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drafter

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Everything posted by drafter

  1. drafter

    BLT

    Im hoping viral load in the tt034 as well as the calimmune patients is what's changed plastic, but after today's aloof message from the chairman i'm not sure it'd be shared with us retail holders when it matters.
  2. drafter

    BLT

    Plastic - i think fair to say the Americans are finally here!
  3. drafter

    BLT

    berkhout's latest paper rnai against HIV. if you haven't been following the CoH trial properly, watch John Rossi's Benitec / HIV video on youtube, then read berkhout's concluding paragraphs. berkhout_RNAi_HIV_251012.pdf
  4. drafter

    BLT

    Here's Dirk's thoughts on ISIS paper - in a nutshell he pretty much thinks it's a pile of the steamy brown stuff. Sunday, September 2, 2012 ISIS ssRNAi Challenge to Gold Standard RNAi Delivery Comes up Short ><http://2.bp.blogspot.com/-lVcduFwNvQY/UEO-O4RVViI/AAAAAAAABXE/8jN4KPRxUeU/s1600/Untitled-1%20copy.jpg The esteemed editors and reviewers of CELL got it wrong this time. Usually, when a high-impact journal like CELL decides to publish back-to-back papers on a given topic, it believes that they mark a turning point of some sort that will be cited all over. In this case (Lima et al.; Yu et al.), the turning point would be nanoparticle, or more precisely SNALP-formulated RNAi delivery 'out', and unformulated, single-stranded RNAi 'in'. For those new to my blog: it is the double-strand feature that is a defining property of the RNAi mechanism. While a single-stranded intermediate is generated in the process, numerous studies, including indeed the one by Lima et al., show that these are contrived, and consequently about 100-fold less potent 'inducers' of RNAi gene silencing. It is therefore surprising that CELL would publish a confirmation of this. What is new though is that the in vivo ssRNAi data involved unformulated ssRNAi application, will previous in vivo ssRNAi work by e.g. Merck involved LNP-mediated delivery (Haringsma et al., 2012; also covered on this blog here), but as detailed below, the efficacy was not impressive. To me, the main point of interest related to chemistry and how this sheds light on the basic RNAi mechanism, which actually made this paper enjoyable to read. For example, the metabolically stable 5'-(E)-vinylphosphonate modification and the positive effect of 2'F on Ago binding. Nevertheless, such biochemical detail is not the groundbreaking stuff that lands you a paper in CELL, but more something for the dedicated aficionado. Does ISIS feel threatened by SNALP delivery? The complexity of SNALP delivery, by which actually the difficulty of re-engineering SNALP technology without access to Tekmira's trade secrets and know-how is meant, is held against the technology also in a commercially competitive sense. If patient outcomes is the main goal, as long as you master complexity, isn't that a good thing, especially in terms of the all-important length of market exclusivity (note that the main cost of SNALP delivery is still the siRNA ingredient)? A common criticism of my writings is that I connect all things to Tekmira's SNALP technology. But read the Lima et al. paper and see for yourself how ISIS equates formulated RNAi delivery with liposomal delivery (start of the abstract e.g.): 'The therapeutic utility of siRNAs is limited by the requirement for complex formulations to deliver them to tissues. If potent single-stranded RNAs could be identified, they would provide a simpler path to pharmacological agents. Here, we describe single-stranded siRNAs (ss-siRNAs) that silence gene expression in animals absent lipid formulation.' Or 'However, in their current state, the therapeutic utility of siRNA is limited by the requirement for complex lipid formulations to deliver siRNA to peripheral tissues (Vaishnaw et al., 2010).' It looks like 1-billion market cap ISIS feels threatened by $40M market cap Tekmira's SNALP technology after all and is a very interested participant in the frivolous patent infringement lawsuit against Tekmira (frivolous for the reason alone that Alnylam expressly congratulated Tekmira on the BMS deal). SNALP requires 1000-10.000-fold less oligonucleotides The assessment that the ssRNAi work by ISIS does not mark a turning point in systemic RNAi delivery is based on simple math. 1000 to 10.000-fold higher amounts of oligonucleotides were required to achieve equivalent knockdowns in mice: conservative 50microgram/kg/month for SNALP vs 50mg/kg/twice a week for ISIS ssRNAi. As with any drug, large doses increase the risk of causing toxicities. In this case, it is particularly the accumulations of large amounts of phosphorothioated oligonucleotides in the liver and kidney that causes such concern. Of course, SNALP LNP delivery is not entirely without its safety issues. For example, in the clinic it still involves the use of transient immune suppression which may e.g. be prohibitive to their use in millions of patients with less severe forms of hypercholesterolemia. Although assuming for a moment that the amount of required oligonucleotides should be irrelevant as long as it was safe, antisense technologies still suffer from poor cost of goods. Last week for example, the CEO of another antisense company, Sarepta Therapeutics (formerly known as AVI Biopharma), wrote in an unsettling Open Letter to the Duchenne Muscular Dystrophy community that the company essentially cannot afford the large, almost nutritional amounts of oligonucleotides that are required for attempting a therapeutic splice correction. Closer to home, instead of acknowledging their current cost of goods, ISIS Pharmaceuticals is only providing estimates for their future oligo manufacturing cost goals. Extrahepatic tissues, which ones please? Another claim by ISIS related to their ssRNAi tech was that it would be applicable beyond the liver ('broadly distributed and active in multiple organs'), also following systemic administration. However, once again, this was directly contradicted by their own data which showed a maximally 35% knockdown (the type of from 100 to 65, not from 100 to 35 mind you) for such a tissue (the kidney) when administering…100mg/kg of oligonucleotides of mice. The accompanying Huntington's Disease paper achieved ssRNAi-mediated knockdown in the brain. This, however, was observed following non-systemic, intraventricular infusion of large amounts of oligonucleotides in small mice brains. Alnylam was right in terminating ssRNAi collaboration Taken together, the publications explain why Alnylam decided two years ago to terminate their ssRNAi collaboration with ISIS. In addition to using Tekmira's intravenously infused SNALP LNPs, Alnylam has been working on GalNAc-siRNA conjugates as a subcutaneously deliverable alternative for gene knockdown in the liver. Although the gene knockdown achievable with that technology still pales in comparison to SNALP LNP, it is about 10-fold more potent than ISIS' ssRNAi, which goes to show that despite the disadvantages in cellular delivery of unformulated, rigid dsRNAs, their dramatically increased potency more than compensates for it. At least Lima and colleagues and I agree on this point (opening statement of the introduction): 'RNA interference (RNAi) is a mechanism by which double-stranded RNA triggers the loss of homologous sequence (Fire et al., 1998).' [Emphasis mine] </h2>
  5. drafter

