Research JAMA Neurology | Original Investigation Ponesimod Compared With Teriflunomide in Patients With Relapsing Multiple Sclerosis in the Active-Comparator Phase 3 OPTIMUM Study A Randomized Clinical Trial Ludwig Kappos, MD; Robert J. Fox, MD; Michel Burcklen, PhD; Mark S. Freedman, MSc, MD; Eva K. Havrdová, MD, PhD; Brian Hennessy, MSc; Reinhard Hohlfeld, MD; Fred Lublin, MD; Xavier Montalban, MD, PhD; Carlo Pozzilli, MD, PhD; Tatiana Scherz, MD, PhD; Daniele D'Ambrosio, MD, PhD; Philippe Linscheid, PhD; Andrea Vaclavkova, MD; Magdalena Pirozek-Lawniczek, MD; Hilke Kracker, PhD; Till Sprenger, MD Supplemental content IMPORTANCE To our knowledge, the Oral Ponesimod Versus Teriflunomide In Relapsing CME Quiz at Multiple Sclerosis (OPTIMUM) trial is the first phase 3 study comparing 2 oral jamacmelookup.com disease-modifying therapies for relapsing multiple sclerosis (RMS). OBJECTIVE To compare the efficacy of ponesimod, a selective sphingosine-1-phosphate receptor 1 (S1P1) modulator with teriflunomide, a pyrimidine synthesis inhibitor, approved for the treatment of patients with RMS. DESIGN, SETTING, AND PARTICIPANTS This multicenter, double-blind, active-comparator, superiority randomized clinical trial enrolled patients from April 27, 2015, to May 16, 2019, who were aged 18 to 55 years and had been diagnosed with multiple sclerosis per 2010 McDonald criteria, with a relapsing course from the onset, Expanded Disability Status Scale (EDSS) scores of 0 to 5.5, and recent clinical or magnetic resonance imaging disease activity. INTERVENTIONS Patients were randomized (1:1) to 20 mg of ponesimod or 14 mg of teriflunomide once daily and the placebo for 108 weeks, with a 14-day gradual up-titration of ponesimod starting at 2 mg to mitigate first-dose cardiac effects of S1P1 modulators and a follow-up period of 30 days. MAIN OUTCOMES AND MEASURES The primary end point was the annualized relapse rate. The secondary end points were the changes in symptom domain of Fatigue Symptom and Impact Questionnaire–Relapsing Multiple Sclerosis (FSIQ–RMS) at week 108, the number of combined unique active lesions per year on magnetic resonance imaging, and time to 12-week and 24-week confirmed disability accumulation. Safety and tolerability were assessed. Exploratory end points included the percentage change in brain volume and no evidence of disease activity (NEDA-3 and NEDA-4) status. RESULTS For 1133 patients (567 receiving ponesimod and 566 receiving teriflunomide; median [range], 37.0 [18-55] years; 735 women [64.9%]), the relative rate reduction for ponesimod vs teriflunomide in the annualized relapse rate was 30.5% (0.202 vs 0.290; P < .001); the mean difference in FSIQ-RMS, −3.57 (−0.01 vs 3.56; P < .001); the relative risk reduction in combined unique active lesions per year, 56% (1.405 vs 3.164; P < .001); and the reduction in time to 12-week and 24-week confirmed disability accumulation risk estimates, 17% (10.1% vs 12.4%; P = .29) and 16% (8.1% vs 9.9; P = .37), respectively. Brain volume loss at week 108 was lower by 0.34% (–0.91% vs –1.25%; P < .001); the odds ratio for NEDA-3 achievement was 1.70 (25.0% vs 16.4%; P < .001). Incidence of treatment-emergent adverse events (502 of 565 [88.8%] vs 499 of 566 [88.2%]) and serious treatment-emergent adverse events (49 [8.7%] vs 46 [8.1%]) was similar for both groups. Treatment discontinuations because of adverse events was more common in the ponesimod group Author Affiliations: Author (49 of 565 [8.7%] vs 34 of 566 [6.0%]). affiliations are listed at the end of this article. CONCLUSIONS AND RELEVANCE In this study, ponesimod was superior to teriflunomide on Corresponding Author: Ludwig annualized relapse rate reduction, fatigue, magnetic resonance imaging activity, brain volume Kappos, MD, Research Center for loss, and no evidence of disease activity status, but not confirmed disability accumulation. Clinical Neuroimmunology and The safety profile was in line with the previous safety observations with ponesimod and Neuroscience Basel, Departments of Medicine, Clinical Research, the known profile of other S1P receptor modulators. Biomedicine and Biomedical TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT02425644 Engineering, University Hospital and University of Basel, Spitalstrasse 2, JAMA Neurol. 2021;78(5):558-567. doi:10.1001/jamaneurol.2021.0405 CH-4031 Basel, Switzerland Published online March 29, 2021. (ludwig.kappos@usb.ch). 558 (Reprinted) jamaneurology.com Downloaded From: https://jamanetwork.com/ on 06/28/2023 Ponesimod Compared With Teriflunomide in Patients With Relapsing Multiple Sclerosis Original Investigation Research M ultiple sclerosis (MS), a chronic autoimmune dis- ease of the central nervous system, is clinically per- Key Points ceived by relapses and progressive loss of neurologi- Question How does the efficacy of ponesimod compare with cal function, primarily attributed to inflammatory attacks that of teriflunomide in a phase 3, multicenter, randomized, leading to demyelination, axonal loss, and gliosis culminat- double-blind, active-comparator superiority study based on ing in long-term multifocal sclerotic plaques in the brain and relapse rate, fatigue, magnetic resonance imaging–defined spinal cord.1-3 Oral disease-modifying therapy (DMT) options disease activity, tissue loss, and disability accumulation in such as teriflunomide,4,5 fingolimod,6 dimethyl fumarate,7,8 patients with relapsing multiple sclerosis, over 108 weeks? and siponimod 9 have broadened disease management Findings In this randomized clinical trial, ponesimod was options in MS. Despite significant progress in MS therapy, significantly superior to teriflunomide in reducing the annualized there is still an unmet need for effective, safe, and conve- relapse rate (−30.5%), Fatigue Symptom and Impact nient treatments that can be used early in the disease Questionnaire–Relapsing Multiple Sclerosis symptom score (−3.57), and combined unique active lesions on magnetic course.10-12 Given the number of alternative options of oral resonance imaging (−56%). treatments, head-to-head comparative trials to inform choices are still lacking.13 Meaning In this study, efficacy of ponesimod was superior Ponesimod is an orally active, highly selective modulator to teriflunomide, and ponesimod