Shingrix, INN-Herpes zoster vaccine (recombinant, adjuvanted)

1 30 Churchill Place Canary Wharf London E14 5EU United Kingdom An agency of the European Union Telephone +44 (0)20 3660 6000 Facsimile +44 (0)20 3660 5520 Send a question via our website 25 January 2018 EMA/88588/2018 Committee for Medicinal Products for Human Use (CHMP) Assessment report Shingrix International non-proprietary name: herpes zoster vaccine (recombinant, adjuvanted) Procedure No. EMEA/H/C/004336/0000 Note Assessment report as adopted by the CHMP with all information of a commercially confidential nature deleted. Assessment report EMA/88588/2018 Page 2/170 Table of contents 1. Background information on the procedure.

2 7 Submission of the dossier .. 7 Steps taken for the assessment of the product .. 8 2. Scientific discussion .. 9 Problem statement .. 9 Disease or condition .. 9 2. Epidemiology and risk factors .. 9 Aetiology and pathogenesis .. 10 Clinical presentation .. 11 Management .. 11 Quality aspects .. 13 Introduction .. 13 Active substance .. 13 Finished medicinal product- AS01B suspension (adjuvant system) vial .. 17 Finished medicinal product- gE finished product .. 20 Discussion on chemical, and pharmaceutical aspects .. 24 Conclusions on the chemical, pharmaceutical and biological aspects .. 26 Recommendation(s) for future quality development.

3 26 Non-clinical aspects .. 26 Introduction .. 26 Pharmacology .. 27 31 Toxicology .. 32 Ecotoxicity/environmental risk assessment .. 35 Discussion on non-clinical 35 Conclusion on the non-clinical aspects .. 35 Clinical aspects .. 35 Introduction .. 35 46 Pharmacodynamics .. 47 Discussion on clinical pharmacology .. 52 Conclusions on clinical pharmacology .. 52 Clinical efficacy .. 52 Dose response 52 Main studies .. 53 Analysis performed across trials (pooled analyses and meta-analysis) .. 95 Clinical studies in special populations .. 111 Supportive studies .. 117 Discussion on clinical efficacy.

4 125 Conclusions on clinical efficacy .. 135 Clinical safety .. 137 Patient exposure .. 139 Adverse events .. 140 Assessment report EMA/88588/2018 Page 3/170 Serious adverse events and deaths .. 144 Laboratory findings .. 148 Safety in special populations .. 148 Safety related to drug-drug interactions and other interactions .. 151 Discontinuation due to adverse events .. 151 Post marketing experience .. 151 Discussion on clinical safety .. 151 Conclusions on the clinical safety .. 155 Risk Management Plan .. 156 Pharmacovigilance .. 160 New Active Substance .. 160 Product information .. 161 User consultation.

5 161 2. Additional monitoring .. 161 3. Benefit-Risk 161 Therapeutic Context .. 161 Disease or condition .. 161 Available therapies and unmet medical need .. 162 Main clinical studies .. 162 Favourable effects .. 162 Uncertainties and limitations about favourable effects .. 164 Unfavourable effects .. 165 Uncertainties and limitations about unfavourable effects .. 166 Effects Table .. 167 Benefit-risk assessment and discussion .. 168 Importance of favourable and unfavourable effects .. 168 Balance of benefits and risks .. 169 Additional considerations on the benefit-risk balance .. 169 Conclusions .. 169 4. Recommendations.

6 169 Assessment report EMA/88588/2018 Page 4/170 List of abbreviations Ab Antibody AE Adverse Event AS Active Substance AS01B Adjuvant System containing 50 g MPL, 50 g QS-21 and liposomes BOI Burden of Illness CD4 Cluster of differentiation marker 4 CD8 Cluster of differentiation marker 8 CDP Clinical Development Program CFC Cells Flow Cytometry CHMP Committee for Medicinal Products for Human Use CHO Chinese Hamster Ovarian cells CI Confidence Interval CLB Concentrated Liposome Bulk CMI Cell Mediated Immunity CPV Continued Process Verification CSR Clinical Study Report DOPC Dioleoyl Phosphatidylcholine ELISA Enzyme-Linked Immunosorbent Assay EMA European Medicines Agency.

7 EU EOS End of Study EPC End-of-Production Cell bank EU European Union FB Final Bulk FC Final Container FDA Food and Drug Administration, US FLU-D-QIV GSK s unadjuvanted quadrivalent seasonal influenza vaccine FP Finished Product GCP Good Clinical Practice gE Glycoprotein E GM Geometric Mean GMP Good Manufacturing Practice GMT Geometric Mean Titre GSK GlaxoSmithKline HCP Host Cell Protein HCT Haematopoietic stem Cell Transplant HI Haemagglutinin Inhibition HIV Human Immunodeficiency Virus HP Hydrogen Peroxide HZ Herpes zoster HZO HZ Ophthalmicus Assessment report EMA/88588/2018 Page 5/170 HZ/su The herpes zoster subunit candidate vaccine (50 g gE/AS01B)

8 , also called gE/AS01B candidate vaccine IC Immunocompromised ICH International Conference on Harmonization IDMC Independent Data Monitoring Committee IFN- Interferon gamma IM Intramuscular IgG Immunoglobulin G IL-2 Interleukin 2 L Litre LB Liquid Bulk LL Lower Limit LPS Lipopolysaccharide MCB Master Cell Bank MGI Mean Geometric Increase MPL 3-O- desacyl-4 -monophosporyl Lipid A NOAEL No-Observed Adverse Effect Level pbmc peripheral blood mononuclear Cell PCR Polymerase Chain Reaction Ph. Eur. European Pharmacopoeia PHN Post-herpetic Neuralgia PIP Paediatric Investigation Plan PM In Process Monitoring PP Process Parameters PPQ Process Performance Qualification PRNT Plaque Reduction Neutralization Test PS80 Polysorbate 80 QA Quality Attributes QC Quality Control QoL Quality of Life QS-21 Quillaja saponaria Molina fraction 21 RCT Randomized Controlled Trial RMP Risk Management Plan RR Relative Risk SAE Serious Adverse Event SC Subcutaneous SCR Seroconversion Rate SmPC Summary of Product Characteristics SPR Seroprotection Rate TNF- Tumour Necrosis Factor alpha TSE

9 Transmissible Spongiform Encephalopathy TTC threshold of toxicological concern TVC Total Vaccinated Cohort Assessment report EMA/88588/2018 Page 6/170 UL Upper Limit VE vaccine Efficacy VHP Vaporised Hydrogen Peroxide VRR vaccine Response Rate VZV Varicella zoster Virus YOA Years Of Age WFI Water For Injection ZBPI zoster Brief Pain Inventory Assessment report EMA/88588/2018 Page 7/170 1. Background information on the procedure Submission of the dossier The Applicant GSK Biologicals SA submitted on 25 November 2016 an application for marketing authorisation to the European Medicines Agency (EMA) for Shingrix, through the centralised procedure falling within the Article 3(1) and point 1 of Annex of Regulation (EC) No 726/2004.

10 The Applicant applied for the following indication: Shingrix is indicated for prevention of herpes zoster (HZ) and HZ-related complications, such as post-herpetic neuralgia (PHN), in adults 50 years of age or older. The legal basis for this application refers to: Article of Directive 2001/83/EC - complete and independent application. The Applicant indicated that Varicella zoster Virus glycoprotein E antigen was considered to be a new active substance. 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 tests or studies.