New Treatment Approved for Rare Genetic Disorder, Acute Hepatic Porphyria

The FDA has approved a new treatment for adult patients with acute hepatic porphyria (AHP) a rare genetic disorder. Givlaari is an RNA interference therapeutic targeting aminolevulinic acid synthase 1.

AHP is a family of ultra-rare, genetic diseases that manifest as debilitating, potentially life-threatening attacks and, for some patients, they negatively impact daily functioning and quality of life. AHP results in a buildup of toxic porphyrin molecules, which are formed during the production of heme, which helps to bind oxygen in the blood.

“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 neurological damage and death,” 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, said in a statement. “Prior to today’s approval, treatment options have only provided partial relief from the intense unremitting pain that characterizes these attacks. The drug approved today can treat this disease by helping to reduce the number of attacks that disrupt the lives of patients.”

Givlaari’s approval comes 4 months after FDA accepted the New Drug Application, and it was based on the ENVISION phase 3 study in 94 patients with AHP. Patients who received Givlaari experienced 70% fewer porphyria attacks compared with placebo.

The most common adverse events (AEs) were nausea (27%) and injection site reactions (25%). Other AEs included rash, serum creatinine increase, transaminase elevations, and fatigue.

“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,” John Maraganore, PhD, chief executive officer of Alnylam Pharmaceuticals, said in a statement.

Tied to the approval of Givlaari, Alnylam announced a new framework for value-based agreements to help patients gain access to the treatment. Under the agreements, participating government and commercial payers would only pay the full value of the therapy if the outcomes in the real-world setting were similar to results demonstrated in the clinical trials.

In addition, a prevalence-based adjustment would trigger rebates to participating payers if the number of diagnosed patients they cover exceeds current epidemiologic estimates for AHP. This approach would offer greater certainty to payers that their financial risk will be adjusted if they are treating a substantially larger number of patients that currently estimated.

"Harvard Pilgrim applauds Alnylam’s efforts to help us manage plan members’ costs if the number of patients treated exceeds initial forecasts based upon existing prevalence models,” Michael Sherman, MD, chief medical officer at Harvard Pilgrim, said in a statement. “This prevalence-based adjustment framework may become a model approach for ultra-rare diseases where few or no therapies have previously existed and where diagnosis rates are uncertain.”

Givlaari’s annual wholesale price tag will be $575,000, according to Bloomberg. Use of the treatment would reduce frequency of attacks and lower, or avoid, the cost of hospitalizations and other interventions, according to Alnylam.