had a safety profile consistent with sphingosine-1-phosphate modulators without any new of the sphingosine-1-phosphate receptor 1 (S1P1) with no ac- safety signals. tive metabolites and is thus a limited potential for drug-drug interaction.14 Ponesimod induces a rapid, dose-dependent, and reversible reduction of peripheral blood lymphocyte counts by perimposed relapses), an EDSS score between 0 and 5.5, and blocking the egress of lymphocytes from lymphoid organs.15,16 recent clinical or magnetic resonance imaging (MRI) activity Rapid elimination of ponesimod and the reversibility of its ef- were enrolled. eAppendix 1 in Supplement 1 presents com- fects on lymphocyte levels allows the rapid return of normal plete inclusion and exclusion criteria. immune system function, which may be beneficial in terms An institutional review board (US) or independent ethics of safety for pregnancy planning, serious infections, or committee (Europe) approved study protocol and amend- vaccinations.17,18 In a randomized, placebo-controlled, dose- ments at each participating center. The study was conducted finding phase 2 study19 in patients with relapsing MS (RMS), in accordance with the Declaration of Helsinki, Good Clinical among doses tested (10 mg, 20 mg, and 40 mg), the 20-mg dose Practice, and applicable regulatory requirements. All partici- was found to significantly reduce both the cumulative num- pants provided written informed consent. ber of new gadolinium-enhancing (Gd+) T1 lesions and new or enlarging T2 lesions compared with placebo. Study Evaluations We report the findings of the global phase 3 superiority The primary efficacy end point was the annualized relapse rate study (the Oral Ponesimod Versus Teriflunomide in Relaps- (ARR) based on the number of confirmed relapses per patient- ing Multiple Sclerosis [OPTIMUM]). This study was designed year from randomization to the end of the study (EOS: end of to compare the efficacy, safety, and tolerability of ponesimod treatment [EOT] plus follow-up time, as per the intention-to- vs teriflunomide, an approved oral therapy in adult patients treat principle). A confirmed relapse was defined as new, wors- with RMS. ening, or recurrent neurological symptoms that occurred at least 30 days after the onset of a preceding relapse, lasted at least 24 hours, occurred in the absence of fever or infection, and was accompanied by a documented increase of the EDSS Methods score or its functional system scores from a previous clinical Study Design assessment. The EDSS scores were assessed by independent, OPTIMUM (NCT02425644) was a phase 3, multicenter, double- trained, and certified evaluators using the standardized Neu- blind, active-comparator, superiority randomized clinical trial rostatus EDSS examination (https://www.neurostatus.net/). designed to compare the efficacy, safety, and tolerability of Secondary efficacy variables were (1) the change from 20 mg of ponesimod vs 14 mg of teriflunomide in patients baseline to week 108 in fatigue-associated symptoms, as with RMS (eFigure 1 in Supplement 1; Trial Protocol in measured by the symptom domain of the Fatigue Symptom Supplement 2). The study was conducted from April 2015 to and Impact Questionnaire–Relapsing Multiple Sclerosis May 2019; 162 centers randomized patients across 28 countries (FSIQ–RMS), a validated patient-reported outcome measure21 in North America, Europe, Mexico, Israel, and Turkey. (eAppendix 1 in Supplement 1); (2) cumulative number of Randomization was stratified by use of MS DMTs in the last 2 combined unique active lesions (CUALs) on MRI, defined as years prior to randomization (presence or absence) and baseline new Gd+ T1 lesions or new or enlarging T2 lesions (without Expanded Disability Status Scale (EDSS) score (≤3.5 or >3.5). double counting of lesions) from baseline to week 108 (assessed in a blinded fashion at a central reading center Patient Population [Medical Image Analysis Center, Basel, Switzerland]); (3) time Adult patients aged 18 to 55 years with RMS as defined by the to 12-week confirmed disability accumulation (CDA) from revised (2010) McDonald diagnostic criteria for MS20 with a re- baseline to the EOS, defined as an increase in the EDSS score, lapsing course (ie, RMS or secondary progressive MS with su- which was confirmed after 12 weeks (by an increase of at jamaneurology.com (Reprinted) JAMA Neurology May 2021 Volume 78, Number 5 559 Downloaded From: https://jamanetwork.com/ on 06/28/2023 Research Original Investigation Ponesimod Compared With Teriflunomide in Patients With Relapsing Multiple Sclerosis Figure 1. Patient Disposition Statistical Analysis The primary statistical analysis was performed on the full analysis set (all participants who were randomized) using 1468 Screened a negative binomial regression model for the number of con- 335 Ineligible firmed relapses from baseline to the EOS adjusting for the log time in the study (in years) as an offset. An overall multiple testing strategy was applied to the planned efficacy analyses, 1133 Randomized which started with testing the primary end point at an overall 2-sided α of .01 for conclusive evidence and .05 for a positive 566 Randomized to receive 14 mg 567 Randomized to receive 20 mg study result, followed hierarchically by a fallback-type proce- of teriflunomide of ponesimod dure for the secondary end points26 (details are in eFigure 2 in Supplement 1). 