FDA raises questions about Onpattro's efficacy in Alnylam's bid to challenge Pfizer in lucrative heart disease use

Ahead of an important advisory committee meeting, the FDA has raised serious questions about Alnylam’s bid to expand Onpattro into a much larger group of patients with transthyretin amyloidosis (ATTR).

For Alnylam’s Onpattro application in ATTR-cardiomyopathy, the drug’s efficacy data in a phase 3 trial were “small, of questionable clinical meaningful, and may not be detectable by patients,” the FDA’s drug reviewers said in a briefing document (PDF).

The file was prepared for an advisory committee meeting scheduled for Wednesday. The FDA is asking external experts to discuss whether the APOLLO-B trial showed a clinically meaningful effect of Onpattro in ATTR-CM. The agency has set Oct. 8 as the target decision date for this use.

Even if the agency eventually decides to reject Onpattro, Alnylam is awaiting a more important readout in ATTR-CM from its second-generation RNA interference therapy, Amvuttra. Topline data from the HELIOS-B trial are expected in early 2024. With or without Onpattro, Amvuttra represents the company’s main growth driver.

For Onpattro’s APOLLO-B study, Alnylam doesn’t have statistically powered cardiovascular outcomes data. Instead, the company relied on two scores that measure patient’s body function and symptoms; the trial hit statistical significance on both endpoints.

On the primary endpoint, Onpattro improved the distance patients could walk in six minutes by 14.7 meters (48.2 feet) compared with placebo by month 12. But the FDA noted that other cardiovascular disease studies using the same test had yielded improvements of between 22 meters and 90 meters.

On a key secondary endpoint using a patient-reported questionnaire called KCCQ, Onpattro did 3.7 points better than placebo. But the FDA argued that number—for a scorecard with a range of 0 to 100—was simply “small.”

Still, the FDA’s reviewers wondered if Onpattro might deserve a smaller approval—if any—in a subgroup of ATTR-CM patients who’ve already taken a rival drug from Pfizer.

A go-ahead in ATTR-CM would give Alnylam a chance to challenge Pfizer’s blockbuster tafamidis franchise of Vyndaqel and Vyndamax, which together generated $2.4 billion in worldwide sales last year. But in a subgroup analysis of APOLLO-B, the FDA found no evidence of a treatment effect for Onpattro in patients who’re already on background tafamidis. And the Alnylam drug performed numerically worse than placebo in these patients.

As to cariovascular outcomes, while the APOLLO-B trial wasn’t designed to show a significant improvement, results did favor Onpattro there.

By comparison, Amvuttra’s HELIOS-B uses CV outcomes as the primary endpoint. Amvuttra’s less frequent dosing makes it a more favorable option than Onpattro.

Depiste the FDA’s questions, analysts at Evercore ISI and William Blair said in separate notes that they still believe Onpattro could get an FDA approval in ATTR-CM. Both teams cited a favorable benefit-risk profile and the need for more treatment options.

Separately, BridgeBio recently found that its acoramidis has shown a reduction in the risk of CV-related death and hospitalization against placebo in a phase 3 ATTR-CM trial. BridgeBio has said it plans to file for an approval by year end.