Phase III results for siponimod in SPMS


Preliminary results from the EXPAND trial show that siponimod significantly reduces disability progression confirmed at three and six months, according to results presented at the annual meeting of the European Committee for Treatment and Research in MS (Kappos et al. ECTRIMS 2016; abstract 250). 

Siponimod (BAF312) is a second-generation sphingosine-1-phosphate (S1P) receptor modulator that is selective to the S1P1 and S1P5 receptors (Pan et al. ACS Med Chem Lett 2013;4:333-337; free full text at Dosing is titrated, which attenuates the first-dose bradycardia associated with S1P modulation (Legangneux et al. Br J Clin Pharmacol 2013;75:831-841). Dosing and safety were previously examined in the phase II BOLD trial (Selmaj et al. Lancet Neurol 2013;12:756-767; Kappos et al. JAMA Neurol 2016;73:1089-1098).

In the EXPAND trial, subjects were enrolled if they had an initial RRMS course followed by a progressive increase in disability over at least six months (Kappos et al. ECTRIMS 2015; abstract P649). Patients were older (mean age 48 years) with a mean time since MS diagnosis of 12 years (mean 3.8 years from onset of SPMS). One-third experienced relapses in the two years prior to entry. Mean EDSS score at baseline was 5.4; 53% had an EDSS score 6.0-6.5. As such, the study population was similar to that of the recent ASCEND trial of natalizumab in SPMS (29% with relapses in the two years prior to entry; 63% with EDSS 6.0-6.5) (Giovannoni et al. ECTRIMS 2016; abstract P1270). In that study, natalizumab was not superior to placebo in the proportion of patients with confirmed disability progression on a composite endpoint (EDSS, Timed 25-Foot Walk [T25FW], 9-Hole Peg Test [9HPT]); improvement was seen on the 9HPT.

For EXPAND, a total of 1651 subjects were randomized to placebo or a starting dose of siponimod 0.25 mg x 6 days, increased to 2.0 mg/day. The primary outcome was time to three-month confirmed disability progression (CDP). Siponimod was associated with a mean 21% reduction in three-month CDP at a mean 21 months’ follow-up (p=0.013); and a 26% reduction in six-month CDP (p=0.006). The percent brain volume change from baseline was 23.4% lower over 12 and 24 months with siponimod versus placebo (p=0.0002). There was no significant difference in time to three-month confirmed worsening >20% in T25FW. Significant differences were seen with siponimod in the change from baseline in T2 lesion volume, and in annualized relapse rate.

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