COVID-19 Vaccine Moderna, INN-COVID-19 mRNA Vaccine ...

1 Official address Do me ni co Scarla ttila an 6 1083 HS Amsterdam T h e N e t herla nd s An agenc y of the European Union Address for visits and deliveries Refer to nd-us Send us a question Go to ma .e uropa .eu/conta ct Telephone +31 (0)88 781 6000 E u ro p e an M e d ici ne s Ag e nc y, 2021. Reproduction is authorised provided the source is acknowledged. 11 March 2021 EMA/15689/2021 *1 Committee for Medicinal Products for Human Use (CHMP) Assessment report COVID-19 Vaccine Moderna Common name: COVID-19 mRNA Vaccine (nucleoside-modified) Procedure No. EMEA/H/C/005791/0000 Note Assessment report as adopted by the CHMP with all information of a commercially confidential nature deleted. 1 *Correction dated 11 March 2021 to clarify ERA statment Assessment report EMA/15689/2021 Pa ge 2/169 Table of contents 1.

2 Background information on the procedure .. 9 Submission of the dossier .. 9 Steps taken for the assessment of the 2. Scientific discussion .. 13 Problem statement ..13 Disease or condition ..13 Epidemiology and risk 2. 1. 3. Aetiology and pathogenesis ..13 Clinical presentation and diagnosis ..14 Management ..14 Quality aspects ..16 Introduction ..16 Active Substance ..16 Finished Medicinal Product ..21 Discussion on chemical, pharmaceutical aspects and biological aspects ..37 Impact on the benefit-risk assessment: ..40 Conclusions on chemical, pharmaceutical and biological Recommendations for future quality development ..43 Non-clinical aspects ..43 Introduction ..43 Pharmacology ..45 Pharmacokinetics ..47 Toxicology ..48 Ecotoxicity/environmental risk assessment ..51 Discussion on non-clinical aspects.

3 51 Conclusion on the non-clinical aspects ..55 Clinical aspects ..55 Introduction ..55 Clinical Pharmacology ..60 Discussion on clinical Conclusions on clinical pharmacology ..79 Clinical eff icacy ..80 Dose response study(ies)..80 Main study ..80 Discussion on clinical efficacy .. 105 Conclusions on the clinical efficacy .. 110 Clinical safety .. 111 Patient 111 Adverse events .. 112 Serious adverse event/deaths/other signif icant events .. 115 Laboratory findings .. 117 Safety in special 117 Immunological events .. 119 Safety related to drug-drug interactions and other interactions .. 119 Assessment report EMA/15689/2021 Pa ge 3/169 Discontinuation due to adverse events .. 119 Post-marketing experience .. 119 Discussion on clinical safety .. 120 Conclusions on the clinical safety.

4 126 Risk Management 127 Pharmacovigilance .. 141 New Active Substance .. 141 Product inf ormation .. 142 User consultation .. 142 Labelling exemptions .. 142 Quick Response (QR) 144 Additional monitoring .. 144 3. Benefit-Risk Balance .. 144 Therapeutic 144 Disease or condition .. 144 Available therapies and unmet medical need .. 144 Main clinical 145 Favourable effects .. 145 Uncertainties and limitations about favourable effects .. 146 Unfavourable effects .. 147 Uncertainties and limitations about unfavourable 148 Effects Table .. 149 Benef it-risk assessment and discussion .. 151 Importance of favourable and unfavourable 151 Balance of benef its and risks .. 152 Additional considerations on the benefit-risk 152 3. 8. Conc lus ions .. 154 4. 154 Assessment report EMA/15689/2021 Pa ge 4/169 List of abbreviations AC adjudication committee AE adverse event AESI adverse events of special interest ALP alkaline phosphatase AR adverse reaction ARDS acute respiratory distress syndrome AST aspartate aminotransferase bAb binding antibody BAL bronchoalveolar lavage BLA Biologics License Application BWP EMA Biologics Working Party CBER Center for Biologics Evaluation and Research CCIT Container Closure Integrity Testing CDC Centers for Disease Control and Prevention CHMP Committee for Medicinal Products for Human Use CI confidence interval CIPC critical in-process control CMA conditional marketing authorisation CMV cytomegalovirus CNS central nervous system CoA Certificates of Analysis COPD chronic obstructive pulmonary disease CoV coronavirus COVID-19 disease caused

5 By the novel 2019 coronavirus CPP critical process parameter CQA Critical Quality Attributes CSR clinical study report CTD common technical document DBL database lock DMID Division of Microbiology and Infectious Diseases DNA deoxyribonucleic acid Assessment report EMA/15689/2021 Pa ge 5/169 DSMB data safety monitoring board DSPC 1,2-distearoyl-sn-glycero-3-phosphocholi ne ECDC European Centre for Disease Prevention and Control ECMO extracorporeal membrane oxygenation eCRF electronic case report form eCTD electronic common technical document ELISA enzyme-linked immunosorbent assay EMA European Medicines Agency EOS eosinophil ETF COVID-19 EMA pandemic Task Force EU European Union ERD enhanced respiratory disease EUA Emergency Use Authorisation EURD European reference date FAS Full Analysis Set FDA Food and Drug Administration FD&C Federal Food, Drug.

