ECTRIMS-ACTRIMS: Phase III data EXPAND on siponimod for secondary progressive multiple sclerosis

ECTRIMS-ACTRIMS: Phase III data EXPAND on siponimod for secondary progressive multiple sclerosis

898 506 Peter Stevenson, PhD

Data presented at the recent 7th joint ECTRIMS-ACTRIMS meeting in Paris delved deeper into the efficacy of siponimod in the treatment of secondary progressive MS (SPMS).

As Robert Fox (Mellen Center for Treatment and Research in Multiple Sclerosis, Neurological Institute, Cleveland, OH, USA) relayed, siponimod is a selective S1P receptor modulator, in particular the S1P1/S1P5 subreceptors. It works like many other S1Ps in that it reduces lymphocyte egress from the lymph nodes, but it also may have some central nervous system (CNS) activity, some of which may have neuroprotective properties.

The goal of the analysis he presented was to evaluate the effect of siponimod versus placebo using MRI measures of disease activity from the Phase III EXPAND trial1, focussing on SPMS patients.

A key secondary endpoint was change in T2 lesion volume, as well as the number of gadolinium-enhancing T1 (Gd+T1) lesions, the number of new or enlarging T2 lesions, and brain volume loss as percentage brain volume change using SIENA (Structural Image Evaluation, using Normalisation, of Atrophy).

Dr Fox referred to previous data in the field, in particular Phase III data showing that 2 mg of siponimod significantly reduces the risk of confirmed disability progression (CDP) when compared to placebo in a “typical” SPMS population.

Turning to EXPAND, he went on to note that the study has an event- and exposure-driven design, i.e. participants enrolled in the study continue until the total number of events are met. A total of 1105 and 546 patients have been included in the siponimod and placebo groups, respectively, with a median trial participation lasting 18 months.

MRI was performed annually over the course of the study, and importantly, patients with six-month CDP had the option to switch to open-label siponimod, other disease-modifying treatments, or no therapy.

“The full analysis set was based on intend-to-treat,” said Dr Fox. “It comprised all randomised subjects, and used all of the data, irrespective of premature study discontinuation.”

He added: “There was also a sensitivity analysis that looked at the per-protocol set, which was just patients who remained on siponimod for the duration of the study.”

The study population was a “fairly typical” SPMS cohort, with an average age of 69, around 60% being women, a 16-17-year disease duration, and about 21% of each group had gadolinium-enhancing lesions at baseline.

Describing the results, Dr Fox noted that the main secondary outcome – change in T2 lesion volume – showed a 75% reduction in the full analysis set in the first year, and an 83% reduction in the change of T2 lesion volume over two years. Sensitivity analysis confirmed this, with an 85% and 94% reduction in T2 lesion volume over one and two years, respectively.

Full analysis for Gd+T1 lesions also showed a reduction at one year (87%) and two years (82%), with sensitivity analysis showing 91% and 88% reductions. Results continued to be significant, with siponimod-treated patients seeing a 73%/86% reduction in the number of new or enlarging T2 lesions at one/two years (full analysis), and 78%/90% in the per-protocol set.

“Atrophy in the first year showed a 39% reduction in progression of brain atrophy in the siponimod-treated subjects, compared to placebo,” continued Dr Fox. “And over the full two years, from baseline to month 24, there was a 15% [reduction].”

He added that sensitivity analysis gave a little more insight into that data, with a 48% reduction in the progression of brain atrophy in the first year, and 31% over the entire two years.

“We will take a little bit of a deeper dive to understand the difference between the results, but I will point out that patients out to month 24 were allowed to change therapies – to go on open-label siponimod, and importantly open-labels of other disease-modifying therapies, some of which have known pseudoatrophy effects, and that may have confounded some of the analysis here,” said Dr Fox.

Offering his conclusions, he began by reiterating that siponimod significantly reduced MRI lesion activity and slowed brain volume loss in patients with SPMS as early as month 12, with effects sustained to month 24. Crucially, treatment benefits in favour of siponimod were observed for all key outcomes and analysis sets investigated.

Furthermore, positive effects on brain volume loss and disability progressions support the potential neuroprotective effects of siponimod.

“These MRI results, together with the clinical outcomes, support the overall beneficial effect of siponimod in patients with SPMS,” he said in closing.


Reference

  1. ClinicalTrials.gov. ‘Exploring the Efficacy and Safety of Siponimod in Patients With Secondary Progressive Multiple Sclerosis (EXPAND)’, https://clinicaltrials.gov/ct2/show/NCT01665144, (accessed October 27 2017).
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