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Multiple sclerosis (MS): Drug teriflunomide may delay early symptoms

  • Radiologically isolated syndrome is diagnosed in people who do not have multiple sclerosis (MS) symptoms but who have lesions (abnormalities) in the brain and/or spinal cord, similar to those seen in MS, but with no other symptoms.
  • The phase 3 TERIS study enrolled individuals with RIS from Europe and Turkey and analyzed the efficacy of the drug teriflunomide (Aubagio®) in delaying the first symptoms of MS.
  • Treatment with teriflunomide resulted in a 63% risk reduction relative to placebo in preventing the first symptoms of MS in individuals with RIS.
  • The findings of the TERIS study support the idea that it may be beneficial to treat RIS with medication that can change the course of the disease before any symptoms of MS appear.

An estimated 2.8 million people worldwide live with multiple sclerosis (MS), an unpredictable, often disabling disease of the central nervous system. Its symptoms range from numbness and tingling to blindness and paralysis, and there is currently no cure.

Some people have lesions (abnormalities) in the brain and/or spinal cord, similar to those seen in MS, but no other symptoms. This is a rare condition known as radiologically isolated syndrome (RIS).

A study published in 2020 found that 51.2% of a group of individuals with RIS went on to develop MS within 10 years.

Researchers have hypothesized that treating RIS at an early stage could prevent the occurrence of the first clinical event and reduce the risk of new lesion development in the brain or spinal cord. This could decrease the risk of permanent neurological damage.

The ARISE study, published in 2022, investigated the use of dimethyl fumarate (Tecfidera; Biogen) in patients with RIS. The study found that treatment with dimethyl fumarate significantly reduced the risk of the first clinical demyelinating event (nerve damage) in people with RIS.

Now, the results of a sister study to ARISE – the TERIS study – have been released. This phase 3 study assessed the efficacy of the drug teriflunomide (Aubagio®) in delaying the first symptoms of MS. Teriflunomide is currently used in the treatment of MS.

“Our study confirms that prescribing a disease-modifying treatment at the preclinical stage of the disease in selected subjects can impact the development of MS and long-term disability.”

– Dr. Christine Lebrun-Frenay, head of the Department of Neurology at the Centre Hospitalier Universitaire de Nice

The study abstract, released April 19, 2023, is being presented at the American Academy of Neurology’s 75th Annual Meeting, held in person in Boston and live online from April 22-27, 2023. The study was funded by Sanofi, which manufactures the drug.

How teriflunomide works

Currently, teriflunomide is prescribed in over 80 countries for treating relapsing-remitting MS and active secondary progressive MS.

It works by targeting specific immune cells (T and B lymphocytes) that are believed to cause damage to the brain and spinal cord in people with MS.

Teriflunomide decreases the amount of activated T and B lymphocytes by inhibiting a mitochondrial enzyme, which leads to fewer immune cells causing inflammation.

Assessing its effect on early MS symptoms

Between September 2017 and October 2022, Dr. Christine Lebrun-Frenay, Ph.D., head of the Department of Neurology at the Centre Hospitalier Universitaire de Nice, in Nice, France, led a team across 23 study locations in France, Switzerland, and Turkey.

The study recruited 124 people with RIS. Of these, 89 participants fulfilled the 2009 RIS Criteria and were randomized 1:1 to receive one 14-mg teriflunomide oral tablet or one placebo tablet daily for 96 weeks. The participant, care provider, investigator, and outcomes assessor were all unaware of which type of treatment each participant received.

The primary outcome measurement was the duration between the start of the study and the appearance of the first neurological symptom of MS. The team also assessed secondary outcomes such as changes in the number of new or enlarging T2 lesions, contrast-enhancing lesions, T2-lesion volumes, and brain atrophy. The study participants underwent brain and spinal cord MRI scans at the start of the study (baseline) and in weeks 48 and 96.

Teriflunomide vs. placebo key findings

Of the 89 people with RIS who received teriflunomide or placebo, 63 (70.8%) were women and their average age was 39.8 years.

During the study follow-up, 28 clinical events were detected, with 20 of them being in the placebo group and 8 in the teriflunomide group. Treatment with teriflunomide resulted in a 63% risk reduction relative to placebo in preventing a first clinical event in participants with RIS.

The teriflunomide group also had fewer patients with gadolinium-enhanced (Gd+) brain lesions, and a lower total number of new or-enlarging T2 brain lesions, compared to the placebo group. However, these results were not statistically significant.

Dr. Mark Freedman, professor of medicine in the field of neurology at the University of Ottawa, and director of the Multiple Sclerosis Research Unit at the Ottawa Hospital – General Campus, who was not involved in the study, remarked that:

“in this study, unlike […] in ARISE, patients were stratified and equally randomized based on the presence or not of cervical spinal cord lesions. This is VERY important, as the latter has been the most predictive o[f] early relapse and if they are unequally allocated to treatment arm and placebo then the results can be skewed.”

When asked about the safety findings of the study, Dr. Lebrun-Frenay told Medical News Today:

“There was no significant adverse event compared to the placebo and no serious adverse event related to the drug. The neurological community already knows teriflunomide is a well-tolerated drug with no increase in adverse events of interest like infections, a decrease in vaccination efficacy, or cancer.”

Clinical implications for MS treatment

Dr. Erin Longbrake, Ph.D., assistant professor and director of neuroimmunology clinical research in the department of neurology at Yale School of Medicine, who was not involved in the study, told MNT that: “[t]his study supports the growing appreciation that the pathophysiologic processes leading to MS begin well in advance of the first clinical symptoms of disease.”

The findings of both the ARISE study and the TERIS study suggest that it’s a good idea to start treating RIS with medication that can change the course of the disease before any symptoms of MS appear.

“Up until now, treatment has only been offered to patients who have had a “clinically manifest” first event or CIS, even though their MRI has shown to accumulate lesions silently long before the disease is evident with signs and symptoms. Should not the goal of therapy be to also prevent the silent disease? This study, as well the ARISE study using DMF shows that this is indeed an effective strategy.”

– Dr. Mark Freedman

At the moment, a disease-modifying therapy for RIS is not yet available, but additional trials are underway, including:

  • A phase 2 study testing the use of the Bacille Calmette-Guérin (BCG) vaccine in individuals with RIS. The study is recruiting 100 participants in Italy. Results are expected at the end of 2023.
  • The phase 4 CELLO study investigating treatment with ocrelizumab (Ocrevus®, Genentech) to prevent clinical MS in individuals with RIS. The study is recruiting 100 participants at multiple sites in the U.S. Results are expected in 2028.

Concerns and future research

The misdiagnosis of RIS is a significant problem. To have a certain diagnosis, physicians must thoroughly examine all clinical, paraclinical, and radiological data, while also reliably ruling out other conditions that may mimic RIS.

“There are many reasons for having MRIs that might mimic MS – the commonest being age, microvascular disease and migraine just to name a few. We are getting better at differentiating these lesions […] but it is still possible to overcall many scans,” Dr. Freedman told MNT.

Future research will need to focus on “more effectively identifying at-risk people as well as generating recommendations about how to manage these at-risk people,” Dr. Longbrake told MNT.

“Both teriflunomide and dimethyl fumarate, the drugs studied to-date in RIS, need to be taken on an ongoing basis for continued effectiveness, and so it is difficult to counsel healthy people who have never had a symptom of MS about whether they truly need to go on these long-term, immunomodulatory medications,” she added.

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