The FDA has accepted Alnylam’s application for Onpattro in a rare heart disease known as cardiomyopathy of transthyretinamyloidosis (ATTR-CM), a blockbuster territory that Pfizer dominates. But there’s a hitch.
Before making a final ruling on the Onpattro ATTR-CM filing—expected by Oct. 8—the FDA will first convene external experts in an advisory committee meeting to discuss the proposal, Alnylam said Tuesday in a press release. The development comes against Alnylam’s past comments to RBC Capital Markets that it didn’t expect an advisory committee meeting.
But to industry watchers, the FDA’s announcement wasn’t a surprise given the controversies around Onpattro’s clinical data in ATTR-CM. Previously, a phase 3 trial coded APOLLO-B met its primary endpoint, as Onpattro showed a significant benefit over placebo in terms of patient function decline as measured by a six-minute walk test. But a subgroup analysis found almost no improvement among patients who had received Pfizer’s tafamidis drugs—Vyndaqel or Vyndamax.
What’s more, on a secondary endpoint, Onpattro failed to confer a statistically significant benefit compared with placebo on a key outcome marker measuring all-cause deaths, cardiovascular events and change in the six-minute walk test after 12 months.
For its part, Alnylam has argued that the totality of data suggests that Onpattro is beneficial to patients. In its application acceptance letter, the FDA stated that it hasn’t identified any review issues, according to Alnylam's Tuesday press release.
Analysts from RBC and Berenberg previously agreed with Alnylam that the drug can be approved in ATTR-CM based on the APOLLO-B data. However, Berenberg’s Zhiqiang Shu, Ph.D., had pointed to the subgroup analyses and questioned whether Onpattro could commercially challenge Pfizer’s Vyndaqel family of therapies, which ginned up $1.25 billion in the U.S. sales alone in 2022, up 37% year-over-year.
In an investor note earlier this month, a “leading cardiologist in the ATTR-CM space” told Shu that Onpattro’s efficacy appears flat. The expert said he wouldn’t prescribe Onpattro in most patients even if it’s approved because of a lack of clear differentiation over Vyndaqel/Vyndamax.
To be fair, Onpattro’s ATTR-CM indication isn’t the most important piece to Alnylam’s business. All eyes are currently on another phase 3 ATTR-CM trial, dubbed HELIOS-B, for the company’s second-generation RNA interference therapy, Amvuttra.
Alnylam has argued that HELIOS-B will show a clearer signal because it’s twice as large and runs three times as long as Onpattro’s APOLLO-B. To ensure a definite answer, Alnylam plans to wait until the final analysis of HELIOS-B and won’t offer any interim look.
The Amvuttra data are expected in early 2024. Shu’s expert expects a positive readout but once again argued that challenging Pfizer’s Vyndaqel franchise “would require clearing a high bar,” including showing a clear additive benefit to the Pfizer drugs.