Article
Teriflunomide Shows Promise as Potential Treatment for Radiologically Isolated Syndrome
Author(s):
Teriflunomide, an FDA-approved therapy for relapsing forms of multiple sclerosis, resulted in an 62% risk reduction relative to placebo in preventing a first clinical event in patients with RIS.
Christine Lebrun-Frenay, MD, PhD, FAAN
Presented at the 2023 American Academy of Neurology (AAN) Annual Meeting, held April 22-27, in Boston, Massachusetts, findings from the phase 3 TERIS study (NCT03122652) showed that treatment with teriflunomide (Aubagio; Sanofi) significantly reduced the time to first clinical event in patients with radiologically isolated syndrome (RIS), often considered the presymptomatic phase of multiple sclerosis (MS).
Introduced in 2009, RIS refers to an entity in which white matter lesions fulfilling the criteria for MS occur in individuals without a history of clinical demyelinating attack or alternative etiology. Some have argued that RIS is not truly a clinical diagnosis and instead is part of a continuum from health to disease that cannot be distinguished on the basis of imaging and clinical features.
The study, led by Christine Lebrun-Frenay, MD, PhD, FAAN, head of CRCSEP and coordinator of the Neurosciences Research Unit at Paris City University, enrolled 124 individuals and randomized 89 who fulfilled the 2009 RIS criteria. Comprised of mostly females (70.8%), the cohort was randomly assigned 1:1 to either 14 mg of teriflunomide, an FDA-approved immunomodulatory agent for relapsing MS, or placebo, with time to first event from study entry as the primary outcome measure.
"The results are positive. We’re glad to announce a demonstrated risk reduction of 63% favoring teriflunomide,” Lebrun-Frenay told NeurologyLive®. "After adjusting for age of diagnosis of RIS, gender, MRI metrics, the risk increased to 72% favoring the active arms. At the earliest stage of disease demyelinating spectrums, or preclinical MS, the study is positive and the prescription of a disease-modifying treatment is efficient to prevent multiple sclerosis."
Standardized MRI studies of the brain and spinal cord were performed at weeks 0, 48, 96, and clinical events. Coming into the trial, index MRI motives for patients included headache (47%), follow-up neurological disease (18%), dizziness/vertigo (13.5%), ophthalmology (7%), and miscellaneous (14.5%).
During follow-up, 28 clinical events were detected, 20 of which were in the placebo group and 8 on teriflunomide. Results from the unadjusted (HR, 0.38; 95% CI, 0.17-0.88; P = .025) and adjusted (HR, 0.34; 95% CI, 0.14-0.82; P = .016) models further demonstrated the superiority of teriflunomide in preventing a first clinical event. Although not statistically significant the number of patients with gadolinium-enhancing lesions (OR, 0.31; 95% CI, 0.08-1.18; P = .087) and the cumulative number of new or enlarging T2 lesions (risk ratio, 0.69; 95% CI, 0.34-1.40; P = .31) were reduced in the teriflunomide group relative to those on placebo.
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"We didn’t have any safety issues, it’s very safe. It’s a drug that’s well known in the field of multiple sclerosis," Lebrun-Frenay added. "We now have 2 drugs that have shown efficacy in phase 3 studies [of RIS]. We have to express recommendation to neurologists in clinical practice to know who will be at risk and who will benefit from an early prescription."
TERIS is a sister study to ARISE (NCT02739542), which was the first trial to demonstrated a disease-modifying effect in patients with RIS. Led by Darin Okuda, MD, a cohort of 87 patients who met the 2009 RIS criteria were randomly assigned to either dimethyl fumarate (Tecfidera; Biogen) or placebo for a 96-week treatment period. A total of 59 (68%) participants completed the study, with dimethyl fumarate reducing the risk of first clinical demyelinating event by 82% during the 96-week treatment period (HR, 0.18; 95% CI, 0.05-0.63; P = .007).
After 96 weeks, 33% of patients on placebo and 7% on active drug demonstrated a first acute neurological symptom associated with central nervous system demyelination. The effect dimethyl fumarate had on patients was evident in adjusted Cox proportional hazards regression model as well, even after adjusting for sex, age at the time of diagnosis, MS family history, Expanded Disability Status Scale (EDSS) score, T2-weighted hyperintense volume, and the presence of gadolinium-enhancing lesions (HR, 0.07; 95% CI, 0.01-0.45; P = .005). When using the Bayesian approach, the HR for the risk of a first clinical event during the 96-week treatment period was 0.20 (95% credible interval, 0.11-0.35) for dimethyl fumarate vs placebo.
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