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Drug may slow disease progression in MS patients

A new drug for multiple sclerosis could slow the progression of symptoms of a form of the disease for which effective treatments have proved elusive, The Guardian reports research suggests.

Secondary progressive MS develops in many people who are initially diagnosed with the relapsing-remitting form, in which individuals experience symptoms in distinct flare-ups, and involves disabilities getting worse over time. The new findings, based on a large international clinical trial, found a drug called siponimod reduced the risk of disabilities becoming worse over time.

“I think this a potentially landmark-type study,” said Dr Matt Craner, clinical lead of the MS clinical trials unit at the University of Oxford, who was involved in the study. While Craner admitted that the effects of the drug were modest, he said the findings were important. “You are looking at a population of patients that have no treatments – there is nothing available currently for secondary progressive MS,” he said.

The report says in the new study, Craner and colleagues describe how 1,055 adults with secondary progressive MS were given siponimod and 545 were given a placebo. Neither the doctors nor participants were aware at the time which treatment was being given, and participants took the drug for anywhere up to 37 months.

Every three months, participants’ levels of disability were assessed, and an increase was dubbed “confirmed” if it persisted for a further three months.

The team found that while 32% of those in the placebo group experienced a progression in disability during the study, the same was true for only 26% of those in the siponimod group – a 21% reduction in risk of such a progression. The findings were strongest for certain groups, including those who had had recent attacks and those with less disability to start with.

No difference was found between the drug groups when researchers repeatedly looked at the time it took for participants to walk 25 feet.

The report says MRI brain scans at the start of the study, and again at 12 and 24 months, showed that those in the siponimod group had a slower rate of brain shrinkage, suggesting less tissue damage, and had less increase in brain scarring. But, the team note, the study setup means that some of those labelled as being in the placebo group could, by the time of the brain scans, be taking siponimod.

However, the report says, an accompanying commentary by Luanne Metz and Wei-Qiao Liu from the University of Calgary struck a downbeat tone, noting the treatment effect was small and that not all measures, such as the walking test, showed improvements under siponimod. That, they write, means the results “do not suggest that siponimod is an effective treatment for” secondary progressive MS.

But Professor Alasdair Coles, an expert in MS from the University of Cambridge, dismissed the walking measure as a “rubbish test” that could be affected by a host of factors and welcomed the findings.

“At a political level this is fantastic because for the first time a drug which is reasonably safe to take has any impact at all on secondary progressive MS,” he said, adding that it will spur on further research into tackling the condition.

He said he had reservations, predicting the National Institute for Health and Care Excellence will not consider the drug cost-effective given the modest size of the effects, and adding that other drugs were known to produce similar results for brain scarring and shrinkage. What’s more, Coles said, the observed benefits of siponimod might only be down to its anti-inflammatory effects, with results only seen among patients with high levels of inflammation and that only showed up because of the large trial size.

But he said there is an additional, far more exciting, possibility: that siponimod might also promote recovery of the insulating sheaths around neurons – coatings that are damaged in MS – and prevent degeneration of connections between neurons.

“That definitely needs to be run down because we desperately need a treatment that does that,” he said.

Summary
Background: No treatment has consistently shown efficacy in slowing disability progression in patients with secondary progressive multiple sclerosis (SPMS). We assessed the effect of siponimod, a selective sphingosine 1-phosphate (S1P) receptor1,5 modulator, on disability progression in patients with SPMS.
Methods: This event-driven and exposure-driven, double-blind, phase 3 trial was done at 292 hospital clinics and specialised multiple sclerosis centres in 31 countries. Using interactive response technology to assign numbers linked to treatment arms, patients (age 18–60 years) with SPMS and an Expanded Disability Status Scale score of 3·0–6·5 were randomly assigned (2:1) to once daily oral siponimod 2 mg or placebo for up to 3 years or until the occurrence of a prespecified number of confirmed disability progression (CDP) events. The primary endpoint was time to 3-month CDP. Efficacy was assessed for the full analysis set (ie, all randomly assigned and treated patients); safety was assessed for the safety set. This trial is registered with ClinicalTrials.gov, number NCT01665144.
Findings: 1651 patients were randomly assigned between Feb 5, 2013, and June 2, 2015 (1105 to the siponimod group, and 546 to the placebo group). One patient did not sign the consent form, and five patients did not receive study drug, all of whom were in the siponimod group. 1645 patients were included in the analyses (1099 in the siponimod group and 546 in the placebo). At baseline, the mean time since first multiple sclerosis symptoms was 16·8 years (SD 8·3), and the mean time since conversion to SPMS was 3·8 years (SD 3·5); 1055 (64%) patients had not relapsed in the previous 2 years, and 918 (56%) of 1651 needed walking assistance. 903 (82%) patients receiving siponimod and 424 (78%) patients receiving placebo completed the study. 288 (26%) of 1096 patients receiving siponimod and 173 (32%) of 545 patients receiving placebo had 3-month CDP (hazard ratio 0·79, 95% CI 0·65–0·95; relative risk reduction 21%; p=0·013). Adverse events occurred in 975 (89%) of 1099 patients receiving siponimod versus 445 (82%) of 546 patients receiving placebo; serious adverse events were reported for 197 (18%) patients in the siponimod group versus 83 (15%) patients in the placebo group. Lymphopenia, increased liver transaminase concentration, bradycardia and bradyarrhythmia at treatment initiation, macular oedema, hypertension, varicella zoster reactivation, and convulsions occurred more frequently with siponimod than with placebo. Initial dose titration mitigated cardiac first-dose effects. Frequencies of infections, malignancies, and fatalities did not differ between groups.
Interpretation: Siponimod reduced the risk of disability progression with a safety profile similar to that of other S1P modulators and is likely to be a useful treatment for SPMS.

Authors
Ludwig Kappos, Amit Bar-Or, Bruce A C Cree, Robert J Fox, Gavin Giovannoni, Ralf Gold, Patrick Vermersch, Douglas L Arnold, Sophie Arnould, Tatiana Scherz, Christian Wolf, Erik Wallström, Frank Dahlke

[link url="https://www.theguardian.com/society/2018/mar/22/new-ms-drug-could-slow-symptoms-of-untreatable-disease"]The Guardian report[/link]
[link url="http://www.thelancet.com/journals/lancet/article/PIIS0140-6736(18)30475-6/fulltext"]The Lancet article summary[/link]
[link url="http://www.thelancet.com/journals/lancet/article/PIIS0140-6736(18)30426-4/fulltext"]The Lancet comment[/link]

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