Comparative Effectiveness of Teriflunomide and Dimethyl Fumarate in P038 Patients With Relapsing-Remitting MS in the Real-World Teri-RADAR Study Robert Zivadinov,1,2 Chakkarin Burudpakdee,3 Michael G Dwyer,1 Niels Bergsland,1 Jeffrey Chavin,4 Karthinathan Thangavelu,4 Matt Mandel,4 Stanley Cohan,5 on behalf of the Teri-RADAR Study Investigators 1Buffalo Neuroimaging Analysis Center, University at Buffalo, Buffalo, NY, USA; 2Translational Imaging Center at Clinical Translational Science Institute, University at Buffalo, Buffalo, NY, USA; 3IQVIA, Fairfax, VA, USA; 4Sanofi, Cambridge, MA, USA;5 Providence Brain and Spine Institute, Portland, OR, USA

OBJECTIVE CONCLUSIONS

• To compare the effectiveness of teriflunomide and dimethyl fumarate • Results from this retrospective study suggest that, in a real-world clinical setting, teriflunomide exhibited similar effectiveness to DMF on a number of MRI and clinical endpoints (DMF) in patients with relapsing forms of MS (RMS) based on real-world • The incidence of treatment-related AEs was similar between groups, with no unexpected safety signals seen for either teriflunomide or DMF data collected retrospectively in the phase 4 Teri-RADAR study • These results reinforce the established real-world effectiveness of teriflunomide 14 mg for the treatment of RMS

–– The majority of patients had received another DMT prior to initiating teriflunomide • Annualized PBVC was significantly lower in the teriflunomide group compared with the DMF Figure 1. Teri-RADAR Study Design INTRODUCTION or DMF, most commonly intramuscular interferon B-1a (56% and 54% of patients group (mean change: –0.2 vs –0.5; median change: –0.1 vs –0.5, P=0.02, Figure 3A) Follow-up MRI Follow-up visit (V+1) in the teriflunomide and DMF groups, respectively) or glatiramer acetate (54% and –– It has previously been suggested that a mean annualized brain volume loss (BVL) rate of First visit (V–1) Baseline MRI 0.4% may represent a pathological threshold for BVL in MS patients.5 In this study, fewer • Teriflunomide and DMF are oral disease-modifying therapies (DMTs) for the treatment of 48%, respectively) patients in the teriflunomide group than the DMF group had PBVC above this threshold relapsing forms of MS1,2 • At follow-up, mean (SD) treatment exposure was 15.2 (3.9) and 15.7 (4.6) months for the (25.9% vs 58.6%, P=0.01) teriflunomide and DMF groups, respectively • Teriflunomide, a once-daily oral immunomodulator, was first approved in the US in Pre-index Pre-index Post-index Post-index Post-index • Annualized percent lateral ventricle volume change was numerically but not significantly September 2012, and has since been approved in 80 countries. As of October 2017, over Month 18 Month 6 Index (V) on 2 weeks Month 9 Month 24 lower in teriflunomide-treated patients vs DMF-treated patients (mean change: 1.5% vs 80,000 patients were being treated with teriflunomide, with a total real-world exposure of teriflunomide Table 1. Patient Demographics and Baseline Disease Characteristics 2.3%; median change: 1.2% vs 3.0%, P=0.287, Figure 3B) or DMF approximately 162,000 patient-years since approval DMF, dimethyl fumarate; V, visit. Teriflunomide Dimethyl fumarate • DMF, a twice-daily oral DMT, was first approved in the US in March 2013 (n=50) (n=50) Figure 3. Change in: (A) Annualized Whole Brain Volumea; and (B) Lateral Ventricle b • Direct head-to-head clinical trials comparing the efficacy and safety of teriflunomide and Volume at Follow-up vs Pre-index Period Study Outcomes Age, mean (SD), y 49.5 (6.8) 48.4 (7.3) DMF have not been conducted. Comparison of treatment outcomes across randomized Female, n (%) 39 (78.0) 36 (72.0) A. Annualized Whole Brain Volumea B. Lateral Ventricle Volumeb controlled trials has many challenges, including differences in study populations and design, • The primary study endpoint was the proportion of patients with new and/or enlarging White, n (%) 48 (96.0) 45 (90.0) Teri 14 mg DMF 240 mg P=0.287 as well as definitions of outcome measures3 T or gadolinium-enhancing (Gd+) T lesions 0.0 4.0 2 1 Time since first diagnosis of MS, mean (SD), y 11.8 (8.6) 11.6 (8.5) • An alternative approach that takes into account differences in study populations – number • Main secondary endpoints included: −0.2 −0.1 3.0 Time since first symptoms of MS, mean (SD), y 13.8 (8.9) 13.1 (9.2) 3.0 needed to treat analysis – has shown that teriflunomide and DMF have comparable efficacy –– Number of new and/or enlarging T and Gd+ T lesions 2 1 Patients with relapse in the 18 months before −0.4 across key clinical outcomes3 11 (22.0) 5 (10.0) −0.5 2.0 –– Whole brain and lateral ventricle volume changes index, n (%) −0.6 • The Teri-RADAR study was conducted to compare real-world effectiveness of teriflunomide 1.2 –– Number and proportion of patients with physician-confirmed relapses, including 1.0 ARR over pre-index period (95% CI) 0.274 (0.154, 0.487) 0.083 (0.036, 0.193) −0.8 and DMF using retrospective data collected across a number of MS centers in the US annualized relapse rate (ARR) Baseline EDSS score Pre-index Period, % Pre-index Period, %

