Cary O Harding1, R Stephen Amato2, Mary Stuy3, Nicola Longo4, Barbara K Burton5, John Posner6, Haoling H Weng7, Markus Merilainen8, Zhonghua Gu9, Joy Jiang10, Jerry Vockley11. 1. Molecular and Medical Genetics, Oregon Health & Science University, 3181 SW Sam Jackson Park Road, Portland, OR 97239, USA. Electronic address: hardingc@ohsu.edu. 2. Medical Genetics and Metabolism, University of Kentucky, 138 Leader Avenue, #119-130, Lexington, KY 40506, USA. Electronic address: stephen.amato@uky.edu. 3. Department of Medical and Molecular Genetics, Indiana University, 975 W Walnut St, Research and Library Building IB 130, Indianapolis, IN 46202, USA. Electronic address: mstuy@iu.edu. 4. Department of Pediatrics, Division of Medical Genetics, University of Utah, 295 Chipeta Way, Salt Lake City, UT 84108, USA. Electronic address: Nicola.Longo@hsc.utah.edu. 5. Department of Pediatrics, Division of Genetics, Birth Defects & Metabolism, Ann & Robert H. Lurie Children's Hospital of Chicago, 225 E Chicago Ave, Chicago, IL 60601, USA. Electronic address: bburton@luriechildrens.org. 6. Department of Life Sciences and Medicine, King's College London Strand, Franklin Wilkins Building, Stamford Street, London, UK. Electronic address: john.posner@talk21.com. 7. BioMarin Pharmaceutical Inc., 105 Digital Drive, Novato, CA 94949, USA. Electronic address: holly.weng@bmrn.com. 8. BioMarin Pharmaceutical Inc., 105 Digital Drive, Novato, CA 94949, USA. Electronic address: mmerilainen@bmrn.com. 9. BioMarin Pharmaceutical Inc., 105 Digital Drive, Novato, CA 94949, USA. Electronic address: kgu@bmrn.com. 10. BioMarin Pharmaceutical Inc., 105 Digital Drive, Novato, CA 94949, USA. Electronic address: joy.jiang@bmrn.com. 11. Department of Pediatrics, Division of Medical Genetics, University of Pittsburgh and Children's Hospital of Pittsburgh, 4401 Penn Avenue, Pittsburgh, PA 15224, USA. Electronic address: vockleyg@upmc.edu.
Abstract
INTRODUCTION: Pegvaliase is a recombinant Anabaena variabilis phenylalanine ammonia lyase (PAL) enzyme under investigation for treatment of adult phenylketonuria (PKU). This manuscript describes results of a randomized discontinuation trial (RDT) designed to evaluate the effects of pegvaliase treatment on blood phenylalanine (Phe) and neuropsychiatric outcomes in adults with PKU. METHODS: PRISM-2 is a 4-part, Phase 3 study that enrolled adults with PKU receiving pegvaliase treatment (initiated in a prior Phase 2 or Phase 3 study). The RDT, Part 2 of PRISM-2, was an 8-week trial that evaluated change in blood Phe concentrations, neuropsychiatric and neurocognitive measures, and safety outcomes in PRISM-2 participants who had achieved at least a 20% blood Phe reduction from pre-treatment baseline with pegvaliase treatment. Participants were randomized 2:1 to either continue pegvaliase (20 mg/day or 40 mg/day) or switch to matching placebo. RESULTS: The pooled pegvaliase group enrolled 66 participants and each placebogroup enrolled 14 participants. The primary endpoint of change in blood Phe concentration from RDT entry to RDT Week 8 was met with clinically meaningful and statistically significant differences between the pegvaliase and placebo groups. Mean (SD) blood Phe at the beginning of the RDT when all participants were receiving pegvaliase was 563.9 μM (504.6) in the group assigned to the 20 mg/day placebo group (n = 14), 508.2 μM (363.7) in those assigned to the 40 mg/day placebo group (n = 14), and 503.9 μM (520.3) in those assigned to continue pegvaliase treatment (n = 58). At Week 8 of the RDT, the least squares mean change (95% confidence interval) in blood Phe was 949.8 μM (760.4 to 1139.1) for the 20 mg/day placebo group and 664.8 μM (465.5 to 864.1) for the 40 mg/day placebo group in comparison to 26.5 μM (-68.3 to 121.3) for the pooled (20 mg/day and 40 mg/day) pegvaliase group (P < 0.0001 for pooled pegvaliase group vs each placebo group). Adverse events (AEs) were usually lower in the pooled placebo group when compared to the pooled pegvaliase group. The most common AEs for the pooled pegvaliase and pooled placebo groups were arthralgia (13.6% and 10.3%, respectively), headache (12.1% and 24.1%), anxiety (10.6% and 6.9%), fatigue (10.6% and 10.3%), and upper respiratory tract infection (1.5% and 17.2%). CONCLUSION:Mean blood Phe reduction was sustained in the pegvaliase group, while placebo groups had meanblood Phe concentration increase toward pre-treatment baseline levels. Results from this study confirmed the efficacy of pegvaliase in maintaining reduced blood Phe concentrations with a manageable safety profile for most participants.
