AMSTERDAM — Siponimod significantly reduces the risk for confirmed disability progression (CDP) in patients with advanced secondary progressive multiple sclerosis (SPMS), results of a randomized trial show.
The study results were released here at the Congress of the European Academy of Neurology (EAN) 2017 by Patrick Vermersch, MD, PhD, Department of Neurology, and currently vice-dean of the faculty of medicine, University of Lille, France.
During an oral session, Dr Vermersch told delegates that siponimod (Novartis) is a selective S1P receptor modulator that “inhibits the egress of lymphocytes from the lymph nodes.” It crosses the blood–brain barrier (BBB) and may have effects within the central nervous system (CNS), said Dr Vermersch.
Its half-life is relatively short, at about 30 hours, and with a washout period of 5 to 6 days, siponimod allows for “fast immune reconstitution,” he said. “That’s important for safety.”
The phase 2 BOLD study found “highly significant data” for patients with relapsing-remitting MS (RRMS), said Dr Vermersch. In that study, siponimod reduced active MRI lesions at month 3 by 72% and annualized relapse rate by 66% at month 6.
The multicountry phase 3 EXPAND study included 1105 patients in the treatment group (who took 2 mg orally a day) and 546 patients in the placebo group.
Study patients were aged 18 to 60 years (mean age, 48 years; about 82% were over age 40 years) and had a history of RRMS. They had to have a secondary progressive course of MS, defined as a progressive increase in disability of at least 6 months in the absence of relapses. They also had to have an Expanded Disability Status Scale (EDSS) score of 3.0 to 6.5. The median EDSS score was 6.0 in both groups.
A “key” inclusion criterion, said Dr Vermersch, was evidence of EDSS progression — of 1 point or more in the previous 2 years if patients had a screening EDSS score of less than 6.0 and of 0.5 points or more if they had an EDSS score of 6.0 or more at screening.
A “high percentage” of patients had a low rate of recent relapse, or no relapses, and there was also “quite a low number” of patients with gadolinium-enhancing (Gd+) T1 lesions (about 25%), noted Dr Vermersch.
Most patients completed the study, Dr Vermersch reported. The completion rates were 82% in the treatment group and 78% in the placebo group.
EXPAND was “an event- and exposure-driven study,” said Dr Vermersch. It required 374 events of 3-month CDP and 1 or more years of exposure for more than 95% of randomly assigned patients.
The median time that patients were receiving the drug was 18 months. The researchers observed 463 events.
Significant Risk Reduction
The primary endpoint was time to 3-month CDP as assessed by the EDSS.
Results showed a significant reduction in risk for confirmed disability progression in favor of siponimod compared with placebo at 3 months (hazard ratio [HR], 0.79; P = .013) and at 6 months (HR, 0.74; P = .006).
A sensitivity analysis showed that the 3-month CDP was sustained until the end of the study. Another sensitivity analysis found that unconfirmed EDSS worsening before discontinuation was also significant in favor of siponimod.
For predefined subpopulations — according to, for example, sex, previous use of interferon, baseline EDSS score, and disease duration — “you see all the results are in favor of siponimod; however, all of them are not significant,” said Dr Vermersch.
But he pointed out that the study was not designed or powered to find significance for all these subgroups.
As for secondary endpoints, the researchers found consistent effects of siponimod on annualized relapse rate, MRI T2 lesion volume, number of new or newly enlarging T2 lesions, and number of Gd+ T1 lesions per scan (all P < .0001 vs placebo) and the percentage change in brain volume (P = .0002 vs placebo).
There was a 6.2% difference (on 3-month worsening by at least 20%) between the treatment and placebo groups in the timed 25-foot walk (T25FW), but it was not significant. This, said Dr Vermersch was “disappointing.”
In the population with a maximum EDSS score of 5.5, the T25FW results were “slightly better,” with an HR of 0.85 (a 15% reduction), but this was still not significant, he said.
Dr Vermersch questioned the usefulness of the T25FW scale “when the population is using walking aids and a large percent had an EDSS score of 6 or 6.5.”
He noted that there were more positive effects on other ambulation-related measures. For example, there was a significant reduction in favor of siponimod vs placebo for the physical subscale of the patient-reported MS Impact Scale, although not for the MS Walking Scale.
Patients with 6-month CDP had the option to switch to open-label siponimod. In the treatment group, 9% of completers are receiving open-label siponimod “rescue” medication (1% in noncompleters). In the placebo group, 14% of completers and 3% of noncompleters are receiving open-label siponimod.
Asked by a delegate to comment on why he believes siponimod crosses the BBB and is active in the CNS, Dr Vermersch said that data in animal models and in cell cultures indicate that a substantial percentage of siponimod penetrates the CNS, although he acknowledged that “to the best of my knowledge,” there are no such data in patients with MS.
Another delegate pointed out that in the predefined subgroup analysis, it looked like younger patients benefited more than did older patients.
“A key point in MS for disability progression is age,” stressed Dr Vermersch. “You probably need to act early in relapsing-remitting MS but also probably in SPMS.”
Over time, and with progression of the disease, immune factors in addition to lymphocytes may be involved in the pathology of MS, he added.
He reiterated that the study wasn’t powered to show an effect of age. “We probably need to include many more patients to have a significant effect in older patients.”
It might also be helpful to follow patients for a longer period, he said. “The median time on the drug was 18 months, which is relatively short to have an impact on progression.”
The safety profile of siponimod is in line with that of other S1P receptor modulators, presented in a separate report at the meeting.
That analysis, led by Gavin Giovannoni, MBBCh, PhD, chair of neurology, Barts and The London School of Medicine and Dentistry, United Kingdom, found similar overall incidence of adverse events (AEs) and serious AEs in the two comparison groups.
The percentages of patients with at least 1 treatment emergent AE were 88.7% in the siponimod group and 81.5% in the placebo group, the analysis found.
The incidence of heart rate and conduction AEs, hypertension, macular edema, and convulsions was higher in the treatment than in the placebo group. The incidence of infections was similar between groups, except for a higher incidence of herpes zoster in the treatment group.
There were no cases of opportunistic infections, including progressive multifocal leukoencephalopathy, and no increased incidence of malignancies, including skin cancers.
EXPAND trial was funded by Novartis Pharma AG, Basel, Switzerland. Dr Vermersch has received honoraria and consulting fees from Biogen Idec, Genzyme-Sanofi, Bayer, Novartis, Merck Serono, GSK, and Almirall and research support from Biogen Idec, Genzyme-Sanofi, Bayer, and Merck Serono. Dr Giovannoni is a steering committee member on the daclizumab trials for AbbVie and a steering committee member of the BG12 and daclizumab trials for Biogen-Idec; has received consultancy fees for advisory board meetings, honoraria for speaking at physicians’ summit, consultancy fees for advisory board meetings, and steering committee participation for oral cladribine trials for Merck-Serono; has been a steering committee member on fingolimod and siponimod trials for Novartis; has been a steering committee member on the laquinimod trials for Teva; has received consultancy fees for advisory board meetings for Genzyme-Sanofi and honoraria for speaking at several medical education meetings; has been a steering committee member on ocrelizumab trials for Roche; has received consultancy fees in relation to DSMB activities for Synthon BV; and is co-chief editor of Multiple Sclerosis and Related Disorders (Elsevier).
Congress of the European Academy of Neurology (EAN) 2017. Abstracts O1217 and PRS1112. Both presented June 24, 2017.
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