Friday, September 10, 2010

Tekmira Delays Hypercholesterolemia Candidate: 2nd Gen Growing Pains or is it ApoB after all?

Tekmira’s ambition to grow a substantial clinical pipeline suffered a setback when it announced today that the IND for its candidate for the treatment of hypercholesterolemia, TKM-ApoB, has been delayed following a review of pre-clinical data. These data indicated that the ‘performance characteristics of the specific lipid nanoparticle formulation [...] have not met the Company’s expectations for the intended application'. This is the second substantial delay of Tekmira's pioneering ApoB program, and comes after the abandonment of a first ApoB candidate earlier this year.

The press release makes it very difficult to understand what the reason for the delay could have been. Given that LNP-siRNA delivery has been successfully demonstrated in hundreds of non-human primates, I have a hard time believing that they suddenly could not find a formulation that was able to potently knock down ApoB in the IND-enabling large animal studies. Even if they had some problems, it should not have led to an open-ended delay. I also don’t think that they could not get rid of the innate immunostimulatory potential of the siRNA they have been working with, because Tekmira had said that new modification patterns for this siRNA were able to abrogate immune stimulation also in the more sensitive ‘whole blood assay’ that they had developed. On the other hand, a clinically desirable profile for a given indication does consist of many more aspects besides potency and immune issues. Given that 2nd gen formulations are relatively recent, whereas DLinDMA-based 1st gen formulations have been quite thoroughly studied, some 2nd gen-related growing pains might be expected.

There have been questions raised about ApoB as a safe target for the treatment of hypercholesterolemia. Data in the RNAi literature itself and from the clinical program of ApoB-antisense molecule mipomersen (ISIS/Genzyme) show that inhibiting ApoB causes some, and sometimes indeed very significant accumulation of fat in the liver. While the medical importance is not clear yet, fatty liver and associated elevations in liver enzymes have raised some concerns. If Tekmira indeed sees the same toxicities that Mirus/Roche and Alnylam have seen (Marina Biotech and RXi also seem to have given up on ApoB), then it may be in the Company’s best interest to abandon the program. Accordingly, the press release was quick to highlight that the development of the company’s other 2 development candidates, one for solid cancers (TKM-PLK1) and one for Ebola infection (TKM-EBOLA) would be accelerated.

TKM-ApoB is also a particularly challenging indication as hypercholesterolemia is a chronic condition where you would have to safely administer a drug for sustained periods of time. Moreover, the regulatory bar for cardiovascular drug candidates has been raised quite a bit in recent years, especially in the US (outcome studies for most populations and increased safety scrutiny). The acute cancer and infectious disease indications may therefore be clinically more straightforward candidates to develop and, with Ebola, also offer earlier financial returns.

What speaks against the abandonment of ApoB as a target were references in the press release that the company would continue to study other formulations with ApoB. This, however, could also be interpreted as boilerplate or even a political move given that ApoB represents one of the five target picks from Alnylam and for that reason alone Tekmira may want to keep it alive at least on paper.

Overall, I am disappointed that the opportunity for TKM-ApoB to provide unequivocal clinical proof-of-concept data of potent gene knockdown with LNP-siRNA in the near-term will be missed. This now falls on the shoulder of Alnylam’s TTR program.

While clearly a bearish development, today’s news also provide some reason for optimism. One is that the strategic re-organization should be slightly positive for Tekmira’s finances as the new lead programs will be partly (PLK1- probably Alnylam and possible NCI support newly mentioned) and fully (Ebola) funded by others. Moreover, the company understands the importance of credible public relations by admitting to difficulties and calling disappointments what they are. It is also not pushing programs into the clinic because it is attractive to do so in the short-term: bonuses for the achievement of milestones; a relatively strong share price especially good if management does not intend to be there in the long run and a sale of the company was intended, etc- we’ve seen it all.

Just as RNAi Therapeutics was heating up, today is a humble reminder that in drug development setbacks can crop up when they are least expected. It will be important for the company to provide more clarity on today's development in the coming weeks, at least to the extent that it does not compromise their strategic position in RNAi triggers.

22 comments:

Anonymous said...

Their website does not mention SNALP anymore. Donno why.

Kevin CC said...

Dirk,

On their recent conference call, Rosetta stated the arbitration process, involving Prometheus, could last until mid 2011.

