Background

Siponimod significantly reduced the relative risk of 3-month (m) confirmed disability progression (CDP) by 21% and 6mCDP by 26% versus placebo in the EXPAND core study. Siponimod also showed a significant benefit on cognitive processing speed (CPS) as measured by change in the Symbol Digit Modalities Test (SDMT).

Objectives

To evaluate the effect of siponimod on CPS in subgroups of patients with active (aSPMS) and non-active (naSPMS) disease from the EXPAND core study.

Methods

EXPAND (N=1651) was a double-blind Phase 3 study that randomized a broad range of SPMS patients to siponimod or placebo (2:1). This subgroup post-hoc analysis included patients with aSPMS (siponimod, n=516; placebo, n=263; defined as presence of relapses in the 2 years before screening and/or ≥1 T1 gadolinium-enhancing lesions at baseline) and naSPMS (siponimod, n=557; placebo, n=270; counterpart of aSPMS). The outcomes analyzed were change in SDMT score from baseline to M24 derived from the mixed model for repeated measures; time to 6m confirmed ≥4-points cognitive worsening/improvement (6mCW/6mCI) on SDMT and a categorical analysis showing the proportion of patients with worsened, stable and improved SDMT scores (worsened/improved by ≥4 points since baseline and until the end of the trial, or otherwise stable) at M24.

Results

Change in SDMT (95% CI) versus placebo from baseline to M24 in the aSPMS and naSPMS groups was 2.34 (0.66; 4.02) and 2.44 (0.67; 4.22; p<0.01 for both), respectively, consistent with the overall EXPAND core population (2.28 [1.09; 3.48]; p<0.001). In patients with aSPMS, siponimod reduced the risk of 6mCW by 27% (hazard ratio [95% CI]: 0.73 [0.53; 1.01]; p=0.06) and improved the chance of 6mCI by 62% (1.62 [1.14; 2.29]; p=0.007) versus placebo. Corresponding values in the naSPMS group were: 6mCW, 24% (0.76 [0.53; 1.09]; p=ns) and 6mCI, 19% (1.19 [0.86; 1.65]; p=ns). In the aSPMS group, a lower proportion of patients worsened (27.3% vs 38.2%, p=0.002) and a higher proportion of patients improved (34.1% vs 22.9%, p=0.001) on SDMT versus placebo. Corresponding proportions for the naSPMS group were: worsened, 21.2% vs 23.7%, p=ns; improved, 35.6 vs 31.2%, p=ns.

Conclusions

Siponimod was associated with relevant benefits in CPS as measured by change in SDMT in patients with active and non-active SPMS. In patients with active disease, both a reduced risk for clinically relevant worsening and an increased chance for clinically relevant improvement were observed.

Background

The missing 1:1 relation of lesion to disability in patients with multiple sclerosis (MS) may be due to processes of functional and structural reorganization and plasticity, which can be summarized as the compensatory reserve. A sensitive and reproducible parameter to measure these mechanisms may be repetitive transcranial magnetic stimulation (rTMS) of the cortex. However, results of previous studies on rTMS-induced plasticity in MS patients are limited due to high variability of their rTMS protocols. Furthermore, the relationship between cortical plasticity and cognition has not been investigated so far.

Objectives

To reliably assess the compensatory mechanisms of motor cortex plasticity in patients with relapsing-remitting MS (RRMS) compared to healthy controls (HC) and to investigate the association of induced plasticity with information processing speed (IPS) and visuospatial memory.

Methods

25 patients with RRMS (mean disease duration=11.0[8.0], median Expanded Disability Status Scale=1.5[0.0-7.5]), and 25 age-, sex-, and education-matched HC entered the study. To assess cortical plasticity, the amplitudes of the motor evoked potentials at the extremities pre and post repetitive transcranial quadripulse stimulation (QPS), a protocol previously reported to show less variability, were recorded. Group comparisons were carried out with generalized linear mixed-effects models. IPS and visuospatial memory were assessed using the Symbol Digit Modalities Test (SDMT) and Brief Visuospatial Memory Test-Revised (BVMT-R), respectively. Associations of these measures with cortical plasticity were investigated with correlational analyses.

Results

Cortical plasticity was induced by QPS in both groups (p<.001). However, a significant intervention^xgroup interaction (p=.032) indicated reduced plasticity in RRMS patients compared to controls. Patients also performed significantly worse on the SDMT (p=.008) and BVMT-R (p=.030) than HC. Correlational analyses revealed significant positive correlations between these parameters and QPS-induced plasticity (SDMT: r_s=0.47, p=.018; BVMT-R: r_s=0.50, p=.012) in the patient sample.

