Clinical practice considerations for restarting pegvaliase in adults with phenylketonuria

To provide key considerations and best practices for restarting pegvaliase based on real-world experiences of healthcare professionals managing individuals with phenylketonuria (PKU).

An in-person advisory board with 11 experienced PKU practitioners identified strategies for restarting pegvaliase after a treatment pause. The advisors presented real-world restart cases detailing treatment history, reasons for discontinuation, restart approach, and outcomes, followed by discussions about best practices for clinical decision-making.

Among 11 restart cases, reasons for treatment discontinuation included adverse events (AEs) (3 cases), limited blood phenylalanine (Phe) response (4 cases), clinical trial participation (1 case), and pregnancy (3 cases). Time off treatment ranged from 3 to 64 months. Eight cases restarted pegvaliase with an expedited titration schedule, while 2 cases resumed with a slowed approach and 1 case used the standard titration. At the time of the advisory board, 9 cases had achieved blood Phe ≤360 μmol/L, 1 case still had elevated blood Phe levels but had not yet completed titration and 1 case discontinued after 18 months on therapy.Key considerations for restarting pegvaliase after AE-related discontinuations include proactively addressing anxiety, optimizing premedications, ensuring access to on-demand medications and using a flexible, individualized titration approach. For individuals discontinuing primarily due to a limited blood Phe response, resuming at the previously tolerated dose and titrating adaptively as tolerated may be considered. For individuals desiring an expedited titration, more frequent blood Phe monitoring may be warranted to guide dietary adjustments and dosing. Life changes, individual preferences and social determinants of health should inform timing and resources for restart. For pregnancy-related discontinuations restart decisions should be made collaboratively with the individual and care team (geneticist, metabolic dietitian, obstetrician, and other relevant caregivers).

Pegvaliase can help achieve blood Phe control, which may mitigate neurocognitive effects and can result in greater dietary flexibility and improved quality of life. Restarting pegvaliase is feasible for most individuals, with many having a better experience during the restart process compared with the first treatment initiation. AEs were reported (eg, injection site reactions, rash, and arthralgia) but were milder compared to the previous treatment course in most cases and some individuals responded at lower doses or after shorter treatment duration. Restarting pegvaliase should be considered as part of a shared decision-making process for individuals seeking to further optimize outcomes.