Battling the B cell- New biologic therapies for Lupus

1. MEDICINE OF THE HIGHEST ORDER Battling the B cell-New biologic therapies for Lupus Jennifer H. Anolik, MD, PhD Division of Allergy, Immunology & Rheumatology University of Rochester Medical Center 2011

2. The ‘traditional treatment armamentarium’

3. Heterogeneity of SLE Brain Salivary, Parotid glands Thyroid Heart, Lungs Serous linings of heart, Lungs, GI tract Special complications of pregnancy Kidneys Kidneys Organ-threatening Skin Non-organ-threatening Joints Blood vessels andBlood cells SLE = Systemic lupus erythematosus Wallace DJ. In: Koopman DJ, ed. Arthritis and Allied Conditions. 13th ed. Vol 2 :1319.

4. IT WORKS FOR ME

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

6. Th1 IFN DC IL-12 CD22 CD20 B-cell T-cell TACI BCMA BAFFR CD40L IL-10 IL-4 CD40 Activation TNF IL-10 CD28/CTLA4 ICOS B7.1/2 B7RP1 TLRs Th2 IL-6 IL-6 IL-1 IL-15 IL-18 MØ PC IL-4, IL-10, IL-15 IFN GM-CSF TNF  autoantibodies SLE Pathogenesis: Immunologic factors

7. SLE Clinical Trials: B cell targeted • Targeting B cell with anti-CD20 • Initial studies • Rituximab in general lupus (Genentech; phase II/III): completed and published in 2010 • Rituximab in proliferative lupus nephritis (LN) (Genentech; phase II/III): completed and reported • Ocrelizumab in LN (Roche; phase III): terminated • Other small molecular anti-CD20: in development • Anti-CD22: phase IIb trial reported superior response rates compared to placebo at week 12 in recent press release; phase III Butterfly study starting • Cytokine blockade

8. Mouse Human IgG1 Rituximab targets CD20 specifically expressed on the surface of B cells

9. B cell depletion therapy (BCDT) is rapidly expanding in the treatment of autoimmune diseases FDA-approved Others • Rheumatoid Arthritis (Anti-TNF failures) • ANCA-mediated vasculitis • Sjogren’s • Scleroderma • Myositis • Anti-phospholipid syndrome • ITP • TTP • Transplant rejection • Inflammatory bowel disease • Chronic Graft-versus-host disease • Blistering skin diseases • Idiopathic membranous nephropathy • Pulmonary hypertension • Hepatitis C cryoglobulinemia • IgM-associated polyneuropathy • Uveitis • Autoimmune paraneoplastic syndromes Phase 3 RCT • RR MS • PP MS • Extra-renal SLE • Renal SLE • Type 1 Diabetes • Early rheumatoid arthritis

10. 100 Non-depleters (6) 10 (Lymphocytes/ul) Depleters (11) CD19+ 1 0.1 0 3 6 9 12 Months In Phase I/II open label studies B cell depletion is variable and correlates with clinical response <0.05 Anolik et al. Arthritis and Rheum 48:455, 2003 Anolik et al. Arthritis Rheum 50:3580, 2004 Anolik et al. Arthritis Rheum 56:3044, 2007

11. Multi-center randomized trial: EXPLORER • 257 SLE patients with moderately severe disease: but no renal or CNS • Subjects were randomized to steroids alone or steroids + rituximab • Both arms had a significant improvement in disease activity Merrill et al. Arthritis and Rheum 62:222, 2010

12. Time to First Flare Over 52 Weeks (post hoc) P = 0.0524

13. Pre-specified Exploratory Analysis: Clinical Response by Ethnicity Other African-Americans/Hispanics p=0.0408 p=0.0995 Responders Responders African-American/Hispanic subgroup showed significant response in the rituximab-treated group compared with the placebo group. The other (ethnic) group trended toward a worsening response with rituximab, but not statistically significant. *p value refers to the test on 3-category endpoints (MCR/PCR/NCR).

14. Biomarkers Anti-dsDNA IgG* p < 0.005 C4 Complement p =0.0045

15. LUNAR Week 16 Treatment Period Rituximab + MMF (n~70) Screening Prednisone taper Follow-up Period Placebo + MMF (n~70) Weeks Weeks Week Week 1 and 2 24 and 26 52 78 (Days 1 and 15) (Days 168 and 182) = Study drug infusion = Prednisone: 1000 mg IV methlypredisolone given at days 1 and then days 2, 3, or 4 oral predisone initiated at 0.75 mg/kg/day after IV steroids and then tapered to 10 mg/day by day 112 • ACR Oct 2009: • Did not meet primary endpoint of renal response at 52 wk

