On November 20, the U.S. Food and Drug Administration (FDA) approved givosiran (Givlaari) for adults with acute hepatic porphyria, a genetic disorder resulting in the buildup of toxic porphyrin molecules which are formed during the production of heme.
Richard Pazdur, MD
“This buildup can cause acute attacks, known as porphyria attacks, which can lead to severe pain and paralysis, respiratory failure, seizures, and mental status changes. These attacks occur suddenly, and can produce permanent neurologic damage and death,” said Richard Pazdur, MD, Director of the FDA’s Oncology Center of Excellence and Acting Director of the Office of Oncologic Diseases in the FDA’s Center for Drug Evaluation and Research. “Prior to [this] approval, treatment options have only provided partial relief from the intense, unremitting pain that characterizes these attacks. The drug approved…can treat this disease by helping to reduce the number of attacks that disrupt the lives of patients.”
Efficacy was evaluated in ENVISION, a randomized, double‑blind, placebo‑controlled, multinational trial enrolling 94 patients with acute hepatic porphyria. Patients were randomized 1:1 to receive once-monthly subcutaneous injections of givosiran 2.5 mg/kg or placebo during a 6‑month double‑blind period.
The primary efficacy outcome measure was the rate of porphyria attacks requiring hospitalizations, urgent health-care visit, or intravenous hemin administration at home. The mean rates of attacks over a 6-month time period were 1.9 (95% confidence interval [CI] = 1.3–2.8) for patients receiving givosiran and 6.5 (95% CI = 4.5–9.3) for those on placebo. On average, patients with acute hepatic porphyria treated with givosiran experienced 70% (95% CI = 60%–80%) fewer porphyria attacks compared those treated with placebo.
The most common adverse reactions (> 20% of patients) included nausea and injection site reactions. The label contains warnings for anaphylactic reactions, hepatic and renal toxicities, and injection site reactions. Hepatic toxicity was mostly transaminase elevation, and renal toxicity was mostly serum creatinine elevation and decreases in estimated glomerular filtration rate.
The recommended givosiran dose is 2.5 mg/kg once monthly by subcutaneous injection.