Assessment report

1 Official address Domenico Scarlattilaan 6 1083 HS Amsterdam The Netherlands An agency of the European Union Address for visits and deliveries Refer to Send us a question Go to Telephone +31 (0)88 781 6000 European Medicines Agency, 2021. Reproduction is authorised provided the source is acknowledged. 25 March 2021 EMA/CHMP/206970/2021 Committee for Medicinal Products for Human Use (CHMP) Assessment report Ponvory International non-proprietary name: ponesimod Procedure No. EMEA/H/C/005163/0000 Note Assessment report as adopted by the CHMP with all information of a commercially confidential nature deleted. Assessment report EMA/CHMP/206970/2021 Page 2/136 Table of contents 1. Background information on the procedure .. 8 Submission of the dossier .. 8 Steps taken for the Assessment of the product.

2 11 2. Scientific discussion .. 12 Problem statement .. 12 Disease or 12 Epidemiology .. 12 Aetiology and pathogenesis .. 12 Clinical presentation, diagnosis and 12 Management .. 13 Quality aspects .. 14 Introduction .. 14 Active Substance .. 15 Finished Medicinal Product .. 17 Discussion on chemical, pharmaceutical and biological aspects .. 20 Conclusions on the chemical, pharmaceutical and biological aspects .. 20 Recommendation for future quality development .. 20 Non-clinical aspects .. 21 Introduction .. 21 Pharmacology .. 21 Pharmacokinetics .. 29 Toxicology .. 33 Ecotoxicity/environmental risk Assessment .. 40 Discussion on non-clinical aspects .. 42 Conclusion on the non-clinical aspects .. 43 Clinical aspects .. 43 Introduction .. 43 Pharmacokinetics .. 46 Pharmacodynamics.

3 54 Discussion on clinical pharmacology .. 57 Conclusions on clinical pharmacology .. 60 Clinical efficacy .. 61 Dose response study .. 61 Main study .. 64 Discussion on clinical efficacy .. 87 Conclusions on the clinical efficacy .. 94 Clinical safety .. 95 Discussion on clinical safety .. 112 Conclusions on the clinical safety .. 115 Risk Management Plan .. 115 127 New Active Substance .. 127 Product information .. 128 Assessment report EMA/CHMP/206970/2021 Page 3/136 User consultation .. 128 Labelling exemptions .. 128 Additional monitoring .. 128 3. Benefit-Risk 128 Therapeutic Context .. 128 Disease or 128 Available therapies and unmet medical need .. 129 Main clinical studies .. 129 Favourable effects .. 129 Uncertainties and limitations about favourable effects.

4 130 Unfavourable effects .. 130 Uncertainties and limitations about unfavourable effects .. 131 Effects Table .. 132 Benefit-risk Assessment and discussion .. 132 Importance of favourable and unfavourable effects .. 132 Balance of benefits and risks .. 134 Additional considerations on the benefit-risk balance .. 134 Conclusions .. 134 4. Recommendations .. 134 Assessment report EMA/CHMP/206970/2021 Page 4/136 List of abbreviations ACT-128800 Ponesimod ADEM Acute Disseminated Encephalomyelitis AE Adverse Events AESI Adverse Events of Special Interest AIA Adjuvant-Induced Arthritis ALT Alanine aminotransferase AST Aspartate aminotransferase ANOVA Analysis of Variance APTT Activated Partial Thromboplastin Time ARR Annualised Relapse Rate AUC Area Under the concentration-time Curve AUCinf Area Under the concentration-time Curve from time 0 to infinity with extrapolation of the terminal phase AUC0-24 Area Under the concentration-time Curve in a dosing interval of 24 hours AUC0-t Area Under the concentration-time Curve from time 0 to the last measurable concentration AUC Area Under the concentration-time Curve during a dose interval ( )