    BLT

    i reckon Stanley still has RNAi envy, but now starting to smell a little of desparation. That's why he's trying to re-badge his old moudly IP with a shiny new RNAi like cover. But he's being misleading and sneaky as is the norm for this guy - RNAi delivery difficulties is yesterday's news. They've cracked that nut, if the reporters bothered to do their research. And the impotency problem for antisense is still there, unless you want to swallow a bucket of the stuff. and what happened to his claims that ISIS IP owns RNAi? He's dropped that cause it's bollocks, is probably still running interference on the side, and knows he is fast running out of time before the engines fire in both siRNA and shRNA forms of RNAi therapy. Once they light up, the snail paced ISIS tech is going to be very sub standard, and ISIS will need to dig into their cash pile and pay through the nose for RNAi IP just to keep up. just the way i see it.
  6. drafter

    BLT

    Plastic, Ognid sends his regards from HC. Cheers, Drafter (so you're therefore not off the hook on those....was it mojitos?)
  7. drafter

    BLT

    nice one plastic. i'll keep my powder dry sunday. as for benitec, any spare change coming my way will be going toward it whilst it allows me to average down. That said, i'd be happy buying up to 20c right now if the market wants to go there. but we know the market won't budge until they get it in writing.
  8. drafter

    BLT

    not much i suspect. whilst Alny are busy trying to hold their IP together, get siRNA delivery going, and debase other siRNA players and TKM, ddRNAi has just gone straight past the whole siRNA field in the clinic. And doesn't look like slowing down any time soon.
  9. drafter

    BLT

    haha - close Plastic. I'm in a bike race on the 4th.
  10. drafter

    BLT

    aerospace sector?! - maybe after they land a ~$300M deal for say the pain therapeutic and share price goes into orbit
  11. drafter