Their stock is hovering around $1.15, market cap is $18.25 million and they are going to need more cash heading into 2011. Yet, they have multiple products and should be generating more revenue if not for the dispute with Prometheus.

What are your thoughts on the situation? Is this an opportunity to buy? Finding it tough to gauge without having any idea what the size of the miRNA diagnostic market is.

tettrazini said...

There have been many setbacks in developing RNAI technolgy. The only company that has successfully moved a drug candidate beyond PI is ISIS. Does ISIS' science gain credibilty as others fail to achieve traction in the clinic?

Dirk Haussecker said...

Anon- they have just changed the name for their liposomal delivery tech from SNALP to LNP. That should explain it.

Kevin- I've been asking myself the same question. The all-important question, of course, is how do they address the cash burn, and after that the potentially changing regulatory landscape for laboratory-developed tests. They do have a lot of valuable assets well worth more than $18M one would think.
CFO away for conference call due for religious reasons...does not instill confidence that everything is under financial control.

Tet- difficult to gauge. ApoB did not meet Tekmira's internal expectations. Expectations may differ within companies. But sure, ISIS has much more valuable experience with their technology in the clinic. LNPs are only starting to be explored for this purpose.

Sconehead said...

Anyone else wondering whether the new hire, Paul Brennan, was a factor in today’s ApoB announcement? Here’s the link on Brennan’s hire:
http://drugdelivery.pharmaceutical-business-review.com/news/tekmira_appoints_svp_of_business_development_100909/
Personally, I’ve never been happy with Tekmira’s choice of ApoB as a target. So, I hope they abandon it altogether and focus on cancer and infectious diseases.

bion4maticist said...

you said:
"Data in the RNAi literature itself and from the clinical program of ApoB-antisense molecule mipomersen (ISIS/Genzyme) show that inhibiting ApoB causes some, and sometimes indeed very significant accumulation of fat in the liver."

May I ask you to document your assertion that there is literature which shows that Mipomersen causes significant (by which, I assume you meant clinically significant) accumulation of fat in the liver?

Because that seems to contradict the opinion of the expert lipidemiologists in the most recent Isis conference call who declared the increase to be clinically irrelevant.

Anonymous said...

Hey Dirk,

MRNA is trading up on some volume after this press release. http://phx.corporate-ir.net/phoenix.zhtml?c=83674&p=irol-newsArticle&ID=1470128&highlight=
Any comments either positive or negative?
Warm regards, Joe

Anonymous said...

Tekmira files form 10-f with SEC per Nasdaq filing requirements.

Dirk Haussecker said...

MicroRNA mimics and RNAi delivery: there is obviously added value in employing the various RNAi trigger delivery technologies for the delivery of microRNA mimics which are almost identical in structure.

Anonymous said...

Dirk

I listened to the Rodman presentation and Dr. Murray stated the company has solved the delivery problem. More than a few folks mentioned this to me.

Have they, and if so why isn't the stock at $25 a share.

Jerry said...

Could any US investor who has invested in Silence please share how you did it?
I see a scarily thinly traded ticker on pink sheets (SLNCF.PK) and ticker on London and Frankfurt exchanges. I am not sure I have the fortitude to invest in this way.

Jerry in Vermont

Dirk Haussecker said...

Tekmira...the proof that Tekmira's delivery works for sure in humans is still outstanding. $25 today would therefore probably be a bit too high. But I agree that the pre-clinical data is very promising.

Silence...Not a US investor, but maybe brokerages like Etrade allow you to trade on the local/overseas exchanges (in this case on the AIM in London).

Jerry said...

MARINA

Dirk, From the recent MRNA PR's it would seem they are presenting their platform as serious competition to Tekmira's LNP technology for delivery.
This is from a recent PR:
"...amphoteric liposomal formulations, including the Company's proprietary SMARTICLES® technology, for delivery of siRNAs ..."
In a future installment, could you comment on the basic science and your view of whether delivery is now more competitive?
Jerry

Dirk Haussecker said...

Jerry- you can find my latest opinion on Marina's new liposomal delivery platform here: http://rnaitherapeutics.blogspot.com/2010/07/marina-biotech-continues-to-drive.html

Jerry said...

Thanks for the link on your MRNA thoughts from July--I missed that entry.

