PMID- 31326288 OWN - NLM STAT- MEDLINE DCOM- 20200417 LR - 20200530 IS - 1096-7206 (Electronic) IS - 1096-7192 (Linking) VI - 127 IP - 4 DP - 2019 Aug TI - Long-term safety and efficacy of glycerol phenylbutyrate for the management of urea cycle disorder patients. PG - 336-345 LID - S1096-7192(19)30323-3 [pii] LID - 10.1016/j.ymgme.2019.07.004 [doi] AB - INTRODUCTION: Glycerol phenylbutyrate (GPB) is currently approved for use in the US and Europe for patients of all ages with urea cycle disorders (UCD) who cannot be managed with protein restriction and/or amino acid supplementation alone. Currently available data on GPB is limited to 12 months exposure. Here, we present long-term experience with GPB. METHODS: This was an open-label, long-term safety study of GPB conducted in the US (17 sites) and Canada (1 site) monitoring the use of GPB in UCD patients who had previously completed 12 months of treatment in the previous safety extension studies. Ninety patients completed the previous studies with 88 of these continuing into the long-term evaluation. The duration of therapy was open ended until GPB was commercially available. The primary endpoint was the rate of adverse events (AEs). Secondary endpoints were venous ammonia levels, number and causes of hyperammonemic crises (HACs) and neuropsychological testing. RESULTS: A total of 45 pediatric patients between the ages of 1 to 17 years (median 7 years) and 43 adult patients between the ages of 19 and 61 years (median 30 years) were enrolled. The treatment emergent adverse events (TEAE) reported in >/=10% of adult or pediatric patients were consistent with the TEAEs reported in the previous safety extension studies with no increase in the overall incidence of TEAEs and no new TEAEs that indicated a new safety signal. Mean ammonia levels remained stable and below the adult upper limit of normal (<35 micromol/L) through 24 months of treatment in both the pediatric and adult population. Over time, glutamine levels decreased in the overall population. The mean annualized rate of HACs (0.29) established in the previously reported 12-month follow-up study was maintained with continued GPB exposure. CONCLUSION: Following the completion of 12-month follow-up studies with GPB treatment, UCD patients were followed for an additional median of 1.85 (range 0 to 5.86) years in the present study with continued maintenance of ammonia control, similar rates of adverse events, and no new adverse events identified. CI - Copyright (c) 2019 The Authors. Published by Elsevier Inc. All rights reserved. FAU - Diaz, George A AU - Diaz GA AD - Icahn School of Medicine at Mount Sinai, New York, NY, USA. FAU - Schulze, Andreas AU - Schulze A AD - University of Toronto and The Hospital for Sick Children, Toronto, ON, Canada. FAU - Longo, Nicola AU - Longo N AD - University of Utah, Salt Lake City, UT, USA. FAU - Rhead, William AU - Rhead W AD - Medical College of Wisconsin, Milwaukee, WI, USA. FAU - Feigenbaum, Annette AU - Feigenbaum A AD - University of Toronto and The Hospital for Sick Children, Toronto, ON, Canada. FAU - Wong, Derek AU - Wong D AD - David Geffen School of Medicine at UCLA, Los Angeles, CA, USA. FAU - Merritt, J Lawrence 2nd AU - Merritt JL 2nd AD - Seattle Children's Hospital/University of Washington, Seattle, WA, USA. FAU - Berquist, William AU - Berquist W AD - Stanford University Medical Center & Lucile Packard Children's Hospital, Stanford, CA, USA. FAU - Gallagher, Renata C AU - Gallagher RC AD - University of California, San Francisco, CA, USA. FAU - Bartholomew, Dennis AU - Bartholomew D AD - Ohio State University and Nationwide Children's Hospital, Columbus, OH, USA. FAU - McCandless, Shawn E AU - McCandless SE AD - Children's Hospital Colorado and University of Colorado Denver, Aurora, CO, USA. FAU - Smith, Wendy E AU - Smith WE AD - Maine Medical Center, Portland, ME, USA. FAU - Harding, Cary O AU - Harding CO AD - Oregon Health & Science University, Portland, OR, USA. FAU - Zori, Roberto AU - Zori R AD - University of Florida, Gainesville, FL, USA. FAU - Lichter-Konecki, Uta AU - Lichter-Konecki U AD - Children's Hospital of Pittsburgh, Pittsburgh, PA, USA. FAU - Vockley, Jerry AU - Vockley J AD - Children's Hospital of Pittsburgh, Pittsburgh, PA, USA; University of Pittsburgh School of Medicine, Pittsburgh, PA, USA. FAU - Canavan, Colleen AU - Canavan C AD - Horizon Therapeutics plc, Lake Forest, IL, USA. FAU - Vescio, Thomas AU - Vescio T AD - Horizon Therapeutics plc, Lake Forest, IL, USA. FAU - Holt, Robert J AU - Holt RJ AD - Horizon Therapeutics plc, Lake Forest, IL, USA. Electronic address: rholt@horizontherapeutics.com. FAU - Berry, Susan A AU - Berry SA AD - University of Minnesota, Minneapolis, MN, USA. LA - eng PT - Journal Article DEP - 20190710 PL - United States TA - Mol Genet Metab JT - Molecular genetics and metabolism JID - 9805456 RN - 0 (Phenylbutyrates) RN - PDC6A3C0OX (Glycerol) RN - ZH6F1VCV7B (glycerol phenylbutyrate) SB - IM MH - Adolescent MH - Adult MH - Canada MH - Child MH - Child, Preschool MH - Disease Management MH - Female MH - Follow-Up Studies MH - Glycerol/adverse effects/*analogs & derivatives/therapeutic use MH - Humans MH - Hyperammonemia/chemically induced MH - Infant MH - Male MH - Middle Aged MH - Neuropsychological Tests MH - Phenylbutyrates/adverse effects/*therapeutic use MH - United States MH - Urea Cycle Disorders, Inborn/*drug therapy MH - Young Adult OTO - NOTNLM OT - Ammonia, glutamine OT - Glycerol phenylbutyrate OT - Long-term treatment OT - Urea cycle disorders EDAT- 2019/07/22 06:00 MHDA- 2020/04/18 06:00 CRDT- 2019/07/22 06:00 PHST- 2019/05/01 00:00 [received] PHST- 2019/06/20 00:00 [revised] PHST- 2019/07/09 00:00 [accepted] PHST- 2019/07/22 06:00 [pubmed] PHST- 2020/04/18 06:00 [medline] PHST- 2019/07/22 06:00 [entrez] AID - S1096-7192(19)30323-3 [pii] AID - 10.1016/j.ymgme.2019.07.004 [doi] PST - ppublish SO - Mol Genet Metab. 2019 Aug;127(4):336-345. doi: 10.1016/j.ymgme.2019.07.004. Epub 2019 Jul 10.