566 Treated 565 Treated 93 Discontinued treatment early 94 Discontinued treatment early 14 Because of an adverse event 37 Because of an adverse or tolerance problem event or tolerance problem Results 30 For other reasons 26 For other reasons 16 Because of prespecified 12 Because of prespecified Patient Disposition and Baseline Characteristics discontinuation criteria discontinuation criteria Of 1468 patients screened, 1133 were randomized (ponesi- 24 Because of efficacy problems 11 Because of efficacy 4 For unknown reasons problems mod, n = 567; teriflunomide, n = 566) and included in the full 2 Were lost to follow-up 6 For unknown reasons analysis set. The study enrolled a representative RMS popu- 2 Died 2 Were lost to follow-up lation (median [range] age, 37.0 [18-55] years; 735 women [64.9%]). Of those randomized, 2 patients in the ponesimod 473 Completed 471 Completed treatment treatment group did not receive study treatment. Of the 1131 patients treated, 471 of 565 (83.1%) receiving ponesimod and 473 of 566 71 Discontinued study participation 77 Discontinued study participation (83.6%) receiving teriflunomide completed the respective treat- 36 Withdrew consent 41 Withdrew consent ments (Figure 1); there were fewer treatment discontinua- 17 Left for other reasons 18 Left for other reasons 3 Had an adverse event 13 Had an adverse event tions in the ponesimod group for efficacy-associated reasons 10 Left because of treatment 3 Left because of treatment (ponesimod, 11 [1.9%]; teriflunomide, 24 [4.3%]). However, efficacy problems efficacy problems 3 Were lost to follow-up 2 Were lost to follow-up treatment discontinuations attributable to adverse events 2 Died or tolerability were more frequent in the ponesimod group (37, vs 14 in the teriflunomide group; Figure 1). In the ponesimod group, no patient discontinued treatment because of Baseline characteristics were comparable between the first-dose cardiac effect. Discontinuation in the ponesimod group was 2 treatment groups (Table 1), with a small imbalance in the pres- attributable to prespecified criteria: macular edema, pregnancy, lymphopenia, ence of enhancing lesions (ponesimod, 226 of 567 [39.9%] or a malignant condition. vs teriflunomide, 256 of 566 [45.4%]). Approximately 35% of patients (202 receiving ponesimod [35.6%] and 200 receiv- least 1.5 with a baseline EDSS score of 0.0, at least 1.0 with ing teriflunomide [35.3%]) were considered to have highly ac- baseline EDSS score of 1.0 to 5.0, or at least 0.5 with a base- tive disease, as defined by different combinations of number line EDSS score of 5.5 or more); and (4) time to 24-week of relapses, MRI activity at baseline, EDSS score, and previ- confirmed CDA from baseline to the EOS. Predefined explor- ous DMT (Table 1). atory measures included the percentage change in brain volume from baseline to week 108 using the Structural Efficacy Image Evaluation, using Normalization, of Atrophy (SIENA) Primary End Point: ARR methodology.22,23 Further exploratory end points were no In total, there were 242 confirmed relapses reported for pon- evidence of disease activity (NEDA)–3 status from baseline up esimod compared with 344 for teriflunomide. Ponesimod to the EOS (a composite of no relapse, no 12-week CDA, no reduced ARR by 30.5% compared with teriflunomide (mean Gd+ T1 or new or enlarging T2 lesions) and NEDA-4 status ARR, 0.202 vs 0.290; rate ratio, 0.695 [99% confidence lim- (a composite of NEDA-3 and no brain volume decrease of its (CLs), 0.536-0.902]; P < .001; Figure 2A; Table 2). Sensi- ≥0.4% from baseline to EOS).24,25 tivity analyses adjusting for presence of enhancing lesions Safety assessments included adverse events recorded showed consistent results (eAppendix 1 and eTable 4 in verbatim and later coded in accordance with MedDRA ver- Supplement 1). sion 21 (International Council for Harmonisation) and pre- defined adverse events of special interest (AESIs) (details on Secondary End Points AESIs are in eAppendix 1 in Supplement 1). Clinical labora- tory tests (hematology, serum chemistry, virus serology, FSIQ-RMS | The change in FSIQ-RMS weekly symptom score serum and urine pregnancy tests, and urinalysis), 12-lead from baseline to week 108 was lower (where higher scores in- electrocardiogram, blood pressure, and pulmonary function dicate more fatigue) for fatigue symptoms in the ponesimod tests were also conducted. group than the teriflunomide group. The least-square means 560 JAMA Neurology May 2021 Volume 78, Number 5 (Reprinted) jamaneurology.com Downloaded From: https://jamanetwork.com/ on 06/28/2023 Ponesimod Compared With Teriflunomide in Patients With Relapsing Multiple Sclerosis Original Investigation Research were 0.01 vs 3.56 (mean difference, −3.57 [95% CLs, −5.83 to Table 1. Demographic and Baseline Characteristics −1.32]; P = .002; Table 2; Figure 2B). in the Full Analysis Set Patients, No. (%) CUALs | Ponesimod reduced the mean number of CUALs per Ponesimod, Teriflunomide, year on annual brain MRIs from baseline to week 108 by 56% 20 mg 14 mg compared with teriflunomide (1.405 vs 3.164; rate ratio, Characteristic (n = 567) (n = 566) 0.444 [95% CLs, 0.364-0.542]; P < .001) (Table 2). Most of Female 363 (64.0) 372 (65.7) CUALs observed were new or enlarging T2 lesions (Table 2; Age, mean (SD), y 36.7 (8.74) 36.8 (8.74) Figure 2C). White race 551 (97.2) 553 (97.7) Baseline Expanded Disability 94 (16.6) 95 (16.8) CDA | The risk of 12-week CDA was not different in the 2 groups Status Scale >3.5 strata (10.1% vs 12.4%; hazard ratio, 0.83 [95% CLs, 0.58-1.18]; Disease-modifying treatment 213 (38) 211 (37) received within 2 y prior P = .29), and the formal testing procedure stopped, render- to randomization ing the subsequent analyses exploratory. In this exploratory Baseline Expanded Disability 2.57 (1.17) 2.56 (1.23) analysis, risk of 24-week CDA was also not different (hazard Status Scale score, mean (SD) ratio, 0.84 [95% CLs, 0.57-1.24]; P = .37; Table 2; Figure 2D; Time since first symptom at 7.63 (6.78) 7.65 (6.78) randomization, mean (SD), y eFigure 3 in Supplement 1). Relapses in last year prior to study 1.2 (0.61) 1.3 (0.65) entry, mean (SD), No. Exploratory Outcomes Multiple sclerosis subtype Relapsing-remitting 552 (97.4) 552 (97.5) Brain Volume Loss | Brain volume loss from baseline to week Secondary progressive 15 (2.6) 14 (2.5) 108 was lower in the ponesimod group vs the teriflunomide group. The least-squares mean percentage change was Fatigue symptom score at baseline, 31.9 (20.4) 32.8 (19.1) mean (SD)a −0.91% vs −1.25% (mean difference, 0.34 [95% CL, 0.17-0.50] Presence of gadolinium-enhancing 226 (39.9) 256 (45.4) percentage points; exploratory P < .001; Table 2; eFigure 4 in T1 lesions at baselineb Supplement 1). Volume of T2-weighted lesions, 8301.4 9489.2 mean (SD), mm3 (10 346.28) (11 265.42) NEDA-3 and NEDA-4 | In the ponesimod group vs the terifluno- Highly active diseasec 202 (35.6) 200 (35.3) mide group, the estimated percentage for NEDA-3 from base- a Based on Fatigue Symptom and Impact Questionnaire–Relapsing Multiple line to week 108 was 25.0% vs 16.4%, respectively; the odds Sclerosis. b ratio for achieving 2-year NEDA-3 was 