3d illustration of a part of an RNA chain to illustrate new RNA therapeutics
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RNA therapeutics pioneers Alnylam have received FDA approval for a new RNAi treatment, Amvuttra (vutrisiran), for the rare disease hereditary transthyretin-mediated (hATTR) amyloidosis.

In 2018, Alnylam was the first company to get a small-interfering RNA (RNAi)-based drug to market with its lead candidate Onpattro (patisiran), also designed to target hATTR amyloidosis.

Since then, Alnylam has had three more RNAi-based therapeutics approved, not including Leqvio (inclisiran), which was initially developed by Alnylam but trialed and marketed by The Medicines Company, a subsidiary of Novartis.

Amvuttra is the first therapy that provides a ‘second generation’ or updated therapy for the same condition. While similar in efficacy, according to the company, it has administration benefits in that it is given by subcutaneously once every three months rather than as an intravenous injection once every three weeks for Onpattro.

The approval is based on 9 months of Phase III study results that show a significant improvement in polyneuropathy, a progressive and hard to treat symptom of the disease. More than 50% of patients given the therapy had reversal or halted progression of their polyneuropathy symptoms.

The study included 164 patients with hATTR amyloidosis, 122 received 25 mg Amvuttra via subcutaneous injection once every three months and 42 received 0.3 mg/kg of Onpattro via intravenous infusion once every three weeks. For compassionate reasons, the placebo group (n=77) results were taken from the initial Phase III study of Onpattro.

Amvuttra met the primary study endpoint, the change from baseline in the modified Neuropathy Impairment Score +7 at 9 months. At the end of the study this score had improved by 2.2 points in the Amvuttra group versus a worsening of 14.8 points in the external placebo group.

The new treatment also met all secondary endpoints in the study including non-inferiority to Onpattro in serum TTR reduction, significant improvement in the Norfolk Quality of Life Questionnaire-Diabetic Neuropathy score and timed 10-meter walk test at study completion. These improvements continued at 18 months after the study began.

Safety and tolerability findings in the study were good, with no drug-related discontinuations or deaths.

“The FDA approval of Amvuttra is very encouraging for the hATTR amyloidosis community, who need additional therapies to address the polyneuropathy of this progressive, life-threatening, multisystem disease,” said Michael Polydefkis, a professor at Johns Hopkins Neurology and an investigator on the Phase III study behind the Amvuttra approval.

“Amvuttra is a new therapeutic option that has demonstrated the potential to halt or reverse polyneuropathy progression in patients with an acceptable safety profile, along with an infrequent, subcutaneous dosing regimen that may also help to improve the disease management experience for patients.”

Amvuttra is currently under review by the European Medicines Agency (EMA), the Brazilian Health Regulatory Agency (ANVISA) and the Japanese Pharmaceuticals and Medical Devices Agency (PMDA).

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