Median Change From P=0.02 Median Change From • Real-world data are increasingly important to support prescribing decisions, and provide a a b −1.0 0.0 –– Disability worsening over the course of the study, as measured by EDSS scores Mean (SD) 3.0 (1.8) 3.3 (1.7) Teri 14 mg DMF 240 mg better reflection of patients encountered in routine clinical practice compared with the highly Median (range) 3.0 (0.0–6.5) 3.0 (1.0–6.5) a b –– Proportion of patients with no evidence of disease activity (NEDA), defined as the Teriflunomide-treated patients, n=27; DMF-treated patients, n=29; teriflunomide-treated patients, n=50; selected populations and controlled environments of clinical trials4 DMF-treated patients, n=49. DMF, dimethyl fumarate. absence of clinically meaningful EDSS score increase, physician-confirmed relapse, and Prior treatment with DMT, n (%) 45 (90.0) 42 (84.0) new/enlarging T or T lesions an=31; bn=34. ARR, annualized relapse rate; CI, confidence interval; DMT; disease-modifying therapy; EDSS, Expanded 2 1 Disability Status Scale. –– Adverse events (AEs) Clinical Endpoints METHODS • Compared with the pre-treatment period, there was a slight decrease in ARR in the Statistical Analysis MRI Endpoints teriflunomide group (from 0.274 to 0.209) and a slight increase in the DMF group (0.083 to 0.119) • Mean (SD) EDSS scores at follow up (available for n=33 and n=34 patients in the teriflunomide Study Design and Patients • Analyses were descriptive; no formal sample-size determination was carried out • At follow-up, the proportion of patients with new and/or enlarging T2 or Gd+ T1 lesions was numerically lower in the teriflunomide group (30.0%) compared with the DMF group (40.0%) and DMF groups, respectively) were 3.1 (1.8) for teriflunomide and 3.2 (1.8) for DMF. For • Teri-RADAR was a retrospective, phase 4, real-world longitudinal cohort study in patients • Logistic regression was used to compare the proportion of patients with new/enlarging (Figure 2A) patients with reported data at both time points (n=31 for teriflunomide, n=34 for DMF), on T or Gd+ T lesions between treatment groups with RMS initiating treatment with teriflunomide or DMF at 5 US MS centers 2 1 average, there was no change in EDSS scores between the pre-index period and follow-up in –– However, this difference did not reach statistical significance (odds ratio [95% confidence • Baseline and follow-up ARR was calculated using a Poisson regression analysis of either treatment group (mean [SD] change: 0.0 [1.1] for teriflunomide and 0.0 [0.7] for DMF) • Anonymized patient data (including patient demographics, Expanded Disability Status Scale interval]: 0.62 [0.26, 1.47]; P=0.28) [EDSS] scores, relapses with associated hospitalizations and corticosteroid use, and MRI relapses that occurred in the 18 months before index, and in the time between index and –– The difference between the groups was primarily driven by a difference in the proportion follow-up, respectively No Evidence of Disease Activity results) were collected from medical charts and MRI scans from the Picture Archiving and of patients with new and/or enlarging T lesions (26.0% vs 40.0%, Figures 2B and 2C) 2 • At follow-up, the proportion of patients with NEDA was the same in both treatment groups Communication System for the following periods, as shown in Figure 1: • Between-group comparisons of percentage changes in whole brain or lateral ventricle (n=23, 46%) –– Pre-index visit (V−1): 6–18 months before initiation of teriflunomide or DMF treatment volumes were performed using Wilcoxon tests, while the comparison of the proportion of Figure 2. Proportion of Patients at Follow-up With: (A) New and/or Enlarging T2 or –– Index (V): treatment start with teriflunomide or DMF (baseline MRI taken in the 6 months patients with whole brain volume loss above the annualized pathological percent whole a Safety and Tolerability 5 Gd+ T1 Lesions; (B) New and/or Enlarging T2 Lesions; and (C) New Gd+ T1 Lesions before, or 2 weeks after, the index date) brain volume change (PBVC) cut-off of –0.4% was performed using a Chi-squared test • Treatment-related AEs were reported in 24% and 28% of teriflunomide- and DMF-treated A. New and/or Enlarging T B. New and/or Enlarging C. Gd+ T Lesions 2 1 patients, respectively –– Follow-up (V+1): 9–30 months after