hypotrichosis eyelashes, soon pattern alopecia and testing for vitiligo

HA (hyaluronic acid): Eye surgery adjuvant (1970's) > atopic dermatitis, osteoarthritis, artificial tears, dermal fillers (Restylane, Juvederm etc)

Tretinoin: Acne > Rhytides and anti-aging (Retin-A)

Stem cell Therapies: Leukemia (1950s) > 1997 sheep Dolly cloned, joint repair, tendon repair, regenerative medicine (anti-aging) still evolving, possibly dementia and autism, ?cure for diabetes


personal note: I just had umbilical cord mesenchymal cells injected into my achilles and IV push, to extend my running life. Outcome pending.


And finally...

AFAMELANOTIDE: EPP > All porphyrias, HHD, XP, vitiligo, solar urticaria, photoprotection, premature graying, tan, lupus, dementia, MS, antibiotic synergist, arthritis, psoriasis, HS, acne, rosacea, atherosclerosis, stroke, RA, stroke, IBS, vasculitis, ARS, ischemia/shock, organ transplantation, ?melanoma through DNA repair...

and the beat goes on, the beat goes on
  Forum: By Share Code

PunkassDerm
Posted on: Oct 7 2018, 08:27 AM


Group: Member
Posts: 418

Looks like Uhoh has already chimed in on this molecule:


https://groups.google.com/forum/#!msg/c...H4/R8vmiusQCQAJ

My thought is there is a niche to fill, not that it is an absolute competitor. What happened to cosmetic product line announcement?
  Forum: By Share Code

PunkassDerm
Posted on: Oct 7 2018, 02:14 AM


Group: Member
Posts: 418

http://lucasmeyercosmetics.com/en/products...5&from=name


Melitaneâ„¢
Healthy Glow

Origin

α-MSH biomimetic peptide

INCI Name

Glycerin (and) Water (and) Dextran (and) Acetyl Hexapeptide-1

Mode of Action

Agonist of α-MSH
Stimulates melanin synthesis
Properties

Strengthens the natural skin photoprotection
Reduces skin erythema and soothes sun-ravaged skin
Limits photoaging and premature aging
Enhance skin pigmentation
Dosage

0.5-5%

In vitro
Ex vivo
Clinical
Applications

Hair Care
Soothing / Sensitive Skin
Sunless Tanning / Tan Accelerator / Sun Care
  Forum: By Share Code

PunkassDerm
Posted on: Oct 7 2018, 02:02 AM


Group: Member
Posts: 418

Another obvious target I have not seen a lot about, but on my mind. Worrying and aging while waiting for Clinuvel has grayed me prematurely. Turn back the Wolgen clock.

For implant or lotion or shampoo?

Canities - Graying

Allergan competitor or acquisition, either fantastic with me.


https://www.ncbi.nlm.nih.gov/pubmed/30222197


Efficacy of an agonist of α-MSH, the palmitoyl tetrapeptide-20, in hair pigmentation.
Int J Cosmet Sci. 2018 Sep 17. doi: 10.1111/ics.12494.

Almeida Scalvino S1, Chapelle A2, Hajem N3, Lati E1, Gasser P1, Choulot JC3, Michel L4, Hocquaux M5, Loing E6, Attia J5, Wdzieczak-Bakala J2.


OBJECTIVE:
Hair greying (i.e., canities) is a component of chronological aging and occurs regardless of gender or ethnicity. Canities is directly linked to the loss of melanin and increase in oxidative stress in the hair follicle and shaft. To promote hair pigmentation and reduce the hair greying process, an agonist of α-melanocyte-stimulating hormone (α-MSH), a biomimetic peptide (palmitoyl tetrapeptide-20; PTP20) was developed. The aim of this study was to describe the effects of the designed peptide on hair greying.

METHODS:
Effect of the PTP20 on the enzymatic activity of catalase and the production of H2 O2 by Human Follicle Dermal Papilla Cells (HFDPC) was evaluated. Influence of PTP20 on the expression of melanocortin receptor-1 (MC1-R) and the production of melanin were investigated. Enzymatic activity of sirtuin 1 (SIRT1) after treatment with PTP20 was also determined. Ex vivo studies using human micro-dissected hairs allowed to visualise the effect of PTP20 on the expression in hair follicle of catalase, TRP-1, TRP-2, Melan-A, ASIP and MC1-R. These investigations were completed by a clinical study on 15 human male volunteers suffering from premature canities.

RESULTS:
The in vitro and ex vivo studies revealed the capacity of the examined PTP20 peptide to enhance the expression of catalase and to decrease (30%) the intracellular level of H2 O2 . Moreover, PTP20 was shown to activate in vitro and ex vivo the melanogenesis process. In fact, an increase in the production of melanin was shown to be correlated with elevated expression of MC1-R, TRP-1 and Melan-A, and with the reduction in ASIP expression. A modulation on TRP-2 was also observed. The pivotal role of MC1-R was confirmed on protein expression analyzed on volunteer's plucked hairs after 3 months of the daily application of lotion containing 10 ppm of PTP20 peptide.

CONCLUSION:
The current findings demonstrate the ability of the biomimetic PTP20 peptide to preserve the function of follicular melanocytes. The present results suggest potential cosmetic application of this newly designed agonist of α-MSH to promote hair pigmentation and thus, reduce the hair greying process. This article is protected by copyright. All rights reserved.
This article is protected by copyright. All rights reserved.
  Forum: By Share Code

PunkassDerm
Posted on: Oct 7 2018, 12:20 AM


Group: Member
Posts: 418

Don't forget HHD. Miracle for these patients. Great label extension or off label use after approval. It initiates long lasting remission in a disease that has no effective treatment.
Add to your numbers.

NOTE: NO SIDE EFFECTS. MODERATE TANNING. NO LAB ABNORMALITIES. SAFE! #whatdoyouknowaboutthat?

Affected Populations

Hailey-Hailey disease affects males and females in equal numbers. According to one estimate, the disorder affects 1 in 50,000 people in the general population. Hailey-Hailey disease often goes misdiagnosed or undiagnosed, making it difficult to determine its true frequency in the general population.


https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4255790/


Clin Exp Dermatol. 2014 Mar; 39(2): 168–175.
Published online 2013 Oct 25. doi: 10.1111/ced.12203

Efficacy of the melanocortin analogue Nle4-D-Phe7-α-melanocyte-stimulating hormone in the treatment of patients with Hailey–Hailey disease
G Biolcati,1 C Aurizi,1 L Barbieri,1 S Cialfi,2 I Screpanti,2 and C Talora2


Snippets from Article:


Background

Hailey–Hailey disease (HHD) is a rare, chronic and recurrent blistering disorder, which is characterized clinically by erosions occurring primarily in intertriginous regions, and histologically by suprabasal acantholysis. Oxidative stress plays a specific role in the pathogenesis of HHD, by regulating the expression of factors playing an important role in keratinocyte proliferation and differentiation.


Conclusions

Afamelanotide is effective for the treatment of skin lesions in HHD.



Introduction

Familial benign chronic pemphigus or Hailey–Hailey disease (HHD; OMIM 169600) is a rare, autosomal dominant genodermatosis. The prevalence of HHD is unknown. HHD is characterized by development of relapsing and recurrent blisters, erosions and crusts in the intertriginous areas. Although lesions generally first appear after adolescence, with peak onset around the age of 30–40 years, they can develop at any age. Lesions can be complicated by heat, rubbing or superinfection, and they can have a substantial negative effect on patients' quality of life (QOL).1

...There is no known cure for HHD, and existing treatments do not provide a long-lasting positive therapeutic result. Therapies for HHD often attempt to control the underlying inflammatory immune response associated with the disease to induce symptomatic remission. The most commonly used therapies include steroids, antifungals and antibiotics, administered either topically or systemically. α-MSH is a peptide hormone member of a family of peptides known as the melanocortins, and can bind to five known melanocortin receptors: MC1R, MC2R, MC3R, MC4R and MC5R.5–7 Many studies have provided evidence that α-MSH has potent protective and antioxidative effects.8–13 At the molecular level, α-MSH affects various pathways implicated in the regulation of inflammation and protection. In particular, in primary keratinocytes, α-MSH increased expression of Nrf2 [Nuclear factor (erythroid-derived 2)-like 2], a key transcription factor involved in orchestrating the expression of antioxidative enzymes.10 Nrf2 has emerged as a master regulator of an intracellular antioxidant response operating through transcriptional activation of an array of genes, including phase II detoxifying enzymes, antioxidants and transporters, which protect cells from toxic and carcinogenic chemicals.14–16 Additionally, reports have shown that α-MSH is capable of inducing expression of both Nrf2 and Nrf-dependent phase II detoxifying enzymes in keratinocytes, suggesting the potential role of α-MSH not only as a pigment inducer but also as a guardian of epidermal homeostasis and oxidative stress balance.10

Nle4-D-Phe7-α-melanocyte-stimulating hormone (afamelanotide) is an α-MSH analogue.17 Deficiency of ATP2C1 in HHD-derived keratinocytes is associated with alterations in proliferation and differentiation, and increased oxidative stress.3,4 In the current study, we aimed to find evidence to support a strategy for the use of afamelanotide as a therapeutic approach for HHD.


Results:

...During the initial 30-day treatment period with afamelanotide, the lesions began to reduce in size, and during the following 30-day period, they reduced further, until by day 60, the lesions had disappeared completely, restoring the skin's natural appearance (Fig.​(Fig.2).2). The clinical remission was reflected in the improved QOL as measured by the SF-36.

There were no side-effects noted. Both patients experienced moderate skin tanning, but no clinically important laboratory abnormalities were detected. After afamelanotide withdrawal, there was no recurrence of clinical disease for 8 months, but signs of recurrence were seen after this point.


Discussion

α-MSH is known to have protective and antioxidative effects, thus in this study, we aimed to assess the clinical potential of an α-MSH analogue, afamelanotide in patients with HHD. Our previously published results had implicated oxidative stress and the response to it as contributing factors to the presentation of HHD.3,4 We hypothesized that afamelanotide might be an effective treatment for HHD by decreasing the level of oxidative stress. Our hypothesis was based on previous observations suggesting that α-MSH defends cells against the detrimental effects of oxidative stress, and may also abate the consequences of this stress.8–13

...The precise mechanism of how afamelanotide affects the course of HHD lesions remains to be determined. Our findings suggest that afamelanotide acts directly on keratinocytes to increase Nrf2 expression, and this may be relevant to its mechanism of action in HHD. However, we cannot exclude the possibility that the anti-inflammatory property of afamelanotide may be the mechanism of action that produces the in vivo effect of afamelanotide in our treated patients. Thus, it will be interesting to measure in future studies if afamelanotide affects the level of inflammatory mediators, e.g. cytokines and regulatory T cells, in patients with HHD.


Conclusion

In summary, this pilot study suggests that afamelanotide has a therapeutic efficacy in patients with chronic and treatment-resistant HHD. Despite the fact that HHD is a rare disease and it is therefore difficult to enrol sufficient patients in a placebo-controlled trial, a much larger number of patients with HHD receiving afamelanotide will be needed to confirm the preliminary data of this small pilot study. An interesting possibility would be use of a therapeutic protocol in which patients are scheduled for treatment with afamelanotide suspension every 6–7 months. Based on the responses of our two patients with HHD to a sustained resorbable implant formulation of afamelanotide in an open-label pilot study, afamelanotide treatment may be able to induce long-term disease remission.

Go to:

Acknowledgments
We would like to thank Clinuvel Pharmaceuticals for providing afamelanotide. The financial support of Telethon – Italy (grant no. GGP12264) is gratefully acknowledged.
  Forum: By Share Code

PunkassDerm
Posted on: Oct 5 2018, 02:30 AM


Group: Member
Posts: 418

I used the Pharos excimer by Ra.
It has an adjustable aperature that made following a lesion easier by adjusting treatment size on the fly instead of masking good skin.

https://www.ramed.com/patients/dermatology/
  Forum: By Share Code

PunkassDerm
Posted on: Oct 4 2018, 01:17 PM


Group: Member
Posts: 418

A good reminder for clinical efficacy. AS FAST AS 2 DAYS???!!!


January 2013

The Efficacy of Afamelanotide and Narrowband UV-B Phototherapy for Repigmentation of Vitiligo
Pearl E. Grimes, MD; Iltefat Hamzavi, MD; Mark Lebwohl, MD; et al Jean Paul Ortonne, MD; Henry W. Lim, MD

JAMA Dermatol. 2013;149(1):68-73. doi:10.1001/2013.jamadermatol.386

Background
Vitiligo is characterized by depigmented patches of skin due to loss of cutaneous melanocytes. Many recent studies have demonstrated defects in the melanocortin system in patients with vitiligo, including decreased circulating and lesional skin levels of α–melanocyte-stimulating hormone (α-MSH). Afamelanotide is a potent and longer-lasting synthetic analogue of naturally occurring α-MSH.

Observations
We describe the preliminary results of 4 patients with generalized vitiligo who developed repigmentation using afamelanotide in combination with narrowband UV-B (NB–UV-B) phototherapy. Patients were treated 3 times weekly with NB–UV-B and starting in the second month received a series of 4 monthly implants containing 16 mg of afamelanotide. Afamelanotide induced faster and deeper repigmentation in each case. All patients experienced follicular and confluent areas of repigmentation within 2 days to 4 weeks after the initial implant, which progressed significantly throughout treatment. All patients experienced diffuse hyperpigmentation.


https://jamanetwork.com/journals/jamadermat...article/1377949


Attached Image

Attached Image

Attached Image
  Forum: By Share Code

PunkassDerm
Posted on: Oct 4 2018, 12:58 PM


Group: Member
Posts: 418

This can be completely overcome by focused NB-UVB in the form of the Excimer laser. 308nm

Focused - Only the affected skin is treated
Higher energy in short time, more effective
Excimer penetrates deeper to recruit surviving melanocytes

Afamelanotide reduced free radial damage and DNA repair, stimulated re-pigmnetation


I used the Pharos Excimer laser at my last clinic. Usually combined with topical steroids alternating with Protopic. Occasional bust of prednisone or IL-Kenalog (steroid injection)

The UVB booth more for extensive Eczema or Psoriasis
PUVA more dangerous never liked and did not start any patients on this, NB-UVB has become the standard




http://www.dermatologytimes.com/ophthalmol...-treatment-time


Excimer laser slashes vitiligo treatment time
Sep 1, 2004


In the treatment of vitiligo, the 308-nm excimer laser (PhotoMedex) achieves results as favorable as those of other phototherapy modalities in one-third the time, according to James M. Spencer, M.D.

The skin disorder is present in 1percent to 2 percent of the world's population and has no predilection for race.

"Vitiligo is characterized by localized loss of pigmentation, which is cosmetically distressing for patients," Dr. Spencer says. "The affected area is very sensitive to sunburn, and treatment with topical steroids and immune response modifiers (e.g., tacrolimus) alone is rarely successful. And the traditional psoralen with ultraviolet-A (PUVA) requires twice-weekly treatments for a year or longer, which is a major commitment (for the patient)."

Dr. Spencer is vice chairman of the department of dermatology at Mt. Sinai School of Medicine in New York.


Other modalities

PUVA has an overall success rate of 50 percent, but that rate can be misleading because it represents an average of all skin types and all parts of the body, according to Dr. Spencer.

"Results vary with skin type and location of the disease," he says. "People with dark skin do better than people with fair skin. The face tends to do well, the hands tend to fail, and the rest of the body is in the middle." Narrow-band UV-B given twice a week for up to a year has a slightly higher reported success rate (53 percent) and a higher safety profile than PUVA, which is associated with the development of skin cancer on normal skin, he adds.

Physicians can almost promise African Americans with facial vitiligo that they will get their color back permanently, Dr. Spencer says.

"As for fair-skinned patients with vitiligo on the hands, the laser and other phototherapies will probably fail, and there is no plan B. Surgical procedures, though effective, can lead to scarring and textural changes," he says.


Excimer has advantages

At Mt. Sinai, Dr. Spencer and his colleagues have been using the 308-nm excimer laser to treat patients with vitiligo.

"The excimer laser penetrates deeply enough to stimulate surviving melanocytes to migrate up hair follicles to the vitiligo patches on the skin," Dr. Spencer says.

The laser has practical and theoretical advantages over non-laser light treatments, according to Dr. Spencer.

"You shine the UV-B light onto only diseased skin and normal skin is spared exposure," he says. "The laser also has high energy, so treatment is more rapid. Theoretically, lasers may also penetrate more deeply, and a given dose is delivered more rapidly. For example, 100 joules given quickly may be more effective than 100 joules given slowly."

Although lasers deliver large doses quickly, they are limited by their small 2 cm-by-2 cm spot size, according to Dr. Spencer.

"Fortunately, most vitiligo is limited," he says.


Time slashed

In a study published in the July issue of Dermatologic Surgery, Dr. Spencer and colleagues reported a 53 percent success rate in patients treated with the excimer laser twice weekly for 15 weeks, one-third of the time required for other phototherapy treatments. Success was defined as 75 percent or greater repigmentation, and patients were of all skin types and had vitiligo at all body locations.

"Just as with PUVA, dark-skinned people do better than light-skinned people," Dr. Spencer says. "The face responds well, the hands respond poorly, and the body's response is in the middle. But the excimer laser is as good as PUVA or narrow-band UV — in a fraction of the time — and normal skin is spared exposure." Dr. Spencer has also found that tacrolimus (Protopic, Fujisawa Healthcare) enhances the effects of the excimer laser.

A temporary "sunburn" is the only adverse effect of treatment, he says.
  Forum: By Share Code

PunkassDerm
Posted on: Sep 27 2018, 09:20 AM


Group: Member
Posts: 418

Isn’t by definition a hedge fund about risk/reward, hedging the market?
Isn’t Lagoda a hedge fund? A substantial holder in Clinuvel.

Plus there’s EMA approval and sales.
  Forum: By Share Code

PunkassDerm
Posted on: Sep 26 2018, 03:53 AM


Group: Member
Posts: 418

Add cosmetic approval/photoprotection en masse...$200 after 2 splits! Always the holy grail.

How long will that take? How many years of safety and proven protection/repair. Against lobby from other forces.
  Forum: By Share Code

PunkassDerm
Posted on: Sep 25 2018, 04:53 PM


Group: Member
Posts: 418

What a year does!

Management is almost forgiven for their sins, SP heals all wounds.
I held off my sell order for now, maybe some profit at 20USD, a little.
All these years, I did everything wrong.
Strong diversfied portfolio with dividends,
Funneled into one crazy obscure molecule.

I can almost smell it...
Independence.

And for medicine, a gem.
Disruptive.
Hopefully the melanocortins live up to my dreams of protection and repair.
And the FDA conducts swiftly with integrity.

Thanks everyone for sharing, contributing.
I hope even Iggy and RC have some shares on the line.

EDIT: 3AM in MA USA and can’t sleep

Attached Image

  Forum: By Share Code

PunkassDerm
Posted on: Sep 20 2018, 01:04 PM


Group: Member
Posts: 418

TURNING JAPANESE I REALLY THINK SO
I didn't realize the prevalence so high. I think necessitates a price drop, just add that to vitiligo. Fair and equitable.

Xeroderma pigmentosum (XP) is a rare disorder of defective UV-radiation induced damage repair that is characterized by photosensitivity with easy skin burning following minimal sun exposure, early freckling and development of lentiginous pigmentation along with other features of poikiloderma and a propensity for developing skin cancer at an early age. In this short review, the clinical, pathological, genetic and molecular aspects of XP are reviewed in the current literature. XP encompasses a spectrum of disease that overlaps with other diseases of DNA repair systems. In addition to cutaneous complications, patients are susceptible to eye conditions, neurodegenerative processes, central nervous system tumors and other tumors as a result of UV radiation exposure and its byproducts. Patients with XP frequently experience a shorter life span due to skin cancer and neurodegenerative sequelae, but aggressive preventative measures to minimize UV radiation exposure and damage can improve the course of disease and prolong life. The disease has served as a model for photoaging and UV radiation-induced cancer and has led to a better understanding of cell processes that prevent development of these disease features in normal individuals.


Xeroderma pigmentosum (XP) is a rare autosomal recessive disorder that has been reported around the world with variable prevalence, affecting 1 per million in the United States, 2.3 per million in Western Europe, and 45 per million in Japan [1]. Affected populations have also been described in North Africa and the Middle East, with less well-understood frequency [1–4].


There is currently no cure for xeroderma pigmentosum, but there is profound benefit in consistent UV-radiation protection, which can substantially decrease the number of skin cancers, and consists of layered clothing along with sunscreen and eye protection [21]. Decreasing UV radiation exposure may not decrease neurodegenerative effects. Patients often require Vitamin D supplementation to offset sun avoidance [21]. Systemic treatment with retinoids has been attempted and shows some benefit in reducing the number of skin cancers [29], though side effects prohibit use in children. Early resection of premalignant and malignant lesions is important for long term survival. Investigative therapies using gene therapy and antioxidants to reduce oxidative damage may result in future treatment options [30].


https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4838978/
  Forum: By Share Code

PunkassDerm
Posted on: Sep 20 2018, 12:06 PM


Group: Member
Posts: 418

I love the new focus on photo-protection / DNA repair.

Fits much better with XP, using as a segway to ubiquitous photo-protection. If anti-skin cancer benefits can be highlighted, we are there.


excerpt:
The sensitivity to UV radiation results in increased freckling, as well as areas of lighter skin pigmentation. They may also have very dry skin. There is a high risk of squamous cell and basal cell skin cancers and melanoma. People with XP also have eye problems, especially with their eyelids.


https://www.cancer.net/cancer-types/xeroderma-pigmentosum
  Forum: By Share Code

PunkassDerm
Posted on: Sep 16 2018, 01:06 AM


Group: Member
Posts: 418

Soon will will be getting ETF SPDR INDEX exposure? Looks like more traction once access to the ASX200, but even now should we see new instos obligated to add CUV?
Broad market and Healthcare? Not my expertise but this will add to organic (hopefully exponential) growth? That list of insto holders should grow now.

Then add NASDAQ

any expert thoughts?

https://www.stockspot.com.au/what-are-etfs/etfs-compared/


  Forum: By Share Code

PunkassDerm
Posted on: Sep 15 2018, 02:17 PM


Group: Member
Posts: 418

Followup on Investek post...

http://www.sachsforum.com/18bef-presenters.html


18TH ANNUAL BIOTECH IN EUROPE FORUM
4TH-5TH OCTOBER 2018 @ CONGRESS CENTER BASEL, SWITZERLAND

CLINUVEL AG

CLINUVEL PHARMACEUTICALS LTD is a global biopharmaceutical company focused on developing and delivering treatments for patients with a range of severe genetic and skin disorders. As pioneers in photomedicine and understanding the interaction of light and human biology, CLINUVEL’s research and development has led to innovative treatments for patient populations with a clinical need for photoprotection and regimentation. These patient groups range in size from 5,000 to 45 million worldwide.

CLINUVEL’s lead compound, SCENESSE® (afamelanotide 16mg), was approved by the European Commission in 2014 for the prevention of phototoxicity (anaphylactoid reactions and burns) in adult patients with the rare genetic disorder erythropoietic protoporphyria (EPP).

As the first ever photoprotective drug, SCENESSE® activates eumelanin, the dark pigment in skin. Eumelanin is capable of selective light absorption, including at the wavelengths of light which excite protoporphyrin IX, the compound which causes phototoxic reactions in patients diagnosed with EPP, a disorder which causes absolute intolerance to light (blue and green spectrum).
​
Headquartered in Melbourne, Australia, CLINUVEL has operations in Europe, Switzerland, the US and Singapore.

http://www.clinuvel.com/
  Forum: By Share Code

PunkassDerm
Posted on: Sep 15 2018, 01:43 PM


Group: Member
Posts: 418

Love to see that in email or letter, go public! FDA promotes a drug for US citizens, shouldn't it be FLASH tracked? Like instant approval!
  Forum: By Share Code

PunkassDerm
Posted on: Sep 12 2018, 01:06 PM


Group: Member
Posts: 418

Bahaha...not quite there. And my holdings unlikely to make a dent in SP.
  Forum: By Share Code

PunkassDerm
Posted on: Sep 11 2018, 12:47 AM


Group: Member
Posts: 418

If I could think of one acquisition for Clinuvel, it would be surmodics, their manufacturing partner. Stock price around 80 and a market cap at 1 billion. Even-Steven but don't know what debt they have. Climb is similar to our baby.


Attached Image

  Forum: By Share Code

PunkassDerm
Posted on: Sep 10 2018, 09:55 PM


Group: Member
Posts: 418

I give myself grief and stress from the same thing, funneled my diversified holdings into one stock. With continued safety this melanocortin platform will be disruptive to medicine, and I can't wait. Almost time for me to take a little profit for the first time, little de-risking. Average 2.50/share now USD.

