PMID- 29973227
OWN - NLM
STAT- MEDLINE
DCOM- 20190415
LR  - 20230926
IS  - 1750-1172 (Electronic)
IS  - 1750-1172 (Linking)
VI  - 13
IP  - 1
DP  - 2018 Jul 4
TI  - Long-term safety and efficacy of pegvaliase for the treatment of phenylketonuria 
      in adults: combined phase 2 outcomes through PAL-003 extension study.
PG  - 108
LID - 10.1186/s13023-018-0858-7 [doi]
LID - 108
AB  - BACKGROUND: Deficiency 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. METHODS: PAL-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 mumol/L. 
      RESULTS: Mean (standard deviation [SD]) plasma Phe at treatment-naive baseline 
      for 80 participants in the parent studies was 1302.4 (351.5) mumol/L. In the 68 
      participants who entered the extension study, plasma Phe decreased 58.9 (39)% 
      from baseline, to 541.6 (515.5) mumol/L at Week 48 of treatment. Plasma Phe 
      concentrations </=120 mumol/L, </=360 mumol/L, and </= 600 mumol/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. CONCLUSIONS: Pegvaliase 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 REGISTRATION: ClinicalTrials.gov , 
      NCT00924703. Registered June 18, 2009, 
      https://clinicaltrials.gov/ct2/show/NCT00924703.
FAU - Longo, Nicola
AU  - Longo N
AD  - Department of Pediatrics, Division of Medical Genetics, University of Utah, 295 
      Chipeta Way, Salt Lake City, UT, 84108, USA. nicola.longo@hsc.utah.edu.
FAU - Zori, Roberto
AU  - Zori R
AD  - Division of Genetics and Metabolism, University of Florida, PO Box 100296 UFHSC, 
      Gainesville, FL, 32610, USA.
FAU - Wasserstein, Melissa P
AU  - Wasserstein MP
AD  - Department of Pediatrics, The Children's Hospital at Montefiore, 3415 Bainbridge 
      Ave, Bronx, NY, 10467, USA.
FAU - Vockley, Jerry
AU  - Vockley J
AD  - Department of Pediatrics, Division of Medical Genetics, University of Pittsburgh 
      and Children's Hospital of Pittsburgh, 4401 Penn Avenue, Pittsburgh, PA, 15224, 
      USA.
FAU - Burton, Barbara K
AU  - Burton BK
AD  - Department of Pediatrics, Division of Genetics, Birth Defects & Metabolism, Ann & 
      Robert H. Lurie Children's Hospital of Chicago, 225 E. Chicago Ave, Chicago, IL, 
      60611, USA.
FAU - Decker, Celeste
AU  - Decker C
AD  - BioMarin Pharmaceutical Inc, 105 Digital Drive, Novato, CA, 94949, USA.
FAU - Li, Mingjin
AU  - Li M
AD  - BioMarin Pharmaceutical Inc, 105 Digital Drive, Novato, CA, 94949, USA.
FAU - Lau, Kelly
AU  - Lau K
AD  - BioMarin Pharmaceutical Inc, 105 Digital Drive, Novato, CA, 94949, USA.
FAU - Jiang, Joy
AU  - Jiang J
AD  - BioMarin Pharmaceutical Inc, 105 Digital Drive, Novato, CA, 94949, USA.
FAU - Larimore, Kevin
AU  - Larimore K
AD  - BioMarin Pharmaceutical Inc, 105 Digital Drive, Novato, CA, 94949, USA.
FAU - Thomas, Janet A
AU  - Thomas JA
AD  - Department of Pediatrics, Section of Clinical Genetics and Metabolism, University 
      of Colorado Hospital, 12605 E. 16th St, Aurora, CO, 80045, USA.
LA  - eng
SI  - ClinicalTrials.gov/NCT00924703
PT  - Clinical Trial, Phase II
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20180704
PL  - England
TA  - Orphanet J Rare Dis
JT  - Orphanet journal of rare diseases
JID - 101266602
RN  - 0 (Recombinant Proteins)
RN  - 47E5O17Y3R (Phenylalanine)
RN  - EC 4.3.1.24 (Phenylalanine Ammonia-Lyase)
RN  - N6UAH27EUV (pegvaliase)
SB  - IM
MH  - Humans
MH  - Phenylalanine/blood
MH  - Phenylalanine Ammonia-Lyase/metabolism/*therapeutic use
MH  - Phenylketonurias/blood/*drug therapy/*metabolism
MH  - Recombinant Proteins/*therapeutic use
PMC - PMC6031112
OTO - NOTNLM
OT  - PKU
OT  - Pegvaliase
OT  - Phenylketonuria
OT  - Recombinant Anabaena variabilis PEGylated phenylalanine ammonia lyase
COIS- ETHICS APPROVAL AND CONSENT TO PARTICIPATE: All individuals consented to 
      participate in the study, which was conducted in accordance with the Declaration 
      of Helsinki of 1975, as revised in 2008. CONSENT FOR PUBLICATION: Not applicable. 
      COMPETING INTERESTS: JV, BKB, RZ, JAT, MPW, and NL are investigators of BioMarin 
      Pharmaceutical Inc. clinical trials, and RZ, JAT, and NL are on the steering 
      committee for the pegvaliase clinical program. NL reports grants (Aeglea, 
      BioMarin, Genzyme, Horizon, Lumos Pharma, Protalix, Retrophin, Shire, Stealth 
      Therapeutics, Ultragenix), consultant fees (Aeglea, BioMarin, Censa 
      Pharmaceuticals, Dimension Therapeutics, Genzyme, Hemoshear, Horizon, Lumos 
      Pharma, Moderna, Mitobridge, Pfizer, Retrophin, Stealth Therapeutics), 
      participation in clinical trials (Aeglea, BioMarin, Genzyme, Horizon, Protalix, 
      Retrophin, Shire, Stealth Therapeutics, Ultragenix), and travel fees (BioMarin, 
      Cello Health Sciences, Lumos Pharma, SigmaTau/AlphaSigma). JV has received 
      research support (BioMarin). BKB has participated in advisory boards (BioMarin, 
      ReGenXBio), received research support (Shire), received consulting fees (Alexion, 
      Shire, BioMarin), and participated as trial investigator (BioMarin, Shire, 
      Ultragenyx, Alexion Armagen, Cytonet). JAT has participated in advisory boards 
      and received research support (BioMarin). CD, ML, KL, JJ, and KL are BioMarin 
      Pharmaceutical Inc. employees and stockholders. PUBLISHER'S NOTE: Springer Nature 
      remains neutral with regard to jurisdictional claims in published maps and 
      institutional affiliations.
EDAT- 2018/07/06 06:00
MHDA- 2019/04/16 06:00
PMCR- 2018/07/04
CRDT- 2018/07/06 06:00
PHST- 2018/02/01 00:00 [received]
PHST- 2018/06/27 00:00 [accepted]
PHST- 2018/07/06 06:00 [entrez]
PHST- 2018/07/06 06:00 [pubmed]
PHST- 2019/04/16 06:00 [medline]
PHST- 2018/07/04 00:00 [pmc-release]
AID - 10.1186/s13023-018-0858-7 [pii]
AID - 858 [pii]
AID - 10.1186/s13023-018-0858-7 [doi]
PST - epublish
SO  - Orphanet J Rare Dis. 2018 Jul 4;13(1):108. doi: 10.1186/s13023-018-0858-7.