LONDON — The investigational agent siponimod (Novartis) has shown encouraging results in a large phase 3 placebo-controlled trial in secondary progressive multiple sclerosis (MS), an indication for which there are currently no well-proven effective treatments.

In the 1651-patient EXPAND trial, siponimod given as an oral tablet once daily reduced the risk for 3-month confirmed disability progression (the primary endpoint) by 21% compared with placebo (P = .013).

The risk reduction for 6-month confirmed disability progression was greater, further supporting the robustness of the data, reported lead investigator, Ludwig Kappos, MD, University Hospital Basel, Switzerland.

"This is a great step forward as we don’t really have any other drugs for secondary progressive MS," Professor Kappos told Medscape Medical News. "β-Interferon is approved in some European countries for secondary progressive MS, but the data are not very convincing. Only one trial out of four showed a benefit, and it was a relatively small trial and there were a higher proportion of patients with the earlier relapsing form of secondary progressive MS in that trial.

"The benefits we saw with siponimod in EXPAND are much more robust. Also the fact that it is an oral treatment and is given as just one pill a day and seems to have a good side effect profile are added advantages," Professor Kappos commented.

The results were presented here at the Congress of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS) 2016.

Siponimod is modulator of the sphingosine-1-phosphate (S1P) receptors found on lymphocytes. It is in the same class as fingolimod but has greater selectivity for the S1P1 and S1P5 receptors.

Other results from the EXPAND study showed improvements compared with placebo in 12- and 24-month annualized relapse rate, the percentage change in brain volume, and change from baseline in the volume of T2 lesions. The difference in change from baseline in the timed 25-foot walk test was, however, not significant.

Siponimod was generally well tolerated, with a relatively "benign" safety profile, Professor Kappos noted.

"We saw what we hoped and expected to see," he said. "The effect was more pronounced in earlier patients with focal inflammation, but patients in the later phase of disease with less inflammation still benefited."

He said that, on the basis of the results, the optimal patient for siponimod would be "younger with earlier, more active disease," but he added that "it is reassuring that others respond, too. Even patients who had had secondary progressive disease for over 3 years and EDSS [Expanded Disability Status Scale] scores of 6.6 seemed to gain some benefit."

Asked whether these data would be enough for regulatory approval of the drug, he said: "Usually two studies are needed for approval, but this is a very large study and there is really no other effective treatment, and the regulators have said they may accept one study if the efficacy is robust enough."

Other MS experts were enthusiastic about the EXPAND results. Co-chair of the ECTRIMS session at which the trial was presented, Hans-Peter Hartung, MD, Heinrich-Heine-University of Dusseldorf, Germany, said they were of "great clinical importance."

Xavier Montalban, MD, MS Center of Catalonia, Spain, commented to Medscape Medical News: "This is a very interesting trial. The effect was moderate, but all the results were going in same direction — MRI and clinical data — so I think it is very promising."

Jeffrey Cohen, MD, Cleveland Clinic, Ohio, added: "The results show convincing benefit (in this study population under the conditions of this study). The benefit was seen in the overall patient population and in subgroups but clearly was more prominent in younger patients with shorter disease duration, less disability, recent relapses, and ongoing MRI lesion activity (ie, patients transitioning from relapsing to secondary progressive MS)."

The EXPAND trial enrolled 1651 patients with secondary progressive MS, (defined as a progressive increase in disability [duration of 6 months or more] in the absence or independent of relapses), aged 18 to 60 years, who had an EDSS score of 3.0 to 6.5. They were randomly assigned (2:1) to receive siponimod 2 mg once daily (following initial dose titration starting at 0.25 mg) or matching placebo.

Baseline characteristics showed that the patients were representative of a typical secondary progressive MS population, Professor Kappos said. Their mean age was 48 years, and 80% of patients were over 40. Mean duration of MS since first symptoms was 8 years; mean time since conversion to secondary progressive MS was 3.5 years in the placebo group and 3.8 years in siponimod group.

Patients had a "relatively high" EDSS score: a mean of 5.4, with 60% having scores of 6 to 6.5 at baseline. Two thirds of patients had purely secondary progressive form of MS and one third had had a relapse in the previous 2 years.

Overall, 1363 (83%) patients completed the core study, with a medium follow-up time of 21 months. There were 449 confirmed disability progression events (each patient could maximally contribute 1 event for the primary endpoint).

The primary endpoint showed a 21% reduction in 3-month confirmed disability progression in the siponimod group (hazard ratio [HR], 0.79; P = .013). The secondary endpoint of 6-month confirmed disability progression was reduced by 26% (HR, 0.74; P = .006).

