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Efficacy and Safety of Teriflunomide in Chinese Patients with Relapsing Forms of Multiple Sclerosis

A Subgroup Analysis of the Phase 3 TOWER Study

Qiu, Wei1,; Huang, De-Hui2,; Hou, Shi-Fang3,; Zhang, Mei-Ni4; Jin, Tao5; Dong, Hui-Qing6; Peng, Hua7; Zhang, Chao-Dong8; Zhao, Gang9; Huang, Yi-Ning10; Zhou, Dong11; Wu, Wei-Ping2; Wang, Bao-Jun12; Li, Ji-Mei13; Zhang, Xing-Hu14; Cheng, Yan15; Li, Hai-Feng16,; Li, Ling17; Lu, Chuan-Zhen18; Zhang, Xu19; Bu, Bi-Tao20; Dong, Wan-Li21; Fan, Dong-Sheng22; Hu, Xue-Qiang1,; Xu, Xian-Hao3, for the TOWER Trial Chinese Group

doi: 10.4103/0366-6999.246067
Original Article
Free

Background: Disease-modifying therapy is the standard treatment for patients with multiple sclerosis (MS) in remission. The primary objective of the current analysis was to assess the efficacy and safety of two teriflunomide doses (7 mg and 14 mg) in the subgroup of Chinese patients with relapsing MS included in the TOWER study.

Methods: TOWER was a multicenter, multinational, randomized, double-blind, parallel-group (three groups), placebo-controlled study. This subgroup analysis includes 148 Chinese patients randomized to receive either teriflunomide 7 mg (n = 51), teriflunomide 14 mg (n = 43), or placebo (n = 54).

Results: Of the 148 patients in the intent-to-treat population, adjusted annualized relapse rates were 0.63 (95% confidence interval [CI]: 0.44, 0.92) in the placebo group, 0.48 (95% CI: 0.33, 0.70) in the teriflunomide 7 mg group, and 0.18 (95% CI: 0.09, 0.36) in the teriflunomide 14 mg group; this corresponded to a significant relative risk reduction in the teriflunomide 14 mg group versus placebo (−71.2%, P = 0.0012). Teriflunomide 14 mg also tended to reduce 12-week confirmed disability worsening by 68.1% compared with placebo (hazard ratio: 0.319, P = 0.1194). There were no differences across all treatment groups in the proportion of patients with treatment-emergent adverse events (TEAEs; 72.2% in the placebo group, 74.5% in the teriflunomide 7 mg group, and 69.8% in the teriflunomide 14 mg group); corresponding proportions for serious adverse events were 11.1%, 3.9%, and 11.6%, respectively. The most frequently reported TEAEs with teriflunomide versus placebo were neutropenia, increased alanine aminotransferase, and hair thinning.

Conclusions: Teriflunomide was as effective and safe in the Chinese subpopulation as it was in the overall population of patients in the TOWER trial. Teriflunomide has the potential to meet unmet medical needs for MS patients in China.

Trial Registration: ClinicalTrials.gov, NCT00751881; https://clinicaltrials.gov/ct2/show/NCT00751881?term=NCT00751881&rank=1

1Department of Neurology, The Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, Guangdong 510000, China

2Department of Neurology, Chinese People's Liberation Army General Hospital, Beijing 100853, China

3Department of Neurology, Beijing Hospital, Beijing 100730, China

4Department of Neurology, The First Hospital of Shanxi Medical University, Taiyuan, Shanxi 030001, China

5Department of Neurology, The First Hospital of Jilin University, Changchun, Jilin 130012, China

6Department of Neurology, Xuanwu Hospital, Capital Medical University, Beijing 100053, China

7Department of Neurology, Shanghai Chang Zheng Hospital, Shanghai 200003, China

8Department of Neurology, The First Hospital of China Medical University, Shenyang, Liaoning 110000, China

9Department of Neurology, Fourth Military Medical University, Xi'an, Shaanxi 710001, China

10Department of Neurology, Peking University First Hospital, Beijing 100034, China

11Department of Neurology, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, China

12Department of Neurology, Baotou Central Hospital, Baotou, Inner Mongolia 014040, China

13Department of Neurology, Beijing Friendship Hospital, Capital Medical University, Beijing 100000, China

14Department of Neurology, Beijing Tian Tan Hospital, Capital Medical University, Beijing 100050, China

15Department of Neurology, Tianjin Medical University General Hospital, Tianjin 300052, China

