Long-term management strategies for pegvaliase use in phenylketonuria: Lessons learned from the phase 3 PRISM open-label extension study.

Purpose: Pegvaliase is an enzyme substitution therapy for phenylketonuria, an autosomal recessive disorder of amino acid metabolism resulting in phenylalanine (Phe) accumulation, intellectual disability, and behavioral/psychiatric disorders. The phase 3 PRISM trials (NCT01819727, NCT01889862, NCT03694353) established pegvaliase efficacy in reducing blood Phe, but its pharmacokinetics differs between individuals, resulting in varying times to achieve clinically meaningful blood Phe targets.

Methods: Using participant-level data from PRISM, we developed a pharmacokinetic/pharmacodynamic model that explains individual-level blood Phe patterns as a function of pegvaliase clearance during the maintenance phase.

Results: As pegvaliase exposure induces immune tolerization, drug clearance declines. A period of high sensitivity of blood Phe to dietary Phe intake and pegvaliase exposure is observed at ∼120-200 μmol/L Phe, reflected in increased blood Phe volatility. This model suggests that this volatility represents impending, but incomplete, tolerization, and that reducing pegvaliase dose or liberalizing dietary Phe intake at or before this stage is premature and can result in marked blood Phe increases. With continued exposure, pegvaliase clearance continues to decline, and dietary Phe intake and blood Phe become uncoupled.

Conclusion: These analyses establish how tolerization presents clinically and suggest a staged therapeutic approach: (1) tolerance induction; (2) diet liberalization; (3) gradual dose adjustment.