Cystic fibrosis (CF), an autosomal recessive condition, is the most common fatal genetic disease affecting children and young adults in Canada. It is caused by mutations in the CF transmembrane conductance regulator (CFTR) gene, located on chromosome seven. This gene encodes for a chloride channel that regulates transport of salt and water across cell membranes. When CFTR is dysfunctional, secretions become tenacious and sticky, resulting in pathology in multiple organ systems, most notably the lungs and gastrointestinal tract.

Although there is no cure for the underlying disease process, current therapies have increased the overall survival of CF patients, with the median life expectancy now at 48 years based on recent Canadian statistics. The goals of CF therapy until now have been: (1) preservation of lung function by minimizing pulmonary infection and inflammation; (2) restoration of baseline pulmonary function, symptoms, and level of inflammation following acute respiratory exacerbations; and (3) maintenance of adequate nutrition. Therapeutic strategy consists of a combination of physiotherapy, pharmacologic drugs (i.e., antibiotics, anti-inflammatory drugs, mucolytic drugs), nutritional treatments (i.e., high-calorie and high-fat diets) and pancreatic enzyme replacement for those with pancreatic insufficiency. To date, no therapies have addressed the underlying genetic defect or corrected the abnormal functioning of CFTR.

Ivacaftor is a first-in-class oral CFTR potentiator approved by Health Canada for the treatment of CF in patients aged six years and older who have G551D, G1244E, G1349D, G178R, G551S, S1251N, S1255P, S549N, S549R, or G970R mutation in the CFTR gene. The drug works by prolonging the time that activated CFTR channels remain open, thereby enhancing the regulation of chloride and water transport across cell membranes. It is available as a 150 mg oral tablet. The Health Canada recommended dose is 150 mg every 12 hours with fat-containing food. The manufacturer is seeking a listing recommendation based on the Health Canada indication.

Accordingly, a systematic review was undertaken to evaluate the beneficial and harmful effects of ivacaftor 150 mg for the treatment of CF in patients age six years and older who have a G551D, G1244E, G1349D, G178R, G551S, S1251N, S1255P, S549N, S549R, or G970R mutation in the CFTR gene.

Contents

• Clinical Review Report
  • ABBREVIATIONS
  • EXECUTIVE SUMMARY
    • Introduction
    • Results and Interpretation
    • Other Considerations
    • Pharmacoeconomic Summary
    • 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 Other Considerations
  • 5. CONCLUSIONS
  • APPENDIX 1 PATIENT INPUT SUMMARY
  • APPENDIX 2 LITERATURE SEARCH STRATEGY
  • APPENDIX 3 EXCLUDED STUDIES
  • APPENDIX 4 DETAILED OUTCOME DATA
  • APPENDIX 5 VALIDITY OF OUTCOME MEASURES
  • APPENDIX 6 SUMMARY OF OTHER STUDIES
  • REFERENCES
• Pharmacoeconomic Review Report
  • ABBREVIATIONS
  • EXECUTIVE SUMMARY OF THE PHARMACOECONOMIC SUBMISSION
    • Background
    • Summary of Economic Analysis
    • Results of Manufacturer’s Analysis
    • Interpretations and Key Limitations
    • Results of CADTH Common Drug Review Analyses
    • Conclusions
  • 1. INTRODUCTION
    • 1.1 Study Question
    • 1.2 Treatment
    • 1.3 Comparators
    • 1.4 Type of Economic Evaluation
    • 1.5 Population
  • 2. METHODS
    • 2.1 Model Structure
    • 2.2 Clinical Inputs
  • 3. RESULTS
    • 3.1 Manufacturer’s Base Case
    • 3.2 Summary of the Manufacturer’s Sensitivity Analyses
    • 3.3 CADTH Common Drug Review Analyses
  • 4. DISCUSSION
    • 4.1 Patient Input
  • 5. CONCLUSIONS
  • APPENDIX 1 COST COMPARISON TABLE FOR DRUGS USED FOR CYSTIC FIBROSIS
  • APPENDIX 2 SUMMARY OF KEY OUTCOMES
  • APPENDIX 3 ADDITIONAL INFORMATION
  • REFERENCES
• CDEC Final Recommendation
  • Recommendation
  • Reasons for the 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 Respirology who provided input on the conduct of the review and the interpretation of findings.

This report was prepared by the Canadian Agency for Drugs and Technologies in Health (CADTH). Through the CADTH Common Drug Review (CDR) process, CADTH undertakes reviews of drug submissions, resubmissions, and requests for advice, and provides formulary listing recommendations to all Canadian publicly funded federal, provincial, and territorial drug plans, with the exception of Quebec.

The report contains an evidence-based clinical and/or pharmacoeconomic drug review, based on published and unpublished material, including manufacturer submissions; studies identified through independent, systematic literature searches; and patient-group submissions. In accordance with CDR Update — Issue 87, manufacturers may request that confidential information be redacted from the CDR Clinical and Pharmacoeconomic Review Reports.

The information in this report 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. The information in this report should not be used as a substitute for the application of clinical judgment with respect to the care of a particular patient or other professional judgment in any decision-making process, nor is it intended to replace professional medical advice. While CADTH has taken care in the preparation of this document to ensure that its contents are accurate, complete, and up-to-date as of the date of publication, CADTH does not make any guarantee to that effect. CADTH is not responsible for the quality, currency, propriety, accuracy, or reasonableness of any statements, information, or conclusions contained in the source documentation. CADTH is not responsible for any errors or omissions or 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 information in this document or in any of the source documentation.

This document is intended for use in the context of the Canadian health care system. Other health care systems are different; the issues and information related to the subject matter of this document may be different in other jurisdictions and, if used outside of Canada, it is at the user’s 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.

CADTH takes sole responsibility for the final form and content of this document, subject to the limitations noted above. The statements and conclusions in this document are those of CADTH and not of its advisory committees and reviewers. The statements, conclusions, and views expressed herein do not necessarily represent the views of Health Canada or any Canadian provincial or territorial government. Production of this document is made possible by financial contributions from Health Canada and the governments of Alberta, British Columbia, Manitoba, New Brunswick, Newfoundland and Labrador, Northwest Territories, Nova Scotia, Nunavut, Ontario, Prince Edward Island, Saskatchewan, and Yukon.