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 B cell survival cytokine from the TNF ligand super family Produced by: myeloid cells, stromal cells, activated lymphocytes, epithelial cells, even some cancer cells

BAFF / BLyS

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

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

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

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

BAFF targeted therapies

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

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

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

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

Belimumab in AAV?

B cell depletion therapy in AAV .

AAV associated with increased BAFF levels 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

BREVAS: belimumab to prevent relapse in AAV

BREVAS: belimumab to prevent relapse in AAV Primary endpoint

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

BREVAS: efficacy There was no difference in attainment of the primary endpoint between the 2 groups

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

BREVAS: safety No new safety signals were identified for belimumab in the overall population Serious and non-serious infections were balanced across treatment arms

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 However in the subgroup of RTX- induced patients, infectious adverse events were higher in the belimumab group compared with the placebo group, primarily driven by non-serious events

Combination therapy: Anti-CD20 + anti-BAFF 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…

Incomplete B cell depletion after rituximab Firstly, there is incomplete B cell depletion in the circulation following rituximab when you look with high sensitivity FACS, Smith (Cambridge), unpublished

Incomplete tissue B cell depletion after rituximab Endobronchial granuloma Lymph node And if you look in the tissue after rtx, you can still see B cells despite appartent peripheral depetion. So we would expect tp get more effective B cell depletion with 2 B cell targetted therapies. Ferraro et al, NDT 2008 Wallin et al, Blood, 2014

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

BAFF rises after Rituximab Following Rituximab there is a surge of BAFF. 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

COMBIVAS N=15 Belimumab N=15 Placebo Months 0 3 6 12 18 24 Rituximab GC N=15 GC Belimumab Rituximab N=15 GC Placebo COMBIVAS is an experimental medicine study to evaluate the mechanistic effect of combination therapy of rituximab plus belimumab on patients with pr3 anca vasculitis. 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

COMBIVAS N=15 Belimumab N=15 Placebo Months 0 3 6 12 18 24 Rituximab GC N=15 GC Belimumab Rituximab N=15 GC 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

Urinary lymphocyte subsets 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 .

Academic/GSK Biomarker Clinical Collaborators Collaborators Cambridge UCL Imperial GSK Glasgow Newcastle Cambridge UCL Imperial Caroline Savage Robbie Henderson Christine Barrett Andre van Maurik B and T cell FACS BlyS, PK, Stevenage David Jayne Rachel Jones Mark McClure Pani Gopaluni Nasal and LN biopsies 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

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

Key exploratory objectives and endpoints 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 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

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

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