250 – Efficacy and safety of siponimod in secondary progressive multiple sclerosis – results of the placebo controlled, double-blind, Phase III EXPAND studyL. Kappos, Basel, Switzerland
Background: There is high unmet need for treatments that delay disability progression in secondary progressive multiple sclerosis (SPMS). Siponimod (BAF312) is an orally active selective modulator of the sphingosine-1-phosphate receptor subtypes 1 and 5. EXPAND is the largest randomised controlled study in SPMS to date.
Objective: EXPAND is a phase 3, multicentre, randomised, double-blind, placebo-controlled study designed to evaluate the efficacy, safety and tolerability of siponimod in treatment of SPMS.
Design/methods: Patients with SPMS, defined by a progressive increase in disability (of ≥6 months duration) in the absence or independent of relapses, aged 18‒60 years and an Expanded Disability Status Scale (EDSS) score from 3.0‒6.5 were enrolled. Eligible patients were randomised (2:1) to receive either 2mg once daily siponimod (following initial dose titration starting at 0.25mg) or matching placebo. The event-driven study design allowed the blinded Core study stop after a pre-specified number of confirmed disability progression (CDP) events occurred. The primary efficacy outcome was time to 3-month CDP measured by EDSS. The key secondary outcomes were time to confirmed worsening of ≥20% from baseline in the timed 25-foot walk test and T2 lesion volume change from baseline. Safety assessments included reporting of adverse events (AEs), serious AEs (SAEs) and clinically notable laboratory abnormalities. Patients who completed the Core phase were offered to receive open-label siponimod in the Extension phase.Results: Overall, 1651 patients were randomised in 31 countries. Baseline demographics and disease characteristics were previously reported, and they are representative of a patient population with SPMS. Overall, 1363 (83%) patients completed the Core study. Median time on study at core study completion was 21 months with majority of patients (87%) participating for ≥1 year. There were 449 CDP events (each patient could maximally contribute one event for the primary endpoint). AEs were reported in 85.3% and SAEs in 16.7% of patients.
Conclusions: Top line efficacy and safety results of the EXPAND study will be presented. The results of this large controlled study that recruited an active SPMS population with and without superimposed relapses will determine if siponimod delays disability progression in SPMS, and will contribute to a better understanding of the natural history of SPMS in a well-controlled trial setting.
COI None ProfG multiple
So here we have it an drug with an effect on SPMS that slows progression in a phase III trial So this is good news.
The bad news I guess, is that the drug only slowed the rate of 3 month progression by 22% over so disease was not halted and an effect on 25 foot walking was not apparent and at the end of the study about 18% decided to withdraw which must mean that they were disatisfied with the outcome.
The question however is is this due an effect on disease activity rather than true progression and the answer is you can’t truly answer this, however it was clear that there were people with relapses in the trial and about 35% had evidence of disease activity and relapses were reduced by about 55% compared to placebo, so just like you would expect for a sphingosine-1-phosphate modulator and indeed people who had MRI activity responded more than people who did not have gadolinium activity, but neverthe less there was still an effect in people without gadolinium at baseline but did they have lesions along the way we will never news.
So whilst this is a start, we have to do better.
Further disappointing news
Fluoxetine in progressive multiple sclerosis (FLUOX-PMS)
M. Cambron1, J. Mostert2, J. Parra3, M. D’hooghe4, G. Nagels4, B. Willekens5, D. Heersema6, J. Debruyne7, W. Van Hecke8, L. Algoed9, N. De Klippel10, E. Fosselle11, G. Laureys12, H. Merckx13, B. Van Wijmeersch14, L. Vanopdenbosch15, W. Verhaegen16, R. Hupperts17, G. Hengstman18, V. Michiels1, A. Van Merhaegen – Wieleman1, J. De Keyser
The trial failed P=0.07 is this a real trend or an indication for the effect of MS-SMART