Alnylam Pharmaceuticals reported positive data from a late-stage clinical trial of its investigational RNAi therapeutic givosiran in development to treat acute hepatic porphyria (AHP) and plans to seek approval in the United States and Europe in mid-2019.

AHP refers to a family of rare, genetic diseases characterized by severe and diffuse abdominal pain, weakness, nausea, and fatigue that negatively impact daily functioning and quality of life. There are four subtypes, each resulting from a genetic defect leading to deficiency in one of the enzymes of the heme biosynthesis pathway in the liver. 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. It is often misdiagnosed and currently there are no treatments approved to prevent debilitating attacks or to treat the chronic manifestations of the disease.

Givosiran is Alnylam’s second rare disease treatment based on RNAi, a natural cellular process of gene silencing.  It targets aminolevulinic acid synthase 1.

Givosiran met the primary endpoint of reduction in the annualized rate of composite porphyria attacks compared to placebo. It also met five of nine secondary endpoints with safety and tolerability profiles that the company believes are encouraging based on the fact that this is a disease with a high unmet need.

The late-stage ENVISION study, a randomized, double-blind, placebo-controlled trial, enrolled 94 patients with AHP (including 89 with genetically-confirmed acute intermittent porphyria, the most common subtype of AHP), at 36 study sites in 18 countries around the world, the largest ever interventional study conducted in AHP.

Patients were randomized 1:1 to givosiran or placebo, with givosiran administered subcutaneously at 2.5 mg/kg monthly. The primary endpoint for the study was reduction relative to placebo in the annualized rate of composite porphyria attacks, defined as those requiring hospitalization, urgent healthcare visit, or hemin administration, in patients with AIP over six months.

At six months, givosiran met the primary endpoint in patients with AIP. All the components of the composite primary endpoint and all subgroup analyses for the primary endpoint favored givosiran. Five secondary endpoints also demonstrated statistically significant favorable differences in the givosiran arm compared to placebo.

The remaining four secondary endpoints did not meet the hierarchical threshold for significance and included: daily worst pain, daily worst fatigue, daily worst nausea, and the physical component summary of the SF-12 health survey in AIP patients, a tool for measuring patient-reported outcomes.

Adverse events were reported in 90 percent of patients who received givosiran and 80 percent of placebo patients. Serious adverse events were reported in 10 of the 48 patients given givosiran. One patient discontinued treatment. There were no deaths in the study. At the end of the double-blind period, all the patients still enrolled moved to the open-label extension study to receive monthly subcutaneous injections.

“These positive ENVISION results represent another landmark event in Alnylam’s pioneering efforts to advance RNAi therapeutics as a whole new class of medicines,” said John Maraganore, CEO of Alnylam. “Notably, givosiran is the first GalNAc-conjugate siRNA to achieve positive phase 3 results, and the second example of Alnylam’s R&D strategy bearing fruit due to our focus on genetically validated targets for the advancement of potential high impact medicines.”

Givosiran has received Breakthrough Therapy and Prime designations by the FDA and EMA, respectively, and has Orphan Drug status in the United States and the European Union for the treatment of AHP.

Photo: John Maraganore, CEO of Alnylam.

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