Siponimod in SPMS
Alemtuzumab – 9-year results
Ocrelizumab in PPMS – extension data
Starting and switching DMTs
RIS – Predictors of CIS/MS
Do real-world people enter real-world studies?
Clinical Tip of the day
Siponimod in SPMS
Siponimod, a sphingosine 1-phosphate receptor-1,5 modulator, was recently approved in the U.S. for the treatment of relapsing forms of MS, including CIS, RRMS and active SPMS. Approval was based on the results of the EXPAND trial, which reported a significant 21% reduction in the risk of 3-month confirmed disability progression (CDP) with siponimod 2 mg versus placebo in SPMS patients (Kappos et al. Lancet 2018;391:1263-1273). In the subgroup (n=779) with active disease (relapses in the two years before screening and/or Gd+ lesions at baseline), 3-month CDP risk was reduced 31% with siponimod vs. placebo; 6-month CDP risk was reduced 37% (Gold et al. ECTRIMS 2019; abstract P750). The risk of 6-month confirmed four-point worsening on the Symbol Digit Modalities Test (SDMT) was reduced by 27% with active treatment. An analysis of the effect of siponimod on cognition was presented at AAN 2019 (Benedict et al. S44.004) (see AAN Daily Report, NeuroSens, May 9, 2019). A separate post-hoc analysis of the EXPAND dataset reported that siponimod reduced the risk of wheelchair dependence (EDSS >7) by 36% in the subgroup of patients with baseline EDSS 6.5 (Vermersch P. ECTRIMS 2019; abstract 158). For the full study cohort, the estimated delay to wheelchair dependence was 4.3 years (from 12.0 to 16.3 years) with siponimod.
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Alemtuzumab – 9-year results
The open-label extension of the CARE-MS I trial of alemtuzumab in previously untreated RRMS patients reported that the annualized relapse rate (ARR) through nine years has remained low (0.13) (Montalban et al. ECTRIMS 2019; abstract P974). Over 9 years, 68% were free of 6-month CDP. Mean EDSS change was 0.10. Most patients (55%) did not require additional therapy after the initial two-year course. The cumulative incidence of thyroid adverse events was 46%. The cumulative incidence of ITP was 2%.
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Ocrelizumab in PPMS – extension data
In the ORATORIO trial, ocrelizumab reduced the risk of 6-month CDP by 25% versus placebo in PPMS patients (Montalban et al. N Engl J Med 2017;376:209-220). Overall, 29.6% of ocrelizumab-treated patients showed worsening disability. In the open-label extension, 33.3% had CDP in the continuous ocrelizumab group at week 168 (12 weeks after the first patients entered the extension) (Wolinsky et al. ECTRIMS 2019; abstract 159). The proportion with 6-month CDP with continuous ocrelizumab was 37.5% at week 192, 48.0% at week 264, and 51.7% at week 312.
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Starting and switching DMTs
A UK analysis of RRMS patients treated during the period 2001-2017 reported that most patients have a prolonged response to a first-line DMT (Fernandes L. ECTRIMS 2019; abstract P812). Among patients started on a lower-efficacy (injectables, teriflunomide) or moderate-efficacy (dimethyl fumarate, fingolimod) DMT, there was no significant worsening of EDSS or QoL scores for up to 10 years.
Minimal evidence of disease activity (MEDA) has been proposed as a more realistic treatment goal rather than switching at the first sign of breakthrough disease activity. A German study looked at different treatment sequences and their impact on loss of MEDA, defined as EDSS progression >1.5 points at any time during the 8-year follow-up (Jürß JP. ECTRIMS 2019; abstract P1030). The study found that time to loss of MEDA was prolonged with a DMF-fingolimod switch compared to an injectable-fingolimod switch (95 vs. 79 months). During the observation period, 18% of DMF-treated patients required a switch to fingolimod. However, it should be noted that the value of MEDA is unclear. An Italian study reported that MEDA was not predictive of disability outcomes (3-month CDP, progression to SPMS, EDSS score 4.0 or 6.0) at seven years (Tsantes et al. ECTRIMS 2019; abstract P1050). In contrast, NEDA status was associated with a significantly lower risk of 3-month CDP at seven years compared to MEDA (odds ratio 0.3).
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RIS – Predictors of CIS/MS
A retrospective analysis of 451 patients with radiologically isolated syndrome found that 53% went on to develop a clinical event during the 10-year follow-up (Lebrun-Frenay et al. ECTRIMS 2019; abstract 97). Significant predictors of a first clinical event were the finding of spinal cord lesions (cervical, thoracic) and patient age < 37 years. The presence of Gd+ lesions or positive CSF were not predictive of a clinical event. The reason for the initial MRI (e.g. headache) was also not predictive of future relapse.
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Do real-world people enter real-world studies?
A systematic review of 23 randomized controlled trials and 62 real-world studies in the period 2005-2019 found that study populations were remarkably similar (Rojas JI et al. ECTRIMS 2019; abstract P995). The drugs under study were injectable DMTs, teriflunomide, DMF, fingolimod and alemtuzumab. There were no significant differences in demographic or clinical variables between the two types of study. The sole exception was the proportion of treatment-naïve subjects, which was higher in RCTs (63% vs. 36%). Real-world studies would be expected to enroll more patients with comorbid medical conditions, but few studies provided data on comorbidities.
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Clinical Tip of the day
Women with RRMS who are contemplating pregnancy should be counselled to try to conceive during a period of relative clinical stability. An analysis of 335 pregnancies over a 5.7-year follow-up period found that a higher number of relapses in the year before pregnancy was predictive of disability worsening (hazard ratio 1.4) (Portaccio E. ECTRIMS 2019; abstract P410). Patient age, duration of MS, EDSS score at conception and treatment prior to pregnancy were not predictive of disability worsening.
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