Disclosures 1 EFFICACY AND SAFETY OF RONTALIZUMAB (ANTI-INTERFERON- • Contracts and Grants ALPHA) IN SLE PATIENTS WITH RESTRICTED – LCTC IMMUNOSUPPRESSANT USE: – NIH/NIAID/ITN – Kirin RESULTS OF A RANDOMIZED, DOUBLE-BLIND, PLACEBO- – Medimmune CONTROLLED PHASE 2 TRIAL – UCB – Biogen Idec – GSK – Genentech • Consultant/Medical Advisory Board K. Kalunian1, JT. Merrill2, R. Maciuca3, W. Ouyang3, JM. McBride3, M. Townsend3, E. Park3, – Anthera X. Wei3, A. Morimoto3, R. Boismenu3, J. Davis, Jr3. and WP. Kennedy3 – Questcor – Merck Serono 1UCSD, Dept. Medicine, La Jolla, CA; 2Oklahoma Medical Research Foundation, Oklahoma – Eli Lilly City, OK; 3Genentech Inc., South San Francisco, CA CONFIDENTIAL INFORMATION – DO NOT COPY OR FORWARD Type 1 Interferons in SLE 2 Rontalizumab [anti-interferon-α] 3 IgG1 Humanized, monoclonal Molecule Rontalizumab •Increased IFN signals play a central role antibody to interferon-alpha in the complex pathogenesis of SLE Neutralizes all 12 known human IFN-a subtypes •Type I IFNs, especially IFNα, have been shown MOA and to associate with lupus disease activity and Biological Evidence Murine analog decreased flares proteinuria in animal model of lupus nephritis Formulation IV and SC Phase I single/multiple dose study1 2 Clinical Phase II study in lupus Studies 1. McBride JM, et al Arthritis Rheum. 2012 2. ACR, 2012 Aghemo, A. Nat Rev Gastro Hep 7(9): 495 [2010] Adapted from Banchereau and Pascual in Immunity 35(3) [2006] CONFIDENTIAL INFORMATION – DO NOT COPY OR FORWARD CONFIDENTIAL INFORMATION – DO NOT COPY OR FORWARD 4 5 The Interferon Signature Metric (ISM) Baseline ISM status defines 4 5 2 sub-populations of SLE patients Many SLE patients have an (1) elevated ISM score compared to (1) Many SLE patients have elevated healthy controls with a distinct expression of ~100 interferon-regulated bimodal distribution genes, the interferon signature ISM-Hi and ISM-Lo (2) Average gene expression from 3 interferon-regulated genes were chosen SLE patients with mild disease to represent the interferon signature (2) activity patients (Phase I) ~ 1:1 ISM-Hi / ISM-Lo (3) (3) The 3 gene signature correlates well with the entire interferon signature SLE patients with moderate-to- severe disease (Phase II) A calculated score for the mean expression ~ 3:1 ISM-Hi / ISM-Lo level for the 3 genes is a novel biomarker for lupus, called the ISM CONFIDENTIAL INFORMATION – DO NOT COPY OR FORWARD CONFIDENTIAL INFORMATION – DO NOT COPY OR FORWARD 1 Rontalizumab Phase 2 Trial (ROSE) Rontalizumab Phase 2 Trial (ROSE) 6 7 Objectives Key Inclusion / Exclusion Criteria • Randomized, placebo-controlled study of the safety and efficacy of • Inclusion criteria: rontalizumab in SLE patients without background immunosuppressants – SLE patients by ACR classification with positive ANA • Objective – Moderate to severe disease with 1 BILAG A or 2 BILAG B domains – Evaluate rontalizumab’s efficacy and safety without background