MS treatment baby-boom: quadruplets!


Good old uncle Frank (a.k.a. Fingolimod) used to be one of the first oral disease-modifying treatment available for pwMS, and enabled many pwMS to move forward from potentially bothersome injections with interferons or Copaxone towards a more convenient oral delivery method. Uncle Frank is part of the ‘sphingosine-1 receptor modulators’ and works by sequestering immune cells (lymphocytes) in the lymph nodes and thereby indirectly blocks trafficking of pro-inflammatory cells into the brain. You might have captured that uncle Frank’s family was recently blessed with a couple of new members: Olga (ozanimod), Sophie (siponimod) and now also Paul (ponesimod). When Frank visits his younger cousins, he is always struck by how much they resemble each other and himself. And indeed, proverbs are always right: Sphingosine apples do not fall far from trees! 

On the birth card of their pivotal phase III trials in which the efficacy of the compounds in MS was established, the following information was provided: 

In 2021, the UK has recorded the lowest birth rate in the history of recordings. Hence, there must be some valid explanation why there has been a shingosine-baby-boom over the preceding years: 

  1. To get rid of fingolimod’s cardiac side effects: This is undoubtedly an important advantage of the newer molecules. When pwMS start on fingolimod, they are required to have cardiac monitoring until 6 hours after the first intake of the drug. This is mostly organised in hospital and therefore not very convenient. The newer agents do not require such first-dose monitoring as the frequency and severity of these cardiac adverse events is much less. Nonetheless, the newer compounds should also not be prescribed in pwMS that have cardiac comorbidities, as all sphingosine family members might aggravate pre-existing heart conditions. 
  1. To facilitate reversibility of the drug: As you can see on the birth cards, the weight of the different compounds is very different. The ‘weight’ or half-life of fingolimod is 6-9 days which translates into a wash-out period of about 2 months. This is the time need for the drug to be completely cleared from the blood. On the contrary, ponesimod has a half-life of 28 hours which implies it’s washout time is about 6 days. This is convenient when people need to be switched to a different treatment, and might be interesting in the context of vaccine readiness. 
  1. To expand usage from relapsing to secondary progressive MS: Although fingolimod is not officially licensed for usage in secondary progressive MS, the distinction between relapsing and secondary progressive MS is not that well-defined. Also before Sophie’s birth in 2021, many people with secondary progressive MS received treatment with fingolimod. However, the siponimod trial has now provided definite proof of efficacy in this disease stage and is the only drug on the market that has the data to back up this policy. An important advantage.

4. They are produced by different pharmaceutical companies that all want their part of the first-line oral drug cake. 

However, some issues remain unresolved with Frank’s new family members as they are most likely ‘genetic’ and what we would call a sphingosine class-effect: 

  • Teratogenicity (being harmful for unborn babies): Spinghosine-1 receptor modulators are known to be teratogenic as a class, and there is no reason this would be different with the newer family members. Given the long half-life of fingolimod, female pwMS can only start trying for a baby two months after stopping with fingolimod. In real-life, pwMS do not always plan when they fall pregnant which makes fingolimod not an attractive choice in young women. The problem is obviously that more than half of new MS diagnoses are women of childbearing age. Some newer family members such as Paul have shorter half-lives and will disappear more quickly from the blood. This implies that Ponesimod could potentially be stopped when pregnancy is confirmed and not before. However, the problem remains that female pwMS not always immediately know when they are pregnant. Moreover, if pwMS stop their MS drug when pregnancy is confirmed, they will not be protected against new MS relapses during pregnancy and soon after giving birth. 
  • Rebound activity: If pwMS treated with fingolimod stop this drug, they are susceptible to what we call rebound clinical activity during a period of about 12 weeks. This means that stopping the drug triggers MS disease activity in some pwMS more than what would be expected from coincidence. This is typically for drugs that impact on lymphocyte trafficking, and I cannot immediately see a reason why this adverse effect would not be present when using the newer compounds. 
  • Vaccine readiness: The data on the humeral response of fingolimod after COVID-19 vaccination are not reassuring. The Israeli data on protective antibody response post-COVID-19 showed that only 3.8% of fingolimod-treated patients reached the cut-off. Importantly, we do not have data on T cell immunity yet. Nonetheless, it’s a disadvantage compared to drugs that do generate sufficiently high antibody levels. Potentially, the antibody responses might be better with the newer agents as the immune cells in your blood are less depleted in comparison with fingolimod. In addition, the newer family members do not target the S1P3 receptor which is different from fingolimod, important for B cell shuttling in the spleen and thus potentially also for adequate vaccine responses. 
  • How do the new compounds behave in comparison to Tecfidera: Phase III trials keep using active comparators such as interferon-beta and teriflunomide (the godfathers) which are almost not used anymore in clinical practice. This is a shame as it precludes relevant comparisons for clinical practice. 