18. Using rituximab in SLE: Where are we now? • Immune thrombocytopenia • Refractory renal or neurological disease • Transverse myelitis or optic neuritis associated with NMO antibody • ?Future clinical trials in subsets of disease

19. BLyS/BAFF and APRIL Functionsand Therapeutic Agents

20. BLyS/BAFF and APRIL Functionsand Therapeutic Agents

21. Belimumab = Benlysta® • FDA approval March 9, 2011 • The first new drug for SLE in over 50 yrs!!! • First biologic for SLE • 10 mg/kg IV • Q2 wk x3 then Q4 wk http://www.youtube.com/watch?v=i24UTvOKK-8

22. Belimumab = anti-BAFF • Very good safety profile • Small effect size – improvement in SRI 51% vs 39% = difference of 12% • Slow onset of action • Not studied in patients with severe renal or CNS disease nor in combination with cyclophosphamide • High price, i.e. $34,000-40,000 • How insurance companies will handle approval is unclear

23. BLISS 52 N=865 P = 0.0006 OR 1.8 P = 0.013 OR 1.6 BAFF Blockade by Belimumab in SLE • SRI: • SELENA-SLEDAI improved >=4 • No new BILAG 1A or 2B flares • No worsening in PGA BLISS 76 N=819 P = 0.021 OR 1.5 P = 0.10 OR 1.3 SV Navarra Lancet 2011

24. Slow onset Lancet 2011

25. BAFF Blockade by Belimumab in SLE P < 0.0001 P < 0.01 MA Petri ACR 2010

26. Belimumab Improved or Stabilized SLE Disease Activity and Reduced Flare Rate during 3 Years of Therapy Furie Eular 2008; Merrill ACR 2011 6 year data

27. Improvements in Fatigue Strand ACR 2011

28. Benlysta Indications • Indicated for the treatment of adult patients with active, autoantibody-positive, SLE who are receiving standard therapy. • Not evaluated in severe active lupus nephritis or central nervous system lupus. Not studied in combination with other biologics or intravenous cyclophosphamide. • In Trial 2 and Trial 3 combined, the SRI response rate in black patients (N=148) in the BENLYSTA groups was less than that in the placebo group (22/50 or 44% for placebo, 15/48 or 31% for BENLYSTA 1 mg/kg, and 18/50 or 36% for BENLYSTA 10 mg/kg). • Who to use it in? Moderate disease on other immunosuppression where taper of steroids is not possible

29. Is Benlysta Safe? • Infusion reactions: rash, fever, HA, nausea, SOB. 17% of treated vs. 15% of PB. Treat with an antihistamine prior to infusion. • Infections: Are common in SLE. 71% vs. 67%, 6% vs. 5.2% for serious infections. The most frequent serious infections included pneumonia, urinary tract infection, cellulitis, and bronchitis. • Depression: In clinical trials, psychiatric events (primarily depression, insomnia, and anxiety) were reported more frequently with BENLYSTA than with placebo (~15%) but really not significantly DIFFERENT from control. Serious psychiatric events, serious depression, and two suicides were also reported. • Most common side effects in clinical trials were nausea, diarrhea, and fever.

30. Take Home Message • Belimumb was effective and safe for SLE in 2 phase III trials. However, the magnitude of the effect is small. • Atacicept has dramatic effects on plasma cells but there are concerns about infections. There is an ongoing trial in non-renal lupus. • Rituximab was not effective in Explorer but showed promise in Lunar. • Abatacept probably has some effect in polyarthritis. There is an ongoing study in combination with cyclophosphamide for lupus nephritis. • Tocilizumab may have clinical efficacy but neutropenia and infections are of concern • Trials of TNF blockade have stopped • Two anti-IFNα monoclonal antibodies are in clinical trials.

31. Treatment of SLE: Into the 21st Century BAFF inhibitors pDC Anti-B cell antibodies sBAFF mBAFF BR3 IFN IFN blockade TLR inhibitors cytokines DC B TLR9 TLR inhibitors B7.1/2 B7.1/2 TLR2 TLR4 TLR6 TLR7 TLR8 IFN blockade CTLA4-Ig Abatacept CD28 CD40 IL-2, 4 IL-10 TNF IFN IL-12p40 IFN T CXCL13 CXCR4 IP-10 S1P CD40L pDC TNF blockade MØ TNF IL-1 IL-6 Cytokine inhibitors IFN- IL-12 IL-23 TNF Lymphocyte signaling inhibitors Chemokine - Lymphocyte trafficking modulators IL-6 blockade Anti-B cell antibodies Adapted from Martin & Chan, 2006. Annu. Rev. Immunol. 24:467-96

32. Thank You!