immunosuppressants (e.g. azathioprine, mycophenylate) – Subjects were allowed steroids at screening but underwent taper by 6 weeks post randomization to ≤ 10mg/day, if tolerated • Key Exclusion: – Immunosuppressants were discontinued at randomization – Unstable anti-phospholipid syndrome – Rescue medication, including immunosuppressants, available to all – Unstable neuropsychiatric lupus patients • Endpoints – Active lupus nephritis – Primary Endpoint: BILAG Responder Index at 24 weeks – Key Secondary Endpoint: SLE Responder Index (SRI) at 24 weeks – Safety – Exploratory measures : steroid reduction and flare rates over time, efficacy correlated to ISM status CONFIDENTIAL INFORMATION – DO NOT COPY OR FORWARD CONFIDENTIAL INFORMATION – DO NOT COPY OR FORWARD ROSE Trial Design 8 Patient Demographics in ROSE Studies 9 Sequential, global studies in SLE patients ROSE IV : IV dosing q4wk Countries Race Gender Patients (%) Patients (%) 6% Male Rontalizumab 750mg IV (N= 81) Steroid taper / Rescue Therapy 94% Female Placebo Mean age : 39yrs IV (N= 41) -4 0 4 8 12 16 20 24 Week Safety follow-up Baseline ISM Status Primary Endpoint (48 wks) (Week 24) 24% Ethnicity lo Open-label ISM ROSE SC : SC dosing q2wk extension 76% . 238 patients total (159 active + 79 placebo) hi . 95-100% completed study through wk 24 ISM . 85-93% completed treatment period Rontalizumab 300mg SC (N= 78) . Demographics, baseline characteristics generally balanced within each Steroid taper / Rescue Therapy cohort, reflecting moderate to severe disease activity (mean SELENA SLEDAI of ~ 10, mean disease duration ~6.5 yrs). Placebo SC (N= 38) -4 0 4 8 12 16 20 24 Week Safety follow-up . More Hispanics were enrolled in Part 2 (SC) compared to Part 1 (IV), 60% Primary Endpoint (48 wks) vs. 40%, respectively due to added sites (Week 24) CONFIDENTIAL INFORMATION – DO NOT COPY OR FORWARD CONFIDENTIAL INFORMATION – DO NOT COPY OR FORWARD Patient Baseline Characteristics 10 Patient Baseline Characteristics 11 ROSE IV ROSE SC Pooled (IV+SC) ROSE IV ROSE SC Pooled (IV+SC) Placebo 750mg Placebo 300mg Placebo Rontalizumab Placebo 750 mg Placebo 300mg Placebo Rontalizumab Subject Number, N 41 81 38 78 79 159 Subject Number, N 41 81 38 78 79 159 Age (yrs), mean (SD) 38.4 37.3 43.7 38.2 40.9 37.8 (11.6) (11.4) (9.0) (11.5) (10.7) (11.4) ISM status, n (%) High 30 (73) 63 (78) 25 (66) 62 (79) 55 (70) 125 (79) SLE duration (yrs), mean (SD) 6.2 (6.2) 6.3 (6.4) 6.9 (6.0) 6.6 (6.5) 6.6 (6.1) 6.4 (6.4) Low 11 (27) 18 (22) 13 (34) 16 (21) 24 (30) 34 (21) BILAG index at screening, % ANA positive (>=1:80), % 90 96 90 89 90 93 >= 2 A 5 10 11 14 8 12 >= 1 A 68 67 79 77 73 72 C3 complement (mg/dL), mean (SD) 101.7 (33.3) 108.5 (33.5) 100.3(34.6) 96.5 (34.2) 101 (33.7) 102.6 (34.3) BILAG index global score, 11.0 Low (<90),% 37 28 34 45 35 37 mean (SD) (3.7) 11.0 (4.3) 12.1 (6.3) 11.1 (4.7) 11.5 (5.1) 11.1 (4.4) SELENA SLEDAI score, mean C4 complement (mg/dL), (SD) 9.7 (2.4) 