5 AVB Atrioventricular Block BAFF B cell-Activating Factor BCRP Breast Cancer Resistance Protein BID Bis In Die: twice a day BP Blood Pressure B/R Benefit / Risk BW Body Weight cAMP Cyclin Adenosine Monophosphate CBC Complete Blood Count CDA Confirmed Disability Accumulation CFA Complete Freund s Adjuvant CFU Colony-Forming Unit CHMP Committee for Medicinal Products for Human Use CHO Chinese Hamster Ovary CIs Confidence Intervals CM Cryptococcal Meningitis Cmax Maximum Observed Plasma Concentration CNS CQA Central Nervous System Critical quality attribute CRP C-Reactive Protein Ctrough Trough plasma concentration Ctrough,ss Trough plasma concentration at steady-state CUAL Combined Unique Active Lesions CV Coefficient of Variation DB Double-Blind DBP Diastolic Blood Pressure DDI Drug-Drug Interactions DMT Disease-Modifying Therapies DNFB Dinitrofluorobenzene DoE Design of experiments DRF Dose Range Finding DSC Differential scanning calorimetry EAE EC Experimental Autoimmune Encephalomyelitis European Commission EC50 Half maximal effective concentration eCRF Electronic Case report form ECG Electrocardiogram ECHO Echocardiograph EFD Embryo-Fetal Development EDSS Expanded Disability Status Scale EMA European Medicines Agency EOS End Of Study EOT End Of Treatment E-R Exposure-Response ERA Environmental Risk Assessment Assessment report EMA/CHMP/206970/2021 Page 5/136 Erk1/2 Extracellular signal-Regulated Kinase 1/2 ESR Erythrocyte

6 Sedimentation Rate ETA EU Endothelin receptor Type A European Union FDA Food and Drug Administration FEV1 Forced Expiratory Volume in 1 second Fpen Factor of market penetration FS Functional Systems FSIQ RMS Fatigue Symptom and Impact Questionnaire-Relapsing Multiple Sclerosis FVC Forced Vital Capacity FAS Full Analysis Set FU GC Follow-up Gas chromatography GCP Good Clinical Practice Gd+ Gadolinium enhancing GLP Good Laboratory Practices GRO/KC human Growth-Regulated Oncogene/ Keratinocyte Chemoattractant GTP GVS Guanosine Triphosphate Gravimetric vapour sorption hERG human ether- -go-go related gene HPLC High-performance liquid chromatography HR ICH ICP-MS Heart Rate, Hazard Ratio International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use Inductively coupled plasma mass spectrometry IC20 20% inhibitory concentration IC50 half-maximal inhibitory concentration LC-MS/MS Liquid Chromatography coupled to Mass Spectrometry LS Least Squares LSC Liquid Scintillation Counting IL Interleukin IFN Interferon LPA Lysophosphatidic Acid Receptors MAA MAH Marketing Authorisation Application Marketing authorisation holder MAIC Matching-Adjusted Indirect Comparison MAO Monoamine Oxidase MAR Missing At Random MATE Multidrug and Toxic Compound Extrusion MBMA Model-Based Meta-Analysis MCP-1 Monocyte Chemoattractant Protein-1 MedDRA Medical Dictionary for Regulatory Activities MI Multiple Imputation MIP-1 Macrophage Inflammatory Protein-1 alpha

7 MMRM Mixed-effect Model Repeated Measurements MOG Myelin Oligodendrocyte Glycoprotein MRI Magnetic Resonance Imaging mRNA messenger Ribonucleic Acid MS Multiple Sclerosis MTD Maximum Tolerated Dose NB Negative Binomial NEDA No Evidence of Disease Activity NK Natural Killer NKT NMR Natural Killer T Nuclear magnetic resonance NOAEL No Observed Adverse Effect Level NOEL No Observed Effect Level OATP Organic Anion Transporting Polypeptide OCT Organic Cation Transporter OECD Organisation for Economic Co-operation and Development OSB Ophthalmology Safety Board QC Quality Control QD Once a day Assessment report EMA/CHMP/206970/2021 Page 6/136 QTcF QT corrected using Fridericia's formula QTcI individually corrected QT QTcI placebo-corrected change from baseline in the PAM PAR Post-Authorisation Measure Proven acceptable range PBRER Periodic Benefit-Risk Evaluation report PBT Persistence, Bioaccumulation and Toxicity PECsw Predicted Environmental Concentrations surfacewater PEF Peak Expiratory Flow PD PDE Pharmacodynamic, Protocol Deviation Permitted daily exposure P-gp P-glycoprotein PFT Pulmonary Function Tests PGI-S Ph.

