Alnylam this morning reported top-line results from a phase
II study of their first clinical candidate based on the GalNAc-siRNA conjugate
delivery technology, ALN-TTRsc for TTR amyloidosis. Accordingly,
average knockdowns of ~85% were seen in the 5mg/kg dose group, thus confirming
the robust potency at around the dose that the company plans to take forward in
later-stage studies.
Such potency, however, came at the apparent expense of relatively frequent injection site reactions (23% of patients), with an additional skin reaction seen outside the area of injection. Moreover, there was a trend towards elevated liver enzymes, a marker of liver toxicity, including one that was adjudicated a serious adverse event (SAE; ~4x ULN deemed mild severity).
Such potency, however, came at the apparent expense of relatively frequent injection site reactions (23% of patients), with an additional skin reaction seen outside the area of injection. Moreover, there was a trend towards elevated liver enzymes, a marker of liver toxicity, including one that was adjudicated a serious adverse event (SAE; ~4x ULN deemed mild severity).
The efficacy data do not come as a surprise given that they
were largely in line with that seen in the phase I study a year ago, which
included the same dose group (5mg/kg) at the same dosing schedule (first 5x
daily, then weekly for 5 weeks). In both
cases average TTR reductions of ~85% were seen, with the difference being that this study involved
23 subjects at this dose (plus 3 subjects at 7.5mg/kg which was not further pursued for undisclosed reasons) while the phase I study involved only 3 comparable subjects.
The efficacy is thus in line with the intravenous ALN-TTR02
which utilizes Tekmira’s liposomal delivery technology and which so far has
been very well tolerated. Critics (aka LNP haters), however, are keen to point out the
use of (transient) immune suppression.
The efficacy of ALN-TTRsc is superior to the antisense compound by ISIS and GSK which
has shown 70% target gene knockdown in a short 4-week phase I study. Assuming maximal knockdown efficacy has not
been reached at this time-point, ISIS-TTRRx is likely to max out between 75 and
80%.
Similar to potency, the injection site reactions were not really a surprise given that in the phase I study this was the most common side
effect. What is new is that there was a
skin reaction that occurred outside the area of injection possibly indicating
systemic immune activation.
The liver enzyme elevations, however, were certainly
new. This could be related to histologic observations of granulations in the cytoplasm of hepatocytes, likely reflecting
storage sites of the fairly stable modified RNAi triggers.
My hope and expectation is that particularly the injection site reactions, but also liver enzyme elevations will
lessen with the lower doses enabled by the more effective second generation ESC GalNAc chemistry. Still, for ALN-TTRsc the safety
profile looks adequate for an indication like FAC (familial amyloidotic
cardiomyopathy), but 23 is still a small number to be sure.
Lastly, if I had to choose between
ALN-TTRsc, ISIS-TTRRx, and ALN-TTR02, I would go with ALN-TTR02 with the best
apparent risk:reward, regardless of whether it's an intravenous procedure or not.
Disclosure: Long ISIS Pharmaceuticals, no positions in Tekmira and Alnylam.
