Janet Thomas1, Harvey Levy2, Stephen Amato3, Jerry Vockley4, Roberto Zori5, David Dimmock6, Cary O Harding7, Deborah A Bilder8, Haoling H Weng9, Joy Olbertz10, Markus Merilainen11, Joy Jiang12, Kevin Larimore13, Soumi Gupta14, Zhonghua Gu15, Hope Northrup16. 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 receivedpegvaliase 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.
RCT Entities:
BACKGROUND:Phenylketonuria (PKU) is caused by phenylalanine hydroxylase (PAH) deficiency that results in phenylalanine (Phe) accumulation. Pegvaliase, PEGylated recombinant Anabaena variabilisphenylalanineammonia 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.
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