By Tristan Manalac

Pictured: Alnylam headquarters in Cambridge, Massachusetts/iStock, hapabapa
The FDA on Monday denied approval of Alnylam Pharmaceuticals’ siRNA therapy Onpattro (patisiran) for the treatment of cardiomyopathy of transthyretin-mediated amyloidosis.
In its Complete Response Letter (CRL), the regulator said that Alnylam had not provided enough evidence of the therapy’s benefit in the proposed indication. At the same time, the FDA did not flag any problems with patisiran’s clinical safety, drug quality, manufacturing processes or study conduct.
“The CRL indicated that the clinical meaningfulness of patisiran’s treatment effects for the cardiomyopathy of ATTR amyloidosis had not been established,” according to the company’s announcement. In light of the rejection, Alnylam will no long work toward an expanded label for Onpattro in the U.S.
Monday’s CRL runs counter to the recommendations of the FDA’s own panel of external advisers. In September 2023, the Cardiovascular and Renal Drugs Advisory Committee voted 9-3 in favor of patisiran, finding that the siRNA therapeutic’s benefits outweigh its risks for cardiomyopathy of ATTR amyloidosis.
Onpattro is an injectable double-stranded siRNA therapeutic that works by binding to the mRNA molecule that encodes for transthyretin, targeting it for destruction. In ATTR amyloidosis, this mechanism of action results in overall lower levels of the protein, which in turn helps avoid the pathological accumulation of misfolded transthyretin in various organs across the body, including the heart.
The FDA first approved Onpattro in August 2018 to treat polyneuropathy associated with ATTR amyloidosis. Monday’s rejection will not affect this indication, nor will it compromise the commercial supply of Onpattro, according to Alnylam.
The company also intends to keep patisiran available for ATTR-cardiomyopathy patients enrolled in an expanded-access protocol and those in the open-label extension phase of its clinical trial.
To support its bid for a label expansion, Alnylam backed its supplemental New Drug Application (sNDA) with data from the Phase III APOLLO-B trial, which demonstrated that patisiran could significantly improve functional capacity after 12 months compared with placebo. The siRNA therapeutic also boosted health status and quality of life.
Over the weekend, at the 2023 annual meeting of the Heart Failure Society of America, Alnylam presented new data from APOLLO-B’s open-label extension phase, further showing that patisiran could sustain its clinical benefits over 24 months of follow-up.
While Alnylam will no longer seek a label expansion for Onpattro, the company will not stop working on a treatment for cardiomyopathy in ATTR amyloidosis. The Massachusetts biotech is currently running the Phase III HELIOS-B study to evaluate its other RNAi candidate, dubbed vutrisiran, in this indication. Vutrisiran previously won the FDA’s approval in June 2022 for hereditary ATTR with polyneuropathy.