Siponimod May Slow Worsening in SPMS

LONDON -- A novel sphingosine-1-phosphate (S1P) receptor modulator may stall disability progression in patients with secondary progressive MS, researchers reported here.

In the EXPAND study, SPMS patients on siponimod had a 21% reduced risk of 3-month confirmed disability progression compared with those on placebo (HR 0.79, 95% CI 0.65 to 0.95, P=0.013), Ludwig Kappos, MD, of University Hospital Basel in Switzerland, reported during a late-breaking session at the ECTRIMS meeting here.

The drug also hit a number of key secondary endpoints, with the exception of the timed 25-foot walk test (T25FW), which trended in the right direction but wasn't significant, Kappos reported.

As seen in earlier studies, it also didn't carry the cardiac initial dosing effects often occurring with fingolimod (Gilenya), he said.

Siponimod is considered a "second generation" version of fingolimod; it targets receptor subtypes 1 and 5, whereas fingolimod more generally hits subtypes 1, 3, 4, and 5. Siponimod works mainly by trapping lymphocytes in lymph nodes, and readily crosses the blood-brain barrier and may have additional effects within CNS, Kappos said.

The study enrolled 1,651 patients in 31 countries who had SPMS defined as a progressive increase in disability of at least 6 months, were age 18 to 60, and had Expanded Disability Status Scale (EDSS) scores ranging from 3 to 6.5.

Patients were randomized 2:1 to either 2 mg daily of oral siponimod or matching placebo, and the primary efficacy outcome was time to 3-month confirmed disability progression as measured by EDSS.

Kappos said the trial was completed when it reached 374 events, plus at least a year of follow up for 95% of patients -- which ultimately totaled 463 events over 37 months.

Overall, patients had a mean age of 48 and a mean EDSS score of about 5.4, and 82% of those on the drug and 78% of those on placebo completed the core study.

In addition to meeting the primary endpoint, there was also 26% reduction in the key secondary endpoint of time to 6-month confirmed disability progression compared with placebo (HR 0.74, 95% CI 0.60 to 0.92, P=0.006).

However, there was no significant difference on another prespecified key secondary endpoint, time to 3-month confirmed worsening of at least 20% from baseline in the T25FW. Risk was reduced by 6.2% compared with placebo, but it was not significant, Kappos said.

Other key secondary endpoints were positive for the drug compared with placebo: annualized relapse rate was reduced by 55.5% (P<0.0001), average change from baseline in T2 lesion volume was about 80% lower (P<0.0001), and change in brain volume from baseline was 23% lower (P=0.0002).

The researchers also conducted subgroup analyses in which they found several groups that fared better. Not surprisingly, these included SPMS patients who had no prior relapses, one or more gadolinium-enhancing lesions, those with more active disease, and younger patients, particularly those with a baseline age of 40.

There were similar rates of adverse events, at 88.7% in the siponimod group and 81.5% in the placebo group. Serious adverse events occurred in 17.9% of those on siponimod and 15.2% of those on placebo, Kappos said.

He added that the researchers did not see a problem with bradycardia at initial dosing, as has been the case for fingolimod, and that strict cardiac monitoring at the first dose of siponimod was discontinued about halfway through the trial.

Researchers at ECTRIMS told MedPage Today it's not clear why siponimod seems to have succeeded where fingolimod failed -- that drug did not reduce disease progression in the phase III INFORMS trial -- although trial design may have played a role, they said.

"They did a very good study that was powered properly," said John Corboy, MD, of the University of Colorado at Denver, who was an investigator of the study. "They showed that the benefit is going to be in younger patients who have a history of relapses over the last 2 years and who have enhancing lesions on their scan. This recapitulates what we've seen in other studies, but [Novartis] was smarter and they did a bigger study."

Other experts noted the modest effect of the drug on the primary outcome.

"I would offer this drug to my patients with the caveat that the efficacy was modest, and that the secondary endpoint of the timed 25-foot walk test was not met," Aaron Miller, MD, of Icahn School of Medicine at Mount Sinai in New York City, who was a site investigator in the trial, told MedPage Today. "Nonetheless, the options are very limited for patients with SPMS."

Dennis Bourdette, MD, of Oregon Health and Science University in Portland, who also was not involved in the study, said the results were "encouraging" and represent a step forward in treatment of progressive disease, but he warned that it "required a very large trial to obtain [statistical significance] on what is a modest effect.

"The effect size was small and the long-term safety of the drug is uncertain," Bourdette told MedPage Today. "We have certainly seen long-term side effects from fingolimod, including de novo cases of progressive multifocal leukoencephalopathy and serious, even fatal, herpetic infections.

"So whether the unknown long-term risks of treatment are worth the modest effect on disease progression is uncertain and if the drug is ultimately released for treating SPMS, decisions about risk-benefits will need to be made on a case-by-case basis," he added.

Comment