George A Diaz1, Andreas Schulze2, Nicola Longo3, William Rhead4, Annette Feigenbaum2, Derek Wong5, J Lawrence Merritt6, William Berquist7, Renata C Gallagher8, Dennis Bartholomew9, Shawn E McCandless10, Wendy E Smith11, Cary O Harding12, Roberto Zori13, Uta Lichter-Konecki14, Jerry Vockley15, Colleen Canavan16, Thomas Vescio16, Robert J Holt17, Susan A Berry18. 1. Icahn School of Medicine at Mount Sinai, New York, NY, USA. 2. University of Toronto and The Hospital for Sick Children, Toronto, ON, Canada. 3. University of Utah, Salt Lake City, UT, USA. 4. Medical College of Wisconsin, Milwaukee, WI, USA. 5. David Geffen School of Medicine at UCLA, Los Angeles, CA, USA. 6. Seattle Children's Hospital/University of Washington, Seattle, WA, USA. 7. Stanford University Medical Center & Lucile Packard Children's Hospital, Stanford, CA, USA. 8. University of California, San Francisco, CA, USA. 9. Ohio State University and Nationwide Children's Hospital, Columbus, OH, USA. 10. Children's Hospital Colorado and University of Colorado Denver, Aurora, CO, USA. 11. Maine Medical Center, Portland, ME, USA. 12. Oregon Health & Science University, Portland, OR, USA. 13. University of Florida, Gainesville, FL, USA. 14. Children's Hospital of Pittsburgh, Pittsburgh, PA, USA. 15. Children's Hospital of Pittsburgh, Pittsburgh, PA, USA; University of Pittsburgh School of Medicine, Pittsburgh, PA, USA. 16. Horizon Therapeutics plc, Lake Forest, IL, USA. 17. Horizon Therapeutics plc, Lake Forest, IL, USA. Electronic address: rholt@horizontherapeutics.com. 18. University of Minnesota, Minneapolis, MN, USA.
Abstract
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 µmol/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.
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 µmol/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.
Authors: Monica Campo; Sarah Heater; Glenna J Peterson; Jason D Simmons; Shawn J Skerrett; Harriet Mayanja-Kizza; Catherine M Stein; W Henry Boom; Thomas R Hawn Journal: Tuberculosis (Edinb) Date: 2021-02-18 Impact factor: 3.131
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