Urea cycle disorders (UCDs) result from genetic mutations that cause defects in any of the five enzymes of the urea cycle in the liver: carbamoyl phosphate synthetase 1 (CPS1), ornithine transcarbamylase (OTC), argininosuccinate synthetase (ASS), argininosuccinate lyase, and arginase; in the co-factor producer N-acetyl glutamate synthetase; or in the ornithine transporter and citrin. The estimated incidence of UCDs ranges from one in 22,179 births to one in 53,717 births. The most recent estimate of incidence of UCDs for the US is around one in 35,000 births. It is estimated that approximately 11 new cases of UCDs will be diagnosed each year in Canada. The incidence of OTC deficiency (one in 56,500 live births) is higher than other UCDs. Deficiencies in the urea cycle may result in excessive ammonia levels due to impaired metabolism, which can be life-threatening and result in permanent neurological damage if left untreated. Treatment should be initiated as soon as a diagnosis of a UCD is suspected and should proceed simultaneously with the diagnostic evaluation.

The goals of long-term management of UCDs are to achieve normal development, to prevent hyperammonemia, and to maintain a good quality of life (QoL). These are achieved through a low-protein diet (and sometimes essential amino acids and other essential nutrients supplementation), pharmacotherapies to increase waste nitrogen excretion, and liver transplantation in selected patients. Sodium phenylbutyrate (NaPBA) is the mainstay of pharmacological therapy in chronic management of UCDs; however, its use is associated with decreased appetite, taste disturbances, body odour and menstrual dysfunction/amenorrhea. More recently, glycerol phenylbutyrate (GPB, brand name Ravicti) was approved as a nitrogen-scavenging therapy. This is a triglyceride containing three molecules of phenylbutyric acid. Its major metabolite, phenylacetic acid, conjugates with glutamine through acetylation in the liver and kidneys to form phenylacetylglutamine, which is excreted by the kidneys. GPB is administered orally with a recommended total dose ranging from 4.5 mL/m² per day to 11.2 mL/m² per day (5.0 g/m² per day to 12.4 g/m² per day). For patients who have been previously treated with NaPBA, the total daily dose of GPB can be calculated based on the total daily dose of NaPBA.

The objective of this systematic review is to examine the beneficial and harmful effects of GPB as a nitrogen-binding agent adjunctive to dietary protein restriction and dietary supplements for chronic management of adult and pediatric (at least two years of age) patients with UCDs.

Contents

• Clinical Review Report
  • ABBREVIATIONS
  • EXECUTIVE SUMMARY
    • Introduction
    • Results and Interpretation
    • Conclusions
  • 1. INTRODUCTION
    • 1.1. Disease Prevalence and Incidence
    • 1.2. Standards of Therapy
    • 1.3. Drug
  • 2. OBJECTIVES AND METHODS
    • 2.1. Objectives
    • 2.2. Methods
  • 3. RESULTS
    • 3.1. Findings from the Literature
    • 3.2. Included Studies
    • 3.6. Patient Disposition
    • 3.7. Exposure to Study Treatments
    • 3.8. Critical Appraisal
    • 3.9. Efficacy
    • 3.10. Harms
  • 4. DISCUSSION
    • 4.1. Summary of Available Evidence
    • 4.2. Interpretation of Results
  • 5. CONCLUSIONS
  • APPENDIX 1. PATIENT INPUT SUMMARY
    • 1. Brief Description of Patient Group(s) Supplying Input
    • 2. Condition-Related Information
    • 3. Current Therapy-Related Information
    • 4. Expectations About the Drug Being Reviewed
  • APPENDIX 2. LITERATURE SEARCH STRATEGY
  • APPENDIX 3. EXCLUDED STUDIES
  • APPENDIX 4. DETAILED OUTCOME DATA
  • APPENDIX 5. VALIDITY OF OUTCOME MEASURES
    • Aim
    • Ammonia and Glutamine
    • Quality of Life
    • Neuropsychological Tests
  • APPENDIX 6. SUMMARY OF EFFICACY AND SAFETY RESULTS IN THREE SHORT-TERM, NON-RANDOMIZED STUDIES: UP 1204-003, HPN-100-005, AND HPN-100-012
    • Objective
    • Findings
    • Summary
  • APPENDIX 7. SUMMARY OF EFFICACY AND SAFETY RESULTS IN THREE LONG-TERM, NON-RANDOMIZED STUDIES: HPN-100-005, HPN-100-007, AND HPN-100-012
    • Objective
    • Findings
    • Limitations
    • Summary
  • REFERENCES
• Pharmacoeconomic Review Report
  • ABBREVIATIONS
  • EXECUTIVE SUMMARY
    • Background
    • Summary of Identified Key Limitations
    • Key Results and Conclusions
  • INFORMATION ON THE PHARMACOECONOMIC SUBMISSION
    • 1. SUMMARY OF THE MANUFACTURER’S PE SUBMISSION
    • 2. MANUFACTURER’S BASE CASE
    • 3. SUMMARY OF MANUFACTURER’S SENSITIVITY ANALYSES
    • 4. LIMITATIONS OF MANUFACTURER’S SUBMISSION
    • 5. CADTH COMMON DRUG REVIEW REANALYSES
    • 6. ISSUES FOR CONSIDERATION
    • 7. PATIENT INPUT
    • 8. CONCLUSIONS
  • APPENDIX 1. COST COMPARISON
  • APPENDIX 2. ADDITIONAL INFORMATION
  • APPENDIX 3. REVIEWER WORKSHEETS
    • Manufacturer’s Model Structure
    • Manufacturer’s Results
    • CADTH Common Drug Review Reanalyses
  • APPENDIX 4. CLINICAL DATA USED IN REANALYSIS
    • Revised Results Based on Reconstructed Model (CDR Baseline)
  • REFERENCES
• CDEC FINAL RECOMMENDATION
  • Recommendation
  • Of Note
  • Other Discussion Points
  • Background
  • Summary of CDEC Considerations
  • Patient Input Information
  • Research Gaps

