Rituximab. B Cell Inhibition in APS. Methods. B Cell Inhibition in APS. Disclosure 11/6/2011

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1 Rituximab in Antiphospholipid Syndrome (RITAPS) A Pilot Open-Label Phase II Prospective Trial for Non-Criteria Manifestations of Antiphospholipid Antibodies (NCT: ) Disclosure Research Support: Lupus Clinical Trials Consortium New York Community Trust Doruk Erkan 1, JoAnn Vega 1, Glendalee Ramon 1, Elizabeth Kozora 2, Michael D. Lockshin 1 1 Hospital for Special Surgery, New York, NY 2 National Jewish Health, Denver, CO Research Grant/Consultant: Genentech Clinical Trial Investigator: HGS, Merck EMD-Serono Rituximab Anti-CD20 Chimeric Monoclonal Ab CD20: (+) Pre-B Cell Mature/Memory B Cell Activated B Cell CD20: (-) Plasma Cell Causes B cell depletion via: Complement dependent cytotoxicity Antibody dependent cellular cytotoxicity Membrane attack complex lysis Cell-mediated cytotoxicity through Fc receptor effector cells Inducing apoptosis in vitro when crosslinked by a secondary Ab Background Rituximab (Rituxan ) is a glycosylated IgG 1 chimeric mouse/human antibody containing murine light- and heavy-chain variable regions and human 1 heavy-chain and light-chain constant regions that binds to CD20 antigen. B Cell Inhibition in APS Background Based on the In Vitro Experience: B cells are involved in apl-related clinical events B-cell activating-factor (BAFF) blockage can prevent the disease onset and prolongs survival in APS mouse models Cytotoxic T-lymphocyte antigen 4 immunoglobulin (CTLA4-Ig) prevents initiation, but not development, of APS in NZW x BXSB F1 APS mouse model. Youinou P, Reneaudineau Y. The APS as a model for B-cell-induced autoimmune diseases. Thromb Res 2004; 114: Kahn P, Ramanujman M, Bethunaickan R, et al. Prevention of murine APS by BAFF blockade. Arthritis Rheum 2008; 58: Akkerman A, Huang W, Wang X, et al. CTLA4Ig prevents initiation but not evolution of APS in NZW/BXSB mice. Autoimmunity 2004; 37: B Cell Inhibition in APS Background Based on the Uncontrolled Clinical experience: Rituximab may be effective for thrombocytopenia, hemolytic anemia, and skin ulcers in apl-positive patients. Rituximab has been used in difficult-to-treat APS patients It is unknown if it is effective against apl-mediated thrombosis It is unknown if it eliminates persistently and significantly positive apl There has been no systematic assessment of rituximab use in persistently apl-positive patients RITAPS TRIAL: Investigator-initiated Single center Open label Phase II Descriptive Pilot trial Tenedios F, Erkan D, Lockshin MD. Rituximab in Primary APS. Arthritis Rheum 2005;52:4078 (abstract) Kumar D, Roubey RA. Use of Rituximab in APS. Curr Rheumatol Rep 2010;12:

2 Primary Objective To Evaluate: The safety of rituximab in 20 apl-positive patients, as assessed by serious and non- serious adverse events (AE) up to 12 months Secondary Objectives To Evaluate: The effect of rituximab on apl profile, as assessed by LA test, acl ELISA, and aβ 2 GPI ELISA up to 12 months The efficacy of rituximab for non-criteria manifestations of apl, as assessed by specific outcome measures up to 6 months Exploratory Objective: To evaluate: The pharmacokintetics of rituximab in apl-positive patients, as assessed by serum rituximab levels and human anti-chimeric antibody (HACA) assay at 6 and 9 months Inclusion Criteria: > 18 years of age, At least one laboratory criterion, and At least one clinical criterion Inclusion Criteria: > 18 years of age, No other systemic autoimmune diseases, At least one laboratory criterion a) positive LA test as defined by the International Society on Thrombosis and Haemostasis, on two or more occasions, at least 12 weeks apart; b) positive acl IgG/M/A isotype, present in > 40U, on two or more occasions, at least 12 weeks apart and/or; c) positive aβ 2 GPI IgG/M/A isotype, present in > 40U, on two or more occasions, at least 12 weeks apart Inclusion Criteria: > 18 years of age, No other systemic autoimmune diseases, At least one laboratory criteria, and At least one clinical criterion 2