10.1 (3.1) 9.3 (4.5) 9.8 (3.1) 9.5 (3.6) 10.0 (3.1) mean (SD) 17.5 (9.4) 16.5 (8.7) 17.0 (8.6) 15.0 (12.1) 17.3 (9.0) 15.7 (10.5) Low (<10), % 32 21 29 44 30 32 59.6 51.9 53.0 56.4 PGA score (mm), mean (SD) 59.2 55.7 (15.1) (14.6) (17.3) (17.5) (16.5) (16.4) Anti-dsDNA (IU/mL) On any immunosuppressant at 29 25 37 24 33 25 median, 68.5 38.8 27.1 85.3 40.1 65.8 screening, % % Positive (>=30) 66 61 42 71 54 66 % on steroids, mean 82, Anti-ENA positive prednisone dose 88, 87, 89, 84, 88, 44 68 63 59 53 64 (9.0) (10.1) (aRo/aLa/aRNP/aSm), % (mg/day) (10.8) (11.3) (12.7) (11.7) CONFIDENTIAL INFORMATION – DO NOT COPY OR FORWARD CONFIDENTIAL INFORMATION – DO NOT COPY OR FORWARD 2 Rontalizumab shows treatment effect in Baseline characteristics of ISM-Hi and ISM- 12 13 Lo subgroups ISM-Lo population using the SRI endpoint Baseline characteristics ISM-Hi ISM-Lo Primary endpoint: BILAG Responder Index Secondary endpoint: SLE Responder Index Active BILAG Index Active % Response Placebo % Response Placebo ≥ 2 A 9% 16% All Patients 46 All Patients 51 ≥ 1 A 70% 79% 41 46 ≥ 1 A or 2 B 100% 100% BILAG global score (mean/median) 11.0/11.0 11.9/12.0 ISM-Hi 45 SELENA-SLEDAI score ISM-Hi 43 (mean/median) 10.0/10.0 9.2 /10.0 38 47 PGA score (mean/median) 57/59 52/57 ISM-Lo 73 Swollen Joints Count 4.6/4 5.1/5 ISM-Lo 55 42 (mean/median) 50 dsDNA+ (≥30 IU/mL) 71% 35% ENA+ (Ro/La/Sm/RNP) 74% 19% C3, C4 (mean) 95, 14 122, 22 . High SRI response rate in ISM-Lo patients given rontalizumab Low C3, Low C4 43%, 39% 16%, 11% (for both IV and SC); treatment difference = 31% (p=0.029) CONFIDENTIAL INFORMATION – DO NOT COPY OR FORWARD CONFIDENTIAL INFORMATION – DO NOT COPY OR FORWARD Exploratory: Rontalizumab Treatment Effect in 14 SELENA SLEDAI over time – all subjects 15 ISM-Lo population with higher SRI thresholds (Mean Change from Baseline) Exploratory: Improvement Threshold by SRI All efficacy-evaluable patients (N=235) % Response in ISM-Lo p<0.05 p<0.01 p<0.05 p>0.15 p>0.15 Active Placebo (n = 33) (n=24) CONFIDENTIAL INFORMATION – DO NOT COPY OR FORWARD CONFIDENTIAL INFORMATION – DO NOT COPY OR FORWARD SELENA SLEDAI over time – IV, SC, pooled SELENA SLEDAI over time – ISM-Lo Group 16 17 (Mean Change from Baseline) (Mean Change from Baseline) All efficacy-evaluable patients (N=235) ISM-Lo patients (N=57) CONFIDENTIAL INFORMATION – DO NOT COPY OR FORWARD CONFIDENTIAL INFORMATION – DO NOT COPY OR FORWARD 3 Reduction in Steroid Use by Week 24 in ISM-Lo Reduction in Flare Frequency 18 19 (exploratory endpoint; pooled IV & SC studies) over time and by Week 24 Frequency of all flares (by SFI) Decrease in prednisone use by week 24 (≤10mg/day) All efficacy-evaluable patients Active % Flares Active Patients (%) (N=235) Placebo Placebo All Patients 65 All Patients 76 76 63 ISM-Hi 68 ISM-Hi 72 76 62 Hazard Ratio ISM-Lo 55 ISM-Lo 91 Ronta vs. 0.61 (0.46-0.81) 75 67 Pbo p=0.0040 750mg IV 0.64 (0.43-0.94) vs. Pbo IV p=0.0553 300mg SC 0.58 (0.39-0.88) vs.