Novel Therapies in Lupus Nephritis Abdulkareem Alsuwaida, FRCPC, MSc Associate Professor King Saud University 2009

Objectives Review the current understanding of systemic lupus erythematosus (SLE) pathogenesis and the implications for targeted biologic therapy Identify potential treatment targets for SLE Summarize data from trials of biologics in SLE

Why new therapies are needed?

Euro Lupus Trial Houssiau et al. Arthritis Rheum, 2002 Aug;46(8):

Prognosis in patients with SLE and sever renal involvement (class III or IV or V) SurvivalAchieved remission Did not achieve remission Patient survival(%) 5 years 10 years Renal Survival 5 years 10 years

Long Term Follow up at 5 Year ResponseMMF (31 patients) PO-CYC (31 patients) Complete75%77% Relapse34%30% Chan TM. ASN 2004

Sequential Immunosuppressive Therapies for Proliferative Lupus Nephritis Contreras G et al. N Engl J Med 2004; 350: %

Why new therapies are needed? Resistant cases High relapse rate Reduce toxicity Avoid steroids Open the possibility for cure

Goals of therapy of Lupus Nephritis Induce autoreactive response without producing immunosupression Reduction in Renal damage Maintenance of immune competency Low cost therapy and safe medications

Pathogenesis of SLE

Clearance of apoptotic cells in a normally functioning immune system In normal individuals apoptotic material is rapidly cleared by phagocytic cells Interactions between macrophages and apoptotic cells lead to the production of anti- inflammatory cytokines

Pathogenesis of SLE

Pathogenesis of SLE Impaired Clearance of Apoptotic Bodies Phagocytosis and clearing of apoptotic cells is defective

Pathogenesis of SLE Impaired Clearance of Apoptotic Bodies Blebs that appear on the surface of apoptotic cells contain Nuclear antigens

Pathogenesis of SLE B cells trap circulating DNA- binding proteins (DNA-bp)

Pathogenesis of SLE The complex presented to T- Helper

Pathogenesis of SLE Production of Auto-Abs directed against nuclear antigens

Pathogenesis of SLE tissue damage caused by auto-Abs deposition with Type II and III hypersensitivity rxns

What lead to the loss of tolerance to apoptotic debris in lupus?

DISEASE ACTIVITY MEASURES British Isles Lupus Assessment Group (BILAG) Systemic Lupus Activity Measure (SLAM) SLE Disease Activity Index (SLEDAI) Safety of Estrogen in Lupus Erythematosus National Assessment (SELENA) SLEDAI

Targeted Therapeutic Approaches in Systemic Lupus Erythematosus

Novel immunosuppressive/modulatory therapies for SLE B-cell targeted therapies Toleragen Co-stimulatory blockade Anti-cytokine therapies Anti-complement therapy Non-specific immunotherapy – Intravenous immunoglobulin – Bone marrow transplantation

Novel immunosuppressive/modulatory therapies for SLE B-cell targeted therapies – B-cell depletion Anti-CD20 mAb Anti-CD22 mAb – B-cell survival factors Anti-BLyS mAb TACI Ig Toleragen – LJP-394 Co-stimulatory blockade – CTLA4-Ig – Anti-CD40 ligand mAb Anti-cytokine therapies – Anti-IL-10 mAb – Anti-TNF- Anti-complement therapy – Anti-C5b-9 mAb Non-specific immunotherapy – Intravenous immunoglobulin – Bone marrow transplantation

B-cell Depletion Therapies Rituximab (anti-CD 20) – CD20: B cell surface marker for maturing B cells except for plasma and early precursor cells – Chimeric monoclonal antibody against CD20 – Mechanism of action: Induce apoptosis Complement mediated cytolysis Fc receptor mediated cell-mediated cytotoxicity

B-cell Depletion Therapies – Rituximab in SLE – Open label, uncontrolled studies/case series – Favorable outcomes in range of refractory disease: nephritis, CNS disease, vasculitis

Rituximab in SLE

A Study to Evaluate the Efficacy and Safety of Rituximab in Subjects With Class III or IV Lupus Nephritis (LUNAR) Phase III randomized, double-blind, placebo-controlled, multi-center study 144 patients with Class III or IV lupus nephritis from 60 sites in the U.S., Canada, Mexico, Argentina and Brazil. Participants were treated with MMF and steroid and were randomized 1:1 to receive Rituxan or placebo in two infusions, 15 days apart. The 1ry outcome: the proportion of patients who achieved a complete or partial remission after 52 weeks of treatment No difference between the two arms

A Study to Evaluate the Efficacy and Safety of Rituximab in Patients With Severe Systemic Lupus Erythematosus (EXPLORER) Phase II/III, RCT, multicenter study in USA Aim: to evaluate the efficacy and safety of rituximab compared with placebo when combined with a single stable background immunosuppressive medication in subjects with moderate to severe SLE. The primary efficacy endpoint of the trial were evaluated at 52 weeks. The study enrolled approximately 257 subjects

A Study to Evaluate the Efficacy and Safety of Rituximab in Patients With Severe Systemic Lupus Erythematosus (EXPLORER) Primary Outcome Measures: Clinical response based on the monthly assessments using the BILAG instrument No difference between the two arms

B-cell Depletion Therapies Epratuzumab – Humanized monoclonal Ab against CD22 – CD22 also B-cell surface marker – Temporary reduction in B-cells – Phase II studies small, open label: modest improvement – Phase III trials to started Alleviate Lupus Affliction with Epratuzumab and Validate Its Autoimmune Safety and Efficacy (ALLEVIATE A), which enrolled patients with severe disease ALLEVIATE B, which enrolled patients with moderate disease

B-cell survival Therapies B-lymphocyte stimulator protein (BlyS) or(BAFF)

