Disclosures 1

EFFICACY AND SAFETY OF RONTALIZUMAB (ANTI-- • 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 – • 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

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Type 1 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 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]

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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

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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 , 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

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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)

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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)

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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)

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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)

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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. Pbo SC p=0.0299 Endpoint: Average daily prednisone dose from Week 8 to Week 24 ≤10mg

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Safety: Adverse Events up to Week 24 Adverse Events by MedDRA Term: 20 21 (Safety Population) Frequency > 5%

ROSE IV ROSE SC Pooled (IV+SC) ROSE IV ROSE SC Pooled (IV+SC) Placebo 750mg Placebo 300mg Placebo Rontalizumab MedDRA Placebo 750mg Placebo 300mg Placebo Rontalizumab Type of Events (n=41) (n=81) (n=38) (n=78) (n=79) (n=159) Preferred Term, n (%) (n=41) (n=81) (n=38) (n=78) (n=79) (n=159) AEs, n (%) 32 (78%) 68 (84%) 34 (90%) 58 (74%) 84% 79% Urinary tract infection 8 (20%) 10 (12%) 3 (8%) 15 (19%) 11 (14%) 25 (16%) Upper respiratory tract SAEs, n (%) 4 (10%) 10 (12%) 5 (13%) 6 (8%) 11% 10% 3 (7%) 11 (14%) 6 (16%) 7 (9%) 9 (11%) 18 (11%) infection Drug-related AEs, n (%) 6 (15%) 13 (16%) 10 (26%) 22 (28%) 20% 22% Headache 4 (10%) 6 (7%) 5 (13%) 10 (13%) 9 (11%) 16 (10%) Nausea 1 (2%) 6 (7%) 2 (5%) 6 (8%) 3 (4%) 12 (8%) Drug-related AEs within 1 (2%) 7 (9%) 5 (13%) 7 (9%) 8% 9% Diarrhea 3 (7%) 8 (10%) 1 (3%) 0 4 (5%) 8 (5%) 24hr of dosing, n (%) Bronchitis 2 (5%) 3 (4%) 0 5 (6%) 2 (3%) 8 (5%) Infection AEs, n (%) 19 (46%) 42 (52%) 20 (53%) 40 (51%) 49% 52%

Infection SAEs, n (%) 1 (2%) 0 2 (5%) 1 (1%) 4% 1% • Urinary tract infection was the most frequent adverse event reported

SLE flares as SAEs, n (%) 1 (2%) 6 (7%) 0 4 (5%) 1% 6% • Generally AEs occurred at similar frequency in placebo and active, however nausea occurred more often in the rontalizumab arms • Rontalizumab appears to have an acceptable safety and tolerability profile in the 2 studies – No deaths in ROSE IV and ROSE SC up to week 24 – Higher frequency of SLE flares as SAEs for rontalizumab (all occurred in ISM-Hi) CONFIDENTIAL INFORMATION – DO NOT COPY OR FORWARD CONFIDENTIAL INFORMATION – DO NOT COPY OR FORWARD

Conclusions from ROSE Phase II Trial Acknowledgments – Thank you to all of our Patients (238) 22 and Principle Investigators (81 Sites in 6 Countries) 23

Argentina Gallacher Mysler Pons-Estel Soriano Spindler ROSE Trial evaluated Colombia Abello Chalem Guzman Jaller Londono ♦ Rontalizumab, an anti-interferon-a , which binds and neutralizes all Maldonado Otero Escalante Pinto Velez 12 isoforms of human IFN-a Mexico Abud-Mendoza Burgos-Vargas Cardiel Rios Carrillo Gutierrez-Urena ♦ ISM, a baseline measure of interferon-regulated gene expression levels, as a biomarker Medrano Sanchez for treatment response Poland Brzezicki Dyczek Gaweda Hrycaj Jeka Results (all patients or ISM-High) Kwiatkowska Leszczynski ♦ Primary Endpoint: No treatment effect on BILAG Response Index Russia Eliseeva Nasonov Salikhov Shilkina USA Alloway Aranow Askanase Ballou Box ♦ Secondary Endpoint: No treatment effect on SRI Brent Cagnoli Chakravarty Chatham Chindalore ♦ Safety: Rontalizumab appears to have an acceptable safety and tolerability profile in the 2 studies Craig Dayal Dooley Freeman Furie Gaylis Geppert Gilkeson Howell Jolly Exploratory Results, pre-specified (ISM-Low sub-population) Kempf Kirou Klein Latinis Lee, Eric ♦ Significant reduction in disease activity by SRI Lee, Susan Legerton Levin Lim Lindsey ♦ Reduction in prednisone use Lisse Looney Manzi McCain McCune McKay Merrill Mishra Neal Neuwelt ♦ Reduction in flare frequency These treatment effects were seen in both the SC and IV studies Olsen Pegram Porges Samuels Stone Utset Vasudevan Wallace Waller Wellborne Wiesenhutter

