GLYCEROL PHENYLBUTYRATE TREATMENT IN CHILDREN WITH UREA CYCLE DISORDERS
Susan A. Berry1, Uta Lichter-Konecki2 , George A. Diaz3, Shawn E. McCandless4, William Rhead5, Wendy
Smith6, Cynthia LeMons7, Dion F. Coakley8, Masoud Mokhtarani8 ,Bruce F. Scharschmidt8, Brendan Lee9
1
University of Minnesota, Minneapolis, MN (S.A.B.);2Children’s National Medical Center, Washington, DC
(U.L-K.);3Mount Sinai School of Medicine, Department of Genetics and Genomic Sciences, Department of
Pediatrics, New York, NY (G.A.D.);4Case Western Reserve University, Cleveland, OH (S.E.M.);5The Medical
College of Wisconsin, Milwaukee, WI (W.R.);6Maine Medical Center, Portland, ME (W.S.); 7National Urea
Cycle Disorders Foundation, 75 S. Grand Ave, Pasadena, CA 91105, 8Hyperion Therapeutics, South San
Francisco, CA (M.M., K.D, T.L.M., D.F.C, B.F.S.); 9Baylor College of Medicine, Houston, TX (S.S-N., B.L.);
Glycerol phenylbutyrate (GPB, HPN-100) has recently been approved for treatment of urea cycle
disorders (UCD) in children ≥2 years of age. We report thepooled analysis of short-term and long-term
data including open-label extension studies to assess ammonia control, amino acids, and
hyperammonemic crises (HAC) in UCD pediatric patients on GPB treatment.
Methods: Systemic exposure to ammonia (NH3), assessed as 24-hour area under the curve (NH3-AUC024hr
17yr) were pooled from 2 short-term studies involving open label switchoverfrom sodium
phenylbutyrate (NaPBA) to GPB (Lichter 2010; Smith 2012). Monthly plasma ammonia levels, amino acid
concentrations, and incidence of hyperammonemic crises (HAC) from three 12-month GPB treatment
studies involving 49 pediatric UCD patients (2 mo-17yr) were similarly pooled.HACs data were
retrospectively collected for 12 months prior to enrollment on NaPBA and prospectively during the 12
months treatment with GPB.
Results:During short-term switchover studies, NH3-AUC0-24hr was significantly lower on GPB vs. NaPBA,
710(159) on NaPBA and 661(164) (p=0.114) after 1 week of treatment with GPB.During long-term GPB
treatment,monthly NH3values were on average well below the upper limit of normal (35 µmol/L) with
monthly means ranging from 17 to 26μmol/L. As compared with the year prior to enrollment on NaPBA
in which 39% of patients reported ≥1 HAC, 22% of patients reported HACs during 12 months of GPB
treatment, with the highest rate in patients ≤6 years of age both before enrollment on NaPBA (66%) and
during long-term GPB treatment GPB (26%). During 12-month treatment with GPB, mean glutamine
levels ranged from 617-728(µmol/L). Plasma levels of branched-chain amino acids were at the lower end
of normal range at the time of enrollment while on NaPBA and remained stable over the long term
treatment with GPB. AEs during the long GPB treatment were generally mild to moderate in severity
and transient and did not increase over time; the most common included abdominal pain, rash, nausea,
vomiting, diarrhea, decreased appetite, hyperammonemia, and headache.
Conclusions:GPB is well tolerated and effectively controlsNH3and glutamine during short and long-term
treatment in pediatric UCD patients. During 12 months of GPB treatment, NH3 averaged well below ULN
and 78% of pediatric patients experience no HACs.