Vesicular Demyelination in MS A Pattern of Humoral Immune Pathology Multiple Sclerosis: B-Cells Take Center Stage

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1 Vesicular Demyelination in MS A Pattern of Humoral Immune Pathology Multiple Sclerosis: B-Cells Take Center Stage Stephen L. Hauser, M.D. CD2 B cells in an MS lesion CD2 B cells in an MS lesion 1

2 CD138 plasma cells in an MS lesion B Cells in the Pathogenesis of MS Possible Roles: Antigen uptake, processing and presentation to T cells (APC) Activation of dendritic cells, microglia Co-stimulation of T cells Recruitment of cells to inflammatory sites Demyelination, myelin opsonization by Ab +/- C Site of Epstein-Barr virus persistence Enhance remyelination* T cell anergy* Regulation by anti-idiotypic Abs* * Potentially beneficial B-Cell Development Short-lived PC (secrete IgM) Death Long-lived PC Anti-CD2 Monoclonal Antibody is a genetically engineered chimeric (mouse-human) monoclonal antibody that targets CD2-positive B lymphocytes Ag APC T cells Ag CD2 is present on B and pre-b lymphocytes but not on stem cells or plasma cells Naïve B cell Ag = antigen APC = antigen-presenting cells PC = plasma cell Activated B cell Germinal center B cell Memory B cell Affinity maturation of B-cell receptor Long duration of action FDA approval for B-cell lymphoma (1997) and RA (26) Maloney DG, Grillo-López AJ, Bodkin D, Ahmed R et al. Immunology of Infectious Diseases; 22:

3 Phase II RRMS Study Design 1 Treatment Cycle and 9 MRIs Over 1Year Screen (4 wks) MRI Week / Infusion Wk 4 MRI to evaluate safety Treatment period (48 wks) Primary Endpoint Total number of Gd-enhancing lesions at Wks 12, 16, 2, and 24 Secondary Endpoints Proportion of patients relapsing Wks -24 New Gd-enhancing lesions T2 lesion volume changes B/L-Wk 24 2:1 Randomization stratified by site, EDSS ( 2.5, >2.5), and prior therapy (none or stopped >6 months or 6 months) Hauser et al. NEJM, in press 28 Primary Endpoint Total New Gd Lesion Count at Weeks 12, 16, 2 and 24 (ITT population) Total new Gd lesion count >-1 >1-2 >2-3 >3 Mean (SD) Minimum, Maximum 19 (54.3%) 3 (8.6%) 5 (14.3%) 1 (2.9%) 7 (2.%) 4.5 (12.58).., 68.7 (n=65) 54 (83.1%) 8 (12.3%) 3 (4.6%).16 (.43).., 2. <.1 1 *The p-value is based on Van Elteren test stratified by EDSS (<2.5, >2.5), prior therapy (<6 months, >6 months), and baseline gad (, >1) Gadolinium-Enhancing Lesions in Each Treatment Group from Baseline to Week 48 Panel B shows the number of new gadolinium-enhancing lesions by week. Missing values were imputed by an average of the available data. Panel A shows the mean total number of gadolinium enhancing lesions by week. Hauser, et. al. NEJM: Awaiting Publication Proportion of Subjects with Relapses During 24, 36 and 48 Weeks Proportion 1 24 Weeks Relative Risk 2 9% CI for RR 3 Proportion 1 Relative Risk 2 9% CI for RR 3 Proportion 1 36 Weeks 48 Weeks Relative Risk 2 9% CI for RR 3 12 (34.3)% 14 (4.)% 14 (4.)% (n=69) 1 (14.5%) 2.31 (1.25,4.26) (n=69) 12 (17.4%) 2.24 (1.3,3.88) (n=69) 14 (2.3%) 1.9 (1.3,3.88) (n=14).238 (n=14).145 (n=14).37 *The p-value is based on CMH test stratified for EDSS and prior treatment 1 The patients who discontinued before analysis are considered relapse-free if they did not experience any relapse during their study period. 2 Relative Risk of having relapse comparing to placebo, 3 9% CI are based on logit-adjusted 3

