14 November 2019 EMA/686622/2019 Committee for Medicinal Products for Human Use (CHMP) Assessment report Sunosi International non-proprietary name: solriamfetol Procedure No. EMEA/H/C/004893/0000 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 Send us a question Go to www.ema.europa.eu/contact Telephone +31 (0)88 781 6000 An agency of the European Union 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 .................................................................................................. 12 2.2.1. Introduction.................................................................................................... 12 2.2.2. Active Substance ............................................................................................. 12 2.2.3. Finished Medicinal Product ................................................................................ 14 2.2.4. Discussion on chemical, pharmaceutical and biological aspects.............................. 16 2.2.5. Conclusions on the chemical, pharmaceutical and biological aspects ...................... 16 2.2.6. Recommendation for future quality development ................................................. 16 2.3. Non-clinical aspects ............................................................................................ 16 2.3.1. Introduction.................................................................................................... 16 2.3.2. Pharmacology ................................................................................................. 17 2.3.3. Pharmacokinetics ............................................................................................ 27 2.3.4. Toxicology ...................................................................................................... 30 2.3.5. Ecotoxicity/environmental risk assessment ......................................................... 34 2.3.6. Discussion on non-clinical aspects ..................................................................... 35 2.3.7. Conclusion on the non-clinical aspects ............................................................... 41 2.4. Clinical aspects .................................................................................................. 41 2.4.1. Introduction.................................................................................................... 41 2.4.2. Pharmacokinetics ............................................................................................ 44 2.4.3. Pharmacodynamics .......................................................................................... 46 2.4.4. Discussion on clinical pharmacology ................................................................... 49 2.4.5. Conclusions on clinical pharmacology ................................................................. 50 2.5. Clinical efficacy .................................................................................................. 51 2.5.1. Dose response study(ies) ................................................................................. 51 2.5.2. Main study(ies) ............................................................................................... 52 2.5.3. Discussion on clinical efficacy ............................................................................ 75 2.5.4. Conclusions on the clinical efficacy .................................................................... 85 2.6. Clinical safety .................................................................................................... 85 2.6.1. Discussion on clinical safety .............................................................................. 99 2.6.2. Conclusions on the clinical safety .................................................................... 106 2.7. Risk Management Plan ...................................................................................... 108 2.8. Pharmacovigilance ........................................................................................... 112 Assessment report EMA/686622/2019 Page 2/128 2.9. New Active Substance ...................................................................................... 112 2.10. Product information ........................................................................................ 113 2.10.1. User consultation ......................................................................................... 113 2.10.2. Additional monitoring ................................................................................... 113 3. Benefit-Risk Balance ........................................................................... 114 3.1. Therapeutic Context ......................................................................................... 114 3.1.1. Disease or condition ...................................................................................... 114 3.1.2. Available therapies and unmet medical need ..................................................... 114 3.1.3. Main clinical studies ....................................................................................... 115 3.2. Favourable effects ............................................................................................ 116 3.3. Uncertainties and limitations about favourable effects ........................................... 117 3.4. Unfavourable effects ......................................................................................... 119 3.5. Uncertainties and limitations about unfavourable effects ....................................... 120 3.6. Effects Table .................................................................................................... 121 3.7. Benefit-risk assessment and discussion ............................................................... 121 3.7.1. Importance of favourable and unfavourable effects ............................................ 121 3.7.2. Balance of benefits and risks .......................................................................... 123 3.7.3. Additional considerations on the benefit-risk balance ......................................... 123 3.8. Conclusions ..................................................................................................... 123 4. Recommendations ............................................................................... 124 5. Appendices .......................................................................................... 126 Assessment report EMA/686622/2019 Page 3/128 List of abbreviations 5-HT 5-Hydroxytryptophan, serotonin AASM American Academy of Sleep Medicine AE Adverse event AEOI Adverse event of interest AHQ Ad hoc query ANOVA analysis of variance AUC Area under the concentration-time curve AUC0-inf Area under the concentration-time curve from time 0 to infinity AUC0-t Area under the concentration-time curve from time 0 to time of last quantifiable concentration AUCtau Area under the concentration-time curve during one dosing interval at steady state AUC50 Effective AUC associated with 50% of the placebo-subtracted drug effect AUC80 Effective AUC associated with 80% of the placebo-subtracted drug effect BCS Biopharmaceutics Classification System BP Blood pressure bpm Beats per minute CGIc Clinical Global Impression of Change CGIs Clinical Global Impression of Severity CHMP Committee for Medicinal Products for Human use CI Confidence interval CL/F Apparent oral clearance CLR Renal clearance Cmax Maximum plasma concentration CPAP Continuous positive airway pressure CQA Critical quality attribute CrCl Creatinine clearance CSR Clinical study report C-SSRS Columbia-Suicide Severity Rating Scale DA Dopamine DAT Dopamine reuptake transporter DBP Diastolic blood pressure DNRI Dopamine and norepinephrine reuptake inhibitor DPA D-Phenylalaninol D-Phe D-Phenylalanine DSC Differential Scanning Calorimetry DSM-5 Diagnostic and Statistical Manual of Mental Disorders, 5th Edition DVS Dynamic vapour sorption EC European Commission ECG Electrocardiogram Emax Maximum effect EOP2 End-of-Phase-2 EDS Excessive daytime sleepiness ESRD End stage renal disease ESS Epworth Sleepiness Scale FDA Food and Drug Administration GFR Glomerular filtration rate HDPE High density