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Division of Experimental Medicine, Department of Medicine

COMBIVAS Rituximab/ Belimumab Combination therapy for PR3-ANCA associated vasculitis Mark McClure. Division of Experimental Medicine, Department of Medicine. BAFF / BLyS. BAFF – B lymphocyte activating factor BLyS – B lymphocyte stimulator

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Division of Experimental Medicine, Department of Medicine

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  1. COMBIVASRituximab/Belimumab Combination therapy for PR3-ANCA associated vasculitisMark McClure Division of Experimental Medicine, Department of Medicine

  2. BAFF/ BLyS BAFF – B lymphocyte activating factor BLyS – B lymphocyte stimulator B cell survival cytokine from the TNF ligand super family Produced by: myeloid cells, stromal cells, activated lymphocytes, epithelial cells, even some cancer cells

  3. BAFF/ BLyS

  4. Hypergammaglobulinaemia Expanded B cell compartment BAFF transgenic mice Autoimmune disease BAFF deficient mice Reduction in mature B cell compartment Hypogammaglobulinaemia

  5. Hypergammaglobulinaemia Expanded B cell compartment BAFF transgenic mice Autoimmune disease BAFF deficient mice Reduction in mature B cell compartment Hypogammaglobulinaemia

  6. Diseases associated with elevated serum BAFF • SLE • Rheumatoid Arthritis • Systemic sclerosis • Sjögren’s syndrome • Immune thrombocytopenia • MS • Myasthenia Gravis • Graves’ disease • Autoimmune pancreatitis • AAV

  7. Diseases associated with elevated serum BAFF • SLE • Rheumatoid Arthritis • Systemic sclerosis • Sjögren’s syndrome • Immune thrombocytopenia • MS • Myasthenia Gravis • Graves’ disease • Autoimmune pancreatitis • AAV Associated with increased autoantibody titre

  8. BAFF targeted therapies

  9. Belimumab in SLE (BLISS 52, BLISS 76) 2 large RCTs in SLE FDA approved for SLE Improved disease activity score (SRI) - 43% vs 33%, p=0.017 Decrease in the frequency of severe flares Decrease steroid dosage Good safety profile Furie et al, Arthritis Rheumatol 201

  10. Belimumab: effects on lymphocytes in SLE Total B cells Naïve B cells Activated B cells Plasmablasts Furie et al, Arthritis Rheumatol 201

  11. Belimumab: effects on lymphocytes in SLE Total B cells Naïve B cells Activated B cells Plasmablasts Memory B cells T cell numbers Furie et al, Arthritis Rheumatol 201

  12. Belimumab: effects on lymphocytes in SLE Total B cells Naïve B cells Activated B cells Plasmablasts Memory B cells T cell numbers Pneumococcal IgG Tetanus IgG Furie et al, Arthritis Rheumatol 201

  13. Belimumab in AAV?

  14. B cell depletion therapy in AAV

  15. BAFF in AAV AAV associated with increased BAFF levels ANCA activated neutrophils release BAFF Krumbholz et al. Journal of Autoimmunity 2005 Holden NJ, et al, Annals of Rheumatic Disease 2011

  16. BREVAS: belimumab to prevent relapse in AAV

  17. BREVAS: belimumab to prevent relapse in AAV Primary endpoint

  18. BREVAS: belimumab to prevent relapse in AAV Primary endpoint N=105

  19. BREVAS: efficacy

  20. BREVAS: efficacy Belimumab (n=53): 6 relapses • RTX induction group (n=14): no relapses • CYC induction group (n=39): 6 relapses Placebo (n=52): 8 relapses • RTX induction group (n=13): 3 relapses • CYC induction group (n=39): 5 relapses

  21. BREVAS: safety

  22. BREVAS: infections • RTX-induced patients: imbalance in infections • Belimumab group: 14 (100%) reported 50 infections (3 serious) • Placebo group: 9 (69%) reported 21 infections (0 serious) • CYC-induced patients: no imbalance in infections

  23. The principle of using multiple agents to target different disease mechanisms is gaining traction in many autoimmune disease settings Combination therapy: Anti-CD20 + anti-BAFF Rationale…

  24. Incomplete B cell depletion after rituximab Smith (Cambridge), unpublished

  25. Incomplete tissue B cell depletion after rituximab Endobronchial granuloma Lymph node Ferraro et al, NDT 2008 Wallin et al, Blood, 2014

  26. BAFF protects against anti-CD20 induced lysis Wild J et al. Leukaemia 2015

  27. BAFF rises after Rituximab • Regulation of BLyS levels post depletion may set a higher stringency for B cell reconstitution selecting out autoreactive B cells Holden G Cambridge et al. Ann Rheum Dis 2008

  28. COMBIVAS Rituximab GC GC N=15 Belimumab Rituximab GC N=15 Placebo Months 0 3 6 12 18 24 lymph node biopsies nasal biopsies Key analysis time points Maximal B cell depletion End of treatment End of follow up Clinical remission Steroid withdrawal

  29. COMBIVAS Rituximab GC GC N=15 Belimumab Rituximab GC N=15 Placebo Months 0 3 6 12 18 24 lymph node biopsies nasal biopsies Key analysis time points Maximal B cell depletion End of treatment End of follow up Clinical remission Steroid withdrawal

  30. COMBIVAS Biomarkers Blood ANCA Immunoglobulins Lymphocyte subsets PK BLyS / cytokines BCR clonality Transcriptomics Tissue Lymph node biopsy Nasal biopsy Urine Urinary lymphocyte subsets Urine proteomics

  31. Academic/GSK BiomarkerClinical Collaborators Collaborators UCL Imperial Cambridge GSK Glasgow Newcastle Cambridge UCL Imperial David Jayne Rachel Jones Mark McClure Pani Gopaluni Nasal and LN biopsies Caroline Savage Robbie Henderson Christine Barrett Andre van Maurik B and T cell FACS BlyS, PK, Stevenage Alan Salama Urinary lymphocyte Phenotyping UCL Ken Smith, Paul Lyons Rachael Bashford Rogers Tissue PR3 specific B cells Autoreactive B cell clones Separated cell transcriptomics Charles Pusey Fred Tam Urine Proteomics Imperial Duncan Richards B and T cell FACS Clinical Unit Cambridge Menna Clatworthy Functional B cell assays Rainer Doffinger ANCA, cytokines

  32. Key objectives and endpoints Primary objective • Compare belimumab (versus placebo) with rituximab and low dose corticosteroids in achieving PR3 ANCA negativity in active AAV Primary Endpoint • Time to ANCA negativity Key Secondary objective • Assess changes in key WBC populations and B and T cell subsets in blood during B cell depletion and B cell reconstitution Key Secondary Endpoint • Change from baseline in B cells, B cell subsets, CD4, CD8 cells – 0,3,12,24 months

  33. Key exploratory objectives and endpoints Exploratory objective • Lymph and nasal tissue • Assess changes in key WBC populations and B and T cell subsets during B cell depletion Endpoint • Change from baseline in B and T cell populations in lymph node and nasal biopsies at 0,3 months Exploratory Objective • Clonality • Assess clonality of reconstituted B cells to investigate differences in central and peripheral selection Endpoint • Differences in repertoire structure (clonality, IgHV-J gene usages, immunoglobulin class usage, and propensity for somatic hypermutation) in blood at 0, 12, 24 months

  34. Safety concerns Potential for more profound hypogammaglobulinemia Increased risk for serious infections Exclusions Infection Pre-existing hypogammaglobulinaemia / neutropenia Robust safety monitoring needed

  35. Thank you

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