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4 Gene Alias Regulatory Function Induction Expression 2424 Elements 25 HECT and RLD FOXD3, FOXO3, Major E3 ligase IFNB1 / IFN-β Testis and to a domain containing E3 CUTL1, NF-κB , HNF- for ISG15 1024 amino acids; lesser degree in ubiquitin protein ligase 3beta, FOXO3b, conjugation 116852 Da, brain, ovary and 5 FOXO3a, associated with placenta. Found Gfi-1, NF-κB1 Positive regulator polyribosomes. in most tissues at HERC5 of innate antiviral Pro-inflammatory low levels response in cells induced by IFN upregulate expression of this In an IFN- gene in stimulated cell, endothelial cells. newly translated In endothelial viral proteins are cells, by TNF, APPENDIX primary targets of IL1B/- ISG15 1B and by LPS. epithelial-stromal GR, GR-β, Brachyury , Up-regulated in 318 amino acids; placenta, small interaction protein 1 POU2F1, POU2F1b, breast carcinomas 36793 Da intestine, spleen, EPSTI1 HSF2, POU2F1a, IRF- kidney, thymus, 7A, POU2F1c, GR-α liver, salivary gland and testes

Expressed in PBMCs from SLE cytidine NF-1 NF-1/L Pax-5, dUTP and dCTP 449 amino acids; monophosphate STAT5A , NF-κB , c- synthesis from 49448 Da, CMPK2 (UMP-CMP) kinase 2, Ets-1, AREB6 , HEN1, monophosphates mitochondria; mitochondria Sox9, NF-κB1 of the pyrimidine upregulated in nucleosides in monocyte / mitochondria macrophage differentiating cells

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Rontalizumab pts on >10mg/day prednisone at baseline had greater SRI rate vs placebo 26 SELENA SLEDAI over time 27 (in both the IV and SC sub-studies) (Mean Change from Baseline) in ISM-Lo Group

Secondary endpoint: SRI-4

Active Patients (%) Placebo ISM-Lo patients (N=57)

p=0.11 p<0.01 p<0.01 p<0.01 p=0.06

(35/64) (8/26)

Baseline Prednisone Pbo IV 750 IV Pbo SC 300 SC (mg/day) 50% 44% 56% 53% <=10 (n=145) (14/28) (23/52) (14/25) (21/40) 23% 56% 38% 54% >10 (n=90) 26 CONFIDENTIAL(3/13) INFORMATION (15/27) – DO NOT COPY OR (5/13)FORWARD (20/37) CONFIDENTIAL INFORMATION – DO NOT COPY OR FORWARD

Time to Flare (SFI) was Shorter in Placebo pts in ROSE IV Reduction in Flare Frequency by Week 24 28 29 and ROSE SC (exploratory endpoint; pooled IV & SC studies)

Frequency of all flares (by SFI) Frequency of moderate/severe flares

All efficacy-evaluable patients (N=235) by week 24 (by SFI-R) by week 24

Active Patients (%) Active Patients (%) Placebo Placebo All-Comer 65 All-Comer 41 (Δ9%) 76 (Δ8%) 49

ISMhi 68 ISMhi 44 (Δ8%) (Δ5%) Hazard Ratio 76 49 Ronta vs. Pbo 0.61 (0.46-0.81) p=0.0040

750mg IV vs. 0.64 (0.43-0.94) p=0.0553 Pbo IV ISMlo 55 ISMlo 30 300mg SC vs. 0.58 (0.39-0.88) p=0.0299 (Δ20%) (Δ20%) Pbo SC 75 50

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5 Reduction in Flare Frequency by Week 24 SRI- 4,5,6,7 RESULTS FOR ISMLO by Study 30 31 (exploratory endpoint; pooled IV & SC studies)

Frequency of all flares (by SFI) Endpoint Pbo IV Ront IV Delta by week 24 SRI - 4 18% (2/11) 71% (12/17) 52% Active % Flares IV Study SRI - 5 9% (1/11) 41% (7/17) 32% Placebo SRI - 6 9% (1/11) 41% (7/17) 32% All Subjects 65 SRI - 7 9% (1/11) 18% (3/17) 9% 76 Endpoint Pbo SC Ront SC Delta SRI - 4 62% (8/13) 75% (12/16) 13% ISM-Hi 68 SC Study SRI - 5 31% (4/13) 69% (11/16) 38% 76 SRI - 6 31% (4/13) 69% (11/16) 38% SRI - 7 23% (3/13) 44% (7/16) 21%

ISM-Lo 55 Endpoint Pbo (IV+SC) Ront (IV+SC) Delta (90% CI) 75 SRI - 4 38% (9/24) 73% (24/33) 31% (9%, 51%) Pooled Studies SRI - 5 21% (5/24) 55% (18/33) 34% (12%, 53%) (SC + IV) SRI - 6 21% (5/24) 55% (18/33) 34% (12%, 53%) SRI - 7 17% (4/24) 30% (10/33) 14% (-9%, 35%) 31

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Flare and Steroids Endpoints Week 24 Results 32 by Study for ISM-Lo Patients

Endpoint Pbo IV Ront IV Delta 1. SFI (any flare) 91% 71% 20% IV Study 2. SFI-R (moderate/ severe flares) 64% 53% 11% 3. Predn <=10mg/day 64% 88% 15%

Endpoint Pbo SC Ront SC Delta 1. SFI (any flare) 62% 38% 13% SC Study 2. SFI-R (moderate/ severe flares) 39% 6% 38% 3. Predn <=10mg/day 69% 94% 25%

Endpoint Pbo (IV+SC) Ront (IV+SC) Delta (90% CI) 1. SFI (any flare) 75% 55% -20.5% (-41.0, 1.6%) Pooled Studies 2. SFI-R (moderate/ -19.7% (SC + IV) severe flares) 50% 30% (-40.6%, 2.6%) 3. Predn <=10mg/day 67% 91% 24.2% (1.8%, 44.7%) 32

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