Abstract
Phenylketonuria (PKU) is caused by phenylalanine hydroxylase (PAH) deficiency, resulting in high blood and brain Phenylalanine (Phe) concentrations that can lead to impaired brain development and function. Standard treatment involves a Phe-restricted diet alone or in conjunction with sapropterin dihydrochloride in responsive patients. The Food and Drug Administration approved pegvaliase enzyme substitution therapy for adults with blood Phe >600 μmol/L in the US. Recently, the European Commission also approved pegvaliase for treatment of PKU patients aged 16 years or older with blood Phe >600 μmol/L. The analyses presented below were conducted to provide comparative evidence on long-term treatment effectiveness of pegvaliase versus standard of care in adults with PKU. Adult patients (≥18 years) with baseline blood Phe >600 μmol/L who had enrolled in the pegvaliase phase 2 and phase 3 clinical trials were propensity score-matched to historical cohorts of patients treated with "sapropterin + diet" or with "diet alone". These cohorts were derived from the PKU Demographics, Outcome and Safety (PKUDOS) registry and compared for clinical outcomes including blood Phe concentration and natural intact protein intake after 1 and 2 years. Propensity scores were estimated using logistic regression with probability of treatment as outcome (i.e. pegvaliase, "sapropterin + diet", or "diet alone") and patient demographic and disease severity covariates as predictors. An additional analysis in adult PKU patients with baseline blood Phe ≤600 μmol/L comparing non-matched patient groups "sapropterin + diet" to "diet alone" using PKUDOS registry data only was also conducted. The analyses in patients with baseline blood Phe >600 μmol comparing pegvaliase with "sapropterin + diet" (N = 64 matched pairs) showed lower mean blood Phe concentrations after 1 and 2 years with pegvaliase (505 and 427 μmol/L) versus "sapropterin + diet" (807 and 891 μmol/L); mean natural intact protein intake after 1 and 2 years was 49 and 57 g/day respectively with pegvaliase versus 23 and 28 g/day with "sapropterin + diet". The analysis comparing pegvaliase with "diet alone" (N = 120 matched pairs) showed lower mean blood Phe at 1 and 2 years with pegvaliase (473 and 302 μmol/L) versus "diet alone" (1022 and 965 μmol/L); mean natural intact protein intake after 1 and 2 years was 47 and 57 g/day with pegvaliase and 27 and 22 g/day with "diet alone". Considerably more patients achieved blood Phe ≤600, ≤360, and ≤120 μmol/L and reductions from baseline of ≥20%, ≥30%, and ≥50% in blood Phe after 1 and 2 years of pegvaliase versus standard treatments. The analysis in patients with baseline blood Phe ≤600 μmol/L showed lower blood Phe after 1 and 2 years with "sapropterin + diet" (240 and 324 μmol/L) versus "diet alone" (580 and 549 μmol/L) and greater percentages of patients achieving blood Phe targets ≤600, ≤360, and ≤120 μmol/L and reductions from baseline of ≥20%, ≥30%, and ≥50% in blood Phe. These results support pegvaliase as the more effective treatment option to lower Phe levels in adults with PKU who have difficulty keeping blood Phe ≤600 μmol/L with "diet alone". For patients with blood Phe ≤600 μmol/L, adding sapropterin to dietary management is an appropriate treatment option, for those responsive to the treatment.