Full TERIS Results Highlight Teriflunomide’s Impact in Preventing First Demyelinating Event

Christine Lebrun-Frenay, MD, PhD, FAAN

Months after initial data was presented at the 2023 American Academy of Neurology Annual Meeting, investigators have published the full dataset of the phase 3 TERIS study (NCT03122652) showing teriflunomide’s (Aubagio; Sanofi) impact in patients with preclinical demyelinating disease. All told, treatment with the agent resulted in an unadjusted risk reduction of 63% and an adjusted risk reduction of 72% relative to placebo, in preventing first clinical demyelinating event.

Led by Christine Lebrun-Frenay, MD, PhD, FAAN, head of CRCSEP and coordinator of the Neurosciences Research Unit at Paris City University, the final analysis featured 89 adults meeting the 2009 radiologically isolated syndrome (RIS) criteria who were randomly assigned 1:1 to oral teriflunomide (n = 44), 14 mg daily, or placebo (n = 45), for a 96-week treatment period. Patients had the option to continue in the randomization arm for up to 144 weeks. The primary outcome was time to a first acute or progressive neurologic event resulting from central nervous system demyelination, expressed as a rate of conversion to clinical MS.

An acute neurologic event was defined by a clinical symptom localized to the optic nerve, brain stem, cerebellum, spinal cord, or long sensory or motor tracts, lasting more than 24 hours and followed by symptom improvement. A progressive event was defined by the onset of a clinical symptom with the temporal profile revealing at least a 12-month progression.

Throughout the study, 18 participants, 9 in each arm, discontinued their involvement, with reasons that included adverse events (16.7%), withdrawal of consent (22.2%), lost at follow-up (27.8%), voluntary discontinuation (22.2%), pregnancy (5.6%), and failure to complete follow-up when study was terminated (5.6%). Follow-up MR studies performed at week 96 were acquired in 62 participants (69.7%), 32 (51.6%) within the placebo group and 30 (48.4%) in the teriflunomide group.

In the study, a total of 28 primary clinical end points were detected, most (85.7%; n = 24) of which met the definition of acute relapses. Overall, the risk of a first clinical event was significantly reduced in the teriflunomide arm (mean time to event, 128.2 [SD, 7.25] weeks) with 8 clinical events (6 acute; 2 progressive) vs the placebo arm (mean time to event, 109.6 [SD, 7.44] weeks) with 20 clinical events (18 acute, 2 progressive) and an unadjusted hazard ratio (HR) of 0.37 (95% CI, 0.16-0.84; P = .02).

"Earlier treatment during the presymptomatic phase of MS may delay disability outcomes even further than treatment after symptomatic MS onset," Lebrun-Frenay et al wrote. "The choice between oral DMTs will depend on the patient discussion, especially in young women, where pregnancy planning may be required as teriflunomide requires a strict washout period. However, before considering any immune intervention, it is essential to highlight the risk of misdiagnosing individuals with nonspecific MRI anomalies as having RIS, underscoring the role of MS tertiary centers in accurately classifying and managing such individuals."

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Results from the adjusted Cox proportional hazards regression model were consistent with those of the unadjusted analysis, with a 72% effect favoring teriflunomide on reducing the risk of the first event after adjusting for sex, age at the time of diagnosis, multiple sclerosis family history, Expanded Disability Status Scale score, T2-weighted hyperintense volume, and the presence of gadolinium-enhancing lesions at baseline (HR, 0.28; 95% CI, 0.11-0.71; P = .007).

Although not statistically different, investigators did observed a numerically lower cumulative number of new and/or newly enlarging T2 lesions (rate ratio [RR], 0.57; 95% CI, 0.27-1.20; P = .14) and the cumulative number of gadolinium-enhancing lesions (RR, 0.33; 95% CI, 0.09-1.17; P = .09). Exploratory outcomes, which included scales such as the Computerized Speed Cognitive Test, European Quality of Life-5 Dimension (EQ-5D-5L), Paced Auditory Serial Addition Test, and Multiple Sclerosis International Quality of Life Questionnaire, did not differ between groups.

For those on teriflunomide, the most common adverse event (AE) reported were gastrointestinal disorders (11.4%), followed by dysmenorrhea (9.1%), benign respiratory infections (6.8%), general disorders/conditions (6.8%), and transient increase in transaminases (4.5%). There was 1 reported severe COVID-19 infection declared as possibly related to the drug and 1 patient who withdrew because of AEs. The AEs justifying the end of allocated treatment were grade 2 diarrhea and grade 1 scabies in the placebo arm and grade 3 neurotropenia in the teriflunomide arm, all of which were resolved after treatment discontinuation.

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).²

REFERENCE
1. Lebrun-Frenay C, Siva A, Sormani MP, et al. Teriflunomide and time to clinical multiple sclerosis in patients with radiologically isolated syndrome: the TERIS randomized clinical trial. JAMA Neurol. Published online August 21, 2023. doi:10.1001/jamaneurol.2023.2815
2. Okuda DT, Kantarci O, Lebrun-Frenay C, et al. Dimethyl fumarate delays multiple sclerosis radiologically isolated syndrome. Ann Neurol. Published online November 18, 2022. doi:10.1002/ana.26555