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 2
nd gen GalNAc to be ‘only' 5x more potent than 1
st
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.
2 comments:
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.
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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