16Department of Neurology, The Affiliated Hospital of Qingdao University, Qingdao, Shandong 266003, China

17Department of Neurology, Hebei General Hospital, Shijiazhuang, Hebei 050051, China

18Department of Neurology, Hua Shan Hospital of the Shanghai Fudan University Medical College, Shanghai 200040, China

19Department of Neurology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325000, China

20Department of Neurology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430030, China

21Department of Neurology, The First Affiliated Hospital of Soochow University, Suzhou, Jiangsu 215000, China

22Department of Neurology, Beijing Hospital, National Center of Gerontology, Beijing 100083, China

Address for correspondence: Prof. Xian-Hao Xu, Department of Neurology, Beijing Hospital, Beijing 100730, China E-Mail: xuxianhao99@163.com Prof. Xue-Qiang Hu, Department of Neurology, The Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, Guangdong 510000, China E-Mail: hxq245600@qq.com

Wei Qiu, De-Hui Huang, and Shi-Fang Hou contributed equally to this work.

Hai-Feng Li now works at Qilu Hospital of Shandong University, Jinan, Shandong 250012, China.

Some of the data from this analysis were presented previously at the Annual Scientific Meeting of the Australian and New Zealand Association of Neurologists (ANZAN), May 09-12, 2017; Gold Coast, QLD, Australia.

Received August 01, 2018

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INTRODUCTION

Multiple sclerosis (MS) is one of the most common neurological diseases in young adults and is the leading cause of nontraumatic disability in young and middle-aged adults.[1] The disease has a major physical, psychological, social, and financial impact on patients and their families and poses a substantial burden to health-care systems worldwide. In 2013, the global prevalence of MS was estimated as 33/100,000; the estimated median prevalence was greatest in North America (140/100,000) and Europe (108/100,000) and considerably lower in China (≤5/100,000).[2] It was defined as a rare disease in China in May 2018. However, with improving disease awareness and diagnostic techniques in China, the prevalence of MS is expected to increase markedly.

Clinically, MS manifests as neurological deficits in the central nervous system (CNS) that demonstrates dissemination in space and time. Diagnosis is made by clinical features and supportive magnetic resonance imaging (MRI), with the evaluation of cerebral spinal fluid according to the 2017 revised McDonald criteria.[3] “Relapsing MS” (RMS) encompasses all forms involving relapses, and these forms are the most frequent presentation.

Therapeutic goals in MS, as categorized according to the 2015 European guidelines for the development of drugs for MS,[4] include the following: (i) treatment of acute relapses to shorten the duration and/or severity of symptoms and/or prevent sequelae; (ii) modification of the natural history of the disease, by preventing or modifying relapses and/or by preventing or delaying disability accumulation through the use of disease-modifying therapies (DMTs); and (iii) improvement of an apparently stable residual disability.

Many DMTs are currently approved in various regions worldwide for the treatment of RMS. These DMTs include alemtuzumab, beta-interferons, dimethyl fumarate, fingolimod, glatiramer acetate, mitoxantrone, natalizumab, ocrelizumab, and teriflunomide. In most regions, beta-interferons and glatiramer acetate have been used widely, both of which can reduce the frequency of relapse by approximately 30% over 2–3 years.[5] However, beta-interferons and glatiramer acetate need to be administered by injection, which makes it difficult for some patients to tolerate. Moreover, missed dosages of interferon therapy are associated with disease progression. Most patients treated with beta-interferons and glatiramer acetate discontinued their treatment within the first 2 years due to a lack of efficacy or side effects such as flu-like symptoms and depression.[6] In addition, glatiramer acetate is not available commercially in China, and the availability of more convenient, noninjectable DMTs, with relatively favorable efficacy, safety, and tolerability profiles, would help to address the current unmet needs of Chinese patients with RMS.

Teriflunomide, an orally active DMT that inhibits lymphocyte proliferation, is approved in more than 70 countries for the treatment of relapsing-remitting MS. Teriflunomide selectively and reversibly inhibits dihydro-orotate dehydrogenase, an enzyme in the de novo synthesis pathway of pyrimidines,[7] resulting in reduced proliferation of peripheral T- and B-lymphocytes, and hence reduced numbers of lymphocytes crossing the blood–brain barrier and causing CNS damage. Teriflunomide appears to induce a shift from pro-inflammatory to regulatory T-cell subtypes, with no detrimental effect on cytokine and proliferative responses. Moreover, teriflunomide maintains the levels of CD4+ T-cell receptor clones in MS patients similar to levels noted in healthy individuals; this effect has not been demonstrated with other DMTs, such as dimethyl fumarate, interferon-β, or mitoxantrone.[8]

