What ’ s New in Lupus: Update on treatment and clinical trials

1. MEDICINE OF THE HIGHEST ORDER What’s New in Lupus: Update on treatment and clinical trials Jennifer H. Anolik, MD, PhD Associate Professor of Medicine Division of Allergy, Immunology & Rheumatology University of Rochester Medical Center 2012 Lupus Education Day

2. Updates • New Treatments • Biomarkers • Diagnosis • Pathogenesis (leads to treatment) • Prognosis

3. What we’re doing at the U of R: • The Rochester Autoimmunity Center of Excellence • NIH-funded multidisciplinary center • Basic mechanisms of lupus and clinical trials • Clinical Cohorts: Lupus Clinical Trials Consortium • 20 centers • Collaborative Longitudinal Lupus Registry • Clinical Trials • The AIR unit has an active program in clinical trials in SLE • Investigation of new, targeted biological interventions in SLE • Anti-IL6, TLR blockade

4. New Treatments for Lupus • Until April 2011 it had been over 50 years since a new drug was approved for lupus! • WHY? • Lupus is hard to study: • Clinical expression is heterogeneous • Pathology is diverse • Disease activity is intermittent • Lack of agreed upon disease activity measures and endpoints • Small patient populations- rare disease • Development costs: Estimated $1 billion to take a drug from the research stage to FDA approval • Lack of a clinical trial infrastructure

5. The ‘traditional treatment armamentarium’ Benlysta

6. Why do we need clinical trials? • We need to know what works • We need better medications for lupus • Many lupus patients have progressive damage to vital organs • Many lupus patients have ongoing symptoms that limit function • Many lupus patients suffer toxicity from medications • We need FDA approval • We need to get insurance companies to pay for medications

7. Steps for drug approval • Pre-clinical studies – Non-Human • Phase I studies – 1st time in humans <100 people • What are the side effects and what dose should be given? • Phase II studies – 100+ people • Does the drug work and are there other side effects? • Phase III studies – 1000+ people • Does the drug work and is it safe long term?

8. Biological Therapies • Proteins that affect cells or signals in the immune system • Usually need to be injected or infused (IV)

9. Examples of success of Biologics: RA • Anti-TNFs • Etanercept • Infliximab • Adalimumab • Anti-cytokine • Kineret (IL-1ra) • Tocilizumab (anti-IL-6) • B cell depletion • Rituximab • Blockade of co-stimulation • Abatacept

10. EBV? Baseline immunological abnormalities Infection Hormonal factors Abnormal (control of) immune responses SLE SLE - Etiology • The etiology of SLE remains unknown • Yet, SLE is clearly multifactorial: • Genetic factors • Immunologic factors • Hormonal factors • Environmental factors Genetic predisposition

11. SLE pathogenesis and treatment targets Proteasome inhibitors B T Stages of autoimmunity Loss of tolerance Innate and adaptive dysregulation End organ targeting FcR, ITGAM Sle1, CD22, C1q, BANK, BAFF Sle2 (B), Sle3 (T, DC), PTPN22 Autoantibodies Immune complex BAFF inhibitors IFN PC mBAFF Anti-B cell antibodies sBAFF mDC BR3 TLR inhibitors TLR9 B7.1/2 B7.1/2 IFN blockade CTLA4-Ig Abatacept CD28 pDC CD40 IFN CD40L TNF IL-1 IL-6 N Lymphocyte signaling small molecule inhibitors TNF blockade IL-6 blockade

12. Belimumab (anti-BAFF)- Benlysta for Treatment of SLE • Blocks a B cell survival factor, inducing B cell death • Recently approved (3/9/2011) for the treatment of SLE • 1ST DRUG APPROVED FOR LUPUS IN OVER 50 YRS • 1ST BIOLOGIC APPROVED FOR LUPUS http://www.youtube.com/watch?v=i24UTvOKK-8

13. Belimumab = anti-BAFF • 10 mg/kg IV Q2 wk x3 then Q4 wk • Very good safety profile • Small effect size – improvement in SRI 51% vs 39% = difference of 12% • Slow onset of action • Indicated in SLE patients with active (autoantibody +) disease despite conventional immunosuppressives (like imuran, cellcept, MTX) • Not studied in patients with severe renal or CNS disease nor in combination with cyclophosphamide • Small number of black patients studied

14. Small effect size and slow onset Lancet 2011

15. Belimumab appears safe over time, with continued increases in efficacy Furie Eular 2008; Merrill ACR 2011 6 year data ACR 2012 7 year data

16. SLE pathogenesis and treatment targets Proteasome inhibitors B T Stages of autoimmunity Loss of tolerance Innate and adaptive dysregulation End organ targeting FcR, ITGAM Sle1, CD22, C1q, BANK, BAFF Sle2 (B), Sle3 (T, DC), PTPN22 Autoantibodies Immune complex BAFF inhibitors IFN PC mBAFF Anti-B cell antibodies sBAFF mDC BR3 TLR inhibitors TLR9 B7.1/2 B7.1/2 IFN blockade CTLA4-Ig Abatacept CD28 pDC CD40 IFN CD40L TNF IL-1 IL-6 N Lymphocyte signaling small molecule inhibitors TNF blockade IL-6 blockade

