Why are we still discussing Teriflunomide?

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Teriflunomide is what I call a dark horse in the DMT family, doesn’t get much air time but every clinical trial of a new agent trumpets its success without meaning to. For example, it’s brain atrophy data makes the anti-CD20s look inadequate, it’s safety profile (despite the overzealous monitoring required by the regulatory authorities) is good, plus you can get rid of the tablet from your body using binding agents if needed, and it’s an oral tablet. I have suggested to Sanofi-Genzyme (who manufacture Teri), in the past that it may be the best step down agent for Alemtuzumab to avoid another round of Alemtuzumab.

And now here is new data suggesting it’s efficacy in Radiologically Isolated Syndrome (RIS). RIS not MS but incidental finding of white matter lesions on MRI Head scans which are performed for other reasons. In the TERIS study they found that Teriflunomide as opposed to placebo (dummy tablet) delayed or prevented the development of clinical MS by ~70%. You can see from the graph below that you have greater chance of being relapse free (event free) if you were on Teriflunomide.

Figure: The time to the first clinical event was significantly extended in the teriflunomide arm compared with placebo, with a risk reduction of 63% before adjustments and 72% after adjustments relative to placebo in preventing a first clinical event.

It’s not the only agent to prevent MS in RIS, in fact Tecfidera or Dimethyl Fumerate (ARISE study) presented at ECTRIMS 2022 demonstrated an 80% risk reduction relative to placebo in the prevention of the first clinical event. And I suppose a more highly active agent may prevent it in entirety. But given that a sizeable fraction of those with abnormal MRI Head scan never go on to develop MS it is a risk/benefit argument around which agent you use for this condition. Whether the regulatory authorities would be on board with this is another topic on its own!

Abstract

JAMA Neurol. 2023 Aug 21;e232815.

Teriflunomide and Time to Clinical Multiple Sclerosis in Patients With Radiologically Isolated Syndrome: The TERIS Randomized Clinical Trial

Christine Lebrun-Frénay Aksel Siva Maria Pia Sormani Cassandre Landes-Chateau Lydiane Mondot1Francesca Bovis Patrick Vermersch Caroline Papeix Eric Thouvenot7Pierre Labauge Françoise Durand-DubiefHusnu Efendi Emmanuelle Le Page Murat Terzi Nathalie Derache Bertrand Bourre Robert Hoepner Rana Karabudak Jérôme De Seze Jonathan Ciron Pierre Clavelou  Sandrine Wiertlewski Omer Faruk Turan Nur Yucear Mikael Cohen Christina Azevedo Orhun H Kantarci Darin T Okuda Daniel Pelletier TERIS Study Group

Importance: Radiologically isolated syndrome (RIS) represents the earliest detectable preclinical phase of multiple sclerosis (MS) punctuated by incidental magnetic resonance imaging (MRI) white matter anomalies within the central nervous system.

Objective: To determine the time to onset of symptoms consistent with MS.

Design, setting, and participants: From September 2017 to October 2022, this multicenter, double-blind, phase 3, randomized clinical trial investigated the efficacy of teriflunomide in delaying MS in individuals with RIS, with a 3-year follow-up. The setting included referral centers in France, Switzerland, and Turkey. Participants older than 18 years meeting 2009 RIS criteria were randomly assigned (1:1) to oral teriflunomide, 14 mg daily, or placebo up to week 96 or, optionally, to week 144.

Interventions: Clinical, MRI, and patient-reported outcomes (PROs) were collected at baseline and yearly until week 96, with an optional third year in the allocated arm if no symptoms have occurred.

Main outcomes: Primary analysis was performed in the intention-to-treat population, and safety was assessed accordingly. Secondary end points included MRI outcomes and PROs.

