Pegvaliase for the treatment of phenylketonuria: Final results of a long-term phase 3 clinical trial program.

Phenylketonuria (PKU) is a genetic disorder caused by deficiency of the enzyme phenylalanine hydroxylase (PAH), which results in phenylalanine (Phe) accumulation in the blood and brain, and requires lifelong treatment to keep blood Phe in a safe range. Pegvaliase is an enzyme-substitution therapy approved for individuals with PKU and uncontrolled blood Phe concentrations (>600 µmol/L) despite prior management. Aggregated results from the PRISM clinical trials demonstrated substantial and sustained reductions in blood Phe with a manageable safety profile, but also noted individual variation in time to and dose needed for a first response. This analysis reports longer-term aggregate findings and characterizes individual participant responses to pegvaliase using final data from the randomized trials PRISM-1 (NCT01819727) and PRISM-2 (NCT01889862), and the open-label extension study 165-304 (NCT03694353). In 261 adult participants with a mean of 36.6 months of pegvaliase treatment, 71.3%, 65.1%, and 59.4% achieved clinically significant blood Phe levels of ≤600, ≤360, and ≤ 120 µmol/L, respectively. Some participants achieved blood Phe reductions with <20 mg/day pegvaliase, although most required higher doses. Based on Kaplan-Meier analysis, median (minimum, maximum) time to first achievement of a blood Phe threshold of ≤600, ≤360, or ≤ 120 µmol/L was 4.4 (0.0, 54.0), 8.0 (0.0, 57.0), and 11.6 (0.0, 66.0) months, respectively. Once achieved, blood Phe levels remained below clinical threshold in most participants. Sustained Phe response (SPR), a new method described within for measuring durability of blood Phe response, was achieved by 85.5%, 84.7%, and 78.1% of blood Phe responders at blood Phe thresholds of ≤600, ≤360, or ≤ 120 µmol/L, respectively. Longer-term safety data were consistent with previous reports, with the most common adverse events (AEs) being arthralgia, injection site reactions, headache, and injection site erythema. The incidence of most AEs, including hypersensitivity AEs, was higher during the early treatment phase (≤6 months) than later during treatment. In conclusion, using data from three key pegvaliase clinical trials, participants treated with pegvaliase were able to reach clinically significant blood Phe reductions to clinical thresholds of ≤600, ≤360, or ≤ 120 µmol/L during early treatment, with safety profiles improving from early to sustained treatment. This study also supports the use of participant-level data and new ways of looking at durable blood Phe responses to better characterize patients' individual PKU treatment journeys.

Long-term comparative effectiveness of pegvaliase versus medical nutrition therapy with and without sapropterin in adults with phenylketonuria.

Phenylketonuria is characterized by intellectual disability and behavioral, psychiatric, and movement disorders resulting from phenylalanine (Phe) accumulation. Standard-of-care treatment involves a Phe-restricted diet plus medical nutrition therapy (MNT), with or without sapropterin dihydrochloride, to reduce blood Phe levels. Pegvaliase is an injectable enzyme substitution treatment approved for adult patients with blood Phe >600 µmol/L despite ongoing management. A previous comparative effectiveness analysis using data from the Phase 3 PRISM trials of pegvaliase (NCT01819727 and NCT01889862) and the Phenylketonuria Demographics, Outcomes and Safety Registry (PKUDOS; NCT00778206) suggested that pegvaliase was more effective at lowering mean blood Phe levels than sapropterin + MNT or MNT alone at 1 and 2 years of treatment. The current work augments and complements the previous analysis by including additional follow-up from the completed studies, robust methods reflecting careful consideration of issues with the distribution of Phe, and alternative methods for adjustment that are important for control of potential confounding in comparative effectiveness. Median blood Phe levels were lower, and median intact protein intakes were higher, in the pegvaliase group (n = 183) than in the sapropterin + MNT (n = 82) and MNT (n = 67) groups at Years 1, 2, and 3. In the pegvaliase group, median blood Phe levels decreased from baseline (1244 µmol/L) to Year 1 (535 µmol/L), Year 2 (142 µmol/L), and Year 3 (167 µmol/L). In the sapropterin + MNT group, median blood Phe levels decreased from baseline (900 µmol/L) to Year 1 (588 µmol/L) and Year 2 (592 µmol/L), and increased at Year 3 (660 µmol/L). In the MNT group, median blood Phe levels decreased slightly from baseline (984 µmol/L) to Year 1 (939 µmol/L) and Year 2 (941 µmol/L), and exceeded baseline levels at Year 3 (1157 µmol/L). The model-estimated proportions of participants achieving blood Phe ≤600 µmol/L were 41%, 100%, and 100% in the pegvaliase group at Years 1, 2, and 3, respectively, compared with 55%, 58%, and 38% in the sapropterin + MNT group and 5%, 16%, and 0% in the MNT group. The estimated proportions of participants achieving more stringent blood Phe targets of ≤360 µmol/L and ≤120 µmol/L were also higher in the pegvaliase group than in the other groups at Years 2 and 3. Overall, our results indicate that, compared with standard therapy, pegvaliase induces a substantial, progressive, and sustained decrease in blood Phe levels - to a much greater extent than sapropterin + MNT or MNT alone - which is expected to improve long-term outcomes in patients with phenylketonuria.

Initial combination therapy compared with monotherapy in diabetic hypertensive patients.

Subgroup analyses were performed for the diabetic and nondiabetic cohorts from 3 randomized clinical trials that had evaluated the systolic blood pressure (SBP)-lowering efficacy and tolerability of an angiotensin receptor blocker, valsartan, alone or in combination with hydrochlorothiazide to determine when and how to initiate combination therapy in hypertensive patients with diabetes. Blood pressure reductions achieved with monotherapy were compared with combination therapy in the diabetic and nondiabetic cohorts. In addition, multivariate models were developed to predict the likelihood of the goal SBP of < 130 mm Hg being reached in a diabetic patient with monotherapy or combination therapy across the range of baseline SBP values. In 2 of the 3 trials, comparable reductions in SBP were seen in the diabetic and nondiabetic cohorts. In all 3 studies, however, combination therapy provided greater blood pressure-lowering efficacy than monotherapy. The probability of achieving goal SBP was greater for diabetic patients started on combination therapy compared with monotherapy.