While disease-modifying therapies are widely used for patients with relapsing-remitting multiple sclerosis (RRMS) to reduce disability progression, there has been little to offer patients who transition to secondary progressive multiple sclerosis (SPMS), particularly when they reach the non-relapsing phase of the illness. The limbic spoke to neurologist Doctor Marion Simpson from the Austin Hospital in Melbourne about the potential benefits of Mayzent®(siponimod), the only treatment reimbursed for SPMS,1,2 and her impressions of the clinical data.
SPMS: challenges in diagnosis
“We’ve come a tremendously long way with disease modifying therapies (DMTs) to treat RRMS but there has been almost nothing to offer our patients with SPMS, who eventually progress to significant disability,” said Dr Simpson. DMTs for MS are indicated for relapsing forms of MS – including SPMS with relapses. However, relapses are absent or infrequent in SPMS.
More than 50% of patients with RRMS transition to SPMS within 15–20 years3,4 Risk factors for transition to SPMS include male sex, older age at onset of multiple sclerosis, and high early relapse frequency.3 This secondary progressive phase of MS leads to severe disability outcomes, resulting from the accumulation of unremitting disability.
Doctor Simpson noted that the effect of DMTs on the transition to SPMS is still unknown. “Older studies – before the use of DMTs – showed that as many as 90% of patients with RRMS would eventually progress to SPMS. We don’t yet know what the effect of early DMT use in RRMS will be – whether DMTs will delay or reduce the number of patients with SPMS,” she said.
SPMS: often a retrospective diagnosis
Identifying the transition from RRMS to SPMS remains a clinical challenge due to the gradual nature of the transition, and it is often a diagnosis made in retrospect, explained Doctor Simpson. “The symptoms tend to get worse over time, but this may not be linear, with periods of plateau and then worsening,” she said.
“For the vast majority of patients, SPMS is a retrospective diagnosis. We don’t have a biomarker to tell when a patient has transitioned to SPMS. So it will be when we look back in the history and find their status is worse than the same time last year but with a scan showing little disease activity. The diagnosis is not simple – it can take a number of years in some cases,” said Doctor Simpson.
Despite these difficulties, the pattern of symptoms can sometimes be used to help identify the transition to SPMS. “Unlike patients with RRMS, patients with SPMS do not experience a sudden decline over a few days, and there’s not much recovery after a decline, and usually not much MRI activity,” explained Doctor Simpson. “Gait difficulty is a very common symptom, and cognitive decline is an under-recognised symptom, which we’re generally not good at asking about or measuring in clinical practice. Fatigue can happen at any stage of the disease but can be a big issue in SPMS, as well as bladder and bowel dysfunction and pain,” she said.
When it comes to discussing the prospect of a transition to SPMS, Doctor Simpson explained that she is guided by what her patients want to know. “I’ve been surprised by how much patients actually want to know about the potential of their transitioning to SPMS,” she said.” I try to talk to patients about this if I can see that they want to talk about it. Practice on this would probably vary widely as it can be a difficult time in their treatment,” she said.
Clinical experience with siponimod
The Austin Hospital had a number of patients enrolled into the international EXPAND trial5 for siponimod, providing Doctor Simpson early experience with the treatment. She has also been able to treat eligible patients with siponimod through an early access scheme. “Initiation and treatment has generally been quite simple,” reported Doctor Simpson. “Some patients have had no side effects at all, although others have experienced significant side effects,” she added.
Efficacy and safety of siponimod in SPMS: data from the EXPAND trial
EXPAND5 is a double-blind trial conducted in 292 hospital clinics across 31 countries, enrolling 1,651 patients with SPMS. Patients with an Expanded Disability Status Scale score of 3.0–6.5 were randomised (2:1) to either once daily siponimod 2mg or placebo for up to three years or until the occurrence of a prespecified number of confirmed disability progression (CDP) events. The primary endpoint was time to three-month CDP.
A total of 1,645 patients were included in the analysis; 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). The majority of patients (64%; n = 1055) had not relapsed in the previous two years.
The investigators found that siponimod reduced the relative risk of disability progression by 21%: at completion of study, 26% of patients receiving siponimod and 32% of patients receiving placebo had three-month CDP (hazard ratio [HR] 0.79; 95% CI: 0.65–0.95; p=0.013). The risk of six-month CDP (a secondary endpoint) was also reduced by siponimod (HR 0.74, 95% CI: 0.60 – 0.92; p=0.0058).5
Adverse events occurred in 89% of patients receiving siponimod versus 82% of patients receiving placebo, with serious adverse events reported in 18% of patients receiving siponimod and 15% of patients receiving placebo. Adverse events occurring more frequently in the siponimod treatment group included lymphopenia, increased liver transaminase concentration, bradycardia and bradyarrythmia at treatment initiation, macular oedema, hypertension, varicella zoster reactivation and convulsions.5
Clinical significance of the EXPAND data
“This was a positive trial, in that it met its primary endpoint, and in a relative short period. The difference between the groups was also persuasive,” Doctor Simpson noted. “The patients enrolled in the study were typical of the patients in which we might use this drug in the clinic: they had secondary progressive disease and were progressing, but their disability status was still moderate rather than severe,” she said.
The authors of the study explained the significance of the findings with respect to disability progression: “For patients who need walking aids (EDSS score of 6.0 to 6.5), disability progression by 0.5 points means dependence on bilateral instead of unilateral support, or becoming unable to walk more than a few steps even with support. Based on estimated risk reduction, between a fifth (three-month CDP) and a quarter (six-month CDP) of clinically relevant worsening of neurological ability is spared when treated with siponimod,” they explained.5
Doctor Simpson provided further context to the relevance of the data to clinical practice: “For an individual patient, the degree that it will impact disability progression is difficult to assess. Neither I nor the patient will know what they will be like in the next six to twelve months. But the data on a group level showed a difference in disability progression with siponimod, and this is important to consider in our decision making,” she said.
The potential impact of early treatment decisions
Subgroup analyses of the EXPAND data suggested that the treatment effect became less pronounced with increasing age, disability, and baseline disease duration, and diminishing signs of disease activity.5
“I think it is important to diagnose early,” said Doctor Simpson. “Starting patients on siponimod at a younger age or earlier in their disease course may result in more benefits from the drug,” she added.
References
- Department of Health, Pharmaceutical Benefits Scheme. Available at: pbs.gov.au.
- Mayzent Approved Product Informationhttps://www.ebs.tga.gov.au/ebs/picmi/picmirepository.nsf/pdf?OpenAgent&id=CP-2019-PI-02212-1&d=202011021016933
- Scalfari A et al. Onset of secondary progressive phase and long-term evolution of multiple sclerosis. J Neurol Neurosurg Psychiatry 2014;85: 67–75. https://pubmed.ncbi.nlm.nih.gov/23486991/
- Tremlett H et al. Natural history of secondary-progressive multiple sclerosis. Mult Scler 2008; 14:314–324.https://journals.sagepub.com/doi/10.1177/1352458507084264
- Kappos L et al. Siponimod versus placebo in secondary progressive multiple sclerosis (EXPAND): a double-blind, randomised, phase 3 study. Lancet 2018;391:1263–1273. https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(18)30475-6/fulltext