Nicola Longo1, George A Diaz2, Uta Lichter-Konecki3, Andreas Schulze4, Michal Inbar-Feigenberg4, Robert L Conway5, Allison A Bannick5, Shawn E McCandless6, Roberto Zori7, Bryan Hainline8, Nicholas Ah Mew9, Colleen Canavan10, Thomas Vescio10, Teresa Kok11, Marty H Porter10, Susan A Berry12. 1. University of Utah, Salt Lake City, UT, USA. 2. Icahn School of Medicine at Mount Sinai, New York, NY, USA. 3. Children's Hospital of Pittsburgh, Pittsburgh, PA, USA. 4. Hospital for Sick Children, University of Toronto, Toronto, Ontario, Canada. 5. Wayne State University School of Medicine, Detroit, MI, USA. 6. University of Colorado Anschutz Medical Campus and Children's Hospital Colorado, Aurora, CO, USA. 7. University of Florida, Gainesville, FL, USA. 8. Indiana University School of Medicine, Indianapolis, IN, USA. 9. Children's National Medical Center, Washington, DC, USA. 10. Horizon Therapeutics plc, Deerfield, IL, USA. 11. Horizon Therapeutics plc, Deerfield, IL, USA. Electronic address: Tkok@horizontherapeutics.com. 12. University of Minnesota, Minneapolis, MN, USA.
Abstract
BACKGROUND/AIMS: Neonatal onset Urea cycle disorders (UCDs) can be life threatening with severe hyperammonemia and poor neurological outcomes. Glycerol phenylbutyrate (GPB) is safe and effective in reducing ammonia levels in patients with UCD above 2 months of age. This study assesses safety, ammonia control and pharmacokinetics (PK) of GPB in UCD patients below 2 months of age. METHODS: This was an open-label study in UCD patients aged 0 - 2 months, consisting of an initiation/transition period (1 - 4 days) to GPB, followed by a safety extension period (6 months to 2 years). Patients presenting with a hyperammonemic crisis (HAC) did not initiate GPB until blood ammonia levels decreased to below 100 µmol/L while receiving sodium phenylacetate/sodium benzoate and/or hemodialysis. Ammonia levels, PK analytes and safety were evaluated during transition and monthly during the safety extension for 6 months and every 3 months thereafter. RESULTS: All 16 patients with UCD (median age 0.48 months, range 0.1 to 2.0 months) successfully transitioned to GPB within 3 days. Average plasma ammonia level excluding HAC was 94.3 µmol/L at baseline and 50.4 µmol/L at the end of the transition period (p = 0.21). No patient had a HAC during the transition period. During the safety extension, the majority of patients had controlled ammonia levels, with mean plasma ammonia levels lower during GPB treatment than baseline. Mean glutamine levels remained within normal limits throughout the study. PK analyses indicate that UCD patients <2 months are able to hydrolyze GPB with subsequent absorption of phenylbutyric acid (PBA), metabolism to phenylacetic acid (PAA) and conjugation with glutamine. Plasma concentrations of PBA, PAA, and phenylacetylglutamine (PAGN) were stable during the safety extension phase and mean plasma phenylacetic acid: phenylacetylglutamine ratio remained below 2.5 suggesting no accumulation of GPB. All patients reported at least 1 treatment emergent adverse event with gastroesophageal reflux disease, vomiting, hyperammonemia, diaper dermatitis (37.5% each), diarrhea, upper respiratory tract infection and rash (31.3% each) being the most frequently reported. CONCLUSIONS: This study supports safety and efficacy of GPB in UCD patients aged 0 -2 months who cannot be managed by dietary protein restriction and/or amino acid supplementation alone. GPB undergoes intestinal hydrolysis with no accumulation in this population.
BACKGROUND/AIMS: Neonatal onset Urea cycle disorders (UCDs) can be life threatening with severe hyperammonemia and poor neurological outcomes. Glycerol phenylbutyrate (GPB) is safe and effective in reducing ammonia levels in patients with UCD above 2 months of age. This study assesses safety, ammonia control and pharmacokinetics (PK) of GPB in UCD patients below 2 months of age. METHODS: This was an open-label study in UCD patients aged 0 - 2 months, consisting of an initiation/transition period (1 - 4 days) to GPB, followed by a safety extension period (6 months to 2 years). Patients presenting with a hyperammonemic crisis (HAC) did not initiate GPB until blood ammonia levels decreased to below 100 µmol/L while receiving sodium phenylacetate/sodium benzoate and/or hemodialysis. Ammonia levels, PK analytes and safety were evaluated during transition and monthly during the safety extension for 6 months and every 3 months thereafter. RESULTS: All 16 patients with UCD (median age 0.48 months, range 0.1 to 2.0 months) successfully transitioned to GPB within 3 days. Average plasma ammonia level excluding HAC was 94.3 µmol/L at baseline and 50.4 µmol/L at the end of the transition period (p = 0.21). No patient had a HAC during the transition period. During the safety extension, the majority of patients had controlled ammonia levels, with mean plasma ammonia levels lower during GPB treatment than baseline. Mean glutamine levels remained within normal limits throughout the study. PK analyses indicate that UCD patients <2 months are able to hydrolyze GPB with subsequent absorption of phenylbutyric acid (PBA), metabolism to phenylacetic acid (PAA) and conjugation with glutamine. Plasma concentrations of PBA, PAA, and phenylacetylglutamine (PAGN) were stable during the safety extension phase and mean plasma phenylacetic acid: phenylacetylglutamine ratio remained below 2.5 suggesting no accumulation of GPB. All patients reported at least 1 treatment emergent adverse event with gastroesophageal reflux disease, vomiting, hyperammonemia, diaper dermatitis (37.5% each), diarrhea, upper respiratory tract infection and rash (31.3% each) being the most frequently reported. CONCLUSIONS: This study supports safety and efficacy of GPB in UCD patients aged 0 -2 months who cannot be managed by dietary protein restriction and/or amino acid supplementation alone. GPB undergoes intestinal hydrolysis with no accumulation in this population.
Authors: Elena Martín-Hernández; Pilar Quijada-Fraile; Patricia Correcher; Silvia Meavilla; Paula Sánchez-Pintos; Javier de Las Heras Montero; Javier Blasco-Alonso; Lucy Dougherty; Ana Marquez; Luis Peña-Quintana; Elvira Cañedo; María Concepción García-Jimenez; Pedro Juan Moreno Lozano; Mercedes Murray Hurtado; María Camprodon Gómez; Delia Barrio-Carreras; Mariela de Los Santos; Mireia Del Toro; María L Couce; Isidro Vitoria Miñana; Montserrat Morales Conejo; Marcello Bellusci Journal: J Clin Med Date: 2022-08-28 Impact factor: 4.964