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CUV, CLINUVEL PHARMACEUTICALS LIMITED
sharelooker
post Posted: Yesterday, 11:37 PM
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In Reply To: sharelooker's post @ Jan 24 2020, 11:32 PM

The take home message of this publication is that activation of MC1R by MT2 oder SC results in the ignition of multiple pathways in order to slow down or prevent melanoma growth. In XP where different XP-proteins are mutated and cannot do their job properly, other mechanisms like downregulation of COX II, upregulation of PTEN etc. can compensate it. Moreover there will be a protective tan.

In my opinion, it makes perfectly sense to test SC in XP.


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sharelooker
post Posted: Yesterday, 12:08 AM
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Further nice work with NDP-MSH. The peptide was conjugated to the checkpoint blocker avelumab. Checkpoint blockers like avelumab, pembrolizumab, ipilimumab etc. are the most effective drugs against melanoma and other solid tumors. With the targeting effect of NDP-MSH they are even more effective!

QUOTE
A tumor-targeted immune checkpoint blocker


Published online 2019 Jul 22

ABSTRACT
To direct checkpoint inhibition to the tumor microenvironment, while avoiding systemic immune activation, we have synthesized a bispecific antibody [norleucine4, d-Phe7]-melanocyte stimulating hormone (NDP-MSH)-antiprogrammed cell death-ligand 1 antibody (αPD-L1) by conjugating a melanocyte stimulating hormone (α-MSH) analog to the antiprogrammed cell death-ligand 1 to (αPD-L1) antibody avelumab. This bispecific antibody can bind to both the melanocortin-1 receptor (MC1R) and to PD-L1 expressed on melanoma cells and shows enhanced specific antitumor efficacy in a syngeneic B16-SIY melanoma mouse model compared with the parental antibody at a 5 mg/kg dose. Moreover, the bispecific antibody showed increased infiltrated T cells in the tumor microenvironment. These results suggest that a tumor-targeted PD-L1-blocking bispecific antibody could have a therapeutic advantage in vivo, especially when used in combination with other checkpoint inhibitors.

Reviewers: P.S.K., Stanford University and Chan Zuckerberg Biohub; and D.A.S., Yale University.


https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6689898/



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sharelooker
post Posted: Jan 24 2020, 11:32 PM
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QUOTE
Topical MTII Therapy Suppresses Melanoma Through PTEN Upregulation and Cyclooxygenase II Inhibition

Published: 20 January 2020

Abstract: Melanotan II (MTII), a synthetic analogue of the alpha-melanocyte stimulating hormone (α-MSH), has been applied for skin tanning in humans. However, the carcinogenic consequence of topical MTII has been equivocal. This study aims to delineate the anti-neoplastic efficacy and mechanism of MTII using the B16-F10 melanoma model in vitro and in vivo. It was found that, despite a lack of influence on proliferation, MTII potently inhibited the migration, invasion, and colony-forming capability of melanoma cells. Moreover, topical MTII application significantly attenuated the tumor progression in mice bearing established melanoma. Histological analysis revealed that MTII therapy induced apoptosis while inhibiting the proliferation and neovaluarization in melanoma tissues. By immunoblot and immunohistochemical analysis, it was found that MTII dose-dependently increased the phosphatase and tensin homolog (PTEN) protein level while reducing PTEN phosphorylation, which resulted in the inhibition of AKT/nuclear factor kappa B (NFκB) signaling. Consistently, MTII treatment inhibited cyclooxygenase II (COX-2) expression and prostaglandin E2 (PGE2) production in melanoma cells. Finally, studies of antibody neutralization suggest that the melanocortin 1 receptor (MC1R) plays a critical role in MTII-induced PTEN upregulation and melanoma suppression. Together, these results indicate that MTII elicits PTEN upregulation via MC1R, thereby suppressing melanoma progression through downregulating COX-2/PGE2 signaling. Hence, topical MTII therapy may facilitate a novel therapeutic strategy against melanoma.


https://www.mdpi.com/1422-0067/21/2/681/htm


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johnnytech
post Posted: Jan 24 2020, 10:48 PM
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In Reply To: Dr Wally's post @ Jan 24 2020, 08:11 PM

I thought you were referring to when JH said this. I'll try and stay out of your feud then.

JH: "If Clinuvel had been ready to distribute at approval, most US patients would be halfway through their 2nd implant by now. That's quite a missed opportunity, both financially and for the patients who have been patiently waiting in the dark."


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macgyver
post Posted: Jan 24 2020, 09:07 PM
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In Reply To: Dr Wally's post @ Jan 24 2020, 08:11 PM

QUOTE
US distribution will be staged and depending on logistics, training & accreditation, final post-marketing
authorization protocol signed off by the FDA before we will see patients on treatment


The only evidence I've seen of preparation for an impending FDA approval was the increase in operations expenditures (an extra $800k-$1mil was allocated in a quarterly report mid 2019 if my memory serves me correctly). As the above quote indicates (as outlined in the investor conference call on Oct 9th 2019, the same day of the FDA approval announcement), there is still work to do before sales can begin.

Is the post marketing authorisation protocol unique to Clinuvel? Its quite possible that a whole range of drugs can start sales immediately if a post-marketing protocol is not required.

Dr Wally, can you provide evidence that the FDA has hindered Clinuvel's progress with Scenesse at every turn and are still doing so? The onus is on you to provide proof to back your 'accusations', because as it stands, the FDA has approved the drug.

 
Dr Wally
post Posted: Jan 24 2020, 08:11 PM
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In Reply To: johnnytech's post @ Jan 24 2020, 05:44 PM

WTH are you going on about JT? “You’re off your rocker.”

“ I doubt it would’ve been possible to have sales straight after FDA approval, if my understanding ??? is correct that post-marketing protocol has to be worked out first. ”



--------------------
“” The discovery of the endogenous melanocortin agonists in the 1950s have resulted in sixty years of melanocortin ligand research.””

The never ending quest to have Afamelanotide (peptide) accepted for its potent ability to stimulate a natural photoprotective,cancer preventative, therapeutic “tan” was accomplished in 2019.

Regulator ignorance, bias, and stubborn resistance to Scenesse are the primary reasons behind this glacial journey. The evidence should be clear to all by now.
 

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seeva222
post Posted: Jan 24 2020, 06:02 PM
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In Reply To: endymion96's post @ Jan 24 2020, 05:07 PM

And. Many cold weather areas are sunny. Denver(I believe) has more sunshine days than many southern cities.

 
johnnytech
post Posted: Jan 24 2020, 05:44 PM
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In Reply To: Dr Wally's post @ Jan 24 2020, 01:11 PM

What are you going on about? JH just mused outloud that if PW was on the ball, they could have sold the drug day 1 after approval, which is the normal allowed parameters of MA... market authorization. Outside the unusual post MA FDA hoops that CUV unusually has, in most cases there is no barrier to selling day 1. He was just going through the exercise of showing the monetary loss by selling slow.


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endymion96
post Posted: Jan 24 2020, 05:07 PM
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In Reply To: Justinian's post @ Jan 20 2020, 01:39 PM

I live near Washington DC. Its been a pretty mild winter so far. So I imagine farther south would be even warmer.

 
macgyver
post Posted: Jan 24 2020, 02:13 PM
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In Reply To: Dr Wally's post @ Jan 24 2020, 01:11 PM

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