17. SLE Clinical Trials: B cell targeted • Targeting B cells with anti-CD20 • Initial studies • Rituximab in general lupus (Genentech; phase II/III): completed • Rituximab in proliferative lupus nephritis (LN) (Genentech; phase II/III): completed • Cytokine blockade: BAFF blockade • Other B cell targeted therapeis: • Anti-CD22: phase II trial promising; phase III EMBODY CURRENTLY ENROLLING • Anti-CD19

18. Rituximab= anti-CD20= B cell depletion • Two large trials of anti-CD20 (rituximab) in SLE failed to meet their primary outcomes • Advances in the field on how to successfully do lupus clinical trials • Rituximab is still thought to be effective in lupus and indicated for a subset of refractory patients

19. TARGETING B CELLS:Multiple Roles in autoimmune disease • Autoantibody Dependent: • A variety of autoantibodies are found in patients with autoimmune disease, including SLE and RA • Autoantibody Independent: • Pathogenic cytokines can be directly produced by activated B cells • TNF-, IL-6, lymphotoxin, IFN • B cells may present antigen to T-cells and also provide costimulatory signals • B cells may form ectopic lymphoid structures and participate in local immune responses

20. Targeting Plasma Cells • Autontibodies in lupus are frequently pathogenic • Current therapies often do not effectively decrease autoantibodies CFZ PR957 BTZ Proteasome inhibition IFN-alpha (pg/ml) No Tx PIs Proteasome inhibitor (nM) Ichikawa and Anolik Arthritis and Rheumatism 2011

21. SLE pathogenesis and treatment targets Proteasome inhibitors B T Stages of autoimmunity Loss of tolerance Innate and adaptive dysregulation End organ targeting FcR, ITGAM Sle1, CD22, C1q, BANK, BAFF Sle2 (B), Sle3 (T, DC), PTPN22 Autoantibodies Immune complex BAFF inhibitors IFN PC mBAFF Anti-B cell antibodies sBAFF mDC BR3 TLR inhibitors TLR9 B7.1/2 B7.1/2 IFN blockade CTLA4-Ig Abatacept CD28 pDC CD40 IFN CD40L TNF IL-1 IL-6 N Lymphocyte signaling small molecule inhibitors TNF blockade IL-6 blockade

22. SLE Clinical Trials: Cytokines • Targeting cytokines of pathogenic importance • Targeting Interferon α • Anti-interferon α (Genentech; phase I): enrollment complete, ROSE • Targeting IL6

23. Anti-IL6 (Pfizer) Butterfly study • Well-tolerated in phase I studies in healthy volunteers and subjects with RA (92). • Never used in lupus but similar drug blocking the IL6R (tocilizumab) was well-tolerated in a small number of patients (16) except for reversible neutropenia • Phase 2 study evaluating the safety and efficacy of 3 doses of anti-IL6 compared to PB in 180 SLE patients with moderately active disease (1:1:1:1) (4 doses q8 wk x 24 wk) is underway • We are currently enrolling

24. Interferon and Toll-like receptors TLR Current Opinion in Rheumatology 2003 Pascual

25. IFN as a common denominator in trigger of flares • Sun exposure • Drug reactions, e.g. sulfa drugs • Infections • Some of our current drugs are now believed to target IFN pathways: e.g. anti-malarials

26. Anti-IFN • Genentech ROSE study (we participated in this) • Preliminary data to be presented at ACR 2012 • No difference in tx vs. PBO response rates in the group as a whole • A subset may respond • SRI response was 55% vs 31% in those on >10 mg prednisone at baseline • Estimated treatment difference of SRI response in rontalizumab and pbo IFN low arms was 31% (90% CI: 9-51%, p=0.0285).

27. TLR antagonists • TLRs are key receptors of the innate immune system that can induce strong inflammatory responses- important in production of IFN • Small molecules inhibitors of Toll-like Receptors (TLRs) 7, 8, and/or 9 are under development • Study of DV1179, a bifunctional inhibitor of TLR7 and TLR9, starting in SLE (we will be a site)

28. Biomarkers: Diagnosis and Disease Subsets

29. What are Biomarkers? • Indicators to monitor disease diagnosis, progress and treatment succcess • Ongoing meetings at the FDA focusing on the development of biomarkers to predict acute worsening of disease, called a flare, and their potential for accelerating lupus clinical trials and new drug approvals Erythrocyte C3d and C4d for monitoring disease activity in systemic lupus erythematosus. Kao AH, Navratil JS, Ruffing MJ, Liu CC, Hawkins D, McKinnon KM, Danchenko N, Ahearn JM, and Manzi S. (2010). Arthritis & Rheumatism 62: 837-844

30. Autoantibodies: Early signs of lupus Clinical criteria for systemic lupus erythematosus precede diagnosis and associated autoantibodies are present before clinical symptoms Arthritis & Rheumatism, Volume 56, Issue 7, July 2007, pp. 2344-235; Arbuckle NEJM 2005