Other secondary endpoints showed the following:

  • Time to 3-month confirmed worsening by greater than 20% from baseline in the timed 25-foot walking test: risk reduced by 6.2% compared with placebo (not significant);

  • Change from baseline in T2 lesion volume: 79.1% lower average change over 12 and 24 months compared with placebo (P < .0001);

  • Annualized relapse rate: reduced by 55% compared with placebo (P < .0001); and

  • Percentage brain volume change from baseline: 23.4% lower average change over 12 and 24 months compared with placebo (P = .0002).

Professor Kappos said the brain atrophy result was "particularly interesting" in view of the INFORMS trial, which failed to show a benefit of fingolimod on disability progression or brain volume loss in primary progressive MS.

Subgroup analysis suggested a better effect in younger patients with earlier disease.

Table. Risk of Reaching 3-Month Confirmed Disability Progression With Siponimod by Predefined Subgroups

Subgroup HR (95% Confidence Interval)
All patients 0.79 (0.65 - 0.95)
Secondary progressive MS group  
  No relapse in prior 2 y 0.87 (0.68 - 1.11)
  Relapses in prior 2 y 0.67 (0.49 - 0.91)
Gd+ lesions at baseline  
  0 0.82 (0.66 - 1.02)
  1 or more 0.64 (0.42 - 0.95)
Previously treated with disease-modifying agents  
  Yes 0.83 (0.67 - 1.03)
  No 0.65 (0.43 - 0.98)
Baseline age  
  20 y 0.61 (0.31 - 1.21)
  40 y 0.74 (0.57 - 0.95)
  60 y 0.89 (0.62 - 1.27)
Baseline EDSS score  
  3 0.64 (0.41 - 1.01)
  4 0.74 (0.52 - 0.95)
  5 0.76 (0.63 - 0.93)
  6 0.83 (0.67 - 1.04)
MS duration since first symptoms  
  10 y 0.77 (0.61 - 0.97)
  20 y 0.82 (0.66 - 1.02)
  30 y 0.88 (0.59 - 1.31)

In terms of side effects, Professor Kappos said siponimod was well tolerated.

"There was a slight increase in infections but no increase in CNS [central nervous system] complications or malignancies," he noted. "In general the side-effect profile was similar to fingolimod, but we didn’t see the early bradycardia that can be seen with fingolimod — maybe because we titrated the dose up slowly over the first week. Also it has a shorter half-life than fingolimod so perhaps the lymphocytes are able to rest and recover a little between doses."

Asked whether these results had any implications for fingolimod in secondary progressive MS, Professor Kappos said, "Fingolimod hasn’t been studied in this population and it has a different selectivity for the various S1P receptors, but of course it is a possibility that fingolimod would also be effective."

Another audience member cited some evidence that the S1P5 receptor may promote remyelination and wondered whether this may explain some of the benefit.

Commenting on the data for Medscape Medical News, Daniel Kantor, MD, past president, Florida Society of Neurology, highlighted the fact that the most benefit was seen in the earlier patients.

"It looked like the best response occurred in patients who had only recently moved to secondary progressive MS. So they had had recent relapses," Dr Kantor noted. "That’s not surprising in that relapsing-remitting patients probably would do well on a medication like siponimod given what we know about fingolimod and the other S1P agents in development. The question is whether it would be of much benefit in a patient who has had secondary progressive for a long time. In the subgroup analysis those ones crossed the line."

Adding to this, Jerry Wolinsky, MD, University of Texas Medical School at Houston, said the distinctions between patients with relapsing-remitting and secondary progressive MS were becoming less defined.

"What I do know is that MS can have a phase of activity that is very intense early in younger people, shown by relapses and subclinical (MRI) and if you stop that you probably won't see progression," he said. "As you move through the age groups you see less activity and you probably need drugs of increased benefit in order to put a dent into the progressive component late."

The EXPAND study was supported by Novartis. Professor Kappos has received steering committee, advisory board, and consultancy fees from Actelion, Addex, Bayer HealthCare, Biogen Idec, Biotica, Genzyme, Lilly, Merck, Mitsubishi, Novartis, Ono Pharma, Pfizer, Receptos, Sanofi, Santhera, Siemens, Teva, UCB, and Xenoport; speaker fees from Bayer HealthCare, Biogen Idec, Merck, Novartis, Sanofi, and Teva; support of educational activities from Bayer HealthCare, Biogen, CSL Behring, Genzyme, Merck, Novartis, Sanofi, and Teva; royalties from Neurostatus Systems GmbH; and grants from Bayer HealthCare, Biogen Idec, European Union, Merck, Novartis, Roche Research Foundation, Swiss MS Society, and the Swiss National Research Foundation.

Congress of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS) 2016. Abstract 250. Presented September 17, 2016.

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