Real world research adds new evidence!

*Only for medical professionals' reference to read without fear of real-world tests, international and Chinese studies have submitted perfect answers.

Multiple sclerosis (MS) is an immune-mediated disease characterized by inflammatory demyelination of the central nervous system.
The main population is the young and middle-aged.
The recurrence rate and disability rate are relatively high.
The heavy economic pressure has been highly valued by governments and medical institutions in various countries.

Initiating disease modification therapy (DMT) during remission can reduce the frequency of patient relapses, reduce the degree of deterioration, delay the natural progression of the disease, and improve the prognosis of patients.

Among them, teriflunomide has been unanimously recommended by domestic and foreign guidelines [1-3], and it is the first-line DMT drug for the treatment of MS.

So, what is the performance of teriflunomide in the treatment of MS? This article will explore the benefits that teriflunomide can bring to patients through a series of real-world studies of teriflunomide.

Before analyzing the effects of teriflunomide, let's discuss what studies we can use to understand the drug.

From "ideal" to "reality", we can obtain evidence that is more in line with clinical reality.
At present, we understand the effectiveness and safety of drugs mainly through real world studies (RWS) and randomized controlled studies (RCT).

In recent years, the clinical reference value of RCT and RWS has been a topic of endless debate.

So what is the difference between the two? Generally speaking, RCT screens the patient population according to strict criteria, and evaluates the efficacy and safety of the drug by observing the therapeutic effect of the drug on the test patient.

Although RCT is the "gold standard" for evaluating the efficacy of new drugs and interventions that are not yet on the market, it can only provide information on the results of interventions in an "ideal" environment.
However, in the real clinical environment, there are medications for special populations, combination medications, and long-term medications.
There are many complicated issues such as the safety test of use.

It is obvious that RCT often cannot fully represent the efficacy and safety of drugs in real clinical use scenarios.

Therefore, as a supplement, we need to use RWS to understand a drug more comprehensively.

The biggest difference between RWS and RCT is that RWS is based on the real clinical scene itself, and does not intervene in the clinical treatment of patients.
It refers to a larger sample size (covering a larger representative population of subjects) and according to patients The actual condition and willingness of the patient instead of randomly selecting treatment measures, carrying out long-term evaluation, and focusing on meaningful outcome treatment, to further evaluate the external effectiveness and safety of intervention measures [4].

Table 1: The main scientific problems solved by real-world research [5] Therefore, compared with RCT, RWS is not only closer to the real clinical scene, but also can include a larger sample size, and conduct a longer time and more perspective on drugs.
Observed.

A larger sample size, longer time, and more observation angles not only provide more evidence for the efficacy of the drug, but more importantly, it can more fully expose the potential risks of the drug.

For example, the famous thalidomide incident was a tragedy caused by the hasty launch of the drug without long and full research.

Therefore, the conclusions drawn from a large sample of RWS are usually more instructive for the clinical application of drugs [6-8].

Table 2: Comparison between traditional clinical trials and real-world research (taking drug evaluation as an example) [5] After understanding the difference between RCT and RWS, let us return to the opening question, the performance of teriflunomide in real-world research How about it? Let us find out! It has been listed abroad for nearly 10 years, without fear of real-world tests, and accumulated rich data.
Teriflunomide was launched in the United States in 2012.
In the past 10 years of clinical application, its efficacy in the treatment of MS and patients’ high satisfaction with the treatment have increased.
It was demonstrated in a RWS: Teri-Pro study [9]: A real-world phase IV study (n=1000) that mainly explored the outcome of patient reports including treatment satisfaction, using the Drug Therapy Satisfaction Questionnaire (TSQM, including Effectiveness, adverse reactions, convenience, and overall satisfaction) when evaluating, MS patients received teriflunomide treatment for 48 weeks after the average TSQM overall satisfaction score is at a high level (68.
2 points), other treatment satisfaction if effective Sex and other scores are also relatively high (66.
3-90.
4 points).