B-cell survival Therapies B-lymphocyte stimulator protein (BlyS) or(BAFF) – Soluble protein within family of tumor necrosis factor – Binds to surface receptors of activated B cells B-cell proliferation and survival B-cell differentiation into plasma cells – Higher levels (seen in active SLE patients) may contribute to autoantibody generation Examples: – Atacicept: soluable rceptor fusion protein of TACI-IgG (Transmembrane activator & cyclophilin ligand interactor ) – Belimumab: human monoclonal Ab against BlyS

B-cell survival Therapies Belimumab: – human monoclonal Ab against Bly – Phase II RCT: drug & standard of care vs. placebo & standard of care—patients with measurable DNA or ANA levels responded by standardized scores, lower anti-DNA, and reduction in immunoglobulins

B-cell survival Therapies 449 SLE patients with SELENA SLEDAI (SS) scores >4 were enrolled in a 52-week, RCT compared the effects of adding belimumab (1, 4, or 10 mg/kg) or placebo to SLE standard-of- care therapy. Neither co-primary end point (%change in SS activity at 24 weeks or time to first flare during 52 weeks) was achieved Wallace DJ. Ann Rheum Dis. 2006;65:62.

T cell Targets Induction of anergy in T may reduce immune response in SLE disease state T-cell activation requires: – binding of the T-cell receptor to the MHC antigen complex – costimulatory signal

T cell Targets Abatacept (also called CTLA4-Ig): – inhibition of co-stimulation prevents CD28 from binding to its counter-receptor, CD80/CD86, due to its higher affinity for CD28 Trials in SLE currently underway

Therapies Inducing Tolerance

SLE characterized by loss of tolerance against self-antigens “Tolergens” use anergic principles – LJP 394 (abetimus sodium) synthetic tolerogen against anti-DNA B cells bind anti-DNA antibodies in circulation reduce anti-DNA antibodies by 40%

Abetimus Sodium (LP 394) Recent trial DB, RCT vs. placebo in 230 SLE patients Weekly 100 mg resulted in significant and persistent reductions in anti-DNA titers End point not met since no prolongation in time to renal flare Alarcon-Segovia D, Tumlin JA, Furie RA, et al. Arthritis Rheum. 2003;48(2):

Fewer SLE Flares with LJP394 in High affinity Abs patients 20% 17% 8% 22% P=NS Alarcon-Segovia D, Tumlin JA, Furie RA, et al. Arthritis Rheum. 2003;48(2):

Abetimus Sodium (LP 394) A second flare prevention study of similar design was performed with major modifications – Weekly administration of 100 mg of abetimus sodium throughout the study – inclusion in the final analysis of only those patients who had high affinity for abetimus sodium. at study termination a statistically significant difference in flares between groups was not observed. Cardiel MH, Tumlin JA, Furie RA, et al. Arthritis Rheum. 2003;48(9):S582.

Novel immunosuppressive/modulatory therapies for SLE B-cell targeted therapies – B-cell depletion Anti-CD20 mAb Anti-CD22 mAb – B-cell survival factors Anti-BLyS mAb TACI Ig Toleragen – LJP-394 Co-stimulatory blockade – CTLA4-Ig – Anti-CD40 ligand mAb Anti-cytokine therapies – Anti-IL-10 mAb – Anti-TNF- Anti-complement therapy – Anti-C5b-9 mAb Non-specific immunotherapy – IV immunoglobulin – Bone marrow transplantation

Anti-Cytokine Therapies

Cytokines are produced by numerous cell types It stimulates B-cell differentiation, maturation, Ig secretion, and T-cell function. Antibodies are possible therapeutic strategies Anti-IL-6: along with INF α stimulate maturation of plasma cells – Tocilizumab recently approved for RA – Trials in use of SLE

Anti-TNF Therapies in SLE Infliximab – Open Label Studies – Efficacy in arthritis, skin, nephritis – Nephritis: effective in 4 infusions – Short-term: antibodies against DNA – Phase III trial currently in progressive for lupus nephritis

Novel targets for immunotherapy utilizes naturally occurring compl regulators (CR1/TP10, C1INH) antibodies to components, or receptor antagonists

Effectors – Complement Proteins C5a, a potent neutrophil and monocyte chemotactic factor, is generated by enzymatic cleavage of complement component C5. Eculizumab, a humanized antibody that blocks C5 cleavage and thereby prevents the generation of the proinflammatory complement components C5a and C5b-9 Phase 1 and 2 in SLE

Role of Soliris (eculizumab)

Peripheral Blood Stem Cell Transplantation (PBSCT) The concept is to try to ‘reset’ the aberrant immune system. a period free from memory T cell influence maturation of new lymphocyte progenitors can occur without recruitment to anti-self activity

Peripheral Blood Stem Cell Transplantation (PBSCT) The survey from the European Blood and Marrow Transplant and European League against Rheumatism (EBMT/EULAR) registry : – 53 patients, treated in 23 centres – 66% having kidney involvement. – cyclophosphamide and G-CSF & peripheral blood stem cells – Outcomes: 33/50 patients, disease activity remitted by 6 months (SLEDAI < 3) but 10/31 relapsed after 6 months. Twelve deaths occurred, In contrast in RA, overall mortality was much less (1.4%) in the EBMT Jayne D, Passweg J, Marmont A et al. Lupus 2004;13:168–76.

Peripheral Blood Stem Cell Transplantation (PBSCT) Stem cell transplantation remains complex, costly, and risky. At least one randomized study is underway in the United States and another is in the planning stages in Europe

Conclusions Biological therapy has not yet met the expectations of permanently silencing autoimmune inflammation. Understanding of the basic mechanism of immunity Too early?

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