In summary, the newer sphingosine family members are more reversible and less subject to cardiac side effects. In addition, they finally confirm what has been clear for many years: immune suppression is useful in any individual with active MS, irrespective of the progressive versus relapsing label. Unfortunately, the newer compounds do not solve the issue of terratogenicty making it a less attractive drug in most women of childbearing age. Uncertainties remain about the likelihood of rebound activity and to what extent humeral and T-cell driven vaccine responses can be expected. Therefore, we would like the sphingosine family to start using birth control measures now and focus on expanding the data that we need to recommend the newer family members for usage in clinical practice, in particular vaccination studies. 

Twitter: @SmetsIde

Disclaimer: Please note that the opinions expressed here are those of Ide Smets and do not necessarily reflect the position of the Barts and The London School of Medicine and Dentistry nor Barts Health NHS Trust.

Ponesimod Compared With Teriflunomide in Patients With Relapsing Multiple Sclerosis in the Active-Comparator Phase 3 OPTIMUM Study: A Randomized Clinical Trial

Ludwig Kappos 1, Robert J Fox 2, Michel Burcklen 3, Mark S Freedman 4, Eva K Havrdová 5, Brian Hennessy 3, Reinhard Hohlfeld 6 7, Fred Lublin 8, Xavier Montalban 9, Carlo Pozzilli 10, Tatiana Scherz 3, Daniele D’Ambrosio 3 11, Philippe Linscheid 3, Andrea Vaclavkova 3, Magdalena Pirozek-Lawniczek 3, Hilke Kracker 3, Till Sprenger 1 12Affiliations expand

  • PMID: 33779698
  • PMCID: PMC8008435
  • DOI: 10.1001/jamaneurol.2021.0405


Importance: To our knowledge, the Oral Ponesimod Versus Teriflunomide In Relapsing Multiple Sclerosis (OPTIMUM) trial is the first phase 3 study comparing 2 oral disease-modifying therapies for relapsing multiple sclerosis (RMS).

Objective: To compare the efficacy of ponesimod, a selective sphingosine-1-phosphate receptor 1 (S1P1) modulator with teriflunomide, a pyrimidine synthesis inhibitor, approved for the treatment of patients with RMS.

Design, setting, and participants: This multicenter, double-blind, active-comparator, superiority randomized clinical trial enrolled patients from April 27, 2015, to May 16, 2019, who were aged 18 to 55 years and had been diagnosed with multiple sclerosis per 2010 McDonald criteria, with a relapsing course from the onset, Expanded Disability Status Scale (EDSS) scores of 0 to 5.5, and recent clinical or magnetic resonance imaging disease activity.

Interventions: Patients were randomized (1:1) to 20 mg of ponesimod or 14 mg of teriflunomide once daily and the placebo for 108 weeks, with a 14-day gradual up-titration of ponesimod starting at 2 mg to mitigate first-dose cardiac effects of S1P1 modulators and a follow-up period of 30 days.

Main outcomes and measures: The primary end point was the annualized relapse rate. The secondary end points were the changes in symptom domain of Fatigue Symptom and Impact Questionnaire-Relapsing Multiple Sclerosis (FSIQ-RMS) at week 108, the number of combined unique active lesions per year on magnetic resonance imaging, and time to 12-week and 24-week confirmed disability accumulation. Safety and tolerability were assessed. Exploratory end points included the percentage change in brain volume and no evidence of disease activity (NEDA-3 and NEDA-4) status.

Results: For 1133 patients (567 receiving ponesimod and 566 receiving teriflunomide; median [range], 37.0 [18-55] years; 735 women [64.9%]), the relative rate reduction for ponesimod vs teriflunomide in the annualized relapse rate was 30.5% (0.202 vs 0.290; P < .001); the mean difference in FSIQ-RMS, -3.57 (-0.01 vs 3.56; P < .001); the relative risk reduction in combined unique active lesions per year, 56% (1.405 vs 3.164; P < .001); and the reduction in time to 12-week and 24-week confirmed disability accumulation risk estimates, 17% (10.1% vs 12.4%; P = .29) and 16% (8.1% vs 9.9; P = .37), respectively. Brain volume loss at week 108 was lower by 0.34% (-0.91% vs -1.25%; P < .001); the odds ratio for NEDA-3 achievement was 1.70 (25.0% vs 16.4%; P < .001). Incidence of treatment-emergent adverse events (502 of 565 [88.8%] vs 499 of 566 [88.2%]) and serious treatment-emergent adverse events (49 [8.7%] vs 46 [8.1%]) was similar for both groups. Treatment discontinuations because of adverse events was more common in the ponesimod group (49 of 565 [8.7%] vs 34 of 566 [6.0%]).

Conclusions and relevance: In this study, ponesimod was superior to teriflunomide on annualized relapse rate reduction, fatigue, magnetic resonance imaging activity, brain volume loss, and no evidence of disease activity status, but not confirmed disability accumulation. The safety profile was in line with the previous safety observations with ponesimod and the known profile of other S1P receptor modulators.

