Giancarlo Comi, M.D. On Behalf of the MS-LAQ-301 (ALLEGRO) Study Group. Assessment of oral laquinimod in preventing progression of Multiple Sclerosis

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1 COMPARISON OF EARLY AND DELAYED ORAL LAQUINIMOD IN PATIENTS WITH RELAPSING- REMITTING MULTIPLE SCLEROSIS: EFFECTS ON DISABILITY PROGRESSION AT 36 MONTHS IN THE ALLEGRO TRIAL Giancarlo Comi, M.D. On Behalf of the MS-LAQ-301 (ALLEGRO) Study Group Assessment of oral laquinimod in preventing progression of Multiple Sclerosis

2 DISCLOSURES G. Comi received consulting fees for advisory boards, consultancy and speaker activities from Novartis, Teva Pharmaceutical Industries, Ltd., Sanofi-Aventis, Merck Serono, and Bayer Schering; and lecture fees from Novartis and Teva Pharmaceutical Industries, Ltd. D. Jeffery has received honoraria and consulting fees from Berlex, Serono, Teva, Glaxo and Pfizer; and financial support for research from Bayer, Serono, Teva, and Pfizer. L. Kappos has received personal compensation from Actelion, Advancell, Allozyne, BaroFold, Bayer Health Care Pharmaceuticals, Bayer Schering Pharma, Bayhill, Biogen Idec, BioMarin, CLC Behring, Elan, Genmab, Genmark, GeNeuro SA, GlaxoSmithKline, and Lilly. X. Montalban has received honoraria for speaking, travel expenses to scientific meetings; is a steering committee member or has participated in advisory boards in clinical trials or has had consulting agreements with Bayer Schering Pharma, Biogen Idec, EMD Merck Serono, Genentech, Genzyme, Novartis, Sanofi- Aventis, and Teva Pharmaceuticals. A. Boyko is a member of advisory boards and participant in clinical trials sponsored by Bayer Schering, Merck Serono, Teva, Novartis, Biogen, Nycomed, Genzyme, and other companies. M. Rocca serves as consultant to Bayer Schering Pharma; received speakers bureaus for Biogen Idec, and receives research support from the Italian Ministry of Health. M. Filippi has received personal compensation for activities with Merck-Serono, Genmab, Biogen Idec, Bayer-Schering, and Teva Neuroscience as a consultant, speaker, and advisory board member. He receives research support from Merck-Serono, Biogen Idec, Bayer-Schering, Teva Neuroscience, Fondazione Italiana Sclerosi Multipla and Italian Ministry of Health.

3 LAQUINIMOD SITE OF ACTION Activated T cell Pro-inflammatory Cytokines IL-1β IFN γ Astrocyte Auto-reactive T cell Proinflammatory Cytokines Activated Astrocytes Activated Astrocytes Glial Scar Formation Microglia TNF-α, NO, O2 AXONAL DAMAGE Oligodendrocyte Myelin residue Oligodendrocyte Damage/Apoptosis Degenerative Trigger

4 ALLEGRO PHASE 3 TRIAL The ALLEGRO study was a Phase 3 trial of oral laquinimod 0.6mg in RRMS patients (N=1106), showing: Percent Brain Volume Change (Months 0-24) 23% Reduction % Reduction in the Risk p= PLACEBO LAQUINIMOD 0.6mg Annualized for Disability Progression Relapse Rate p= No signal of immunosuppression No evidence of cardiac events % Transient elevations of liver enzymes, without clinical signs of liver damage/bilirubinemia Safety & Tolerability: 0 Increased incidence of abdominal pain and back pain without needing -1.30% to stop laquinimod PLACEBO LAQUINIMOD 0.6mg % Reduction in Brain Volume Loss p<0.0001

5 ALLEGRO S 36 MONTH OPEN-LABEL EXTENSION OBJECTIVE Compare progression of disability and safety of patients treated with laquinimod for 36 months to patients originally treated with placebo in the double-blind phase and switched to laquinimod treatment in the open-label extension

6 STUDY DESIGN Double-Blind Phase Oral Laquinimod 0.6mg once daily OPEN-LABEL EXTENSION PHASE Matching Oral Placebo once daily Oral Laquinimod 0.6mg once daily Mo Mo 6 Mo 9 Mo 12 Mo 15 Mo 18 Mo 21 Mo 24 Mo 30 Mo 36 EDSS Safety MRI

