Rare Daily Staff

The U.S. Food and Drug Administration approved Alnylam Pharmaceuticals’ RNAi drug Givlaari for treatment of adults with acute hepatic porphyria, a family of ultra-rare, genetic diseases characterized by debilitating, potentially life-threatening attacks.

Acute hepatic porphyria disproportionately impacts women of working and childbearing age, and symptoms of the disease vary widely. Severe, unexplained abdominal pain is the most common symptom, which can be accompanied by limb, back, or chest pain, nausea, vomiting, confusion, anxiety, seizures, weak limbs, constipation, diarrhea, or dark or reddish urine.

Givlaari is an RNAi therapeutic targeting aminolevulinic acid synthase 1 (ALAS1) for the treatment of adults with AHP. In the pivotal study, Givlaari was shown to significantly reduce the rate of porphyria attacks that required hospitalizations, urgent healthcare visits or IV hemin administration at home compared to placebo. It is Alnylam’s first commercially-available therapeutic based on its Enhanced Stabilization Chemistry ESC-GalNAc conjugate technology to increase potency and durability.

“We believe the approval of Givlaari represents a landmark event for the advancement of precision genetic medicines, providing new hope for patients and their caregivers living with the debilitating manifestations of AHP and unpredictable nature of AHP attacks, as well as for the doctors who diagnose and treat these patients,” said John Maraganore, CEO of Alnylam.

The FDA approval of Givlaari came less than four months after acceptance of the company’s application and was based on positive results from the ENVISION phase 3 study, a randomized, double-blind, placebo-controlled, multinational study of 94 patients with AHP. In ENVISION, AHP patients on Givlaari experienced 70 percent fewer porphyria attacks compared to placebo. Treatment with Givlaari also resulted in a similar reduction in intravenous hemin use, as well as reductions in urinary aminolevulinic acid, and urinary porphobilinogen.

In the pivotal ENVISION study, the most common adverse reactions (reported in at least 20 percent of patients) with Givlaari were nausea (27 percent) and injection site reactions (25 percent). Other adverse reactions seen in patients treated with Givlaari (occurring over 5 percent more frequently than placebo) include rash, serum creatinine increase, transaminase elevations and fatigue. One patient in the Givlaari clinical development program experienced an anaphylactic reaction that resolved with medical management.

“The FDA approval of Givlaari is an important milestone for our community, as we now have a new treatment option for adults living with acute hepatic porphyria,” said Kristen Wheeden, executive director, American Porphyria Foundation. “AHP can have a profound impact on the lives of patients and their families. Porphyria attacks are associated with severe, incapacitating pain, often requiring hospitalization for management. In addition, many patients struggle on a daily basis with chronic symptoms related to their disease.”

Givlaari was reviewed by the FDA under Priority Review and had previously been granted Breakthrough Therapy and Orphan Drug Designations in the United States. Givlaari is currently being reviewed under accelerated assessment by the European Medicines Agency for the treatment of patients with AHP, after receiving Priority Medicines Designation and Orphan Drug designation from the EMA.


Photo: John Maraganore, CEO of Alnylam

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