Rare Daily Staff

The European Commission has granted marketing authorization to Alnylam Pharmaceuticals for Amvuttra, an RNAi therapeutic for the treatment of the rare and fatal condition hereditary transthyretin-mediated amyloidosis in adult patients with stage 1 or stage 2 polyneuropathy.

Hereditary transthyretin-mediated (hATTR) amyloidosis is an inherited, progressively debilitating disease caused by mutations in the TTR gene. TTR protein is primarily produced in the liver and is normally a carrier of vitamin A. Variants in the TTR gene cause abnormal amyloid proteins to accumulate and damage body organs and tissue, such as the peripheral nerves and heart, resulting in intractable peripheral sensory-motor neuropathy, autonomic neuropathy, and/or cardiomyopathy, as well as other disease manifestations. The median survival is 4.7 years following diagnosis, with a reduced survival (3.4 years) for patients presenting with cardiomyopathy.

Amvuttra is an RNAi therapeutic, which is designed to target and silence specific messenger RNA, blocking the production of wild-type and variant TTR protein before it is made. Amvuttra utilizes Alnylam’s delivery platform, designed for increased potency and high metabolic stability to allow for quarterly, and potentially biannual, subcutaneous administration. Vutrisiran is also in development for the treatment of ATTR amyloidosis with cardiomyopathy, which encompasses both hereditary ATTR and wild-type ATTR amyloidosis.

The EC approval is based on positive 18-month results from the HELIOS-A phase 3 study, where Amvuttra significantly improved the signs and symptoms of hATTR amyloidosis, with more than 50 percent of patients experiencing halting or reversal of their polyneuropathy manifestations.

“Although the considerable research into hATTR amyloidosis over the past few years has resulted in a more positive outlook for those diagnosed with the condition, there remain unmet needs in treatment for patients living with this rapidly progressive, multi-system disease,” said David Adams, head of the Neurology department at Bicêtre hospital AP-HP at the University of Paris-Saclay and lead investigator for the HELIOS-A Study. “Results from the HELIOS-A study have shown the potential Amvuttra has to benefit patients with hATTR amyloidosis with stage 1 or stage 2 polyneuropathy, whilst also helping reduce treatment burden through subcutaneous dosing once every three months.”

HELIOS-A was a global, randomized, open-label, multicenter, phase 3 study that evaluated the efficacy and safety of Amvuttra across a diverse group of patients with hATTR amyloidosis with stage 1 or stage 2 polyneuropathy. Results of the HELIOS-A study were published in the journal Amyloid in July 2022.

In the HELIOS-A study, Amvuttra met the primary and all secondary endpoints of the study at both 9 months and 18 months, demonstrating reversal in neuropathy impairment and an encouraging safety and tolerability profile. Amvuttra demonstrated improvement in the mean change from baseline in modified Neuropathy Impairment Score + 7 (mNIS+7) at 18 months (the primary endpoint for the EU), as compared to external placebo data from the landmark APOLLO phase 3 study of patisiran.

After 18 months of dosing, the most frequently occurring adverse reactions in Amvuttra-treated patients were arthralgia (joint stiffness) and pain in extremity (pain in arms and legs). Other less frequent adverse reactions reported with Amvuttra were dyspnea (shortness of breath), injection site reaction and an increase in blood alkaline phosphatase (a liver enzyme).

Vutrisiran was previously granted Orphan Drug designation in the European Union and United States for the treatment of ATTR amyloidosis and in Japan for transthyretin type familial amyloidosis with polyneuropathy. In June 2022, the U.S. Food and Drug Administration approved Amvuttra for the treatment of the polyneuropathy of hATTR amyloidosis in adults. Vutrisiran is under review by the Brazilian Health Regulatory Agency and the Japanese Pharmaceuticals and Medical Devices Agency.