Conclusions

We provide evidence for reduced cortical plasticity in patients with RRMS compared to closely matched HC, emphasizing the promising role of transcranial magnetic QPS as a sensitive and reliable biomarker to measure compensatory reserve. Moreover, our data demonstrate, for the first time, that QPS-induced plasticity is positively associated with neuropsychological outcome measures of IPS and visuospatial memory in patients with RRMS.

Background

CLADQoL is a non-interventional study (NIS) in patients with RMS treated with cladribine tablets, focusing on quality of life. This is the first publication on the change in quality of life (examined by MSQoL-54) of patients treated with cladribine tablets in real world conditions at baseline and after 12 months. The recruitment period has ended in April 2020. Patient follow-up will continue and is planned for four years.

Objectives

Describing the patient population including pre-treatment and relapse rate and evaluating changes in patients’ quality of life (MSQoL-54 physical health and mental health composite scores) under therapy with cladribine tablets 12 months after treatment initiation.

Methods

Quality of life (QoL) was evaluated from the patient subset where MSQoL-54 was available both at baseline and month 12. Cut-Off date for analysis was January 31^st 2020.

Results

87 of 254 recruited patients were evaluated so far (mean age 37 years; 78.2% female; 93.1% RRMS). Most frequent last previous therapy for treated patients was fingolimod, dimethyl fumarate, glatiramer acetate and daclizumab.

For the subsets with valid MSQoL-54 at baseline and month 12 the physical health composite score showed a decrease -0.942 ±14.08 whereas the mental health composite score revealed an increase 0.711 ±17.33 (Change 12 months vs. baseline). None of the differences reached significance.

The number of relapses decreased from 1.0 ±1.09 (Mean ±SD) at baseline to 0.2 ±0.58 (Mean ±SD) at month 12.

Regarding safety, evaluation was performed for the overall study population (N=254). 82 patients experienced at least one AE and 15 patients at least one SAE.

Conclusions

Within the first year of treatment with cladribine tablets in patients with RRMS or SPMS with superimposed relapses there were minimal changes in QoL scores.

We observed a decrease in relapses and the safety results were in line with known safety profile of cladribine tablets.

The NIS is ongoing and patient subset is being followed up.

Background

Natalizumab proved to be very effective in patients with active relapsing-remitting multiple sclerosis but harbors the risk of progressive multifocal leukoencephalopathy (PML), especially in combination with specific risk factors. Accordingly, a safe and an equally effective therapeutic alternative is warranted in this patient group. A high efficacy therapy for Relapsing Multiple Sclerosis are cladribine tablets, representing a short course oral therapy. It has been approved in Europe since 2017 and in the USA since April 2019.

Objectives

Safety of switching from natalizumab to cladribine tablets has been investigated in a limited number of patients and with limited observational time. We therefore analyzed this safety issue with a longer follow-up time in the subgroups of post-natalizumab patients in 2 non-interventional studies (NIS).

Methods

46 patients who switched from natalizumab to oral cladribine were reviewed. They originated from 2 cohorts analyzed separately: 23 patients each from the still ongoing NIS CLEVER (in Germany, 24 weeks follow-up as per study duration) and CLADQoL (in Germany and Austria, mean follow-up 11 months). Different study designs accounted for different timings in data collection. Patients were closely monitored, and data was collected regarding MS relapses, disease progression, or possible adverse events.

Results

The NIS CLEVER provides data from 23 patients (mean age 41.6 years; 78% female; 87% RRMS). The most frequent reason for therapy switch was increased JCV antibody titer/risk of PML or lack of efficacy. Median time on natalizumab was 26.6 months and median gap between therapies 3.2 months. 1 out of 15 evaluable patients at week 24 experienced relapses. For 7 patients at least one AE was reported and no SAE.

The NIS CLADQoL provides data from 23 patients (mean age 38.8 years; 70% female; 91% RRMS). The most frequent reason for therapy switch was increased JCV antibody titer/risk of PML. Median time on natalizumab was 40.1 months and median gap between therapies 3.4 months. 2 out of 10 evaluable patients at month 12 experienced relapses. 6 patients experienced at least one AE and 3 patients one SAE (Anterior Myocardial Infarction (among underlying risk factors), Multiple sclerosis relapse, Dyspnoea).

Conclusions

Based on data from 46 patients, switching from natalizumab to cladribine tablets continued to be safe in a larger patient population and after a longer follow-up. Especially no cases of PML were observed.

Abstract

Title

Treatment of cognitive deficits in MS

Background

Despite the high prevalence of cognitive impairment in Multiple Sclerosis (MS) and its tremendous effects on working ability and quality of life, evidence-based and effective treatment strategies are still an unmet need and solutions urgently requested.