7 PARTICIPANTS Early Start patients Those randomized to laquinimod during the DB phase and continuing on treatment in the OL extension Delayed Start patients Those randomized to placebo during the DB phase and began laquinimod treatment during the OL extension

8 OUTCOME MEASURES Relapses Patients are instructed to call sites indicating any symptoms suggestive of a relapse lasting for 48 hours or more and confirmed by a physician within 7 days of onset. Disability Safety Progression of disability defined as an increase from baseline EDSS score of 1.0 or more points if baseline EDSS is 0 to 5.0 or 0.5 points if baseline EDSS is 5.5 or higher, sustained for 6 months. Adverse events, laboratory tests including liver enzymes and complete blood counts, physical exams and ECGs were assessed.

9 PATIENT DISPOSITION Randomized (n = 1106) Laquinimod 0.6mg (N = 550) Placebo (N = 556) Completed 24 Months of Double Blind Treatment n = 437 n = 427 Entered Open Label Extension Early Start n = 423 Delayed Start n = 416 Completed 12 Months of Open Label Extension Early Start n = 372 (87%) Delayed Start n = 368 (87%)

10 BASELINE DEMOGRAPHICS OF PATIENTS ENTERING OL PHASE MS LAQ 301 Early Start (n = 423) Delayed Start (n = 416) Age mean ± SD 39.1 ± ± 9.1 Female n (%) 298 (70.4%) 271 (65.1%) Time since diagnosis (years) mean ± SD 5.4 ± ± 4.8 Time since 1st symptom (years) mean ± SD 9.0 ± ± 6.4 Baseline converted EDSS mean ± SD 2.6 ± ± Relapse in 1 yr prior to screening (%) 394 (93.1%) 391 (94.0%) Number of relapses mean ± SD 1.2 ± ± 0.7 Number of GdE-T1 lesions mean ± SD 1.8 ± ± 4.3 % Patients with GdE-T1 lesions 1 at baseline 40.0% 46.6%* Volume of T2 lesions (cm 3 ) mean ± SD 10.0 ± ± 9.7 * Significantly different

11 REASONS FOR STUDY TERMINATION Early Start (n = 52) Delayed Start (n = 53) 4% 4% 4% 2% 4% 6% 2% 4% 8% 21% 50% Patient withdrew consent Adverse Event 23% 55% 15% Physician withdrew consent Protocol violation Pregnancy Lost to Followup Death

12 RESULTS: ANNUALIZED RELAPSE RATE 1.4 Annualized Relapse Rate Early Start (n=547) Delayed Start (n=556) Early Start patients have a lower cumulative 3 year relapse rate compared to Delayed Start patients (0.274 vs 0.340, -19.4% P = ). Delayed Start Laquinimod 0.6 mg Week on Study

13 YEARLY RELAPSE RATES Early Start Delayed Start RR = p = <0.01 RR = p = RR = p = <0.01 RR = p = Year 1 DB Year 2 DB Year 1 OL 0 Year 1 DB Year 2 DB Year 1 OL

14 PROPORTION OF PATIENTS WITH 6 MONTH CONFIRMED DISABILITY AT 36 MONTHS MS-LAQ-301 All patients Patients on laquinimod during DB and Early Start in OL (n = 550) Patients on placebo during DB and Delayed Start in OL (n = 556) N % N % Progression Free Progressed

15 CONFIRMED 6 MONTH DISABILITY PROGRESSION FOR ALL PATIENTS IN ALLEGRO DB AND OL PHASES % of Patients with Confirmed Progression 30% 25% 20% 15% 10% 5% 0% Delayed Start Early Start Delayed Start Laquinimod 0.6 mg Delayed Start n= Early Start n= Time to Progression (Days) HR = P =

16 ADVERSE EVENTS Percent (%) of Patients Reporting the AE Laquinimod 0.6 mg Placebo DB Phase Early Start Delayed Start OL Phase *Adverse events reported by 5% of patients that occurred with 1% higher incidence with laquinimod in the pooled data set compared with placebo. ALT = alanine aminotransferase; UTI = urinary tract infection

