Long-term safety and efficacy of pegvaliase for the treatment of phenylketonuria in adults: combined phase 2 outcomes through PAL-003 extension study

Abstract

BackgroundDeficiency of phenylalanine hydroxylase causes phenylketonuria (PKU) with elevated phenylalanine (Phe) levels and associated neuropsychiatric and neurocognitive symptoms. Pegvaliase (PEGylated phenylalanine ammonia lyase) is an investigational agent to lower plasma Phe in adults with PKU. This study aimed to characterize the long-term efficacy, safety, and immunogenicity of pegvaliase in adults with PKU.MethodsPAL-003 is an ongoing, open-label, long-term extension study of the pegvaliase dose-finding parent phase 2 studies. Participants continued the dose of pegvaliase from one of three parent studies, with dose adjustments to achieve a plasma Phe concentration between 60 and 600 μmol/L.ResultsMean (standard deviation [SD]) plasma Phe at treatment-naïve baseline for 80 participants in the parent studies was 1302.4 (351.5) μmol/L. In the 68 participants who entered the extension study, plasma Phe decreased 58.9 (39)% from baseline, to 541.6 (515.5) μmol/L at Week 48 of treatment. Plasma Phe concentrations ≤120 μmol/L, ≤360 μmol/L, and ≤ 600 μmol/L were achieved by 78.7, 80.0, and 82.5% of participants, respectively. Mean (SD) protein intake at baseline was 69.4 (40.4) g/day (similar to the recommended intake for the unaffected population) and remained stable throughout the study. All participants experienced adverse events (AEs), which were limited to mild or moderate severity in most (88.8%); the most common AEs were injection-site reaction (72.5%), injection-site erythema (67.5%), headache (67.5%), and arthralgia (65.0%). The AE rate decreased from 58.3 events per person-year in the parent studies to 18.6 events per person-year in the extension study.ConclusionsPegvaliase treatment in adults with PKU produced meaningful and persistent reductions in mean plasma Phe concentration with a manageable safety profile for most subjects that continued with long-term treatment.Trial registrationClinicalTrials.gov, NCT00924703. Registered June 18, 2009, https://clinicaltrials.gov/ct2/show/NCT00924703Electronic supplementary materialThe online version of this article (10.1186/s13023-018-0858-7) contains supplementary material, which is available to authorized users.

Pharmacokinetic, pharmacodynamic, and immunogenic rationale for optimal dosing of pegvaliase, a PEGylated bacterial enzyme, in adult patients with phenylketonuria

“…Demographics and baseline characteristics for patients enrolled in the pegvaliase clinical trials have been presented in detail elsewhere. 19 , 21 , 22 , 23 , 24 , 25 , 26 In brief, the 5 studies discussed herein enrolled a total of 337 patients (range per study: 16–261). The range of mean baseline ages was 26.1–32.2 years, body mass index was 26.5–29.5, and blood Phe concentration was 1178.7–1482.1 μmol/L.…”

“…The methods for studies reported herein were previously published. 19 , 21 , 22 , 23 , 24 , 25 , 26 In brief, PAL‐002 was an open‐label, multicenter, single‐arm phase II study in which pegvaliase was administered via subcutaneous injection in weekly doses of 0.001–0.1 mg/kg/day over an 8‐week induction phase followed by an 8‐week titration phase. 19 , 23 In the open‐label, multicenter phase II PAL‐004 trial, daily doses of 0.06–0.8 mg/kg/day were administered for 13 weeks.…”

“…However, subsequent phase II and III efficacy, safety, and immunogenicity data (NCT00924703, NCT01560286, NCT00925054, NCT01212744, NCT01819727, and NCT01889862) supported more frequent dosing with the inclusion of an induction/titration/ maintenance (I/T/M) dosing regimen that led to substantial reductions in blood Phe levels with a manageable safety profile for most subjects. 19,[21][22][23][24][25][26] Herein, we describe the PK and PD following multiple doses of pegvaliase and the effects of immunogenicity in determining a safe, tolerable, and efficacious long-term dosing regimen.…”

“…However, subsequent phase II and III efficacy, safety, and immunogenicity data (NCT00924703, NCT01560286, NCT00925054, NCT01212744, NCT01819727, and NCT01889862) supported more frequent dosing with the inclusion of an induction/titration/maintenance (I/T/M) dosing regimen that led to substantial reductions in blood Phe levels with a manageable safety profile for most subjects. 19 , 21 , 22 , 23 , 24 , 25 , 26 …”

Prospects for Cell-Directed Curative Therapy of Phenylketonuria (PKU)

“…Administered by daily subcutaneous injection, pegvaliase circulates in blood and converts Phe to trans-cinnamic acid and ammonia. Several phase 1, 2, and 3 clinical trials have demonstrated the effi cacy of pegvaliase in decreasing blood Phe concentration in adults, even down to the normal range, while liberalizing dietary Phe intake [16][17][18][19] . This revolutionary treatment approach is increasingly available in the US and Europe, yet still demands daily injections and is associated with immune-mediated hypersensitivity reactions in some individuals.…”