Despite an endorsement from an advisory committee, the FDA has come to a different conclusion on the benefit-risk profile for Alnylam’s Onpattro in the rare heart disease transthyretin amyloidosis cardiomyopathy (ATTR-CM).
In a complete response letter, the FDA declined to approve Alnylam’s Onpattro in ATTR-CM, the company said Monday. The decision doesn’t affect Onpattro’s existing indication in another form of ATTR called polyneuropathy that affects the peripheral nerves.
As Alnylam’s second-generation RNA interference therapy, Amvuttra, nears its own phase 3 readout in ATTR-CM, the company said it has decided not to pursue any additional indications for Onpattro in the U.S.
The rebuff also gives Pfizer a reprieve. Had Onpattro received the approval, the drug would have challenged Pfizer’s blockbuster tafamidis, which became the first FDA-approved ATTR-CM treatment in 2019. Tafamidis is sold under the brand names Vyndamax and Vyndaqel.
With the rejection, the FDA surprisingly overruled the opinion of an advisory committee, which last month voted 9 to 3 that Onpattro’s benefit outweighs its risk in ATTR-CM.
During a conference call Monday morning, an “extremely disappointed” Alnylam CEO Yvonne Greenstreet said the FDA’s decision flew in the face of the agency’s prior stance.
The phase 3 trial used to support Onpattro’s application, APOLLO-B, was designed in consultation with the FDA, Greenstreet said. The trial met its primary endpoint, showing a statistically significant improvement for Onpattro takers on a six-minute walk test.
The drug also demonstrated a significant edge over placebo on a patient-reported survey called KCCQ-OS and a trend toward better cardiovascular outcomes.
But the FDA argued that Onpattro’s treatment effect is simply not clinically meaningful. The six-minute walk test also lacks an anchor to corroborate the findings because only a subset of KCCQ-OS metrics directly assesses a patient’s physical function, the FDA has said in its own review.
During an advisory committee meeting last month, independent experts agreed with the FDA that Onpattro’s efficacy was small, with one expert describing it as a “slight breeze.” Eventually, the committee members suggested that the drug’s efficacy outweighs its minimal side effects, but several argued that the Alnylam drug shouldn’t be used as an equal alternative to tafamidis.
Onpattro’s rejection marks a setback for Alnylam, but it’s not the end of the company’s ambitions in ATTR-CM. The RNA interference specialist has always billed Onpattro as a stepstone—or a “bridging strategy,” as Greenstreet called it—to prepare for the launch of Amvuttra.
While Onpattro is given intravenously once every three weeks, Amvuttra is administered under the skin every three months. Efforts are already underway to switch ATTR-PN patients to Amvuttra since the newer med’s approval last year.
Amvuttra’s HELIOS-B trial in ATTR-CM is expected to read out in early 2024. Unlike Onpattro’s APOLLO-B, HELIOS-B uses cardiovascular outcomes—including death and hospitalization—as the primary endpoint. The study is about twice as large and three times as long as Onpattro’s study.
With its convenient quarterly subcutaneous dosing regimen and potential positive outcomes data, Amvuttra could become a “transformative therapy with a market-leading profile” in ATTR-CM, Greenstreet said on the Monday call.
ATTR-CM is a key market for Alnylam. In the first six months of 2023, Pfizer’s tafamidis drugs grew U.S. sales by 46% year over year to reach $818 million. By comparison, the combined global sales of Onpattro and Amvuttra in the same period were $427 million.