The selection of two doses of teriflunomide, 7 mg and 14 mg, for use in the current analysis was based on previous efficacy and safety data for these two doses from a phase 2, 36-week, double-blind, placebo-controlled study[9] and its long-term extension.[10] Importantly, data from the global, phase 3 Teriflunomide Oral in People with RMS (TOWER; ClinicalTrials.gov Identifier: NCT00751881) study of teriflunomide have been published previously and revealed statistically significant relative risk reductions for teriflunomide 14 mg versus placebo in annualized relapse rate (ARR; −36.3%, P = 0.0001) and 12-week confirmed disability worsening (CDW; −31.5%; P = 0.0442).[11] Importantly, the primary objective of the current analysis was to assess the efficacy and safety of two teriflunomide doses (7 mg and 14 mg) specifically in the subgroup of Chinese patients in the TOWER study.

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METHODS

Ethical approval

The study was approved by the relevant independent 32 Ethics Committees and Institutional Review Boards, 15 of which received ethical approval from the main center (Beijing Hospital; approval number: 2009022), and 17 centers received ethical approval from their respective sub-centers, and all patients provided written informed consent before entry into the study. The study was done in accordance with the International Conference on Harmonisation Guidelines for Good Clinical Practice and the Declaration of Helsinki.

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Study design

The methodology of the overall TOWER trial has been described previously.[11] Briefly, TOWER was a multicenter, multinational, randomized, double-blind, parallel-group (three groups), placebo-controlled study. Patients were randomly assigned to receive either teriflunomide 7 mg, teriflunomide 14 mg, or placebo, in a ratio of 1:1:1.

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Study participants

Inclusion and exclusion criteria for the overall TOWER study population have been described previously.[11] Briefly, eligible patients were aged 18–55 years and had RMS (meeting 2005 McDonald criteria)[12] and an Expanded Disability Status Scale (EDSS) score ≤5.5 at screening. Patients also had at least one relapse in 12 months before randomization or at least two relapses in 24 months before randomization.

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Objectives

The primary objective of the current subgroup analysis was to assess the efficacy of both teriflunomide doses (7 mg and 14 mg), relative to placebo, on the frequency of MS relapses in Chinese patients with RMS. The key secondary objective was to assess the efficacy of both teriflunomide doses, relative to placebo, on CDW in Chinese patients with RMS. Other secondary objectives were to evaluate the effects of teriflunomide versus placebo on fatigue and health-related quality of life and to assess the safety and tolerability profiles of teriflunomide.

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Study assessments

The primary efficacy variable for this study was the ARR, defined as the number of relapses per patient-year in patients with RMS. A relapse was defined as the appearance of a new clinical sign/symptom or clinical worsening of a previous sign/symptom (one that had been stable for at least 30 days) that persisted for a minimum of 24 h in the absence of fever.

Other endpoints included 12-week CDW, time to first relapse, proportion of patients free from relapses, proportion of patients free of CDW, and change from baseline in EDSS score. All study assessments and their evaluation time points have been defined previously.[11]

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Statistical analysis

No specific sample size or power calculations were considered for patients enrolled in China alone, and sample size and power considerations for the overall TOWER study population have been described previously.[11] Continuous variables were expressed as mean ± standard deviation (SD), and categorical variables were expressed as number (percent). The modified intention-to-treat population (all randomly assigned patients who received at least one dose of study drug or placebo) was used for all efficacy analyses. All inferential statistical analyses were done at the two-sided 5% level of significance. A Poisson regression model with robust error variance, including factors for treatment and baseline EDSS scores (stratified by scores ≤3.5 or >3.5), was used to analyze ARR. Two-sided 95% confidence intervals (CIs) of the rate ratio as well as risk difference are provided for the comparisons of each active treatment versus placebo. The estimated relapse rate and its 2-sided 95% CIs and the gross estimate of ARR are provided for each treatment group. The primary endpoint was analyzed using the generalized estimating equation (GEE) model instead of the regular Poisson model, since the GEE estimator was robust against violation of the correlation structure and the distributional assumptions. The time to disability progression was analyzed using the log-rank test with time to disability progression as the dependent variable, the treatment group as test variable, and baseline EDSS strata as stratification factors. The hazard ratio (HR) estimates for each teriflunomide treatment group versus placebo were estimated using a Cox regression model with treatment group and baseline EDSS strata as covariates. The Kaplan-Meier method was used to estimate the time to disability progression rate specific to each group, based on the ITT population. Kaplan-Meier graphs were generated and quartiles and point probabilities were calculated. Interval estimates were calculated using 95% point-wise CIs. All summaries and statistical analyses were carried out using SAS version 9.2 (SAS Institute Inc., Cary, NC, USA).

