Abstract
Background
Multiple sclerosis (MS) is a chronic immune‐mediated disease of the central nervous system, with an unpredictable course. Current MS therapies such as disease‐modifying therapies focus on treating exacerbations, preventing new exacerbations and avoiding the progression of disability. Siponimod (BAF312) is an oral treatment, a selective sphingosine‐1‐phosphate (S1P) receptor modulator, for the treatment of adults with relapsing forms of MS including active, secondary progressive MS with relapses.
Objectives
To assess the benefits and adverse effects of siponimod as monotherapy or combination therapy versus placebo or any active comparator for people diagnosed with MS.
Search methods
We searched the Cochrane Multiple Sclerosis and Rare Diseases of the CNS Trials Register, which contains studies from CENTRAL, MEDLINE and Embase, and the trials registry databases ClinicalTrials.gov and WHO International Clinical Trials Registry Platform (ICTRP) on 10 September 2021. We also handsearched relevant journals and screened the reference lists of published reviews and retrieved articles and searched reports (2004 to September 2021) from the MS societies in Europe and America.
Selection criteria
We included randomised parallel controlled clinical trials (RCTs) that evaluated siponimod, as monotherapy or combination therapy, versus placebo or any active comparator in people with MS. There were no restrictions on dose or administration frequency.
Data collection and analysis
We used standard methodological procedures expected by Cochrane. We discussed disagreements and resolved them by consensus among the review authors. Our primary outcomes wereworsening disability , relapse and adverse events, and secondary outcomes were annualised relapse rate, gadolinium‐enhancing lesions, new lesions or enlarged pre‐existing lesions and mean change of brain volume. We independently evaluated the certainty of evidence using the GRADE approach. We contacted principal investigators of included studies for additional data or confirmation of data.
Main results
Two studies (1948 participants) met our selection criteria, 608 controls and 1334 treated with siponimod. The included studies compared siponimod with placebo. Overall, all studies had a high risk of bias due to selective reporting and attrition bias.
Comparing siponimod administered at a dose of 2 mg to placebo, we found that siponimod may reduce the number of participants with disability progression at six months (56 fewer people per 1000; risk ratio (RR) 0.78, 95% confidence interval (CI) 0.65 to 0.94; 1 study, 1641 participants; low‐certainty evidence) and annualised relapse rate (RR 0.43, 95% CI 0.34 to 0.56; 2 studies, 1739 participants; low‐certainty evidence). But it might lead to little reduction in the number of participants with new relapse (166 fewer people per 1000; RR 0.38, 95% CI 0.15 to 1.00; 1 study, 94 participants; very low‐certainty evidence). We observed no evidence of a difference due to adverse events for siponimod at 2 mg compared to placebo (14 more people per 1000; RR 1.52, 95% CI 0.85 to 2.71; 2 studies, 1739 participants, low‐certainty evidence). In addition, due to the high risk of inaccurate magnetic resonance imaging (MRI) data in the two included studies, we could not combine data for active lesions on MRI scans. Both studies had high attrition bias resulting from the unbalanced reasons for dropouts among groups and high risk of bias due to conflicts of interest. Siponimod may reduce the number of gadolinium‐enhancing T1‐weighted lesions at two years of follow‐up (RR 0.14, 95% CI 0.10 to 0.19; P < 0.0001; 1 study, 1641 participants; very low‐certainty evidence). There may be no evidence of a difference between groups in the number of participants with at least one serious adverse event excluding relapses (113 more people per 1000; RR 1.80, 95% CI 0.37 to 8.77; 2 studies, 1739 participants; low‐certainty evidence) at six months. No data were available regarding cardiac adverse events.
In terms of safety profile, the most common adverse events associated with siponimod were headache, back pain, bradycardia, dizziness, fatigue, influenza, urinary tract infection, lymphopenia, nausea, alanine amino transferase increase and upper respiratory tract infection. These adverse events have dose‐related effects and rarely led to discontinuation of treatment.
Authors’ conclusions
Based on the findings of the RCTs included in this review, we are uncertain whether siponimod interventions are beneficial for people with MS. There was low‐certainty evidence to support that siponimod at a dose of 2 mg orally once daily as monotherapy compared with placebo may reduce the annualised relapse rate and the number of participants who experienced disability worsening, at 6 months. However, the certainty of the evidence to support the benefit in reducing the number of people with a relapse is very low.
The risk of withdrawals due to adverse events requires careful monitoring of participants over time. The duration of all studies was less than 24 months, so the efficacy and safety of siponimod over 24 months are still uncertain, and further exploration is needed in the future. There is no high‐certainty data available to evaluate the benefit on MRI outcomes. We assessed the certainty of the body of evidence for all outcomes was low to very low, downgraded due to serious study limitations, imprecision and indirectness. We are uncertain whether siponimod is beneficial for people with MS.