A subgroup analysis showed that patients who had previously taken other DMT drugs and then switched to teriflunomide had an improvement in treatment satisfaction compared to baseline at the 48th week of treatment.

For example, among 74 patients who had previously received dimethyl fumarate therapy, after switching to teriflunomide therapy, their satisfaction with drug effectiveness, adverse reactions, and convenience was significantly improved compared with baseline; Among the 29 patients who had previously received fingolimod therapy, after switching to teriflunomide therapy, the patients' satisfaction with the convenience of taking the drug increased significantly.

Figure 1: Patients who previously took other DMT drugs switched to teriflunomide treatment satisfaction (ES: effect size, effect size; NS: nonsignficant, no significant difference) TAURUS-MS study [10]: a multicenter A prospective, longitudinal observational study.
1128 MS patients were enrolled from 307 centers in Germany, and 75.
2% of the patients had received DMT in the past.

The study showed that compared with the same period before enrollment, the annual recurrence rate (ARR) of patients after receiving teriflunomide treatment was halved; for patients who had previously received MS treatment, after switching to teriflunomide treatment, treatment satisfaction obvious improvement.

Figure 2: Changes in the annual recurrence rate after 24 months of treatment (left) and changes in the TSQM-9 score after switching to teriflunomide in patients previously treated with DMT (right) Teri-FAST study [11] : Fatigue is one of the common symptoms of MS patients, which can have a significant impact on the work and life of patients.

The Teri-FAST study evaluated the performance of teriflunomide in improving patient fatigue symptoms.

This is a 2-year prospective, observational study.
The study showed that the EMIF-SEP fatigue score of patients treated with teriflunomide decreased by 1.
54 points from the baseline in the second year, and the average score was 31.
3.
In theory There was a significant difference (P <0.
0001) compared with the fatigue score of untreated patients (a 9-point increase from baseline).

From baseline to the second year of taking teriflunomide, the patient's fatigue score remained stable.

Teri-LIFE and TACO study: Controlling MS symptoms and slowing down the progression of the disease are important for patients to maintain a good physical and mental state.
The Teri-LIFE study evaluated the effects of teriflunomide on both physical function and mental state.
The treatment effect of MS patients [12].

The study used the SF-36 scale to score the physical function and mental state of patients during treatment with teriflunomide.

The results showed that the patient's physical function and mental state score remained relatively stable during the 24 months of follow-up.

Table 3: Changes in SF-36 physical function and mental status scores of patients at baseline and at 6, 12, and 24 months.
The TACO study [13] also obtained similar results.
The study showed that patients were treated with teriflunomide 24 During the month, the quality of life was stable and the disease activity was low.

Safety data analysis of multiple RWS studies: MS patients need to take long-term treatment drugs during the remission period, so the adverse drug reactions have become a key factor in determining the patient's treatment experience.

If the patient cannot tolerate the adverse effects of the drug, it is very likely that the patient will not be able to follow the doctor's advice for a long time to take the drug, which will affect the treatment effect.

RWS is based on real clinical treatment scenarios.
The adverse effects of drugs in RWS and the impact on patients can reflect the real clinical situation better than RCT.

The aforementioned Teri-Pro, TERI-LIFE and other studies [9-12] also observed the adverse effects of teriflunomide.

Among these RWS, teriflunomide showed the main adverse reactions: thinning of the hair and diarrhea, and these adverse reactions were mostly mild to moderate, and usually did not lead to treatment cessation.

At the same time, none of the studies found that patients had serious opportunistic infections.

The safety of teriflunomide has been further verified in clinical use for up to 10 years in the world.

The first oral DMT in China, using Chinese population data to speak for real world strength.
Teriflunomide was launched in China in 2018.
As the first oral first-line DMT drug to land in China, Chinese MS patients have officially entered the era of oral DMT.
Greatly improve patient compliance.