I am left wondering how to weigh the relative merits of the delivery technology of MRNA vs TKM. It seems so technical and locked in jargon that even my medical background is clueless about how things will shake out.

It seems to me that a reasonable investment thesis at this point would be that these two companies (and their licensees) have the dominant IP likely to play major roles in RNAi delivery. So, why not invest in both? There are certainly enough targets to go around if they both successfully navigate into human clinical trials. And maybe success of either will float the other. Thoughts?

Anonymous said...

Not sure if anyone has noticed, but ALNY and ISIS are preparing to monetize their investment in Regulus. A recent job posting includes as part of it's job parts and description that they are seeking someone to assist in the preparation of an IPO in the US.

My guess re timing would be 1H 2011.

Tettrazini said...

Hi Dirk, regarding bion4’s question what the literature shows regarding the relationship between inhibiting ApoB and hepatic steatosis here is a journal article demonstrating such does not seem to be a problem in murine models. The article is authored by ISIS scientists and mice are quite different from humans.

http://www.jlr.org/content/46/5/872.full

Anonymous said...

Anonymous, do you have the link to the job posting citing experience in IPOs?

Anonymous said...

Attached is the link to the Regulus job posting for a new Financial Reporting Manager.

http://www.regulusrx.com/careers/details.php?id=48

Job Description Details (Note items are preparation for IPO):

1. Monitor and ensure timely identification and compliance with evolving accounting guidance, provide US GAAP interpretation and prepare technical memorandums that document issues in a clear, logical and comprehensive manner
Create SOX procedures to ensure that Regulus is fully compliant and ready to become a publicly traded organization.

2. Preparing the quarterly and annual reports on Form 10-Q/K and manage the internal and external review for these documents – post IPO

3. Assist in the coordination of annual audit and quarterly review activities of external auditors – post IPO.

4. Create, implement and maintain comprehensive accounting policy documents to improve clarity and consistency

5. Implement and maintain reporting procedures to comply with internal control requirements
Perform continuous assessment of the close process and process re-engineering to reduce the timing to close the financial period
Prepare a full analysis of company contracts

6. Perform stock compensation accounting

7. Participate in other projects as required

Anonymous said...

Hey Dirk,

MRNA had some news today. Please update us on your blog as to how important this might be. Seems to me you are super fast in reporting on Tekmira but a little slow to mention other developments, especially MRNA. I really enjoy this blog and I click here every day to see what you are up to. Warm regards from Joe, Miami Beach.

Dirk Haussecker said...

Marina vs Tekmira- both companies have significant efforts in liposomal siRNA delivery. Marina, however, seems to more and more have ambitions beyond liposomal RNAi Therapeutics, e.g. antisense and diagnostics. I just very much like the scientific literature surrounding Tekmira's delivery technology. It is unique in that regard in the RNAi Therapeutics space.

Joe- I've seen the Marina/Smarticle news. It is not an RNAi Rx candidate so I'm much less likely to dedicate an entry to it. But yes, it is positive for the delivery technology that Marina has just acquired.

On a side not, I've been traveling over the last couple of days, which also explains my being quiet despite mostly good things happening again in RNAi Rx.

Anonymous said...

Thank you Dirk, That answered my question. I appreciate your hard work in maintaining this highly educational blog. I will continue to visit you daily Dirk, as I am always learning something worthwhile reading your excellent blog. TY, Joe, Miami Beach

By Dirk Haussecker. All rights reserved.

Disclaimer: This blog is not intended for distribution to or use by any person or entity who is a citizen or resident of, or located in any locality, state, country or other jurisdiction where such distribution, publication, availability or use would be contrary to law or regulation or which would subject the author or any of his collaborators and contributors to any registration or licensing requirement within such jurisdiction. This blog expresses only my opinions, they may be flawed and are for entertainment purposes only. Opinions expressed are a direct result of information which may or may not be accurate, and I do not assume any responsibility for material errors or to provide updates should circumstances change. Opinions expressed in this blog may have been disseminated before to others. This blog should not be taken as investment, legal or tax advice. The investments referred to herein may not be suitable for you. Investments particularly in the field of RNAi Therapeutics and biotechnology carry a high risk of total loss. You, the reader must make your own investment decisions in consultation with your professional advisors in light of your specific circumstances. I reserve the right to buy, sell, or short any security including those that may or may not be discussed on my blog.