FDA Rejects Approval of Alnylam’s sNDA for Patisiran to Treat Cardiomyopathy of ATTR Amyloidosis

Rare Daily Staff

The U.S. Food and Drug Administration issued a Complete Response Letter to Alnylam Pharmaceuticals in response to the company’s supplemental New Drug Application for patisiran for the treatment of the cardiomyopathy of transthyretin-mediated amyloidosis.

Transthyretin-mediated (ATTR) amyloidosis is an underdiagnosed, rapidly progressive, debilitating, and fatal disease caused by misfolded transthyretin (TTR) proteins, which accumulate as amyloid deposits in various parts of the body, including the nerves, heart, and gastrointestinal tract. Patients may present with polyneuropathy, cardiomyopathy, or both manifestations of disease. There are two different forms of ATTR amyloidosis – hereditary ATTR (hATTR) amyloidosis, which is caused by a TTR gene variant and affects approximately 50,000 people worldwide, and wild-type ATTR (wtATTR) amyloidosis, which occurs without a TTR gene variant and impacts an estimated 200,000 to 300,000 people worldwide.

Patisiran is the brand name for Onpattro, which is approved by the FDA for the treatment of the polyneuropathy of hereditary ATTR amyloidosis in adults.

Although the FDA’s Cardiovascular and Renal Drugs Advisory Committee met in September to discuss the supplemental application for patisiran and voted 9:3 that the benefits of patisiran outweighed its risks for the treatment of the cardiomyopathy of ATTR amyloidosis, the FDA said there was insufficient evidence of clinical meaningfulness of patisiran’s treatment effects for the cardiomyopathy of ATTR amyloidosis, and therefore, the sNDA for patisiran could not be approved in its present form. The complete response letter did not identify any issues with respect to clinical safety, study conduct, drug quality or manufacturing.

As a result of the complete response letter, Alnylam will no longer pursue an expanded indication for patisiran in the United States. Alnylam said it will continue to focus on the HELIOS-B phase 3 study of vutrisiran, an investigational RNAi therapeutic subcutaneously administered once every three months in development for the treatment of the cardiomyopathy of ATTR amyloidosis, and ALN-TTRsc04, which utilizes the company’s IKARIA technology, with the potential for greater than 90 percent TTR knockdown with once annual dosing.

“We remain confident in the HELIOS-B phase 3 study of vutrisiran and look forward to sharing topline results in early 2024,” said Yvonne Greenstreet, CEO of Alnylam Pharmaceuticals. “If successful, we believe vutrisiran will offer convenient, quarterly subcutaneous dosing with a therapeutic profile that may potentially include cardiovascular outcome benefits. Beyond vutrisiran, we are excited about the potential for ALN-TTRsc04, which may allow for greater TTR knockdown and less frequent dosing, providing patients with ATTR amyloidosis an optimized treatment regimen.”

The supplemental application for patisiran was supported by positive results from the APOLLO-B phase 3 study in which patisiran met the primary endpoint as well as the first secondary endpoint at Month 12, demonstrating a significant difference compared to placebo in functional capacity, as measured by the 6-Minute Walk Test (6-MWT), and health status and quality of life, as measured by the Kansas City Cardiomyopathy Questionnaire Overall Summary (KCCQ-OS) score, respectively.

New results from an interim analysis of the ongoing open-label extension period of the APOLLO-B phase 3 study demonstrated the sustained treatment effect of patisiran on functional status, health status and quality of life and cardiac biomarkers over 24 months. These findings reinforce the long-term treatment effect of TTR silencing by an RNAi therapeutic in patients with ATTR amyloidosis and provide strong support for the Company’s continued evaluation of vutrisiran and ALN-TTRsc04.

Alnylam said it intends to maintain availability of patisiran for patients with the cardiomyopathy of ATTR amyloidosis who are enrolled in the open-label extension period of the APOLLO-B phase 3 study and patisiran U.S. expanded access protocol.

Photo: Yvonne Greenstreet, CEO of Alnylam Pharmaceuticals