EPP patients, HHD, Vitiligo, XP, and TBD indications...so many will benefit
  Forum: By Share Code

PunkassDerm
Posted on: Sep 10 2018, 01:47 PM


Group: Member
Posts: 418

Mkt cap 859.88M

Exponential growth or takeover, OK!
  Forum: By Share Code

PunkassDerm
Posted on: Sep 10 2018, 12:07 PM


Group: Member
Posts: 418

25K implant price will keep off-label use down. Even 5K won't bring out cosmetic/photoprotection for the masses.
  Forum: By Share Code

PunkassDerm
Posted on: Sep 10 2018, 02:07 AM


Group: Member
Posts: 418

Regulation of p53 by MC1R signaling

p53, also known as TP53 or tumor protein (EC :2.7.1.37) is a gene that codes for a protein that regulates the cell cycle and hence functions as a tumor suppression. It is very important for cells in multicellular organisms to suppress cancer.

ergo - Aids in melanoma prevention. And in the absence of ionizing radiation, SUN. It's the sun not the tan that causes DNA damage. This is lost on many including EXPERTS that assume tan increases risk of melanoma, without reading all these studies.


http://mcr.aacrjournals.org/content/molcan.../6/778.full.pdf


Alpha-Melanocyte–Stimulating Hormone Suppresses Oxidative Stress through a p53-Mediated Signaling Pathway in Human Melanocytes
Ana Luisa Kadekaro1, Juping Chen1,2, Jennifer Yang1, Shuna Chen1, Joshua Jameson1, Viki B. Swope1, Tan Cheng1,3, Madhavi Kadakia4, and Zalfa Abdel-Malek1

Abstract

Epidermal melanocytes are skin cells specialized in melanin production. Activation of the melanocortin 1 receptor (MC1R) on melanocytes by a-melanocyte–stimulating hormone (a-MSH) induces synthesis of the brown/black pigment eumelanin that confers photoprotection from solar UV radiation (UVR). Contrary to keratinocytes, melanocytes are slow proliferating cells that persist in the skin for decades, in an environment with high levels of UVR-induced reactive oxygen species (ROS). We previously reported that in addition to its role in pigmentation, a-MSH also reduces oxidative stress and enhances the repair of DNA photoproducts in melanocytes, independent of melanin synthesis. Given the significance of ROS in carcinogenesis, here we investigated the mechanisms by which a-MSH exerts antioxidant effects in melanocytes. We show that activation of the MC1R by a-MSH contributes to phosphorylation of p53 on serine 15, a known requirement for stabilization and activation of p53, a major sensor of DNA damage. This effect is mediated by the cAMP/PKA pathway and by the activation of phosphoinositide 3-kinase (PI3K) ATR and DNA protein kinase (DNA-PK). a-MSH increases the levels of 8-oxoguanine DNA glycosylase (OGG1) and apurinic apyrimidinic endonuclease 1 (APE-1/Ref-1), enzymes essential for base excision repair. Nutlin-3, an HDM2 inhibitor, mimicked the effects of a-MSH resulting in reduced phosphorylation of H2AX (g -H2AX), a marker of DNA damage. Conversely, the p53 inhibitor pifithrin-a or silencing of p53 abolished the effects of a-MSH and augmented oxidative stress. These results show that p53 is an important target of the downstream MC1R signaling that reduces oxidative stress and possibly malignant transformation of melanocytes. Mol Cancer Res; 10(6); 778–86. !2012 AACR.
  Forum: By Share Code

PunkassDerm
Posted on: Sep 10 2018, 02:01 AM


Group: Member
Posts: 418

Reduced but not absent function in loss of function MC1R individuals is how I read it. Simplistically, if given proper stimulation can be (partially) corrected. Maybe the sort sequence afamelanotide more effective binder? Definitely not a biochemist but I think this is what we're looking for.


Your quote seems to support this (in vivo):
"Two trials in human volunteers showed that neither MC1R variants nor fair skin reduced the afamelanotide-induced increase in skin pigmentation."

translation, it still works

And as we clearly see stated over and over, it is not only the eumelanin tan but DNA repair and free radical scavenging that augments the anti-cancer potential.



https://academic.oup.com/hmg/article/10/21/2397/2901534


Functional variation of MC1R alleles from red-haired individuals

Eugene Healy Siobhán A. Jordan Peter S. Budd Ruth Suffolk Jonathan L. Rees Ian J. Jackson
Human Molecular Genetics, Volume 10, Issue 21, 2 October 2001, Pages 2397–2402, https://doi.org/10.1093/hmg/10.21.2397
Published: 02 October 2001

Red hair in humans is associated with variant alleles of the αMSH receptor gene, MC1R. Loss of MC1R function in other mammals results in red or yellow hair pigmentation. We show that a mouse bacterial artificial chromosome (BAC) which contains Mc1r will efficiently rescue loss of Mc1r in transgenic mice, and that overexpression of the receptor suppresses the effect of the endogenous antagonist, agouti protein. We engineered the BAC to replace the mouse coding region with the human MC1R sequence and used this in the transgenic assay. The human receptor also efficiently rescued Mc1r deficiency, and in addition, appeared to be completely resistant to the effects of agouti, suggesting agouti protein may not play a role in human pigmentary variation. Three human variant alleles account for 60% of all cases of red hair. We engineered each of these in turn into the BAC and find that they have reduced, but not completely absent, function in transgenic mice. Comparison of the phenotypes of αMSH-deficient mice and humans in conjunction with this data suggests that red hair may not be the null phenotype of MC1R.


DISCUSSION

We have demonstrated that Mc1r-containing BAC transgenes are able to very efficiently rescue the yellow, loss-of-function phenotype of Mc1re homozygous mice. Furthermore, the transgenic mice show a strong dosage-sensitive phenotype. Addition of only one or two copies in excess of the normal diploid complement darkens the coat by reduction of the yellow, agouti-induced band on the hair. A total Mc1r complement of approximately six copies almost completely suppresses the effect of agouti. We do not know whether the suppression of agouti is due to the increase in MC1R on the melanocyte surface saturating out a limited amount of agouti protein or whether there is normally a low level of signalling from the receptors even in the presence of agouti, which has an additive effect with increased receptor number and overcomes the antagonism.

Transgenic mice expressing human MC1R show a much greater suppression of agouti. Indeed, mice expressing only the normal diploid complement of human MC1R have no detectable phaemelanin and are completely black. This is not due to a lack of activity of mouse agouti protein on the human receptor, as others have demonstrated that in cells in culture the human MC1R is 10-fold more sensitive to mouse agouti than to the human protein (14). There is evidence to suggest that human MC1R is more sensitive to stimulation by hormone than the mouse receptor and this may be sufficient to overcome the antagonsim by agouti. It also appears that the density of MC1R on human melanocytes is considerably lower than the receptor density on mouse melanocytes (24). The transgenic system we describe here, in which the human receptor is expressed from the mouse promoter, may result in MC1R being present at non-physiological, high levels. The variant human MC1R receptors in transgenic mice do respond to agouti protein, as shown by the phaeomelanic patterning on their hairs. These receptors have attenuated signalling (demonstrated by the pale eumelanin synthesized on a non-agouti background) which appears to allow agouti to act.

Our data indicate that although the variant MC1R proteins are clearly defective, in accordance with population and family data associating them with red hair, none has complete loss of function when assayed in transgenic mice. Rare patients mutated in the POMC gene and thus lacking αMSH, have red hair that is apparently the same as the MC1R-associated red hair (20). However, POMC-deficient mice do not have the same phenotype as loss of Mc1r (15). Our finding that red-hair associated variant human receptors still allow significant eumelanin synthesis, may indicate that red hair is not the null phenotype. Although a few MC1R frameshift alleles that clearly do not produce functional protein have been described (17,26,27), they are rare and no homozygotes have been found. Whether MC1R-null individuals have different or additional phenotypes which means they have not been included in case control or population studies is unclear at this stage. MC1R has been suggested to have a role in melanocyte proliferation and in various non-melanocytic functions such as inflammation. There is no evidence that MC1R-associated red-haired individuals have any additional phenotype. However, identification and study of individuals homozygous for MC1R loss of function might reveal further roles for MC1R in humans.
  Forum: By Share Code

PunkassDerm
Posted on: Sep 5 2018, 01:37 PM


Group: Member
Posts: 418

Maybe they should have invested that brilliant and exhorbitant dividend into a team of regulatory experts.

So this doesn’t freaking happen.

Again

That’s my 2cents...literally
  Forum: By Share Code

PunkassDerm
Posted on: Sep 5 2018, 12:34 PM


Group: Member
Posts: 418

Where is this guy BTW? In the corner with baby and the poor dude from Blair Witch no doubt.


Attached Image


Nobody puts Wolgy in the corner!
It's Karma for killing Frilly
  Forum: By Share Code

PunkassDerm
Posted on: Sep 5 2018, 10:56 AM


Group: Member
Posts: 418

ALLERGAN
COMPETENCE
TAKEOVER


edit: unless tweak ensures PR

edit: sigh

edit: How many mulligans do you get and still receive performance rights as if on point?
  Forum: By Share Code

PunkassDerm
Posted on: Sep 4 2018, 12:35 AM


Group: Member
Posts: 418

Yes, cautious optimism. Botox was around a long time before cosmetic applications arose. FDA since seems to have clamped down on similar paths. Hence Melanotan to Scenesse and the long road for Clinuvel and our ragtag bunch of investors. Still Allergen is the model in my opinion, and the perfect company to get this accomplished. If it took this long to see EPP, and Vitiligo appears to have no urgency...it will be awhile before we see photoprotection. Hopefully that all changes with new class melanocortin status with FDA. I pray your optimism for speed is founded Wally.

If in the meantime: If the SP shoots up nicely and I can take some profits to live comfortably, I'll be happy to leave a big chunk to ride on a lifestyle drug. Get my photo-medicine boutique clinic up and running.

Queue the Wolgen clock.



A HISTORY OF BOTOX INJECTION THERAPY

By Dr. Scott W. Mosser

Botox® is a highly purified form of botulinum toxin Type A, which is produced by the bacteria clostridium botulinum. It was developed in the 1970’s by a San Francisco doctor searching for ways to correct strabismus, or crossed eyes. He discovered that a purified form of this potentially lethal poison (a toxin once commonly produced by bacteria in improperly processed food) when injected in the appropriate overactive muscles caused a temporary relaxation or paralysis which allowed other eye muscles to take over normal eye function.

Allergan, Inc., small drug company specializing in products for use in the fields of ophthalmology and dermatology, purchased the rights to the discovery in 1987, and the toxin was marketed for use in correcting eye muscle disorders such as blepharospasm (uncontrollable blinking) and strabismus (crossed eyes). This form of botulinum toxin A was licensed by Allergan, Inc. in 1989.

Over the following decade, doctors found additional uses for botulinum toxin Type A, including the treatment of cervical dystonia, a disorder that causes severe neck and shoulder contractions, as well as reducing the stiffness and tremors that often follow a stroke.

“FOUNTAIN OF YOUTH” TREATMENT CAUSES A MEDIA BLITZ
In the mid 1990’s, word of mouth among ophthalmologists and dermatologists in the U.S. and Canada spread the fame of the exciting cosmetic side effects observed after injecting the purified toxin – reduction of forehead wrinkles, facial creases and crow’s feet, resulting in a fresher, more youthful facial contour.

When the FDA approved the use of Botox® for cosmetic purposes in 2002, it triggered wide media coverage and catapulted the demand for Botox® injections specifically for cosmetic effect onto the world stage.

This huge demand led to a period of misuse of Botox® injections by non-medically trained cosmeticians, or in back-door treatments under non-medical condition, which resulted in reports of ineffectiveness or unpleasant side effects. It was only as the public became more informed and Board-Certified Plastic Surgeons and dermatologists began adding Botox® injection procedures to their non-surgical facial cosmetic programs that the full benefits became apparent and the safety and efficacy of Botox® injection therapy became mainstream.

The use of Botox® treatments to relax or eradicate wrinkles and frown lines on the forehead and around the eyes is currently the most popular non-cosmetic procedure in the United States, Europe and many other countries. When injected directly into overactive facial muscles, Botox® inhibits the release of acetylcholine, a neurotransmitter that causes muscles to contract. The result is inhibition, or relaxation, of the muscles, an effect that can last up to several months.

According to Allergan, almost 3.3 billion Botox® Cosmetic procedures were performed in 2005 alone.

A CONTINUING POPULARITY
The huge popularity of Botox® injections is likely due to its non-surgical nature (leaving no scars), little or no recovery time, its effectiveness, and its relatively low cost compared to surgical face lifts or other procedures. Its safety is also an important factor. Botox® has been widely used for more than a dozen years and there have been no documented systemic complications associated with Botox® injections when administered by qualified medical personnel in accordance with the recommended dosage and guidelines.

The United States Food and Drug Administration (US FDA) cautions that Botox® is a prescription drug that should be administered by a qualified physician in an appropriate medical setting. Any other venue runs the risks of improper technique, inappropriate dosages and unsanitary conditions. The FDA also recommends that Botox® Cosmetic be injected no more frequently than once every three months, and that the lowest effective dose should be used.

The continuing popularity of Botox® cosmetic treatments among men and women in every walk of life (from the glamour industry to the housewife to executives) and the familiarity with which the term is used, has perhaps somewhat obscured the history of the toxin and its original uses. However, physicians and medical researcher have not forgotten and recent developments of new medical uses for Botox are causing renewed excitement.

A NEW WRINKLE FOR AN ANTI-WRINKLE TREATMENT
This unusual substance, which started life as a life-threatening toxin, was later purified for use in treating eye disorders, and then met fame and fortune as an anti-wrinkle treatment, has in the past few years been found to have exciting new health applications: most notably, in the treatment of migraine headaches.

Again, plastic surgeons using Botox® injections on patients who were incidentally migraine headache sufferers began to notice that in addition to a smoother, more youthful facial contour, patients were reporting a lessening in the strength and frequency of migraine attacks.
  Forum: By Share Code

PunkassDerm
Posted on: Sep 3 2018, 12:04 AM


Group: Member
Posts: 418

Then pricing:

Vitiligo approval: 5000USD per implant

Fastforward 10-15 years....

Photo protection/antioxidant/DNA repair "supplement" : 500USD

let her rip
  Forum: By Share Code

PunkassDerm
Posted on: Sep 2 2018, 11:50 PM


Group: Member
Posts: 418

I emailed Mr Hay in 2004 asking why Vitiligo is not in their sights, always the prize and agree with recent posts. See below prevalence stats that I pulled, trying to find average values.
Vitiligo market potentially much lager than I had ever hoped, yet psoriasis gets all of the attention. Inevitably through pharma marketing and awareness. Yet Vitiligo carries same emotional disability about self image. This is huge. See prevalence number below and the worldwide psoriasis market of about 11.5 billion and growing.

Then understand the psoriasis biologic market alone saturated with new products. I count at least 13 injectables.

Translate that to a wide open and underserved vitiligo market with no adequate clinically efficacious treatment. There is room for multiple drugs, JAK and melanocortins. Maybe great synergies and so much opportunity for Scenesse and new topical formulations. First in class, with EMA and FDA approval.

Also, new indication for approved drug should be smoother/faster with existing safety and pharmacokinetics data in place.

Eyes wide open.

Punk



New indications for already-approved drugs: an analysis of regulatory review times.

DiMasi JA1, Kaitin KI, Fernandez-Carol C, Lasagna L.

A survey of the U.S. pharmaceutical industry was conducted to obtain data on the length of the review process for supplemental indications of already-approved new chemical entities (NCEs). Responses were received from 51 firms and covered supplemental indications of 348 NCEs that were approved during 1963 to 1988. Since extensive toxicity and safety evaluation would generally not be required for supplemental indication reviews, one would expect supplemental indications, on average, to be reviewed more quickly than applications for the associated original indications. The mean +/- standard deviation review time for the 172 supplemental indications in the sample is 21.5 +/- 18 months; the average review time for the associated 94 original indications is 23.5 +/- 18 months. The difference in average review times is not statistically significant. Analysis of review times for indications grouped by Food and Drug Administration (FDA) reviewing division showed a statistically significant difference between supplemental and associated original indication review times only in the cardio-renal division. In that division, average review times were longer for supplemental indications (25.6 vs. 19.3 mo; P less than .05). Analysis of time trends showed a significant increase in average supplemental indication review time for 1985 to 1988 approvals relative to the average associated original indication review time (P less than .01) and to average supplemental indication review time for earlier time periods (P less than .01). These results suggest the need for a close examination of the supplemental indication review policy of the FDA.


PREVALENCE:

Psoriasis Worldwide: up to 2 - 3%
As many as 7.5 million Americans— 125 million people worldwide

Vitiligo Worldwide: 0.5 - 2%
Reports show 65-95 million people affected



Vitiligo is an acquired skin disorder characterized by patchy depigmentation of the skin [1]. Vitiligo affects approximately 0.5% to 2% of the population worldwide, and the prevalence appears to be equal between men and women [2,3]. The pathogenesis of vitiligo is still not fully understood and mounting evidences have suggested that it might be related to autoimmunity and oxidative stress [4]. Although neither life-threatening nor symptomatic, the effect of vitiligo can be cosmetically and psychologically devastating, resulting in low selfesteem, poor body image and other negative effects [5-7].


Prevalence of vitiligo

Although vitiligo occurs worldwide, it is known that its prevalence varies between races and regions. Recent studies have revealed the prevalence from 0.06-2.28% [8-28]. Howitz et al. [8] reported that the prevalence of vitiligo in Denmark was 0.38%. Mehta et al. [9] reported that the prevalence was 0.49% in rural areas of Indian and 1.78% in urban areas. Abdel-Hafez et al. [10] performed a survey in Upper Egypt and found the prevalence of vitiligo to be 1.2%. In USA, the prevalence of vitiligo was 0.74% [11]. Other studies have shown a prevalence of 0.17% in Italy [12], 0.5-1% in the French West Indies [13], and 0.28% in France [14]. In China, several studies have been performed and the prevalence of vitiligo ranged from 0.10 to 0.3% [15-19]. Lu et al. [15] conducted a survey in Shaanxi province, northwest China and found that the prevalence of vitiligo was 0.10%.


CONTRAST PSORIASIS BIOLOGIC MARKET ALONE

The global psoriasis therapeutics market size was valued at USD 11.5 billion in 2016 and is estimated to grow at a CAGR of 9.3% during the forecast period. Increasing awareness about treatment and rising demand for improved healthcare infrastructure are major factors expected to drive the psoriasis market.

The changing lifestyle of people leading to increased alcohol consumption and smoking, unhealthy diet and a sedentary living makes more people prone to this condition. Psoriasis is a genetic condition that may not be present at birth. The condition may be triggered by certain environmental and genetic factors.

According to the International Federation of Psoriasis Association, approximately 5.0% people suffer from one or more forms of psoriasis, globally. In the U.S. alone, the condition affects nearly 7.5 million people, which is roughly 2.0% of the population. Moreover, approximately 100,000 new cases are registered and reported every year.

Plaque psoriasis is spearheading the segment with more than 80.0% patients suffering at a global level. Guttate psoriasis is the second most common type, affecting about 10.0% of the patients. Erythrodermic psoriasis is the rarest but the most dangerous type. This condition demands a medical emergency, often leading to hospitalization of patients.

The market space can be divided into various therapeutic classes such as Tumor Necrosis Factor (TNF)-inhibitors, Interleukin inhibitors and Vitamin D Analogues. TNF inhibitors have dominated the therapeutic space. However, they are likely to lose shares over the forecast. The marketed TNF-inhibitors used for psoriasis are Humira (adalimumab), Enbrel (etanercept) and Remicade (infliximab).

Interleukin (IL) inhibitors are expected to witness the fastest growth over the forecast period due to their improved safety and efficacy profiles and rising adoption among end users. Marketed interleukin inhibitors include Stelara (ustekinumab), Cosentyx (secukinumab), Taltz (ixekizumab), Siliq (brodalumab) and Tremfya (guselkumab).

Just the biologics are numerous:

Tumor necrosis factor-alpha (TNF-alpha) inhibitors

Cimzia (certolizumab pegol), Enbrel (etanercept), Humira (adalimumab), Remicade (infliximab), Simponi (golimumab) and Simponi Aria (golimumab) are drugs that block TNF-alpha. TNF-alpha is a cytokine, or a protein, that prompts the body to create inflammation. In psoriasis and psoriatic arthritis, there is excess production of TNF-alpha in the skin or joints. That leads to the rapid growth of skin cells and/or damage to joint tissue. Blocking TNF-alpha production helps stop the inflammatory cycle of psoriatic disease.

Interleukin 12 and 23 (IL-12/23) inhibitors

Stelara (ustekinumab) works by selectively targeting the proteins, or cytokines, interleukin-12 (IL-12) and interleukin 23 (IL-23). Interleukins-12/23 are associated with psoriatic inflammation.

Interleukin 17 (IL-17) inhibitors

Cosentyx (secukinumab), and Taltz (ixekizumab) block a cytokine, or protein, called interleukin-17 (IL-17), which is involved in inflammatory and immune responses. Siliq (brodalumab) blocks the receptor of this cytokine, IL-17 receptor A (IL-17 RA) through which IL-17 mediates the inflammatory and immune responses. There are elevated levels of IL-17 in psoriatic plaques. By interfering with IL-17 signaling, Cosentyx, Siliq and Taltz interrupt the inflammatory cycle of psoriasis. This can lead to improvement in symptoms for many people who take it.

T cell inhibitors

Orencia (abatacept) targets T cells in the immune system. T cells are a type of white blood cell that is involved in the inflammation in psoriasis and psoriatic disease. Orencia inhibits T cells from becoming activated to reduce inflammation.

Interleukin 23 (IL-23) inhibitors

Tremfya (guselkumab) and Ilumya (tildrakizumab-asmn) work by targeting interleukin 23 (IL-23). This cytokine is linked with inflammation in psoriasis and psoriatic arthritis. Tremfya and Ilumya work to reduce psoriatic symptoms and slow disease progression.
  Forum: By Share Code

PunkassDerm
Posted on: Sep 2 2018, 01:45 AM


Group: Member
Posts: 418

FDA's Expedited Approval Mechanisms for New Drug Products
Erin E. Kepplinger


https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4326266/


Modern medicine and science have made incredible strides in improving and extending lives. Nonetheless, many diseases and conditions still lack adequate therapies. According to a report issued by the President's Council of Advisors on Science and Technology (PCAST) in September 2012 on Propelling Innovation in Drug Discovery, Development, and Evaluation, roughly 30 million Americans suffer from 7,000 rare diseases, but only 350 therapies are approved as treatments.1 Indeed, “[96] percent of orphan diseases, including rare cancers, lack effective therapies.”2 Other conditions demand improved therapies as well. For example, “[h]eart disease and stroke remain leading causes of mortality.”3 The public health need for continued research and development of new drug and biologic products for significant diseases is clear and compelling.

But beyond these important health reasons for stimulating research and development of new compounds, there are ancillary and supportive economic considerations for propelling innovative research and development. According to the Pharmaceutical Research and Manufacturers of America (PhRMA),4 the United States' biopharmaceutical industry contributes substantially to the U.S. economy. PhRMA reports that the industry directly employs over 800,000 workers in well-paid jobs and diverse fields, and supports an additional 2.5 million jobs across the country.5 Moreover, PhRMA asserts that it supports over $789 billion in total economic output.6 For several years, though, the increased time and money necessary to develop a new compound, the failure rate of prospective products, and a decrease in venture capital investments, among other strains on the industry, have propelled concerns that innovative research in the U.S. might wither, stop, or move to other nations or regions, decreasing the potential short term access for U.S. patients to some new products, potentially leaving others unexplored entirely, and hurting a significant segment of the U.S. economy.

As a result, Congress, the Food and Drug Administration (FDA), and the pharmaceutical industry have sought to nurture an “ecosystem” conducive to the development of innovative, safe, and effective new compounds in the U.S. Among the mechanisms developed are four expedited approval mechanisms, the most recent of which—the Breakthrough Therapy designation—Congress created in 2012 through the Food and Drug Administration Safety and Innovation Act (FDASIA). Sponsors of new drug and biologic products (sponsors) have embraced the new Breakthrough Therapy designation: as of roughly December 2014, FDA reported having received 260 requests for Breakthrough Therapy designation, of which it granted 74 and denied 139.7 Of the 41 designated compounds, four have been approved for marketing.
  Forum: By Share Code

PunkassDerm
Posted on: Aug 30 2018, 09:46 AM


Group: Member
Posts: 418

My beef with Lachlan Gay started with this very issue. Said he'd get back to me about voting shares and never did. Now no replies to anything. Great Investor relations.
  Forum: By Share Code

PunkassDerm
Posted on: Aug 30 2018, 09:09 AM


Group: Member
Posts: 418

Maybe I'm wrong and not an investment guru, but I don't think anything has to change for Clinuvel to trade on the NASDAQ. It simply goes from the OTC to NASDAQ exchange. Not super complicated and no tax implications.

For example I held and traded BP for years. BP is an ADR on the NYSE (6:1 ADR to common stock).

I think I was able to vote my shares too. Clinuvel chooses to deny this right, in their purview to allow or not.
  Forum: By Share Code

PunkassDerm
Posted on: Aug 29 2018, 11:20 AM


Group: Member
Posts: 418

We pool together and build a compound off Greece. I hear Mykonos is great!
  Forum: By Share Code

PunkassDerm
Posted on: Aug 29 2018, 10:44 AM


Group: Member
Posts: 418

If this girl is good to me and goes 30+ I'm willing to take the penalty. Cash out my 600K+ investment to do some things I've been waiting for, way too long. Majority long term holdings as well. Assuming Taxachusetts not unlike Cali. No plans for shelters, happy to come out on top with money for play and re-invest.

