New secondary data analysis from the EXPAND study (NCT01665144) showed that patients with secondary progressive multiple sclerosis (SPMS) treated with siponimod (Mayzent; Novartis) experienced a significant benefit on the Symbol Digit Modalities Test (SDMT), suggesting that the oral selective sphingosine-1-phosphate (S1P) receptor modulator can improve cognitive processing speed.

The between-group difference for the siponimod vs placebo groups in mean change from baseline in SDMT scores was 1.08 (95% CI, 0.23-1.94; 

 = .0132) at 12 months, and 1.23 (0.25-2.21; 

 = .0135) at month 18, and 2.30 (1.11-3.50; 

 = .0002) at month 24. The data also showed a lower risk of having a decrease of 4 or more points and a higher risk of having an increase of 4 or more points on the SDMT for siponimod-treated patients.

First author Ralph HB Benedict, PhD, professor of neurology, Jacobs School of Medicine & Biomedical Sciences, University at Buffalo, and colleagues wrote that the data offer Class II evidence for the benefits of siponimod treatment. They noted that the data are at “a magnitude of change accepted as clinically meaningful.”

EXPAND, or “Exploring the Efficacy and Safety of Siponimod in Patients With Secondary Progressive Multiple Sclerosis,” consisted of 1651 patients with SPMS randomized in 2-to-1 fashion to either 2 mg per day siponimod or placebo. In addition to the assessment of change in SDMT scores, Benedict et al also evaluated cognitive performance with the Paced Auditory Serial Addition Test (PASAT), and the Brief Visuospatial Memory Test-Revised (BVMT-R). All outcome measures were administered at baseline, then at 6-month intervals until the end of treatment.

How Big Data Can Drive Advancements in MS Research

Notably, PASAT and BVMT-R scores did not differ significantly between the 2 treatment groups (

The patients treated with siponimod were at a significantly lower risk for having a 4-point sustained decrease in SDMT score (hazard ratio [HR], 0.79 [95% CI, 0.65-0.96]; 

 = .0157), while their chance for having a 4-point sustained increase in SDMT score was significantly higher (HR, 1.28 [95% CI, 1.05-1.55]; 

These are just the latest secondary data from EXPAND to be published, with a number of analyses submitted for presentation at the 2020 American Academy of Neurology annual meeting suggesting the Novartis agent’s impact on physical disability progression and cognition.

One of the prior datasets from EXPAND included 1124 patients (74% of randomized patients), all of whom received ≥1 dose of randomized treatment. Those data showed that those who continued on siponimod treatment (n = 878) were less likely to experience both 3-month confirmed disability progression (CDP; 

= .0048) compared to those who switched from placebo (n = 346). As well, incidence rates of adverse events per 100 patient-years in the long-term follow-up were consistent with the controlled treatment period, with no new safety findings observed.

That efficacy analyses included time-to-3- and 6-month CDP on the Expanded Disability Status Scale (EDSS), time-to-6-month confirmed worsening—defined as ≥4 points on SDMT—and annualized relapse rate (ARR). A reduction in ARR of 52% was observed for the continuing group (0.054) compared to the switch group (0.097; 

As well, a third, post-hoc analysis from EXPAND suggested that siponimod consistently reduced cortical grey matter and thalamic atrophy in those with SPMS. Across all subgroups, the reduction in cortical grey matter atrophy compared to placebo ranged from 48% to 116% (

<.01 at both 1 year and 2 years), and thalamic atrophy was reduced by 30% to 68% (

 <.05 at both 1 year and 2 years). Although, thalamic atrophy was not significantly reduced for those with a disease duration >15 years after 1 year (

At the 2020 Americas Committee for Treatment and Research in MS (ACTRIMS) Forum, Le Hua, MD, director, Multiple Sclerosis Program, Cleveland Clinic Lou Ruvo Center for Brain Health, discussed the subanalysis findings from EXPAND—which she presented—and what it taught her about the 

. “[These data] really [do] get into the question of, can we dichotomize our patients? We know there is a younger group and an older group, and we really wanted to look at if there was a difference in the drug working on one group or the other,” she said.

