Pegvaliase for the treatment of phenylketonuria: Results of a long-term phase 3 clinical trial program (PRISM).
Abstract | BACKGROUND: METHODS: Two Phase 3 studies, PRISM-1 and PRISM-2, evaluated the efficacy and safety of pegvaliase treatment using an induction, titration, and maintenance dosing regimen in adults with PKU. In PRISM-1, pegvaliase-naïve participants with blood Phe >600 μmol/L were randomized 1:1 to a maintenance dose of 20 mg/day or 40 mg/day of pegvaliase. Participants in PRISM-1 continued pegvaliase treatment in PRISM-2, a 4-part clinical trial that includes an ongoing, open-label, long-term extension study of pegvaliase doses of 5 mg/day to 60 mg/day. RESULTS: Of 261 participants who received pegvaliase treatment, 72.0% and 32.6% reached ≥12 months and ≥ 24 months of study treatment, respectively, and 65% are still actively receiving treatment. Mean (SD) blood Phe was 1232.7 (386.4) μmol/L at baseline, 564.5 (531.2) μmol/L at 12 months, and 311.4 (427) μmol/L at 24 months, a decrease from baseline of 51.1% and 68.7%, respectively. Within 24 months, 68.4% of participants achieved blood Phe ≤600 μmol/L, 60.7% of participants achieved blood Phe ≤360 μmol/L, below the upper limit recommended in the American College of Medical Genetics and Genomics PKU management guidelines, and 51.2% achieved blood Phe ≤120 μmol/L, below the upper limit of normal in the unaffected population. Improvements in neuropsychiatric outcomes were associated with reductions in blood Phe and were sustained with long-term pegvaliase treatment. Adverse events (AEs) were more frequent in the first 6 months of exposure (early treatment phase) than after 6 months of exposure (late treatment phase); 99% of AEs were mild or moderate in severity and 96% resolved without dose interruption or reduction. The most common AEs were arthralgia (70.5%), injection-site reaction (62.1%), injection-site erythema (47.9%), and headache (47.1%). Acute systemic hypersensitivity events consistent with clinical National Institute of Allergy and Infectious Diseases and the Food Allergy and Anaphylaxis Network anaphylaxis criteria were observed in 12 participants (17 events); of these, 6 participants remained on treatment. Acute systemic hypersensitivity events including potential events of anaphylaxis were not associated with immunoglobulin E, and all events resolved without sequelae. CONCLUSION: Results from the PRISM Phase 3 program support the efficacy of pegvaliase for the treatment of adults with PKU, with a manageable safety profile in most participants. The PRISM-2 extension study will continue to assess the long-term effects of pegvaliase treatment.
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Authors | Janet Thomas, Harvey Levy, Stephen Amato, Jerry Vockley, Roberto Zori, David Dimmock, Cary O Harding, Deborah A Bilder, Haoling H Weng, Joy Olbertz, Markus Merilainen, Joy Jiang, Kevin Larimore, Soumi Gupta, Zhonghua Gu, Hope Northrup, PRISM investigators |
Journal | Molecular genetics and metabolism
(Mol Genet Metab)
Vol. 124
Issue 1
Pg. 27-38
(05 2018)
ISSN: 1096-7206 [Electronic] United States |
PMID | 29653686
(Publication Type: Clinical Trial, Phase III, Journal Article, Randomized Controlled Trial, Research Support, Non-U.S. Gov't)
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Copyright | Copyright © 2018 The Authors. Published by Elsevier Inc. All rights reserved. |
Chemical References |
- Recombinant Proteins
- Phenylalanine
- Phenylalanine Ammonia-Lyase
- pegvaliase
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Topics |
- Adult
- Female
- Humans
- Male
- Phenylalanine
(blood)
- Phenylalanine Ammonia-Lyase
(administration & dosage, adverse effects, therapeutic use)
- Phenylketonurias
(drug therapy)
- Recombinant Proteins
(administration & dosage, adverse effects, therapeutic use)
- Time Factors
- Young Adult
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