8 Eur. Patient Global Impression of Severity European Pharmacopoeia PIF Peak Inspiratory Flow PIP Paediatric Investigation Plan PK Pharmacokinetics PL Package Leaflet PLGF2 Placental Growth Factor PML Progressive Multifocal Leukoencephalopathy popPK Population pharmacokinetic PPS Per-Protocol analysis set PPND Pre- Postnatal Developmental POEM Pregnancy Outcomes Enhanced Monitoring PRAC Pharmacovigilance Risk Assessment Committee PRES Posterior Reversible Encephalopathy Syndrome PRO Patient-Reported Outcome PT Prothrombin Time, Preferred Term PUVA QTPP Psoralen and Ultraviolet A Quality target product profile Rac1 Ras-related C3 botulinum toxin substrate 1 RANKL Receptor Activator of Nuclear factor Kappa- Ligand RANTES Regulated upon Activation, Normal T Cell Expressed and Presumably Secreted RBC Red Blood Cell RDST RH Repeated Dose Toxicity Studies Relative humidity RMS Relapsing forms of Multiple Sclerosis RRMS Relapsing Remitting Multiple Sclerosis RWG Resonant Waveguide Grating SA Scientific Advice SAP Statistical Analysis Plan SBP Systolic Blood Pressure SLE Systemic Lupus Erythematosus SmPC Summary of Product Characteristics SOC System Organ Classes SPMS Secondary Progressive Multiple Sclerosis SRBC Sheep Erythrocytes S1P Sphingosine 1-Phosphate receptor S1P1 Sphingosine 1-phosphate receptor 1 S1P2 Sphingosine 1-phosphate receptor 2 S1P3 Sphingosine 1-phosphate receptor 3 S1P4 Sphingosine 1-phosphate receptor 4 S1P5 Sphingosine 1-phosphate receptor 5 TDAR T-Dependent Antibody Response TEAEs Treatment-Emergent Adverse Events TEMSO Teriflunomide Multiple

9 Sclerosis Oral tmax Time at maximum plasma concentration t1/2 Elimination half-life TP Treatment Period TFUQ TGA TSE Targeted Follow-Up Questionnaire Thermogravimetric analysis Transmissible spongiform encephalopathy Assessment report EMA/CHMP/206970/2021 Page 7/136 UGT Uridine Diphosphate Glucuronosyltransferases ULQC Upper Limit of Quantification ULN UV Upper Lower Normal Ultraviolet UVB Ultraviolet B Vd (Apparent) Volume of distribution Vdss Volume of Distribution at Steady State VZV Varicella Zoster Virus WBC XRPD White-Blood Counts X-ray powder diffraction Assessment report EMA/CHMP/206970/2021 Page 8/136 1. Background information on the procedure Submission of the dossier The applicant Janssen-Cilag International submitted on 2 March 2020 an application for marketing authorisation to the European Medicines Agency (EMA) for Ponvory, through the centralised procedure falling within the Article 3(1) and point 3of Annex of Regulation (EC) No 726/2004.

10 The eligibility to the centralised procedure was agreed upon by the EMA/CHMP on 20 September 2018. The applicant applied for the following indication treatment of adult patients with relapsing forms of multiple sclerosis (RMS) with active disease defined by clinical or imaging features. The legal basis for this application refers to: Article of Directive 2001/83/EC - complete and independent application The application submitted is composed of administrative information, complete quality data, non-clinical and clinical data based on applicants own tests and studies and/or bibliographic literature substituting/supporting certain test(s) or study(ies). Information on Paediatric requirements Pursuant to Article 7 of Regulation (EC) No 1901/2006, the application included an EMA Decision(s) P/0128/2018 on the agreement of a paediatric investigation plan (PIP).