6 And Cosmetic FMEA failure mode and effects analysis GCP good clinical practice GLP good laboratory practice GM geometric mean GMFR geometric mean fold-rise GMP good manufacturing practice GMT geometric mean titer hMPV human metapneumovirus HIV human immunodeficiency virus HR hazard ratio IA interim analysis IA#1 interim analysis #1 IBD international birth date ICH International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use ICS intracellular cytokine staining ID50 50% inhibitory dilution Assessment report EMA/15689/2021 Pa ge 6/169 IgG immunoglobulin G IM intramuscular IN intranasal IND Investigational New Drug (application) INN international non-proprietary name IP investigational product IRT interactive response technology IT intratracheally ITT intent-to-treat IVT in vitro transcription LL lower limit LLOQ lower limit of quantification LOD limit of detection LNP lipid nanoparticle LOD limit of detection LSS lipid stock solution LTCF long-term care facilities MA marketing authorisation MAA marketing authorisation application MAAE medically attended adverse event MAH marketing authorisation holder MCB master cell bank MERS-CoV Middle East respiratory syndrome coronavirus mITT modified intent-to-treat MO major objection MN microneutralisation MN50 50% microneutralisation mRNA messenger RNA MRL Minimum Release Limit MS member state nAb neutralising antibody NE not evaluable NIAID National Institute of Allergy and Infectious Diseases Assessment

7 Report EMA/15689/2021 Pa ge 7/169 NHP Nonhuman primates NP nasopharyngeal NTP nucleoside triphosphates OCABR Official Control Authority Batch Release OMCL Official Medicines Control Laboratory PaO2/FiO2 arterial oxygen partial pressure to fractional inspired oxygen PASS post-authorisation safety study PBMC peripheral blood mononuclear cell PBS phosphate-buffered saline PEG Polyethylene glycol PEG2000-DMG 1-monomethoxypolyethyleneglycol-2,3-dimy ristylglycerol with polyethylene glycol of average molecular weight 2000 Ph. Eur. Pharmacopoeia Europaea PhV pharmacovigilance PI product information PIV3 parainfluenza virus type 3 PL package leaflet PP per-protocol PPQ process performance qualification PRNT plaque-reduction neutralisation test PSUR periodic safety update report PsVNA pseudotyped lentivirus reporter single-round-of-infection neutralisation assay PsVNT50 50% pseudotyped lentivirus reporter test PT preferred term QR quick response RBD receptor binding domain REC recommendation (EMA Post-Authorisation Measure - PAM) RMP risk management plan RNA ribonucleic acid RT-PCR reverse transcription polymerase chain reaction S-2P spike (S)

8 Protein modified with 2 proline substitutions within the heptad repeat 1 domain SAE serious adverse event SAP statistical analysis plan SARS-CoV severe acute respiratory syndrome coronavirus Assessment report EMA/15689/2021 Pa ge 8/169 SARS-CoV-2 2019 novel coronavirus SM-102 heptadecan-9-yl 8-((2-hydroxyethyl)(6-oxo-6-(undecyloxy) hexyl)amino)octanoate SMC safety monitoring committee SmPC summary of product characteristics SMQ Standardised MedDRA Query SOC system organ class sSAP supplementary statistical analysis plan TEAE treatment-emergent adverse event Th1 T-helper 1 Th2 T-helper 2 Tris- HCl tris(hydroxymethyl)aminomethane-hydrochl oride; VRC = Vaccine Research Centre TSE transmissible spongiform encephalopathy ULOQ upper limit of quantification US United States USP United States Pharmacopeia UTR untranslated region UV ultraviolet VAED Vaccine -induced enhancement of disease VAERD Vaccine -associated enhanced respiratory disease VE Vaccine efficacy WCB working cell bank WHO World Health Organization Assessment report EMA/15689/2021 Pa ge 9/169 1.

9 Background information on the procedure Submission of the dossier The applicant Moderna Biotech Spain, S. L. submitted on 30 November 2020 an application for marketing authorisation to the European Medicines Agency (EMA) for COVID-19 Vaccine Moderna, through the centralised procedure falling within the Article 3(1) and point 1 of Annex of Regulation (EC) No 726/2004. The eligibility to the centralised procedure was agreed upon by the EMA/CHMP on 12 October 2020. The applicant applied for the following indication: active immunisation to prevent COVID-19 caused by SARS-CoV-2 virus in individuals 18 years of age and older . 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).

10 Information on Paediatric requirements Pursuant to Article 7 of Regulation (EC) No 1901/2006, the application included an EMA Decision P/0481/2020 on the agreement of a paediatric investigation plan (PIP). At the time of submission of the application, the PIP P/0481/2020 was not yet completed as some measures were deferred. Information relating to orphan market exclusivity Similarity Pursuant to Article 8 of Regulation (EC) No 141/2000 and Article 3 of Commission Regulation (EC) No 847/2000, the applicant did not submit a critical report addressing the possible similarity with authorised orphan medicinal products because there is no authorised orphan medicinal product for a condition related to the proposed indication. Applicant s requests for consideration Conditional marketing authorisation The applicant requested consideration of its application for a Conditional marketing authorisation in accordance with Article 14-a of Regulation (EC) No 726/2004.