REFERENCE
1. Benedict RHB, Tomic D, Cree BA, et al. Siponimod and Cognition in Secondary Progressive Multiple Sclerosis: EXPAND Secondary Analyses. 

. 2021;96(3):e376-e386. doi: 10.1212/WNL.0000000000011275
2. Kappos L, et al. Long-term Efficacy and Safety of Siponimod in Patients with SPMS: EXPAND Extension Analysis up to 5 Years. 

. 2020; 94 (15 Supplement): 4128.
3. Fox R, et al. Siponimod Reduces Grey Matter Atrophy in Patients with Secondary Progressive Multiple Sclerosis: Subgroup Analyses from the EXPAND study. 

Articles

Siponimod (Mayzent; Novartis) improved Symbol Digit Modalities Test scores in patients at 12, 18, and 24 months compared to placebo.

Siponimod Offers Benefit to Cognitive Processing Speed in SPMS

Data from the phase 3 EXPAND clinical trial (NCT01665144) of siponimod (Mayzent; Novartis) demonstrated the treatment’s ability to reduce the risk of confirmed disability progression (CDP) in patients with secondary progressive multiple sclerosis (SPMS) with or without relapses.

The risk reductions in non-relapsing patients in the 1 and 2 years before the study were 18% (hazard ratio [HR], 0.82; 95% CI, 0.66—1.02) and 13% (HR, 0.87; 95% CI, 0.68–1.11), respectively. For 3-and 6-month CDP, the risk reductions were 25% (HR, 0.75; 95% CI, 0.59–0.96) and 18% (HR, 0.82; 95% CI, 0.62–1.08), respectively.

2020 Consortium of Multiple Sclerosis Centers (CMSC) Virtual Annual Meeting

, May 26-29, 2020 revealed risk reductions of 33% and 33% for 3-month CDP in years 1 and 2, and 30% and 37% for 6-month CDP in years 1 and 2, respectively, in relapsing patients.

Bruce Cree, MD, PhD, MAS, lead author, and neurologist, UCSF Multiple Sclerosis Center, and colleagues found that siponimod reduced 3-month CDP by 14% to 20% and 6-month CDP by 29% to 33% in non-relapsing patients across the Month 12, Month 18, and Month 24 timepoints.

Cox model censoring at relapse confirmed these beneficial effects, reaching nominal statistical significance for 6-month CDP (HR, 0.77; 95% CI, 0.62—0.96).

Evobrutinib Shows Long-Term Efficacy and Safety in Phase 2 Study

The goal of the EXPAND trial was to assess the impact of siponimod on CDP in patients with and without relapses to uncouple treatment effects of CDP from those on relapses. EXPAND contained patients aged 18 to 60 years with SPMS and EDSS scores ranging from 3.0 to 6.5, and administered once-daily oral siponimod 2 mg or placebo for up to 3 years.

Previously reported results from the trial showed that siponimod reduced the risk of 3- and 6-month CDP by 21% and 26%, respectively, compared with placebo, in patients with SPMS. Additionally, a subgroup analysis of EXPAND suggested that a proportion of the effect of siponimod on CDP was attributable to effects on relapse-independent disability progression. The therapy’s 3-month CDP reductions in EXPAND helped 

lend support to its FDA approval in March 2019

. It became the first drug approved for patients with SPMS in more than a decade.

Findings from EXPAND also suggested that patients with SPMS who are 

treated with siponimod experience a sustained benefit

, with a slowing of physical disability progression and additional cognitive protection. Of the 1099 who were administered the sphinogosine 1-phosphate (S1P) receptor modulator and 546 given placebo, significant treatment effects were detected over the 36-month period for Expanded Disability Status Scale (EDSS) scores (

 =.20), as well as both the Motor Integration (MI; 

1. Cree BAC, Fox RJ, Giovannoni G, et al. Siponimod affects disability progression in patients with secondary progressive multiple sclerosis independent of relapse activity: Results from the phase 3 EXPAND study. 

