FDA approves novel enzyme therapy for adults with rare and serious genetic disease

The U.S. Food and Drug Administration today approved Palynziq (pegvaliase-pqpz) for adults with a rare and serious genetic disease known as phenylketonuria (PKU). Patients with PKU are born with an inability to break down phenylalanine (Phe), an amino acid present in protein-containing foods and high-intensity sweeteners used in a variety of foods and beverages. Palynziq is a novel enzyme therapy for adult PKU patients who have uncontrolled blood Phe concentrations on current treatment.

"This is a novel enzyme substitution therapy that helps address a significant unmet need in PKU patients who have been unable to control their blood Phe levels with current treatment options," said Julie Beitz, M.D., director of the Office of Drug Evaluation III in FDA's Center for Drug Evaluation and Research. "This new approval demonstrates our commitment to approving advancements in treatment that will give patients living with PKU different options for care."

PKU affects about 1 in 10,000 to 15,000 people in the United States. If untreated, PKU can cause chronic intellectual, neurodevelopmental and psychiatric disabilities. Lifelong restriction of phenylalanine intake through the diet is needed to prevent buildup of Phe in the body, which can cause long-term damage to the central nervous system.

The safety and efficacy of Palynziq were studied in two clinical trials in adult patients with PKU with blood phenylalanine concentrations greater than 600 µmol/L on existing management. Most PKU patients in the Palynziq trials were on an unrestricted diet prior to and during the trials. The first trial was a randomized, open-label trial in patients treated with increasing doses of Palynziq administered as a subcutaneous injection up to a target dose of either 20 mg once daily or 40 mg once daily. The second trial was an 8-week, placebo-controlled, randomized withdrawal trial in patients who were previously treated with Palynziq. Patients treated with Palynziq achieved statistically significant reductions in blood phenylalanine concentrations from their pre-treatment baseline blood Phe concentrations.

The most common adverse events reported in the Palynziq trials included injection site reactions, joint pain, hypersensitivity reactions, headache, generalized skin reactions lasting at least 14 days, pruritus (itchy skin), nausea, dizziness, abdominal pain, throat pain, fatigue, vomiting, cough and diarrhea. Hypersensitivity reactions occurred in most patients, likely due to formation of antibodies to the product.

The most serious adverse reaction in the Palynziq trials was anaphylaxis, which occurred most frequently during upward titration of the dose within the first year of treatment. Because of this serious risk, the labeling for Palynziq includes a Boxed Warning and the product is available only through a restricted program under a Risk Evaluation and Mitigation Strategy (REMS) called the Palynziq REMS Program. Notable requirements of the Palynziq REMS Program include the following:

• Prescribers must be certified by enrolling in the REMS program and completing training
• Prescribers must prescribe auto-injectable epinephrine with Palynziq
• Pharmacies must be certified with the program and must dispense only to patients who are authorized to receive Palynziq
• Patients must enroll in the program and be educated about the risk of anaphylaxis by a certified prescriber to ensure they understand the risks and benefits of treatment with Palynziq
• Patients must have auto-injectable epinephrine available at all times while taking Palynziq

The FDA granted approval of Palynziq to BioMarin Pharmaceutical Inc.