PARIS — The investigational drug siponimod (Novartis) can slow brain atrophy and decrease lesion activity in patients with secondary progressive multiple sclerosis (SPMS), new research suggests.
MRI outcomes from the phase 3 EXPAND trial, which assessed more than 1600 patients with SPMS, showed that those who received the active treatment had significantly less change in brain volume and T2 lesion volume, fewer new and enlarging T2 lesions, and fewer gadolinium-enhancing and T1 (Gd+T1) lesions up to 24 months later than patients who received placebo.
Dr Robert J. Fox
Robert J. Fox, MD, staff neurologist at the Cleveland Clinic, Ohio, presented the findings here at the 7th Joint European Committee for Treatment and Research in Multiple Sclerosis-Americas Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS-ACTRIMS) 2017 meeting.
“Treatment benefits in favor of siponimod were observed for all of the key outcomes and analysis sets investigated,” said Dr Fox.
The MRI results, together with clinical outcomes reported previously, “support the overall beneficial effect” of the drug in patients with SPMS, he added.
S1P Receptor Modulator
Siponimod is a selective sphingosine-1-phosphate (S1P) receptor modulator and “reduces lymphocyte egress from lymph nodes,” Dr Fox told meeting attendees.
The full EXPAND trial included 1651 patients aged 18 to 60 years (mean age, 48 years; 60% women; mean duration of MS, 16 to 17 years) who were randomly assigned 2:1 to receive oral siponimod tablets at once-daily doses of 2 mg (n = 1105) or matching placebo (n = 546).
The main trial findings showed that the participants receiving the active treatment had a 21% risk reduction in 3-month confirmed disability progression, the primary endpoint, compared with those receiving placebo (P = .01). They also had a 26% risk reduction at 6 months (P = .006).
Patients with 6-month confirmed disability progression were allowed to switch to open-label siponimod or other therapy options — or no therapy at all.
In further analyses, the full set “is based on the intent-to-treat principle,” said Dr Fox. It comprised all randomly assigned patients, including those who prematurely discontinued treatment and those who switched to open-label treatment.
The per-protocol analysis set was the same, except that it included data only up to discontinuation of medication during the study’s core phase.
New MRI Outcomes
In the full analysis set, the siponimod group had a 75% lower adjusted mean change in T2 lesion volume (the main secondary outcome) from baseline to months 0 to 12 than did the placebo group and an 83% lower change from baseline to months 0 to 24 (P < .001 for both comparisons).
In the per-protocol set, the active treatment group had 85% and 94% lower changes in T2 lesion volume over months 0 to 12 and 0 to 24, respectively, compared with the placebo group (P < .001 for both comparisons).
Compared with the placebo group, the siponimod group also had significantly less brain volume loss, measured as percentage brain volume change (PBVC), as well as fewer new and enlarging T2 lesions and fewer Gd+T1 lesions.
Table. MRI Outcomes in Siponimod vs Placebo Treatment Groups
| Outcome | Full Data Set (Reduction) | Per-Protocol Set (Reduction) | ||
|---|---|---|---|---|
| Number of Gd+T1 lesions | ||||
| At mo 12 | 0.08 vs 0.64 (87%)a | 0.05 vs 0.60 (91%)a | ||
| At mo 24 | 0.07 vs 0.42 (42%)a | 0.07 vs 0.57 (88%)a | ||
| Number of new, enlarging T2 lesions | ||||
| At mo 0 – 12 | 1.00 vs 3.78 (73%)b | 0.74 vs 3.32 (78%)b | ||
| At mo 13 – 24 | 0.49 vs 3.44 (86%)b | 0.31 vs 3.13 (90%)b | ||
| PBVC | ||||
| At mo 0 – 12 | –0.28 vs –(39%)b | –0.24 vs –(48%)b | ||
| At mo 0 – 24 | –0.71 vs –0.84 (15%)c | –0.63 vs –(31%)b | ||
| aP < .001. bP < .0001. cP < .02. |
||||
“Siponimod significantly reduced MRI lesion activity and slowed brain volume loss in patients…as early as month 12, with effects sustained to month 24,” said Dr Fox.
“Positive effects on brain volume loss and disability progression support potential neuroprotective effects” of the drug, he added.
Session co-chair Alan J. Thompson, MD, dean of the University College London Faculty of Brain Sciences, United Kingdom, asked during the question-and-answer phase for a better explanation for the term “neuroprotective.” “What exactly do you mean by that?” he asked.
“Our measures of acute inflammation, of lesions and brain atrophy, gives us a glimpse into protecting the brain from the ongoing injury of progressive MS, whether that be from the acute injury or from the degenerative or other aspects of secondary progressive MS,” answered Dr Fox.
“Unfortunately, [we] were unable to tease apart what contributions may come from a prevention of new lesions versus a direct neuroprotective effect on the brain,” he said. “I think some more sophisticated analyses would need to be done to try to disentangle the direct anti-inflammatory effects of siponimod on brain atrophy from the direct, potentially neuroprotective effects.”
Questions Remain
After the presentation, the other session co-chair, Jerry S. Wolinksky, MD, professor emeritus and professor of neurology and MS at the University of Texas Health Science Center, Houston, noted that the MRI data “seemed supportive” of the clinical data previously released.
Dr Jerry S. Wolinksky
“If it hadn’t, I would have worried about what happened in the primary” part of the trial, Dr Wolinksky told Medscape Medical News.
“I think the issue, in the long-run, is how S1P inhibitors are differentiating themselves in progressive disease; and unfortunately I don’t have an answer for that.”
He added that teasing out that information is especially important because “without those answers, depending on what or when things happen with regulatory authorities, we’re going to have problems in making treatment choices for our patients.”
The study was funded by Novartis Pharma AG. Dr Fox has received consulting or speaker fees from Allozyne, Avanir, Biogen Idec, Questcor, and Teva, and he has received consulting or speaker fees and research support from Novartis. Dr Wolinsky was not involved with EXPAND but reports having worked before with Novartis on researching other agents.
7th Joint European Committee for Treatment and Research in Multiple Sclerosis-Americas Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS-ACTRIMS) 2017. Parallel session 6, oral presentation 129. Presented October 26, 2017.
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