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Ide Smets


  • It’s interesting that Ofatumumab wasn’t showing a significant BVL advantage over Teri, but Ponesimod does. It never made sense to me, guess the profile of participants plays a much bigger role?

    • You are right, but for example ofatumumab did have significance on the 12 and 24 week confirmed disability progression while this was not the case for ponesimod. There are just many ways/outcomes to look at indirect neuroprotection, and the differences with teriflunomide are clearly small. The reason why some of the outcomes are significant and others aren’t is, in my opinion, mainly an issue of the power of the study cohort to detect small differences.

      • Thank you Ide, very informative. Looking at the size of ofatumumab vs teri study, both arms had ~940 participants. I still think the profile, status (disease duration etc.) of participants was the main reason. I can see and understand the differences are small, but I expect some kind of consistency (drugs more potent at stopping relapses also prevent BVL better, maybe except teri, but I’m really comparing Ponesimod vs ofatumumab as they are now slightly more comparable.).

        • This is obviously the problem if the pharmaceutical companies keep comparing new drugs to drugs that are actually not used anymore in clinical practice. That requires us to speculate.

          But as far as I can deduct the pwMS in the ofatumumab study were relatively comparable to the ones in the ponesimod trial (time since first symptom 8.3 yr ofatumumab, vs 7.6yr ponesimod). In both studies about 40% of pwMS had Gd+ lesions on their scan. Number of relapses in the year before inclusion 1.2/1.3. If these small differences in demographics determine significance on the neuroprotective outcome, then the effects must be very overall small.

          But it is true that ofatumumab seems to be doing better in terms of halting inflammation without clear superiority on the BVL/CDA outcomes compared to ponesimod. Potentially the FU of these studies is not sufficiently long to quantify the full effect of halting inflammation on neuroprotection.

  • I cannot believe they keep bringing same type of drugs to market. Yes they solved some secondary problems but where is the innovation? Did they stop ms? $$$$

    • Hi Maria
      It’s yet another example of the well known “Me too” phenomenon we see so often from pharma. Thoughto be fair, sometimes the subsequent drugs may have better side-effect profiles than the originals.

    • Yes, I agree. This newer drugs have less side effects, which is good, but are clearly not the ‘cure’ pwMS need.

  • Why is siponimod the only one with a licence for active spms. Is the difference in the medicine or in the way the trail was done?

    • Yes, it’s the only drug that is currently officially licensed for secondary progressive MS. This is because the trial specifically included people with SPMS who had shown progression in disability in the two years before inclusion. Some claim that siponimod is more effective in SPMS because it also targets the S1P5 receptor which is present in the brain. This receptor is involved in neuronal plasticity.

      However, it’s unclear whether this is clinically relevant and to be honest I don’t think it is. Most likely the trial was finally sufficiently powered to detect small effects of anti-inflammatory drugs on the disability outcomes in SPMS individuals who are typically less likely to have a lot of inflammation. The trial namely included 1105 pwMS in the siponimod arm, which is a really big number of participants. In comparison, the ponesimod trial in RRMS ‘only’ included 567 individuals. The bigger the patient numbers, the smaller differences you can detect between groups.

  • The other issue that seems to be being pointed to in a few posts here is that fingolimod is not a great agent to change from- ie a chance it makes the next drug less effective(eg case study in cladribine). Has this become any clearer or could it be coincidental? Is it likely a class issue too? Perhaps the sip are best left to later/older pwms if/after other agents have failed and pregnancy is off the cards

    • This is entirely true, and indeed probably a class effect. It links both to the reversibility of the drug and the rebound activity.

      If you want to switch from fingolimod to another DMT such as CD20, it is important that lymphocyte counts return to normal. Because otherwise lymphocytes that are still sequestered in the lymph nodes escape treatment. The problem is that with fingolimod this will take about 2 months, and meanwhile you are susceptible to rebound disease activity. So if you start CD20 too fast, there is less chance for rebound but more chance that CD20’s effectiveness will be suboptimal.

      This problem will not disappear with the newer agents. However, the faster lymphocytes recover to normal, the faster you can initiate another drug, which leaves less time for new disease activity to develop. If you could switch to a different DMT one week after stopping for example ponesimod, I would expect the odds of rebound activity to be lower than when the interval needs to be 2 months. But no data to back this up, and super important in clinical practice.

      • Would it be sensible to start CD20 treatment before the washout completes?
        1. As there still might be a considerable amount of antibodies left in blood say if CD20 were started 2 weeks after stopping fingolimod.
        2. Or do two administrations of CD20, the first one at 2 weeks after stopping FTY, and follow up at 6/8 weeks after stopping, the first infusion to prevent rebound, the second infusion to kill the B cells escaped the first round.

        • Interesting strategy, and very sensible given the half-life of ocrelizumab. Ideally, this should be included in the SmPC.



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