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RESULTS

Of the 1165 patients included in the intent-to-treat (ITT) TOWER population, 148 (12.7%) were Chinese. In this subgroup, a total of 218 Chinese patients from 32 centers were screened and 148 were randomized: 54 to placebo, 51 to teriflunomide 7 mg, and 43 to teriflunomide 14 mg [Figure 1]. Among the randomized patients, 57 did not complete treatment. Discontinuation rates were similar among the three groups: placebo group 40.7%, teriflunomide 7 mg group 33.3%, and teriflunomide 14 mg group 41.9%. The most frequent cause for discontinuation was adverse events (AEs; 23 patients: 6 in the placebo group, 7 in the teriflunomide 7 mg group, and 10 in the teriflunomide 14 mg group), other (18 patients; many of these resulted from patient decision), and lack of efficacy (9 patients). No randomized patients were excluded from the ITT population. The median duration of study treatment was similar across all three groups: placebo, 469 (range 10–847) days; teriflunomide 7 mg, 506 (1–807) days; and teriflunomide 14 mg, 458 (7–762) days. Demographic and baseline characteristics of the Chinese population were comparable to the overall population [Table 1] with two exceptions: Chinese patients had a shorter time since first symptoms of MS compared with the overall population and fewer Chinese patients had received another DMT therapy within the last 2 years compared with the overall population.

Figure 1

Figure 1

Table 1

Table 1

Of the 148 patients in the ITT population, adjusted ARRs using the Poisson regression model were 0.63 (95% confidence interval [CI]: 0.44, 0.92) in the placebo group, 0.48 (95% CI: 0.33, 0.70) in the teriflunomide 7 mg group, and 0.18 (95% CI: 0.09, 0.36) in the teriflunomide 14 mg group [Table 2]. These results revealed a significant reduction of relative risk in the teriflunomide 14 mg group (71.2%, P = 0.0012), while no statistically significant relative risk reduction was observed in the teriflunomide 7 mg group (24.0%, P = 0.3108). The effect of teriflunomide 14 mg on ARR was independent of the specific subgroups examined (i.e., gender, age <38 vs. ≥38 years, baseline EDSS score ≤3.5 vs. >3.5, and number of relapses in the last 1 or 2 years before randomization; data not shown).

Table 2

Table 2

The estimated percentages of patients free of 12-week CDW at week 48 using the Kaplan–Meier method were 86.5% in the placebo group, 83.7% in the teriflunomide 7 mg group, and 94.1% in the teriflunomide 14 mg group [Table 2]. Up to week 48, compared with placebo, the risk of 12-week CDW was reduced and the hazard ratio was 0.319 (95% CI: 0.068, 1.505) with teriflunomide 14 mg [Figure 2].

Figure 2

Figure 2

The proportion of patients with treatment-emergent AEs (TEAEs) was similar across all three groups (72.2% in the placebo group, 74.5% in the teriflunomide 7 mg group, and 69.8% in the teriflunomide 14 mg group) [Table 3]. The incidence of treatment-emergent serious AEs was similar between the placebo and teriflunomide 14 mg groups (11.1% and 11.6%, respectively) but was lower in the teriflunomide 7 mg group (3.9%). TEAEs leading to permanent treatment discontinuation were reported with higher frequency in teriflunomide-treated patients than placebo recipients (13.7% in the teriflunomide 7 mg group, 23.3% in the teriflunomide 14 mg, and 9.3% in placebo group). Two patients died during the study: one patient in the placebo group died due to respiratory infection and one patient in the teriflunomide 14 mg group who had a 2-year history of depression died from suicide. However, neither of these events was considered related to study treatment. Frequencies of infections and infestations in both teriflunomide groups were similar to those in the placebo group. Raised alanine aminotransferase (ALT; >1 × the upper limit of normal [ULN]) occurred more often in the teriflunomide groups than in the placebo group, while the incidence of elevated ALT levels (>5 × ULN) was similar among the study groups. No patients met Hy's law criteria. None of the patients had hypertension, and only one patient (in the placebo group) developed peripheral neuropathy [Table 3].

