Regulatory Decision Summary for Amvuttra

This New Drug Submission New Active Substance was filed to obtain market authorization for Amvuttra (vutrisiran sodium subcutaneous injection) as a new active substance for the treatment of hereditary transthyretin mediated amyloidosis (hATTR amyloidosis) in adults. After review, Amvuttra was recommended for the treatment of stage 1 or stage 2 polyneuropathy in adult patients with hereditary transthyretin-mediated amyloidosis (hATTR amyloidosis).

This New Drug Submission for a New Active Substance (NDS-NAS) sought marketing approval for Amvuttra (vutrisiran sodium subcutaneous injection) for the treatment of hereditary transthyretin mediated amyloidosis (hATTR amyloidosis) in adults. Vutrisiran is a second-generation ribonucleic acid interference (RNAi) therapeutic consisting of a synthetic, chemically modified double-stranded small interfering RNA (siRNA) that specifically targets variant and wild-type transthyretin (TTR) messenger RNA (mRNA). Vutrisiran contains a ligand containing three N-acetylgalactosamine (GalNAc) residues to enable targeted delivery of the siRNA to hepatocytes. Through RNA interference, vutrisiran causes the catalytic degradation of TTR mRNA in the liver, resulting in a reduced production of TTR protein, potentially limiting TTR amyloid deposits in tissues. The recommended dosage of subcutaneous (SC) vutrisiran is 25 milligrams (mg), once every 3 months (q3M). Amvuttra is supplied as a single use prefilled syringe with stainless steel 29 gauge needle with a needle shield, and should only be administered by a healthcare professional.

The submission was supported by a single pivotal, randomized, open-label 18-month study evaluating the safety and efficacy of Amvuttra 25 mg SC q3M in patients with hATTR amyloidosis polyneuropathy (Study HELIOS-A). The pharmacodynamic effect of Amvuttra on reducing serum TTR levels was shown to be non-inferior to the within-study patisiran reference arm through Month 18. All efficacy endpoints were measured against an external placebo group from study APOLLO (a pivotal efficacy study with patisiran).

The primary pre-specified efficacy analysis showed a statistically and clinically significant change from baseline favouring Amvuttra over placebo in the modified Neurologic Impairment Score (mNIS+7) after 9 months of treatment (17.0-point improvement, p<0.001), with benefits also sustained after 18 months of treatment (28.6-point improvement, p<0.001). Change from baseline in the key secondary endpoint, change from baseline in Norfolk Quality of Life-Diabetic Neuropathy (QoL-DN) total score, also favored Amvuttra over placebo at Month 9 (16.2-point improvement, p<0.001) and Month 18 (21.0-point improvement, p<0.001). Statistically significant improvements were also detected for other secondary endpoints including the 10-meter walk test (at Month 9 and 18), and the modified body mass index and the Rasch-Built Overall Disability Scale (at Month 18). As no patients with Familial Amyloid Polyneuropathy (FAP) stage 3 were included in study HELIOS-A, the proposed indication was revised to stage 1 or stage 2 polyneuropathy in adult patients with hATTR amyloidosis.

The overall safety profile of Amvuttra was considered favorable. As the safety was informed primarily by the pivotal 18-month trial, limited data was available to address the long-term safety of Amvuttra beyond 18 months. Amvuttra was approved by the United States Food and Drug Administration and European Medicines Agency on June 13, 2022, and September 15, 2022, respectively, thus providing limited post-market experience. Vutrisiran was generally safe and well-tolerated in patients. The most commonly reported adverse events (AEs) were pain in extremities and arthralgia. Important identified potential risks of Amvuttra included vitamin A deficiency, and its associated ocular and reproductive issues. Due to the limited number of patients exposed to vutrisiran in the clinical trials (n = 122), the occurrence and frequency of uncommon AEs remains uncertain. The safety of vutrisiran in pregnant or breast-feeding women, as well as in patients with renal or hepatic insufficiency was not established. The impact of switching from another TTR-reducing agent on the safety and efficacy of Amvuttra also remains unclear, as the prior use of TTR-reducing agents was an exclusion criteria for study HELIOS-A. All concerns have been thoroughly addressed, through labelling and ongoing pharmacovigilance activities. A Risk Management Plan for Amvuttra was submitted to Health Canada by the sponsor, and, following review by the Marketed Health Products Directorate was considered to be acceptable.

Based on the above, the Benefit-Harm-Uncertainty of Amvuttra in the treatment of the polyneuropathy in adult patients with stage 1 and stage 2 hereditary transthyretin mediated amyloidosis (hATTR amyloidosis) was considered favourable. A Notice of Compliance was therefore recommended.

For further details about Amvuttra please refer to the Product Monograph, approved by Health Canada and available through the Drug Product Database.