Tuesday, November 29, 2011

SNALP Delivery Keeps On Giving: Tekmira Receives OK for Ebola Clinical Studies

On Monday, Tekmira announced that it has received the Green Light from the FDA to go ahead with clinical studies of its SNALP-enabled biodefense candidate for the treatment of Ebola infection. Tekmira is developing TKM-EBOLA under a $140M contract from the US Department of Defense following spectacular results in non-human primates reported last year in The Lancet. Depending on whether you want to count in the stalled TKM-ApoB program or not, this marks the 5th or 6th SNALP-enabled candidate in clinical development, illustrating the strength of this systemic RNAi trigger delivery platform: TKM-ApoB, ALN-VSP02, TKM-PLK1, ALN-TTR01, ALN-PCS02, and TKM-EBOLA.

In other words, 6 of the last 7 systemic RNAi INDs or IND equivalents were for SNALP-enabled product candidates (period: 2008-2011). This plus the unparalleled, strong pre-clinical track record of this platform demonstrating efficient knockdown in the liver, solid tumors, and viral infections not only in rodents, but also a number of non-human primate models supports the notion that Tekmira’s SNALP is the industry’s most advanced and valuable RNAi delivery platform. There are thankfully other promising RNAi delivery technologies lining up behind SNALP, but this is not Lake Wobegon where everybody can be above average

Next Steps for TKM-EBOLA

Since TKM-EBOLA, as a treatment for a disease in which controlled human studies are ethically or practically impossible, is being developed under the Animal Rule, this phase I study will not only have to demonstrate adequate safety, but more importantly yield pharmacokinetic and potentially biomarker data that replicates what is seen in the successful treatment of the pre-clinical animal models of the infection. At the same time, it may be worth trying to test the limits of how long treatment can be delayed after symptom onset in the animal models as a common criticism of these studies is that in the real world it may take some time before Ebola victims are identified and treated. In The Lancet studies, rhesus monkeys received first treatments already 30 minutes after exposure to the virus which may model a needle stick scenario in an Ebola research laboratory, but not exposure of the civilian population e.g. in a subway system. Similarly, achieving similar pre-clinical efficacies with 1mg/kg as with the tested 2mg/kg dose in The Lancet studies may bring it more in line with the clinical SNALP safety experience so far. On the manufacturing front, it would be helpful if Tekmira succeeded in providing SNALP in lyophilized form which would increase its utility in the field.

On the other hand, the fact that the rhesus model seems to closely replicate, if not represent a particularly severe form of the human disease, and the absence of a (experimental) therapy for Ebola that has shown comparable promise, should position TKM-EBOLA well for stockpiling despite any lingering real-world concerns. From an Army point-of-view, as long as it has been shown to be safe and well tolerated in humans, having the most promising treatment as a stand-by for a virus as deadly as Ebola is better than nothing at all, a consideration that may result in stockpiling even before, or in the absence of FDA licensure.

In that regard, TKM-EBOLA will be mainly competing with AVI Biopharma’s morpholino antisense candidate AVI-6002 which is being developed under an essentially identical contract with the DoD. A Nature Medicine paper published last year reported that this candidate was successful in rescuing ~60% of infected rhesus macaques, although this represents a roughly 3-fold increase in risk of dying compared to the highly comparable SNALP studies in The Lancet. Nevertheless, AVI Biopharma still enjoys a slight time advantage as it has already begun phase I safety studies earlier this year. A late-October 2011 update by AVI stated that treatment in the first 5 of 6 dose-escalating cohorts was well tolerated and that the Data Safety Monitoring Board recommended further escalation to the last 9mg/kg cohort. Nevertheless, once years behind the AVI program, Tekmira has done well catching up with the competition.

Importance beyond TKM-EBOLA

Besides representing an invaluable strategic asset for Tekmira (it is earning the company significant hard cash now and revenues from stockpiling may come well ahead of the customary 5-10 years it usually takes a normal drug to navigate the FDA approval maze), the approval of the IND further demonstrates that SNALP is indeed the productive delivery platform that also I have long had hopes for it to be, with applications not only for knockdown in the liver and solid cancers, but also phagocytic cells (an important target cell population for the Ebola indication). It is also a stamp of approval by various regulatory agencies around the world that SNALP (including reliable manufacturing) is fit for clinical development. An IND for ALN-TTR02 and phase I results for ALN-PCS02 are next.

Comment on Roche Partnership with PTC

Roche disclosed today that it has signed a collaboration with PTC Therapeutics for the treatment of Spinal Muscular Atrophy, including a $30M upfront fee for pre-clinical assets. This follows a similar deal by AstraZeneca and PTC in oncology earlier this year. PTC develops a platform for the modulation of post-transcriptional processes using orally available small molecules.