Table 3

Table 3

As shown in Table 3, TEAEs (Medical Dictionary for Regulatory Activities version 15.0; preferred terms) were neutropenia (11.8% in the teriflunomide 7 mg group, 20.9% in the teriflunomide 14 mg group, and 3.7% in the placebo group), increased ALT (15.7% in the teriflunomide 7 mg group, 14.0% in the teriflunomide 14 mg group, and 7.4% in the placebo group), hair thinning (3.9% in the teriflunomide 7 mg group, 14.0% in the teriflunomide 14 mg group, and none in the placebo group), reduced white blood cell count (7.8% in the teriflunomide 7 mg group, 7.0% in the teriflunomide 14 mg group, and 1.9% in the placebo group), and headache (5.9% in the teriflunomide 7 mg group, 2.3% in the teriflunomide 14 mg group, and none in the placebo group). Conversely, nasopharyngitis, urinary tract infection, constipation, and pruritus were more common in the placebo group than in the teriflunomide groups [Table 3].

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DISCUSSION

To the best of our knowledge, the TOWER study was the first placebo-controlled, international confirmatory study of teriflunomide efficacy and safety in MS that included a Chinese subgroup.[11] The number of Chinese subgroup patients enabled meaningful analyses and data interpretation.

ARR is a more sensitive endpoint than CDW, for which lack of sensitivity is a well-recognized challenge in clinical trials. The demonstration of teriflunomide efficacy in our analysis is based primarily on ARR. Comparison of teriflunomide 14 mg with placebo for the Chinese subgroup revealed a statistically significant relative risk reduction in ARR of 71.2% (P = 0.0012), which is consistent with the findings for the overall TOWER population.[11] The high level of statistical significance reached for ARR in our analysis (P = 0.0012) confirms the marked extent of teriflunomide efficacy. Teriflunomide efficacy regarding secondary endpoints was also similar in the Chinese subpopulation and overall TOWER study population [Table 2].

For both ARR and disability worsening, effect sizes in the Chinese subpopulation were numerically greater than those for the overall TOWER population, that is, in the teriflunomide 14 mg versus placebo group, ARR was reduced by 71.2% in Chinese patients and by 36.3% in the overall population. One possible explanation for differences in the efficacy of teriflunomide between the Chinese subpopulation and the overall TOWER population may be due to differences in plasma teriflunomide concentrations. Based on a population pharmacokinetic analysis, with data pooled from Asian patients (90/121 were Chinese) and non-Asian patients (n = 1687), the model predicted a median value for the area under the plasma teriflunomide concentration versus time curve (0–24 h) in Chinese patients, which was 51.5% higher than that in non-Asian patients (data on file; Sanofi China). Polymorphisms in the breast cancer resistance protein gene (BCRP; also known as ATP-binding cassette subfamily G member 2 [ABCG2]) may contribute to moderately higher teriflunomide exposure in Asian patients. Indeed, Chinese patients have a higher frequency of the allelic gene ABCG2 (single-nucleotide polymorphism rs2231142) than non-Asian patients, which results in a less active form of BCRP,[13] a protein that functions as an efflux transporter that may limit teriflunomide transport in the gastrointestinal tract, liver, and brain and that may also be involved in enterohepatic recycling. In addition, the differences in patients' characteristics between Chinese patients and the overall population may also have played a role in efficacy. Chinese patients had shorter disease duration compared to the overall population, which may suggest the benefits of earlier treatment.

Besides consistency with data from the overall TOWER trial,[11] findings from our analysis endorse results from the earlier phase 3 TEMSO trial,[14] in which teriflunomide 14 mg significantly reduced ARR and the risk of 12-week CDW; although teriflunomide 7 mg also significantly reduced ARR, it did not significantly influence disability progression. Interestingly, the study designs of the TEMSO and TOWER trials were relatively similar, such that pooled data analysis was possible: teriflunomide 14 mg significantly reduced ARR by 34% and significantly reduced the proportion of patients with sustained CDW at 108 weeks.[15] A recent meta-analysis of seven randomized controlled trials in patients with RMS reported that teriflunomide 14 mg versus placebo significantly reduced disability progression, and the ARR associated with investigator-assessed sequelae.[16]

