Merck’s press release on the Evobrutinib vs Teriflunomide phase 3 EVOLUTION trials says more about teriflunomide than evobrutinib, but they do raise questions about all the other Bruton Tyrosine Kinase Inhibitors (BTKi) in clinical trials in MS and other autoimmune diseases.
05 DEC 2023 | DARMSTADT, GERMANY
“Results from the EVOLUTION clinical trials showed evobrutinib did not meet its primary endpoint of annualized relapse rate for up to 156 weeks compared to oral teriflunomide in both studies.
Merck, a leading science and technology company, today announced that its two Phase III EVOLUTION clinical trials (evolutionRMS 1 and evolutionRMS 2) investigating the efficacy and safety of evobrutinib did not meet their primary endpoints of reducing annualized relapse rates (ARR) in people with relapsing multiple sclerosis (RMS) compared to oral teriflunomide (0.11 vs. 0.11 in evolutionRMS 1 and 0.15 for evobrutinib vs. 0.14 for teriflunomide in evolutionRMS 2, p=NS in both trials). Of note, teriflunomide ARR values were lower than reported in other recent Phase III studies. The overall safety and tolerability profile was consistent with results from the previously reported Phase II trial. The company will complete a full evaluation of the data from the EVOLUTION clinical trials and will work with investigators on the future presentation and publication of the results.”
Teriflunomide clearly performed much better than expected and surprised Merck. Why?
I changed my mind about teriflunomide several years ago. I now think teriflunomide is the most underrated DMT in our therapeutic armamentarium. I also predict it will eventually become one of the most used MS DMTs once its alternative mode of action becomes widely known, we understand its efficacy profile, and we change how we use it in MS. There are several reasons for this.
Teriflunomide is much more effective as a DMT than we realise
As we reinterpret old data and new data emerge, it is clear that when we go beyond focal inflammation (relapses and MRI activity), teriflunomide is much more effective than we would expect based on its impact on relapses and MRI activity. Despite reducing relapses by, on average, a third, teriflunomide has a remarkably robust effect on disability progression and slows the accelerated brain volume loss due to MS.
The head-2-head studies of ofatumumab and ublituximab (anti-CD20 therapies) against teriflunomide show that despite both anti-CD20 agents being superior to teriflunomide in suppressing relapses and focal MRI activity, only ofatumumab was more effective than teriflunomide when it came to reduced disability worsening. The latter difference, however, was very small and not clinically significant. The difference was mainly driven by relapse-associated worsening (RAW), as the absolute differences between ofatumumab and teriflunomide on PIRA (progression independent on relapse activity) are small (EAN 2020). Please note that ublituximab was no better than teriflunomide on disability progression (see figures below). When assessing the more objective brain volume loss, an integrator of end-organ damage, teriflunomide, was equivalent to both these agents in slowing MS-related accelerated brain volume loss (BVL) (see figure below).
Relapses and focal MRI activity are not MS and are likely to represent the immune system’s response to what is causing MS (see ‘Hot topic AAN 2023: smoldering MS’; 24-April-2023). My position on this is based on many observations, one of which is how teriflunomide dissociates the treatment effect on relapses and focal MRI activity from disability worsening and brain volume loss.
Teriflunomide is more effective when used as a switch agent
Another interesting observation regarding teriflunomide is that it is more effective when used second or third-line than as a first-line agent in DMT-naive patients. This observation is robust and is the only DMT to do this. What happens to the biology of MS over time that makes teriflunomide more effective? This observation is important because, in contemporary phase 3 clinical trials, more subjects are not naive to DMTs. Therefore, teriflunomide is likely more effective than anticipated from the phase 3 trial of teriflunomide. For example, in a recent French real-world study no difference in efficacy between dimethyl fumarate and teriflunomide (see paper below).
The teriflunomide real-world data and the negative Evobrutinib studies will have all the other Pharma companies with BTKi programmes sitting on tenterhooks. The relapsing MS BTK inhibitor trials, which are currently running, are all using teriflunomide as the active comparator (ClinicalTrials.gov Identifiers: NCT04338022, NCT04338061, NCT04410991, NCT04410978, NCT04586023, NCT04586010, NCT05147220, NCT05156281). The only exception is the fenebrutinib primary progressive trial, where the active comparator is ocrelizumab (ClinicalTrials.gov Identifier: NCT04544449). The reason for the latter is that ocrelizumab is the only licensed therapy for PPMS and, hence, is considered the standard of care.
The billion-dollar question now arises: Will any of the other BTKi’s be superior to teriflunomide?
Before drawing too many negative conclusions, we really need to see the other data in the EVOLUTION trials, in particular the disability progression, brain volume and other end-organ damage markers. However, based on teriflunomide’s ability to impact end-organ damage in MS, I would be surprised if evobrutinib is superior to teriflunomide in protecting the end organ or the brain and spinal cord in pwMS.