1.70 (95% CLs, 1.27- From the central reader. c 2.28; Table 2). The most frequent reason for not achieving Two or more relapses within the 1 year prior to study entry, a baseline Expanded Disability Status Scale score more than 2, and baseline magnetic NEDA-3 was the presence of new or enlarging T2 lesions resonance imaging or 1 or more gadolinium-enhancing T1 lesion; or any (all randomized patients: ponesimod, 301 [53.4%]; terifluno- disease-modifying treatment received within 12 months prior to mide, 364 [65.2%]). The estimated percentage achieving randomization and 1 or both of the following: (1) 1 or more relapse within 1 year NEDA-4 from baseline to week 108 was 11.4% vs 6.5% in the prior to study entry and baseline magnetic resonance imaging either with 1 or more gadolinium-enhancing T1 lesion and/or 9 or more T2-weighted lesions or ponesimod vs teriflunomide groups (odds ratio, 1.85 [95% CLs, (2) a number of relapses within 1 year prior to study entry equal to or greater 1.24-2.76]; P = .003). A total of 171 patients (32.5%) in the pon- than the number of relapses between 2 years and 1 year prior to study entry, esimod and 225 patients (42.3%) in the teriflunomide groups, for patients with 1 or more relapse within the 2 years prior to study entry. respectively, had annual brain volume losses of 0.4% or more compared with baseline values. 1 of coronary artery insufficiency and 1 of MS (adjudicated as Safety sudden cardiac death). Both deaths were considered by the in- Overall, the proportion of patients who experienced at least vestigators to be not associated with the study drug. Overall, 1 treatment-emergent adverse event (TEAE) was similar be- TEAEs leading to treatment discontinuation were more tween the 2 groups (ponesimod, 502 [88.8%]; teriflunomide, frequent in the ponesimod group (49 of 565 [8.7%] vs 34 of 499 [88.2%]) (Table 3). The most common TEAEs (≥10% in 566 [6.0%]); dyspnea (6 [1.1%] vs 0), an increased ALT level either group) were an increased alanine aminotransferase (ALT) (5 [0.9%] vs 6 [1.1%]), an increased aspartate aminotransfer- level (110 [19.5%] vs 53 [9.4%]), nasopharyngitis (109 [19.3%] ase level (3 [0.5%] vs 5 [0.9%]), and macular edema (6 [0.9%] vs 95 [16.8%]), headache (65 [11.5%] vs 72 [12.7%]), upper vs 0) were the most commonly reported reasons. respiratory tract infection (60 [10.6%] vs 59 [10.4%]), and The overall incidence of first-dose heart rate and rhythm alopecia (18 [3.2%] vs 72 [12.7%]) in the ponesimod vs teriflu- AESIs on day 1 (at a 2-mg dose) of up-titration (eTable 1 in nomide groups, respectively. Supplement 1) or treatment reinitiation was 2.1% in the pon- The proportions of patients who experienced at least esimod group (n = 12) compared with 0.4% (n = 2) in the teri- 1 treatment-emergent serious adverse event were similar in flunomide group, with none reported as serious or leading both treatment arms (49 [8.7%] vs 46 [8.1%]). Overall, no pat- to treatment discontinuation (eTable 2 in Supplement 1). No tern or clustering of serious events was observed in either treat- second-degree or higher-degree atrioventricular blocks oc- ment group. Two patients in the teriflunomide group died: curred. The maximum mean (SD) reduction in heart rate from jamaneurology.com (Reprinted) JAMA Neurology May 2021 Volume 78, Number 5 561 Downloaded From: https://jamanetwork.com/ on 06/28/2023 Research Original Investigation Ponesimod Compared With Teriflunomide in Patients With Relapsing Multiple Sclerosis Figure 2. Primary and Secondary End Points in the Full Analysis Set A Confirmed annualized relapse rate B FSIQ-RMS symptoms score 0.4 6 Rate ratio, 0.695 (99% CL, Ponesimod, 20 mg Teriflunomide, 14 mg P = .002 LS mean change from baseline 0.536-0.902); 30.5%; 5 P < .001 Annualized relapse rate 0.3 4 P = .25 P = .21 P = .006 P = .009 3 2 0.2 1 0 0.1 –1 –2 0 –3 Ponesimod, Teriflunomide, 12 24 60 84 108 20 mg 14 mg (n = 567) (n = 566) Week No. of patients Ponesimod, 20 mg (n = 567) 412 417 409 386 344 Teriflunomide, 14 mg (n = 566) 421 422 417 389 328 C Combined unique active lesions/y D Time to 3-month confirmed disability accumulation 4 20 Combined unique active lesions/y Rate ratio, 0.44 Risk reduction, 17% (95% CL, (95% CL, 0.36-0.54); –18% to 42%); P = .29 56%; P < .001 Patients with event, % Teriflunomide, 3 15 14 mg 13.2% 10.8% 2 10 Ponesimod, 20 mg 1 5 0 0 Ponesimod, Teriflunomide, 0 12 24 36 48 60 72 84 96 108 120 20 mg 14 mg (n = 539) (n = 536) Time after randomization, wk No. at risk Ponesimod, 20 mg 567 533 517 503 492 480 469 458 449 315 Teriflunomide, 14 mg 566 548 528 513 491 481 467 460 439 290 A, Confirmed relapses up to end of study, with annualized relapse rate from magnetic resonance scans up to week 108; 56% indicates risk reduction. negative binomial regression for ponesimod (0.202) and teriflunomide (0.290); D, Time to 12-week confirmed disability accumulation. With regardt to 30.5% indicates risk reduction. B, Symptoms domain of Fatigue Symptom and nonsignificant results, the formal testing procedure stopped. The stratified Impact Questionnaire–Relapsing Multiple Sclerosis (FSIQ-RMS): change from log-rank test P value and stratified Cox regression risk reduction estimate are baseline to week 108. C, Number of combined unique active lesions per year on displayed. CL indicates confidence limits; LS, least squares. predose to postdose on day 1 was observed at 2 hours post- A similar proportion of patients in the ponesimod group dose in the ponesimod group (−8.7 [8.68] beats per minute), (45 [8.0%]) and teriflunomide group (44 [7.8%]) experienced compared with −1.7 (8.95) beats per minute in the terifluno- at least 1 AESI of hypertension. Three patients in the ponesi- mide group, with 3 patients having an asymptomatic post- mod group discontinued the study treatment because of dose heart rate of 40 beats per minute or less; all 3 of these hypertension AESIs, and 1 patient in each group had a serious patients had a pretreatment heart rate of less than 55 beats hypertension AESI. per minute. The most frequently reported pulmonary AESI was dys- An overview of treatment-emergent AESIs up to the EOT pnea (ponesimod: 30 [5.3%]; teriflunomide: 7 [1.2%]); prema- plus 15 days is shown in Table 3. To address the concern re- ture treatment discontinuation due to