Alnylam Pharmaceuticals, Inc. announced that the European Commission (EC) has granted marketing authorization for Givlaari (givosiran), an injection for subcutaneous use targeting aminolevulinic acid synthase 1 (ALAS1) for the treatment of acute hepatic porphyria (AHP) in adults and adolescents aged 12 years and older. AHP is an ultra-rare condition in which patients can experience debilitating attacks of severe abdominal pain, vomiting and seizures, which can be life-threatening due to the possibility of paralysis and respiratory arrest during attacks. Many patients also experience chronic symptoms, including pain, which continue to be present between attacks.
The marketing authorization was based on positive data from the ENVISION Phase III trial, a randomized, double-blind, placebo-controlled, global, multicenter study to evaluate the efficacy and safety of givosiran in patients with a documented diagnosis of acute hepatic porphyria (AHP). The primary endpoint was reduction relative to placebo in the annualized rate of composite porphyria attacks, defined as those requiring hospitalization, urgent healthcare visit, or intravenous hemin administration at home, in patients with acute intermittent porphyria (AIP, the most common subtype of AHP) over six months. The trial enrolled 94 patients with AHP, at 36 study sites in 18 countries around the world and is 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. Upon completion of dosing in the double-blind period, all eligible patients (99%) enrolled in the ENVISION open-label extension (OLE) to receive givosiran on an ongoing basis.
In the study, givosiran demonstrated a 74% reduction in the annualized composite rate of porphyria attacks in AIP patients relative to placebo. 50% of patients on givosiran were attack-free during the six-month treatment period as compared to 16.3% of placebo-treated patients. Patient-reported daily worst pain was significantly improved with givosiran vs placebo in patients with AIP (p<0.05). givosiran reduced use of hemin, as well as urinary aminolevulinic acid (ala), and urinary porphobilinogen (pbg). a greater proportion of patients on givosiran reported improvements in their overall health, pain, daily functioning, compared to placebo. the most frequently occurring adverse reactions reported in patients treated with givosiran are injection site reactions (36%), nausea (32.4%) and fatigue (22.5%). other adverse reactions seen in givosiran treated patients (occurring greater than 10% more frequently than placebo) include transaminase elevations, rash and glomerular filtration rate decrease.>0.05).>