FDA Expands Use of BioMarin PKU Drug

Rare Daily Staff

The U.S. Food and Drug Administration has granted expanded approval to BioMarin Pharmaceutical for its enzyme substitution therapy Palynziq to include adolescents 12 years of age and older with phenylketonuria, a rare inherited metabolic disorder.

Phenylketonuria (PKU), or phenylalanine hydroxylase (PAH) deficiency, is a genetic condition caused by a deficiency of the PAH enzyme, which is required for metabolizing phenylalanine (Phe)—an essential amino acid present in most protein-containing foods. If this enzyme is lacking in sufficient quantity, Phe accumulates to abnormally high levels in the blood and becomes toxic to the brain, leading to severe complications such as intellectual disability, seizures, tremors, behavioral issues, and psychiatric symptoms.

The condition can be managed with a strict Phe-restricted diet, often supplemented with low-protein modified foods and Phe-free medical formulas. However, maintaining lifelong adherence at the level required for proper metabolic control is difficult for most patients. Dietary management during childhood can prevent major developmental and neurological complications, but poor control in adolescence and adulthood is associated with a range of neurocognitive deficits that significantly affect daily functioning.

Palynziq, a PEGylated form of phenylalanine ammonia lyase, substitutes for the deficient enzyme to break down Phe in the bloodstream, allowing many patients to liberalize their diet.

The expanded approval is supported by results from the pivotal phase 3 PEGASUS trial, which showed that adolescents treated with Palynziq achieved statistically significant reductions in blood Phe levels compared with those managed with diet alone. In the study, 55 adolescents aged 12 to 17 with uncontrolled blood Phe levels above 600 micromoles per liter were randomized to receive either Palynziq or dietary management only. After 72 weeks, participants receiving Palynziq experienced a mean decline from baseline of approximately 473 micromoles per liter, compared with an average reduction of 19 micromoles per liter in the diet-only group—representing a treatment difference of about 409 micromoles per liter.

Palynziq’s safety profile in adolescents is consistent with that observed in adults, with most adverse events occurring during the induction and titration phases and decreasing over time. The most common adverse reactions (≥20% incidence) include injection site reactions, arthralgia, headache, pyrexia, hypersensitivity reactions, dizziness, nausea, vomiting, fatigue, and pain in an extremity. Because of the risk of anaphylaxis, Palynziq is available only through a restricted Risk Evaluation and Mitigation Strategy (REMS) program, and its prescribing information carries a boxed warning outlining key precautions.

“Adolescence is a period of increasing independence and academic demands, and represents a particularly challenging time for individuals with PKU. The ultra-restrictive diet required for PKU management may become unsustainable, and poor blood Phe control leads to adverse neurocognitive outcomes. Palynziq is the only genotype-independent medication which may bring Phe into the normal range while allowing an unrestricted diet,” said Stephanie Sacharow, director of the Dr. Harvey Levy Program for PKU and Related Conditions at Boston Children’s Hospital. “In my clinic we have found that Palynziq treatment adherence is even more successful in teens under age 18, while they are living at home with family support, and this approval allows us to extend this therapeutic option to adolescents who may benefit most.”