Alnylam Pharmaceuticals has announced that its investigational therapy givosiran achieved the primary efficacy and the majority of secondary endpoints in the ENVISION Phase 3 trial with acute hepatic porphyria patients.
Treatment with givosiran significantly reduced the annualized rate of porphyria attacks requiring hospitalization, urgent healthcare visits, or hemin administration at home — a standard therapy for acute attacks — after six months of treatment compared to a placebo (control).
Additionally, givosiran significantly reduced the levels of aminolevulinic acid (ALA) — a key biomarker of acute hepatic porphyria — at three and six months of treatment, and porphobilinogen (PBG), whose levels increase during an attack or “crisis” of acute porphyria, by month six compared with a placebo.
Givosiran had no positive impact on patients’ daily worst pain, fatigue, or nausea. Also no benefits were seen in overall health-related quality of life, measured with the SF-12 health survey, in patients with genetically confirmed acute intermittent porphyria, the most common subtype of acute hepatic porphyria.
No deaths have been reported during the trial. Serious adverse events were experienced by 20.8% and 8.7% of patients in both givosiran and placebo groups, respectively.
Alnylam will now complete its ongoing submission to the FDA looking for approval of givosiran as a treatment for acute hepatic porphyria, along with a Marketing Authorisation Application by June.
“Patients living with [acute hepatic porphyria] experience debilitating and sometimes life-threatening neurovisceral attacks as well as chronic disease manifestations, which negatively impact their quality of life. We believe the ENVISION results demonstrate a robust therapeutic benefit of givosiran treatment on the debilitating aspects of this disease,” Akshay Vaishnaw, MD, PhD, and president of R&D at Alnylam, said in a press release.
“Based on these results, we believe givosiran has the potential, if approved, to be a transformative medicine for AHP patients and their families,” Vaishnaw said. “We extend our profound thanks to all the patients, investigators, and study staff who participated in the ENVISION study.”
ENVISION (NCT03338816) was a randomized, double-blind, placebo-controlled, multicenter Phase 3 study, evaluating the safety and effectiveness of givosiran compared to placebo in 94 AHP patients (including 89 with acute intermittent porphyria), at 36 sites in 18 countries. Patients were randomized to givosiran, injected into the skin at 2.5 mg/kg monthly or placebo monthly.
Participants who completed the ENVISION trial will move to the ENVISION open-label extension (OLE) study, in which they will be able to continue the therapy for up to 30 months.
Early data from an interim analysis of 41 patients had already shown that patients treated with givosiran had significantly less ALA in their urine compared to those treated with a placebo.
The full results of ENVISION, Phase 3 trial will be presented at the European Association for the Study of the Liver (EASL) International Liver Congress on April 13 in Vienna, Austria.
Givosiran is an investigational RNA interference (RNAi) therapy designed to block the activity of the aminolevulinic acid synthase 1 (ALAS1) enzyme to prevent the accumulation of toxic molecules that cause acute hepatic porphyria.
“These positive ENVISION results represent another landmark event in Alnylam’s pioneering efforts to advance RNAi therapeutics as a whole new class of medicines. 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,” said John Maraganore, PhD, CEO of Alnylam.
“Assuming favorable regulatory review, we very much look forward to adding givosiran as the second product in our global commercialization efforts. Indeed, we believe [this] brings us one important step closer to meeting our Alnylam 2020 goals of building a multi-product, global commercial company with a deep clinical pipeline for continued growth and a robust product engine for sustainable innovation,” Maraganore said.