3 a) Persistent active thrombocytopenia (diagnosed by platelet counts < 100 / nl at least twice 12 weeks apart and confirmed based on the updated APS Classification Criteria recommendations); b) Persistent active autoimmune hemolytic anemia (diagnosed by anemia with positive Coombs test at least twice 12 weeks apart); c) Cardiac valve disease (diagnosed by echocardiography within 12 months of the study entry and confirmed based on the updated APS Classification Criteria recommendations 1 ); d) Chronic skin ulcers (non-infected livedoid vasculitis-like skin ulcer and/or large skin ulceration resembling pyoderma gangremosum, for at least 3 months prior to the screening, diagnosed by physical examination); e) apl-nephropathy (diagnosed by kidney biopsy within 12 months of the study entry, confirmed based on the updated APS Classification Criteria recommendations, and urine protein to creatinine ratio > 1.0) and/or; f) Cognitive dysfunction (confirmed by neuropsychological batteries) with/without white matter changes (diagnosed by brain magnetic resonance imaging within 12 months of the study entry) Exclusion Criteria: > 4/11 ACR Classification Criteria for SLE Other Systemic Autoimmune Diseases Acute thrombosis History of stroke (only for patients with cognitive dysfunction) Other general exclusion criteria considerations: absolute neutrophil count < 1.5 x 10 3 ; LFTs >2.5 x upper limit of normal; positive Hepatitis B or C serology; history of positive HIV; acute/chronic pancreatitis; any investigational agent within four weeks of screening or five half-lives of the investigational drug (whichever is longer); live vaccine within four weeks prior to randomization; previous treatment with rituximab or natalizumab; history of allergic or anaphylactic reactions to humanized or murine monoclonal ab; history of recurrent significant infection or history of recurrent bacterial infections; known active bacterial, viral fungal mycobacterial, or other infection; pregnancy or lactation; concomitant malignancies or previous malignancies Study Procedures (Visits): Screening Visit >>> 5-10 days later >>> Day 1 Infusion (Rituximab 1000 mg) Acetaminophen, Diphenhydramine, Solumedrol 100 mg Day 15 Infusion (Rituximab 1000 mg) Acetaminophen, Diphenhydramine, Solumedrol 100 mg Month Visits (Safety & Efficacy) 9-12 Month Visits (Safety & apl) Week Visits (CD19) Study Procedures (Medications 0-6 months): Antiplatelet/Anticoagulant Agents No Initiation, Discontinuation, or Dose/Target INR Change Unless Indicated for Bleeding or New Thrombosis Corticosteroids No Initiation or Dose Increase Unless Indicated for Reactions or Other Co-morbidites Immunosuppressive Agents No Initiation, Discontinuation, or Dose Change ACE or ARB At the screening visit for all apl-nephropathy patients if not receiving DSMB + Primary Outcome Measures (throughout the study) Serious Adverse Event Death Life-threatening Event Hospitalization Disabling (i.e. the AE resulted in a substantial disruption of the patient s ability to carry out normal life functions) Congenital anomaly/birth defect Adverse Event Any untoward medical occurrence in a patient participating in an investigational trial or protocol regardless of causality assessment Secondary Outcome Measures ( w) LA test: Complete Response (CR): Negative test No Response (NR): Positive test acl/aβ 2 GPI ELISA Complete Response (CR): < 20 U Partial Response (PR): U No Response (NR): > 40 U 3

4 Secondary Outcome Measures Specific Clinic Outcome Measures CR: Complete Response 6 months PR: Partial Response 6 months NR: No Response 6 months Recurrence was evaluated at 6 months in patients with baseline positivity and who had complete response for that specific outcome measure before 6 months. Secondary Outcome Measures platelet counts, CR > 150 /nl, PR /nl, and NR < 100/nl hemolytic anemia, CR normal hemoglobin with a (-) Coombs test; PR low hemoglobin with (-) Coombs test, and NR low hemoglobin with (+) Coombs cardiac valve disease, CR disappearance of echo lesions, PR > 50% improvement of echo lesions, and NR no change or worsening of echo lesions chronic skin ulcers, CR disappearance of skin ulcers by PE and digital pictures, PR > 50% improvement of skin ulcers by PE and digital pictures, and NR no change or worsening of skin ulcers by PE and digital pictures; apl-nephropathy, CR normal serum creatinine, inactive urinary sediment, and UP/C < 0.5, PR creatinine < 15% above BL, RBCs/HPF < 50% above baseline with no RBC casts, and 50% improvement in the UP/C, and NR absence of CR/PR; cognitive dysfunction, CR was the normalization of the cognition tests, PR was more than 50% improvement in the cognition tests, and NR was no change Results (Preliminary) Results Demographics: N: 19 Female 11 Mean Age: (20-61) APS Vasc: 7 Livedo: 6 APS Preg: 2 ACR SLE: 2.37 (1-3) APS Vasc/Preg: 2 Results Results Primary Outcome Severe Infusion Reaction/Early Termination 2 Diffuse Skin Rash 1 Chest pain with fever/chills/back pain 1 Total Adverse Events (AE) 59 Serious AE Hospitalization Unlikely 12 Non-serious AE Within 48h Likely 7 Non-serious AE After 48h Unlikely 35 Non-serious AE After 48h Possibly 5 * 1 LMWH 4

5 LA test: n: 17/19 % Complete Response: Negative Test No Response: Positive Test acl IgG ELISA n: 13/19 % aβ 2 GPI IgG ELISA n: 10/19 % Complete Response: < 20 U Partial Response: U No Response: > 40 U Complete Response: < 20 U Partial Response: U No Response: > 40 U Baseline Mod-to-Sev MR, Thickened MV, No Veg Mild MR, Thickened MV, No Vegetation Mild-to-Mod AR, No Thickening, 5x8mm Vegetation No Change 6 month No Change except No Thickening Same, 6x12mm Vegetation #: 4/5 #: 2/5 (1 Early Term.) 5

6 BL BL 24w 24w (Week 52 = No Active Skin Disease) 52w BL 4w 36w 24w 52w Creatinin e Baseline 6 month C3/4 68/11 74/12 U P/C #: 1/2 6

7 Conclusion Baseline 6-month 1 9/12 2/12 2 8/12 5/12 3 7/12 2/12* 4 4/12 3/12* 5 4/12 5/12* Based on the preliminary analysis of our ongoing pilot study of rituximab-receiving apl-positive patients with non-criteria apl manifestations: Safety appears to be consistent with rituximab s known safety profile although 11% of our patients could not complete the treatment protocol due to reactions; B cell depletion appears to be effective in controlling some apl manifestations during 6 month of follow-up; and No substantial change in apl profiles was observed in patients who completed 12 month of follow-up. No Change in White Matter Lesions #: 5/6 Acknowledgments The cost of the laboratory tests during the study period and the study medication are covered by Genentech. THANK YOU Doruk Erkan, MD erkand@hss.edu 7