Teriflunomide is also an outlier in terms of memory B-cells
Teriflunomide is an outlier in terms of its impact on memory B-cells. We have made the point in the past that all of our licensed MS DMTs either reduce or stop the trafficking of memory B-cells into the CNS. Teriflunomide doesn’t have a significant effect on memory B-cells. The percentage of circulating memory B cells does not change. However, in some instances, the absolute number of B cells may decrease slightly, but this is likely to be non-specific to memory B-cell and represents the impact of teriflunomide on total lymphocyte counts. Although teriflunomide has been labelled as an immunosuppressive therapy, its profile is not immunosuppressive. In most treated pwMS, it doesn’t cause significant leukopaenia or lymphopaenia; it is not associated with opportunistic infections, or secondary malignancies and vaccine responses are not blunted.
Teriflunomide has broad-spectrum antiviral activity, including activity against the herpes viruses, which includes EBV. Our group has shown that teriflunomide reduced salivary shedding of EBV in subjects with MS. I have therefore hypothesised that teriflunomide is working as an antiviral in MS. Please note this observation is not unique to teriflunomide but is relevant to the class of agents that are dihydroorotate dehydrogenase inhibitors (DHODHI), leflunomide, vidofludimus or ASLAN003.
I have hypothesised that teriflunomide and the class of DHODHIs will work best as second or third-line agents, particularly maintenance therapies after induction with a B-cell-depleting agent. Underpinning this hypothesis is to allow B-cell reconstitution to occur in the presence of an antiviral agent that targets EBV. This is the foundation of the so-called iTeri study (see ‘EBV immunotherapy for MS’; 11-Jan-2023).
The EVOLUTION or Evobrutibib study results will further support the uptake of teriflunomide as the go-to agent for de-escalating pwMS off chronic immunosuppressive therapies when they start encountering problems with infections, hypogammaglobulinaemia or poor vaccine responses. The latter is particularly an issue with older patients on anti-CD20 or other immunosuppressive therapies who are developing immunosenescence.
Teriflunomide is a low-cost DMT
Another driver is economics. Teriflunomide is either off-patent or coming off-patent very soon in many countries. As a small molecule, teriflunomide’s price will plummet by more than 90% with the launch of generics. Generic teriflunomide is already the cheapest DMT in the USA. The wholesale cost of generic teriflunomide has been reported to be between $32.40 - $2,058.90 per 30-day supply. In comparison, Aubagio, the innovator formulation of teriflunomide, costs approximately $9,155.25 per month (18 April 2023, National Multiple Sclerosis Society).
In countries where teriflunomide is still on-patent or not available, you can use leflunomide instead; 20 mg or 10 mg of leflunomide is metabolised into the equivalent of 14 mg or 7 mg of teriflunomide, respectively. In my opinion, there is not much difference between teriflunomide and leflunomide. Leflunomide is a prodrug converted into teriflunomide in the body, so if you live in a resource-poor environment and are paying for your DMTs, please ask for generic leflunomide instead. Many neurologists in resource-poor settings are reluctant to prescribe leflunomide instead of teriflunomide.
Call to arms
If you are a wealthy philanthropist or funder, please consider funding a large phase 3 international iTeri study. I have little doubt that teriflunomide after induction with a depletion therapy (alemtuzumab, mitoxantrone, cladribine, AHSCT or anti-CD20) will revolutionise the management and outcome of pwMS.
Paper
Objective: In this study, we compared the effectiveness of teriflunomide (TRF) and dimethyl fumarate (DMF) on both clinical and MRI outcomes in patients followed prospectively in the Observatoire Français de la Sclérose en Plaques.
Methods: A total of 1,770 patients with relapsing-remitting multiple sclerosis (RRMS) (713 on TRF and 1,057 on DMF) with an available baseline brain MRI were included in intention to treat. The 1- and 2-year postinitiation outcomes were relapses, increase of T2 lesions, increase in Expanded Disability Status Scale score, and reason for treatment discontinuation. Propensity scores (inverse probability weighting) and logistic regressions were estimated.
Results: The confounder-adjusted proportions of patients were similar in TRF- compared to DMF-treated patients for relapses and disability progression after 1 and 2 years. However, the adjusted proportion of patients with at least one new T2 lesion after 2 years was lower in DMF compared to TRF (60.8% vs 72.2%, odds ratio [OR] 0.60, p < 0.001). Analyses of reasons for treatment withdrawal showed that lack of effectiveness was reported for 8.5% of DMF-treated patients vs 14.5% of TRF-treated patients (OR 0.54, p < 0.001), while adverse events accounted for 16% of TRF-treated patients and 21% of DMF-treated patients after 2 years (OR 1.39, p < 0.001).
Conclusions: After 2 years of treatment, we found similar effectiveness of DMF and TRF in terms of clinical outcomes, but with better MRI-based outcomes for DMF-treated patients, resulting in a lower rate of treatment discontinuation due to lack of effectiveness.
Classification of evidence: This study provides Class III evidence that for patients with RRMS, TRF and DMF have similar clinical effectiveness after 2 years of treatment.
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Please note that the opinions expressed here are those of Professor Giovannoni and do not necessarily reflect the positions of Queen Mary University of London or Barts Health NHS Trust. The advice is intended as general and should not be interpreted as personal clinical advice. If you have problems, please tell your healthcare professional, who will be able to help you.
Evobrutinib is no better than teriflunomide