Alnylam Pharmaceuticals, Inc. announced that the HELIOS-A Phase 3 study of vutrisiran, an investigational RNAi therapeutic in development for the treatment of transthyretin-mediated (ATTR) amyloidosis, met its primary and baoth secondary endpoints at nine months in patients with hATTR amyloidosis with polyneuropathy. The primary endpoint was the change from baseline in the modified Neuropathy Impairment Score (mNIS+7) at 9 months as compared to historical placebo data from the APOLLO Phase 3 study of patisiran. The two secondary endpoints were changes in quality of life assessed by the Norfolk Quality of Life Questionnaire-Diabetic Neuropathy (Norfolk QoL-DN) and gait speed assessed by the timed 10-meter walk test (10-MWT) compared to historical placebo. Vutrisiran met the primary endpoint (p less than 0.001) and achieved statistically significant results (p less than 0.001) for each of the Norfolk QoL-DN and 10-MWT secondary endpoints. In addition, vutrisiran treatment showed improvement compared to placebo on the exploratory cardiac biomarker endpoint, NT-proBNP (nominal p less than 0.05). Vutrisiran also demonstrated an encouraging safety and tolerability profile. Based on these positive results, the Company plans to submit a New Drug Application (NDA) for vutrisiran with the U.S. Food and Drug Administration (FDA) in early 2021, and to follow with regulatory filings in additional countries, such as Brazil and Japan. The Company plans to submit a Marketing Authorisation Application (MAA) in the EU upon obtaining the results of the 18-month analysis – expected in late 2021 – as previously aligned with the European Medicines Agency (EMA). HELIOS-A (NCT03759379) is a Phase 3 global, randomized, open-label study to evaluate the efficacy and safety of vutrisiran. The study enrolled 164 patients with hATTR amyloidosis with polyneuropathy at 57 sites in 22 countries. Patients were randomized 3:1 to receive either 25mg of vutrisiran (N=122) via subcutaneous injection once every three months or 0.3 mg/kg of patisiran (N=42) via intravenous infusion once every three weeks (as a reference comparator) for 18 months. The primary endpoint is the change from baseline in mNIS+7 score at 9 months1, relative to historical placebo. Secondary endpoints at 9 months are the change from baseline in the Norfolk QoL-DN score and the timed 10-MWT, relative to historical placebo. Changes from baseline in NT-proBNP were evaluated as an exploratory endpoint at 9 months. The efficacy results of vutrisiran in HELIOS-A are compared to historical placebo control data from the landmark APOLLO Phase 3 study, which evaluated the efficacy and safety of patisiran in a patient population similar to that studied in HELIOS-A. Additional secondary endpoints at 18 months will be evaluated in the HELIOS-A study, including change from baseline in mNIS+7, Norfolk QoL-DN, 10-MWT, modified body mass index (mBMI), Rasch-built Overall Disability Scale (R-ODS), and serum transthyretin (TTR) levels. Additional exploratory cardiac endpoint data at the 18-month time point will be evaluated, including NT-proBNP, echocardiographic measures and cardiac amyloid assessments with technetium scintigraphy imaging. Following the 18-month study period, all patients are eligible to receive vutrisiran for an additional 18 months as part of an open-label extension study. Full 9-month results will be presented at a medical conference in early 2021 and topline 18-month results, including further exploratory cardiac endpoint data, are expected to be announced in late 2021. Vutrisiran demonstrated an encouraging safety profile. There were two study discontinuations (1.6%) due to adverse events in the vutrisiran arm by Month 9, both due to deaths, neither of which was considered related to study drug. There were two serious adverse events (SAEs) deemed related to vutrisiran by the study investigator, consisting of dyslipidemia and urinary tract infection. Treatment emergent adverse events (AEs) occurring in 10% or more patients included diarrhea, pain in extremity, fall and urinary tract infections, with each of these events occurring at a similar or lower rate as compared with historical placebo. Injection site reactions (ISRs) were reported in five patients (4.1%) and were all mild and transient. There were no clinically significant changes in liver function tests (LFTs).