Thursday, September 8, 2011

Tekmira’s SNALP Delivery Technology Yields yet another Development Candidate: ALN-APC for Hemophilia

You will see this theme continue: Systemic RNAi delivery technologies that have proven themselves in non-human primate and clinical studies will continue to yield pipeline candidates and attract potential partners. Today’s announcement by Alnylam at the Annual OTS Meeting that it has chosen SNALP-enabled ALN-APC targeting the liver-expressed Protein C in hemophilia as its 5x15TM development candidate no. 4 confirms this.

As a reminder, and despite of Alnylam’s claims of SNALP being only one of its many systemic delivery options, all four of Alnylam’s nominated 5x15TM candidates are based on Tekmira’s SNALP technology, which also means that 5 out of 6 of Alnylam’s development candidates are SNALP-based (in temporal order): ALN-VSP02, ALN-TTR, ALN-PCS, ALN-HPN, ALN-APC. Only Alnylam’s (historical) first candidate, the aerosolized naked and unmodified ALN-RSV01 is not a SNALP product. Add to this Tekmira’s own TKM-ApoB, TKM-PLK1, and TKM-EBOLA development candidates, and one can see the promise of RNAi Therapeutics become reality [correction September 9, 2011: the Huntington's program should have been noted here, although that one in some regards is quite similar to ALN-RSV01].

ALN-APC is indicated for the treatment of hemophilia patients, especially those that have developed resistance to their first-line therapy in the form of inhibitory antibodies against their recombinant protein replacements. As activated Protein C shifts the hemostatic balance towards bleeding, knocking this exclusively liver-expressed gene down is predicted to reduce the propensity of hemophilia patients to bleed. This, importantly, is also suggested by human genetics as there are apparently hemophilia patients that have a genetic resistance against or deficiency in Protein C, and consequently have less frequent bleeding compared to hemophilia patients without these concomitant mutations. Boding well for the safety of this approach, especially a concern when one starts to meddle with coagulation, these patients do not have a known increased risk of thrombosis.

Tekmira’s SNALP technology, as predicted based on strong science, is leading the way in this pipeline expansion paradigm by targeting particularly liver, but also solid tumor-expressed genes in a variety of diseases. The only other systemic RNAi delivery technology that has about reached the stage where one can feel comfortable similarly entering new pipeline candidates is Silence Therapeutics’ Atuplex technology for knocking down genes in vascular endothelial cells.

RNAi Therapeutics development does not have to be complicated. The simple trick is to let science lead the way…


Anonymous said...

Hi Dirk:

I did not find either in Alnylam's Press release or in their presentation that ALN-APC uses Tekmira's SNALP delivery technology. Are you dreaming! Liposomes were first described by British haematologist Dr Alec D Bangham in 1961 (published 1964), at the Babraham Institute, in Cambridge. Since then there are more than dozen different liposomal drug delivery systems are in the clinic. What makes you think that Alnylam is using SNALP for ALN-APC. Though Tekmira was advanced in the manufacture of LNPs for the delivery of siRNA that does not mean they are the only one in the world to know how to manufacture formulations.
Keep dreaming Dirk!
Good luck with your investment in Tekmira!

Anonymous said...

Anonymous - what a good example of an unqualified comment (at least in my humble opinion, sorry). You might know something about Liposomes (from Wikipedia?)but certainly nothing about SNALP/LNP/Lipoplexes and Protiva's developments at that time. But I might be wrong and you are telling us that Alnylam is using Lipidoids for ALN-APC... Keep on playing with your BlackBerry!

Anonymous said...

Hello Dirk,

A good "hollywood:twist"! I wonder if you will be kind enough to share your information source. You surely know a lot more than the press release.

Dirk Haussecker said...

You give me too little credit. Liver-expressed gene, ED50 of 0.02mg/kg, persistent silencing following single can bet your house that it is a liposomal formulation, and I'm sure what will be entered into the clinic is not using a 'lipidoid', but using something from the allegedly misappropriated SNALP-line of research (MC3 would be my guess) that Alnylam would like to claim for itself now.

Anonymous said...

They did indicate LNP formulated siRNA. Could it be the new generation of lipidoid they announced last year? The new generation lipidoid do have lower ED50.

Dirk Haussecker said...

You are right. These guys can be confusing: "the LNP-formulated siRNA achieved 90 percent silencing of protein C mRNA within 24 hours with effects lasting for over two weeks."

If it's LNP, it's NOT going to be from the lipidoid line of research.

Anonymous said...

1st gen SNALP has been a failure (TKM-ApoB, ALN-VSP). It's only the 2nd gen lipid materials that might give it a chance to work in the clinic.

And MC3 misappropriated by Alnylam? More like misappropriated by former-Protiva management wanting to claim someone's work for themselves.

Unknown said...

check this press release then

Unknown said...

We and our collaborators continue to achieve major breakthroughs in systemic delivery of RNAi therapeutics. Some key highlights from the OTS meeting include the discovery of a novel class of third generation LNPs, so-called 'reLNPs,' that show dramatic improvements in therapeutic index based on our current analysis. Further, we are excited about the MD1 lipid discovered in our MIT collaboration resulting in LNPs with gene silencing potency of approximately 0.002 mg/kg, approaching picogram/kilogram levels and setting a new benchmark," said John Maraganore, Ph.D., Chief Executive Officer of Alnylam. "Moreover, we have now achieved a robust performance level for our conjugate platform that enables clear translation into the clinic. Specifically, our GalNAc-siRNA conjugates demonstrate potent, dose-dependent, and durable target gene silencing with subcutaneous administration at single digit milligram/kilogram dose levels. We now fully expect this platform to deliver clinical candidates for the future."

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