treatment start (9–24 months for MRI data) or Gd+ T Lesions T Lesions 1 2 –– As shown in Table 2, the most common treatment-related AEs (seen in >10% of • Patients receiving DMF were age-matched within ±3 years of patients receiving 50 50 50 patients in either group) were diarrhea (n=8, 16%) and skin reaction (n=6, 12%) in the teriflunomide 40.0 40.0 RESULTS 40 40 40 teriflunomide-treated group and rash (n=14, 28%) in the DMF-treated group • Key inclusion criteria were as follows: 30.0 30 30 26.0 30 –– Aged 18–65 years at index Patients Table 2. Most Commona Treatment-Related Adverse Events –– 20 20 20 16.7 Diagnosis of RMS on index date or during pre-index period 12.8 • In total, 100 patients were enrolled in the study; 50 received teriflunomide 14 mg and Patients, % Patients, % Patients, % Teriflunomide Dimethyl fumarate Adverse event, n (%) –– ≥1 baseline MRI scan with 1.5T or 3T scanner in the 6 months before, or 2 weeks after, 50 received DMF 240 mg. Patient demographics and baseline disease characteristics were 10 10 10 (n=50) (n=50) the index date generally similar across groups (Table 1), with the following exceptions: 0 0 0 Rash 0 14 (28) Teri 14 mg DMF 240 mg Teri 14 mg DMF 240 mg Teri 14 mg DMF 240 mg –– ≥1 physician visit within 12 months of either the index date or baseline MRI scan, –– The proportion of patients with relapse in the 18 months prior to index date was higher in Diarrhea 8 (16) 1 (2) a Skin reaction 6 (12) 0 whichever occurred earlier the teriflunomide group vs the DMF group (22% vs 10%); similarly, ARR in the pre-index Proportion of patients with Gd+ lesions based on number of patients with follow-up scans: n=48 for teriflunomide 14 mg, n=47 for DMF. DMF, dimethyl fumarate; Gd+, gadolinium enhancing. a • The earliest physician visit within the 12 months was defined as the V−1 visit period was also higher in the teriflunomide group (0.274 vs 0.083) Treatment-related adverse events reported in >10% of patients in either treatment group. –– ≥1 MRI scan 9–24 months after index date • The physician visit closest to the post-index MRI scan was defined as the V+1 visit –– Ability to walk 25 meters at index date References Acknowledgments and Disclosures 1. FDA. Aubagio (teriflunomide). Prescribing Information. Nov 2016. This poster was reviewed by Alex Lublin, PhD, Darren P Baker, PhD, Karyn Myers, PhD, and Jonathan Valenzano, PharmD, of Sanofi. Editorial support for this poster was provided by Margarita Lens of Fishawack Communications, and was funded by Sanofi. • Patients initiated treatment with teriflunomide 14 mg once daily or DMF 240 mg twice daily, 2. FDA. Tecfidera (dimethyl fumarate). Prescribing Information. Dec 2017. RZ: Speaking and consultant fees (Celgene, Claret Medical, EMD Serono, Genzyme, Novartis); editorial boards (BioMed Res Int, BMC Med, BMC Neurol, Clinical CNS Drugs, Conf Pap Neurosci, J Alzh Dis, Vein and Lymphatics); financial support for research activities continuing for ≥3 months (Claret Medical, Genzyme, Intekrin-Coherus, Novartis, Penumbra, Protembis, QuintilesIMS). CB: Employee of IQVIA, consulting fees (Genzyme). MGD: Consulting fees (Claret Medical, EMD Serono). NB: Nothing to disclose. JC: Employee of Sanofi. 3. Freedman et al. Mult Scler Relat Disord. 2016;10:204. KT and MM: Employees of Sanofi, with ownership interest. SC: Employment, consulting, scientific advisory board, speaking, or other activities (Acorda, Biogen, Genentech, Novartis, Sanofi Genzyme); advisory boards, research steering committees, research support, –– Patients initiating DMF could start treatment with 120 mg twice daily, but must have 4. Boster et al. Neurol Ther. 2017;6:91. speaker honoraria, (Biogen, Mallinckrodt, Novartis, Opexa, Roche Genentech, Sanofi Genzyme). received DMF 240 mg twice daily for ≥3 months to be included in the study 5. De Stefano et al. J Neurol Neurosurg Psychiatry. 2016;87:93. Teriflunomide is approved in many countries, including the US and the European Union, for the treatment of relapsing multiple sclerosis or relapsing-remitting multiple sclerosis. This material may contain information that is outside of the approved labeling in some countries.

Presented at the Americas Committee for Treatment and Research in Multiple Sclerosis (ACTRIMS) Forum, February 1–3, 2018, San Diego, CA, USA Funding provided by Sanofi