Detailed Genetic Modeling Triggers Change in Hemophilia RNAi Target Gene Selection: ALN-APC Out, ALN-AT3 In

This week, Alnylam presented data for its hemophilia program which aims at providing particularly those patients that have developed antibodies ('inhibitors') against the recombinant factor VIII and IX standard-of-care with a treatment alternative.  After ALN-TTR for TTR amyloidosis, this is the second of the two programs the company wants to focus its internal development resources on.  The presentation, however, showed that the timelines have been delayed due to a change in target gene selection.  So with an IND planned for this program in 2013, it thus appears that the original 5x15^TM, which stated that the company wanted to move 5 clinical candidates into late-stage development by 2015, is more and more turning into a ‘1 out of 5’- if all goes well.  What a difference 18 months can make!

Sarcasm aside, the reason for the change in target gene selection is due to modeling the impact of various degrees of gene knockdown on the desired biological outcome: a 50% knockdown of antithrombin (AT) goes much further in terms of thrombin generation (the biomarker used in the study) than a 50% knockdown of the target gene in ALN-APC, protein C.

The type of detailed genetic analysis behind this realization is actually a very important one that companies should think more about when selecting RNAi target genes.  All too often, target gene selection is based on classical black-and-white gene knockout genetics which can be misleading.  Indeed, the VEGF component in ALN-VSP02 may be one of those. 

In the presentation, Alnylam further emphasized that ALN-AT3 utilizes a conjugate-siRNA approach amenable to subcutaneous administration.  Although the hemophilia community is very familiar with the intravenous route of drug administration, the company essentially claims that this is ‘a highly preferred mode of administration in the setting of hemophilia’.  

Really?  In any case, adopting GalNac-siRNA conjugation as an alternative to the gold-standard SNALP delivery would also make strategic sense for Alnylam.  Alnylam has become overly dependent on Tekmira’s technology to the extent that it apparently/allegedly felt compelled to mis-appropriate the technology which is subject to a high-profile ongoing litigation.  Not a good position to be in when the supplier (and owner) of that technology could pull the plug any day.  

On the other hand, the scientific evidence, particularly the shallow dose response in non-human primates which suggest that antisense-type large amounts of drug would be needed (3-10mg/kg), suggest that just maybe GalNac conjugation is not ready yet for prime time.   . 

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…