What is disappointing to me is that these are examples of Big Pharma companies with an interest in RNA Therapeutics (note that AstraZeneca has a relationship with Silence Therapeutics for which a go/no-go is imminent), but which feel more comfortable risking their money on a technology based on phenotypic tissue culture screens with considerable uncertainty as to clinical relevance and the safety risks inherent in modulating very general gene regulatory mechanisms, instead of using the much more straight-forward oligonucleotide approaches. The reason? Oral bioavailability and coziness with small molecule chemistry. The fate of these collaborations will be an important test case of whether putting patient convenience and other marketing considerations ahead of what is the scientifically best approach will bring Big Pharma the desired outcome. Of note, only a few months ago, Genzyme handed back PTC a candidate for the treatment of Duchenne Muscular Dystrophy and Cystic Fibrosis after spending more than $100M on it.

My view: Technical success trumps patient convenience when it comes to diseases as severe as SMA, DMD, or cancer.

Interested in the Chinese market for RNAi Therapeutics, but language barriers exist? Get expert help from somebody that understands RNAi.


Dan said...

I just wanted to say thanks for your blog. I would not have been investing in RNAi without it. I admittedly knew very little about any biotechnology companies - let alone RNAi companies - when I started getting to know the landscape. The blog keeps me informed and makes the whole process fun to participate in. Its really nice to have somebody thats knowledgeable in the field share their thoughts and observations. It makes the whole thing accessible to people like me. I am reading your blog from the very beginning to catch up on my history.

Thanks again for making following my investment exciting.


Anonymous said...

Dan I'm very pleased for you finding losing money exciting!Unless you've been buying Silence this past few months anyhting else in the narrow RNAi listed sector has gone only one way.I agree Dirk produces a very good RNAi insight although when you check the history he appears to always be incurably bullish on Tekmira.I've never seen him bullish on any of the others.In the past year or so Tekmira has dropped from $8 to $1.65.

Anonymous said...

To the first Anonymous poster, please don't try to force color-tinted glasses onto Dan. Tekmira management, to its credit, has pretty much lived up to progress projections and pinched the penny fairly well. The only significant mistake, and it has been a BIG one, is they cuddled too closely with Alnylam management. Were it not for Alnylam brandishing Tekmira's IP as its own, Tekmira's price-per-share would be much higher. The current $1.65 pps reflects impatient investors who in the aggregate, on a daily average, have sold 2000 to 8000 shares per day at discounted prices while Roche, Novartis, and a couple of other big pharmas were perceived as running away from RNAi. If Dan is investing in the leaders of RNAi now or recently (e.g., Alnylam and Tekmira), he's timing it right, given recent RNAi progress, and has significant potential upside on his investment. Both Alnylam and Tekmira are very undervalued at current price-per-share.

Dirk Haussecker said...

At least scientifically I believe I have been somewhat validated by, among other developments, this week's IND and last week's TTR results for identifying SNALP as the leading systemic delivery technology.

Until just 9 months ago, Tekmira had been by far the most successful RNAi investment since 2008. I attribute, however, a good part of the dismal performance since and the recent dilution to Alnylam's actions. Maybe I should have foreseen that, but at least I had been increasingly warning 1-2 years ahead of Tekmira filing the lawsuit that Alnylam is taking a little bit too much credit for SNALP for my liking, essentially behaving as if SNALP (and Tekmira) were its own. I also don't think that you can accuse me of just accepting what had happened.

Anonymous said...

Dirk, I would also like to add my thanks for your continued informative posts on this blog. It helps in keeping the focus on the promising scientific progress rather than the cratering share prices. Keep posting!!


Anonymous said...

Well. Dirk's blog pages provide breaking news on RNAi area, editorials and an open forum. Of course, "editorials" are personal opinions, each viewer has to use their own judgement. As a good journalist, Dirk's report was never fictitious. Comments often reveal oposing opinions as it should be. What else can we expect? Keep up the good work for everyone involved, particularly Dirk. As the RNAi field is heating up, we should spread the word on this site to encourage more audience participation. I certainly learned a lot from reading the reports and comments.

Anonymous said...

Hi Dirk,

Thanks for this informative update. As it concerns, RNAi delivery in this field, I did look at you blog re: Arrowhead data post nature article ("the time has passed" comment you reference) in the prior blog's Q&A. It seemed to me your skepticism was more toward CALAA-01 being a good therapeutic, versus the potential of Rondel to be a solid transport system? It also seems that the company feels the real value is with Rondel, as well.