4 Change in T2 Lesion Volume T2 Lesion Volume at Baseline, mm 3 Mean ± SD Mean ± SD 432 T2 Lesion Volume Change from Baseline to Week 24**, mm ± ± 1188 T2 Lesion Volume Change from Baseline to Week 36**, mm 3 Mean ± SD (N=35) 5723 ± ± (N=68) 6452 ± ± P- Value* *Based on ANCOVA (ranked data), adjusted for baseline T2 lesion volume and stratification factors of EDSS ( 2.5, >2.5) and prior therapy (none or >6 months, 6 months) **Last observation carried forward median peripheral CD19+ B cell count CD19 Counts weeks placebo Ritxuan Effect of on Ig Levels HACA (Human Anti-Chimeric Antibodies) Relationship to Primary Outcome Values Below LLN at Week 48 (% at 24wks) Week Week Week 24 Week 48 Rituxan HACA + /69 (%) /62 (%) 14/58 (24 %) IgG IgM IgA (3.1%) (8.8%) 9.8% (6.3%) 21.6% (13.4%) Outcome Gad Mean (SD) Proportion relapse-free at week 48 HACA+ (N=14).5 (.85) 12(85.7%) HACA- (N=55).53 (2.2) 43(78.2%) 9% CI (7%, 1%) (69%, 87%) There was no apparent relationship between the HACA data and these outcomes 4

5 AEs within 24 Hours of Infusion (Infusion-Associated AEs) Drug-Related* AEs 1% (N=35) (N=69) 1 Any Drug-Related AE 17 (48.6%) 53 (76.8%) % patients st Infusion N=35 N=69 N=35 N=67 2nd Infusion No glucocorticoids given prior to infusion Infusion AEs markedly decreased with 2nd infusion One serious AE (pyrexia) was reported with first rituximab infusion Chills Headache Nausea Pruritus Pyrexia Fatigue Throat Irritation Pharyngolaryngeal Pain *As assessed by investigator 7 (2%) 4 (11.4%) 2 (5.7%) 14 (2.3%) 13 (18.8%) 12 (17.4%) 11 (15.9%) 9 (13.%) 8 (11.6%) 8 (11.6%) 7 (1.1%) Safety Summary Most AEs were mild to moderate in severity (Grade 1-2); none were serious Infusion-associated AEs decreased with each infusion and were mild to moderate in severity Reported infections were mild to moderate and were comparable between the rituximab and placebo groups Nearly one-quarter of patients became HACA-positive at 48 weeks (higher than in RA) Conclusions In RRMS, treatment with rituximab (2 x 1 mg) led to significantly (P<.1) fewer inflammatory brain lesions over 6 months compared with the placebo group a 91% relative reduction The proportion of patients with relapses during 24 weeks was also significantly reduced in the rituximab-treated group compared with the placebo group (P=.238) a 58% relative reduction Patients receiving rituximab showed a significant (P=.77) reduction from baseline to Week 24 in T2 lesion volume compared with placebo group was generally safe and well tolerated These data provide proof of principle that B cells play a role in the pathophysiology of RRMS 5

6 Phase I RRMS Study 2 Cycles of MRI: Study Drug: Week: -2 to Screen (4 weeks) Endpoint Primary Secondary Treatment period (72 wks) Study Outcome Measures Safety through Wk Frequency of relapse 2. MRI evaluation of activity (descriptive) Bar-Or et al. Ann Neurol, in press 28 Phase 1 RRMS Study Mean Total Gd Lesions at Each Timepoint Mean Gd-Enhanced Lesion Count Treatment 1 (Wk + 2) Retreatment (Wks ) Weeks (N=26) in Neuromyelitis Optica Pre- and Post-Treatment Attack Rate Annual Attack Rate Pre- p =.78 Time Of Follow-up = 12 months Post- Phase II/III PPMS Study Design 4 Cycles of and 5 MRIs over 126 Weeks Cree et al. Neurol 64:127, 25 6

7 Progressive Multifocal Leukoencephalopathy (PML) Cases of PML have been reported in patients with lymphoid malignancies and in patients with autoimmune diseases including SLE and vascultitis, during or up to one year after treatment with rituximab No cases of PML have been reported in MS patients exposed to rituximab either within or outside of the rituximab clinical development program The UCSF MS Group 7