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Blog by Dirk Haussecker
Wednesday, July 29, 2015
Alnylam Rushes HBV RNAi Candidate towards Clinic
Alnylam last night revealed their preclinical RNAi candidate for the treatment of HBV infection, ALN-HBV. This is now the third RNAi candidate in development with ARC-520 by Arrowhead Research, the most advanced, blazing the trail with a 3-year first-mover advantage (clinical studies commenced in the first half of 2013) over ALN-HBV. Tekmira’s candidate (TKM-HBV) is the third one in the mix having initiated a phase I study in January of this year.
The main differentiating feature of Alnylam’s candidate is that it involves a single RNAi trigger and can be administered subcutaneously. By contrast, the candidates by Arrowhead and Tekmira involve multi-trigger formulations that are administered intravenously.
Genome coverage and resistance
Before the revelation of ALN-HBV, I was taking a multi-trigger formulation for granted. I thus had expected this to be either the first 2-trigger simple GalNAc-conjugate formulation or, more interestingly, perhaps Alnylam resorting to Tekmira’s LNP technology.
A multi-trigger formulation is desirable for two reasons. Firstly, viruses tend to have a high mutation rate so that selection pressure in the form of drug treatment may promote the growth of resistant strains. In the case of DNA viruses the problem is less the emergence of new sequence variants, but particularly growth of those RNAi trigger-mismatched populations that may pre-exist in the pool of sequences at the time the drug is first given.
Combination treatment with a powerful nuke would prevent the outgrowth of such strains. It remains to be seen, however, whether nukes will end up being part of the HBV cure cocktail in the future. But even in this case, the fraction of mismatched targets may become rate-limiting in terms of maximally achievable knockdown.
Secondly, and related to this issue, HBV isolates come in many different sequence flavors so that with just one RNAi trigger, a few percent (~3% of isolates estimated by Alnylam to be mismatched to ALN-HBV) of the HBV population is expected to either respond much less, or not at all, to ALN-HBV.
ALN-HBV suffers from higher needle burden
Being 3 years behind Arrowhead has seemingly resulted in a quick-and-deficient rushed candidate. It is therefore not surprising that Alnylam is making loud noises regarding the apparent convenience of subcutaneous (ALN-HBV) versus intravenous delivery of the competition (ARC-520, TKM-HBV). But is this really an advantage?
Given that the goal of the knockdown candidates is to facilitate a finite treatment regimen for HBV, I doubt that ALN-HBV would be an at-home treatment. Assuming an every-6-week regimen for ARC-520 and a biweekly regimen for ALN-HBV, the actual needle (and doctor’s office visit!) burden for ALN-HBV is 3x higher than for ARC-520: 15 for ALN-HBV (incl. 3 weekly starting doses) and 5 for ARC-520.
As a busy stock market junky, I would choose ARC520 over ALN-HBV from a convenience point of view alone any day. In addition to the broader sequence coverage, apparent higher potency (based on the mouse episomal model data presented), and the 3-year head-start of ARC-520, the scientific and clinical rationales for developing a candidate like ALN-HBV at this point are not clear to me.
Posted by Dirk Haussecker at 2:43 PM |
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发表于 2015-7-30 14:54