Hold onto 150K shares for photo protection approval.
  Forum: By Share Code

PunkassDerm
Posted on: Aug 29 2018, 02:41 AM


Group: Member
Posts: 418

My portfolio jumped 200K just now! Announcement known to Clinuvel and a select few? Instos?
  Forum: By Share Code

PunkassDerm
Posted on: Aug 22 2018, 08:31 PM


Group: Member
Posts: 418

Vitiligo studies, test doses? States Scenesse doses to date? Not just EPP?
  Forum: By Share Code

PunkassDerm
Posted on: Aug 14 2018, 11:27 PM


Group: Member
Posts: 418

But who's the black sheep? to quote my old rap friends...
It would change the product (wool) in this case.

Attached Image
  Forum: By Share Code

PunkassDerm
Posted on: Aug 7 2018, 10:40 PM


Group: Member
Posts: 418

Instead of becoming dangerously over-leveraged and bloated for a small company. Why don't they utilize a portion of those funds and hire the right staff/scientists/regulatory experts to fund an expert vitiligo trial and application. Or merger, or partnership...or be acquired.

...and Free Frilly
  Forum: By Share Code

PunkassDerm
Posted on: Aug 6 2018, 12:33 PM


Group: Member
Posts: 418

Approaching recent high...

Next milestone @21AUD to reach 1 billion valuation. correct?
  Forum: By Share Code

PunkassDerm
Posted on: Aug 4 2018, 03:48 AM


Group: Member
Posts: 418

read on....I understand as the latter

In 1998, the first year of Fast Track, the FDA received 27 requests, of which 21 were granted (78%). The number has increased steadily year over year, with 187 requests received in 2016, of which 131 were granted (70%).

Ultimately, the Fast Track program has been deemed a success, with approximately two thirds of all 770 Fast Track requests approved by the FDA from 2007 to 2015, according to the Government Accountability Office (GAO).
  Forum: By Share Code

PunkassDerm
Posted on: Aug 4 2018, 02:43 AM


Group: Member
Posts: 418

770 Fast Track 2005-2017
approximately 2/3 approved
see below


https://www.centerwatch.com/news-online/201...ch-20th-year-2/


FDA Fast Track designations reach 20th year
SUNDAY, OCTOBER 1, 2017


Twenty years after its inception, the FDA’s Fast Track designation program is going strong, with many signs that it has achieved its goal of bringing novel drugs to the market faster. Now, even with a new FDA Commissioner at the helm, the Fast Track program is unlikely to change substantially, although it may adjust to more explicitly address current areas of high-unmet medical need such as antibiotic resistance and cardiovascular disease.


Introduced in 1997 as part of the Food and Drug Administration Modernization Act (FDAMA), the Fast Track designation became the FDA’s third expedited review program after Priority Review and Accelerated Approval.

Launched in the wake of the AIDS crisis, these expedited review programs were designed to speed up drug development for life threatening illnesses. “Given that one of the primary goals of the Fast Track program was to be more inclusive and to apply to a wider swath of products, the qualifying criteria for the program were intentionally set quite low,” said Mark Mathieu, director, Publications, Parexel. “FDA guidance notes that a Fast Track designation can be obtained quite early in development, based on nonclinical evidence or even a mechanistic rationale,” Mathieu continued.

In 1998, the first year of Fast Track, the FDA received 27 requests, of which 21 were granted (78%). The number has increased steadily year over year, with 187 requests received in 2016, of which 131 were granted (70%).

If granted, Fast Track can bolster a company’s stock valuation by 18%, making it attractive to smaller biotechs. According to a 2009 review of the program, Fast Track was the most significant factor among variables affecting the chances of first-cycle approval, with 78% of Fast Track applications accomplishing this milestone.

The barriers to entry have risen over time. “Although many experts today would argue that a bit more is typically needed to gain Fast Track status (e.g., early biological response data in humans), it’s clear that the evidentiary hurdle remains reasonably low,” Mathieu said. “The success rates for Fast Track applications submitted to FDA’s Center for Drug Evaluation and Research (CDER) have ranged between 70% and 80% over the last three years.”

Once Fast Track is granted, there are significant benefits to a sponsor company, including the ability to “put in parts of your application piecemeal” and less risk of an “action by the FDA that would slow things down,” said Christopher-Paul Milne, director of Research, Tufts Center for the Study of Drug Development (CSDD).

“Basically, that’s what Fast Track is designed to do—head off problems while you’re in your normal development cycle,” Milne said. In addition, the program may trim the cost of drug development by shorting research timelines, opening up the opportunity of early approval.

Ultimately, the Fast Track program has been deemed a success, with approximately two thirds of all 770 Fast Track requests approved by the FDA from 2007 to 2015, according to the Government Accountability Office (GAO). The Fast Track program has “withstood the test of time” and is unlikely to be curtailed under the new FDA Commissioner Scott Gottlieb, said Milne.AO). The Fast Track program has “withstood the test of time” and is unlikely to be curtailed under the new FDA Commissioner Scott Gottlieb, said Milne.
  Forum: By Share Code

PunkassDerm
Posted on: Aug 1 2018, 11:44 AM


Group: Member
Posts: 418

Still like to paddle my own, GT3 Manual.
  Forum: By Share Code

PunkassDerm
Posted on: Aug 1 2018, 10:57 AM


Group: Member
Posts: 418

I originally had dreams of 200-300/share in 2007. Today, just happy to see her hold ground. Should it be organically higher? Is some unknown entity holding the stock back as part of a plan? $30 would just be a nice endpoint for me to justify these last 14 years. I can live with that now. Timeline unknown, deadlines and goals are disappointing.

How about, before a competing melanocortin is approved?

Goals: Finish the home that diverted funds went to CLVLY, add a nice pool, put a Porsche in the garage bay.
  Forum: By Share Code

PunkassDerm
Posted on: Aug 1 2018, 01:23 AM


Group: Member
Posts: 418

I think Wolgen won't give up until he maxes out all his performance rights. Then maybe buyout/merger. I'd love to see 30AUD, a fair evaluation and be forced to be done. How many hours do we all spend watching these boards, researching and fretting? A good positive run and out, back to living. I for one fret much!
  Forum: By Share Code

PunkassDerm
Posted on: Jul 25 2018, 09:23 AM


Group: Member
Posts: 418

Begs the question...what's next. Is beef cultured from a cell line still beef?
Biosimilar meat for PETA, here it comes. They hate monsanto GMO, but this I bet they approve.

http://www.fdalawblog.net/2018/04/what-is-beef-round-two/

What is Beef? Round Two

April 20, 2018
By Riëtte van Laack —

As we previously reported, the United States Cattlemen’s Association (USCA) filed a Petition with the Food Safety and Inspection Service (FSIS), asking that FSIS establish formal definitions of “meat” and “beef” that exclude what petitioners call lab grown meat and products prepared from plant or insect protein. Until April 17, the majority of comments submitted have been in support of the petition.

The National Cattlemen’s Beef Association, (NCBA), however, does not support the Petition. As described in its comment to the Petition, the NCBA does not believe that the action requested by USCA “will adequately provide meaningful protection for beef nomenclature.” In contrast to the USCA, the NCBA wants FSIS to assert jurisdiction over foods produced from cell or tissue culture that are derived from livestock and poultry animals or their parts, so as to ensure a level playing field. NCBA takes the position that, since cell-cultured or lab-grown meat products are derived from parts of a carcass, in this case stem cells, these products fall squarely within the definition of meat food product. Even if this were not the case, NCBA believes that “FSIS should assert jurisdiction as a means of ensuring regulatory equity.”

As to the labeling of the product, NCBA seems of two minds. It asserts that the cultured meat should not be permitted to be marketed as beef. Yet, it argues that, if the producers of lab-grown or cultured meat products wish to call these products meat, they must adhere to the same food safety inspection standards and comply with the same labeling standards as traditional meat food products; only in that way can “arbitrary marketing claims,” such as “clean meat,” be avoided.
  Forum: By Share Code

PunkassDerm
Posted on: Jul 25 2018, 09:06 AM


Group: Member
Posts: 418

Biosimilar is actually the "generic" form of a biologic drug. These days often a monoclonal antibody. Whereas traditional drugs are made with a recipe and chemical reactants (can be exactly reproduced) a biosimilar can never be exactly the same. As I understand (hopefully correctly) there are often made from bacteria or cell lines. A rip-off biosimilar can have as similar structure and therapeutic effect, but is never ever identical, hence bio-SIMILAR. I think Harris was referring to biologics in general and likely JAK inhibitors.

The FDA discussing biosimilars has nothing to do with traditional drugs, i.e. afamelanotide; but to making cheap versions of established biologic drugs like Humira, Stelara and cancer drugs like Zelboraf and Yervoy... etc


Understanding biologics: How they differ from drugs and why they cost more

https://www.everydayhealth.com/columns/zimn...they-cost-more/


Because second-generation biologics are complex proteins they can't yet be made by following a chemical recipe. We just don't know how to do that. But since all living cells know how to make proteins, that's basically what they do for a living, so to speak, second-generation biologics are made by exploiting this fact. We "trick" certain cells to make the proteins for us using biotechnology. A variety of cells have been used to make biologics, but the key is that they have to be alive and fully functioning. We've used yeast and bacteria (E coli), and even cells that come from mammals. One of the most widely used mammalian cells is called CHO because it originally came from the Chinese hamster (the "O" signifies that the specific cell used came from the ovary).

There are two fundamental requirements for making a biologic. One is that the cells in which the product will be made have to be grown in extremely large quantities. You need huge vats of yeast, bacteria or CHO cells, and they have to be maintained under conditions that allow them to live and to function normally. But if you think that's complicated, it's the second requirement that's the real mind blower. Since the cellular instructions for making all proteins are carried by the DNA in the genes, if you could either isolate or create the right gene you'd have the blueprint that would tell the cell how to make the protein you want.



What is a biosimilar, from the FDA

https://www.fda.gov/downloads/Drugs/Develop...s/UCM585738.pdf
  Forum: By Share Code

PunkassDerm
Posted on: Jul 25 2018, 02:14 AM


Group: Member
Posts: 418

https://www.umassmed.edu/vitiligo/about/dir...-harris-md-phd/


Director: John E. Harris, MD, PhD

John Harris: Dr. Harris is a tenure-track Assistant Professor in the Dermatology Division, Department of Medicine at the University of Massachusetts Medical School (UMMS) in Worcester, MA. Dr. Harris directs the Vitiligo Clinic and Research Center at UMMS, which incorporates a specialty clinic for the diagnosis and treatment of patients with vitiligo, as well as a vitiligo research laboratory. He uses basic, translational, and clinical research approaches to better understand autoimmunity in vitiligo, with a particular focus on developing more effective treatments.

He earned his MD and PhD degrees at UMMS, and his PhD thesis was focused on the loss of autoimmune tolerance in juvenile diabetes. He entered a combined research/residency program in dermatology at the University of Pennsylvania in Philadelphia, PA, and his postdoctoral research focused on the development of a mouse model of vitiligo with epidermal depigmentation. He now advises multiple graduate students, MD/PhD students, and postdoctoral fellows in his research laboratory at UMMS, and teaches medical students and residents in his vitiligo clinic.

He has authored multiple research publications and textbook chapters on vitiligo and other topics, and serves on a number of advisory boards and committees, including the Dermatology Foundation, Skin of Color Society, Vitiligo Working Group, Vitiligo Research Foundation, National Alopecia Areata Foundation, American Academy of Dermatology and the New England Dermatology Society, among others. He is an advisor and collaborator with multiple pharmaceutical companies, including AbbVie, Combe Inc, Genzyme/Sanofi, and Pfizer.

Dr. Harris is an ad hoc reviewer on grant applications for the National Institutes of Health (NIH), Dermatology Foundation, and National Alopecia Areata Foundation, as well as multiple research journals, including Science Translational Medicine, the Journal of Clinical Investigation, the Journal of Investigative Dermatology, Pigment Cell & Melanoma Research, Experimental Dermatology, the Journal of the American Academy of Dermatology, JAMA Dermatology, and others. He receives generous grant support from the NIH, Dermatology Foundation, Kawaja Vitiligo Initiative, and the Vitiligo Research Foundation. He has lectured on vitiligo and other topics to local, regional, national, and international audiences.
  Forum: By Share Code

PunkassDerm
Posted on: Jul 25 2018, 12:27 AM


Group: Member
Posts: 418

Vitiligo pathogenesis and emerging treatments
Mehdi Rashighi, MD and John E. Harris, MD, PhD


https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5362109/


Afamelaotide mentioned, and may compliment JAK inhibitors...as a multi-therapeutic approach. Same John Harris from UMASS.
Another little fact, Abbvie has a research facility literally across the street from UMASS main campus.



Attached Image




see below proximity Abbvie bio-research to UMASS medical school. Abbvie highly active in JAK inhibitors.

Attached Image

  Forum: By Share Code

PunkassDerm
Posted on: Jul 24 2018, 11:51 PM


Group: Member
Posts: 418

Interesting!

I've also noticed afamelanotide has disappeared from Dr Harris' vernacular, giving way to memory-T research and melanocyte transplantation (performed in house BTW by Dr Dorie Goldberg). Has has group turned their backs in order to monetize a different avenue? Why did he not even mention afamelanotide as a promising alternative given he was involved in studies?
  Forum: By Share Code

PunkassDerm
Posted on: Jul 24 2018, 01:59 PM


Group: Member
Posts: 418

MagellanRx Pipeline - July 2018
p24


ETA of Feb 25, 2019


https://www1.magellanrx.com/media/773130/mr...y-2018_0718.pdf


Attached Image

  Forum: By Share Code

PunkassDerm
Posted on: Jun 25 2018, 10:48 PM


Group: Member
Posts: 418

https://www.nasdaq.com/press-release/fda-to...-20180625-00168

FDA to Review Australian Drug for Genetic Disorder of Absolute Light Intolerance
By GlobeNewswire, June 25, 2018, 06:00:00 AM EDT



Historic treatment proposed for rare disease causing burns, ulcerations and lifelong isolation of patients forced to live in the dark
MELBOURNE, Australia, June 25, 2018 (GLOBE NEWSWIRE) -- In a landmark case, the US Food and Drug Administration (FDA) has begun a review of an innovative drug developed for patients who carry a rare genetic blood disorder known as erythropoietic protoporphyria (EPP). EPP patients suffer extreme biochemical reactions when they expose their skin to any light source, particularly the spectrum of visible light, restricting their ability to function properly and forcing them to lead an isolated life in the dark.


The pharmaceutical innovation - known as SCENESSE® or afamelanotide 16mg - was developed for EPP over the past 14 years by the Australian pharmaceutical company CLINUVEL.

Due to a genetic defect, EPP patients carry a deficiency in one of their key enzymes to produce heme, and consequently accumulate a chemical substance in their blood which immediately reacts when patients are exposed to light, including sun, ambient and artificial sources. Patients incur physical burns and ulcers, and are in a state of crisis following light exposure, summarized as phototoxicity. This usually occurs within minutes of exposure to bright lights, especially sunlight. Phototoxic reactions last from days to weeks, and are unresponsive to any other medications.

SCENESSE®, which is already authorized in Europe for adult EPP patients, uses the body's own defensive systems to protect EPP patients from light.1 The drug, administered as a subcutaneous dose every two months, activates melanin (pigment) in skin, which acts as a physical protective barrier to shield the chemicals in the blood from light. CLINUVEL has now submitted a new drug application to the FDA requesting SCENESSE® be authorized for distribution in the US, and expects the review to be completed in 2019.

"The innovation developed as SCENESSE® activates an umbrella of melanin which shields patients' skin cells from light sources," CLINUVEL's Chief Scientific Officer Dr Dennis Wright said.

Professor Elisabeth Minder, head of Biochemical Laboratory Analytics at Triemli Hospital in Zurich, was involved in the first clinical trials of the product in EPP and continues to treat EPP patients.

"My patients tell me, since 2006, that this treatment facilitates a life which was unthinkable for them and their immediate families," Prof Minder said. "Therefore, I am delighted that this treatment finally nears the point of becoming available to all American EPP patients."

Over 800 patients have received SCENESSE®, including 350 EPP patients in clinical trials. Results from these trials showed the drug is able to reduce the number and severity of phototoxic reactions, and allows a life which patients could never lead before. Two Phase III trials, from the US and Europe, were published in the New England Journal of Medicine, noting good tolerance to the drug.2 CLINUVEL continues to monitor the drug's ongoing use in Europe, and will establish a similar program in the US, if approved.

"We are proud to have worked so hard to be in a position where SCENESSE® may become available to US EPP patients as early as next year," Dr Wright said. "EPP is a significantly neglected disease, one which our team have focused on since 2005. It is fantastic news for US patients and their families that there is finally hope of receiving a treatment that will allow them to come out of the dark. The US EPP patients have proven to be very motivated during the clinical trials and deserve adequate medical care."

1 SCENESSE® (afamelanotide 16mg) is approved in Europe as an orphan medicinal product for the prevention of phototoxicity in adult patients with EPP. Information on the product can be found on CLINUVEL's website at www.clinuvel.com.
  Forum: By Share Code

PunkassDerm
Posted on: Jun 25 2018, 10:20 AM


Group: Member
Posts: 418

15 today for CUV? More? bets?

I could cry
  Forum: By Share Code

PunkassDerm
Posted on: Jun 23 2018, 11:42 PM


Group: Member
Posts: 418

that logo...
is painful
  Forum: By Share Code

PunkassDerm
Posted on: Jun 22 2018, 01:33 PM


Group: Member
Posts: 418

Refocused? Shopping for a GT3!
  Forum: By Share Code

PunkassDerm
Posted on: Jun 21 2018, 01:00 PM


Group: Member
Posts: 418

we got marketing team, new blood.
  Forum: By Share Code

PunkassDerm
Posted on: Jun 21 2018, 12:53 PM


Group: Member
Posts: 418

I propose rebranding in a new direction:

CLINUSNAIL

Attached Image

  Forum: By Share Code

PunkassDerm
Posted on: Jun 21 2018, 12:28 PM


Group: Member
Posts: 418

What I really have a difficult time grasping...

Palatin in a short amount of time gets their FDA-NDA accepted for a FEMALE BONER DRUG

Yet Clinuvel's keystone cops can't get their shit together for an efficacious drug geared towards an ULTRA-ORPHAN DISEASE with no effective treatment.

EVERY FREAKING DELAY, AND THIS GOES BACK...SHOULD RESULT IN PERFORMANCE RIGHTS PENALTIES FOR CORPORATE SILLY NANNIES!
  Forum: By Share Code

PunkassDerm
Posted on: Jun 20 2018, 04:55 AM


Group: Member
Posts: 418

I know this is medicine and all...

But no news IS NOT good news.

tick tock I can't stand it
  Forum: By Share Code

PunkassDerm
Posted on: Jun 16 2018, 06:13 AM


Group: Member
Posts: 418

With many prayers, YES. If I'm right and if it shoots up to 15, happy to give to an EPP sufferer either way!


A step further, I'll donate to the APF:

http://www.porphyriafoundation.com/content...yria-foundation



Then the American Vitiligo Foundation:

http://www.avrf.org/
  Forum: By Share Code

PunkassDerm
Posted on: Jun 14 2018, 03:01 AM


Group: Member
Posts: 418

Genius or stupid, hopefully lucky. I just scooped up 5k more in 2500 blocks. Maybe why you didn’t execute. Outta cash, that’s all I got.
  Forum: By Share Code

PunkassDerm
Posted on: Jun 12 2018, 11:34 PM


Group: Member
Posts: 418

Troll by definition is Ignoretidine, and Administrators should take note. Wally like most on here, attempts to stimulate discussion and ideas. That's the point.

In Internet slang, a troll (/troʊl, trɒl/) is a person who sows discord on the Internet by starting quarrels or upsetting people, by posting inflammatory,[1] extraneous, or off-topic messages in an online community (such as a newsgroup, forum, chat room, or blog) with the intent of provoking readers into an emotional response[2] or of otherwise disrupting normal, on-topic discussion,[3] often for the troll's amusement.
  Forum: By Share Code

PunkassDerm
Posted on: Jun 12 2018, 01:07 AM


Group: Member
Posts: 418

For better or worse, secured another 5K CLVLY @ 9.20USD. I'm ready for announcement and 15-20 range.
  Forum: By Share Code

PunkassDerm
Posted on: Jun 9 2018, 07:10 AM


Group: Member
Posts: 418

Wanted to catch some more shares one last time, hoping for that rocket launch come July. No takers for 5000 CLVLY at 9.20 USD. Left it go GTC. I'd be just as happy if it took off.
  Forum: By Share Code

PunkassDerm
Posted on: May 29 2018, 10:17 AM


Group: Member
Posts: 418

Glad you’re on board y’all. Should probs buy on the iPhone stock dip, can’t beat zero for a buy-in. Good opportunity!
  Forum: By Share Code

PunkassDerm
Posted on: May 28 2018, 12:26 AM


Group: Member
Posts: 418

All of these studies point to PREDNISONE v2.0 with positive effects rather than side effects. That's why I've been hanging on since 2004. Truly disruptive medicine.

I'd love to get myself on Scenesse along with cord blood infusions to hold off aging.
  Forum: By Share Code

PunkassDerm
Posted on: May 28 2018, 12:19 AM


Group: Member
Posts: 418

https://www.hindawi.com/journals/bmri/2014/874610/


BioMed Research International
Volume 2014, Article ID 874610, 10 pages
http://dx.doi.org/10.1155/2014/874610


Alpha-Melanocyte Stimulating Hormone: An Emerging Anti-Inflammatory Antimicrobial Peptide
Madhuri Singh1,2 and Kasturi Mukhopadhyay1



Abstract

The alpha-melanocyte stimulating hormone (-MSH) is a neuropeptide belonging to the melanocortin family. It is well known for its anti-inflammatory and antipyretic effects and shares several characteristics with antimicrobial peptides (AMPs). There have been some recent reports about the direct antimicrobial activity of -MSH against various microbes belonging to both fungal and bacterial pathogens. Similar to -MSH’s anti-inflammatory properties, its C-terminal residues also exhibit antimicrobial activity parallel to that of the entire peptide. This review is focused on the current findings regarding the direct antimicrobial potential and immunomodulatory mechanism of -MSH and its C-terminal fragments, with particular emphasis on the prospects of -MSH based peptides as a strong anti-infective agent.


Until two decades ago this neuropeptide was primarily known as melanogenic hormone; however, later its immunomodulatory role was discovered and its anti-inflammatory effects were implicated in the cure of many inflammatory conditions [55]. The following section describes the in-depth understanding of anti-inflammatory mechanisms of -MSH.

7. Modulation of Immune Response by -MSH to Cure Inflammatory Conditions

In mammals, as described above, besides its hormonal effects, -MSH is also recognized for regulating the level of effector molecules implicated in inflammatory conditions [31, 55, 56]. -MSH performs anti-inflammatory action by binding to different MCRs, such as MC1R, MCR3, and MCR5 [32]. However, it has specific affinity for MC1R, which primarily signals through the cyclic AMP-protein kinase A (cAMP-PKA) pathway to exert immunomodulatory actions [29, 51]. Inflammation is characterized by increased level of various effector molecules including proinflammatory cytokines (IL-6, IL-1, TNF-, and IFN-), chemokines, and reactive oxygen and nitrogen species [57]. The expression level of -MSH increases in response to the above effector molecules and thus it modulates immune reactions to reinstate immune homeostasis in both brain and peripheral organs and protect them from inflammatory damages [58–60].

The universal underlying mechanism behind the immunomodulation of -MSH is the cAMP-PKA signaling pathway, followed by the inhibition of nuclear factor (NF-) activation, subsequently shutting down all the downstream effector proinflammatory mechanisms [61]. Stimulation of MC1R by -MSH is induced in the presence of inflammatory signals, that is, proinflammatory cytokines or antigens. Activated MC1R elevates the cAMP level, which causes activation of protein kinase A (PKA) and inhibits i kinase (IKK), thus stabilizing the i and preventing the translocation of nuclear factor- (NF-) from cytosol to nucleus [11, 62]. This leads to the following downstream effector mechanisms: (i) downregulation of proinflammatory cytokines and iNOs; (ii) upregulation of anti-inflammatory/immunosuppressive cytokine (IL-10); and (iii) suppression of chemotaxis. All these reactions eventually result in the inhibition of inflammatory symptoms [63]. However, evidence has shown -MSH-mediated inhibition of inflammation by involving additional signaling pathways, namely, calcium signaling pathway from MC1R and MC3R and Jak/STAT activation from MC5R [33, 56].

