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Mol Genet Metab. 2018 May;124(1):27-38. doi: 10.1016/j.ymgme.2018.03.006. Epub 2018 Mar 31.

Pegvaliase for the treatment of phenylketonuria: Results of a long-term phase 3 clinical trial program (PRISM).

Author information

1
Department of Pediatrics, Section of Clinical Genetics and Metabolism, University of Colorado School of Medicine, Aurora, CO 80045, USA. Electronic address: Janet.Thomas@childrenscolorado.org.
2
Division of Genetics and Genomics, Boston Children's Hospital, Boston, MA 02115, USA. Electronic address: harvey.levy@childrens.harvard.edu.
3
Pediatric Genetics and Metabolism, University of Kentucky, Lexington, KY 40506, USA. Electronic address: stephen.amato@uky.edu.
4
Department of Pediatrics, Division of Medical Genetics, University of Pittsburgh and Children's Hospital of Pittsburgh, Pittsburgh, PA 15224, USA. Electronic address: vockleyg@upmc.edu.
5
Genetics and Metabolism, University of Florida, Gainesville, FL 32610, USA. Electronic address: zorirt@peds.ufl.edu.
6
Rady Children's Institute for Genomic Medicine, San Diego, CA 92123, USA. Electronic address: ddimmock@rchsd.org.
7
Molecular and Medical Genetics, Oregon Health & Science University, Portland, OR 97239, USA. Electronic address: hardingc@ohsu.edu.
8
Psychiatry, University of Utah, Salt Lake City, UT 84108, USA. Electronic address: deborah.bilder@hsc.utah.edu.
9
Research and Development, BioMarin Pharmaceutical Inc., Novato, CA 94949, USA. Electronic address: holly.weng@bmrn.com.
10
Research and Development, BioMarin Pharmaceutical Inc., Novato, CA 94949, USA. Electronic address: joy.olbertz@bmrn.com.
11
Research and Development, BioMarin Pharmaceutical Inc., Novato, CA 94949, USA. Electronic address: mmerilainen@bmrn.com.
12
Research and Development, BioMarin Pharmaceutical Inc., Novato, CA 94949, USA. Electronic address: joy.jiang@bmrn.com.
13
Research and Development, BioMarin Pharmaceutical Inc., Novato, CA 94949, USA. Electronic address: KLarimore@bmrn.com.
14
Research and Development, BioMarin Pharmaceutical Inc., Novato, CA 94949, USA. Electronic address: soumi.gupta@bmrn.com.
15
Research and Development, BioMarin Pharmaceutical Inc., Novato, CA 94949, USA. Electronic address: kgu@bmrn.com.
16
Department of Pediatrics, Division of Medical Genetics, McGovern Medical School, The University of Texas Health Science Center at Houston, Houston, TX 77030, USA. Electronic address: Hope.Northrup@uth.tmc.edu.

Abstract

BACKGROUND:

Phenylketonuria (PKU) is caused by phenylalanine hydroxylase (PAH) deficiency that results in phenylalanine (Phe) accumulation. Pegvaliase, PEGylated recombinant Anabaena variabilis phenylalanine ammonia lyase (PAL), converts Phe to trans-cinnamic acid and ammonia, and is a potential enzyme substitution therapy to lower blood Phe in adults with PKU.

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.

KEYWORDS:

PEGylated phenylalanine ammonia lyase; PRISM; Pegvaliase; Phenylalanine; Phenylketonuria; Recombinant Anabaena variabilis

PMID:
29653686
DOI:
10.1016/j.ymgme.2018.03.006
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