Atacicept Atacicept in IgA Nephropathy MS700461-0035 Final V2.0

Statistical Analysis Plan

Clinical Trial Protocol MS700461 – 0035 Identification No.

Title: A Phase II, Randomized, Double-blind, Placebo- Controlled Study to Evaluate the Efficacy and Safety of Atacicept in IgA Nephropathy

Trial Phase Phase II

Investigational Medicinal Atacicept 25 mg, 75 mg or 150 mg or Placebo Product(s)

Clinical Trial Protocol 27 November 2018 / Version 5.0 Version

Statistical Analysis Plan PPD Author

Statistical Analysis Plan 15 February 2019 / Final 2.0 Date and Version

Statistical Analysis Plan PPD Reviewers PPD

PPD

PPD – Medical Responsible

PPD , EMD Serono –PPD

PPD , EMD Serono –PPD

PPD , EMD Serono – PPD

PPD , EMD Serono – Medical Responsible

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1 Signature Page

Statistical Analysis Plan: MS700461 – 0035

A Phase II, Randomized, Double-blind, Placebo-Controlled Study to Evaluate the Efficacy and Safety of Atacicept in IgA Nephropathy

Anne Le Hénanff

Trial Biostatistician PPD

PPD

PPD

PPD PPD

PPD

Medical Responsible PPD

PPD

Medical Responsible EMD Serono

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2 Table of Contents 1 Signature Page ...... 2 2 Table of Contents...... 3 3 List of Abbreviations and Definition of Terms ...... 6 4 Modification History ...... 9 5 Purpose of the Statistical Analysis Plan ...... 9 6 Summary of Clinical Trial Features ...... 9 7 Sample Size/Randomization...... 19 7.1 Sample Size ...... 19 7.2 Randomization...... 21 8 Overview of Planned Analyses...... 22 8.1 Interim analysis for Part A...... 22 8.2 Primary and Final analysis for Part A...... 23 9 Changes to the Planned Analyses in the Clinical Trial Protocol for Part A...... 24 10 Protocol Deviations and Analysis Sets...... 26 10.1 Definition of Protocol Deviations and Analysis Sets ...... 26 10.2 Definition of Analysis Sets and Subgroups for Part A...... 26 11 General Specifications for Statistical Analyses...... 29 12 Study Subjects ...... 32 12.1 Disposition of Subjects and Discontinuations ...... 32 12.2 Protocol Deviations ...... 33 12.2.1 Important Protocol Deviations...... 34 12.2.2 Reasons Leading to the Exclusion from an Analysis Set ...... 34 13 Demographics and Other Baseline Characteristics...... 34 13.1 Demographics...... 34 13.2 Medical History ...... 35 13.2.1 Medical History ...... 35 13.2.2 IgA Nephropathy Characteristics at Baseline...... 35 13.3 Other Baseline Characteristics...... 36 14 Prior or Concomitant Medications/Procedures...... 36 15 Treatment Compliance and Exposure...... 38

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15.1 Treatment Exposure...... 38 15.2 Dose Frequency Reduction...... 40 16 Endpoint Evaluation ...... 41 16.1 Primary Endpoint Analyses ...... 41 16.2 Secondary Endpoint Analyses ...... 41 16.3 Other Endpoint Analyses...... 42 16.4 Exploratory Endpoint Analyses...... 44 16.4.1 Biomarkers...... 44 16.4.2 Renal biopsy ...... 46 16.5 Analysis of PK Endpoints and Population PK/PD Modeling...... 46 16.5.1 PK Evaluation...... 46 16.5.2 Population PK/PD Modeling ...... 47 16.5.2.1 PK Modeling...... 48 16.5.2.2 IgA, IgG, IgM Modeling ...... 48 16.5.2.3 Proteinuria Modeling...... 49 16.5.2.4 Data Specifications for PK/PD Modeling...... 49 17 Safety Evaluation...... 49 17.1 Adverse Events ...... 49 17.1.1 Adverse Events Leading to Treatment Discontinuation...... 52 17.1.2 Exposure Adjusted Incidence Rate...... 52 17.1.3 Serious Adverse Events ...... 53 17.1.4 Deaths ...... 53 17.1.5 Other Adverse Event Assessments ...... 53 17.2 Clinical Laboratory Evaluations...... 54 17.2.1 Summary tables over-time...... 56 17.2.2 Shift tables ...... 56 17.2.3 Immunoglobulin ...... 57 17.2.4 Proteinuria...... 58 17.2.5 Anti-drug antibody...... 58 17.2.6 Vital Signs ...... 58 17.3 Other Safety or Tolerability Evaluations...... 59 18 Benefit Risk Assessment ...... 60

