Pegvaliase Demonstrates Long-Term Safety & Efficacy in Patients with Phenylketonuria


PAL-003 phase 2 extension study of long-term pegvaliase treatment in patients with phenylketonuria demonstrates substantial efficacy in maintaining reduced blood Phe concentration.

Pegvaliase produced meaningful and persistent reductions in mean plasma phenylalanine (Phe) concentration while maintaining a manageable safety profile when used as a long-term treatment in adults with phenylketonuria (PKU), authors of a new study report.

The recessive disorder affects about 1 in 16,500 newborns in the United States and is caused by a phenylalanine hydroxylase deficiency. The enzyme converts Phe to tyrosine, and Phe builds up in the blood and brain. In some patients, these elevated levels of Phe can negatively affect developmental, neurocognitive, and neuropsychiatric processes, according to the study authors.

Even with the current advances in treatment—the American College of Medical Genetics and Genomics recommend lifelong treatment to maintain plasma Phe levels—between 20% and 65% of adults with PKU do not reach full metabolic control. This is due to a variety of factors, such as medication nonadherence, access to care, and limited efficacy of available interventions.

In order to identify the safety, efficacy, and immunogenicity of pegvaliase in adults with PKU, investigators from the University of Utah continued their analysis of the longest duration of pegvaliase treatment, to date. From January 2010 to October 2016, the study participants continued their dosage of pegvaliase from 1 of the 3 parent studies they took part in or started at a higher dose. For each participant, dose level and frequency were adjusted so that a plasma Phe concentration between 60 and 600 μmol/L could be achieved.

For the study, published in the Orphanet Journal of Rare Diseases, investigators increased the mean dose of pegvaliase from 5.3 mg/day in the parent studies to 26.2 mg/day for a mean treatment duration of 167 weeks, the researchers said, adding that two-thirds of the patients received pegvaliase for at least 2 years and about 40% received the treatment for at least 4 years.

In the 68 participants enrolled in the extension study, plasma Phe decreased 58.9 (39%) from baseline to 541.6 (515.5) μmol/L at week 48 of treatment, the authors report. Additionally, 78.7%, 80.0%, and 82.5% of patients were found to achieve plasma Phe concentrations of ≤ 120 μmol/L, ≤360 μmol/L, and ≤ 600 μmol/L, respectively. As the pegvaliase dose increased over time, the average plasma Phe concentration decreased, the authors write.

All participants reported at least 1 adverse events (AE), ranging from mild to moderate in severity. The most common AEs reported included injection-site reaction, injection-site erythema, headache, or arthralgia. Investigators report that the rate of AE decreased from 58.3 events per person-year in the parent studies to just 18.6 events per person-yaer in the extension study.

The researchers did not require the study participants to stick to a specific Phe-restricted diet; however, patients were encouraged to maintain protein intake throughout the duration of the study. This was important, as the investigators wanted to ensure that the patients' protein intake did not influence Phe levels at the study's conclusion.

“I think the general conclusions between Phase 2 and 3 are the same,” Cary O. Harding, MD, professor of Molecular and Medical Genetics, and Pediatrics, and medical director of Biochemical Genetics at Knight Diagnostic Laboratories at Oregon Health & Science University told Rare Disease Report®. While not involved in the study, Dr. Harding has commented on pegvaliase and its efficacy in Rare Disease Report® in the past. “Palynziq [pegvaliase] successfully lowers blood Phe while dietary Phe intake is normal and the safety profile is manageable.”

The study authors said that their findings prove that pegvaliase can support “meaningful and sustained reduction in mean plasma Phe concentration” in these patients.

“Pegvaliase may address an unmet need for many individuals with PKU who have difficulty controlling blood Phe concentration,” the study authors concluded, adding that overall, the safety profile was manageable in the majority of subjects and those patients who were able to continue with long-term treatment saw vast improvement. Almost half of the patients had reached the upper limit of the recommended plasma Phe concentrations at the 4-year mark.

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