More new studies with robust methodology and longer follow‐up are needed to evaluate the benefit of siponimod for the management of MS and to observe long‐term adverse effects. Also, in addition to comparing with placebo, more new studies are needed to evaluate siponimod versus other therapeutic options.
PICOs
Population (6)
Intervention (1)
Comparison (1)
Outcome (3)
The PICO model is widely used and taught in evidence-based health care as a strategy for formulating questions and search strategies and for characterizing clinical studies or meta-analyses . PICO stands for four different potential components of a clinical question: Patient, Population or Problem; Intervention; Comparison; Outcome
See more on using PICO in the Cochrane Handbook.
Plain language summary
Is siponimod an effective treatment for multiple sclerosis (MS) and does it cause unwanted effects?
Key messages
· We don’t know whether siponimod is an effective treatment for people with multiple sclerosis (MS). At a dose of 2 mg once a day, siponimod may reduce recurrence of symptoms (relapse, calculated as an annual rate) after six months of treatment and may reduce the number of participants whose disability worsens after three months of treatment.
· We don’t know if siponimod causes unwanted effects because studies did not last long enough to fully assess them.
· Future studies should last longer in order to monitor unwanted and beneficial effects of siponimod better, and should use more robust methods. They should compare siponimod with other medicines.
What is multiple sclerosis?
Multiple sclerosis (MS) is a condition caused when the body’s immune system – which defends the body against disease and infection – mistakenly attacks parts of the central nervous system (the brain and spinal cord). Symptoms include problems with balance and walking, and blurred vision. MS is a lifelong condition that can cause serious disability. Some people’s symptoms may develop gradually. However, most people experience ‘attacks’ when new symptoms develop or existing symptoms worsen (called ‘relapse’), followed by periods with no changes to their symptoms (called ‘remittance’). This type of MS is called ‘relapsing remitting’ MS. Eventually, the course of their MS may change. These periods when there are no symptoms, or no worsening of symptoms, may stop and then symptoms may worsen continually. This is called ‘secondary progressive MS’.
How does siponimod work?
Siponimod is a medicine that attaches to the white blood cells (lymphocytes) that attack the central nervous system. This causes the lymphocytes to stay in the lymph glands instead of circulating in the blood to the brain. Fewer lymphocytes reach the brain so the attack by the immune system is reduced. Siponimod is a tablet taken once a day.
What did we want to find out?
We wanted to know if siponimod is an effective treatment for MS and whether it causes any unwanted effects.
We were interested in the number of people:
· who experienced relapses;
· whose disability worsened;
· who left the studies because of unwanted effects of siponimod;
· who developed new or larger brain lesions (damage to the brain); and
· who experienced serious unwanted effects, and which unwanted effects they experienced.
What did we do?
We searched for studies that investigated siponimod compared with placebo (a sham medicine that looks and tastes the same as siponimod but with no active ingredients) or another medicine to treat MS. Studies could investigate siponimod alone or combined with another treatment, at any dose over any length of time. Participants had to be aged over 18 years, with confirmed MS.
We compared and summarised the results of the studies and rated our confidence in the evidence, based on factors such as study methods and sizes.
What did we find?
We found two studies with 1948 participants. Both studies compared siponimod with placebo. One study included 1651 people with secondary progressive MS, who were given 2 mg siponimod for up to 3 years. The other study included 297 participants with relapsing remitting MS, who were given siponimod at doses of 10 mg, 2 mg or 0.5 mg for 6 months, or 1.25 mg or 0.25 mg for 3 months. We report the results for 2 mg daily because both studies looked at this dose.
At 2 mg a day, compared to placebo:
· siponimod may lead to a small reduction (166 fewer people per 1000) in the number of people with a new relapse up to six months after starting treatment, and may also reduce relapses when calculated at an annual rate;
· siponimod may reduce the number of people whose disability worsened during the six months after starting treatment (by 56 people per 1000);
· there may be no difference to the number of people (14 more per 1000) who left the studies in the six months after starting treatment due to unwanted effects;
· siponimod may reduce the number of brain lesions of different types after six months and after two years of follow‐up.
· siponimod may make no difference to the number of people with at least one serious unwanted effect in the six months after starting treatment. The most common unwanted effects associated with siponimod were headache, back pain, dizziness, tiredness, influenza, urinary tract infection, reduced white blood cells (lymphopenia), feeling sick, possible liver damage, and infections in the mouth and nose. No information was available about heart‐related unwanted effects.
What are the limitations of the evidence?
Our confidence in the evidence is limited because we found only 2 studies. They did not provide information about everything we were interested and they included people with different types of MS. Also, they did not last long enough to judge the impact of unwanted effects. Both studies were funded by the company that makes siponimod.