2. Novartis receives FDA approval for Mayzent® (siponimod), the first oral drug to treat secondary progressive MS with active disease [press release]. Basel, Switzerland: Novartis; Published March  26, 2019. novartis.gcs-web.com/Novartis-receives-FDA-approval-for-Mayzent-siponimod-the-first-oral-drug-to-treat-secondary-progressive-MS-with-active-disease. Accessed March 26, 2019.

3. Cutter G, Meng X, Bar-Or A, et al. Effect of Siponimod on Disability in EXPAND Re-examined with Two New Subscales of the Expanded Disability Status Scale in Patients with SPMS.

The Novartis agent showed benefit in patients who had multiple sclerosis both with and without relapses.

Siponimod Reduces Risk of Disability Progression Regardless of Prior Relapses in MS

Multiple sclerosis (MS) is a difficult disease for physicians to treat, even with the relatively vast arsenal of therapeutics available as treatment options.

Additionally, a wide variety of factors, from the patient’s age at diagnosis to the duration of the disease, can influence the physician’s decisions in managing its progression. Currently, the disease-modifying therapies (DMTs) for MS treatment target the early phase of the disease course—characterized by lesion activity and inflammation&mdash;while treatments for progressive disease have required a modified approach.

To find out more about the questions MS specialists are facing and the relationship between age, disease duration, and treatment in patients, as well as what can be gleaned from the age-based subanalysis of the EXPAND clinical trial, NeurologyLive sat with Le Hua, MD, director, Multiple Sclerosis Program, Cleveland Clinic Lou Ruvo Center for Brain Health.

NeurologyLive: How much do we know about the correlation between disease duration and age in MS?

Le Hua, MD: Disease duration and age go hand-in-hand, right? The older you are, the longer you're likely to have the disease, as the pretty general rule. However, there are some nuances, like late-onset MS. Patients who have onset when they're a kid will have longer disease duration even though they're younger, rather than someone who has the first manifestation in their late 30s. But, in general, age will correlate with disease duration.

When we take a different look at the natural history of the disease overall, early on we see a lot of peripheral inflammation, a lot of relapse, there's a lot of MRI activity. A lot of the studies have shown that the older you get, the fewer relapses there are, the less MRI changes, the less disease activity, and it's been brought up a couple of times at ACTRIMS and in different analyses—we don't have a really good idea if we should be treating older patients differently, and if what's actually underlying the disease is different. For instance, early on patients have a lot of disease activity, a lot of peripheral inflammation&mdash;drugs are targeting that. As they get older and their relapse is decreased and MRI changes decrease, do the drugs still treat the current pathophysiology of the disease? We believe that the older patients, when they start having more of the progression and the neurodegeneration, that it's more smoldering inflammation and compartmentalized inflammation and then loss in metabolic pathways that really aren't reliant on the peripheral immune system anymore. Our drugs aren't really targeting that either. As patients get older, they also have different risks. They have greater infection risk. We don't really understand what the role of our medication is in that age group. We understand that the disease reduces, but we're not quite sure if our medications still treat what we want to treat in the older age group. That's kind of what's the most lacking at this time.

How has age entered the discussion around treatment decisions in MS?

The first MS DMT was approved in 1993, so we're really talking about a short amount of time, and because our main focus for this time is really the need to get therapies out there—we need to get stronger therapies&mdash;we haven't really thought of age as a factor to consider, until now. We're seeing that because we're doing so much better at earlier diagnosis and at treating, the prevalence of MS is shifting. It used to be younger, but now the average age of an MS patient is getting older. That's because we're doing much better job at treating and taking care of them, so they're living longer, they're able to survive, and then we've had them on treatments for a long time. Now, we're actually starting to think about age in a way that we never had before.

