25 March 2021 EMA/CHMP/236249/2021 Committee for Medicinal Products for Human Use (CHMP) Assessment report Copiktra International non-proprietary name: duvelisib Procedure No. EMEA/H/C/005381/0000 Note Assessment report as adopted by the CHMP with all information of a commercially confidential nature deleted. Official address Domenico Scarlattilaan 6 ● 1083 HS Amsterdam ● The Netherlands Address for visits and deliveries Refer to www.ema.europa.eu/how-to-find-us An agency of the European Union Send us a question Go to www.ema.europa.eu/contact Telephone +31 (0)88 781 6000 © European Medicines Agency, 2021. 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 2. Scientific discussion .......................................................................... 10 2.1. Problem statement ............................................................................................. 10 2.1.1. Disease or condition......................................................................................... 10 2.1.2. Epidemiology .................................................................................................. 10 2.1.3. Biologic features.............................................................................................. 10 2.1.4. Clinical presentation, diagnosis ......................................................................... 11 2.1.5. Management ................................................................................................... 11 2.2. Quality aspects .................................................................................................. 15 2.2.1. Introduction.................................................................................................... 15 2.2.2. Active substance ............................................................................................. 15 2.2.3. Finished medicinal product ............................................................................... 18 2.2.4. Discussion on chemical, and pharmaceutical aspects............................................ 21 2.2.5. Conclusions on the chemical, pharmaceutical and biological aspects ...................... 21 2.2.6. Recommendations for future quality development ............................................... 22 2.3. Non-clinical aspects ............................................................................................ 22 2.3.1. Introduction.................................................................................................... 22 2.3.2. Pharmacology ................................................................................................. 22 2.3.3. Pharmacokinetics ............................................................................................ 29 2.3.4. Toxicology ...................................................................................................... 33 2.3.5. Ecotoxicity/environmental risk assessment ......................................................... 44 2.3.6. Discussion on non-clinical aspects ..................................................................... 45 2.3.7. Conclusion on the non-clinical aspects................................................................ 47 2.4. Clinical aspects .................................................................................................. 48 2.4.1. Introduction.................................................................................................... 48 2.4.2. Pharmacokinetics ............................................................................................ 55 2.4.3. Pharmacodynamics .......................................................................................... 70 2.4.4. Discussion on clinical pharmacology ................................................................... 74 2.4.5. Conclusions on clinical pharmacology ................................................................. 78 2.5. Clinical efficacy .................................................................................................. 79 2.5.1. Dose response study(ies) ................................................................................. 79 2.5.2. Main studies ................................................................................................... 80 2.5.3. Discussion on clinical efficacy .......................................................................... 139 2.5.4. Conclusions on the clinical efficacy................................................................... 146 2.6. Clinical safety .................................................................................................. 147 2.6.1. Discussion on clinical safety ............................................................................ 193 2.6.2. Conclusions on the clinical safety..................................................................... 195 2.7. Risk Management Plan ...................................................................................... 196 assessment report EMA/CHMP/236249/2021 Page 2/206 2.8. Pharmacovigilance............................................................................................ 197 2.9. New Active Substance....................................................................................... 198 2.10. Product information ........................................................................................ 198 2.10.1. User consultation ......................................................................................... 198 2.10.2. Additional monitoring ................................................................................... 198 3. Benefit-Risk Balance ....................................................................... 199 3.1. Therapeutic Context ......................................................................................... 199 3.1.1. Disease or condition....................................................................................... 199 3.1.2. Available therapies and unmet medical need ..................................................... 199 3.1.3. Main clinical studies ....................................................................................... 199 3.2. Favourable effects ............................................................................................ 200 3.3. Uncertainties and limitations about favourable effects ........................................... 200 3.4. Unfavourable effects ......................................................................................... 201 3.5. Uncertainties and limitations about unfavourable effects ....................................... 202 3.6. Effects Table .................................................................................................... 202 3.7. Benefit-risk assessment and discussion ............................................................... 204 3.7.1. Importance of favourable and unfavourable effects ............................................ 204 3.7.2. Balance of benefits and risks........................................................................... 205 3.7.3. Additional considerations on the benefit-risk balance ......................................... 205 3.8. Conclusions ..................................................................................................... 205 4. Recommendations .......................................................................... 205 assessment report EMA/CHMP/236249/2021 Page 3/206 List of abbreviations Abbreviation Definition AKT Protein kinase B ALC Absolute lymphocytic count AT All Treated BID Twice daily BOR Best overall response BTK Bruton’s tyrosine kinase CI Confidence interval CLL Chronic lymphocytic leukaemia CR Complete response/remission CRi Complete response/remission with incomplete marrow recovery CT Computed tomography CSR Clinical study report CSR-07 Clinical study report Study IPI-145-07 CSR-06 Clinical study report Study IPI-145-06 DE Dose-escalation DOR Duration of response EC Expansion cohort ECOG Eastern Cooperative Oncology Group eCRF Electronic Case Report Form ESMO European Society of Medical Oncology EWB Emotion well-being FACIT Functional Assessment of Chronic Illness Therapy-Fatigue FACT Functional Assessment of Cancer Therapy-General FAS Full analysis set FL Follicular lymphoma FLIPI Follicular Lymphoma International Prognostic Index FWB Functional well-being assessment report EMA/CHMP/236249/2021 Page 4/206 Abbreviation Definition HR Hazard ratio HRQoL Health-related quality of life IGHV Ig heavy chain V-111 iNHL Indolent non-Hodgkin lymphoma IRC Independent Review Committee ITT Intent-to-Treat IV Intravenously IWCLL International Workshop on Chronic Lymphocytic Leukaemia IWG International Working Group LDH lactate dehydrogenase LNR Lymph node response LNRR Lymph node response rate MID Minimal important difference MTD Maximum tolerated dose MZL Marginal zone lymphoma ORR Overall response rate OS Overall survival p-AKT Phosphorylated protein kinase B PD Progressive disease/Pharmacodynamic PFS Progression-free survival PI3K Phosphoinositide 3-kinase PK pharmacokinetic PBMC peripheral blood mononuclear cell PO By mouth PP Per-Protocol PR Partial response/remission