RCT Entities:
INTRODUCTION: Pegvaliase is a recombinant Anabaena variabilisphenylalanine ammonia lyase (PAL) enzyme under investigation for treatment of adult phenylketonuria (PKU). This manuscript describes results of a randomized discontinuation trial (RDT) designed to evaluate the effects of pegvaliase treatment on blood phenylalanine (Phe) and neuropsychiatric outcomes in adults with PKU. METHODS: PRISM-2 is a 4-part, Phase 3 study that enrolled adults with PKU receiving pegvaliase treatment (initiated in a prior Phase 2 or Phase 3 study). The RDT, Part 2 of PRISM-2, was an 8-week trial that evaluated change in blood Phe concentrations, neuropsychiatric and neurocognitive measures, and safety outcomes in PRISM-2 participants who had achieved at least a 20% blood Phe reduction from pre-treatment baseline with pegvaliase treatment. Participants were randomized 2:1 to either continue pegvaliase (20 mg/day or 40 mg/day) or switch to matching placebo. RESULTS: The pooled pegvaliase group enrolled 66 participants and each placebo group enrolled 14 participants. The primary endpoint of change in blood Phe concentration from RDT entry to RDT Week 8 was met with clinically meaningful and statistically significant differences between the pegvaliase and placebo groups. Mean (SD) blood Phe at the beginning of the RDT when all participants were receiving pegvaliase was 563.9 μM (504.6) in the group assigned to the 20 mg/day placebo group (n = 14), 508.2 μM (363.7) in those assigned to the 40 mg/day placebo group (n = 14), and 503.9 μM (520.3) in those assigned to continue pegvaliase treatment (n = 58). At Week 8 of the RDT, the least squares mean change (95% confidence interval) in blood Phe was 949.8 μM (760.4 to 1139.1) for the 20 mg/day placebo group and 664.8 μM (465.5 to 864.1) for the 40 mg/day placebo group in comparison to 26.5 μM (-68.3 to 121.3) for the pooled (20 mg/day and 40 mg/day) pegvaliase group (P < 0.0001 for pooled pegvaliase group vs each placebo group). Adverse events (AEs) were usually lower in the pooled placebo group when compared to the pooled pegvaliase group. The most common AEs for the pooled pegvaliase and pooled placebo groups were arthralgia (13.6% and 10.3%, respectively), headache (12.1% and 24.1%), anxiety (10.6% and 6.9%), fatigue (10.6% and 10.3%), and upper respiratory tract infection (1.5% and 17.2%). CONCLUSION: Mean blood Phe reduction was sustained in the pegvaliase group, while placebo groups had mean blood Phe concentration increase toward pre-treatment baseline levels. Results from this study confirmed the efficacy of pegvaliase in maintaining reduced blood Phe concentrations with a manageable safety profile for most participants.
Authors: Deborah A Bilder; Georgianne L Arnold; David Dimmock; Mitzie L Grant; Darren Janzen; Nicola Longo; Mina Nguyen-Driver; Elaina Jurecki; Markus Merilainen; Gianni Amato; Susan Waisbren Journal: Am J Med Genet A Date: 2021-11-26 Impact factor: 2.578
Authors: Nicola Longo; Roberto Zori; Melissa P Wasserstein; Jerry Vockley; Barbara K Burton; Celeste Decker; Mingjin Li; Kelly Lau; Joy Jiang; Kevin Larimore; Janet A Thomas Journal: Orphanet J Rare Dis Date: 2018-07-04 Impact factor: 4.123
Authors: Jerry Vockley; Steven F Dobrowolski; Georgianne L Arnold; Ruben Bonilla Guerrero; Terry G J Derks; David A Weinstein Journal: Mol Genet Metab Date: 2019-07-19 Impact factor: 4.797
Authors: Friedrich Trefz; Ania C Muntau; Kim M Schneider; Julia Altevers; Christian Jacob; Sebastian Braun; Wolfgang Greiner; Ashok Jha; Mohit Jain; Ignacio Alvarez; Paul Lane; Claudia Zeiss; Frank Rutsch Journal: Mol Genet Metab Rep Date: 2021-05-13