pulmonary AESI was garding confounding effects of the accelerated elimination pro- reported in 7 patients (1.2%) receiving ponesimod (6 with cedure for teriflunomide on liver enzymes, an analysis up to dyspnea). Treatment-emergent AESIs of macular edema were the EOT plus 1 day was also performed. Most frequently oc- reported in 6 patients receiving ponesimod and none receiv- curring AESIs (up to the EOT plus 15 days, unless otherwise ing teriflunomide; all cases resolved with treatment discon- specified) with ponesimod vs teriflunomide were in the cat- tinuation, including 1 with sequelae. egories of hepatobiliary disorders or liver enzyme abnormali- Four patients with macular edema AESIs had a relevant ties (up to EOT plus 1 day) (128 [22.7%] vs 69 [12.2%]), hyper- medical history or concomitant eye disorder, and 1 patient had tension (57 [10.1%] vs 51 [9.0%]), pulmonary events (45 [8.0%] diabetes. In the ponesimod group, 8 patients (1.4%) experi- vs 15 [2.7%]), and herpetic infection (each 27 [4.8%]). A total enced seizures, compared with 1 patient (0.2%) receiving teri- of 6 patients (2 receiving ponesimod and 4 receiving teriflu- flunomide. Of the 8 patients in the ponesimod group, 5 pa- nomide) had a serious hepatobiliary disorder or liver enzyme tients had concomitant neurologic diseases at baseline abnormality AESI (up to EOT plus 1 day). (epilepsy: n = 2; partial seizures with secondary generaliza- 562 JAMA Neurology May 2021 Volume 78, Number 5 (Reprinted) jamaneurology.com Downloaded From: https://jamanetwork.com/ on 06/28/2023 Ponesimod Compared With Teriflunomide in Patients With Relapsing Multiple Sclerosis Original Investigation Research Table 2. Summary of Efficacy Results in the Full Analysis Set Ponesimod, Patients Teriflunomide, Patients RR (99% CL) or End point from baseline 20 mg included in 14 mg included in Difference, RR, to week 108 (n = 567) analysis, No. (n = 566) analysis, No. or HR (95% CL) P value Primary end point Mean annualized relapse rate/y 0.202 (0.173-0.235) 567 0.290 (0.254-0.331) 566 0.695 <.001 (95% CL)a (0.536-0.902)b Secondary end points LS mean FSIQ-RMS weekly −0.01 (−1.60 to 1.58) 449 3.56 (1.96-5.16) 458 −3.57 (−5.83 to .002 symptoms score change (95% CL)c −1.32)d Mean cumulative combined unique 1.405 (1.215-1.624) 539 3.164 (2.757-3.631) 536 0.444 (0.36-0.54)f <.001 active lesions/y (95% CL)e Patients with first 12-wk confirmed 57 (10.1) 567 70 (12.4) 566 0.83 (0.58-1.18)h .29 disability accumulation, No. (%)g Exploratory end points Patients with first 24-wk confirmed 46 (8.1) 567 56 (9.9) 566 0.84 (0.57 to 1.24)h .37 disability accumulation, No. (%)g Mean cumulative new 0.18 (0.141-0.224) 540 0.43 (0.351-0.525) 538 0.42 (0.31-0.56)f <.001 gadolinium-enhancing T1 lesions/scan (95% CL) LS mean change in brain volume, % −0.91 (−1.03 to −0.79) 436 −1.25 (−1.36 to −1.13) 434 0.34 (0.17 to 0.50)d <.001 (95% CL)i j Estimated mean NEDA-3, % 25.0 (21.4-29.0) 564 16.4 (13.5-19.8) 558 1.70 (1.27 to 2.28) <.001 (95% CL)i Estimated mean NEDA-4, % 11.4 (8.7-14.6) 526 6.5 (4.7-9.0) 532 1.85 (1.24-2.76)j .003 (95% CL)k Abbreviations: CL, confidence limit; DMT, disease-modifying therapy; offset of log time (years) up to last magnetic resonance imaging scan and EDSS, Expanded Disability Status Scale; FSIQ-RMS, Fatigue Symptom and covariates of EDSS strata (ⱕ3.5 or >3.5), DMT within the 2 years prior to Impact Questionnaire–Relapsing Multiple Sclerosis; HR, hazard ratio; LS, least randomization, and gadolinium-enhancing T1 lesions at baseline. squares; NEDA, no evidence of disease activity; OR, odds ratio; RR, rate ratio. f RR (95% CL). a Confirmed relapses up to the end of the study; a negative binomial model was g Change from baseline to end of study; stratified by EDSS category and DMT applied with Wald CLs and P value, the offset log time (years) to the end of the within 2 years, Cox regression with 95% Wald CLs and a log-rank P value. study, and covariates of EDSS strata (ⱕ3.5 or >3.5), DMT in the last 2 years h HR (95% CL). prior to randomization strata, and the number of relapses in the year prior i study entry (ⱕ1 or ⱖ2). Mixed model with linear time effect and covariates of EDSS strata (ⱕ3.5 or b >3.5), DMT within the 2 years prior to randomization strata, gadolinium- RR (99% CL). enhancing T1 lesions at baseline, and baseline brain volume. c Mixed-effects, repeated-measurements model with unstructured covariance, j OR (95% CL). treatment, visit, treatment by visit interaction, baseline by visit interaction as k fixed effects, baseline FSIQ-RMS score, EDSS strata (ⱕ3.5 or >3.5), and DMT Logistic regression with treatment as factor, adjusted for covariates EDSS in the 2 years prior to randomization as covariates. A negative change from strata (ⱕ3.5 or >3.5), DMT in the 2 years prior to randomization, the number baseline indicates an improvement in fatigue symptoms. of relapses in the year prior to study entry (ⱕ1 or ⱖ2), and the presence of d gadolinium-enhancing T1 lesions at baseline. Difference (95% CL). e Negative binomial model was applied with Wald 95% CIs, a P value, and an tion: n = 1; hydrocephalus: n = 1; polyneuropathy: n = 1). Three seizure AESIs among patients receiving ponesimod were re- Discussion ported as serious, and 1 event resulted in discontinuation of the study treatment. OPTIMUM is, to our knowledge, the first phase 3 study com- The proportion of patients who experienced an ALT level paring efficacy and safety of 2 oral DMTs in RMS. Ponesimod increased 3 or more times greater than the upper limit of nor- is an orally active, selective S1P1 receptor modulator that causes mal (ULN) levels (reference range: men, 44 U/L; women, 33 U/L dose-dependent sequestration of lymphocytes in lymphoid or- [to convert to microkatals per liter, multiply by 0.0167]; EOT gans. High selectivity for the S1P1 receptor, a low potential for plus 1 day) was higher in the ponesimod group compared with drug-drug interactions, rapid onset, and reversibility of phar- the teriflunomide group (97 [17.3%] vs 47 [8.3%]), while the macological effects, along with an up-titration regimen that proportion with an ALT level increased 8 or more times greater mitigates cardiac adverse effects, provides added benefits to than the ULN (the EOT plus 1 day) was higher in the terifluno- ponesimod over