As for the MS disease itself, the disease characteristics of different populations are different.
The incidence of MS in Caucasians and Asian populations is quite different.
Studies have shown that the positive rate of cerebrospinal fluid (CSF) oligoclonal zone in MS patients in Asian countries (including China) is lower than White people[1].

The TOWER China subgroup data published on the occasion of the domestic listing of teriflunomide in November 2018 showed that teriflunomide can reduce ARR by 71.
2%[14], which is far better than 36.
3% of the global population of TOWER[15] Therefore, it is particularly important to carry out RWS in China to evaluate the efficacy and safety of teriflunomide.

In the 23rd National Neurology Conference of the Chinese Medical Association in 2020, Professor Chen Bo and Bu Bitao from Tongji Hospital of Tongji Medical College of Huazhong University of Science and Technology published a retrospective analysis in the 2018-2020 Wuhan area Study on the efficacy of teriflunomide in MS patients.

The study included a total of 38 MS patients, 71% of which were women, 55% of the patients had been treated with other DMT drugs in the past, and the median time of patients receiving teriflunomide treatment was 13 months.

The results showed that teriflunomide can significantly reduce the ARR of Chinese MS patients (0.
27 after treatment vs.
1.
14 before treatment) by 76.
3% (P＜0.
01), and the patients’ extended disability scale (EDSS) score during treatment No significant increase was seen.

In terms of safety, teriflunomide has a low incidence of adverse reactions and is generally well tolerated [16].

In the recently held 26th International Conference of the International Society for Pharmacoeconomics and Outcomes Research (ISPOR), a Chinese real-world study of teriflunomide was announced [17].

The study was led by Professor Zhou Hongyu from West China Hospital of Sichuan University.
It is a single-center, retrospective, observational, real-world study.
The study included 74 patients with MS.
The median time that the patients received teriflunomide (14mg/d) treatment For 9 months.

The primary endpoint of the study is ARR.

The results of the study showed that teriflunomide treatment can significantly reduce the ARR of MS patients (0.
20±0.
47 at the last follow-up vs.
1.
02±0.
81 before treatment), a reduction of 78% (P=0.
005).

The patient's disability status remained stable during the study, and the EDSS score was numerically lower than the baseline.

In addition, up to 75% of patients treated with teriflunomide remained relapse-free during the study period; up to 82% of patients did not develop disability progression.

In terms of safety, up to 66.
4% of patients did not experience any adverse events, and no serious adverse events were reported.

Figure 3: Changes in ARR of MS patients before and after teriflunomide treatment.
Overall, the efficacy and safety of teriflunomide in the above two real-world studies are consistent with previous clinical research data, and its overall tolerance is good.
Discover new security issues.

Experts comment that MS is a slowly progressive disease, and there is currently no cure.
Therefore, its treatment is a long-term process.
The efficacy and safety of the drug and the patient's treatment satisfaction are the key factors that determine whether the patient can follow the doctor's prescription for a long time.

Most of the current clinical practice guidelines recommendations are from RCTs and lack the support of real-world data.
RWS, as a supplement to RCTs, can better reflect the true effects and safety of actual medications and provide important reference materials for daily medical activities.

DMT in remission can significantly reduce the frequency of patient relapses and delay the progression of disability.
Among them, teriflunomide was approved for marketing in the United States in 2012 and officially entered China in 2018.
It has accumulated rich evidence-based medicine data in many years of clinical application.
In particular, RWS data show that in the treatment process of real clinical practice, teriflunomide can significantly reduce the ARR of MS patients with good safety and no new and unexpected adverse events.

However, these real-world studies still have some limitations, such as small sample size and short follow-up time.
In the future, a larger sample size and longer follow-up are needed to verify their effectiveness and safety.

In short, the real-world efficacy and safety performance of teriflunomide in the Chinese population is consistent with the overall global population, which also provides a solid evidence-based basis for the clinical application of Chinese patients.

