S1169 Twelve-Month Interim Analysis of Efficacy and Safety of Givosiran, an Investigational RNAi Therapeutic for Acute Hepatic Porphyria, in the ENVISION Open Label Extension

Abstract

INTRODUCTION: Acute hepatic porphyria (AHP) is a family of rare genetic diseases due to enzyme defects in hepatic heme biosynthesis. Induction of 5-aminolevulinic acid synthase 1 (ALAS1), the rate-limiting step in heme biosynthesis, can lead to accumulation of toxic heme intermediates 5-aminolevulinic acid (ALA) and porphobilinogen (PBG), causing neurovisceral attacks and chronic manifestations. Givosiran, an investigational RNAi therapeutic, targets liver ALAS1 to reduce ALA/PBG and ameliorate attacks and clinical manifestations. METHODS: ENVISION (NCT03338816) is an ongoing Phase 3 global, multicenter, randomized, placebo-controlled trial, evaluating the efficacy and safety of subcutaneous monthly doses of 2.5 mg/kg givosiran in AHP patients in a 6-month double-blind (DB) period and an open label extension (OLE) period (up to 30 months). During the OLE, patients received either 2.5 mg/kg or 1.25 mg/kg monthly givosiran. Outcome measures included composite annualized attack rate (AAR) requiring hospitalization, urgent care, or IV-hemin at home, ALA/PBG levels, hemin use, daily worst symptoms, and quality of life (QoL). Analyses were descriptive. RESULTS: As of July 23, 2019, 93 patients entered the OLE: 56 (placebo/givosiran = 29; givosiran/givosiran = 27) received 2.5 mg/kg monthly givosiran, and 37 (placebo/givosiran = 17; givosiran/givosiran = 20) received 1.25 mg/kg. In givosiran patients (both doses), median AAR was 1.1 (range: 0–20.5) through Month 12. In placebo patients who crossed over to givosiran in the OLE, median AAR (DB = 10.65; OLE = 1.81) and proportion of attack-free patients (DB = 17.4%; OLE = 42.2%) were similar to the givosiran group in the DB period (median AAR = 1.04; attack free patients = 48.9%). In addition, sustained lowering of ALA/PBG in the OLE was accompanied by reductions in hemin use, daily worst pain and analgesic use, and improvements in QoL. Among patients on givosiran through Month 12, 62% had ≥1 drug-related adverse event (AE) and 3% had ≥1 drug-related serious AE. There were no new AEs leading to discontinuation and no deaths. No new safety concerns occurred in the OLE. There was a trend toward increased efficacy with the 2.5 mg/kg dose compared to 1.25 mg/kg dose, and safety was acceptable at both doses. CONCLUSION: In an ongoing Phase 3 study, givosiran 2.5 mg/kg monthly demonstrated maintenance or enhancement of clinical efficacy and an acceptable safety profile consistent with that observed in the 6-month DB period.