EXPAND

EXPAND [97] was a double-blind, randomized phase III study of 1645 adults, age 18–60, with SPMS and an EDSS score of 3.0–6.5. Patients were assigned (2:1) to once daily oral SPM 2 mg or placebo for up to three years, or until the occurrence of a pre-specified number of CDP events. The primary endpoint was time to three-month CDP. At baseline, the mean time since first MS symptoms was 16.8 years and time since conversion to SPMS was 3.8 years. Sixty-four percent of patients (*n* = 1055) had not had a relapse in the previous two years; 56% (*n* = 918) needed walking assistance. Twenty-six percent (288/1096) of patients receiving SPM and 32% (173/545) receiving placebo had three-month CDP (hazard ratio 0.79, 95% CI 0.65–0.95), a relative risk reduction of 21% (*p* = 0.013). Of the secondary endpoints, there was no significant difference between SPM and placebo-treated patients in the time to three-month confirmed worsening of at least 20% in Timed 25 Foot Walk (T25FW). The increase in T2 lesion volume from baseline was significantly lower in SPM-treated versus placebo-treated patients, with a between group difference of −695.3 mm<sup>3</sup> (95% CI –877.3 to –513.3; *p* < 0.0001). Numerically more patients receiving SPM were free of Gd+ lesions (89% vs. 67%) and of new or enlarging T2 lesions (57% vs. 37%) than their placebo-treated counterparts. Siponimod was approved for the treatment of "active forms" of SPMS, defined as patients having had a relapse in the previous 2 years, because this was the only subgroup in which the primary end-point was achieved. Following completion of the core EXPAND trial, an open label extension was initiated which is expected to conclude in 2024.