    BLT

    new study paper from Pfizer regarding the Tacere HCV / TT-034 programme attached (less diagrams so i could get it to upload). note in reference section reference number 35. Pfizer_HCV_Paper_271211.pdf
  12. drafter

    BLT

    actually it's blt that are on my payroll - and i'd be disappointed not to see a return because the science is promising and the ip secured. blt management the other big part of the equation - to date i'm impressed with the strategy being rolled out by Peter French. It's a biotech so I'm prepared of course to play it with a longer timeframe. It's also a specky so i can live without the cash should heaven forbid your prediction of it being the world's biggest con be true (i doubt it), or should it get a legal buffeting again instigated by less than useful folk such as towarnicki (also less than likely nowdays).
  13. drafter

    BLT

    i take it nothing more detail than big pharma anything but finished with RNAi space and all that it entails. anti-sense may find it's place too but it'll be a horses for courses approach. astonishing turn around of biopress sentiment toward RNAi underway
  14. drafter

    BLT

    anyone able to get the full article open on this? http://www.genomeweb.com/rnai/rnai-efforts...c-one-two-years
  15. drafter

    BLT

    well it does - because it will take money to flow before anyone would want to make any transaction, and big pharma won't talk serious until delivery cracked. there a lot of interdependencies, direct and indirect. For the next couple of years at least if not more what's good for Alny is good for Benitec, and good for RNAi. Consider them the Collingwood Football Club of RNAi. if the promise of ddRNAi therapeutics was safely tucked behind a big seemingly impenetrable wall, lately that wall has developed some significant structural cracks. i put this on HC and worth copying it here as very likely this news will impact benitec for the better over the next year or two The Burrill Report (November 28, 2011): Will Alnylam Results Reignite Fervor for RNAi (.MP3,12.74 Mb)
  16. drafter

    BLT

    it's good for anti-sense, and more broadly olignucleotide methods. so much for pfizer shutting Sandwich UK and walking away from their oligonucleotide work. For the anti-sense part of va RNAi note it's on the skin - at least there they can put a much bigger dose to overcome the issue that anti-sense has about 1% of the therapeutic grunt of RNAi. back to pfizer - Catherine Puchuk never lost her job, she is based in Grocon, and she is with the group working on the Tacere HCV program. She issued a paper reporting on the Nucleonics HBV study (at least the data they got - see Dirk's entry on it) some months after Sandwich 'got shuttered' and her details had her at Pfizer Grocon. And as for Pfizer's operation at Sandwhich - they now reduced the cull and have 650 staff staying on...
  17. drafter

    BLT

    funny - the market gets back on it's feet and the specky rearguard stops. it seems to me some folks sooner or later get blurred vision when trying to distinguish the difference between prudent investing, high risk / high reward, and just plain old gambling. there was a lot of selling down while the blue chips were going south, but equally for benitec there's been a hell of a lot getting on board. this is a rip tide. and the incoming tide is being driven by the big advances that have all been made in the last 12 months in benitec's IP, (enabling) its rebooted therapeutic programs, gene therapy, and very recently RNAi being conclusively proven to be systemically delivered and effective, in man. seems to me some investors panic in the rip, and others seem to be diving right in and enjoying the free ride. Rossi, Ken Reed, Mick Graham, et al would not have bothered getting back on board and coming to Sydney two weeks ago if this stock were nothing more than a thin manila folder of a few ASIC forms in a lawyer's drawer. as objective as I can be - the share price Vs the rest of this stock's critical parameters are at the greatest differential they have ever been. big pharma are undoubtedly watching very closely on the sidelines. the biotech press have gone to ground - they've know they now will shortly have to pitch the re-birth of RNAi so shortly after they sold the demise of it. ssRNAi has done sweet naff all for too long, anti-sense has, after what - 20 years?, eeked out a living of sorts. Gene therapy is up and motoring, RNAi is back up on its feet. This stock is both of those. so plastic - will it be pina coladas, or a big hairy pineapple?
  18. drafter

    BLT

    nb P17 comment on Pfizer / Tacere HCV programme - 'close to moving to clinical trial'. This is stating more than just the status quo of the Tacere deal from Jan last year. It's an update of material significance, just without the detail - probably about all Benitec got from Pfizer who now run the programme 100%. Tacere don't. Significant at a time when Pfizer are supposed to be one of the big pharma to have walked away from RNAi.
  19. drafter