The inflammatory diseases cured by -MSH can be classified into two categories. The first one comprises inflammatory disorders of the brain including traumatic head injury, cerebral vasospasm like subarachnoid hemorrhage (SAH), multiple sclerosis, meningitis, and brain reperfusion injury [29, 63]. The second category comprises inflammatory disorders of the peripheral organs, including the inflammatory bowel disease (Crohn's disease and ulcerative colitis), arthritis (rheumatoid and gout), systemic inflammation (septic shock syndrome), allergic inflammation of skin, eyes, and lungs, and reperfusion injuries of the gut and heart [29, 64]. Besides, inflammation is also one of the pathologies of several neurodegenerative diseases such as Alzheimer’s and others [63, 65]. The pathogenesis of Alzheimer’s disease (AD) involves upregulation of several inflammatory cytokines like TNF- and loss of cholinergic neurons [49, 63]. As mentioned earlier, the production of these cytokines is under the control of NF- activation, and being a potent inhibitor of NF- activation, -MSH limits the progression of AD. Furthermore, very recently, it has been reported that -MSH administration in mouse models of Alzheimer’s disease prevents the GABAergic neuronal loss and thus ameliorates the cognition [47, 52–54].

Besides anti-inflammation, -MSH/MC1R signaling plays a significant role in immunosuppression in case of allergic reactions [4]. Recently, a study uncovered the mechanism of immune-suppressive behavior of -MSH in the case of skin inflammatory diseases. It discovered that -MSH inhibits inflammation and suppresses the immune system in mouse model of psoriasis-like skin inflammation by suppressing the activation and proliferation of the effector T cells through MC1R signaling [60].

Reports have confirmed that the minimum sequence required for anti-inflammatory activity of -MSH is the C-terminal tripeptide, Lys-Pro-Val (KPV) [62]. Furthermore, a dimer of C-terminal tripeptide of -MSH (Cys-Lys-Pro-Val)2—that is, (CKPV)2—has been found to be a better anti-inflammatory agent than the full-length -MSH and KPV for both in vitro and in vivo models of inflammation [66]. A study conducted by Capsoni et al. [7] has revealed that -MSH full-length peptide and its C-terminal synthetic derivative (CKPV)2 can reverse the inflammatory effect of urate crystal formation in gout (a type of arthritis). Moreover, both -MSH and (CKPV)2 possess the capacity to prevent crystal-induced chemoattraction of neutrophils [7, 66, 67].
  Forum: By Share Code

PunkassDerm
Posted on: May 28 2018, 12:11 AM


Group: Member
Posts: 418

If you read the article I referenced, it mentions a possible mechanism for neurodegenerative disease. Anti-inflammatory mechanism, along with up regulation of neurotransmitter and receptor activity. And to Clinhope, yes that more studies are needed including human trials. I think we'd definitively know if human trials underway (or at least I hope so).

I try to add yummy highlights and not burden with long snippets.


https://www.degruyter.com/downloadpdf/j/bmc...c-2015-0023.pdf




Highlights

The recent developments in the field of melanocortins point to:

– A definitively established therapeutic efficacy in multiple sclerosis, West’s syndrome, gout attack, and nephrotic syndromes.

– A by now no more justified delay of the use (as intravenous bolus injection) of tetracosactide as first-aid, life-saving treatment ‘in the field’ in case of massively bleeding wounds and polytraumatisms, respiratory arrest, cardiac arrest, and any form of shock.

– The need for clinical trials that verify in humans the remarkable results obtained in several animal models of organ-limited ischemia or ischemia/reperfusion (especially stroke and myocardial infarction).

– Further efforts in the research for selective, well tolerated, and efficacious MC4R agonists and antagonists for the treatment of obesity and cachexia (in addition to non-pharmacological treatments, when advisable).

– Further experimental verification in different animal models of the possible effect of melanocortins in neurodegenerative diseases and, in case, verification also in clinical setting.



Neurodegenerative diseases


α-MSH has long been known as a trophic factor for the nervous tissue (112–116). In mammals, humans included, α-MSH is the most important trophic factor for fetal brain development (112, 117) and is present in high concentra- tions in the human fetal brain and pituitary. On the other hand, its concentration is significantly reduced in the brain of aging mammals (118) as well as in defined brain areas of patients with Alzheimer’s disease (119). It stimu- lates the turnover of acetylcholine in the hippocampus and the central cholinergic neurotransmission [for reviews, see Ref. (112, 120), whereas aging is characteristically associ- ated with progressive impairment of the brain choliner- gic function (121, 122). The components of the behavioral syndrome induced by melanocortins (compulsive groom- ing, stretchings, yawnings, penile erections) are frequent in young and more and more rare in old animals (123). In humans, yawning and stretching are already present at birth, and spontaneous penile erections occur very fre- quently in babies, whereas old people rarely yawn and even more rarely stretch or display full penile erections. More- over, self-care and body cleaning (equivalent of groom- ing) are often neglected in the old. Melanocortins increase general arousal, improve the level of attention, and facili- tate short-term memory (120): all of them are deteriorated in the elderly and most severely in Alzheimer’s disease. In the fetal rat, injection of α-MSH antisera causes a decrease in fetal brain weight (124), whereas administration of α-MSH prenatally and neonatally improves the behavior of rats when juvenile and adult (125).

A role for melanocortins in neurodegenerative dis- eases, particularly Alzheimer’s and Parkinson’s diseases, has been repeatedly suggested and supported by many experimental data [for reviews, see Ref. (1, 2)]. Already 35 years ago, Landfield et al. (126) showed that the long- term treatment of middle-aged rats with the α-MSH-4-9 analog Org 2766 retarded both the morphological cor- relates of brain aging and the behavioral deficits that gradually develop during aging. α-MSH is reduced in the brain and cerebrospinal fluid of Alzheimer’s patients, and α-MSH autoantibody levels correlate with cogni- tive dysfunction (119, 127). Moreover, α-MSH exhibits neuroprotective effects that may rescue neuronal degen- eration: upregulation of CREB protein phosphorylation (128), induction of BDNF (129), and increased viability of hippocampal pyramidal cells (83, 130). Besides induc- ing BDNF expression, α-MSH induces MC4R expression and activates ERK and cFos in the rat brain (131). Most important, melanocortins have a quite peculiar, direct anti-inflammatory effect, and chronic inflammation plays a fundamental pathogenetic role in many neurodegenera- tive diseases: Alzheimer’s disease, Parkinson’s disease, multiple sclerosis, and amyotrophic lateral sclerosis (132–134). To our knowledge, the first, explicit hypothesis concerning α-MSH deficiency as a cause of Alzheimer’s disease was formulated about 30 years ago (135). And the first, unequivocal (albeit indirect) experimental data allowing to suggest a beneficial effect of melanocortins in Alzheimer’s disease were produced 20 years ago (136): in aged rats, the s.c. administration by constant infusion (10 nmol/rat/h) of an α-MSH-(4-9) analog (ebirtide), for 4 weeks, elevated the choline acetyltransferase activity in the septum (35% over controls), neocortex (79% over controls), and hippocampus (89% over controls). On the basis of these results, the authors suggested that ebirtide might prove beneficial in the therapy of brain degenera- tive disorders, especially Alzheimer’s disease. Some years later, an ‘in vitro’ study (cultured murine microglia cell line) (137) showed that α-MSH inhibits the accumulation of iNOS and TNF-α mRNAs triggered by the β amyloid pro- teins Aβ(1-42) and Aβ(25-35). The authors suggested that α-MSH might be used to moderate the brain response to amyloid beta deposition in Alzheimer’s disease. Behav- ioral and histological data showing a protective effect of α-MSH in a mouse model of Alzheimer’s disease have been quoted in Ref. (1): α-MSH had been loaded into polymeric nanoparticles specifically engineered with a glycopeptide and thus able to cross the blood-brain barrier and to target neurons and glial cells within the brain [for a review, see Ref. (138)]. More recently (139), it has been shown that in a mouse model of Alzheimer’s disease of moderate severity (3xTg-AD) the daily i.p. treatment with MT-I for 18 weeks, starting at the age of 12 weeks, reduced both phospho- rylation and levels of several biomarkers of Alzheimer’s disease in cerebral cortex and hippocampus and improved spatial memory. These effects were prevented by the selec- tive blockade of MC4Rs. In another contemporary study that used a different model of Alzheimer’s disease (Tg CRND8 mice), a 4-week treatment with α-MSH failed to decrease the β-amiloid peptide load in the brain; however, it improved spatial memory by attenuating the loss of GABAergic neurons in the hippocampus, thus preserving the appropriate excitatory-inhibitory balance required for memory formation that is impaired in Alzheimer’s disease (140). In another quite recent paper (141), the authors have confirmed their previous data (see above) using the same strain of mice and the same treatment and shown an increased number of mature, functionally integrated neurons in the dentate gyrus of the hippocampus of MT-I-treated animals.
A long-acting formulation of ACTH is used for the treatment of acute exacerbations of relapsing-remitting multiple sclerosis in alternative to high-dose methyl- prednisolone for patients who do not tolerate high doses of corticosteroids. According to a recent review (142), at least 55%–60% of patients who are steroid failures may respond to such ACTH formulation in different degrees. The effectiveness of ACTH in the treatment of acute exac- erbations of multiple sclerosis in patients who have failed corticosteroids is explained by the different mechanisms of action of the melanocortin. ACTH is indeed a universal agonist for the five melanocortin receptors (MCs), all of which show a strong affinity for it. Thus, ACTH, besides stimulating the MC2Rs of the adrenal cortex, so mimicking the effect of corticosteroids, has high affinity and intrinsic activity also for MC1, MC3, MC4, and MC5 receptors. All these receptors (particularly MC1, MC3, and MC5 subtypes) are involved in the complex, direct, adrenal-independent, anti-inflammatory action of melanocortins (within the brain, it is predominantly due to activation of MC4Rs): as reminded above, chronic, uncontrolled inflammatory pro- cesses in brain structures play a fundamental role in the pathophysiology of neurodegenerative diseases.
Many data are suggestive of a possible beneficial effect of melanocortins in Parkinson’s disease, and it has been repeatedly hypothesized that melanocortin ago- nists may slow its progression (1 ,2, 143). The striatum is innervated by melanotropinergic fibers originating from α-MSH-containing cell bodies of the dorso-lateral hypo- thalamus (112, 144). α-MSH and several other melano- cortin peptides increase the firing of nigral dopamine neurons and the striatal dopamine turnover (145, 146). Components of the behavioral syndrome induced by melanocortins (excessive grooming, crises of stretchings and yawnings) involve the activation of the nigrostriatal dopaminergic pathway (147), and it has long been known that parkinsonian patients rarely yawn and never stretch (148). In rats subjected to traumatic hemisection at the diencephalic level, with discontinuation of, among other pathways, the nigro-striatal connections, treatment with MT-I prevented the development of dopamine receptor supersensitivity in the striatum of the lesioned side and caused an increase in the dopamine receptors of the intact side (99).
  Forum: By Share Code

PunkassDerm
Posted on: May 27 2018, 01:16 PM


Group: Member
Posts: 418

You are so right Ignoretidine.

Not just acne, but imagine a topical, VLRX001, that can affect any number of dermatologic disorders of sebum production AND AGING SKIN.


http://www.clinuvel.com/investors/news/ite...new-indications

Singaporean subsidiary VALLAURIX completes preliminary evaluation of VLRX001



https://patents.justia.com/patent/20060030604

Melanocortins are neuropeptides that arise from pro-opiomelanocortin (POMC), which is most prevalently expressed in the arcuate nucleus of the hypothalamus, pituitary lobes, and the nucleus tractus solarius of the brainstem. [Gantz, I., et al., Molecular Cloning, Expression, and Gene Localization of a Fourth Melanocortin Receptor, J. Biolog. Chem., 1993, 268, 15174-15179.] These peptides include ACTH, α-MSH, β-MSH, γ1-3-MSH, and synthetic analogue NDP-αMSH (Wikberg, J E S, Melanocortin receptors: new opportunities in drug discovery, Exp. Opin. Ther. Patents, 2000, 11(1), 61-76).

These peptides bind to five types of melanocortin receptors (MC1-MC5), which are G-protein coupled receptors that all positively modulate adenylate cyclase. The MC4 and MC5 receptors are widely distributed in the brain and spinal cord, whereas the MC3 receptor is located mainly in the hypothalamus. [Gantz, I., et al., supra.] The MC4 receptor is selectively activated by αMSH and can induce neurite outgrowth in Neuro 2A cells. (Adan R. A. H, et al., Molecular Brian Research, 1996, 36, pp 37-44; Mountjoy, K. G., Mortud, M. T., Low, M. J., Simerly, R. B. and Cone, R. D., Mol. Endocrinol., 1994, 8, pp 1298-1308). ACHT is a less potent activator of the MC4 receptor than αMSH. (Adan, R. A. H., Cone, R. D., Burbach, J. P. H. and Gispen, W. H., mol. pharmacol., 1994, 46, pp 1182-1190). The MC5 receptor is activated, in order of degree, by NDP≈α-MSH>ACHT (1-24)≧α MSH ACHT (1-39)=β MSH>>γMSH (The Melanocortin Receptors, Cone, R. D., Editor, Human Press Inc., Totowa, N.J., 2000, Chen, W., pp 449-472)

The MC5 receptor is known to be expressed in human sebaceous glands, and may be involved in the regulation of human sebaceous lipid synthesis. Human MC5-R has been cloned and characterized (Chhajlani, V., Muceniece, R., Wikberg, J E S., Biochem. Biophys. Res. Commun. 195, 866-873, 1993). Moreover, presence of MC5-R m RNA in human sebaceous glands has been shown by RT-PCR and the protein was detected by immunohistochemistry and Western blot analysis (Thiboutot, D., Sivarajah, Gililand, K., Cong, Z. and Clawson, G., J. Invest. Dermatol. 115(4), 614-619, 2000).

Implications for:

dry eyes, acne, dry skin, aged skin, seborrheic dermatitis, rosacea, excessive ear wax, meibomian gland disorder, pseudofolliculitis, yeast infections, dandruff, hidradenitis suppurativa, ocular rosacea and eccrine gland disorder.
  Forum: By Share Code

PunkassDerm
Posted on: May 27 2018, 11:22 AM


Group: Member
Posts: 418

Looks like Scenesse has it with activity on MC3R/MC4R, against ischemia, shock and inflammation.

God I hope...Billions
#cimetidine


https://www.degruyter.com/downloadpdf/j/bmc...c-2015-0023.pdf


Developments and new vistas in the field of melanocortins
Sheila Leone, Giorgio Noera and Alfio Bertolini*
BioMol Concepts 2015; 6(5-6): 361–382


The results have shown without exception that the administration of a melanocortin peptide (α-MSH) or of melanocortin analogs [Melanotan I (MT-I), Semax (Met-Glu-His-Phe-Pro-Gly-Pro)] with agonist activity at MC4R and/or MC3R reduces to a highly significant degree the consequences of ischemia and ischemia-reperfusion either in terms of survival or of morphological and func- tional damage of the lesioned organ. In some cases, the therapeutic effect of melanocortins has been observed even when treatment started some hours after ischemia, this being of self-evident importance in medical practice.
  Forum: By Share Code

PunkassDerm
Posted on: May 25 2018, 01:14 PM


Group: Member
Posts: 418

Agreed...Someday photoprotection, say $500USD like getting botox. Insurance coverage for disease states. Billions.

With time and continued safety profile. Maybe some good proof of DNA repair, adjuvant therapy and preventative against Melanoma.
  Forum: By Share Code

PunkassDerm
Posted on: May 25 2018, 12:54 PM


Group: Member
Posts: 418

I agree with Iggy on one point, with a caveat.

Agree to drop price to around 10K USD per implant, allowing 6 implants per year for proper protection...

That is IF they are granted AUTOMATIC LABEL EXTENSION for:

1. Vitiligo
2. All the porphyrias
3. HHD and Darier's Disease

This pricing on par for Rheumatology Biologic therapies, still a smaller patient population comparatively.
  Forum: By Share Code

PunkassDerm
Posted on: May 25 2018, 12:43 PM


Group: Member
Posts: 418

Didn't they meet their deadline for the awesome rebranding/logo/webdesign?

#savefrilly
#diana-artemis
#cimetidine
#deadlanguage
  Forum: By Share Code

PunkassDerm
Posted on: May 14 2018, 09:59 AM


Group: Member
Posts: 418

Cimetidine toxicity, good luck on the final stretch.
  Forum: By Share Code

PunkassDerm
Posted on: May 13 2018, 04:28 AM


Group: Member
Posts: 418

The ShareScene Clinuvel Collective Global Fund

SCCGFX

A diversified group of investors for sure, that’s us.
  Forum: By Share Code

PunkassDerm
Posted on: May 13 2018, 12:22 AM


Group: Member
Posts: 418

200K CLVLY. I'm thinking about contacting E-Trade, an international platform. Closed weekends. If they will convert to CUV for free I may jump. I want voting rights.

And IF they can preserve my cost average data.
  Forum: By Share Code

PunkassDerm
Posted on: Apr 20 2018, 01:04 PM


Group: Member
Posts: 418

[Adjusted] All time high, 2007?

Attached Image

  Forum: By Share Code

PunkassDerm
Posted on: Apr 20 2018, 12:48 PM


Group: Member
Posts: 418

and market cap crossed 1/2 billion
  Forum: By Share Code

PunkassDerm
Posted on: Apr 18 2018, 05:14 AM


Group: Member
Posts: 418

Some justifications for pricing of afamelanotide, a new and more targeted therapy that is SAFER!

Acthar indicated for MS, infantile spasm, dermatomyositis/polymyositis, nephrotic syndrome, lupus, sarcoidosis. SO MANY POSSIBILITIES

It is probably not the corticosteroid properties but the melanocortin system effective that make it unique.

Afamelanotide stimulates MC1R receptors, without the side effects of corticosteroids (ACTH/Acthar).



In 2018, a single 5mL dose vial sells for +/- $38,000 to $41,000

https://www.goodrx.com/h.p.-acthar



Questcor Finds Profits, at $28,000 a Vial
Old article, 2012 but interesting.

https://www.nytimes.com/2012/12/30/business...000-a-vial.html




DIRECTLY FROM ACTHAR WEBSITE:

https://www.actharrheumatology.com/mechanis...anism-of-action


Potential Mechanism of Action

The Melanocortin System
Acthar and Melanocortin Receptors
Acthar Potential Mechanism of Action Video
The melanocortin system potentially plays an integral role in inflammation associated with many rheumatic conditions1-33

The melanocortin system impacts multiple immune cells and cytokines involved in the inflammatory cascade1-33
The melanocortin system, composed of melanocortin peptides and the 5 melanocortin receptors (MCRs), has potential anti-inflammatory and immunomodulatory effects1-24
MCRs are expressed on multiple immune cells, structural cells, and other organs and tissues throughout the body1-33




Acthar Website:

https://www.acthar.com/healthcare-professional


Acthar Indication Statements

H.P. Acthar® Gel (repository corticotropin injection) is an adrenocorticotropic hormone (ACTH) analogue used for:

Treatment during an exacerbation or as maintenance therapy in selected cases of systemic lupus erythematosus

Monotherapy for the treatment of infantile spasms in infants and children under 2 years of age

The treatment of acute exacerbations of multiple sclerosis in adults. Controlled clinical trials have shown H.P. Acthar Gel to be effective in speeding the resolution of acute exacerbations of multiple sclerosis. However, there is no evidence that it affects the ultimate outcome or natural history of the disease

Inducing a diuresis or a remission of proteinuria in nephrotic syndrome without uremia of the idiopathic type or that due to lupus erythematosus

Treatment during an exacerbation or as maintenance therapy in selected cases of systemic dermatomyositis (polymyositis)

The treatment of symptomatic sarcoidosis

Adjunctive therapy for short-term administration (to tide the patient over an acute episode or exacerbation) in: psoriatic arthritis, rheumatoid arthritis, including juvenile rheumatoid arthritis (selected cases may require low-dose maintenance therapy), ankylosing spondylitis

Treatment of severe acute and chronic allergic and inflammatory processes involving the eye and its adnexa such as: keratitis, iritis, iridocyclitis, diffuse posterior uveitis and choroiditis, optic neuritis, chorioretinitis, anterior segment inflammation
  Forum: By Share Code

PunkassDerm
Posted on: Apr 11 2018, 01:07 AM


Group: Member
Posts: 418

Patent application does say alone or with phototherapy. Lights enhance therapy.
  Forum: By Share Code

PunkassDerm
Posted on: Apr 11 2018, 12:51 AM


Group: Member
Posts: 418

Interesting aside...

I have a friend with Vitiligo since childhood and family history of same. He has had steroids, protopic and previously burned in a broad spectrum UVB (not NB-UVB) booth in his early teens. Now in his late 30's, has recently exhibited spontaneous remission on his arms. Face has always been spared, probably keeping him from seeking care since the childhood second degree burns. I read up after hearing this, and there are such cases. Another possible casual relationship with celiac disease/gluten allergy. Cases of remission with the introduction of gluten free diets.



Vitiligo and Autoantibodies of Celiac Disease


https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3604853/


The relationship between celiac disease and vitiligo is controversial. Some authors have described cases of vitiligo in patients with celiac disease,[19,21] but one serological screening study for celiac disease in patients with vitiligo did not show any correlation between these two immunological disorders[23]

On the other hand, improvement of some disorders like dermatitis herpetiformis,[24] psoriasis,[25] and even vitiligo,[26] in those who were seropositive for celiac auto antibodies, has been reported by gluten free diet.

The aim of this research was to study the relationship between vitiligo and celiac disease. If this study show increased frequency of celiac autoantibodies in vitiligo patients, the second aim would be to try gluten free diet in these patients in future studies.
  Forum: By Share Code

PunkassDerm
Posted on: Apr 11 2018, 12:42 AM


Group: Member
Posts: 418

mea culpa!

I did not see that mention of afamelanotide. I probably blew up looking at cost cutting measures in UK and absence of MSH in the New Advances section p17, good thorough read on your part!

I don't think or hope that combo MSH plus UVB will be proprietary and patented. Currently excimer laser makes most sense, in that the areas of disease can be targeted specifically with regards to location and energy applied. I have used this in past, in conjunction with topical and/or injected steroid alternating with topical calcineurin inhibitors (Protopic/Elidel). Results pretty good for face, underwhelming or temporary in other locations. And steroid carries such high risk for atrophy with long term use, I have gotten away from except in a pulse fashion. I am so excited about the prospect of afamelanotide from study photos alone!

Thanks for clarification/correction.

D



308nm Excimer Laser in Dermatology

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4290518/




"Speaking of Vitiligo..."
Afamelanotide tested as a new treatment for vitiligo

Posted On: Sunday, September 21, 2014

Attached Image


https://www.umassmed.edu/vitiligo/blog/blog...t-for-vitiligo/


The successful treatment of vitiligo requires suppression of the autoimmune response, followed by regrowth of melanocytes back into the white skin to produce pigment and reverse the white spots. Afamelanotide, produced by Clinuvel, is a synthetic, simplified form of alpha-melanocyte stimulating hormone (a-MSH), which is a natural hormone produced in the skin that stimulates melanocytes to grow and produce melanin pigment. Narrow band UVB suppresses the autoimmune response in the skin and stimulates the melanocyte to start regrowing into the white skin. The authors reasoned that adding afamelanotide to nbUVB treatment would speed up the process of repigmentation by stimulating the melanocytes to regrow and produce melanin faster.

Patients who entered the study were randomized into either nbUVB treatment 2-3 times per week alone, or combined treatment with nbUVB and afamelanotide. Those in the combined treatment group started with 1 month of nbUVB and then received an implant that contained 16 mg of afamelanotide deep in their skin, just above their hip, and nbUVB treatment was continued. The drug diffused out into the entire body, providing a stimulus for all of the melanocytes in the patient’s skin. A new implant was inserted every month for 3 more months, and the amount of repigmentation of the white spots was measured.

The results show that subjects who received afamelanotide in addition to nbUVB therapy regained their pigment faster and to a greater extent than the ones who only received nbUVB therapy. The pigment came back on average 20 days sooner with the afamelanotide, and more pigment returned as well. It worked best for those with darker skin. There were some side effects of the treatment – all of the subjects that received afamelanotide developed darker skin, and 2 of the subjects quit the study because of this. Nausea was reported in 18% and fatigue in 11% of those who were treated with the drug. Some are concerned about the effect of afamelanotide on moles and an increased risk for melanoma, although there was no evidence of changing moles in this study, and there is no evidence of increased risk of melanoma to date.

It is currently not known whether using a larger dose of afamelanotide, using it more frequently, or using it for a longer period of time would produce even better results. The authors didn’t test whether afamelanotide would work on its own, without nbUVB. More studies will be required to determine this, but this certainly looks like a good start!
  Forum: By Share Code

PunkassDerm
Posted on: Apr 9 2018, 11:17 PM


Group: Member
Posts: 418

The UK announces "New Advances" in Vitiligo therapy. Trials for at home NB-UVB plus topical steroids. Yes this is the dark ages style cutting edge. The Knights that say NO NICE.

Goes on to discuss skin cancer prevention, HS, eczema...all likely targets for afamelanotide. Academics chasing their tails while safe effective treatment already exists.

afamelanotide plus NB-UVB
JAK inhibitors
melanocyte transplantation
Humira
Dupixent


None of the above even mentioned.

https://www.nottingham.ac.uk/research/group...t-aw-forweb.pdf


What is vitiligo?

Vitiligo is a skin disease that results in white patches on the skin. These patches are not painful, but they can easily burn in sunlight and the patches can affect how people – particularly those with dark skin - feel about themselves and how they interact with others.