This review report was prepared by the Canadian Agency for Drugs and Technologies in Health (CADTH). In addition to CADTH staff, the review team included a clinical expert in Metabolic Genetics who provided input on the conduct of the review and the interpretation of findings.

The information in this document is intended to help Canadian health care decision-makers, health care professionals, health systems leaders, and policy-makers make well-informed decisions and thereby improve the quality of health care services. While patients and others may access this document, the document is made available for informational purposes only and no representations or warranties are made with respect to its fitness for any particular purpose. The information in this document should not be used as a substitute for professional medical advice or as a substitute for the application of clinical judgment in respect of the care of a particular patient or other professional judgment in any decision-making process. The Canadian Agency for Drugs and Technologies in Health (CADTH) does not endorse any information, drugs, therapies, treatments, products, processes, or services.

While care has been taken to ensure that the information prepared by CADTH in this document is accurate, complete, and up-to-date as at the applicable date the material was first published by CADTH, CADTH does not make any guarantees to that effect. CADTH does not guarantee and is not responsible for the quality, currency, propriety, accuracy, or reasonableness of any statements, information, or conclusions contained in any third-party materials used in preparing this document. The views and opinions of third parties published in this document do not necessarily state or reflect those of CADTH.

CADTH is not responsible for any errors, omissions, injury, loss, or damage arising from or relating to the use (or misuse) of any information, statements, or conclusions contained in or implied by the contents of this document or any of the source materials.

This document may contain links to third-party websites. CADTH does not have control over the content of such sites. Use of third-party sites is governed by the third-party website owners’ own terms and conditions set out for such sites. CADTH does not make any guarantee with respect to any information contained on such third-party sites and CADTH is not responsible for any injury, loss, or damage suffered as a result of using such third-party sites. CADTH has no responsibility for the collection, use, and disclosure of personal information by third-party sites.

Subject to the aforementioned limitations, the views expressed herein are those of CADTH and do not necessarily represent the views of Canada’s federal, provincial, or territorial governments.

This document is prepared and intended for use in the context of the Canadian health care system. The use of this document outside of Canada is done so at the user’s own risk.

This disclaimer and any questions or matters of any nature arising from or relating to the content or use (or misuse) of this document will be governed by and interpreted in accordance with the laws of the Province of Ontario and the laws of Canada applicable therein, and all proceedings shall be subject to the exclusive jurisdiction of the courts of the Province of Ontario, Canada.

The statements, findings, conclusions, views, and opinions contained and expressed in this publication are based in part on data obtained under license from IMS Health Canada Inc. concerning the following information service: DeltaPA. All Rights Reserved. Subject to the aforementioned limitations, the views expressed herein are those of CADTH and do not necessarily represent the views of Canada’s federal, provincial, or territorial governments or any third-party data supplier.