other S1P1 receptor modulators.14 Ponesi- mide group (4 [0.7%] vs 12 [2.1%]) (eTable 3 in Supplement 1). mod was superior to teriflunomide, an oral pyrimidine syn- All ALT level increases of 3 or more times greater than the ULN thesis inhibitor approved for the treatment of MS,13 on the pri- resolved despite continued ponesimod treatment (n = 86) or mary study outcome, reduction of ARR ( by −30.5%). after treatment discontinuation (n = 11). Most cases of biliru- Superiority vs teriflunomide was also shown in the analysis of bin increases of 2 or more times greater than the ULN (5 of 8 2 key secondary outcomes: the reduction of CUAL, an estab- patients; reference, 5.1 to 20.5 μmol/L, irrespective of sex; lished MRI measure of focal inflammatory disease activity EOT plus 1 day) occurred in patients with a medical history of (−56%),27 and improvement of MS-associated fatigue, as mea- Gilbert syndrome. sured with the FSIQ-RMS weekly symptom score (mean dif- jamaneurology.com (Reprinted) JAMA Neurology May 2021 Volume 78, Number 5 563 Downloaded From: https://jamanetwork.com/ on 06/28/2023 Research Original Investigation Ponesimod Compared With Teriflunomide in Patients With Relapsing Multiple Sclerosis Table 3. Overview of Adverse Events in Safety Analysis Set Table 3. Overview of Adverse Events in Safety Analysis Set (continued) Patients, No. (%) Patients, No. (%) Ponesimod, Teriflunomide, Ponesimod, Teriflunomide, 20 mg 14 mg 20 mg 14 mg Characteristics (n = 565) (n = 566) Characteristics (n = 565) (n = 566) TEAEs 502 (88.8) 499 (88.2) Hepatobiliary disorders 2 (0.4) 7 (1.2) ≥1 TEAEs in either group leading to 49 (8.7) 34 (6.0) Investigations 2 (0.4) 3 (0.5) treatment discontinuation, by system organ class termsa Respiratory, thoracic, and mediastinal 2 (0.4) 1 (0.2) disorders Investigations 12 (2.1) 10 (1.8) Vascular disorders 2 (0.4) 2 (0.4) Respiratory, thoracic, and mediastinal 7 (1.2) NA disorders Blood and lymphatic system disorders 1 (0.2) 1 (0.2) Eye disorders 5 (0.9) NA Psychiatric disorders 1 (0.2) 2 (0.4) Gastrointestinal disorders 4 (0.7) 4 (0.7) Cardiac disorders 0 2 (0.4) Blood and lymphatic system disorders 3 (0.5) 2 (0.4) Metabolism and nutrition disorders 0 1 (0.2) General disorders and administration 3 (0.5) 2 (0.4) Abbreviations: NA, not applicable; TEAE, treatment-emergent adverse events. site conditions a Only system organ classes with at least 2 events in at least 1 treatment arm are Hepatobiliary disorders 3 (0.5) 2 (0.4) displayed. Pregnancy, puerperium, and perinatal 3 (0.5) 3 (0.5) b Up to end of treatment plus 15 days, unless otherwise specified. conditions c Infection adverse event of special interests were identified by the adverse Vascular disorders 3 (0.5) NA events from the infections and infestations system organ class, only if Nervous system disorders 2 (0.4) 4 (0.7) reported as serious or severe. d Social circumstances 2 (0.4) 1 (0.2) Adverse event macular hole was not confirmed as macular edema. e Cardiac disorders 1 (0.2) 2 (0.4) Two with basal cell carcinoma, 2 with excision of preexisting benign lesions (nevus), and 1 with malignant melanoma. Skin and subcutaneous 1 (0.2) 2 (0.4) f tissue disorders One with basal cell carcinoma. g Adverse event of special interestb One because of coronary artery insufficiency and 1 because of multiple sclerosis. Hepatobiliary disorders or liver test result abnormality ference, −3.57). Despite the well-known negative implica- End of treatment plus 1 d 128 (22.7) 69 (12.2) tions on quality of life and the high socioeconomic burden End of treatment plus 15 d 145 (25.7) 82 (14.5) associated with fatigue,21,28-30 no previous phase 3 study in MS ≥1 Serious adverse event 2 (0.4) 4 (0.7) has addressed fatigue prospectively as a key outcome. This may Hypertension 57 (10.1) 51 (9.0) have been partially because of the poor sensitivity and speci- Pulmonary events 45 (8.0) 15 (2.7) ficity of the currently available patient-reported outcomes used Effect on heart rate and rhythm 12 (2.1) 2 (0.4) for the assessment of fatigue. In this study, fatigue was as- plus hypotension on day 1 sessed using a validated patient-reported outcome measure Herpetic infection 27 (4.8) 27 (4.8) specifically developed to assess fatigue in patients with RMS, Infectionc 9 (1.6) 5 (0.9) the FSIQ-RMS scale.21 Seizure 8 (1.4) 1 (0.2) However, no statistically significant difference was seen Macular edema 6 (1.1) 1 (0.2)d in the outcome on the predefined key secondary outcome, 12- Skin malignant condition 5 (0.9)e 1 (0.2)f week CDA. Baseline EDSS scores (mean, 2.6) and the propor- Nonskin malignant condition 1 (0.2) 1 (0.2) tion of patients with EDSS scores of 3.5 or less (83.5%) are in- Fatal TEAEs NA 2 (0.4)g dicative of a relatively low level of disability, and few 12-week CDA events were observed in both the ponesimod and teriflu- Serious adverse events (n ≥1 in either 49 (8.7) 46 (8.1) group by system organ class terms nomide groups, leading to a limitation in the ability to detect Nervous system disorders 9 (1.6) 6 (1.1) significant differences between treatment groups. This low rate Infections and infestations 7 (1.2) 4 (0.7) of CDA in both arms and the fact that teriflunomide is the only Gastrointestinal disorders 6 (1.1) 4 (0.7) approved oral DMT for RMS to demonstrate a significant ben- Neoplasms, benign, malignant, 6 (1.1) 3 (0.5) efit on 12-week confirmed disability progression vs placebo in and unspecified, including cysts 2 separate pivotal trials in relapsing-remitting MS4,5 suggests and polyps that OPTIMUM was underpowered to detect a difference within Surgical and medical procedures 5 (0.9) 1 (0.2) the 2-year treatment period. Interestingly, in the preplanned Injury, poisoning, and procedural 4 (0.7) 7 (1.2) exploratory analyses of brain volume change after 2 years in complications Kidney and urinary disorders 4 (0.7) 1 (0.2) the study, patients randomized to receive ponesimod had less brain volume loss than those receiving teriflunomide (a 0.34% Musculoskeletal and connective 3 (0.5) 4 (0.7) tissue disorders difference). A body of evidence supports a correlation at the Reproductive system and breast 3 (0.5) 6 (1.1) group level of brain volume loss with medium-term and long- disorders term disability progression, as reflected by the EDSS scores or (continued) neuropsychological assessments.31-33 Together, the effect of 564 JAMA Neurology May 2021 Volume 78, Number 5 (Reprinted) jamaneurology.com Downloaded From: https://jamanetwork.com/ on 06/28/2023 Ponesimod Compared With Teriflunomide in Patients With Relapsing Multiple Sclerosis Original Investigation Research ponesimod on fatigue and the reduction of brain volume loss, teria for liver abnormalities observed in OPTIMUM, com- shown against a drug with an established effect on brain vol- pared with the phase 2 ponesimod study, was likely because ume loss,34 suggests that ponesimod’s benefits are not re- of the more conservative definition of ULN, along with more stricted to suppressing relapses and focal lesions reflecting frequent testing. A systematic review of the available serious short-term events in the pathogenesis of MS but extend to the adverse event reports from patients discontinuing the drug dur- prevention of tissue damage accumulation. In accordance with ing OPTIMUM and the phase 2 study and its extension fol- ponesimod’s effects on the individual outcome measures, a low-up phase have not revealed any reports of rebound or higher proportion of patients receiving ponesimod remained severe relapses after ponesimod discontinuation.38 free of disease activity, both after applying the 3 established criteria for NEDA-3 (no relapse, no confirmed disease worsen- Limitations ing, and no new or enlarging MRI lesions) and after adding the There were a few limitations associated with this study. First, criterion of no brain volume change in excess of the upper limit there was low power to provide a robust evaluation of the obtained in healthy controls (NEDA-4).24,25 effect of ponesimod on disability accumulation vs an active Treatment discontinuation rates were similar in the 2 treat- comparator. Second, there were a limited number of patients ment groups. These were at the lower end compared with with secondary progressive MS recruited. Finally, the effect frequencies reported in other phase 3 studies in relapsing of the accelerated elimination procedure during the safety MS.4,6-8,35-37 More patients in the teriflunomide group discon- follow-up period could not be excluded. tinued treatment because of reasons of efficacy, consistent with the greater benefit of ponesimod observed across multiple ef- ficacy end points, whereas discontinuations attributable to ad- verse events or tolerability were more frequent in the ponesi- Conclusions mod group. Treatment discontinuations attributed to adverse In conclusion, OPTIMUM, as the first (to our knowledge) phase events in the ponesimod group were mainly by protocol- 3 study comparing 2 oral DMTs in RMS, showed that ponesi- mandated, study-specific discontinuation criteria associated mod is superior to teriflunomide, an approved oral DMT, on the with anticipated S1P1 modulator class effects on the respira- primary end point, ARR, and also on 2 of 3 secondary end points: tory system and macular edema and protocol-mandated study MRI activity and fatigue, a most debilitating MS symptom that specific discontinuation criteria. until now appears not to have been shown in a prospective In general, the pattern and nature of reported AEs were in phase 3 study to be effectively addressed by other DMTs. Su- line with previous experience with ponesimod13,19 and other periority of ponesimod was also shown on the exploratory end S1P receptor modulators.21 The 14-day up-titration regimen ap- points of brain volume loss and NEDA status. Ponesimod was plied in this trial resulted in an overall low incidence of first- well tolerated, and the safety results were in line with previ- dose heart rate and rhythm AESIs (2.1%). None of these day 1 ous observations in its phase 2 dose-finding study19 and find- events was reported as serious or leading to treatment discon- ings on other S1P receptor modulators in controlled studies,39 tinuation. The higher proportion of patients meeting cutoff cri- including their extensions and postmarketing observations. ARTICLE INFORMATION Germany (Hohlfeld); Icahn School of Medicine at Montalban, Pozzilli, Scherz, D'Ambrosio, Accepted for Publication: January 28, 2021. Mount Sinai, New York, New York (Lublin); Vaclavkova, Pirozek-Lawniczek, Kracker, Sprenger. Department of Neurology-Neuroimmunology, Statistical analysis: Burcklen, Hennessy, Scherz, Published Online: March 29, 2021. Multiple Sclerosis Center of Catalonia, Vall d’Hebron Vaclavkova, Kracker. doi:10.1001/jamaneurol.2021.0405 University Hospital, Barcelona, Spain (Montalban); Administrative, technical, or material support: Open Access: This is an open access article Sant’Andrea Multiple Sclerosis Centre, Sapienza Burcklen, Hennessy, D'Ambrosio, distributed under the terms of the CC-BY-NC-ND University of Rome, Rome, Italy (Pozzilli); Now with Pirozek-Lawniczek. License. © 2021 Kappos L et al. JAMA Neurology. Clinical Research Department, Galapagos GmbH, Supervision: Kappos, Burcklen, Hennessy, Pozzilli, Author Affiliations: Neurology and Research Basel, Switzerland (D'Ambrosio); DKD Helios Klinik Scherz, D'Ambrosio, Vaclavkova, Sprenger. Center for Clinical Neuroimmunology and Wiesbaden, Wiesbaden, Germany (Sprenger). Conflict of Interest Disclosures: In the last 3 years, Neuroscience Basel, Departments of Medicine, Author Contributions: Dr Kappos had full access to Dr Kappos’ institution (University Hospital Basel) Clinical Research, Biomedicine and Biomedical all the data in the study and takes responsibility for received steering committee, advisory board, Engineering University Hospital and University the integrity of the data and the accuracy of the consultancy fees, and/or support for educational of Basel, Basel, Switzerland (Kappos, Sprenger); data analysis. activities exclusively for research support at the Cleveland Clinic, Cleveland, Ohio (Fox); Actelion Concept and design: Kappos, Burcklen, Hennessy, Department from Actelion (step 2A), Allergan, Pharmaceuticals, Part of Janssen Pharmaceutical Pozzilli, D'Ambrosio, Linscheid, Vaclavkova, Almirall, Baxalta, Bayer Healthcare, Biogen, Companies, Allschwil, Switzerland (Burcklen, Sprenger. Celgene/Receptos, CSL-Behring, Desitin, Excemed, Hennessy, Scherz, D'Ambrosio, Linscheid, Acquisition, analysis, or interpretation of data: Eisai, Genzyme, Japan