Wednesday, December 10, 2014

Alnylam’s Second-Generation GalNAc Data Impress

Earlier this week at the American Society of Hematology meeting in San Francisco, Alnylam presented first multi-dose knockdown data in humans for its second-generation GalNAc-siRNA conjugate technology (ESC-GalNAc).  Accordingly, an almost 60% knockdown was seen in the first (and so far only) patient dosed at 0.045 mg microgram per kilogram ESC-GalNAc siRNA with the knockdown yet having to reach its nadir.  Moreover, further knockdown benefits are likely to accrue with dosing beyond 3 times weekly as was the case in this study.

At these low doses, no remarkable adverse events were reported, including injection site reactions or increases in liver enzymes which were seen with first-generation GalNAc-siRNAs in humans at much higher doses.

Though the data from this phase I study of ALN-AT3 in hemophilia patients is still early and there will be gene target-dependent differences in knockdown potency, they do support Alnylam’s claim that second generation GalNAc is indeed considerably, as much as 50x more potent than first-generation GalNAcs.  Only last week I had speculated that it may be more appropriate to estimate 2nd gen GalNAc to be ‘only' 5x more potent than 1st gen GalNAcs.

I was wrong.

In non-human primates, ALN-AT3 had an ED90 of 0.5mg/kg with weekly dosing.  Based on the phase I data thus far, I expect the corresponding ED90 dose in humans to be a ~ weekly 0.075mcg/kg 0.075mg/kg for a ~7-fold improvement in potency in humans versus non-human primates, a relative potency improvement that is not seen for first-generation GalNAcs.  Add to this the inherent 5x improved intra-species potency of second- versus first-gen GalNAc (Nair et al 2014), it is indeed possible that ESC-GalNAc enjoy an up to 50x improved potency advantage.

In other words, it should be possible to now achieve highly potent knockdown with a once-monthly dosing regime and sub-1 ml subcutaneous injection volumes. 

The value of this for the ALN-AT3 program, which harnesses a unique mechanism in an otherwise crowded hemophilia field which in general is moving towards less frequent dosing/infusion regimens and less immunogenic molecules, remains to be seen.  The slow enrolment pace of the phase I trial, ~5 hemophilia patients enrolled in 6 months, gives cause for commercial concern.     

The competition

While the improved potency is great for Alnylam, the gene knockdown competition is unlikely to yield the liver to Alnylam.  Highly potent knockdowns are possible with other platforms by Arrowhead, ISIS, Tekmira, and possibly Dicerna, too. Beyond route of administration [subQ for Alnylam GalNAc, ISIS (GalNAc-) ASOs, Arrowhead’s single molecule DPCs, and Dicerna GalNAc versus intravenous for Arrowhead’s 2-molecule DPCs and Tekmira’s SNALP LNPs], differentiation will come from safety/tolerability and dosing frequencies.

The next datapoints in this regard will come from the R&D Day by Dicerna early next week (Dicer-substrate GalNAcs) and the 4mg/kg phase I data from the immensely exciting anti-miR122 program by Regulus Therapeutics (employing GalNAc-antisense chemistry) in January 2015.


Anonymous said...

I had made a comment in your earlier blog that you were wrong in your claim of only 5X improvement in Alnylam's second generation GalNAc over its first generation GalNAc delivery technology. It is great that you admitted that you are wrong. It shows your humility.

I do believe Tekmira will have a hard time to compete for chronic liver targets unless it develops Subq delivery. So far Alnylam is the only company that has a proven Subq delivery in RNAi space and it has substantial lead over competition. It will be tough to dethrone Alnylam from its leadership position.

Anonymous said...

AT3 has the best profile to treat hemophilia and it will prevail in the market if successfully developed. There is nothing in development currently that would challenge the superior drug profile of AT3. The only long term threat I can see to AT3 is the gene therapy.

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