AAN 2021 – Helios backs Alnylam’s sunny forecasts
Full data from the Helios-A trial support vutrisiran’s profile as a more convenient Onpattro, though that’s probably as good as it gets.
Since Alnylam first toplined vutrisiran’s Helios-A study data in January the sellside has marked up forecast revenues for the amyloidosis project by a third. Full data from this phase 3 trial, which is key to the group’s franchise extension, suggest this upgrade to have been justified.
This is despite Alnylam’s strange coyness about how vutrisiran did versus its marketed incumbent, Onpattro, the active comparator in Helios-A. There seems no reason for the company to play down the comparison, and perhaps the bigger concern is that the latest data do not suggest that vutrisiran’s label will include the disease’s cardiomyopathy subtype.
Onpattro, an IV drug, has been sold for the polyneuropathy subtype of hereditary ATTR amyloidosis since 2018. Like Onpattro vutrisiran is an RNAi project, but a key difference is that it is dosed subcutaneously, and thus could be more convenient.
Head to head
Helios-A compared one against the other, and measured change from baseline in nine-month mNIS+7, a score that quantifies impairment due to nerve injury, as primary endpoint.
Despite the trial's active comparator, data Alnylam presented yesterday at the American Academy of Neurology virtual meeting focused on demonstrating how vutrisiran stacked up not against Onpattro but against the placebo cohort from a separate trial, notably Onpattro’s own Apollo study.
As had already been suggested in January, vutrisiran “beat” historical placebo by a wide margin on the primary endpoint, as well as on two key secondary measures: Norfolk QoL-DN score, a patient-reported measure of disease severity, and the 10-metre walk test, with very strong statistical significance (Alnylam’s franchise-extension plan bears fruit, January 7, 2021).
However, how vutrisiran performed against Onpattro was glossed over, and the figures buried towards the end of the group’s presentation. There was no apparent need for this: in Helios-A Onpattro behaved much as it had done in Apollo on the primary endpoint and 10-metre walk, and did numerically worse on the Norfolk score.
Overall the data for the comparator seemed as expected, with Onpattro’s Norfolk score underperformance in Helios-A flattering the effect of vutrisiran numerically.
|Within-trial and cross-trial comparisons of Onpattro and vutrisiran|
|Endpoint||Vutrisiran in Helios-A||Onpattro in Helios-A||Onpattro in Apollo||Placebo in Apollo|
|*p≤0.0003 vs placebo in Apollo. Note: mNIS+7=modified neuropathy impairment score, higher scores indicate more neurologic impairment; Norfolk QOL, higher scores indicate worse quality of life; 10MWT=10-metre walk test.|
Alnylam surely has what it needs to justify vutrisiran’s approval for polyneuropathy subtype amyloidosis. The next questions are to what extent this will cannibalise Onpattro, and whether the group could score a label for the disease’s cardiomyopathy subtype too – a potentially much bigger use.
The answer to the second question appears to be no. Vutrisiran’s effect on cardiac markers in Helios-A were somewhat unconvincing: the nine-month adjusted geometric fold change ratio for NT-proBNP (a measure of cardiac stress) versus historic placebo was 0.60 in Helios-A’s cardiac subpopulation.
The corresponding ratio for Onpattro in Apollo’s cardiac subpopulation was 0.63, according to a supplement published in Circulation. And, crucially, with these data Onpattro failed to secure a cardiomyopathy subtype amyloidosis label.
As for cannibalisation, this is inevitable; while in January sellside 2026 revenue forecasts had stood at $971m for Onpattro and $1.3bn for vutrisiran, three months later the respective numbers are $742m and $1.8bn, according to Evaluate Pharma consensus.
And how Anlylam’s franchise as a whole does in the market will be down to competition against a much bigger fish, Pfizer’s oral Vyndaqel/Vyndamax, which has a broad US amyloidosis label that does include cardiomyopathy.