Investigative drug candidate givosiran significantly reduced porphyria attacks in two clinical trials, according to a recent presentation at the European Association for the Study of the Liver (EASL) 53rdAnnual International Liver Congress, in Paris, France.
The presentation on the safety and efficacy data of givosiran in patients with acute hepatic porphyria was titled “Phase 1/2, Randomized, Placebo Controlled and Open Label Extension Studies of Givosiran, an Investigational RNA Interference (RNAi) Therapeutic, in Patients with Acute Intermittent Porphyria.”
Givosiran, an investigational RNA-based therapy developed by Alnylam Pharmaceuticals, was 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.
The U.S. Food and Drug Administration (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 drug candidate as treatment for acute hepatic porphyrias.
Part C of the Phase 1 (NCT02452372) study evaluated the safety and efficacy of givosiran in 17 patients with acute intermittent porphyria (AIP) who experienced recurrent crisis. The patients were initially monitored for three months and those who experienced one porphyria attack were eligible to receive once monthly injections of 2.5 or 5.0 mg/kg givosiran or placebo for six months.
Results showed that givosiran rapidly induced a durable inhibition of ALAS1, resulting in about 80% reduction of ALA and PBG molecules, which are believed to be the main neurotoxic components causing the disease. The lower-tested dose of 2.5 mg/kg promoted a mean reduction of 83% in annualized attack rate and a reduction of 88% of hemin use compared to placebo. Increasing this dose did not result in better outcomes.
Patients who completed the Phase 1 trial had the opportunity to continue treatment with givosiran in the Phase 1/2 (NCT02949830) open-label extension (OLE) study.
Interim data collected until Feb. 26, 2018, showed that at 22 months of therapy, patients were still experiencing a robust beneficial effect from givosiran. Patients who received the investigative drug during the Phase 1 and the OLE trials experienced a mean reduction in attack rates per year of 93% and of annualized hemin use of 94% compared to baseline. Patients who crossed over from placebo to givosiran treatment also showed significant improvements in reduction of relapse rates and hemin use.
About 44% of the patients in the OLE study achieved an annualized attack rate of zero upon a mean treatment duration of 8.5 months.
“We view these new results with givosiran as very encouraging,” Akin Akinc, vice president and general manager of the Givosiran Program at Alnylam, said in a press release. “We believe the clinical activity and overall safety profile for givosiran continue to support an accelerated Phase 3 development plan.”
During the OLE study one patient experienced an allergic reaction to the drug after the third injection. The adverse event was solved with adequate treatment and the patient discontinued the treatment. The most common adverse effects reported in the studies included abdominal pain, nausea, injection site redness and itchiness, headache, fatigue, and inflammation of the nasal cavity and pharynx (nasopharyngitis).
Alnylam is currently recruiting participants for givosiran’s ENVISION Phase 3 trial (NCT03338816). The study is being conducted in more than 20 countries and is expected to enroll about 75 patients with confirmed acute hepatic porphyrias. Visit the trial’s Contacts and Locations page for more information.
The participants will be randomized to receive once monthly 2.5 mg/kg doses of givosiran or a placebo for up to six months of treatment. All patients who complete the six-month treatment period will be eligible to continue treatment on an open-label extension (OLE) study, in which they will receive givosiran therapy for up to 30 months.
“We are pleased to announce today that we expect to enroll the thirtieth patient into ENVISION in the coming weeks in support of the planned interim analysis in mid-2018, which, if positive, would support a potential NDA [New Drug Application] filing for givosiran by end of this year,” Akinc said.
Alnylam is also sponsoring a natural history study (NCT02240784) on acute hepatic porphyria with recurrent attacks. The trial is expected to enroll 700 participants across Europe and the United States.
As of November 21, 2017, 112 patients had been enrolled who were found to experience both acute attacks and chronic symptoms in between attacks, resulting in a diminished quality of life. They had about 3.7 porphyria attacks per year, with mean duration of 7.3 days. About 76% of the cases were resolved with hemin treatment or upon hospitalization.
These preliminary EXPLORE trial data were also presented at the EASL 2018 meeting, in the presentation titled “EXPLORE: A Prospective, Multinational, Natural History Study of Patients with Acute Hepatic Porphyrias (AHPs) with Recurrent Attacks.”