Alnylam has achieved full patient accrual in its ENVISION Phase 3 study of givosiran, an investigational RNAi therapeutic targeting aminolevulinic acid synthase 1 (ALAS1) for the treatment of acute hepatic porphyrias (AHPs). Enrollment was completed with 94 AHP patients randomized across 36 sites in 18 countries, surpassing the initial target of approximately 75 patients due to high patient demand.

The company reiterated its previous guidance that it expects to report topline results of the interim analysis by the end of September in support of a potential accelerated approval, and topline results on the primary endpoint of annualized attack rate after six months of treatment in early 2019. The interim analysis is based on lowering of urinary aminolevulinic acid (ALA) levels from approximately 30 patients at three months of treatment as a surrogate biomarker that is reasonably likely to predict clinical benefit. Pending company and FDA review of the program at the time of interim analysis and assuming positive results and acceptable safety, the company continues to expect to submit an NDA at or around year-end 2018, seeking an accelerated approval.

"We’re pleased to have completed enrollment in the ENVISION Phase 3 study, and we’re thankful to the porphyria community for their support in helping to raise awareness about the importance of clinical trials in rare diseases," said Akin Akinc, Vice President and General Manager, Givosiran Program at Alnylam. "The fact that we achieved this important milestone significantly ahead of schedule – in addition to exceeding the initial enrollment target – highlights the urgent demand and high unmet need for novel therapies in this disease setting. We remain committed to advancing givosiran, which we believe has the potential to transform the treatment landscape for patients with AHPs."

The ENVISION Phase 3 trial is a randomized, double-blind, placebo-controlled, global, multicenter study to evaluate the efficacy and safety of givosiran in 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. The primary endpoint is the annualized rate of porphyria attacks requiring hospitalization, urgent healthcare visit or hemin administration at home over the 6-month treatment period. The planned interim analysis will evaluate reduction of a urinary biomarker – ALA – in approximately 30 patients after three months of dosing, as a surrogate endpoint reasonably likely to predict clinical benefit. Key secondary and exploratory endpoints will evaluate reductions in the hallmark symptoms of AHPs, such as pain, nausea, and fatigue, as well as impact on quality of life.

All patients completing the 6-month treatment period are eligible to continue on an open-label extension (OLE) study in which they will receive treatment with givosiran for up to 30 months.

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