The data is actually fairly lacking because it's just kind of a recent phenomenon that we're looking at. For me, how I kind about age is: what's actually happening in their disease? If they're a new diagnosis of MS, is it because they had a new enhancing lesion or a new change or new relapse? Or did they finally just come in, they've had symptoms for 30 years but they finally just started coming to a doctor? Those are 2 different patients—1 has most likely had the disease, they've just never seen anyone, and with the other there's something new going on. I treat them kind of differently, in that anyone with any new disease activity, new inflammation, there's still evidence of peripheral inflammation&mdash;we treat them just like a brand-new diagnosis. If more likely they've had the disease for a while and there's really no new evidence, then I'm treating them as I would a progressive patient, in that what are their comorbidities, what are their risk factors, is there any real benefit of instituting a medication now versus can we watch it and wait? If I don't think that they have active disease, I'll watch them, I'll check MRIs and then we'll monitor for disease activity. If they do have active disease, then we treat just like a presenting patient who has new disease activity.

Overall, in both cases, we're also looking at comorbidities, we're looking at symptom management, do they have spasticity or leg weakness, would they benefit from physical therapy exercise, do I counsel them on nutrition? Older patients will likely have more comorbidities, so what is their risk of heart disease, risk of cancer? And then their social networks—are they able to kind of do some of the interventions that I talked about? Can they come to clinic and drive, are there social barriers that would affect that? That kind of also seems to correlate with age as well.

How does the subanalysis data from the EXPAND study fit into this discussion of age in MS?

The subanalysis is very unique and I think it's great because it really does get into that question of can we dichotomize our patients? We know that there's a younger group and there's an older group. We really wanted to then look at if there is a difference in the drug working on 1 group or the other. Siponimod is an S1P1 selective, P1P5 selective modulator, so we know it has a peripheral effect. It definitely will reduce peripheral lymphocytes, it should have an effect on inflammation and attacks, which then would make us  think that if younger patients have more inflammation, they would also have more effect. But an older patient group which has less peripheral information, is there still an effect?

Now the original siponimod study was looking at secondary progressive MS patients and looking for their primary outcome of 3-month confirmed disability followed by 6-month confirmed disability progression, and in the overall trial, there was a benefit when you looked at the overall group on both of those endpoints. Then we split it because siponimod was approved for active secondary progressive MS, we then defined the subgroup in looking at just active secondary progressive MS patients—they were defined as active if they had either a clinical relapse or a new GD enhancing lesion within the last 2 years. In that subgroup, we then split them into younger than 45 years and older than and including 45 years, and in both groups,  it actually looked fairly similar in their efficacy on both of those 2 end points. So, it didn't seem that age mattered, the drug worked in both age groups on at least disability end points.

The other part of that was then if there were any safety signals that were different between the 2 groups, and they looked fairly similar there as well. The decreasing lymphocytes, lymphopenia, liver abnormalities, and infection risks were similar younger than 45 as well as greater than and including 45. That's kind of reassuring that this drug works in both a younger population and older population, and safety seems to be about the same. We still kind of need a tease out if 45 is really the age we should be splitting patients into, but the reason why 45 was picked is that it gave us well-balanced numbers to actually be able to make a comparison. If you have way too many patients in 1 group and the other 1, then you're introducing other biases that might not be as appropriate.

1. Bar-Or A, Cohan SL, Coyle PK, Lublin FD, Meng X, Su W, Cree BA. Analysis of the effects of disease duration on the efficacy and safety of siponimod in patients with active SPMS from the Expand study. Presented at 2020 ACTRIMS Forum. February 27-29, 2020; West Palm Beach, FL. Abstract P030.

2. Hua L, Bar-Or A, Lublin FD, Meng X, Su W, Cree BA, Fox R. Analyses Of The Effect Of Baseline Age On The Efficacy And Safety Of Siponimod In Patients With Active SPMS From The Expand Study. Presented at 2020 ACTRIMS Forum. February 27-29, 2020; West Palm Beach, FL. Abstract P029.

