Alnylam’s expansion plan for Onpattro blocked by FDA

Alnylam has abandoned plans to add cardiomyopathy to the label for transthyretin-mediated amyloidosis (ATTR) therapy Onpattro after the FDA turned down its marketing application, going against the recommendations of its own advisors.

Onpattro (patisiran) has been approved in the US since 2018 as a treatment for polyneuropathy caused by ATTR, but Alnylam was hoping to expand its use to include patients with the disease who are experiencing cardiac complications of the disease.

ATTR is characterised by the formation of amyloid fibril deposits in tissues and organs, in the heart in the case of patients with cardiomyopathy, causing the left ventricle to become stiff and weak and raising the risk of heart failure.

Last month, an FDA advisory committee voted by nine to three that the benefits of Onpattro outweighed its risks as a treatment for ATTR cardiomyopathy, despite a briefing document by FDA reviewers that was sceptical of the data supporting the marketing application.

Alnylam said today that the FDA had issued a complete response letter (CRL) for Onpattro, citing “insufficient evidence of clinical meaningfulness” for the data filed in support of the drug, which came mainly from the phase 3 APOLLO-B study.

In that trial, Onpattro met the primary endpoint of a statistically significant improvement in functional capacity, as measured by the 6-minute walk test (6-MWT), compared to placebo, with patients on the drug able to walk almost 15 metres further than the control group at 12 months, and also seeing improvements in health status and quality of life.

The FDA said the differences were small, however, and there seemed to be no benefit for Onpattro when used with Pfizer’s Vyndamax (tafamidis), a widely-used therapy for ATTR cardiomyopathy that, along with sister drug Vyndaqel (tafamidis meglumine), had sales of $2.5 billion last year.

“First and foremost, our hearts go out to patients with the cardiomyopathy of ATTR amyloidosis who are living with a rapidly progressive, debilitating, and fatal disease and face significant unmet need,” commented Yvonne Greenstreet (pictured above), Alnylam’s chief executive.

She added that Alnylam is disappointed by the decision, but, rather than continue to develop Onpattro for this indication, the company will focus on follow-up drug vutrisiran, which is in the phase 3 HELIOS-B trial in ATTR cardiomyopathy with results due in early 2024.

“If successful, we believe vutrisiran will offer convenient, quarterly subcutaneous dosing with a therapeutic profile that may potentially include cardiovascular outcome benefits,” said Greenstreet. Onpattro requires intravenous dosing every three weeks.

She also noted that Alnylam is working on another ATTR therapy – ALN-TTRsc04 – which could offer even greater potency and less frequent dosing.

Onpattro is Alnylam’s top-selling drug, adding $588 million to its top line last year, and the company was hoping that adding cardiomyopathy to its label could push it over the $1 billion threshold.