Expert profile Professor Bu Bitao Deputy Director, Professor, Chief Physician, Department of Neurology, Tongji Hospital Affiliated to Tongji Medical College, Huazhong University of Science and Technology, Deputy Director, Institute of Neurology, Doctoral Supervisor, Director of the Editorial Department of the Journal of Neurological Injury and Functional Reconstruction, Hubei Provincial Society of Integrative Medicine Neurology Committee Chairman, Chinese Medical Association Neurology Branch Committee Member of the Myopathology Group and Immunology Group Director, Tongji Branch of the Chinese Neuromuscular Disease Diagnosis and Treatment Standard Training Center, Standing Committee Member of the Neuroimmune Branch of the Chinese Stroke Society Member of the Peripheral Neuropathy Collaboration Group of the Chinese Medical Association Neurology Branch Wuhan The head of the immunology group of the Neurology Branch of the Municipal Medical Association.
Overseas members of the American Society of Neuroscience.
The research direction is neuroimmune diseases, muscle diseases and neuropathology, focusing on myasthenia gravis, multiple sclerosis, neuromyelitis optica, immune myopathy and Peripheral neuropathy in J Neuroscience, Annals of Neurology, Joumal of Neurology, Brain Pathology, Neurobiology of Aging, Scandinavia Joumal of Neurology, Radiology, Scientific Reports, Neurology India, Pediatric Neurology, Chinese Medicine Joumal.
of Experimental rheumatology, Chinese Journal of Neurology, etc.
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This information is for medical and scientific research reference only.
Sanofi does not recommend using Use this product in any way that is inconsistent with the prescription information approved by your country,Chin Med J (Engl).
2018 Dec 5; 131(23): 2776-2784.
[15] Confavreux C, O'Connor P, Comi G, et al.
Oral teriflunomide for patients with relapsing multiple sclerosis (TOWER): a randomised, double-blind, placebo-controlled, phase 3 trial[J].
Lancet Neurol.
2014 Mar; 13(3): 247-56.
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The 23rd National Neurology Branch of the Chinese Medical Association.
[17] Effectiveness and safety of teriflunomide in patients with multiple sclerosis: a real-world study from West China hospital, China .
ISPOR 2021.
This information is for medical and scientific reference only.
Sanofi does not recommend using this product in any way that is inconsistent with the prescription information approved by your country.
Chin Med J (Engl).
2018 Dec 5; 131(23): 2776-2784.
[15] Confavreux C, O'Connor P, Comi G, et al.
Oral teriflunomide for patients with relapsing multiple sclerosis (TOWER): a randomised, double-blind, placebo-controlled, phase 3 trial[J].
Lancet Neurol.
2014 Mar; 13(3): 247-56.
[16] Chen Bo, Bu Bitao.
Clinical observation of multiple sclerosis patients from statistics Characteristics and efficacy analysis of teriflunomide.
The 23rd National Neurology Branch of the Chinese Medical Association.
[17] Effectiveness and safety of teriflunomide in patients with multiple sclerosis: a real-world study from West China hospital, China .
ISPOR 2021.
This information is for medical and scientific reference only.
Sanofi does not recommend using this product in any way that is inconsistent with the prescription information approved by your country.
The 23rd National Neurology Branch of the Chinese Medical Association.
[17] Effectiveness and safety of teriflunomide in patients with multiple sclerosis: a real-world study from West China hospital, China.
ISPOR 2021.
This information is for medical and For scientific research reference, Sanofi does not recommend using this product in any way that is inconsistent with the prescription information approved by your country.
The 23rd National Neurology Branch of the Chinese Medical Association.
[17] Effectiveness and safety of teriflunomide in patients with multiple sclerosis: a real-world study from West China hospital, China.
ISPOR 2021.
This information is for medical and For scientific research reference, Sanofi does not recommend using this product in any way that is inconsistent with the prescription information approved by your country.