Tobacco, Merck, Minoryx, Vaclavkova, Pirozek-Lawniczek, Kracker); Kappos, Fox, Burcklen, Freedman, Havrdová, Novartis, Pfizer, F. Hoffmann–La Roche Ltd, Roche, Department of Medicine, University of Ottawa, Hennessy, Hohlfeld, Lublin, Montalban, Pozzilli, Sanofi Aventis, Santhera, and Teva and license fees The Ottawa Hospital Research Institute, Ottawa, Scherz, Linscheid, Vaclavkova, Pirozek-Lawniczek, for Neurostatus-UHB products. The research of the Ontario, Canada (Freedman); Department of Kracker, Sprenger. MS Center in Basel has been supported by grants Neurology, First Medical Faculty, Charles University, Drafting of the manuscript: Kappos, Burcklen, from Bayer, Biogen, Novartis, the Swiss MS Society, Prague, Czech Republic (Havrdová); Institute of Hennessy, Pozzilli, Scherz, Linscheid, Vaclavkova, the Swiss National Research Foundation, Clinical Neuroimmunology, Ludwig Maximilians Pirozek-Lawniczek. Innosuisse, the European Union, and Roche University Munich, Munich, Germany (Hohlfeld); Critical revision of the manuscript for important Research Foundations. Drs Burcklen, Hennessy, Munich Cluster of Systems Neurology (SyNergy), intellectual content: Kappos, Fox, Burcklen, Linscheid, Pirozek-Lawniczek, Vaclavkova, and Ludwig Maximilians University Munich, Munich, Freedman, Havrdová, Hennessy, Hohlfeld, Lublin, Kracker are employees of Actelion Pharmaceuticals, jamaneurology.com (Reprinted) JAMA Neurology May 2021 Volume 78, Number 5 565 Downloaded From: https://jamanetwork.com/ on 06/28/2023 Research Original Investigation Ponesimod Compared With Teriflunomide in Patients With Relapsing Multiple Sclerosis a Janssen Pharmaceutical company of Johnson & National Multiple Sclerosis Society outside the PhD, and Robert Achenbach, Janssen Global Johnson. Dr Hennessy holds stock in Johnson & submitted work. Dr Sprenger’s institution has Services LLC. These individuals were compensated. Johnson, Novo Nordisk, Arena Pharmaceuticals, received honoraria for speaking and consultation Additional Information: See eAppendix 2, and Galapagos and reported being a salaried from Actelion, Biogen Idec, Desitin, Eli Lilly, eTable 5, and eTable 6 in Supplement 1 for details employee of Actelion Pharmaceuticals Ltd during Janssen, Johnson & Johnson, Novartis, Roche, on the independent data monitoring committee, the conduct of the study. Drs Burcklen, Vaclavkova, Sanofi Genzyme, Electrocore, Merck, and Teva. ophthalmology safety board, major adverse and Kracker hold stock in Johnson & Johnson. Dr Pozzilli has served on scientific advisory boards cardiovascular event adjudication committee, Dr D'Ambrosio was an employee of Actelion for Novartis, Merck, Biogen, Sanofi, Genzyme, Teva, MRI reading center, and investigators. In addition, Pharmaceuticals, a Janssen Pharmaceutical and Actelion; received funding for travel and the data-sharing policy of Janssen Pharmaceutical company of Johnson & Johnson, during the speaker honoraria from Biogen, Teva, Sanofi Companies of Johnson & Johnson is available at conduct of the study. Dr Scherz is an employee of Genzyme, Actelion, and Novartis; and received https://www.janssen.com/clinical-trials/ Actelion Pharmaceuticals, a Janssen research support from Biogen, Teva, Novartis, and transparency. As noted on this site, requests for Pharmaceutical company of Johnson & Johnson, Genzyme. Dr Lublin has received funding for access to the study data can be submitted through and a former employee of Novartis Pharma AG; research from Novartis, Actelion, Biogen, Sanofi, the Yale Open Data Access Project site at https:// she also holds stock in Johnson & Johnson. National Multiple Sclerosis Society, the National yoda.yale.edu/. Dr Freedman reported having received personal Institutes of Health, and Brainstorm Cell fees from Bristol Myers Squibb/Celgene during Therapeutics; has had consulting agreements or REFERENCES the conduct of the study; honoraria from Actelion, participated in advisory boards or data safety Atara Biotherapeutics, Bayer Healthcare, Biogen monitoring boards for Biogen, EMD Serono, 1. Thompson AJ, Baranzini SE, Geurts J, Hemmer B, Idec, Bristol Myers Squibb/Celgene, Chugai, Clene Novartis, Teva, Actelion/Janssen, Sanofi/Genzyme, Ciccarelli O. Multiple sclerosis. Lancet. 2018;391 Nanomedicine, EMD Canada, Genzyme, Hoffman Acorda, Roche/Genentech, MedImmune/Viela Bio, (10130):1622-1636. doi:10.1016/S0140-6736(18) La–Roche Ltd, MedDay, Merck Serono, Novartis, Receptos/Celgene, Bristol Myers Squibb, TG 30481-1 Sanofi-Aventis/Sanofi Genzyme, and Teva Canada Therapeutics, Medday, Atara Biotherapeutics, 2. Dobson R, Giovannoni G. 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Placebo-controlled phase 3 membership, and/or speaker's honoraria from study; collection, management, analysis, and study of oral BG-12 or glatiramer in multiple Biogen, Novartis, Roche, Sanofi, and Actelion and interpretation of the data; preparation, review, or sclerosis. N Engl J Med. 2012;367(12):1087-1097. board membership for Celgene and Merck during approval of the manuscript; and decision to submit doi:10.1056/NEJMoa1206328 the conduct of the study, as well as advisory board the manuscript for publication. 8. Gold R, Kappos L, Arnold DL, et al; DEFINE membership and speaker's honoraria from Biogen, Meeting Presentation: Parts of the results of this Study Investigators. 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The authors thank of natalizumab in patients with relapsing multiple boards of clinical trials in the past years with Lisa Ford, MD, a paid employee of Janssen Research sclerosis: subgroup analyses of AFFIRM and Actelion, Alexion, Bayer, Biogen, Celgene, EMD & Development LLC, for her critical scientific and SENTINEL. J Neurol. 2009;256(3):405-415. Serono, Genzyme, Immunic, Medday, Merck, medical review and editorial contributions. Writing doi:10.1007/s00415-009-0093-1 Mylan, Nervgen, Novartis, Roche, Sanofi-Genzyme, assistance was provided by Anupama Singh, CMPP, 11. Ontaneda D, Tallantyre E, Kalincik T, Teva Pharmaceutical, TG Therapeutics, Excemed, and Shweta Pitre, CMPP, SIRO Clinpharm Pvt Ltd, Planchon SM, Evangelou N. Early highly effective Multiple Sclerosis International Federation, and funded by Janssen Global Services. 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