The FDA has raised significant concerns about Alnylam’s attempt to expand the use of Onpattro for the treatment of transthyretin amyloidosis (ATTR). In a briefing document prepared ahead of an advisory committee meeting, the FDA questioned the efficacy data for Onpattro in a phase 3 trial for ATTR-cardiomyopathy, suggesting that the data were small and of questionable clinical significance.
The FDA has scheduled an advisory committee meeting to discuss whether the APOLLO-B trial demonstrated a clinically meaningful effect of Onpattro in ATTR-cardiomyopathy, with a target decision date of October 8 for this indication.
Despite the FDA’s concerns, Alnylam is awaiting crucial results from its second-generation RNA interference therapy, Amvuttra, in ATTR-cardiomyopathy. Topline data from the HELIOS-B trial are expected in early 2024, and regardless of the outcome for Onpattro, Amvuttra is considered the company’s primary growth driver.
In the APOLLO-B study for Onpattro, Alnylam lacked statistically powered cardiovascular outcomes data and relied on two endpoints related to patient function and symptoms. On the primary endpoint, Onpattro demonstrated a modest improvement in the distance patients could walk in six minutes compared to placebo. However, the FDA noted that similar cardiovascular disease studies had shown greater improvements in patient outcomes.
On a key secondary endpoint measured using the KCCQ patient-reported questionnaire, Onpattro showed a relatively small improvement compared to placebo. The FDA suggested that this improvement was not clinically significant.
The FDA’s reviewers also questioned whether Onpattro might have a role in a subset of ATTR-cardiomyopathy patients who have previously taken Pfizer’s rival drug. In a subgroup analysis, Onpattro did not demonstrate a treatment effect in patients who had received background tafamidis (Pfizer’s drug) and even performed worse than placebo in these individuals. However, the APOLLO-B trial was not designed to show a significant improvement in cardiovascular outcomes, although the results favored Onpattro in this aspect.
Amvuttra is seen as a more favorable option than Onpattro due to its less frequent dosing. Additionally, BridgeBio has reported positive results for its acoramidis in a phase 3 trial for ATTR-cardiomyopathy, with plans to seek approval by the end of the year. These developments highlight the competitive landscape in the ATTR-cardiomyopathy treatment market and the importance of robust clinical data.