A trio of papers based on deep dives into findings from the pivotal EXPAND trial of siponimod reported at the CMSC 2020 virtual meeting add to the accumulating data about the benefit of this newcomer to the multiple sclerosis armamentarium.
These latest analyses, presented as poster by alternating principal investigators Bruce A.C. Cree MD, PhD, of the Department of Neurology, UCSF Weill Institute for Neurosciences, University of California San Francisco, San Francisco, and Amit Bar-Or of the Center for Neuroinflammation and Experimental Therapeutics and Department of Neurology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, address three areas of concern:
- The effect of siponimod on disability progression independent of relapse activity.
- The effect of disease duration on siponimod’s efficacy and safety.
- The first-dose effect of siponimod among patients concomitantly receiving SSRIs.
Taking these one at a time, Cree and colleagues confirmed disability progression (CDP) to determine the relationship between CDP and relapses to tease out the effect of siponimod on CDP independent of relapse. As previously described, the EXPAND trial enrolled patients with secondary progressive MS with expanded disability status scores (EDSS) ranging from 3.0 to 6.5.
The trial enrolled 1,651 patients and assigned 1,105 to siponimod (2 mg once daily) and 546 to placebo. Compared to placebo, siponimod treated patients were 21% less likely to increase 3-month CDP and 26% less likely to increase 6-month CDP for up to 3 years of trial participation.
In their poster, Cree and colleagues conducted a subgroup analysis to determine the impact of relapses on CDP, examining patients with or without relapses in the 1 to 2 years prior to the study.
Among those patients with no relapses during the 1 and 2 years prior to the study, the risk reductions were “18% (hazard ratio [HR], 0.82 [confidence interval (CI):0.66; 1.02]) and 13% (0.87 [0.68; 1.11]), respectively, for 3m-CDP and 25% (0.75 [0.59; 0.96]) and 18% (0.82 [0.62; 1.08]), respectively, for 6m-CDP,” they wrote.
For relapsing patients, the risk reductions were greater: 33% and 33% (3m-CDP), and 30% and 37% (6m-CDP), respectively, in years 1 and 2.
“In principal stratum estimates, siponimod reduced 3m-CDP by 14-20% and 6m-CDP by 29-33% in non-relapsing patients across the 3 timepoints, suggesting that these patients achieved a large proportion of the effect in the overall population. Cox model censoring at relapse confirmed beneficial effects, reaching nominal statistical significance (6m-CDP: HR 0.77 [0.62;0.96]),” they wrote.
Based on those findings, they concluded that siponimod’s benefit in reducing disability progression is “largely independent” of its benefit in reducing relapses.
Bar-Or was first author on two additional posters that mined the EXPAND data. In the first post hoc analysis, he and his colleagues assessed the potential impact of MS disease duration. The mean disease duration for patients enrolled in EXPAND was 16.8 years from initial MS diagnosis and 3.8 years since conversion to secondary progressive MS (SPMS).
In this analysis, the researchers looked at two groups: those whose MS symptoms were apparent less than 16 years and those with MS for 16 or more years. They performed their analysis in patients with active SPMS—meaning those with a relapse in the 2 years prior to EXPAND screening or those with one or more T1 Gadolinium-enhancing (Gd+) lesions at baseline.
They identified 779 patients with active SPMS, of whom 427 had MS duration of less than 16 years while 352 had a duration of 16 years or longer. Of those who had MS for less than 16 years, 285 had received siponimod in the original expand study and 142 were randomized to placebo. Among the group with MS for 16 years or longer, 231 were in the siponimod group and 121 were in the control arm.
Among the findings:
- Among those with MS less than 16 years, siponimod reduced 3- and 6-month CDP relative risk by 32.4% and 42.7%, respectively, highly significant in both cases.
- Among those with MS for 16 years or longer, “siponimod had a trend towards reduced 3 and 6 month CDP risk of 31.9% and 27.1%, respectively, versus placebo (3 month: siponimod, n=61 [26.4%]; placebo, n=43 [35.5%]; HR, [95% CI]: 0.68, [0.46, 1.01]; P=0.0540; 6 month, siponimod, n=51 [22.1%]; placebo, n=34 [28.1%]; HR, [95% CI]: 0.73, [0.47, 1.13]; P=0.1544).”
The conclusion was that siponimod achieved a greater benefit in those with shorter disease duration, but Bar-Or and colleagues cautioned that the finding may reflect a difference in sample size.
In the third poster presented — again with Bar-Or as first author—the issue of concomitant SSRI (citalopram and escitalopram) use was analyzed. Those SSRIs are “associated with prolonged QTc and torsades de pointes” which is of concern, since “transient heart rate decrease at initiation is a known effect of S1P modulators” such at siponimod.
The authors noted that “[F]irst-dose observation with siponimod is only required in certain cardiac conditions,” but it was unknown if concomitant SSRI use would set up a drug-drug scenario and thus also increase heart risk.
In EXPAND, 167 of 1,105 patients randomized to siponimod were also taking an SSRI on day 1. The SSRI subgroup included 85 who were taking citalopram or escitalopram.
“For those with extended monitoring, in the overall siponimod group, and the any SSRI and citalopram/escitalopram subgroups, most were discharged at 6 h post first dose (91.1%, 91.4% and 89.6%, respectively). Day 1 after first dose, 4 patients (0.4%) in the overall siponimod group had serious AEs (SAEs), 2 (0.2%) had bradycardia and 1 (0.1%) had second-degree atrioventricular (AV) block; no SAEs occurred in the any SSRI or citalopram/escitalopram subgroups,” they wrote.
Overall, in the siponimod group, “3 patients discontinued the drug due to first- or second-degree AV block or bradycardia. No patient receiving SSRIs had a cardiac AE causing treatment discontinuation.”
Be aware that the findings in this report are based on poster presentations at a virtual meeting and as such they have not been subject to publication peer-review, so the results should be cautiously interpreted.
Be aware that siponimod’s benefit appears to be greatest in patients with an MS disease duration of less than 16 years.
Peggy Peck, Editor-in-Chief, BreakingMED
The EXPAND trial was funded by Novartis.
Bar-Or disclosed consulting fees from Atara Biotherapeutics, Bayer, Bayhill Therapeutics, Berlex, Biogen Idec, BioMS, Celgene/Receptos, Diogenix, Eli Lilly, F Hoffman-La Roche, Genentech, GlaxoSmithKline, Guthy-Jackson/GGF, Immunic, Janssen/Actelion, MAPI, Medimmune, Merck/EMD Serono, Novartis, Ono Pharmacia, Roche/Genentech, Sanofi-Genzyme, Teva Neuroscience, and Wyeth.
Cree disclosed consulting fees from Akili, Alexion, Atara, Biogen, EMD Serono, Novartis, and TGTherapeutics.
Cat ID: 130
Topic ID: 82,130,730,130,36,764,192,925,763