    BLT

    i'm still around - HC contributors doing great job of providing updates in the latest research of interest to blt and holders. it's not all pump BS over there - i'd say pretty balanced. you of all people should be following the bigger investment environment for this biotech plastic - it matters. why is the sp so cr*p? - i'm of the opinion it's people selling out to cover their other positions ie: they couldn't afford the spec play anyway. when they are done all the better - as the science for the stock in detail, and the wider picture for RNAi and gene silencing looking better every week. In 2003 it took sp 6months to catch up to reality - why would this be any different. All we can do is our research to work out what that reality is, and try to keep objectivity up there as much as possible with it.
  20. drafter

    BLT

    you'd be specifically talking about Gradalis i think plastic. to everyone's surprise, it seems, they are now underway with patient recruitment for PII for their shRNA employing 'FANG' vaccine for advanced melanoma. See NIH clinical trial website. Their solid tumor trial PI shRNA employing FANG vaccine trial is still recruiting and due for completion mid 2012. The fact is they've kept this work well below the radar, which is 'enigmatically' the same as Calimmune (due to start shRNA HIV PI trial early next year). My understanding is neither of these Co's have to pay a licence until they want to commercialise the drug - but obviously that'll get a hell of a lot dearer as the risk of the drug failing reduces and its prospective market share solidifies. So to me the upside risk is still well there for blt holders. it's almost as if at least two companies have used the so called falling out of love of RNAi (really actually siRNA) by big pharma to keep their profiles low. This would be smart as they don't want to encourage any competition for as long as they can. the crappola sp of late is another strange thing - all of the going's on materially around this stock say it should be going in the other direction. and it can't be a single critical flaw in a single drug or programme, as there are too many totally distinct shRNA programmes and labwork going on around the world all at different stages and many with good progress. where there's money to be had people are likely to be behaving badly is my guess
  21. drafter

    BLT

    maybe it's just come up because there's little else explaining the recent hike for ALNY's sp
  22. drafter

    BLT

    plastic - take overs are more your thing than mine. what do you make of this? http://seekingalpha.com/article/302265-3-b...rce=marketwatch
  23. drafter

    BLT

    interesting paper from the Gradalis folk just published attached fyi. Also - NIH website shows Gradalis are getting ready for PII trial with their 'FANG' shRNA solid tumor vaccine (against advanced melanoma). As far as I know, this is first phase II clinical trial using shRNA. possible licencee for benitec?? RNAi_In_Cancer_Therapy_Gradalis_191011.pdf
  24. drafter

    BLT

    RNAi and small interfering RNAs in human disease therapeutic applications Monica R. Lares, John J. Rossi, http://www.sciencedirect.com/scidirimg/entities/REemail.gif, Dominique L. Ouellet Department of Molecular and Cellular Biology, Beckman Institute at City of Hope, 1500 East Duarte Road, Duarte, CA 91010, USAAvailable online 15 September 2010. Small interfering RNAs (siRNAs) have been shown to effectively downregulate gene expression in human cells, giving them potential to eradicate disease. Prospects for clinical applications are discussed in this review, along with an overview of recent history and our current understanding of siRNAs used for therapeutic application in human diseases, such as cancer and viral infections. Over recent years, progress has been made in lipids, ligands, nanoparticles, polymers and viral vectors as delivery agents and for gene-based expression of siRNA to enhance the efficacy and specificity of these methods while at the same time reducing toxicity. It has become apparent that given the recent advances in chemistry and delivery, RNAi will soon prove to be an important and widely used therapeutic modality. (my emphasis) http://www.sciencedirect.com/science/artic...167779910001253
  25. drafter

    BLT

    no idea what the Rothchild's are doing. Making money somewhere no doubt. the whole RNAi space is moving into a very different phase now. the consolidation Dirk predicted 2 - 3 years ago is now in full swing (note RXi exit), with the genuine IP holders fast becoming the only ones left in the game, and the lightweights out of puff. it's on the far side of the moon now - into clinical trials in humans, and we will need to keep an ear out for when the signals start coming back. Rossi very recently said RNAi as a therapeutic is here to stay. On this battlefield, even though he's outnumbered by journo's and big pharma execs running in one direction, i'm choosing to stick close to him. And he does have the likes of Kay & Baltimore right alongside him.
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