At the moment, the only medicine specifically licensed for vitiligo in the UK is cosmetic camouflage (cover-up make-up), although other treatments can be used such as steroid creams, light treatment and psychological support.

During this Programme Grant we have established the groundwork for running a large, national trial of vitiligo treatments.
Why is this important?

We are delighted to say that as a result of our work, major funding has now been secured from the National Institute for Health Research for a full-scale trial involving 440 patients with vitiligo across the UK. This will be by far the largest vitiligo trial ever conducted. It will compare the use of steroid ointments applied to the skin with hand-held NB-UVB light therapy, and the combination of both steroid ointment and NB-UVB light therapy together.

This research is important as the treatments being tested were identified as key areas for future research in our Priority Setting Partnership (see pages 7-8), and the use of light therapy at home to treat small patches of vitiligo when they first appear, has not been tested before.

Until now, light therapy for vitiligo patients has generally been limited to people with severe and widespread disease. As light therapy is usually provided two or three times a week in a hospital setting using full-body units, it is likely to add to the burden on the patient and is not suitable for children.
Should home light therapy prove to be an effective treatment for vitiligo patients, this could be an extremely useful addition to the care options available.
Recruitment into the full trial is anticipated to start in 2014 (see www.nottingham.ac.uk/dermatology for further details).

What did we do?

We laid the foundations for this large, national trial in the following ways:

• Reviewing the existing evidence for vitiligo treatments and
updating the Cochrane systematic review of interventions
for vitiligo

• Talking to patients and health professionals to decide what
questions needed to be answered most urgently

• Establishing how ‘treatment success’ has been captured in
previous trials, and working with patients to see if the right
things are being measured

• Leading an international collaborative effort to achieve
consensus over core outcome measures that should be
captured in all future vitiligo trials

• Conducting a ‘pilot’ randomised controlled trial involving 29
patients, to see if a large national trial is feasible and practical • Developing a standardized training package for people who
would like to use narrow band ultraviolet B light therapy (NB- UVB) at home. The package is designed to be used with support from local hospital phototherapy teams. This training video is freely available at www.nottingham.ac.uk/dermatology
  Forum: By Share Code

PunkassDerm
Posted on: Mar 19 2018, 11:26 PM


Group: Member
Posts: 418

OR...

I finally got my board spot. Give me some shares! Thanks
  Forum: By Share Code

PunkassDerm
Posted on: Mar 19 2018, 11:18 PM


Group: Member
Posts: 418

http://www.cosxoeo.clinuvel.com/index.php


Alternate site? Appears to mirror exactly. What does cosxoeo prefix mean?
  Forum: By Share Code

PunkassDerm
Posted on: Mar 18 2018, 11:54 PM


Group: Member
Posts: 418

Marketing Manager?
Global Business Development?
Bahahaha...refund please

Free Frilly!

Attached Image

  Forum: By Share Code

PunkassDerm
Posted on: Mar 11 2018, 11:47 PM


Group: Member
Posts: 418

Back in the Epitan days, they did have a little Australia only Dermatology topical portfolio...


https://www.labonline.com.au/content/life-s...ducts-104821656


Epitan goes shopping: acquires three dermatology products
By Melissa Trudinger
Monday, 19 July, 2004
Epitan (ASX: EPT) has acquired three dermatological products in its push to become a specialty dermatology pharmaceuticals company.

Two of the products, Linotar and Exorex, for the treatment of eczema and psoriasis respectively, were acquired from TransDermal Pharmaceuticals Australia. The products are already TGA-registered and generating sales in Australia, in a market potentially worth AUD$10 million per year.

The third product acquired is Zindaclin, a clindamycin-based anti-acne gel licensed from UK-based Strakan Pharmaceuticals. The product has been submitted to the TGA for registration.

Financial details of the transactions were not disclosed.

Epitan CEO Wayne Millen said the company expected the three products would generate more than $3 million revenues in the 2005-2006 financial year. The company's lead drug candidate Melanotan, which is currently completing Phase II clinical trials as a tanning and sun burn injury prevention drug, is not likely to reach the market before late 2006 or early 2007.

He said other acquisitions and in-licensing opportunities would be actively pursued to provide future growth in sales.
  Forum: By Share Code

PunkassDerm
Posted on: Mar 1 2018, 12:43 PM


Group: Member
Posts: 418

Latin prophecy:

akeovertay ownay easeplay
  Forum: By Share Code

PunkassDerm
Posted on: Feb 27 2018, 10:45 PM


Group: Member
Posts: 418

Movie about XP, a shadow chaser. What timing to coincide with FDA review!

http://midnightsunmov.com


MIDNIGHT SUN is a romantic tearjerker about 17-year-old Katie Price (Bella Thorne), sheltered at home since childhood with a rare genetic condition, a life-threatening sensitivity to sunlight. Having only her father Jack (Rob Riggle) for company, Katie's world opens up after dark when she ventures outside to play her guitar. One night, her dreams come true when she’s noticed and asked out by her longtime crush Charlie (Patrick Schwarzenegger), whom she’s secretly watched from her bedroom window for years. As they embark on nightly summer excursions, Katie’s risk to sunlight grows and she’s presented with the gut-wrenching dilemma of whether she can live a normal life with her newfound soul

add...then she enrolled into an afamelanotide study and everything changed
  Forum: By Share Code

PunkassDerm
Posted on: Feb 26 2018, 11:32 AM


Group: Member
Posts: 418

Just remembered a reptilian skin line...from Australia
Also for protection from UVR

No Wonderman master, nice design


Attached Image

  Forum: By Share Code

PunkassDerm
Posted on: Feb 26 2018, 08:27 AM


Group: Member
Posts: 418

Case for Frilly v2:

Survives in harsh desert environment with protection from full sun
Frill neck looks like a shield
Not lizard skin but Scenesse as amour
Fierce protector, raptor-like
Aussie identity, homage to indigenous people. Global branding can have local DNA.
Has established identity and clean

vs

Dead language
Old looking font
Lizard STILL INCLUDED, looking like a condom wrapped-dog sidekick
Looks like drawn by a high school newspaper or sports team
Condom-dog-lizard looks like its bleeding, is this a case of friendly fire?
Amateur

But hey, I'm a Dermatology PA who tinkers with Illustrator. What do I know?
  Forum: By Share Code

PunkassDerm
Posted on: Feb 26 2018, 05:56 AM


Group: Member
Posts: 418

Thanks for compliment! Before PreMed/Bio, I was a graphic design/illustration major. Tough to be creative and "whip something up." I'm more a slow meticulous artist, science in many ways was easier, study and regurgitate. It was a perfect combination for Dermatology. Both recognizing lesions and procedures, surgery/filler/botox. I found my niche. So tinkering with lllustrator is now fun, but I am certainly not advanced. Logos should be easier, flat and scalable, as someone had already posted. Having a sense of design, someone really fucked up with this Artemis shit.

Again, please management...Roll it back. I'd trade you my idea for some shares, how about some of PW's next performance rights?

The original Frilled Dragon was a great idea, adding Primitive Indigenous Art enhances it. Dot style lends itself great to design work.
  Forum: By Share Code

PunkassDerm
Posted on: Feb 26 2018, 05:14 AM


Group: Member
Posts: 418

Frilly 2.0 in Aboriginal Folk Style. To me matches everything an Aussie company should be trying to embrace/project.
Oh and it looks like a logo. And it builds upon existing identity.

Lachlan’s boss, please reach out and we’ll replace that garbage.

Attached Image



Attached Image

  Forum: By Share Code

PunkassDerm
Posted on: Feb 23 2018, 01:50 PM


Group: Member
Posts: 418

Attached Image

  Forum: By Share Code

PunkassDerm
Posted on: Feb 23 2018, 12:09 PM


Group: Member
Posts: 418

That lizard condom sock puppet sidekick is atrocious.100% rollback. Anyone reach to the Lachlan Lackey for comment?
  Forum: By Share Code

PunkassDerm
Posted on: Feb 22 2018, 11:15 PM


Group: Member
Posts: 418

Just rollback website, save Frilly

Look was crisp clean and professional, old was new and new looks old

Add some dead latin if it makes you feel better

But update content, inform the stakeholders, meet IMPORTANT DEADLINES

Give all shareholders voting rights, a shareholder seat on BOD
  Forum: By Share Code

PunkassDerm
Posted on: Feb 22 2018, 11:05 PM


Group: Member
Posts: 418

Found January 2018. Still listed as TBD, p26.
Comes out quarterly.

https://www1.magellanrx.com/media/713547/mr...19_0118_web.pdf
  Forum: By Share Code

PunkassDerm
Posted on: Feb 22 2018, 02:09 PM


Group: Member
Posts: 418

https://www1.magellanrx.com/media/687866/mr...19_1017_web.pdf


Looks like a comprehensive listing of FDA pipeline. Estimated approval dates stretch out to Oct 2018. Clinuvel on TBD.

Also intriguing is number of biosimilar candidates for Abbvie's Humira.



p25.
Attached Image

  Forum: By Share Code

PunkassDerm
Posted on: Feb 22 2018, 01:43 PM


Group: Member
Posts: 418

Looks like Management did some modding of their own. Can blame Mark Lewis for initial inspiration, and Clinuvel for the unholy hybridization.

Another clue, they are getting in to gene-editing and cloning. CRISPRpocalypse

I miss you already Frilly


https://www.marklewisillustration.com/line-...ustrations.html



Attached Image





Attached Image

  Forum: By Share Code

PunkassDerm
Posted on: Feb 21 2018, 07:39 AM


Group: Member
Posts: 418

Right on! I still have a purchased copy from circa 2007. The point is simple and clean, this is pharma not Harry Potter or Jagermeister. Definitely see lizard head logo as a great design and would lead to global brand recognition. A nod to Aussie company for bringing first in class melanocortin to market. It's truly a shame.
  Forum: By Share Code

PunkassDerm
Posted on: Feb 21 2018, 05:04 AM


Group: Member
Posts: 418

Personally, the old logo and and scheme are much cleaner. This is a step backwards, looks like madmen era. I would vote to roll it back, but alas my CLVLY shares cannot.

I also tried to envision Artemis and sun along with protection, tried to come up with something more simple. For some reason, a solar flare says something to me. Tinkered with illustrator last night with my energy of disgust, but no professional (obviously neither is Clinuvel marketing/branding team).


Attached Image


Attached Image
  Forum: By Share Code

PunkassDerm
Posted on: Feb 20 2018, 02:04 PM


Group: Member
Posts: 418

Pharma logos are (should be) simple:

Attached Image



Even font sucks, so disappointed
  Forum: By Share Code

PunkassDerm
Posted on: Feb 20 2018, 01:39 PM


Group: Member
Posts: 418

It’s like Captain Rogers before Vita Rays...but she’s got moxie

Wa Wa Waaaaaaa

I think email campaign to congratulate the accomplishment, worst ever.
  Forum: By Share Code

PunkassDerm
Posted on: Feb 20 2018, 11:17 AM


Group: Member
Posts: 418

Artemis lizard? This is a joke right?

They were hacked by Anonymous

Announcement:

https://yourir.info/resources/fee77b1d1a878...positioning.pdf
  Forum: By Share Code

PunkassDerm
Posted on: Feb 10 2018, 11:53 AM


Group: Member
Posts: 418

Maybe difficulty to quantify, but Scenesse works. Quality of Life improvement is obvious. Endpoint was never to be zero phototoxic reaction or zero pain, an unattainable/unreasonable goal.


http://www.ema.europa.eu/docs/en_GB/docume...WC500182309.pdf



Additional expert consultation

On 29 April 2014 an Ad Hoc Expert Group Meeting was convened at the EMA in the context of the ongoing assessment of the MAA for Scenesse (afamelanotide). Patients affected by EPP, patient representatives, and expert physicians participated in this meeting (Minutes and Answers to Questions: EMA/CHMP/601433/2014).
The positions of the group are summarized below.


Responses from the ad-hoc expert group

1. The expert group is invited to give a general discussion (i.e. without regard to this particular dossier) on the challenges in conducting clinical trials in this patient population, with particular regard to recruitment, definition of the patient population to be included, choice of control arm, and appropriate clinical outcome measures considering well-established patient behaviour.


The panel shared the view that EPP is a condition that is very difficult to investigate in clinical studies. The key challenge is to overcome the learnt behaviour of EPP patient aiming at a life-long avoidance of sunlight because of the intense pain it induces, which is established in childhood. Due to their experience with phototoxicity EPP patients are generally reluctant to modify their behaviour. The time it takes to change the behaviour creates an inherent difficulty of designing clinical trial studies. In terms of duration, an observation period of six months of less in this population makes it challenging to show significant
Assessment report
EMA/CHMP/601433/2014 Page 86/107


efficacy as EPP patients tend to require a long time until they trust an intervention and dare to expose themselves to sunlight. This was highlighted by both clinicians and patients. It was noted by the experts that in the studies with afamelanotide the pain scores were low across treatment arms suggesting that patients didn’t expose themselves to sunlight.
An additional difficulty is to measure improvement of quality of life, which was considered by the experts a very important measure in this condition. However, too limited data was collected in the programme to make a meaningful evaluation and no validated quality of life questionnaire tailored for EPP patients is available. Methodologically it was noted by one expert that there is a lack of a device to measure the natural solar light exposure (in “lux”2) making it difficult to quantify the amount of total light exposure EPP patients exposed themselves to. In this regard, one expert mentioned that an increase of 2 minutes in sunshine corresponds to an increase of exposure of more than 4 hours in the shade. The expert panel concurred that it is not necessary the direct sunlight exposure itself, but also the light exposure even in the shade that is relevant to patients, and that few minutes exposure increase may translate into more when light exposure in considered in a wider sense.


2. The applicant has conducted a number of randomised controlled trials with pre-specified primary endpoints. Which of the endpoints included in the pivotal trials should be prioritised when assessing the therapeutic efficacy of Scenesse?

The expert panel considered sun/light exposure and symptoms (like pain) as primary endpoint for clinical trials. A combination of the two was broadly supported. It was noted that each patient has his/her own threshold, and that behavioural changes do not come rapidly (see response to question 1).
One expert expressed the view that one important endpoint would be the asymptomatic period of sun exposure (the symptoms patients would experience such as tingling, pain...) as any of these symptoms would be enough for patients to stop their exposure to the sun. Regarding pain, both acute pain felt and duration of pain should be considered. Pooling asymptomatic periods without symptoms such as pain (total number of pain free days) from the placebo-controlled trials is however challenging as EPP patients would have been trying to avoid pain as part of their behaviour.
The expert panel discussed that total light exposure time would be a good endpoint in a standardised environmental setting. However in the clinical trials performed the EPP patients would have exposed themselves to different environmental settings influenced by weather conditions making total light exposure difficult to measure. In addition it was recognised that the disease presentation could also vary depending on the season which also affected the amount of light they were exposed to.
When asked for the usefulness of the prodromal phase for clinical study design, the panel considered this too difficult to reliably measure and therefore not appropriate as outcome measure in the context of a clinical trial.


3. Scenesse is associated with a tanning effect, which is not present in the control arm, effectively unblinding the trial. Patient behaviour is cited as a challenge for establishing efficacy for Scenesse (patients unwilling to expose themselves to sunlight). Is it plausible that patient behaviour will be influenced by knowledge of treatment assignment? Can this influence be quantified?

The expert panel, and particularly the patients, acknowledged that study subjects will likely have had the knowledge of the treatment assignment due to the tanning effect of afamelanotide on their skin but did not consider it measurable on the perceived effect. This is because beta carotene that was evaluated in EPP patients and causes tanning has no treatment effect and therefore do not translate in a change in the EPP patient’s behaviour.
2 SI unit of illuminance and luminous emittance, measuring luminous flux per unit area
Assessment report
EMA/CHMP/601433/2014 Page 87/107

The expert panel did reflect on a double-dummy trial design with supportive care to blind the tanning character of afamelanotide (e.g. UV therapy), however did not consider this feasible.
Asked about their experience with exposure to sunlight, patients expressed that based on experience they are able to individually judge how much they can tolerate and that this exposure is fairly constant over time.

4. Based on the clinical trial data alone, are the estimated effects statistically and clinically persuasive in light of the unblinding, analytical and GCP issues identified?

The experts stated that the magnitude of effects observed in the clinical trials were minimal and in a way disappointing but the expert panel argued that the totality of evidence was perceived convincing. Relative small changes were observed in a minority of individuals with small increase in sun light exposure observed and might be an underestimation of the true beneficial effect due to the patient behaviour. At the same time the experts noted that a translation of the small effect in terms of exposure to direct sunlight can translate into a significant time in the shade (see response to question 1). The so-called ‘super-responders’ were noted with interest even if no explanation to this response could be given.
Important for the expert panel was that the data were pointing to the same positive direction. Overall the experts, clinicians and patients, were reasonably convinced of the trial data showing an effect of afamelanotide.
The expert panel considered to explore a behavioural psychology test sub-analysis on the super-responders. This test would help to better understand how the results were strikingly different from other patients in the clinical trials.


5. The applicant emphasizes that there is a substantial and consistent clinical benefit reported informally by expert physicians/patients (e.g. letter dated 3 July 2013). How would the group value this evidence?

Some clinical experts reported preliminary reluctance to afamelanotide but were later more in favour due to patient reports coming in from the compassionate use. Two countries (Italy and Switzerland) are providing afamelanotide to EPP patients through national compassionate use programmes. One clinician reported from her experience where 39 out of 40 patients were responding to afamelanotide through increased daily sun light exposure and number of pain free days. What the expert panel has drawn from the experience on the individual reports/compassionate use is the EPP patients is an increased record of daily sun light exposure and pain free days through a change of behaviour over a prolonged period which translated into taking up outdoor activities such as sports or commute to work.
Overall the experts and patients considered that additional evidence through individual case description has its value and should be taken into account in particular for this condition.


6. Is it possible to identify, based on pre-treatment characteristics, any subpopulation of EEP patients who will experience benefit of treatment with Scenesse?

The expert panel agreed that there were no scientific grounds to support the creation of EPP subpopulations. The expert panel added that behavioural analysis would maybe conclude in a possible characterisation of patients that would be more likely to benefit the treatment with afamelanotide through their earlier and more progressive behavioural adjustment which includes increased exposure to daily light. The expert panel also acknowledged that there is a need to encourage patients under treatment and change lifestyle to understand the value of the treatment.


7. To the perspectives of patients and treating physicians, is the level of benefit that is established for Scenesse of relevance and how will this benefit manifest in everyday life?

Assessment report
EMA/CHMP/601433/2014 Page 88/107

The expert panel agreed that the beneficial evidence (increased exposure to light with absence of pain) of afamelanotide by the nature of the chronically debilitating EPP condition translated into significant improvement of their quality of life enabling them to taking up jobs and sports and being more integrated into society. Also of value that even if pain episodes occur, these were reported by EPP patients as being of considerable shorter duration.

The expert panel unanimously supported a strict follow up of the EPP patients taking afamelanotide through EPP reference centres and creation of a disease register, should afamelanotide be granted a marketing authorisation in the EU. The challenges caused by the impact of behavioural changes could be addressed through further data collection to assess the efficacy of afamelanotide in EPP patients in everyday use.
  Forum: By Share Code

PunkassDerm
Posted on: Feb 10 2018, 10:27 AM


Group: Member
Posts: 418

Quick literature review. As suspected, afamelanotde does not itself decrease porphyrin levels (burden) so the potential for phytotoxic events ever-present. Afamelanotide it seems, works more by anti-inflammatory, free radical scavenging and photoprotective effects. So if a patient has a higher porphyrin profile or maybe overindulges on sun exposure with new freedom, may have attacks anyway. The take-home is increase QOL, not reduced number of attacks. Lastly, every individual responds different to medication. Maybe its not total dose of frequency but total time under treatment. It does appear 2-3 month dosing schedule optimal.


https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4279155/


3.7.2.1. Pathogenesis

Classical EPP usually occurs as a result of the inheritance of a mutated ferrochelatase (FECH) allele from one parent and inheritance of a low expression allele (IVS3-48T/C) from the other. The Fech gene is located on chromosome 18, and more than 135 Fech loss-of-function mutations have been identified. More recently, 5%–10% of subjects with a typical EPP phenotype have instead been found to have an X-linked variant of EPP (termed XLPP) resulting from a gain-of-function mutation of the Alas2 gene, which have thus far been concentrated in exon 11 [104]. Fech is the final enzyme in heme biosynthesis, and it catalyzes the insertion of iron into the protoporphyrin ring to generate heme (Figure 1). Enzyme activity is reduced to 10%–35% of normal in all tissues, though the excess protoporphyrin is mainly produced in bone marrow.

3.7.2.2. Clinical Features

Similar to CEP, EPP/XLPP has variable clinical expression. The first comprehensive description of EPP was published by Magnus et al. in 1961 [105]. Most patients present during infancy or early childhood upon Sun exposure. Accumulation of lipid soluble free protoporphyrin in skin and dermal blood vessels and subsequent photoactivation by sunlight results in the characteristic cutaneous manifestations of EPP. Children with the disorder develop pain, redness, swelling and pruritus within minutes of exposure to sunlight. These symptoms can last for hours to several days. Unlike CEP, vesicles and bullae are uncharacteristic, only occurring in 10% of cases. Chronic skin changes, such as lichenification, pseudovesicles and labial grooving, can develop after repeated photosensitivity episodes. These chronic findings are most prominent in a malar distribution on the face and on the knuckles of the hands.

Patients with EPP and XLPP may develop a variety of hepatobiliary complications. Pigment gallstones, composed partially of protoporphyrin, can cause symptomatic cholelithiasis and biliary obstruction in up to 20% of patients. Protoporphyrin can crystallize in hepatocytes and biliary radicles, impair bile flow and lead to pigmentary cirrhosis in 3%–5% of patients. More mild liver disease characterized by elevated aminotransferases is also seen.



---------------------------------------------------------



https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5161401/

A 70% increase in the duration of pain-free time in direct sunlight was seen in the patients who received afamelanotide (69.4 hours vs 40.8 hours; p=0.04).34 However, there was no significant change in the total number of phototoxic reactions in patients who received afamelanotide as compared to placebo after 6 months (46 vs 43; p=0.60).34 Quality of life improved with afamelanotide therapy, with a significant difference (as measured by the EPP quality of life questionnaire) on days 60 (p<0.001), 120 (p<0.001), and 180 (p=0.02).34



----------------------------------------------------------



http://www.nejm.org/doi/pdf/10.1056/NEJMoa1411481

Pain was scored on an 11-point Likert pain- intensity scale (with scores ranging from 0 to 10, and higher scores indicating greater severity of symptoms). Phototoxic reactions and their dura- tions were defined as pain with a Likert score of 4 or higher occurring in light-exposed skin for one or more consecutive days.
Quality of life was assessed with the use of the Erythropoietic Protoporphyria Quality-of-Life (EPP-QOL) questionnaire (scores range from 0 to 100, with higher scores indicating a better qual- ity of life) and the Dermatology Life Quality In- dex (scores range from 0 to 30, with lower scores indicating improved quality of life) (see the Supplementary Appendix, available at NEJM.org). Photoprovocation testing was performed in 21 U.S. patients (details are provided in the Supple- mentary Appendix).

Efficacy

There were differences between the two trials with respect to the end points, the number of study-drug doses administered, the duration of the trial, the recruitment periods, and the data collected from the diaries. However, in both tri- als, the primary end point — the length of time during which patients were pain-free in direct sunlight — was significantly longer among patients who received afamelanotide than among patients who received placebo. After 6 months in the U.S. trial, the pain-free time in direct sun- light was 70% longer among patients who re- ceived afamelanotide than among patients who received placebo (median, 69.4 hours vs. 40.8 hours; P=0.04); the duration of pain-free time was also significantly longer among patients who received afamelanotide than among those who received placebo after 9 months in the European Union trial (median, 6.0 hours vs. 0.8 hours; P = 0.005) (Table 2).
The total number of phototoxic reactions af- ter 9 months was reduced among patients in the European Union trial (77 vs. 146, P=0.04), although no significant changes were seen after 6 months in the U.S. trial (46 and 43 reactions, respectively; P=0.60). In both studies, placebo recipients tended to have more pain relative to the time spent in direct sunlight, and they had more days with moderate-to-severe pain (Table 3).

To provide an objective measure of light toler- ance, photoprovocation under standardized con- ditions was performed in 21 U.S. patients. As compared with patients who received placebo, patients who received a second afamelanotide implant had a significantly higher tolerance to light on the dorsum of the hand and the lower back. At day 90 (30 days after dose 2), the median change from the baseline minimum symptom dose in J per square centimeter on the hand was 208.3 in the afamelanotide group versus 56.2 in the placebo group (P = 0.01); on the lower back, the median change was 227.5 versus −2.4 (P<0.001). At day 120 (60 days after dose 2 and before dose 3), the median change from the baseline minimum symptom dose was 162.1 ver- sus 30.0 (P = 0.045) on the hand and 82.5 versus 12.1 (P = 0.03) on the lower back (Table S3 in the Supplementary Appendix).

