Progressive MS studies


REPORT FROM AAN – BOSTON, MA, APRIL 22-28, 2017 AAN 2017: There is a growing body of data on the use of disease-modifying therapies in patients with progressive multiple sclerosis. The following is a summary of key studies presented at AAN 2017.

Ocrelizumab: In the phase III ORATORIO trial in primary-progressive MS, a significantly lower proportion of patients had 24-week confirmed disability progression with ocrelizumab 600 mg q24 weeks versus placebo (32.9% vs. 39.3%; 24% reduction) (Montalban et al. N Engl J Med 2017;376:209-220). A new analysis of ORATORIO examined a novel composite measure, NEPAD (for no evidence of progression or active disease), from baseline to week 120 (Wolinsky et al. AAN 2017; abstract P4.384).

Progression was assessed using EDSS and Timed 25-Foot Walk (T25FW); active disease was defined as no relapses or new MRI activity (new Gd+ T1, new/enlarging T2 lesions). The proportion of patients achieving NEPAD at week 120 was 29.9% with ocrelizumab vs. 9.4% with placebo (risk ratio 3.15).

Natalizumab: ASCEND was a phase III trial in SPMS that was terminated when active treatment failed to significantly delay disability progression versus placebo, however, an extension is ongoing (Hartung et al. AAN 2017; abstract P5.330). A total of 63.7% participated in the extension; median follow-up was 160.4 weeks for the continuous NTZ group, and 156.9 weeks for the placebo-NTZ group. Patients on continuous NTZ vs. placebo-NTZ were less likely to demonstrate progression on the composite endpoint (52% vs. 61%). Benefits were more evident on 9-Hole Peg Test than on EDSS or T25FW. The authors suggested that results support the idea of a therapeutic lag, a concept that was proposed at last year’s ECTRIMS (Sormani et al. ECTRIMS 2016; abstract 215) (see ECTRIMS slide deck, NeuroSens, October 24, 2016).

Teriflunomide: A small number of patients enrolled in the phase III TEMSO and TOWER trials had SPMS (n=60) or PPMS (n=62); 59% completed the core studies (Nelson et al. AAN 2017; abstract S33.008). During the 9-year extension, 80.3% of progressive patients experienced no 12-week confirmed disability progression; median EDSS score was unchanged from baseline.

Siponimod: This novel agent is a sphingosine-1-phosphate (S1P) receptor modulator selective for S1P1 and S1P5 receptors. The clinical development program includes EXPAND, a phase III trial in SPMS (Kappos et al. AAN 2017; CT.002). Subjects received placebo or siponimod 2 mg/day after a 6-day dose titration. The proportion of patients with 24-week confirmed disability progression was 19.9% with siponimod vs. 25.5% with placebo; relative risk reduction was 26%. A subgroup analysis reported a significant reduction in disability risk in patients without active inflammation (no relapses in prior 2 years; no Gd+ lesions at baseline). There were also significant effects on T2 lesion volume and percent brain volume change from baseline with siponimod. (Fox and colleagues. AAN 2017; S33.007). In the safety analysis, the rate of discontinuation due to adverse effects was 7.6% with siponimod vs. 5.1% with placebo (Fox et al. AAN 2017; abstract S33.007). The most common adverse effects with siponimod were headache, nasopharyngitis, UTI, falls and hypertension. The incidence of infections and malignancies was similar with siponimod and placebo. There were few episodes of bradyarrhythmia with dose titration.

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