The interim analysis of the EXCHANGE trial suggest that, for patients with relapsing multiple sclerosis, immediate conversion from oral/injectable disease modifying therapies to siponimod without any washout period (within 24 hours) had a good safety and tolerability profile. Physician’s Weekly interviewed Prof. Amit Bar-Or, neurologist and neuroimmunologist at the University of Pennsylvania, who presented the interim findings of the EXCHANGE trial (NCT03623243) at the MSVirtual2020: 8th Joint ACTRIMS-ECTRIMS Meeting September 11–13, 2020 [1].

EXCHANGE is a six-month multicenter open label single arm prospective study to assess the impact of immediate conversion to dose-titrated siponimod from oral and injectable disease modifying therapies (DMTs) in patients with advancing relapsed multiple sclerosis (RMS). The rationale behind this study is that understanding washout requirements when converting from other DMTs to siponimod is important in clinical practice and should be assessed prospectively. The primary endpoint is incidence of drug-related adverse events (AEs). Secondary endpoints include cardiac safety analysis, treatment satisfaction, and patient adherence. The study will include a parallel but separate novel remote patient cohort (about 100 patients) with recruitment and assessment performed in patients’ homes using telemedicine tools, but that data is still immature.

A total of 112 patients from 42 US centers were Included in the analysis, of whom 70.5% were female and the median age was 45.5 years. Patients had an Expanded Disability Status Scale (EDSS) score of >2.0 to 6.5 (the median was 3.5), and had been receiving continuous oral/injectable DMTs for ≥3 months at time of consent. Participants were immediately converted to siponimod, except those whose previous regimen was teriflunomide who required 11-14 days washout (with cholestyramine or activated charcoal). Siponimod was titrated up from 0.25 mg to 2 mg during days 1-6.

Among the patients, 74.1% (n=83) had RMS, 21.4% (n=24) had secondary progressive multiple sclerosis (SPMS), 3.6% (n=4) had primary progressive MS and 0.9% (n=1) had a single demyelinating event. During the prior 12 months 42.0% (n=47) had ≥1 relapse. In the safety analysis set, ≥1 drug-related AE was reported in 34.8% of patients (n=39; 95% confidence interval [CI] 26.2-44.5); 4.5% (n=5) had ≥1 serious AE and 5.4% (n=6) had ≥1 AE leading to drug discontinuation. In the subgroup of patients who had completed or discontinued from the study (n=74), 40.5% (n=30; 95% CI 29.5-52.6) had ≥1 treatment-related AE. Importantly, the change from baseline in heart rate to 6 hours post first dose did not signify a reduction in heart rate, which was a concern because of that safety signal from the related drug fingolimod. No new safety signals for AEs were reported, regardless of prior DMT.

In conclusion, these early data from EXCHANGE showed that conversion from oral/injectable DMTs to siponimod without washout had a good safety and tolerability profile with no unexpected findings. Subsequent analyses will examine conversion to siponimod from infusible (natalizumab/ocrelizumab) DMTs.

When asked by Physician’s Weekly to comment on his study, Amit Bar-Or, MD, FRCP, FAAN, FANA, lead author of EXCHANGE, is a research and clinical care collaborator with the MS and Neuroinflammatory Disorders Clinic at Children’s Hospital of Philadelphia. commented: “In essence, the study sought to answer a very relevant question to clinicians. With the approval of siponimod for patients with various forms of multiple sclerosis, comes the question of whether switching from an existing disease-modifying therapy to siponimod is safe without actually having a washout. Presumably, the patient is switching to siponimod because their previous treatment was either insufficiently controlling their disease, or is not being well tolerated. In either case, this will be patient struggling to manage their MS. By introducing a new drug with a different mode of action that impacts the immune system, you have to ask yourself, from the safety and tolerability perspective in particular, is there really a need for a washout? The study was designed to look at conversion without washouts, and the answer is that that approach has an acceptable safety and tolerability profile.”

No decreased heart rate

“One of the questions we wanted to answer was whether or not the initial exposure to siponimod will cause a decrease in heart rate. The founder drug in the class of sphingosine-1-phosphate receptor modulators to which siponimod also belongs, fingolimod, has required first-dose monitoring due to heart rate concerns. Consequently, siponimod is given as a dose-titration initially, but patients do not seem to experience the same reduction in heart rate. The data from EXCHANGE compellingly suggest that siponimod does not require first dose observation; there is no evidence of a reduction in the heart rate in initiating siponimod in either the overall group or in the group that was stratified based on previous DMT. Overall, this study provides quite clinically relevant real-life information for practitioners, with some guidelines for switching patients to siponimod from another DMT.”

Cognition benefit?

“There was post hoc data presented at MSVirtual that illustrated that siponimod improved cognitive processing speed and delayed time to disability in multiple sclerosis [2]. The reason that it is particularly interesting to ask about cognition in the context of siponimod, is because siponimod, like other agents in the family of the sphingosine-1-phosphate receptor modulator family, will sequester or trap the peripheral immune cells, disabling them to participate in immune disease activity. This mode of action will impact all aspects of relapsing disease biology. Thus, sphingosine-1-phosphate receptor modulators seem to be effective at limiting injury by normalizing the biology. It was this shared relapsing biology across the MS spectrum that facilitated the extrapolation by the FDA to approve siponimod for not only SPMS with activity, but also for Relapsing-Remitting MS and even for Clinically Isolated Syndrome.”

“One of the attractive things about siponimod is that by eliminating the relapsing biology, it allows researchers to tease out the non-relapsing progressive biology of MS. It is attractive to think that monitoring cognition is a way to clinically capture those processes. The rationale is that because people with MS usually have their cognitive issues progress gradually over time, not as an acute or unpredictable sequence of new cognitive attacks, researchers can predict natural decline. Medical intervention could therefore be measured against predicted decline. Cognition may be one important manifestation of progressive MS biology that clinicians can use to show whether a drug like siponimod favorably impacts cognition. That research is important and could be relevant for progressive disease and even for repair. This is one of several really interesting possibilities that need to be more formally proven in patients in clinical trials. The observation that cognition is favorably impacted in terms of less progression over time is perhaps an indication that siponimod might have an impact on MS progressive diseases above and beyond the relapsing aspects.”


  1. Bar-Or A, et al. Safety and tolerability of conversion to siponimod in patients with relapsing multiple sclerosis: interim results of the EXCHANGE study. Presented at MSVirtual2020: 8th Joint ACTRIMS-ECTRIMS Meeting; September 11–13, 2020; September 2020. Poster P0233.
  2. Giovannoni G, J, et al. Sustained reduction of disability and cognitive decline with long-term siponimod treatment in patients with active SPMS: EXPAND data up to 5 years. Presented at MSVirtual2020: 8th Joint ACTRIMS-ECTRIMS Meeting; September 11–13, 2020. Poster P0238.