It seems we are awaiting further p1-b data effects on Calando, given a new lower initial dosing schedule to desensitize patients, so as to provide much higher dosing later in the treatment cycle. Anyway, it seems that each tissue type and disease state may require different transport, as well (who else is as far along on solid tumor in the clinic as Calando?), so given ARWR's myriad of transport system's now, would that not provide a possible one-stop shop and furhter de-risk partnering issues?.

I'm still trying to understand why Roche would choose Arrowhead to partner $500M of assets they bought, given all the likely interested suitors out there. It also seems Roche's comfort and understanding of liposomal/SNALP would be much better than the complexity of cyclodextrin/Rondel. I mean they have loaded a tiny company with little cash with roughly 10x the per annum cash burn now, so wouldn't they be possibly accelerating the company's (and their own equity stake's) demise, unless there was some significant prospect of potential for Calando to partner, or etc? I would appreciate any thoughts. Could Roche even be a potential partner seeing how they gave so much up in assets already to them (I know they now have a large equity stake in ARWR)? Seems very confusing out there right now... Keep up the great work and informative commentary. Seems there's been some fairly robust readership and follow up on your blog more recently-maybe a good sign, albeit not statistically significant to the entire investor market. Thanks.

Dan said...

Re: Anonymous comment,

About my enthusiasm...

I don’t find losing money exciting. I find the prospect of a new class of treatments for sick patients exciting. People donate their money all the time to organizations that improve the lives for some of the very people RNAi companies are trying to help. Why can’t I just invest in companies and maybe make a buck or 2 while I’m at it? It keeps me interested in the whole thing to have some skin in the game. I find it sad that your are trying to kill my enthusiasm when new non PhD investors like me are exactly what this industry needs. It needs to capture the promise of a better tomorrow with a new class of medicine. Judging by your sarcastic tone towards me, i suspect you started with the same attitude, but have been jaded by stock prices. I just see the low stock prices as a good time for me to enter the field.

About Tekmira losing share holder value...

I know what I expected with RNAi when I bought into the sector. The stock outcome for many RNAi companies is likely going to be bankruptcy or making it in a big way. I don’t know why any investor would expect any different. It’s not a short term investment where I worry about the ups and down of the share prices. I will lose it all, or make a whole bunch. I invest with the appropriate expectations. Until there is substantial and measurable revenue generated by bringing a drug to market, it will remain volatile. It’s hard to convince people to invest biotech when other(safer and more profitable) stocks are trading at such a discount. All I can do in the meantime is focus on all the exciting science and commentary that Dirk provides us with.

Let’s assume for a moment that the stock market gets over its woes in Europe and people begin to be more optimistic. We see people invest in TKMR and drive the share price up not directly based on any progress with the science. Would you be happy with the bullish Tekmira stance then? He’s bullish on TKMR because he believes in their science. Hes guess about the market is probably just as good as yours and mine - because none of us can predict the attitude of prospective investors. He’s not trying to hide anything. It’s not as though you need to secretly read in-between the lines to find what he thinks about the company. He saw Tekmira making progress with research and data and increased his position with them. If Tekmira goes belly up, was Dirk wrong? Not necessarily. If you run out of money, good science probably won’t save you.

Alnylam is the biggest company and probably gets the most attention in RNAi, and hardly anybody pays attention to THEM. When Tekmiras claim to fame is providing a company that the general public isn’t aware of with technology, you have to be very patient for that to digest into the average persons mind. Rest assured that the casual investor is not staying up to date on RNAi as those that check this blog.

Anonymous said...

Hi Dan,
I think that your comments and observations are quite fair and to the point. I agree with you. Welcome to the world of RNAI. Good luck to everyone here who cares for a new therapy and invests in TKMR and ALNY.

Anonymous said...


Very interesting comments on your latest post. I have a question I would like for you to address. Are any of the RNAi companies looking at the use of Seattle Genetic's or Immunogen's technology to bind RNAi for protection against degradation and delivering it to the desired cell types for release? If feasible, it might be a solution to the problem of delivering RNAi to tissues outside the liver.

Dirk Haussecker said...

Tekmira's collab with Genentech on antibody-targeted SNALPs probably comes closest. As far as I know, Genentech has been collaborating with SGEN on antibody-conjugates and I would not be surprised if Tekmira has been talking to SGEN just because of the geographical proximity (I believe Mark Murray is from Seattle).

FMS said...

Hi, and thanks to Dirk for continuing insight. So, everyone thinks MRNA is dead?

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