The director of the Multiple Sclerosis Program at Cleveland Clinic Lou Ruvo Center for Brain Health discussed the correlation between age and disease duration in MS, as well as what was learned from a subanalysis of the EXPAND study of siponimod.

What Role Does Age Play in Multiple Sclerosis?

Findings from the phase 3 EXPAND trial of siponimod demonstrate a significantly greater reduction in risk for confirmed disability progression (CDP) at 3 and 6 months in patients with active secondary progressive multiple sclerosis (SPMS) with a disease duration of <16 years. The findings were presented at the 

2020 America’s Committee for Treatment and Research in Multiple Sclerosis (ACTRIMS) Forum

, February 27-29, 2020, in West Palm Beach, Florida.

In March 2019, siponimod became the first FDA approved drug in more than a decade for the treatment of active SPMS. The approval was granted based on data from the EXPAND trial, which included 1600 patients with SPMS. Results from that trial demonstrated a 21% and 26% reduction in risk for 3- and 6-month CDP (

Additionally, the drug, a selective sphingosine 1-phosphate receptor modulator, has been approved in the US for treatment of clinically isolated syndrome and relapsing-remitting MS.

In this sub-group, post hoc analyses, investigators sought to understand whether the efficacy of siponimod would change based on MS disease duration less than or greater than 16 years at baseline.

The primary end point was time to 3- and 6-month CDP measured using the Expanded Disability Status Scale (EDSS) scores. Adverse events (AEs), serious AEs, and AEs leading to treatment discontinuation were also assessed.

Among the 779 patients with active SPMS, 427 had an MS disease duration <16 years and 352 had an MS disease duration of 

16 years. Of that, 285 and 231 were randomly assigned to receive 2 mg siponimod once daily, respectively.

In patients with an MS disease duration of <16 years, risk for 3- and 6-month CDP was reduced by 32.4% and 42.7%, respectively, compared with placebo (3 month: siponimod, n = 68 [23.9%]; placebo, n = 48 [33.8%]; HR 0.68; 95% CI, 0.47-0.98; 

= .0378; 6 month: siponimod, n = 48 [16.8%]; placebo, n = 40 [28.2%]; HR 0.57; 95% CI, 0.38-0.87; 

Among those with a disease duration ≥16 years at baseline, treatment with siponimod was associated with a trend towards reduced CDP risk of 31.9% and 27.1% at 3 and 6 months, respectively, compared with  placebo (3 month: siponimod, n = 61 [26.4%]; placebo, n = 43 [35.5%]; HR 0.68; 95% CI, 0.46-1.01; 

 = .0540; 6 month, siponimod, n = 51 [22.1%]; placebo, n = 34 [28.1%]; HR 0.73; 95% CI, 0.47-1.13; 

AEs in patients with <16 years of MS disease duration occurred in 84.9% and 75.4% in siponimod and placebo groups, respectively, compared with 89.2% and 81.8% of patients with MS disease duration ≥16 years in the siponimod and placebo groups, respectively.

The investigators concluded that the results may be reflective of the more advanced MS disease in patients with a disease duration of ≥16 years.

Bar-Or A, Cohan SL, Coyle PK, Lublin FD, Meng X, Su W, Cree BA. Analysis of the effects of disease duration on the efficacy and safety of siponimod in patients with active SPMS from the Expand study. Presented at 2020 ACTRIMS Forum. February 27-29, 2020; West Palm Beach, FL. Abstract P030. 

Advances in Multiple Sclerosis

Siponimod Offers Benefit to Cognitive Processing Speed in SPMS

Siponimod Reduces Risk of Disability Progression Regardless of Prior Relapses in MS

What Role Does Age Play in Multiple Sclerosis?

Siponimod Significantly Slows MS Disability Progression in Patients With Shorter Disease Duration