Long‐Term Safety and Efficacy of Pegvaliase in Japanese Adults With Phenylketonuria: Final Results of a Phase III Trial

ABSTRACT Phenylketonuria (PKU) is an inborn error of metabolism leading to phenylalanine (Phe) accumulation and consequent neurological, neurocognitive, and psychiatric symptoms. Pegvaliase, a pegylated recombinant phenylalanine ammonia lyase that metabolizes Phe, effectively reduced blood Phe in phase III studies in the United States. This multicenter, open‐label, phase III study (jRCT2080224573) evaluated efficacy and safety of up to 4 years of pegvaliase treatment in 12 adult Japanese participants with PKU (blood Phe > 600 μmol/L). Subcutaneous pegvaliase followed an induction/titration/maintenance dosing regimen up to a maximum of 60 mg/day. After Week 52, diet and pegvaliase dose could be adjusted if blood Phe was ≤ 360 μmol/L. Mean (standard deviation SD) treatment duration was 166.4 (66.5) weeks. At Week 192 ( n = 10), mean (SD) blood Phe was 296.2 (430.7) μmol/L, a 71.2% decrease from baseline, and daily protein intake from intact and medical food was 49.9 (21.4) g (68.0% increase) and 7.6 (16.2) g (64.2% decrease), respectively. All participants had ≥ 1 treatment‐emergent adverse event (TEAE) during induction/titration, most commonly injection site erythema and injection site swelling (83.3% each); nine of 10 had a TEAE during maintenance. Of 395 TEAEs recorded during maintenance, 82 occurred between the 2‐year interim analysis and the 4‐year final analysis. One serious TEAE (allergic arthritis) was considered pegvaliase related. The exposure‐adjusted rate of pegvaliase‐related events was 17.0 per person‐year (41.2 during induction/titration, 8.9 during maintenance). Pegvaliase effectively lowered blood Phe in Japanese participants with PKU, with no new safety issues with long‐term treatment, and many participants were able to liberalize their diet.