Alnylam presented results from their phase 3 ENVISION trial, which assessed givosiran for acute hepatic porphyria (AHP), at the European Association for the Study of the Liver (EASL) International Liver Congress in Vienna, Austria.
ENVISION was a randomized, double-blind, placebo-controlled, global, multicenter study in more than 20 countries to evaluate the efficacy and safety of givosiran in 94 patients with a documented diagnosis of AHPs. Patients were randomized on a 1:1 basis to receive 2.5 mg/kg of givosiran or placebo subcutaneously administered monthly, over a 6-month treatment period. Results demonstrated a 74% mean and 90% median reduction in the primary endpoint measure of annualized rate of composite attacks in patients on givosiran relative to placebo during the six-month double-blind period. In addition, givosiran achieved statistically significant positive results for five of nine secondary endpoints. The overall safety and tolerability profile was described as “encouraging”. Adverse events (AEs) were reported in 89.6% of givosiran patients and 80.4% of placebo patients; serious adverse events (SAEs) were reported in 20.8% of givosiran patients and 8.7% of placebo patients. Of the 94 patients who participated in the trial, 93 enrolled in the open-label extension (OLE) period of the study.
Based on the ENVISION results, the Company plans to complete its rolling submission of a New Drug Application (NDA) and file a Marketing Authorization Application (MAA) in mid-2019.
About Acute Hepatic Porphyria
Acute hepatic porphyria (AHP) refers to a family of rare, genetic diseases and is comprised of four subtypes, each resulting from a genetic defect leading to deficiency in one of the enzymes of the heme biosynthesis pathway in the liver: acute intermittent porphyria (AIP), hereditary coproporphyria (HCP), variegate porphyria (VP), and ALAD-deficiency porphyria (ADP). These defects cause the accumulation of neurotoxic heme intermediates aminolevulinic acid (ALA) and porphobilinogen (PBG), with ALA believed to be the primary neurotoxic intermediate responsible for causing both attacks and ongoing symptoms between attacks. Common symptoms of AHP include severe, diffuse abdominal pain, weakness, nausea, and fatigue. Long term symptoms and complication can include chronic neuropathic pain, hypertension, chronic kidney disease and liver disease. Currently, there are no treatments approved to prevent attacks or to treat the chronic manifestations of the disease.
Givosiran is a subcutaneously administered RNAi therapeutic targeting aminolevulinic acid synthase 1 (ALAS1). Monthly administration of givosiran has the potential to significantly lower induced liver ALAS1 levels in a sustained manner and thereby decrease neurotoxic heme intermediates, aminolevulinic acid (ALA) and porphobilinogen (PBG), to near normal levels. By reducing accumulation of these intermediates, givosiran has the potential to prevent or reduce the occurrence of severe and life-threatening attacks, control chronic symptoms, and decrease the burden of the disease. Givosiran utilizes Alnylam’s Enhanced Stabilization Chemistry ESC-GalNAc conjugate technology, which enables subcutaneous dosing with increased potency and durability and a wide therapeutic index.
Givosiran has been granted Breakthrough Therapy Designation by the U.S. FDA and PRIME Designation by the European Medicines Agency (EMA). Givosiran has also been granted Orphan Drug Designations in both the U.S. and the EU for the treatment of AHP.