Hypophosphatasia (HPP) is a genetic disorder causing loss of function of tissue-nonspecific alkaline phosphatase (TNSALP) enzyme, which is necessary for bone mineralization. Clinically, the manifestation of this disease is variable; the severity of the presentation is largely determined by the age of the onset of symptoms: the earlier the onset, the more severe the condition.^1–3 In its most severe presentation, infants affected by the disease die in utero or shortly after birth, while patients who manifest HPP as infants (i.e., within six months after birth) would have severe presentation, with irreversible bone deformities, rachitic chest changes affecting respiratory functions, and exhibiting an overall one-year survival rate of around 50%.^1–5 In the mildest presentation, patients suffer from teeth loss with little or no other skeletal manifestation.^1–3,5 The incidence of the prenatal and infantile forms of HPP in Canada is estimated to be 1:100,000 live births.⁶ The incidence is much higher within the Canadian Mennonite population; it has been reported to be one in every 2,500 births in Manitoba.^7,8

Currently, except for asfotase alfa (Strensiq), there are no approved treatments for HPP. The main stream of therapy focuses on supportive care, including respiratory support, orthopedic surgery, physiotherapy, a low calcium diet, pain relief, and dental care. Asfotase alfa is a therapeutic protein that acts in place of the defective endogenous TNSALP enzyme.⁹

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
    • 3.3. Patient Disposition
    • 3.4. Exposure to Study Treatments
    • 3.5. Critical Appraisal
    • 3.6. Efficacy
    • 3.7. Harms
  • 4. DISCUSSION
    • 4.1. Summary of Available Evidence
    • 4.2. Interpretation of Results
    • 4.3. Potential Place in Therapy
  • 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. ADDITIONAL CLINICAL EVIDENCE
    • Reviewed Studies
    • Interventions
    • Patient Disposition
    • Exposure to Study Treatments
    • Critical Appraisal
    • Efficacy
    • Harms
  • APPENDIX 5. DETAILED OUTCOME DATA
  • APPENDIX 6. VALIDITY OF OUTCOME MEASURES
    • Aim
    • Findings
  • APPENDIX 7. NATURAL HISTORY OF Hypophosphatasia
  • REFERENCES
• Pharmacoeconomic Review Report
  • ABBREVIATIONS
  • EXECUTIVE SUMMARY
    • Background
    • Summary of Identified Limitations and Key Results
    • Conclusions
  • INFORMATION ON THE PHARMACOECONOMIC SUBMISSION
    • 1. SUMMARY OF THE MANUFACTURER’S PHARMACOECONOMIC SUBMISSION
    • 2. MANUFACTURER’S BASE CASE
    • 3. SUMMARY OF MANUFACTURER’S SENSITIVITY ANALYSES
    • 4. LIMITATIONS OF MANUFACTURER’S SUBMISSION
    • 5. CADTH COMMON DRUG REVIEW REANALYSIS
    • 6. ISSUES FOR CONSIDERATION
    • 7. PATIENT INPUT
    • 8. CONCLUSIONS
  • APPENDIX 1. COST COMPARISON
  • APPENDIX 2. SUMMARY OF KEY OUTCOMES
  • APPENDIX 3. ADDITIONAL INFORMATION
  • APPENDIX 4. REVIEWER WORKSHEETS
    • Manufacturer’s Model Structure
    • Manufacturer’s Results
    • Summary of Manufacturer’s Sensitivity Analysis
    • CADTH Common Drug Review Reanalyses
  • REFERENCES
• CDEC FINAL RECOMMENDATION
  • Recommendation
  • Reasons for Recommendation
  • Of Note
  • Background
  • Summary of CDEC Considerations
  • Other Discussion Points
  • 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 pediatrics who provided input on the conduct of the review and the interpretation of findings.

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