Quality of life, as measured with the use of the Dermatology Life Quality Index in both studies, did not change over time in either study- drug group. However, in both studies, the EPP- QOL questionnaire (Table S1 in the Supplemen- tary Appendix) revealed marked improvements in the afamelanotide group (Table 4). In the European Union trial, the mean absolute scores at day 120 were 78.8 in the afamelanotide group, versus 63.6 in the placebo group (P=0.005); at day 270, these scores were 79.7 and 67.2, respec- tively (P = 0.06). In the U.S. trial, the mean change in the score at day 60 relative to the baseline score was 44.0 in the afamelanotide group, ver- sus 23.4 in the placebo group (P<0.001); at day 120, the mean change was 49.8 versus 30.4 (P<0.001), and at day 180, the mean change was 51.1 versus 36.8 (P=0.02).

In the absence of specific strategies to increase mutant ferrochelatase activity or to deplete the accumulated phototoxic erythroid protoporphyrin, afamelanotide provided a safe and effective treatment of symptoms in patients with erythropoietic protoporphyria. Afamelanotide has been approved on a compassionate-use basis for patients with confirmed erythropoietic proto-
porphyria in Italy and Switzerland for more than 8 years. The high rate of adherence to the use of this drug and the low rate of side effects indicated extended benefit from the drug over 8 years.37 Moreover, these patients, who also were moni- tored by means of the EPP-QOL questionnaire, had a significantly increased quality of life (expressed as the percentage of the maximum 100% quality) over that at baseline (74% vs. 31%) that was sustained over time. On the basis of the results of our clinical trials, the European Medi- cines Agency and the European Commission recently approved the use of afamelanotide in patients with confirmed erythropoietic proto- porphyria.

In summary, afamelanotide had an acceptable side-effect profile and improved tolerance to sun- light in patients with erythropoietic protoporphyr- ia. Afamelanotide-induced eumelanin synthesis provided photoprotection that enabled patients to have more exposure to visible light and decreased the consequences of phototoxicity. Patients who received afamelanotide had significantly improved quality of life.
  Forum: By Share Code

PunkassDerm
Posted on: Feb 10 2018, 09:23 AM


Group: Member
Posts: 418

No doubt how it goes down:

1. Shares issued, dilute retail investor
2. Performance rights, given to BOD and CEO BOD
3. FDA approval discovered by Royco or FarmaZ and posted
4. 3 days after everyone knows, Clinuvel makes announcement

Maybe 3.5...typical chatter from the usual suspects hear. I can smell it.
  Forum: By Share Code

PunkassDerm
Posted on: Jan 31 2018, 01:16 PM


Group: Member
Posts: 418

Maybe a speculative run up, if justified...will stop the stock manipulation that artificially lowers price so certain individuals/groups can accumulate. I would dare to say this product is undervalued severely, so more of a correction than run up. I'd go on to postulate some big mouths here are part of that machine.
  Forum: By Share Code

PunkassDerm
Posted on: Jan 31 2018, 02:45 AM


Group: Member
Posts: 418

And to remember it was the individual investors, not institutional investors, that kept Clinuvel afloat for past 14+ years. Obviously 2 schools of thought. I don't think any pro-transparency proponents are asking for stock pumping. But it is clear that sharescence and similar boards are the ONLY place to get ANY information. It is not a private company. I have bankrolled my fair share of performance rights, and don't even get a vote for my 200K shares. And yet I choose to stay IN SPITE of Wolgen et al, because of the promise of a new class of medicine.

On a second note, if Uhohinc is having a hard time getting google groups up and running I welcome him to post here (once again). I know he was turned off by harassment couple of years ago but many welcomed his contributions. I did not contribute there but often peeked.
  Forum: By Share Code

PunkassDerm
Posted on: Jan 29 2018, 11:06 PM


Group: Member
Posts: 418

Agreed, fill the board with Patsies. How about say, a retired pharma CEO or similar. Someone with FDA or business acumen?

This is a continued play for complete control by PW. Why have a board at all?
  Forum: By Share Code

PunkassDerm
Posted on: Jan 24 2018, 09:36 PM


Group: Member
Posts: 418

F suffix is foreign stock, this is the common share NOT ADR. There is no reason these should not be votable. Total BS and interference from management. They go to extraordinary lengths to block voting rights. (of course its for performance rights). I feel for you Johnny H, I almost converted my own for almost 10K. And fuckface Lachlan didn't even respond to queries regarding voting rights after a first, "looking into it."

Royco...think we will actually hear final module accepted? Won't come from FDA util decision correct? Has to come from ugh, Corporate. Someone here will likely find it first!

Below is a list of all of the fifth-letter identifiers on the Nasdaq, which was last updated on Jan. 7, 2016:

A - Class A Shares
B - Class B Shares
C - NextShares Exchange Traded Managed Funds
D - New Issue - This is temporarily used to denote a corporate reorganization.
E - N/A - The letter used to stand for delinquent in regard to SEC filings. Nasdaq now uses the Financial Status Indicator to denote delinquent regulatory filings, but notes other markets may still use "E" for this purpose.
F - Foreign Issue (if the issuer requests it)
G - First Convertible Bond
H - Second Convertible Bond
I - Third Convertible Bond
J - Voting - This is temporarily used to denote a shareholder vote situation.
K - Non-voting
L - Miscellaneous Situations, such as certificates of participation, preferred participation and stubs (research is required to investigate the exact reason for the identifier being attached)
M - Fourth Preferred Issue
N - Third Preferred Issue
O - Second Preferred Issue
P - First Preferred Issue
Q - N/A - The letter used to stand for bankruptcy. Nasdaq now uses the Financial Status Indicator to denote when a compant has filed for bankruptcy, , but notes other markets may still use "Q" for this purpose.
R - Rights Issue
S - Shares of Beneficial Interest
T - Securities With Warrants or Rights
U - Units
V - When issued or when distributed (shares that are set to split or have another similar pending corporate actions)
W - Warrants
X - Mutual Fund Quotation Service (MFQS) Instrument
Y - American Depository Receipt (if the issuer requests it)
Z - Miscellaneous Situations, such as certificates of preferred when issued (research is required to investigate the exact reason for the identifier being attached)
  Forum: By Share Code

PunkassDerm
Posted on: Jan 24 2018, 12:29 PM


Group: Member
Posts: 418

ADR holders can’t even vote. Wouldn’t it be great Frogster!
  Forum: By Share Code

PunkassDerm
Posted on: Jan 22 2018, 09:47 AM


Group: Member
Posts: 418

Not just about a tan, its DNA repair, oxidative stress and anti-inflammatory properties. Future of melanocortins?
But the safe tan will come

https://www.jscimedcentral.com/Dermatology/...logy-1-1001.pdf


Additional Roles of A-MSH/MC1R Signaling in Melanomagenesis
Beyond Melanogenesis

Fangzheng Dong, Rutao Cui, and Fang Liu

α-MSH/MC1R in DNA repair

p53 activation represents a “UV sensor/effector” for skin pigmentation, with its key mechanistic role being the transcriptional activation of POMC [14].The tumor-suppressor protein, p53, plays a central role in the cellular response to UV-induced DNA damage in melanocytes [16-20]. We further demonstrated a novel pigmentation-independent mechanism that underlies MSH-mediated DNA repair following UVB irradiation. We found that α-MSH binds to MC1R and the complex activates adenylate cyclase activity, which in turn activates XPA binding protein 1 (XAB1) that induces nuclear translocation of XPA, a critical factor in controlling nucleotide excision repair (NER) signaling pathways [21] (Figure 1).
  Forum: By Share Code

PunkassDerm
Posted on: Jan 22 2018, 09:22 AM


Group: Member
Posts: 418

Anti-aging/anti-skin cancer cream

https://pdfs.semanticscholar.org/ca6c/05f65...cd920827872.pdf


Cosmeceuticals and peptides Lijuan Zhang, PhD, Timothy J. Falla, PhD
Clinics in Dermatology (2009) 27, 485–494


The use of analogs of α-MSH that function as MC1-R agonists has been attempted for potential topical agents to prevent skin photocarcinogenesis. Tetrapeptide α-MSH analogs, Ac-His-D-Phe-Arg-Trp-NH2, N-pentadecanoyl- and 4-phenylbutyryl-His-d-Phe-Arg-Trp-NH2, have been shown on cultured human melanocytes to be more potent than α-MSH in stimulating the activity of melanogenesis, reducing apoptosis and release of hydrogen peroxide, and enhancing repair of DNA photoproducts in melanocytes exposed to UV radiation.
  Forum: By Share Code

PunkassDerm
Posted on: Jan 21 2018, 01:21 AM


Group: Member
Posts: 418

L'Oreal is huge. They have a line of dermatology quality products in US now, LaRoche Posay. Used to be exclusive to France. Thanks investek, you've been on fire with these finds!

Question is for me...can a ligand (functional bits) itself be patented or more importantly enforced? Its like saying they control ALL of the melanocortins without doing the research on individual compounds. Seems very vague for a patent. Wonder if that can be easily challenged?

Aside...there are many quality contributors still here. I have a little biochem and medical knowledge, but can see big picture things. What I lack is the investment side and regulatory prowess. I appreciate the varied contributions from most well intentioned posters. I really enjoy learning from all of you. Took a nice break from data mining yesterday to design my own 911 GT3. Love to finally enjoy this investment going on 14 years now. I sure hope there is announcement when FDA accepts to full application and clock starts. I have seen glimmers of greatness and truly hope all long term investors can hold on long enough to see a huge reward. And so many patients should have improved quality of life!



D
  Forum: By Share Code

PunkassDerm
Posted on: Jan 19 2018, 10:31 AM


Group: Member
Posts: 418

Looking at effects of MSH on IL-10 and implications from your excerpt:


Attached Image



Melanocortins: Multiple Actions and Therapeutic Potential

1. Safety, rapid degradation
2. Small size peptide and can be manipulated easily for transdermal administration, analogs even smaller chains
3. Suppression of TNF (ala Humira, Enbrel and Remicade)
4. Up-regulates IL-10, potent anti-inflammatory effects with implications for inflammatory conditions
5. Anti-microbial activity, anti-yeast activity but up-regulation of neutrophils



********************************************************************************




Also below IL-10 shows promise but a large expensive molecule to produce. Up-regulation by administration of MSH accomplishes same??

https://www.ncbi.nlm.nih.gov/books/NBK6507/

Interleukin-10 and Psoriasis
K. Asadullah, W. Sterry, and H. D. Volk.


Interleukin (IL)-10 is an important immunoregulatory cytokine. One of its main biological function seems to be the limitation and termination of inflammatory responses. Remarkably, a relative deficiency in IL-10 expression is found in psoriasis, a frequent inflammatory skin disease, characterized by a type 1 cytokine pattern. Induction of IL-10 expression was found by conventional antipsoriatic therapies, suggesting that IL-10 may be a key cytokine in psoriasis and that application of this cytokine may have therapeutic effects. In first clinical trials over 3-7 weeks in patients with established psoriasis IL-10 was well tolerated and clinical efficient. In a long term trial in patients with psoriasis in remission, IL-10 therapy decreased the incidence of relapse and prolonged the disease free interval. Laboratory investigations suggest that IL-10 exerts its antipsoriatic activity by effects on different cell populations including antigen pre-senting cells and T-cells. IL-10 led to a lasting type 1/ type 2 cytokine balance shift. Direct effects of IL-10 on keratinocytes, however, are unlikely to have contributed to the clinical response, since IL-10 unresponsiveness of keratinocytes was found in vitro. IL-10 seems to have major importance in psoriasis. Further investigations are necessary to determine whether its application may represent a promising new therapeutic approach.

...

So far, IL-10 as a cytokine is therapeutically has been used as a recombinant protein i.e., a large molecule. Therefore its quite expensive to produce, must be administered by injection, which is quite inconvenient for the patient, and the induction of neutralizing antibodies, which might limit their effect, has to be excluded for long term application. Identification of molecules mediating the effects of this cytokine which are suitable for pharmacological interven-tion with small molecules will, therefore, of increasing interest. Interference of protein–protein interaction with small molecules, however, is almost impossible. Therefore, it is unlikely that IL-10 receptor agonists suitable for oral application will be discovered. Molecules acting down-stream of the cytokine receptors targeting for example certain kinases or phosphatases or signal transduction molecules might represent much better “drugable” approaches.
  Forum: By Share Code

PunkassDerm
Posted on: Jan 18 2018, 01:48 PM


Group: Member
Posts: 418

Using bacteria vector to deliver MSH to gut for colitis?
IBD is big business as well


http://www.tandfonline.com/doi/abs/10.3109...44.2015.1122672


Oral Bifidobacterium longum expressing alpha-melanocyte-stimulating hormone to fight experimental colitis
Pijin Wei, Yan Yang, Zhaobing Liu, Junli Huang, Yahui Gong & Hanxiao Sun
Pages 2058-2064 | Received 20 Jul 2015, Accepted 31 Aug 2015, Published online: 16 Dec 2015


Abstract
The oral delivery of peptides is a highly attractive treatment approach. However, the harsh environment of the gastrointestinal tract limits its application. Here, we utilize Bifidobacterium as a delivery system to orally deliver a potent anti-inflammatory but short duration peptide alpha-melanocyte-stimulating hormone (α-MSH) against experimental colitis. The aim of our study was to facilitate the efficient oral delivery of α-MSH. We designed a vector of pBDMSH and used it to construct a Bifidobacterium longum expressing α-MSH. We then determined the bioactivity of recombinant Bifidobacterium in lipopolysaccharide-induced inflammatory models of HT-29 cells. Finally, we used Bifidobacterium expressing α-MSH against dextran sulfate sodium (DSS)-induced ulcerative colitis mice. Results based on the myeloperoxidase activity, the levels of inflammatory cytokines TNF-α, IL-1β, IL-6, and IL-10 and the histological injury of colon tissue reveal recombinant Bifidobacterium was efficient in attenuating DSS-induced ulcerative colitis, suggesting an alternative way to use Bifidobacterium as a delivery system to deliver α-MSH for DSS-induced ulcerative colitis therapy.
  Forum: By Share Code

PunkassDerm
Posted on: Jan 18 2018, 01:32 PM


Group: Member
Posts: 418

One more...

Interesting that MSH inhibited nickel contact dermatitis? Safe steroid-like cream without causing skin atrophy? HUGGGGGGEEEEEEEE!
Get on this PW!


http://www.jbc.org/content/279/8/6959.full


Collagen Metabolism Is a Novel Target of the Neuropeptide α-Melanocyte-stimulating Hormone



Abstract

Suppression of collagen synthesis is a major therapeutic goal in the treatment of fibrotic disorders. We show here that α-melanocyte-stimulating hormone (α-MSH), a neuropeptide well known for its pigment-inducing capacity, modulates collagen synthesis and deposition. α-MSH in vitro suppresses the synthesis of collagen types I, III, and V and down-regulates the secretion of procollagen type I C-terminal peptide (PICP) in human dermal fibroblasts treated with the fibrogenic cytokine transforming growth factor-β1 (TGF-β1). α-MSH did not interfere with TGF-β1 signaling, because TGF-β1-induced expression of collagen mRNA was not affected, implying a posttranscriptional mechanism. Human dermal fibroblasts in vitro express a high affinity binding site for MSH, which was identified by reverse transcription PCR and immunofluorescence analysis as the melanocortin-1 receptor (MC-1R). Immunohistochemical studies on normal adult human skin confirmed MC-1R expression in distinct dermal fibroblastic cells. The MC-1R on fibroblasts appears to be functionally relevant because α-MSH increased the amount of intracellular cAMP, and coincubation with a synthetic peptide corresponding to the human Agouti signaling protein abrogated the inhibition of TGF-β1-induced PICP secretion by α-MSH. To assess the in vivo relevance of these findings, a mouse model was used in which dermal fibrosis was induced by repetitive intracutaneous injections with TGF-β1. The inductive activity of TGF-β1 on collagen deposition and the number of dermal cells immunoreactive for vimentin and α-smooth muscle actin was significantly suppressed by injection of α-MSH. Melanocortins such as α-MSH may therefore represent a novel class of modulators with potential usefulness for the treatment of fibrotic disorders.


from Discussion

Our findings on the modulating activity of α-MSH on collagen synthesis finally highlight a novel biological activity that may be exploited in the treatment of fibrotic disorders. α-MSH is a small molecule with a molecular mass of 1.66 kDa. Preliminary data have been shown that nickel-induced contact dermatitis in humans can be suppressed by a topical α-MSH (100 μM) (11). It is known that systemic or intradermal injection of α-MSH or its analogue, NDP-MSH, into humans is well tolerated and has little toxicity (47, 48). The latter α-MSH derivative was found to be 10-1000-fold active than α-MSH, depending on the applied bioassay (49). In the past, a variety of α-MSH analogues with increased potency and prolonged activity have been synthesized (49). These bioactive peptides include minimal fragment analogues of α-MSH containing the core sequences 6-9 and 7-9. The truncated α-MSH peptides are active at micromolar concentrations and are MC-R subtype-specific. The low molecular weight of such peptide fragments may render them suitable for transdermal delivery in vivo.
  Forum: By Share Code

PunkassDerm
Posted on: Jan 18 2018, 01:19 PM


Group: Member
Posts: 418

http://www.tandfonline.com/doi/full/10.1586/edm.12.32


Delivery of drugs applied topically to the skin
Vânia Rodrigues Leite-Silva, Mariana Mandelli de Almeida, Aurélie Fradin, Jeffrey Ernest Grice & Michael Stephen Roberts
Pages 383-397 | Published online: 10 Jan 2014


The stratum corneum is a formidable physical, environmental and microbial barrier, protecting mammalian organisms from external insult and maintaining homeostasis. If the skin is to be used as a route of topical drug delivery, the barrier must be overcome, but this can normally only be achieved with small, relatively lipophilic molecules. Strategies to increase the range of substances that are suitable for transdermal delivery and to improve the permeation of particular substances include advanced formulation and the use of chemical and physical enhancement techniques. Nanomaterials are increasingly being exploited as carriers to deliver materials such as drugs, dyes, vaccines or gene fragments to specific cell targets for therapeutic or diagnostic purposes.


**********************************************************************


https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2700785/


Transdermal drug delivery
Mark R. Prausnitz1 and Robert Langer2


Abstract

Transdermal drug delivery has made an important contribution to medical practice, but has yet to fully achieve its potential as an alternative to oral delivery and hypodermic injections. First-generation transdermal delivery systems have continued their steady increase in clinical use for delivery of small, lipophilic, low-dose drugs. Second-generation delivery systems using chemical enhancers, non-cavitational ultrasound and iontophoresis have also resulted in clinical products; the ability of iontophoresis to control delivery rates in real time provides added functionality. Third-generation delivery systems target their effects to skin’s barrier layer of stratum corneum using microneedles, thermal ablation, microdermabrasion, electroporation and cavitational ultrasound. Microneedles and thermal ablation are currently progressing through clinical trials for delivery of macromolecules and vaccines, such as insulin, parathyroid hormone and influenza vaccine. Using these novel second- and third-generation enhancement strategies, transdermal delivery is poised to significantly increase impact on medicine.
  Forum: By Share Code

PunkassDerm
Posted on: Jan 18 2018, 01:15 PM


Group: Member
Posts: 418

https://espace.curtin.edu.au/handle/20.500.11937/2261

Problem is fragility and breakdown of peptides. Thats why GI absorption does not work, for example insulin.

DERMAPORTATION - Rapid transit across stratum corneum
Iontohoresis (current) is used
?nanoparticles
?electromagnetic, magnetophoresis
?micro-needles


Development of novel carriers for transdermal delivery of peptides
193268_Namjoshi2009.pdf (2.214Mb)


Abstract

Recent developments in genetic engineering and biotechnology have resulted in anincrease in availability of therapeutic peptides and small anti-cytokines. Oraladministration is inappropriate as these molecules are unstable in the gastrointestinaltract and are subject to hepatic first-pass effect. Transdermal delivery is an attractivealternative as the skin exhibits less enzymatic activity and allows for a controlled,sustained local therapeutic drug concentration over a prolonged period of time.However, the skin’s lipophilic stratum corneum acts as a major barrier to thedelivery of hydrophilic molecules, including peptides, resulting in lack of efficacy ofthese compounds if applied topically. Considerable research effort has beenfocussed on the development of skin penetration enhancement techniques. However,many of these techniques have been limited by insufficient penetration enhancementand/or induced irritancy.We have investigated three approaches to enhance the delivery of peptides that havetherapeutic or cosmetic effect in the skin. These approaches include the use ofphysical energy to enhance the delivery of Alanine-Tryptophan (Ala-Trp), lipoaminoacid (LAA) conjugation to increase the permeability of a HNE inhibitor Ala-Ala-Pro-Val (AAPV) and a cosmetic peptide, acetyl hexapeptide-3 and cyclisation to enhancethe delivery of a core peptide (CP) which has anti-inflammatory activity.In vitro permeation studies across human epidermis were performed in Pyrex glassFranz-type diffusion cells. Ala-Trp was selected as a small molecular weight modeldipeptide to study the penetration enhancement effects of Dermaportation, which is anewly developed pulsed electro magnetic field (PEMF) technology. The dipeptidewas found to be unstable on exposure to skin at 37°C and Dermaportation (Pulsedelectromagnetic field technology) significantly increased the in vitro permeabilitycoefficient of Ala-Trp across human epidermis from 7.7 x 10-4 cm/h with passivediffusion to 1.94 x 10-2 cm/h with Dermaportation over an 8 h period.Dermaportation thus may provide an effective means of delivering molecules that arehighly susceptible to degradation like dipeptides, in higher amounts and in arelatively short duration.The effectiveness of coupling a short chain lipoamino acid to enhance transepidermaldelivery of a model human neutrophil elastase (HNE) inhibitor (Ala-Ala-Pro-Val) was assessed. The optimal conjugate structure for skin penetration andbiological activity of this therapeutic peptide with anti-inflammatory activity wasdetermined. In order to enhance the trans-epidermal delivery of the peptide,lipophilic derivatives with LAAs of chain length C6, C8, and C10 were prepared bysolid phase synthesis. Conjugation to a C6-LAA enhanced epidermal permeability ofthe tetrapeptide. Stereoselective permeation of the lipopeptide diastereomers acrossthe human epidermis was observed. The amount of C6(D)-LAA-AAPV (467.94μg/cm2) was significantly higher than C6(L)–LAA-AAPV (123.04 μg/cm2). Thesame was observed with C8(D)-LAA-AAPV. The effect of donor concentration andskin hydration on skin permeability of C8(D,L)-LAA-AAPV and C10(D,L)-LAAAAPVwas also assessed and it was observed that there was higher permeation ofC10(D,L)-LAA-AAPV at a higher donor concentration. The lipoamino acid conjugates were more stable than the native tetrapeptide and biological activity was retained after coupling of the tetrapeptide to C6, C8 and C10 LAA.A cosmetic peptide, acetyl hexapeptide-3 was coupled to individual diastereomers ofC12 (A)-LAA and C12 (B)-LAA. The preliminary study was designed to assess theeffect of coupling of a LAA of higher molecular w
  Forum: By Share Code

PunkassDerm
Posted on: Jan 18 2018, 01:02 PM


Group: Member
Posts: 418

Remember, even with larger molecule size there may be optimizing transdermal delivery systems. We even co-administer drugs such as hydroquinone (bleaching agent) with tretinoin (retin-a) to enhance absorption. For example the Galderma bleaching cream, TriLuma.

I bet some of those new patents from University of Arizona cover smaller peptide chains.
  Forum: By Share Code

PunkassDerm
Posted on: Jan 18 2018, 12:25 PM


Group: Member
Posts: 418

https://encrypted.google.com/patents/WO2006037188A1?cl=ru

AstraZeneca is in there!


Compositions and methods for inducing melanogenesis in a subject


Attached Image

  Forum: By Share Code

PunkassDerm
Posted on: Jan 18 2018, 12:17 PM


Group: Member
Posts: 418

http://www.freepatentsonline.com/8569234.html


REFERENCES SUPER POTENT DERIVATIVE OF MELANOTAN, SEE BELOW



Inventors:
Kleinig, Michael John (Brunswick, AU)
Kirby, Kenneth B. (Palm Beach Gardens, FL, US)
Pettersson Jr. I, Berno (Perry, GA, US)
Application Number:
11/664879
Publication Date:
10/29/2013
Filing Date:
10/07/2005
Export Citation:
Click for automatic bibliography generation
Assignee:
Clinuvel Pharmaceuticals Limited (Melbourne, AU)

Primary Class:
514/10.7
Other Classes:
514/18.6, 530/312, 530/317
International Classes:
A61K38/08; A61K38/10; A61K38/12; A61K38/34; C07K5/12; C07K7/00; C07K7/06; C07K7/08; C07K14/68
View Patent Images:
Download PDF 8569234 PDF help
US Patent References:
6787152 Compositions for rapid and non-irritating transdermal delivery of pharmaceutically active agents and methods for formulating such compositions and delivery thereof 2004-09-07 Kirby et al.
6444234 Compositions for rapid and non-irritating transdermal delivery of pharmaceutically active agents and methods for formulating such compositions and delivery thereof 2002-09-03 Kirby et al.
5049547 Composition for stimulating integumental melanocytes 1991-09-17 Hruby et al.
4918055 Method of stimulating melanocytes by topical application of analogs of alpha-MSH, and compositions for use in same 1990-04-17 Hruby et al.
4866038 Method of stimulating integumental melanocytes by topical application of analogs of alpha-msh 1989-09-12 Hruby et al.


