26 July 2018 EMA/CHMP/581111/2018 Committee for Medicinal Products for Human Use (CHMP) Assessment report Eladynos International non-proprietary name: abaloparatide Procedure No. EMEA/H/C/004157/0000 Note Assessment report as adopted by the CHMP with all information of a commercially confidential nature deleted. 30 Churchill Place ● Canary Wharf ● London E14 5EU ● United Kingdom Telephone +44 (0)20 3660 6000 Facsimile +44 (0)20 3660 5555 Send a question via our website www.ema.europa.eu/contact An agency of the European Union © European Medicines Agency, 2019. Reproduction is authorised provided the source is acknowledged. Table of contents 1. Background information on the procedure .............................................. 7 1.1. Submission of the dossier ...................................................................................... 7 1.2. Steps taken for the assessment of the product ......................................................... 8 1.3. Steps taken for the re-examination procedure ......................................................... 9 2. Scientific discussion .............................................................................. 10 2.1.1. Disease or condition ......................................................................................... 10 2.1.2. Epidemiology and risk factors, screening tools / prevention .................................. 10 2.1.3. Aetiology and pathogenesis .............................................................................. 10 2.1.4. Clinical presentation and diagnosis .................................................................... 10 2.1.5. Management ................................................................................................... 11 2.1.6. About the product ............................................................................................ 11 2.2. Quality aspects .................................................................................................. 12 2.2.1. Introduction .................................................................................................... 12 2.2.2. Active Substance ............................................................................................. 12 2.2.3. Finished Medicinal Product ................................................................................ 18 2.2.4. Discussion on chemical, pharmaceutical and biological aspects .............................. 24 2.2.5. Conclusions on the chemical, pharmaceutical and biological aspects ...................... 25 2.2.6. Recommendations for future quality development ............................................... 25 2.3. Non-clinical aspects ............................................................................................ 25 2.3.1. Pharmacology ................................................................................................. 25 2.3.2. Pharmacokinetics............................................................................................. 31 2.3.3. Toxicology ...................................................................................................... 35 2.3.4. Ecotoxicity/environmental risk assessment ......................................................... 40 2.3.5. Discussion on non-clinical aspects...................................................................... 40 2.3.6. Conclusion on non-clinical aspects ..................................................................... 42 2.4. Clinical aspects .................................................................................................. 42 2.4.1. Introduction .................................................................................................... 42 2.4.2. Pharmacokinetics............................................................................................. 46 2.4.3. Pharmacodynamics .......................................................................................... 49 2.4.4. Discussion on clinical pharmacology ................................................................... 51 2.4.5. Conclusions on clinical pharmacology ................................................................. 52 2.5. Clinical efficacy .................................................................................................. 52 2.5.1. Dose response studies and main clinical studies .................................................. 52 2.5.2. Discussion on clinical efficacy ............................................................................ 78 2.5.3. Conclusions on clinical efficacy .......................................................................... 85 2.6. Clinical safety .................................................................................................... 86 2.6.1. Discussion on clinical safety ............................................................................ 104 2.6.2. Conclusions on clinical safety .......................................................................... 110 2.7. Risk Management Plan ...................................................................................... 112 2.8. Pharmacovigilance ............................................................................................ 115 2.9. New Active Substance ....................................................................................... 115 Assessment report EMA/CHMP/581111/2018 Page 2/157 2.10. Product information ........................................................................................ 115 2.10.1. User consultation ......................................................................................... 115 2.10.2. Additional monitoring ................................................................................... 116 3. Benefit-Risk Balance............................................................................ 116 3.1. Therapeutic Context ......................................................................................... 116 3.1.1. Disease or condition ....................................................................................... 116 3.1.2. Available therapies and unmet medical need ..................................................... 116 3.1.3. Main clinical studies ....................................................................................... 117 3.2. Favourable effects ............................................................................................ 117 3.3. Uncertainties and limitations about favourable effects ........................................... 118 3.4. Unfavourable effects ......................................................................................... 119 3.5. Uncertainties and limitations about unfavourable effects ....................................... 120 3.6. Effects Table .................................................................................................... 122 3.7. Benefit-risk assessment and discussion ............................................................... 123 3.7.1. Importance of favourable and unfavourable effects ............................................ 123 3.7.2. Balance of benefits and risks ........................................................................... 124 3.7.3. Additional considerations on the benefit-risk balance ......................................... 126 3.8. Conclusions ..................................................................................................... 126 4. Recommendations ............................................................................... 126 5. Re-examination of the CHMP opinion of 22 March 2018 ...................... 127 5.1. Risk Management Plan ...................................................................................... 139 6. Benefit-risk balance following re-examination .................................... 139 6.1. Therapeutic Context ......................................................................................... 139 6.2. Favourable effects ............................................................................................ 140 6.3. Uncertainties and limitations about favourable effects ........................................... 141 6.4. Unfavourable effects ......................................................................................... 142 6.5. Uncertainties and limitations about unfavourable effects ....................................... 143 6.6. Effects Table .................................................................................................... 146 6.7. Benefit-risk assessment and discussion ............................................................... 149 6.7.1. Importance of favourable and unfavourable effects ............................................ 149 6.7.2. Balance of benefits and risks ........................................................................... 151 6.8. Conclusions ..................................................................................................... 152 7. Recommendations following re-examination ....................................... 152 Appendix ................................................................................................. 154 Divergent position – Eladynos (EMEA/H/C/004157) ............................... 157 Assessment report EMA/CHMP/581111/2018 Page 3/157 List of abbreviations ABL Abaloparatide ABL-IV Abaloparatide intravenous ABL-SC Abaloparatide subcutaneous ABL-TD Abaloparatide transdermal ADA Anti-drug antibodies AE Adverse event AESI Adverse