Results: Among 124 individuals assessed for eligibility, 35 were excluded for declining to participate, not meeting inclusion criteria, or loss of follow-up. Eighty-nine participants (mean [SD] age, 37.8 [12.1] years; 63 female [70.8%]) were enrolled (placebo, 45 [50.6%]; teriflunomide, 44 [49.4%]). Eighteen participants (placebo, 9 [50.0%]; teriflunomide, 9 [50.0%]) discontinued the study, resulting in a dropout rate of 20% for adverse events (3 [16.7%]), consent withdrawal (4 [22.2%]), loss to follow-up (5 [27.8%]), voluntary withdrawal (4 [22.2%]), pregnancy (1 [5.6%]), and study termination (1 [5.6%]). The time to the first clinical event was significantly extended in the teriflunomide arm compared with placebo, in both the unadjusted (hazard ratio [HR], 0.37; 95% CI, 0.16-0.84; P = .02) and adjusted (HR, 0.28; 95% CI, 0.11-0.71; P = .007) analysis. Secondary imaging end point outcomes including the comparison of the cumulative number of new or newly enlarging T2 lesions (rate ratio [RR], 0.57; 95% CI, 0.27-1.20; P = .14), new gadolinium-enhancing lesions (RR, 0.33; 95% CI, 0.09-1.17; P = .09), and the proportion of participants with new lesions (odds ratio, 0.72; 95% CI, 0.25-2.06; P = .54) were not significant.

Conclusion and relevance: Treatment with teriflunomide resulted in an unadjusted risk reduction of 63% and an adjusted risk reduction of 72%, relative to placebo, in preventing a first clinical demyelinating event. These data suggest a benefit to early treatment in the MS disease spectrum.

About the author

Neuro Doc Gnanapavan

14 comments

    • Approx 1/3 at 5 years go onto CIS but this number increases the longer you monitor for. If you’re oligoclonal band positive or have a spinal cord lesion the likelihood of developing CIS increases.

      • So 66,66% are still ” free “of ms after 5 years

        The data for this study says that Teri gives you 2,76 years =144 weeks

        protection

        Should we trying to find good biomarkers to know which Ris needs treatment

        Instead of treating everyone?

        Thanksfor reply

        • RIS is MS. It’s early stage MS, but still MS. I suspect that at the early stage of MS eg RIS, some people’s immune system puts out whatever is driving the disease, or at least limits the damage until much later on.

          • The radiologically isolated syndrome (RIS), is it already MS?

            Conclusions: Many experts groups in the USA, Europe and South America have proposed guidelines to follow the RIS subjects. The recommendation is not to treat off label these subjects as 2 phases 3 studies are ongoing in the USA and Europe with dimethyl fumarate and teriflunomide. A phase IV with ocrelizumab is starting in the USA

            https://ectrims2021.abstractserver.com/program/#/details/presentations/179

        • I would think banding in the CSF is a good bio marker for RIS patients and subsequent conversion, unfortunately it isn’t very practical, too bad NFL light chains didn’t work out as a reliable bio marker in the blood.

    • Lets just say I’m not discussing 2 year brain atrophy data! But, on the topic of brain atrophy which is negative integer over time makes the slope valuable in the short term. If your drug trajectory is the same going forward then this is concerning until you hit 40 where the percentage brain volume loss starts to increase per decade as part of aging.

      • would be great if you can shed some insight how you reach to below opinion: “for example, it’s brain atrophy data makes the anti-CD20s look inadequate”. The ofatumumab vs Teri data is not convincing for me and I think it is too far to suggest Teri is better option there to control brain atrophy.

        • Good question. The sample calculations in the clinical trials are built for demonstrating superiority rather than non-inferiority and equivalence. I think we need to understand more about what these MRI brain measures actually mean in the context of drug treatment effects outside of what is seen in retrospective and prospective patient monitoring which all point to end organ damage (in this case brain volume loss at a rate greater than normal ageing) to be a bad outcome. Until we understand this, should we stop doing brain atrophy measures in clinical trials, don’t know.

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