Introduction:
Phenylketonuria (PKU) is an autosomal recessive disorder of amino acid metabolism characterized by chronic elevations of blood phenylalanine (Phe). Pegvaliase is a blood Phe-lowering enzyme substitution therapy approved for adults (US) or patients aged ≥16 years (Europe) with PKU and Phe >600 μmol/L. OPAL is a phase 4, multicenter, observational study to assess the real-world safety and efficacy of pegvaliase. Here we report findings from the second interim analysis of the impact of pegvaliase treatment on blood Phe levels and health-related quality of life outcomes.   

Methods:
Adults with PKU either currently receiving (prevalent) or recommended to receive (incident) pegvaliase, with blood Phe >600 μmol/L were eligible to enroll in OPAL. Blood Phe levels and patient-reported outcomes (PROs) are collected according to standard of care. Disease-specific PRO measures assessed in the study included the PKU Quality of Life (PKU-QOL) Questionnaire and the Adult PKU Symptom Severity and Impacts Scale (PKU-SSIS; psychometric validation ongoing), which includes 6 domains relevant to PKU symptoms (Emotional, Mood and Psychological; Cognitive, Executive and Intellectual Function; Physical; General Wellbeing; Self-care; Social Relations; Level of Independence). PKU-QOL and PKU-SSIS scores both range from 0 to 100: higher PKU-QOL scores indicate greater impact on quality of life; higher PKU-SSIS scores indicate greater severity of PKU symptoms and associated impacts.

Results:
As of the second interim data cut (March 2024), 76 patients (48 incident, 28 prevalent) were enrolled, and the majority of participants had completed at least 48 weeks in the study. Fifty-one participants (29 incident, 22 prevalent) who had baseline Phe and screening/pre-study PRO measurements and at least 24 weeks of follow-up in the study were included in the analysis. Mean (SD) blood Phe level was 1029 (259) μmol/L at baseline and declined over follow up: to 651 (391) μmol/L at week 24 (n=47), 569 (428) μmol/L at week 48 (n=39), and 293 (294) μmol/L at week 96 (n=16); representing a mean (SD) change of -393 (375), -470  (435), and -711 (416) μmol/L, respectively. Mean (SD) PKU-QOL overall impact scores showed improvement over follow-up: from 29.0 (16.7) at baseline (n=47) to 23.2 (12.9) at week 24 (n=46), 23.2 (14.9) at week 48 (n=40), and 18.4 (14.0) at week 96 (n=31); representing a mean (95% confidence interval) change from baseline of -5.7 (-9.4, -2.0), -6.1 (-10.1, -2.1), and -12.4 (-18.0, -6.8), respectively. Similarly, mean (SD) PKU-SSIS total scores declined from 31.8 (16.4) at baseline (n=50) to 25.8 (13.5) at weeks 24 (n=46), 27.6 (14.5) at week 48 (n=40), and 23.4 (12.3) at week and 96 (n=31);  representing a mean (95% confidence interval) change from baseline of -5.3 (-9.5, -1.1), -3.4 (-8.4, 1.5), and -11.8 (-16.9, -6.6), respectively.  

Conclusion:
The OPAL study provides the first real-world data demonstrating the impact of pegvaliase treatment on blood Phe levels and health related quality of life outcomes. These preliminary findings show that blood Phe reductions observed with pegvaliase treatment in the real-world setting are consistent with findings from clinical trials. Moreover, improvements in patient-reported outcomes were observed in the study cohort.