Foreign References:
AU7082887A 1987-08-25
WO2002080878A2 2002-10-17 FILTERING SUNTAN PRODUCT
Other References:
Defintion of analog from http://cancerweb.ncl.ac.uk/omd/about.html, pp. 1-5. Accessed Jul. 7, 2005.
WO 02/080878 Machine translation of specification. 2002.
WO 02/080878 Machine translation of claims. 2002.
Dawson B. V. et al., The Journal of Investigative Dermatology, vol. 94, No. 4 (Apr. 1990) pp. 432-435.
Schwartzmann-Solon A.M. et al., Brazilian Journal of Medical and Biological Research, vol. 31, No. 12 (1998), pp. 1557-1564.
Dorr R. T. et al., Investigational New Drugs, vol. 6, No. 4 (Dec. 1998), pp. 251-258.
Primary Examiner:
Ha, Julie
Attorney, Agent or Firm:
Birch, Stewart, Kolasch & Birch, LLP.
Parent Case Data:
This National Phase application claims priority under 35 U.S.C. 119(e) to U.S. Provisional Application No. 60/617,359 filed on Oct. 8, 2004. The entire contents of these applications are herein fully incorporated by reference.
Claims:
The invention claimed is:

1. A topical composition for the transdermal delivery of an active agent, wherein the active agent is [Nle4, D-Phe7]-alpha MSH, and wherein the composition comprises: (a) at least one non-aqueous non-toxic solvent selected from the group consisting of lower aliphatic mono- and poly-hydroxy compounds; (b) limonene, lemon oil, or a mixture of limonene and lemon oil; © methylsulfonylmethane; (d) a solute modifier comprising at least one compound selected from the group consisting of 3,3′-thiodipropionic acid or an ester or salt thereof, an oxindole alkaloid, a polyphenolic flavonoid, a sugar adduct of a gluconuride, an isoflavone, phosphatidyl serine, phosphatidyl choline, Vitamin D3 and Vitamin K1; (e) at least one substance which induces in situ generation of cAMP or cGMP, wherein the at least one substance comprises forskolin; and (f) a skin stabilizer comprising at least one compound selected from the group consisting of an aliphatic carboxylic acid having from about 8 to about 32 carbon atoms, an ester of said aliphatic carboxylic acid with an aliphatic alcohol having from to about 20 carbon atoms wherein said ester has a total of from about 9 to about 36 carbon atoms, and Vitamin D3, and wherein the composition further comprises one or more absorption modifiers selected from isopropyl myristate and benzophenone.

2. The composition of claim 1, wherein the amount of alpha-MSH analogue in the formulation is 0.001 to 20% by weight.

3. The composition of claim 2, wherein the amount of alpha-MSH analogue in the formulation is 0.05 to 10% by weight.

4. A method for inducing melanogenesis in a subject comprising topically administering to the subject a composition of claim 1.

5. The method of claim 4, comprising administering said composition to provide alpha-MSH analogue in an effective amount and time to induce melanogenesis by the melanocytes in epidermal tissue of the subject without inducing homologous desensitization of the melanocortin-1receptors of the subject.

6. The method of claim 4, comprising administering alpha-MSH analogue at a level not exceeding 10 ng/ml in the plasma of the subject for a period of at least 4 hours.

Description:
BACKGROUND
The melanocortins include a family of peptide hormones that induce pigmentation by interaction with melanocortin-1 receptors (MC1R) in the epidermis.1 The primary pigmentary hormone that is released from the pars intermedia of the pituitary gland in some non-human animals, and from UV exposed keratinocytes in human skin, is alpha melanocyte stimulating hormone (alpha-MSH).1 This 13 amino acid peptide binds to MC1R to induce cyclic AMP-mediated signal transduction, which leads to the synthesis of melanin polymers from DOPA precursors.1 Two types of melanins can be expressed in humans. The brownish-black pigment eumelanin is believed to convey protection from sun damage, whereas the reddish, sulfur-containing pigment, pheomelanin, is often expressed in light-skinned human populations that report a poor tanning response to sunlight.2 These poorly-tanning, easily-burning populations often possess defects in the MC gene3 and are generally thought to be at a greater risk of developing both melanoma and non-melanoma skin cancers.4,5

It has previously been disclosed that a super-potent derivative of alpha-MSH, MELANOTAN (Nle4-D-Phe7-alpha MSH, also referred to herein as “MELANOTAN-1” or “MT1”), can induce tanning in human volunteers.6 MELANOTAN ([Nle4, D-Phe7]-alpha-MSH) contains two amino acid substitutions and is approximately 100 to 1,000-fold more potent than the native hormone at inducing pigmentation in experimental systems such as the frog skin bioassay or in cultured human keratinocytes.7 In humans, MELANOTAN ([Nle4, D-Phe7]-alpha-MSH) primarty induces eumelanin synthesis in the skin in concert with its tanning effect.8 Although melanotropins have been postulated to affect immunologic changes,9,10,11 all of the prior trials reported only minimal side effects such as facial flushing and transient GI upset, unless doses greater than those needed for tanning were administered.12

There is compelling evidence that melanotropic peptides may provide a potential for increasing melanin pigmentation of human skin. Synthetic MSH may be used to enhance skin pigmentation of normal or light-skinned individuals to protect them from the hazards of solar radiation. Several studies have suggested that individuals whose skin tends to burn easily on exposure to the sun and does not tan readily are at higher risk of both nonmelanoma skin tumors and of cutaneous melanoma.16,17,18 There is unambiguous evidence that UV radiation is responsible for skin cancer in humans. In the face of increased deterioration of the ozone layer and the increasing incidence of and mortality from skin cancer, the ability to stimulate the skin's own “protective mechanism” of tanning may prove extremely important as photoprotective strategy.

Accordingly, described herein are compositions and methods for inducing melanogenesis in a human subject by topically administering alpha-MSH analogues to the subject which surprisingly leads to increased melanin density levels in the subject. By increasing melanin levels in a subject, it is possible to reduce or prevent the occurrence of UV radiation-induced skin damage in the subject.

SUMMARY
Described herein are compositions and methods for inducing melanogenesis in a subject. The advantages of the invention will be set forth in part in the description which follows, and in part will be obvious from the description, or may be learned by practice of the aspects described below. The advantages described below will be realized and attained by means of the elements and combinations particularly pointed out in the appended claims. It is to be understood that both the foregoing general description and the following detailed description are exemplary and explanatory only and are not restrictive.
  Forum: By Share Code

PunkassDerm
Posted on: Jan 18 2018, 12:10 PM


Group: Member
Posts: 418

http://www.evaluategroup.com/Universal/Vie...y&id=262551



Clinuvel Granted US Topical Formulation Patent

Source Press Release
Company Clinuvel Pharmaceuticals
Tags Patent, Dermatology
Date November 08, 2011

Protection granted for novel formulations of new class of melanin activating drugs

Clinuvel Pharmaceuticals Limited (ASX: CUV; XETRA-DAX: UR9; ADR: CLVLY) today announced that the United States Patent and Trademark Office (USPTO) has granted Clinuvel pivotal patent protection for the delivery of melanocortins as photoprotective agents in transdermal formulations. Clinuvel has two melanocortin drugs in development (afamelanotide and CUV9900 ), both of which are analogues of the naturally occurring hormone alpha-Melanocyte Stimulating Hormone (alpha-MSH).

Patent 20110263508 grants Clinuvel exclusive rights for compositions of alpha-MSH analogues and transdermal delivery systems and methods of inducing melanogenesis by topical administration.

Clinuvel’s Chief Scientific Officer, Dr Hank Agersborg, said, “This has been a long time coming but our program has demonstrated the importance of melanocortins in inducing melanogenesis and thus protecting skin. This patent will allow the company a further extension of the use of afamelanotide and CUV9900 in non-invasive formulations.

This patent enhances the value of our current portfolio of intellectual property in the major markets of the world. ”
  Forum: By Share Code

PunkassDerm
Posted on: Jan 18 2018, 09:58 AM


Group: Member
Posts: 418

? New molecule...a short chain MSH analog
Probably not afamelanotide

https://www.ncbi.nlm.nih.gov/m/pubmed/3573985/



Topical application of a melanotropic peptide induces systemic follicular melanogenesis.
Hadley ME, et al. Life Sci. 1987.

Abstract
We determined the relative effectiveness of alpha-MSH and a highly potent melanotropin analogue, [Nle4, D-Phe] - alpha-MSH, in stimulating a shift from pheomelanogenesis to eumelanogenesis within hair bulbs of mice. The analogue proved to be at least a hundred times more effective than the native hormone when injected subcutaneously. The two melanotropins were then incorporated into an ointment base and topically applied to a shaved area of the skin on the back of a yellow strain of mice (C57BL/6JAY). Within 24-48 hours eumelanin production was visible within hair bulb melanocytes in both treated and untreated areas of animals. The presence of melanized organelles (eumelanosomes) within melanocytes was confirmed by electron microscopy. These results document the delivery of a peptide hormone through the skin and into the systemic circulation. This is the first demonstration of the delivery of a peptide hormone by percutaneous absorption and may provide a model for a similar route of delivery of other peptide hormones. The hormone analogue has also been delivered across human skin in vitro. Delivery of a melanotropin by a transdermal route may prove to be clinically useful in the treatment of some integumental hypopigmentary disorders in humans.

PMID 3573985 [PubMed - indexed for MEDLINE]
  Forum: By Share Code

PunkassDerm
Posted on: Jan 10 2018, 12:27 PM


Group: Member
Posts: 418

I hope we have FDA approval and Vitiligo well underway before any movie gets made! Quick-like!
  Forum: By Share Code

PunkassDerm
Posted on: Jan 1 2018, 02:19 AM


Group: Member
Posts: 418

DISRUPTIVE MEDICINE - to me still the prize and goal

Protection from UVR through melanogenisis (tan as a sunscreen)
Reduction of oxidative stress
DNA repair


a-MSH tripeptide analogs activate the melanocortin 1 receptor and reduce UV-induced DNA damage in human melanocytes
Zalfa A. Abdel-Malek1, Andrew Ruwe2, Renny Kavanagh-Starner1, Ana Luisa Kadekaro1, Viki Swope1, Carrie Haskell-Luevano3, Leonid Koikov2 and James J. Knittel2
Pigment Cell Melanoma Res. 22; 635–644
PUBLICATION DATA Received 27 April 2009, revised and accepted for publication 16 June 2009


http://onlinelibrary.wiley.com/store/10.11...buyt4n2620aac5b


Significance

Effective prevention strategies for skin cancer, particularly the most fatal melanoma, are urgently needed to reduce its mounting incidence. Given the photoprotective effects of eumelanin, there has been sub- stantial interest in developing agents, particularly a-melanocortin (a-MSH) analogs that induce ‘sunless tanning’. We have discovered that a-MSH not only stimulates melanogenesis, but also reduces the DNA damaging effects of ultraviolet radiation by diminishing the generation of reactive oxygen species and enhancing the repair of DNA photoproducts. We have translated these findings into designing and syn- thesizing small fragment analogs of a-MSH for the long term goal of developing topical application for skin cancer and melanoma prevention. Success in developing such a strategy will have tremendous impact on reducing the incidence of skin cancer that surpasses that of all human cancers combined.


Summary

One skin cancer prevention strategy that we are developing is based on synthesizing and testing melanocor- tin analogs that reduce and repair DNA damage resulting from exposure to solar ultraviolet (UV) radiation, in addition to stimulating pigmentation. Previously, we reported the effects of tetrapeptide analogs of a-melano- cortin (a-MSH) that were more potent and stable than the physiological a-MSH, and mimicked its photopro- tective effects against UV-induced DNA damage in human melanocytes. Here, we report on a panel of tripeptide analogs consisting of a modified a-MSH core His6-D-Phe7-Arg8, which contained different N-capping groups, C-terminal modifications, or arginine mimics. The most potent tripeptides in activating cAMP forma- tion and tyrosinase of human melanocytes were three analogs with C-terminal modifications. The most effective C-terminal tripeptide mimicked a-MSH in reducing hydrogen peroxide generation and enhancing nucleotide excision repair following UV irradiation. The effects of these three analogs required functional MC1R, as they were absent in human melanocytes that expressed non-functional receptor. These results demonstrate activation of the MC1R by tripeptide melanocortin analogs. Designing small analogs for topical delivery should prove practical and efficacious for skin cancer prevention.


Discussion

Constitutive pigmentation and the ability to tan are important determinants of skin cancer risk (Epstein, 1983; Gilchrest et al., 1999; Halder and Bridgeman- Shah, 1995; MacLennan et al., 1992; Sober et al., 1991). By synthesizing melanin, epidermal melanocytes in human skin play a major photoprotective role against UV-induced skin cancer. When malignantly transformed, melanocytes give rise to melanoma, the deadliest form of skin cancer. Enhancing skin pigmentation is envi- sioned as an effective means for skin cancer prevention. Melanin, particularly eumelanin containing melanosomes form supranuclear caps that protect the nucleus from impinging UV rays, and thus reduce the extent of DNA damage that causes mutations, and ultimately skin can- cer (Hauser et al., 2006; Kaidbey et al., 1979; Kobayashi et al., 1998; Smit et al., 2001; Tadokoro et al., 2003). The inverse relationship between melanin content and UV-induced skin cancer is supported by extensive epide- miological data showing increased skin cancer in individ- uals with light skin and poor tanning capacity compared with individuals with dark skin (Epstein, 1983; Gilchrest et al., 1999; Halder and Bridgeman-Shah, 1995; MacLennan et al., 1992; Sober et al., 1991). Melanin through its function as a sunscreen is expected to inhibit mutations in the tumor suppressor p53, an early marker of non-melanoma skin cancer, as observed after sunscreen application (Ananthaswamy et al., 1998). Moreover, the role of melanin as scavenger of reactive oxygen species should further contribute to reduction of UV-induced DNA damage and skin carcinogenesis (Bustamante et al., 1993).

In addition to pigmentation, there are other risk fac- tors that determine skin cancer susceptibility, an impor- tant one of which is DNA repair capacity. The best evidence for this is the remarkable increase in skin can- cer risk in xeroderma pigmentosum patients that have deficiency in repairing DNA photoproducts because of mutations in nucleotide excision repair genes (Kraemer et al., 1994). Also, individuals with mutations in the melanoma susceptibility locus CDKN2A have reduced nucleotide excision repair capacity (Sarkar-Agrawal et al., 2004). In addition to DNA photoproducts, oxidative DNA damage results from UV exposure and is implicated in melanoma. The activating V600E mutation in BRAF that is considered an early marker of melanocyte transforma- tion is thought to be caused by oxidative DNA damage (Landi et al., 2006).

An important regulator of skin pigmentation and the UV response of melanocytes is a-MSH, which binds the MC1R and stimulates eumelanin synthesis (Hunt et al., 1995; Im et al., 1998; Suzuki et al., 1996). We have reported that in addition to stimulating melanogenesis, a-MSH reduces UV induced oxidative DNA damage by inhibiting the generation of hydrogen peroxide, and enhances the repair of DNA photoproducts (Bohm et al., 2005; Kadekaro et al., 2005). Recently, we and others found that activation of MC1R upregulates the expression of DNA repair genes (unpublished data) (Smith et al., 2008). We also observed that the immedi- ate reduction of UV-induced hydrogen peroxide by a- MSH (Figure 4A) was dependent on cAMP, as it was inhibited by the Protein Kinase A inhibitor H-89, and was mediated by instant increase in catalase activity (unpublished data). Epidemiological studies found a strong association between MC1R loss-of-function alle- lic variants and increased melanoma risk, suggesting that inability to respond to a-MSH increases the chance for malignant transformation of epidermal melanocytes to melanoma (Box et al., 2001; Kennedy et al., 2001; Palmer et al., 2000). The effects of a-MSH on the UV response linked the activated MC1R to DNA repair and antioxidant pathways, and revealed molecular mecha- nisms that explain the function of MC1R as a melanoma susceptibility gene.

An attractive strategy for skin cancer prevention is to utilize potent analogs of a-MSH to induce ‘sunless tan- ning’, which should reduce the damaging effects of, and prevent mutations resulting from, repetitive UV exposures. In support of the efficacy of using a-MSH analogs for photoprotection are recent intriguing findings that increased melanocortin synthesis and MC1R expression are part of the DNA damage response to UV exposure. Exposure of mice to UV resulted in stimula- tion of the transcriptional activity of p53 in epidermal keratinocytes, which induced the expression of the gene for proopiomelanocortin, the precursor for ACTH and a-MSH (Cui et al., 2007). Also, using T-oligonucleo- tides, which activated the DNA damage response, resulted in increased melanogenesis via increasing MC1R expression (Atoyan et al., 2007). These studies underscore the role of melanocortins and functional MC1R in protecting the skin from UV-induced DNA damage. Moreover, activation of the cAMP pathway, the main signaling pathway of melanocortins, by forskolin, a direct activator of adenylate cyclase, had the same effects as a-MSH on the UV response of human mela- nocytes, and reduced the extent DNA photoproducts in UV-irradiated mouse skin as well as human skin substi- tutes [Figures 3B and 5B; (D’Orazio et al., 2006; Passer- on et al., 2009)].

The best known analog of a-MSH is the tridecapep- tide NDP-MSH, which has more potent and longer last- ing effects than a-MSH on cultured human melanocytes (Abdel-Malek et al., 2006; Suzuki et al., 1996). The pig- mentary effect of NDP-MSH has been demonstrated in vivo (Barnetson et al., 2006; Levine et al., 1991), and its ability to reduce UV-induced DNA photoproducts has been recently confirmed (Barnetson et al., 2006; Levine et al., 1991). The drawback of using NDP-MSH is that it is too large for topical application, and is not specific for MC1R. Actually, the non-pigmentary effects of NDP- MSH were reported in the first clinical study utilizing this analog (Levine et al., 1991). Thus, there is a need to develop more specific and smaller analogs that can be delivered transdermally.
  Forum: By Share Code

PunkassDerm
Posted on: Jan 1 2018, 12:52 AM


Group: Member
Posts: 418

WOW!!! Many thanks


An expansion of the article I posted, 6 years later and with additional collaborators. PW must have read this early on...

Melanoma prevention
Melanoma Metastasis
Septic shock
I'm hoping spinal cord injury

These indications include significant morbidity/mortality implications. Shove this down NICE's pie hole!


Several human disorders could benefit from melanocortin treatment. Obesity has become a major health problem in Western countries. Synthetic MC4R agonists are very promising candidates to treat this disorder; clinical trials are already in progress. The anti-cytokine action and the inhibitory effect on inflammatory cell migration make melanocortins potential new drugs for treatment of acute, chronic, and systemic inflammation. The neuroprotective action in vascular and inflammatory brain injury is likewise well established. Melanocortins could form a novel class of therapeutic agents for several disorders of the nervous system. Through activation of MC1R, •-MSH confers photoprotection to human melanocytes and reduces DNA damage caused by exposure to solar ultraviolet radiation. Based on these actions, MC1R agonists are promising agents for melanoma prevention strategies.
The severe disability caused by obesity, neurological, and inflammatory disorders has very high costs in terms of decrease in quality of life and ability to work. These conditions thus entail a heavy economic price for both the patients and the society. It is clear that effective treatments would be a beneficial response to significant needs. As research described in this book indicates, melanocortins have a remarkable potential for treatment of many dire conditions.

Anna Catania, MD
  Forum: By Share Code

PunkassDerm
Posted on: Dec 31 2017, 02:52 PM


Group: Member
Posts: 418

Great Overview - Older publication, 2004


http://pharmrev.aspetjournals.org/content/...56/1/1.full.pdf


Targeting Melanocortin Receptors as a Novel Strategy to Control Inflammation


MCR subtypes
Attached Image




Anti-inflammatory mechanisms
Attached Image




Therapeutic targets
Attached Image

  Forum: By Share Code

PunkassDerm
Posted on: Dec 31 2017, 01:57 PM


Group: Member
Posts: 418

Traumatic Brain Injury, Ischemic Stroke and Brain Hemorrhage
Anti-inflammatory, immunomodulation and anti-apoptotic

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3733710/


PLoS One. 2013; 8(8): e71056.
Published online 2013 Aug 5. doi: 10.1371/journal.pone.0071056
PMCID: PMC3733710

Single Administration of Tripeptide α-MSH(11–13) Attenuates Brain Damage by Reduced Inflammation and Apoptosis after Experimental Traumatic Brain Injury in Mice

Discussion

The present data demonstrate for the first time a neuroprotective effect of the α-MSH tripeptide fragment (11–13) in an experimental TBI model. A single injection of α-MSH(11–13) diminishes secondary brain lesion expansion possibly by reducing apoptotic cell damage. Despite the well described anti-inflammatory effects of α-MSH(11–13) it did not influence the posttraumatic gene expression of TNF-α and IL-1β as well as the total amount of Iba-1 positive cells. The degree of activation of Iba-1 positive cells in the ipsilateral hemisphere was distinctly reduced by the tripeptide. These data suggest that neuroprotection by α-MSH(11–13) might be mediated not exclusively by its immunomodulatory action but also by its anti-apoptotic effect.

Due to the beneficial modulating effects of α-MSH and its derivatives on inflammation, infectious processes, or energy homeostasis, these proteins have attracted attention of many investigators [20]–[23]. Decreased α-MSH plasma levels were associated with poor neurologic outcome in a rat model of middle cerebral artery occlusion and also in patients with ischemic stroke [24], [25]. Also in humans, α-MSH concentrations were lessened in critically injured trauma patients as well as after subarachnoid hemorrhage or TBI [26], [27].

To understand the role of α-MSH after brain injury, the first part of the study characterized the trauma-induced changes of proteins associated with the production and function of α-MSH. Therefore, the influence of TBI on the cerebral regulation of the precursor hormone POMC, of which α-MSH is endogenously derived, as well as the melanocortin receptors MC1R and MC4R, which orchestrate the pleiotropic effects of the melanocortin peptides, were investigated. In the central nervous system POMC is expressed in various cell types - inter alia in neurons of hypothalamus, arcuate nucleus, and the brain stem [28]. MC1R is primarily expressed in peripheral tissues, but also detectable in astrocytes, neurons of periaqueductal gray, and microvascular endothelial cells [29]–[31]. Its main physiological functions are the regulation of pigmentation and inflammatory response [32]. MC4R is expressed in brain primarily in astrocytes of cortex, thalamus, hypothalamus, and the brain stem [33]–[36]. The central anti-inflammatory actions of α-MSH are in part attributed to MC4R action [33], [37]. Furthermore, the melanocortin analog [Nle, D-Phe]-α-MSH demonstrated a MC4R-dependent protective effect in a diffuse rat TBI model [38]. The mRNA analysis in pericontusional tissue at 15 min, 6, 12, 24, and 48 h post TBI of the present study revealed that expression of POMC and MC4R is not influenced by mechanical brain lesion. This suggests that α-MSH levels are not endogenously upregulated upon injury via the precursor hormone and that MC4R expression is not regulated to modulate posttraumatic melanocortin-induced effects. In contrast, MC1R mRNA expression was about 3-fold increased at 12 h and remained elevated at 24 h and 48 h post injury. These results could indicate an increased interaction of melanocortins with MC1R following TBI, which is known for its high receptor affinity and association to regulation of inflammatory as well as immunomodulatory functions [39].
  Forum: By Share Code

PunkassDerm
Posted on: Dec 28 2017, 09:52 PM


Group: Member
Posts: 418

The melanocortin platform has unlimited potential. Make deals with these payers to drop price as indications allowed, commensurate with population size. 2500 USD per implant and regulatory/insurance blockade will crash.
  Forum: By Share Code

PunkassDerm
Posted on: Dec 28 2017, 09:37 PM


Group: Member
Posts: 418

Substance abuse


https://www.frontiersin.org/articles/10.338...2014.00128/full


Targeting central melanocortin receptors: a promising novel approach for treating alcohol abuse disorders
Front. Neurosci., 03 June 2014 | https://doi.org/10.3389/fnins.2014.00128


Conclusion

For more than a decade, significant progress has been made in elucidating the role of the MC system in the neurobiological responses to ethanol. Indeed, ethanol has been shown to significantly alter the functionality of the central MC system (see Table 1) and that compounds that target the MC system can protect against ethanol consumption and other ethanol-related behaviors (see Table 2). Together, these findings hold promise for the MC system as a potential target for therapeutic intervention for AUDs. In fact, a number of therapeutic drugs targeting the MC system are currently under development for other clinical disorders. Given the commonalities between AUDs and other disorders- such as eating disorders- the utilization of these available drugs as potential means to alleviate the symptoms associated with alcohol use and abuse may be a beneficial avenue to pursue in the future.
  Forum: By Share Code

PunkassDerm
Posted on: Dec 28 2017, 09:27 PM


Group: Member
Posts: 418

Diabetes and Obesity? Now that's a non-orphan population.


https://www.jci.org/articles/view/12954


Central melanocortin receptors regulate insulin action


Energy balance and insulin action are tightly coregulated. Leptin regulates energy intake and expenditure partly by modulation of the melanocortin pathway in the hypothalamus. Here we demonstrate potent effects of the melanocortin pathway on insulin action and body distribution of adiposity. Conscious rats received week-long infusions of either a melanocortin receptor agonist, α-melanocyte-stimulating hormone (α-MSH), or antagonist, SHU9119, in the third cerebral ventricle while food intake was maintained constant in each group. α-MSH decreased intra-abdominal fat and markedly enhanced the actions of insulin on both glucose uptake and production, while SHU9119 exerted opposite effects. Our findings elucidate a neuroendocrine network that is likely to play a central role in the coupling of energy intake and insulin action.
  Forum: By Share Code

PunkassDerm
Posted on: Dec 21 2017, 11:34 PM


Group: Member
Posts: 418

for contrast...

