APPLICATION FOR INCLUSION OF FEXINIDAZOLE IN THE WHO MODEL LIST OF ESSENTIAL MEDICINES (ADULT & CHILDREN) Date: 28-Nov-2018 Total number of pages: 45 Page 1 Application for inclusion in WHO Model List of Essential Medicines 28-Nov-2018 - fexinidazole TABLE OF CONTENTS TITLE PAGE ................................................................................................................................................... 1 TABLE OF CONTENTS .................................................................................................................................. 2 LIST OF TABLES ........................................................................................................................................... 4 LIST OF FIGURES .......................................................................................................................................... 4 ABBREVIATIONS ........................................................................................................................................... 5 1 SUMMARY STATEMENT OF THE PROPOSAL FOR INCLUSION .............................................. 6 2 RELEVANT WHO TECHNICAL DEPARTMENT AND FOCAL POINT (IF APPLICABLE) - NAME OF THE FOCAL POINT IN WHO SUBMITTING OR SUPPORTING THE APPLICATION. ................................................................................................................................ 7 3 NAME OF ORGANIZATION(S) CONSULTED AND/OR SUPPORTING THE APPLICATION ................................................................................................................................. 7 4 INTERNATIONAL NONPROPRIETARY NAME (INN) AND ANATOMICAL THERAPEUTIC CHEMICAL (ATC) CODE OF MEDICINE ............................................................ 7 5 DOSE FORM(S) AND STRENGHTH(S) PROPOSED FOR INCLUSION, INCLUDING ADULT AND AGE APPROPRIATE PAEDIATRIC DOSE FORMS/STRENGTHS ........................ 8 6 WHETHER LISTING IS REQUESTED AS AN INDIVIDUAL OR AS REPRESENTATIVE OF A PHARMACOLOGICAL CLASS ............................................................................................. 9 7 TREATMENT DETAILS (REQUIREMENTS FOR DIAGNOSIS, TREATMENT AND MONITORING) ................................................................................................................................. 9 7.1 THERAPEUTIC INDICATION .......................................................................................................... 9 7.2 POSOLOGY AND METHOD OF ADMINISTRATION ..................................................................... 9 7.2.1 Special populations ........................................................................................................................ 11 7.3 WHO GUIDELINES........................................................................................................................ 11 8 INFORMATION SUPPORTING THE PUBLIC HEALTH RELEVANCE ....................................... 12 8.1 EPIDEMIOLOGY ............................................................................................................................ 12 8.2 ASSESSMENT OF CURRENT USE ............................................................................................. 16 8.3 TARGET POPULATION ................................................................................................................ 19 9 REVIEW OF BENEFITS: SUMMARY OF EVIDENCE OF COMPARATIVE EFFECTIVENESS .......................................................................................................................... 19 Page 2 Application for inclusion in WHO Model List of Essential Medicines 28-Nov-2018 - fexinidazole 9.1 IDENTIFICATION OF CLINICAL EVIDENCE ................................................................................ 19 9.2 SUMMARY OF AVAILABLE DATA ................................................................................................ 20 9.2.1 Primary analysis for efficacy results ............................................................................................... 20 9.2.2 Secondary analyses ....................................................................................................................... 22 9.2.3 Follow-up analysis.......................................................................................................................... 24 10 REVIEW OF HARMS AND TOXICITY: SUMMARY OF EVIDENCE OF SAFETY ...................... 25 10.1 ESTIMATE OF TOTAL PATIENT EXPOSURE TO DATE ............................................................ 25 10.2 DESCRIPTION OF THE ADVERSE EFFECTS/REACTIONS AND ESTIMATES OF THEIR FREQUENCY ................................................................................................................................. 26 10.3 SUMMARY OF AVAILABLE DATA ................................................................................................ 28 10.3.1 Adverse events in clinical trials ...................................................................................................... 28 10.3.1.1 In HAT patients .............................................................................................................................. 29 10.3.1.2 Other patient populations ............................................................................................................... 34 10.3.2 Clinical laboratory data .................................................................................................................. 36 10.3.3 Pregnancy and lactation ................................................................................................................ 36 10.3.4 Interactions ..................................................................................................................................... 37 10.4 SAFETY CONCLUSIONS .............................................................................................................. 39 11 SUMMARY OF AVAILABLE DATA ON COMPARATIVE COST-EFFECTIVENESS OF THE MEDICINE ............................................................................................................................. 40 12 SUMMARY OF REGULATORY STATUS AND MARKET AVAILABILITY OF THE MEDECINE .................................................................................................................................... 40 13 AVAILABILITY OF PHARMACOPOEIAL STANDARDS (BRITISH PHARMACOPOEIA, INTERNATIONAL PHARMACOPOEIA, US PHARMACOPOEAIA, EUROPEAN PHARMACOPOEIA ....................................................................................................................... 41 14 REFERENCES ............................................................................................................................... 42 15 ANNEX ........................................................................................................................................... 45 Page 3 Application for inclusion in WHO Model List of Essential Medicines 28-Nov-2018 - fexinidazole LIST OF TABLES Table 1 - Posology of fexinidazole in adults and children ............................................................................. 10 Table 2 - Summary of current treatment options for HAT ............................................................................. 17 Table 3 - List of studies in the fexinidazole clinical development programme .............................................. 20 Table 4: FEX004 Primary Analysis: Success rate at M18 per randomized treatment group and Non- inferiority test – mITT population ................................................................................................................... 21 Table 5: FEX005 Primary Analysis: Success rate at M12 ............................................................................. 21 Table 6: FEX006 Primary Analysis: Success rate at M12 (ITT population) .................................................. 22 Table 7 – Efficacy outcome at 12 and 18 months after the end of treatment with fexinidazole or NECT (primary efficacy population, clinical efficacy studies in HAT) ....................................................................... 22 Table 8 - Treatment success at 18 months according to baseline CSF-WBC count .................................... 23 Table 9 - Comparison between 18 and 24 months and between primary and follow-up analysis ................ 24 Table 10 - List of studies in the fexinidazole clinical development programme ............................................ 25 Table 11 - Adverse Reactions by decreasing frequency reported in at least 2 patients treated with fexinidazole .................................................................................................................................................... 27 LIST OF FIGURES Figure 1 - fexinidazole structure ...................................................................................................................... 8 Figure 2 – Distribution of cases and risk of T. b. gambiense infection in Africa (2010-2014) ....................... 15 Page 4 Application for inclusion in WHO Model List of Essential Medicines 28-Nov-2018 - fexinidazole ABBREVIATIONS AE: Adverse event ALP: Alkaline phosphatase ALT: alanine aminotransferase AST: aspartate aminotransferase ATC: Anatomical Therapeutic Chemical BBB: Blood Brain Barrier CD: Chagas disease CI: Confidence Interval CNS: Central Nervous System CSF: Cerebrospinal fluid DBL: Database lock DNDi: Drugs for Neglected Diseases initiative DRC: Democratic Republic of Congo ECG: