30 January 2020 EMA/CHMP/86002/2020 Committee for Medicinal Products for Human Use (CHMP) Assessment report Trepulmix International non-proprietary name: treprostinil sodium Procedure No. EMEA/H/C/005207/0000 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 ................................................................................ 9 2.1. Introduction ........................................................................................................ 9 2.2. Problem statement ............................................................................................... 9 2.2.1. Disease or condition .......................................................................................... 9 2.2.2. Epidemiology .................................................................................................... 9 2.2.3. Aetiology and pathogenesis .............................................................................. 10 2.2.4. Clinical presentation, diagnosis ......................................................................... 10 2.2.5. Management ................................................................................................... 11 2.3. Quality aspects .................................................................................................. 13 2.3.1. Introduction.................................................................................................... 13 2.3.2. Active substance ............................................................................................. 13 General Information .................................................................................................. 13 Manufacture, process controls and characterisation ....................................................... 13 2.3.3. Finished medicinal product ............................................................................... 15 Description of the product and Pharmaceutical Development .......................................... 15 Manufacture of the product and process controls .......................................................... 16 Product specification, analytical procedures, batch analysis ............................................ 17 Stability of the product .............................................................................................. 17 Adventitious agents .................................................................................................. 18 2.3.4. Discussion on chemical, and pharmaceutical aspects ........................................... 18 2.3.5. Conclusions on the chemical, pharmaceutical and biological aspects ...................... 18 2.3.6. Recommendations for future quality development ............................................... 18 2.4. Non-clinical aspects ............................................................................................ 18 2.4.1. Introduction.................................................................................................... 18 2.4.2. Ecotoxicity/environmental risk assessment ......................................................... 19 2.4.3. Discussion on non-clinical aspects ..................................................................... 20 2.4.4. Conclusion on the non-clinical aspects ............................................................... 20 2.5. Clinical aspects .................................................................................................. 20 2.5.1. Introduction.................................................................................................... 20 2.5.2. Pharmacokinetics ............................................................................................ 21 2.5.3. Pharmacodynamics .......................................................................................... 22 2.6. Clinical efficacy .................................................................................................. 22 2.6.1. Dose response study........................................................................................ 22 2.6.2. Main study ..................................................................................................... 23 2.6.3. Discussion on clinical efficacy ............................................................................ 42 2.6.4. Conclusions on the clinical efficacy .................................................................... 46 2.6.5. Clinical safety ................................................................................................. 46 2.6.6. Post marketing experience ............................................................................... 53 Assessment report EMA/CHMP/86002/2020 Page 2/65 2.6.7. Discussion on clinical safety .............................................................................. 53 2.6.8. Conclusions on clinical safety ............................................................................ 56 2.7. Risk Management Plan ........................................................................................ 56 2.8. Pharmacovigilance ............................................................................................. 58 2.9. Product information ............................................................................................ 58 2.9.1. User consultation ............................................................................................ 58 3. Benefit-risk balance .............................................................................. 58 3.1. Therapeutic Context ........................................................................................... 58 3.1.1. Disease or condition ........................................................................................ 58 3.1.2. Available therapies and unmet medical need ....................................................... 59 3.1.3. Main clinical studies ......................................................................................... 59 3.2. Favourable effects .............................................................................................. 59 3.3. Uncertainties and limitations about favourable effects ............................................. 60 3.4. Unfavourable effects ........................................................................................... 60 3.5. Uncertainties and limitations about unfavourable effects ......................................... 61 3.6. Effects Table ...................................................................................................... 62 3.7. Benefit-risk assessment and discussion ................................................................. 62 3.7.1. Importance of favourable and unfavourable effects .............................................. 62 3.7.2. Balance of benefits and risks ............................................................................ 63 3.7.3. Additional considerations on the benefit-risk balance ........................................... 63 3.8. Conclusions ....................................................................................................... 63 4. Recommendation .................................................................................. 64 Similarity with authorised orphan medicinal products ........................................... 64 Outcome ................................................................................................................. 64 Assessment report EMA/CHMP/86002/2020 Page 3/65 List of abbreviations 6MWD 6-minute-walk-distance AE Adverse event ADR Adverse drug reaction ANCOVA Analysis of covariance ASMF Active Substance Master File ATP Adenosine triphosphate AUC Area under the plasma concentration-time curve AUC0-inf Area under the plasma concentration-time curve from zero to infinity AUCss Area under the plasma concentration-time curve at steady state BMI Body mass index BMPR2 Bone morphogenetic protein receptor type 2 bpm Beats per minute cAMP Cyclic adenosine monophosphate CI Cardiac index CI Confidence interval Cmax Maximal concentration CO Cardiac output CTEPH Chronic thromboembolic pulmonary hypertension CTPA Computed tomography pulmonary angiogram CYP Cytochrome p450 DP1 Prostaglandin D2 receptor E2 Prostaglandin E2 receptor ECG Electrocardiogram EIF2AK4 Eukaryotic translation initiation factor 2 alpha kinase 4 ERA Endothelin receptor antagonist ERS European Respiratory Society ESC European Society of Cardiology FC Functional class GC Gas chromatography GI Gastrointestinal Assessment report EMA/CHMP/86002/2020 Page 4/65 GTP Guanosine triphosphate HIV Human immunodeficiency virus HPLC-MS/MS High-performance liquid-chromatography pressure ionisation tandem mass spectrometry HR Heart rate ICH The International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human