FDA OKs Novel Enzyme Therapy for Rare Disease Phenylketonuria

Megan Brooks

May 25, 2018

The US Food and Drug Administration (FDA) has approved pegvaliase-pqpz (Palynziq, BioMarin Pharmaceutical Inc) for adults with phenylketonuria (PKU) whose uncontrolled blood phenylalanine (Phe) concentration is greater than 600 µmol/L on current therapy.

Palynziq, a PEGylated recombinant phenylalanine ammonia lyase enzyme, is the first approved enzyme substitution therapy to target the underlying cause of PKU by helping the body metabolize Phe, the company said in a news release.

"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," Julie Beitz, MD, director of the Office of Drug Evaluation III in the FDA's Center for Drug Evaluation and Research, said in an FDA press statement announcing approval.

"This new approval demonstrates our commitment to approving advancements in treatment that will give patients living with PKU different options for care," added Beitz.

PKU is a rare genetic disease that is diagnosed in roughly 1 in 12,500 neonates in the United States each year. PKU is marked by an inability to metabolize Phe, an essential amino acid found in most foods that contain protein and in some artificial sweeteners. Infants are screened at birth to ensure early diagnosis and treatment. Lifelong dietary restriction to avoid ingestion of Phe is required to prevent buildup of the amino acid in the body. Phe can cause serious, long-term damage to the central nervous system.

The safety and efficacy of Palynziq were demonstrated in two clinical trials in adult patients with PKU whose blood Phe concentrations were greater 600 µmol/L on current therapy. Most PKU patients in the Palynziq trials continued with an unrestricted diet before and during the trials.

The first trial was a randomized, open-label trial in patients treated with increasing doses of Palynziq administered by subcutaneous injection to a target dose of either 20 mg or 40 mg once daily. The second trial was an 8-week, placebo-controlled, randomized withdrawal trial in patients who had previously undergone treatment with Palynziq.

According to the FDA, patients treated with Palynziq achieved statistically significant reductions in blood Phe concentrations from their pretreatment baseline concentrations.

The most common adverse events seen with Palynziq treatment were injection site reactions, joint pain, hypersensitivity reactions, headache, generalized skin reactions lasting at least 14 days, pruritus, nausea, dizziness, abdominal pain, throat pain, fatigue, vomiting, cough, and diarrhea. Hypersensitivity reactions occurred in most patients, likely as a result of the formation of antibodies to the product, the FDA said.

Anaphylaxis was the most serious adverse reaction seen in clinical trials. It occurred most often during upward titration of the dose within the first year of treatment. Because of this risk, the labeling for Palynziq includes a boxed warning, and the product is available only through the Palynziq risk evaluation and mitigation strategy (REMS) program.

Prescribers must enroll in the REMS program, complete training, and prescribe autoinjectable epinephrine with Palynziq. Pharmacies must also be certified with the program and must dispense only to patients who are authorized to receive Palynziq.

Patients must also enroll in the program and receive education about the risk for anaphylaxis from a certified prescriber. In addition, autoinjectable epinephrine must be available to the patients at all times while taking the medication.

The approval of Palynziq comes during National PKU Awareness Month.

"Palynziq has the potential to be a game-changing therapy for adults in the PKU community who have struggled throughout their lives to control their Phe levels, despite rigorous management," Christine Brown, MS, executive director of the National PKU Alliance, said in the BioMarin news release.

The company expects Palynziq to be available in the United States by the end of June.

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