Interim data from the ENVISION Phase 3 trial (NCT03338816) revealed Alnylam Pharmaceuticals’ lead candidate, givosiran, can effectively reduce the levels of a key biomarker of acute hepatic porphyria compared to a placebo.
As of Aug. 22, 2018, approximately 46% of the participants (43/94) had completed at least three months of treatment, during which they received monthly 2.5 mg/kg doses of givosiran or a placebo.
The interim analysis included 41 patients with acute intermittent porphyria (AIP), one with variegate porphyria (VP), and one with hereditary coproporphyria (HCP).
During this period, patients with AIP who were treated with givosiran had significantly less aminolevulinic acid (ALA) in their urine compared to those treated with a placebo.
ALA is one of the major neurotoxic compounds that is accumulated due to genetic mutations that lead to acute hepatic porphyria, and is considered the primary cause of both attacks and ongoing symptoms of these diseases. Given so, reduction of ALA levels is likely to be associated with clinical benefits in these patients.
Givosiran is an investigational RNA-based therapy designed to inhibit the ALAS1 enzyme and prevent the accumulation of toxic molecules that cause acute hepatic porphyria. Acute attacks are usually treated with hemin.
To date, no deaths have been reported during the trial; serious adverse events were experienced by 22% and 10% of patients in both givosiran and placebo groups. One patient who was receiving givosiran discontinued treatment due to a large increase in liver enzyme levels, which was resolved afterward.
“We are pleased and encouraged that the interim analysis of the ENVISION Phase 3 study demonstrated that givosiran treatment was associated with statistically significant lowering of ALA, a disease biomarker reasonably likely to predict clinical benefit,” Akshay Vaishnaw, MD, PhD, president of research and development at Alnylam, said in a press release.
Alnylam plans to discuss these results and the overall benefit-risk profile of givosiran with the U.S. Food and Drug Administration (FDA) to better define the progression of the study and the regulatory path to pursue.
Pending the outcome of the meeting, the company intends to submit a New Drug Application with the FDA around the end of 2018 to support a potential accelerated approval of givosiran as treatment for acute hepatic porphyria.
The FDA has granted givosiran Breakthrough Therapy designation, and the European Medicines Agency (EMA) has given it PRIME designation. Both regulatory agencies have also granted orphan drug status to the therapeutic candidate as treatment for acute hepatic porphyria. These recognitions are expected to expedite the clinical development and regulatory review of givosiran, and facilitate marketing approval.
“If clinical efficacy and acceptable safety are confirmed in the full [ENVISION] study, we believe givosiran has the potential to transform the lives of patients living with acute hepatic porphyria,” Vaishnaw said.
Meanwhile, researchers are going to continue dosing givosiran in the 94 patients who were enrolled in the ENVISION study. Topline results of the full study, including effects of the treatment in the annualized attack rate after completion of six months of treatment, are expected to be announced in early 2019.