17 LIVER ENZYME ELEVATIONS EARLY START (no. of patients/total no. of patients (%) DB Phase OL Phase ALT Increase only in OL Phase >1 and 3 ULN 151/504 (30%) 43/387 (11.1%) 12/43 (27.9%) >3 and 5 ULN 18/504 (3.6%) 2/387 (0.5%) 1/2 (50.0%) >5 and 8 ULN 3/504 (0.6%) 4/387 (1.0%) 2/4 (50.0%) >8 ULN 3/504 (0.6%) 0 0 DELAYED START DB Phase OL Phase ALT Increase only in OL Phase >1 and 3 ULN 91/515 (17.7%) 104/388 (26.8%) 71/104 (68.2%) >3 and 5 ULN 2/515 (0.4%) 5/388 (1.3%) 3/5 (60%) >5 and 8 ULN 3/515 (0.6%) 0 0 >8 ULN 3/515 (0.6%) 0 0

18 SAEs EARLY START (Laquinimod/Laquinimod) Serious Adverse Events No. Incident (No. and % patient) DB Phase (n = 550) Diarrhoea 2 (2, 0.4%) - Vomiting 3 (1, 0.2%) - Fever 2(2, 0.4%) - Peripheral Edema 2 (2, 0.4%) - OL Phase (n = 423) Appendicitis 5 (5,0.9%) 3 (3, 0.7%) Cellulitis 2 (2, 0.2%) 1 (1, 0.2%) Hypokalemia 4 (2,0.4%) 1 (1, 0.2%) Uterine leiomyoma 2 (2, 0.4%) 1 (1, 0.2%) Headache 2(2, 0.4%) - Abdominal pain 1(1,0.2%) 2 (2, 0.4%) C-reactive protein increase - 3 (3, 0.7%) Back pain 1(1, 0.2%) 1 (1, 0.2%) Chest pain - 1(1, 0.2%)

19 SAEs DELAYED START (Placebo/Laquinimod) Serious Adverse Events No. Incident (No. and % patient) DB Phase (n = 556) OL Phase (n = 416) Diarrhoea - - Vomiting - - Fever - - Peripheral Edema - - Appendicitis 1 (1,0.2%) 2 (2, 0.4%) Cellulitis - - Hypokalemia - - Uterine leiomyoma 1 (1, 0.2%) - Headache - - Abdominal pain 2 (2, 0.4%) 1 (1, 0.2%) C-reactive protein increase - - Back pain - - Chest pain 4 (3, 0.5%) 1 (1, 0.2%) Gastritis 2 (2, 0.4%) - Cholelithiasis 2 (2, 0.4%) - Liver Disorder 2 (2, 0.4%) - Pneumonia 2 (2, 0.4%) - Dyspnea 2(2, 0.4%) -

20 SAE - MALIGNANCIES DB Phase OL Phase Laquinimod Placebo (n = 550) (n = 556) Basal-cell carcinoma 1 (0.2) 1 (0.2) Breast cancer 3 (0.5) 1 (0.2) Lung neoplasm 1 (0.2) 0 Lymphoma 1 (0.2) 0 Esophageal adenocarcinoma 1 (0.2) 0 Ovarian cancer 0 2 (0.4) Prostate cancer 0 1 (0.2) Glioblastoma 1 (0.2) 0 Rectal cancer 0 1 (0.2) Early Start Delayed Start (n = 423) (n = 416) Thyroid cancer 0 1 (0.2) Skin cancer 0 1 (0.2) Breast cancer 1 (0.2) 0 Bone cancer 1 (0.2) 0

21 DEATHS 5 deaths in the ALLEGRO trial DB Phase 1 placebo patient died from complications due to pneumonia 1 placebo patient had a train accident 1 placebo patient committed suicide OL Phase 1 patient had an acute coronary attack 1 patient committed suicide

22 CONCLUSIONS Patients who shifted from placebo to laquinimod in OL phase had a significant reduction in relapse rate Patients on early treatment compared to those on delayed treatment had a significant reduction in risk of disability progression No new safety concerns emerged in the open-label in the early treatment or those exposed to laquinimod beginning in the openlabel phase For patients who were on early treatment, there was a global tendency to decrease the incident of SAEs from the double-blind to the open-label phase. For patients who were exposed for the first time in the open-label phase, the AEs were similar to those seen previously with laquinimod in the double-blind phase.