Post hoc data from TEMSO also revealed that teriflunomide 14 mg versus placebo significantly reduced the annualized rate of neurologic sequelae (an increase in EDSS/Functional Status Score ≥30 days after relapse) by 36%. A dose-dependent decrease (teriflunomide vs. placebo) in the frequency of relapses requiring hospitalization was also noted.[17] Extension trials following on from phase 2 and 3 evaluations of teriflunomide also demonstrated that long-term efficacy of the drug was maintained for up to 9 years.[1018]

In our analysis, both doses of teriflunomide were well tolerated by Chinese patients and with a manageable safety profile which is consistent with that for the overall TOWER population. There were no new or specific safety concerns in the Chinese subpopulation, and the total incidence of TEAEs was slightly lower in Chinese patients (72.3%) than in the overall population (85.1%). The TEAE incidence was similar between the 7 mg group and 14 mg group in the Chinese and overall populations. For treatment-emergent serious AEs, the incidence was similar in the placebo and teriflunomide 14 mg groups in the Chinese population (11.1% and 11.6%, respectively) and overall population (12.0% and 12.0%, respectively); however, the incidence in the teriflunomide 7 mg group was lower in the Chinese subpopulation (3.9%) than in the overall population (13.0%). TEAEs leading to permanent treatment discontinuation showed a similar pattern in the Chinese and overall populations, with higher frequencies in the teriflunomide groups (13.0–23.3%) than the placebo group (6.0–9.3%).

Compared with the placebo group, the most frequently reported TEAEs with the higher incidence in the teriflunomide treatment groups were neutropenia, elevated ALT, and hair thinning. similar trends were evident in the overall population. Furthermore, in both the Chinese subpopulation and overall TOWER population, ALT elevations >2 × ULN and >3 × ULN were more common with teriflunomide 14 mg than in the placebo group. The incidence of ALT elevations >5 × ULN was well balanced between the three study groups in both the Chinese and overall populations. Clinically significant elevations in ALT >3 × ULN were generally reversible in all study groups, even during treatment, and there were no cases of Hy's law in the Chinese subpopulation. Altogether, the safety profile of teriflunomide in the Chinese subpopulation was similar to profiles in the overall TOWER population, in previous studies,[1014] and in a large pooled analysis of safety and tolerability data collated over >12 years.[19]

TOWER did not include any MRI endpoints, which might be regarded as a limitation of the study. However, data from the phase 2 trial[9] and TEMSO trial[14] confirmed that teriflunomide significantly and dose dependently reduced MRI markers of disease activity and burden.[20] Brain volume loss was also reduced significantly in patients treated with teriflunomide in a reanalysis of the TEMSO MRI data set employing the Structural Image Evaluation using Normalisation of Atrophy method.[21] An additional limitation is the high discontinuation rate, although the rate was similar to that reported in other studies of oral DMTs in RMS.[2223]

In conclusion, teriflunomide was as effective, safe, and tolerable in the Chinese subpopulation as it was in the overall population of patients with RMS in the TOWER trial. The best benefit–risk ratio was attained with teriflunomide at a dose of 14 mg once daily in both the Chinese subgroup and the overall population. Thus, teriflunomide has the potential to meet unmet medical needs for MS patients in China.

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Financial support and sponsorship

Nil.

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Conflicts of interest

This study was funded by Sanofi (China) Investment Co., Ltd.

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Acknowledgments

The authors thank the study participants and their families and caregivers. We thank the following investigators and institutions: Jiang Wu, The First Hospital of Jilin University; Biao Chen, Xuanwu Hospital Capital Medical University; Zhong-Xin Zhao, Shanghai Chang Zheng Hospital; Zhi-Bin Chen, The Affiliated Hospital of Hainan Medical University; Lei Wang, The Second Artillery General Hospital of People's Liberation Army; En Xu, The Second Affiliated Hospital of Guangzhou Medical University; Qing Di, Nanjing Brain Hospital Affiliated to Nanjing Medical University; Xing-Yue Hu, Sir Run Run Shaw Hospital, College of Medicine, Zhejiang University; Tong Zhang, China Rehabilitation Research Center, Beijing Boai Hospital; Jian-Zhong Bi, The Second Hospital of Shandong University; Yun Xu, Gulou Hospital Affiliated to Medical College of Nanjing University; Zheng-Yi Li, The First Affiliated Hospital of Xi'an Jiaotong University; Xin Li, The Second Hospital of Tianjin Medical University.

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Edited by: Qiang Shi

Keywords:

Chinese Patients; Efficacy; Phase 3; Relapsing Multiple Sclerosis; Safety; Teriflunomide; TOWER

© 2018 Chinese Medical Association