Siliq licensed to Valeant and is coming to market despite below, FDA is concerned with a tan as side effect? Safety concerns, come on people.

By-the-way, its a great drug, I had some patients in the the trials. Turns off psoriasis like a spigot.



https://www.thepharmaletter.com/article/fda...q-for-psoriasis


FDA staff concerned on suicide risk of Valeant’s Siliq for psoriasis

Briefing documents prepared for a US Food and Drug Administration advisory committee have raised concerns on a potential suicide risk involving Siliq (brodalumab), a psoriasis treatment being developed by Canada’s Valeant Pharmaceuticals (VRX.TO).

Valeant has submitted a biologics licensing application to the regulator for Siliq to treat moderate to severe plaque psoriasis in adults who are candidates for systemic therapy or phototherapy.

It is to be considered by the FDA’s Dermatologic and Ophthalmic Drugs Advisory Committee tomorrow (Tuesday), and this panel has been presented with a report written by agency staff which analyses Valeant’s application.

The report states that the efficacy of Siliq is supported by the three pivotal Phase III placebo-controlled clinical trials, all of which showed superiority to placebo in primary and secondary endpoints.

However, the report continued: “The safety review of brodalumab presented challenges. Late into the clinical studies, a suicide signal emerged with four completed suicides occurring in the Phase III clinical trials.

“A total of six completed suicides in all brodalumab clinical trials were reported – four in psoriasis, one in rheumatoid arthritis, and one in psoriatic arthritis. However, one suicide was later adjudicated as indeterminate due to possible accidental drug overdose. The Phase III clinical trials were terminated early by the sponsor, thereby preventing further assessment of safety.”

A comprehensive evaluation of suicidal ideation and behavior (SIB) was undertaken by both Valeant and the FDA, and this will be discussed at length during the committee meeting, as will Siliq's potential link to major cardiovascular adverse events (MACE).

The report adds: "In addition to SIB safety issues, the increase in IL-17 that results from IL-17 receptor blockade could theoretically affect cardiovascular outcomes and MACE.

"It has been hypothesized that IL-17 receptor inhibition may lead to an increase in other cytokines involved in inflammation, thereby resulting in an increase in MACE events."

The committee will make a recommendation on whether to approve the drug, which will then be considered by the FDA as it makes it final decision.

Brodalumab was originally co-developed by UK pharma major AstraZeneca (LSE: AZN) and US biotech Amgen (Nasdaq: AMGN) via a 2012 partnership, which the latter withdrew from last year citing "events of SIB" that would likely lead to restrictive labeling.

AstraZeneca later licensed exclusive brodalumab rights to Valeant in an agreement that was recently amended, terminating the Canadian drugmaker's rights to the therapy in Europe.
  Forum: By Share Code

PunkassDerm
Posted on: Dec 20 2017, 10:46 PM


Group: Member
Posts: 418

?Bargaining chip

Time for patient advocate groups to raise holy hell.


Highly Specialised Technology Evaluation
Afamelanotide for treating erythropoietic protoporphyria [ID927]
Evaluation Report


https://www.nice.org.uk/guidance/GID-HST100...ommittee-papers



Afamelanotide for treating erythropoietic protoporphyria [ID927]: Evaluation consultation: 1

https://www.nice.org.uk/guidance/indevelopm...on/html-content

Afamelanotide for treating erythropoietic protoporphyria [ID927]: Evaluation consultation: 1
The Department of Health has asked the National Institute for Health and Care Excellence (NICE) to produce guidance on using afamelanotide in the context of national commissioning by NHS England. The highly specialised technologies evaluation committee has considered the evidence submitted by the company and the views of non-company consultees and commentators, clinical experts, patient experts and NHS England.

This document has been prepared for consultation with the consultees. It summarises the evidence and views that have been considered, and sets out the draft recommendations made by the committee. NICE invites comments from the consultees and commentators for this evaluation and the public. This document should be read along with the evidence (see the committee papers).

The evaluation committee is interested in receiving comments on the following:

Has all of the relevant evidence been taken into account?
Are the summaries of the criteria considered by the committee, and the clinical and economic considerations reasonable interpretations of the evidence?
Are the provisional recommendations sound and a suitable basis for guidance on the use of afamelanotide in the context of national commissioning by NHS England?
Are there any aspects of the recommendations that need particular consideration to ensure we avoid unlawful discrimination against any group of people on the grounds of race, gender, disability, religion or belief, sexual orientation, age, gender reassignment, pregnancy and maternity?

Note that this document is not NICE's final guidance on this technology. The recommendations in section 1 may change after consultation.

After consultation:

The evaluation committee will meet again to consider the evidence, this evaluation consultation document and comments from the consultees.
At that meeting, the committee will also consider comments made by people who are not consultees.
After considering these comments, the committee will prepare the final evaluation determination.
Subject to any appeal by consultees, the final evaluation document may be used as the basis for NICE’s guidance on using afamelanotide in the context of national commissioning by NHS England.
For further details, see the interim process and methods of the highly specialised technologies programme.

The key dates for this evaluation are:

Closing date for comments: 17th January 2018

Second evaluation committee meeting: 20th February 2018

Details of membership of the evaluation committee are given in section 6.

Note that this document is not NICE's final guidance on this technology. The recommendations in section 1 may change after consultation.
  Forum: By Share Code

PunkassDerm
Posted on: Dec 20 2017, 01:28 PM


Group: Member
Posts: 418

Allegory of the Melanocortin

Perception is relative...what is your reality? Ascend from the cave shadows.
Transparency
Accountability



Attached Image

  Forum: By Share Code

PunkassDerm
Posted on: Dec 4 2017, 11:28 AM


Group: Member
Posts: 418

Apologies if already posted. I think Uho has already commented on selectivity and half life. With sustained release implant, I think we have the sweet spot. And it may be beneficial in this case to have multiple targets (but still MCR1 selective).



https://prevention.cancer.gov/funding-and-g...nts/R21CA191761


QUOTE
Melanoma prevention by MC1R selective small peptide analogs of alpha MSH

DESCRIPTION (provided by applicant): This revised application will test the hypothesis that small peptide analogs of ?-melanocortin (?-MSH) that are selective agonists of the melanocortin 1 receptor (MC1R) will prevent melanoma tumor formation in transgenic mouse melanoma models by enhancing repair of ultraviolet radiation (UV)-induced DNA damage and stimulating melanogenesis. We have pioneered the research on the MC1R and its agonist ?-melanocyte stimulating hormone (?-MSH), and discovered their role in reducing the extent of UV-induced DNA damage by activating DNA repair and antioxidant pathways. These findings illuminated how the MC1R functions as a melanoma predisposition gene, and why expression of loss-of-function MC1R allelic variants that are strongly associated with red hair phenotype increases melanoma risk. Our research on MC1R/?-MSH axis led us to begin developing a melanoma chemoprevention strategy based on targeting the MC1R by highly selective small analogs of ?-MSH. We have designed and tested a large panel of small ?-MSH analogs, tri- and tetrapeptides that are full agonists of the MC1R and mimic the physiological ?-MSH in all its effects on human melanocytes. In this project, we are proposing to test one tripeptide, LK 514, and one tetrapeptide, LK 467, that were selected based on their potency on human melanocytes, and importantly, for their unique selectivity for the MC1R, stability, and lipophilicity. Neither peptide had any cytotoxic effects in cell- and tissue-based assays. We will test the efficacy of these analogs to prevent melanomagenesis in two mouse models that are relevant to human melanoma, i) K14- SCF;Mc1r e/+ transgenic mice, heterozygous for the recessive yellow mutation in Mc1r, a model for humans heterozygous for a red hair MC1R variant who represent a large sector of the white population in the U.S.A. and Northern Europe and have increased risk for melanoma due to reduced MC1R activity, and; ii) HGF transgenic mice, a model for UV-inducible melanoma. We will investigate the ability of these analogs to reduce the extent of UV-induced DNA damage, stimulate eumelanin synthesis, and inhibit melanocytic hyperplasia, melanoma formation, progression and multiplicity. These in vivo experiments are crucial in order to advance these analogs towards a Phase I Clinical Trial. In the absence of a cure for metastatic melanoma, this application is significant due to the critical need for effective melanoma prevention strategies that will reduce the mortality and morbidity associated with the disease, and halt the continuous increase in its incidence. Our proposed strategy is innovative, since our analogs have the unique feature of being highly selective to MC1R, which reduces off-target effects due to binding to other MC receptors, in addition to their small size, stability and lipophilicity that should allow for topical delivery and long lasting effcts. This strategy should benefit millions of high risk individuals with fair skin and poor tanning ability, including those heterozygous for MC1R variant, or harboring mutations in other melanoma predisposition genes, such as p16.





http://blogs.sciencemag.org/pipeline/archi...#comment-287402


QUOTE
Melanocortin: It’s Not Just For Lizards Any More


By Derek LoweNovember 29, 2017

If you’re looking for a good example of evolution-as-a-tinkerer, the melanocortin receptors would be a good place to start. From a single starting point, they’ve ended up as a family of related proteins that do completely different things. And the hormones that bind to them have radiated out as well: they’re all derived by processing of a common precursor, pro-opiomelanocortin (POMC), and the first big split was the differentiated function of two of those cleavage products into what we would now call adrenocorticotrophic hormone (ACTH) and melanocyte-stimulating hormone (MSH). By now, humans have three forms of the latter (alpha, beta, and gamma MSH), and the receptor proteins have branched into five different MCxR subtypes as well. (Evolutionary molecular biology puts a lot of this back into roughly the lamprey/lungfish stage of things – the splits seem to have developed though gene duplication events during the periods of jawed fish and tetrapod evolution).

Along the way, they’ve each landed in their own niches. MC1R is the receptor signaling mechanism for melanin production, and is activated by MSH. The MC3R, MC4R, and MC5R receptors also respond to the different MSH subtypes in varying degrees, and these regulate things like (among others) hunger/satiety, immune response, sexual arousal, and sebaceous gland secretion – a bizarre collection indeed, which is exactly what you get after a billion years of “Hey man, whatever works”. Adding to the fun are the endogenous agouti peptides, which seem to be inverse agonists of the receptors and make their signaling ever more complex. Those have the same splits in function – agouti-signaling peptide was discovered through its effects on coat color in animals, while agouti-related peptide is a potent appetite stimulant.

This makes for quite a selectivity problem if you’re going to try to develop drugs in this area. A number of compounds have been worked on over the years, but not much has made it through, despite the marketing potential of a drug combination that could simultaneously make you lose weight, increase your sexual appetite, and give you a tan. That last one sounds fairly trivial, but it’s the target of a marketed drug, Scenesse (afamelanotide), which is a modified synthetic version of MSH. It’s administered by subcutaneous implant to people with skin pigmentation disorders, but it’s not very selective at all. Side effects (nausea, headache, decreased appetite, etc.) are quite noticeable, and since you’ve been dosed with a two-month supply, there’s not much to be done about them. (Update: I should also note bremelanotide, another MSH-like peptide with a very long and convoluted history in the clinic, which is currently heading to the FDA for a controversial female sexual dysfunction indication).

So here’s a new paper on efforts to develop a more selective MSH peptide from the same group at Arizona that discovered afamelanotide. They’d found a candidate in their earlier work, but it had several noncanonical amino acids, which slowed down potential development. The new paper is an attempt to replicate (or better) that selectivity while only using standard amino acids – in other words, to improve on nature directly. And so far, this looks possible: their new species has better selectivity than endogenous MSH, and a longer half-life in human plasma (MSH’s is five minutes, afamelanotide’s is 30 minutes, and the new species is 17 minutes).

Attached Image

And it certainly does the job on MC1R. Shown is an experiment on a green anole lizard (their color-changing abilities mean that they have a lot of melanocytes in their skin). Injection of afamelanotide, as shown, turns the lizard black within sixty seconds, an effect that takes two weeks to completely wear off (no doubt to the lizard’s consternation). The new peptide has exactly the same effect, but the lizard is back to his green self within 24 hours.I have to say that while I’ve had compounds go into all sorts of animal models in my career, the Ninja Lizard assay is a new one on me. The compound is still only a partial agonist (54% of maximum effect in the cell assays), but that certainly seems to be good enough, and it’s 16-fold selective for the MC1R subtype.

So this looks like a promising candidate for a second-generation therapy. If it’s safe enough, the hope is that such a drug could move into a broader market protecting people who at are higher risk for melanoma, since darkening the skin without having to expose people to lots of UV to start with would be an ideal way to accomplish that. I’ll leave the sociological implications to others, noting only that suntans themselves have moved over the years in the Western countries from a sign of being a fieldhand, to a sign of being wealthy and leisured, to a sign (in excessive cases) of spending too much money on tanning beds and body sprays. Anole lizards no doubt have their own take.
  Forum: By Share Code

PunkassDerm
Posted on: Dec 2 2017, 03:20 PM


Group: Member
Posts: 418

Defuse the PW bomb!
Please feel free to meme away

Attached Image

  Forum: By Share Code

PunkassDerm
Posted on: Dec 2 2017, 09:27 AM


Group: Member
Posts: 418

Big takeaway for me...6 implants per year give patients much more consistent coverage. And for sales, no winter dip. If approved, huge.
  Forum: By Share Code

PunkassDerm
Posted on: Dec 2 2017, 04:56 AM


Group: Member
Posts: 418

https://seekingalpha.com/article/4128951-cl...horse-qualities

Clinuvel: Turtle Or Race Horse? Both Have Their Qualities

Minus Sinus – Value Investing

Summary
Clinuvel Pharmaceuticals (CLVLY) held their annual general shareholder meeting (AGM) on November 28th, 2017, revealing new pockets for growth and a re-positioning of the company.

Against (partially) self-imposed high expectations, the revealed strategy forward did not offer too much inspiration for the future perspective of the company.

However, some elements give valuable information about upcoming steps and business potentials in the mid-term future.

Clinuvel Pharmaceuticals (OTCPK:CLVLY) held their annual general shareholder meeting on November 28th, 2017, publishing updates on product and application roadmaps (Presentation slides).

Being blunt, the company disappointed many shareholders by a very ordinary presentation, as they had raised expectations in the last company newsletter and annual report that something big was lining up: (e.g. "preparing the Group for expansion"). Compared to the expectations, one could be slightly disappointed by what the company revealed, and there is actually light and shadow. Let's have a look:

Quarterly cash-flow


The company mapped out the quarterly cash-flow development since 2006 in the following slide [p. 19]:

While the data is all known, it is interesting that they chose one of the revenue scenarios (or cash-ins to be accurate) from their 2015 AGM - and they went for the "high" scenario. While they refuse to give financial guidance, this choice shows the confidence to deliver on the upper range of their own expectations.

European roll-out

For the European roll-out, they published a map of the expert centers for administering Scenesse for EPP - the availability and capicity of the expert centers was one of the bottlenecks that slowed down the roll-out of Scenesse in the past 2 years [p. 28]:

With 42 expert centres now in place, this should help increasing patient access; still UK has centers qualified, but did not release the drug yet; and France and Spain with 1 or 2 centers looks a little bit anemic, too.

Moreover, they were able to achieve their "uniform pricing" across countries; however, especially the very vivid community on sharescene.com (thank you, guys!) questions whether this is the task of a small start-up to introduce an innovative pricing scheme. Curiosity kills cats, I am not sure what stubbornness does to Australian start-ups (maybe inflates their timelines).

More details on EPP target markets and revenue expansion

For the US market, Clinuvel expects around 2300 patients in EPP; for Japan and Australia, a combined potential of 500. The US figure is lower than in my previous estimates (4000, source: American Porphyria Association). As I assumed also a very low penetration of 20%, I would keep up my revenue estimate accordingly (4000 seemed a bit too much).

Interesting news are the label extensions on cutaneous porphyrias that has a comparably high prevalence (1 out of 10 000, Source: APF).

Rather nice is also the dosage increase from 4 to 6 implants per annum (if it happens at same price per dose), so a sales upside of up to 50%.

The mentioned new orphan indication is so far left to imagination, so I am not going to speculate about that.

Delays in FDA approval timeline

I think the most disappointing element of the AGM (apart from the absence of the great shiny plan ahead) was the delay of the FDA approval timeline for Scenesse on EPP. While the first announcement mentioned that Clinuvel would submit its NDA dossier in first half of 2017, it was later (almost silently) postponed to end of 2017. My speculation that the company had already filed the NDA (based on bits and pieces of their communication) turned out to be wrong, as the following slide shows:

Clinuvel now expects to submit the NDA by what appears to be end of February 2018 (a 3 months delay vs last announcements). Then, after a review period of 8 or 12 months (depending on priority review), the drug approval would be around Dec 2018 to April 2019. Moreover, and I think that was the most shocking news, the company expects to treat first patients in the US by ~ Nov 2019 (further 7 months down the road).

These two bad news re-opened some old scars of Epitan/Clinuvel investors: First, the company keeps missing their own timelines, even very close to expected completion, and even if they don't appear overly ambitious. Second, you would expect that after learning painfully in Europe how long it takes to install patient register, set up administration centers and documentation, you would think the company would be able to be fast on this.

Summary

Even if the annual general meeting did not produce the big bang for the next level of the company's development and ambitions for the future, the company revealed some relevant bits and pieces of short- to mid-term business development and plans. However, I get the feeling that the company continues to act as the cash-tight, few-headcounts start-up organization that is has been in the past, tackling all challenges one-by-one instead of parallelizing activities, branching the organization into functional profiles (sales vs R&D vs ...) and horizons (operational fixes vs long-term strategy). I hope I get proven wrong!
  Forum: By Share Code

PunkassDerm
Posted on: Nov 30 2017, 10:48 PM


Group: Member
Posts: 418

What do you base this on? I would love to believe it but there is no going on feeling with this company and verified facts/data are scarce. Timelines useless.

I've counted my chickens for over a decade now, eggs are rotting. Lazarus my hopes.
  Forum: By Share Code

PunkassDerm
Posted on: Nov 29 2017, 02:13 PM


Group: Member
Posts: 418

https://www.fda.gov/Drugs/ResourcesForYou/C...s/ucm100101.htm


OTC drugs are:

Drugs that do NOT require a doctor's prescription

Bought off-the-shelf in stores

Regulated by FDA through OTC Drug monographs. OTC drug monographs are a kind of "recipe book" covering acceptable ingredients, doses, formulations, and labeling. Monographs will continually be updated adding additional ingredients and labeling as needed. Products conforming to a monograph may be marketed without further FDA clearance, while those that do not, must undergo separate review and approval through the "New Drug Approval System."

For instance multiple former Rx, now available OTC:
Reflux
Antihistamines
Recently Differin for acne
  Forum: By Share Code

PunkassDerm
Posted on: Nov 27 2017, 12:22 PM


Group: Member
Posts: 418

or...

ASPIS - Greek for shield. Goes nicely with Artemis.

Attached Image



Collectively, SS should have 1 seat on the Board.
  Forum: By Share Code

PunkassDerm
Posted on: Nov 24 2017, 11:31 PM


Group: Member
Posts: 418

In the dark for so many years, SS became my beacon for information. I do not wish to migrate, like to format here and most posters have provide insight I lack on the investment side.

1. Please take note SS moderators, if it's an easy programming fix, let us block certain posters on our own feed. I still choose to hear it all, even distorted balance is balance. I have learned to "manually" ignore the BS unless I can enlighten to the contrary. Else, sounds like an exodus in the works.

2. Or ban repeat offenders that are obviously not contributing to content.

3. Valuable posters, please continue to contribute new information.

13 years, 200K shares...and no voting rights. Take over at 30 usd by Allergan, yes please. I'll just use my gains to buy some Allergan shares.

Cheers,

D
  Forum: By Share Code

PunkassDerm
Posted on: Nov 11 2017, 02:39 PM


Group: Member
Posts: 418

Clinuvel: High Cash Returns - Catalysts For Growth Lined Up

Nov. 10, 2017 5:11 PM ET


https://seekingalpha.com/article/4123549-cl...ts-growth-lined



QUOTE
Summary

Clinuvel closed the first profitable fiscal year end of June, showing an impressive 41.9% of net profitability on 13 million USD sales (Europe only).

Dossier filed with FDA for market approval in US - decision expected by June 2018 or October 2018, unlocking potential of large US market (revenue upside of 80 million USD).

Patent granted for Vitiligo (65-95 million potential patients); patent applied for central nervous system diseases like Parkinson's, Alzheimer's etc. sparks imagination on further growth.
  Forum: By Share Code

PunkassDerm
Posted on: Nov 11 2017, 01:49 PM


Group: Member
Posts: 418

JH

Did a quick literature search and found that there is no consistency, specifically with regards to dementia. Probably not true Alzheimer's but a collection of dementias of various etiologies given "juvenile" designation. "Infantile" "childhood" used as well.


Adrenoleukodystrophy
Alexander disease
Autism (Infantile)
Batten disease
Canavan disease
Juvenile Huntington’s disease
Metabolic diseases
Niemann-Pick Type C
Subacute-sclerosing Panencephalitis (SSPE)
Tay Sachs disease

I did not see the prion diseases listed but should be included. Prions are infectious proteins that causes amyloid plaques, and associated rapid decline "Alzheimer's-like illness. Can be inherited or transmitted like an infection. Scary stuff.

Kuru (cannibals) infectious
Fatal Familial insomnia (FFI) inherited or spontaneous
Creutzfeldt-Jakob disease (CJD) inherited spontaneous or infectious
Gertsmann-Straussler-Scheinker syndrome (GSS) inherited
Scrapie (sheep)
Mad cow

Good catch, yes sloppy although sometimes utilized

I would love to see MSH emerge as treatment for regulation of Parkinson's and the dementias.
  Forum: By Share Code

PunkassDerm
Posted on: Nov 11 2017, 01:23 AM


Group: Member
Posts: 418

Juvenile is a medical term, usually referring to "juvenile onset" or diseases that start in childhood. Refers to all ages before adulthood (18y/o) and a bit more encompassing than pediatric, which connotes children. Commonly used for arthritis and diabetes. Just to clarify, not an ambiguous term.

Early onset means early onset, completely different terms and not interchangeable.

Attached Image

  Forum: By Share Code

PunkassDerm
Posted on: Oct 28 2017, 10:54 PM


Group: Member
Posts: 418

Priority review status it seems not known until application accepted and review starts?


http://clinuvel.com/investors/news/item/50...esse-fda-filing

QUOTE
US REGULATORY STATUS: ORPHAN DRUG AND FAST TRACK DESIGNATION

The FDA has recognised that afamelanotide meets an unmet clinical need and treats a severe genetic condition for patients who are life-long deprived of light. SCENESSE® was granted orphan drug designation by the FDA in 2008 for the treatment of EPP patients and Fast Track Designation (FTD) in 2016, allowing for a ‘rolling review’ of the NDA. The orphan drug designation provides R&D and review incentives for drugs which may not otherwise be commercially viable to develop, while FTD assists to ensure that innovative drugs reach the patient population earlier than would be the case during a standard review process. The ‘rolling review’ under the FTD allows the FDA to start the review of the scientific dossier only when all modules have been submitted and have passed formal validation, a two-month process after submission of the final NDA module.

CLINUVEL obtained a positive FDA answer on acceptance of the current safety data, as the FDA issued a carcinogenicity waiver in 2017.

This year CLINUVEL applied for a Priority Review which would secure a maximum review period of six months, compared to the standard ten months. It is expected that the FDA will answer the request for Priority Review at the start of the review period.

The FDA has initiated a regulatory pilot scheme to involve patients in explaining the impact of diseases on their lives. The Division for Dental and Dermatology Products hosted a scientific workshop on EPP in October 2016.2
  Forum: By Share Code

PunkassDerm
Posted on: Oct 25 2017, 04:19 AM


Group: Member
Posts: 418

October 20, 2014. That was a buy volume day, what we need to see.

659,300 shares CLVLY

Attached Image

  Forum: By Share Code

PunkassDerm
Posted on: Oct 18 2017, 08:27 PM


Group: Member
Posts: 418

This is Artemis (Diana). Is there an Artemis group or pharma?

https://imythology.wikispaces.com/Diana
  Forum: By Share Code

3 Pages (Click to Jump) V   1 2 3 >

Cant find what you are looking for? Show all active topics from the last 3 months


New Posts  New Replies
No New Posts  No New Replies
Hot topic  Hot Topic (New)
No new  Hot Topic (No New)



TERMS OF USE  -  CONTACT ADMIN  -  ADVERTISING