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19 References...... 60 20 Appendices ...... 60 20.1 Appendix 1: Important protocol deviations...... 61 20.2 Appendix 2: Firewall Team Charter...... 61 20.3 Appendix 3: Important protocol deviations...... 61 20.4 Appendix 4: Reference SAS code used for EAIR 95% confidence interval calculation by Poisson model ...... 61 20.5 Appendix 5: Details on Pharmacometry Evaluation ...... 62 20.5.1 Software...... 62 20.5.2 Modeling Methodology ...... 62 20.2.2.1 Population PK/PD Modeling ...... 63 20.2.2.1.1 Exploratory Data Analysis...... 64 20.2.2.1.2 Structural Model Development...... 64 20.2.2.1.3 Statistical Model Development...... 64 20.2.2.1.4 Covariate Analysis...... 65 20.2.2.1.5 Final Model Refinement...... 66 20.2.2.1.6 Sensitivity Analysis of Fixed Parameter Values ...... 66 20.2.2.1.7 Model Evaluation...... 66

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3 List of Abbreviations and Definition of Terms

ACEi Angiotensin converting enzyme inhibitor AE Adverse event AESI Adverse event of special interest AIC Akaike information criterion APRIL A proliferation-inducing ligand APRIL-SLE Clinical trial 27646 in systemic lupus erythematosus ARB Angiotensin receptor blockers AUC Area Under the Curve BLyS B lymphocyte stimulator (also called B-cell activating factor or BAFF) BMI Body Mass Index BP Blood pressure CDISC Clinical Data Interchange Standards Consortium CI Coordinating Investigator CIC Circulating immune complexes CKD-EPI Chronic Kidney Disease Epidemiology Collaboration CPU Central Processing Unit CRCL Creatinine clearance CRO Contract Research Organization CS Corticosteroid(s) CTP Clinical trial protocol DBPC Double-blind placebo-controlled DFR Dose frequency reduction ECG Electrocardiogram eCRF Electronic case report form eGFR Estimated glomerular filtration rate EOW Every other week ESRD End-stage renal disease ET Early Termination FOCE First-order conditional FOCEI First-order conditional with interaction

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FU Follow-up GCP Good Clinical Practice Gd-IgA1 Galactose deficient-IgA1 ICF Informed consent form ICH International Council for Harmonization IDMC Independent Data Monitoring Committee Ig Immunoglobulin IgA, G, M, G1 Immunoglobulins A, G, M, G1 IgAN IgA nephropathy IMP Investigational Medicinal Product IOV Interoccasion variability ISR Injection site reaction ITT Intention-to-treat IV Intravenous(ly) IWRS Interactive Web Response System LLN Lower Limit of Normal LN Lupus nephritis MCP-Mod Multiple comparison procedures with modeling techniques MedDRA Medical Dictionary for Regulatory Activities mITT Modified Intent-to-treat MMRM Mixed effects model for repeated measures MS Multiple sclerosis NCI-CTCAE National Cancer Institute-Common Terminology for Adverse Events PD Pharmacodynamic(s) PGx Pharmacogenetics PK Pharmacokinetic(s) PP Per protocol PsN Pearl-speaks NONMEM RA Rheumatoid arthritis RAM Random Access Memory SAE Serious adverse event SAP Statistical analysis plan

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SC Subcutaneous SCM Stepwise covariate model SD Standard Deviation SLE Systemic lupus eryt