31. New silicon chips help identify patients with lupus • No single laboratory test can determine if someone has lupus • A team at Stanford engineered a silicon computer chip containing thousands of subtly different protein segments derived from a single protein (known as a histone 2B), which is a common target of autoantibodies in lupus • Testing blood from lupus patients by applying the sample directly on to the chip, revealed specific H2B epitopes that are recognized by autoantibodies in individuals with systemic lupus erythematosus who have elevated disease severity (elevated interferon signature) Nature Medicine 2012 PJ Utz group

32. Proteins on Blood Cells More Accurately Predict Lupus Diagnosis and Disease Activity • Current measures of disease activity and prediction of flare have severe limitations • Lupus patients have higher levels of C3d and C4d bound to red blood cells than healthy people and those with other rheumatic diseases and this correlates with disease activity • Recent studies indicating this test can be a helpful biomarker in lupus nephritis • Recently, the company Exagen announced a new test using C4d (CB-CAPs=cell bound complement activation products) to help physicians make a faster and more accurate diagnosis of lupus (AVISE SLE) Ahearn and Manzi Lupus 2011; Erythrocyte C3d and C4d for monitoring disease activity in systemic lupus erythematosus. Kao AH, Navratil JS, Ruffing MJ, Liu CC, Hawkins D, McKinnon KM, Danchenko N, Ahearn JM, and Manzi S. (2010). Arthritis & Rheumatism 62: 837-844

33. Interferon dysregulation • Interferon is a key dysregulated cytokine in lupus • Recent serum chemokine (IFN regulated) test that can predict flare now licensed for commercial development • Gene expression transcriptional finger-prints: nanostring Baechler-Gillespie, Arthritis and Rheum 2009 Pascual, Immunity 2008

34. Predicting flares with B cell biomarkers African Amer. Low Comp. IFN-a DNA RNP Sm Ro La “ACTIVE-DISEASE” CLUSTER Active Disease Like Cluster Healthy Like Cluster p=0.04 “HEALTHY-LIKE” CLUSTER -3 0 3 Days from Baseline Anolik and Sanz, Rochester ACE funding

35. EBV? Baseline immunological abnormalities Infection Hormonal factors Abnormal (control of) immune responses SLE SLE - Etiology • The etiology of SLE remains unknown • Yet, SLE is clearly multifactorial: • Genetic factors • Immunologic factors • Hormonal factors • Environmental factors Genetic predisposition

36. Genetics and Lupus • Lupus is more common in families with lupus or other immune system diseases; twin data • Some groups, such as African Americans, Hispanics, and Asians get lupus more commonly and with more severe symptoms • Intense efforts: SLEGEN- consortium to conduct large genome wide association studies with 2.5 million genetic markers • ImmunoChip: technology offers the ability to study 250,000 genes and their variants in each of a large number of participants • Over 40 SLE associated genes identified Kaiser and Criswell, Curr Opin Rheum 2010

37. Genetics and Lupus • ImmunoChip technology • Comparison of SLE vs. ANA negative individuals • Preliminary analysis anticipates 15-20 new SLE associated genes • Toll-like receptors are coming up as a big common pathway Arthritis Research Center of Canada Lupus Symposium 2012

38. Things to Remember Tomorrow • SLE is a heterogeneous autoimmune disease that typically affects young women in their child bearing years • SLE can be mild and is almost always treatable • Although lupus can affect almost any part of the body, most people experience symptoms in only a few organs. • Classification criteria help with diagnosis but ongoing management requires additional multi-parameter assessment • Consider the balance of treatment of active disease vs. complications of treatment

39. Some Take Home Messages • Treatment in the future may be driven by the patient’s genetic makeup: personalized medicine • The pathogenesis of SLE is complex with dysregulation of multiple arms of the immune system • Despite improvement in mortality, new treatments are needed given resistant disease and the side effects of current immunosuppressives • A number of biologic molecules critical to the lupus disease process are emerging as logical targets for treatment • Information about disease pathogenesis is leading to targeted biologic therapies

40. Learn More • www.lupusresearch.org/research/research_update.html • LupusTrials.org • www.clinicaltrials.gov • www.niams.nih.gov/Health_Info/Lupus/ • The National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS) has developed a strategic plan for reducing health disparities. Lupus is included as an area of research focus. Further information on disparities in lupus and the strategic plan is available at: http://www.niams.nih.gov/an/stratplan/strategicplanhd/strategicplanhd.htm • Some references: Targeted therapies in systemic lupus erythematosus: successes, failures and future. Hahn BH. Ann Rheum Dis. 2011 Mar;70 Suppl 1:i64-i66. Review.; The genetics of systemic lupus erythematosus and implications for targeted therapy. Ann Rheum Dis. 2011 Mar;70 Suppl 1:i37-43. Review.; Targeting BLyS in rheumatic disease: the sometimes-bumpy road from bench to bedside.Curr Opin Rheumatol. 2011 May;23(3):305-10; B-cell biology and related therapies in systemic lupus erythematosus. Ahmed S, Anolik JH. Rheum Dis Clin North Am. 2010 Feb;36(1):109-30, viii-ix.

41. Thank You