Objectives

To provide an overview on the efficacy of pharmacological and non-pharmacological approaches in managing cognitive deficits in MS.

Methods

This part of the teaching course will review and critically discuss whether pharmacological and non-pharmacological treatment options have the potential to treat cognitive impairment in MS.

Results

Overall, patients receiving immunotherapy show better cognitive performance than patients under placebo. Since head-to-head studies are missing no clear statement about superiority can be given. Non-pharmacological treatment strategies (e.g. exercise, cognitive training, cognitive behavioral approaches, meditation) have the potential to support cognitive reserve and self-efficacy which in turn helps to manage cognitive impairment.

Conclusions

Immunotherapies are able to stabilize cognitive performance over time or even to improve cognitive status by targeting on inflammation. From all data available it can be assumed that the earlier we treat, the better the cognitive outcome in the long run.

Non-pharmacological treatment strategies offer the opportunity to improve patients’ self-efficacy and cognitive performance, do not have considerable side-effects, are cost-efficient and therefore highly recommendable in treating MS patients with cognitive problems.

Background

Siponimod significantly reduced the relative risk of 3-month (m) confirmed disability progression (CDP) by 21% and 6mCDP by 26% versus placebo in the EXPAND core study. Siponimod also showed a significant benefit on cognitive processing speed (CPS) as measured by change in the Symbol Digit Modalities Test (SDMT).

Objectives

To evaluate the effect of siponimod on CPS in subgroups of patients with active (aSPMS) and non-active (naSPMS) disease from the EXPAND core study.

Methods

EXPAND (N=1651) was a double-blind Phase 3 study that randomized a broad range of SPMS patients to siponimod or placebo (2:1). This subgroup post-hoc analysis included patients with aSPMS (siponimod, n=516; placebo, n=263; defined as presence of relapses in the 2 years before screening and/or ≥1 T1 gadolinium-enhancing lesions at baseline) and naSPMS (siponimod, n=557; placebo, n=270; counterpart of aSPMS). The outcomes analyzed were change in SDMT score from baseline to M24 derived from the mixed model for repeated measures; time to 6m confirmed ≥4-points cognitive worsening/improvement (6mCW/6mCI) on SDMT and a categorical analysis showing the proportion of patients with worsened, stable and improved SDMT scores (worsened/improved by ≥4 points since baseline and until the end of the trial, or otherwise stable) at M24.

Results

Change in SDMT (95% CI) versus placebo from baseline to M24 in the aSPMS and naSPMS groups was 2.34 (0.66; 4.02) and 2.44 (0.67; 4.22; p<0.01 for both), respectively, consistent with the overall EXPAND core population (2.28 [1.09; 3.48]; p<0.001). In patients with aSPMS, siponimod reduced the risk of 6mCW by 27% (hazard ratio [95% CI]: 0.73 [0.53; 1.01]; p=0.06) and improved the chance of 6mCI by 62% (1.62 [1.14; 2.29]; p=0.007) versus placebo. Corresponding values in the naSPMS group were: 6mCW, 24% (0.76 [0.53; 1.09]; p=ns) and 6mCI, 19% (1.19 [0.86; 1.65]; p=ns). In the aSPMS group, a lower proportion of patients worsened (27.3% vs 38.2%, p=0.002) and a higher proportion of patients improved (34.1% vs 22.9%, p=0.001) on SDMT versus placebo. Corresponding proportions for the naSPMS group were: worsened, 21.2% vs 23.7%, p=ns; improved, 35.6 vs 31.2%, p=ns.

Conclusions

Siponimod was associated with relevant benefits in CPS as measured by change in SDMT in patients with active and non-active SPMS. In patients with active disease, both a reduced risk for clinically relevant worsening and an increased chance for clinically relevant improvement were observed.

Background

CLADQoL is a non-interventional study (NIS) in patients with RMS treated with cladribine tablets, focusing on quality of life. This is the first publication on the change in quality of life (examined by MSQoL-54) of patients treated with cladribine tablets in real world conditions at baseline and after 12 months. The recruitment period has ended in April 2020. Patient follow-up will continue and is planned for four years.

Objectives

Describing the patient population including pre-treatment and relapse rate and evaluating changes in patients’ quality of life (MSQoL-54 physical health and mental health composite scores) under therapy with cladribine tablets 12 months after treatment initiation.

Methods

Quality of life (QoL) was evaluated from the patient subset where MSQoL-54 was available both at baseline and month 12. Cut-Off date for analysis was January 31^st 2020.

Results

87 of 254 recruited patients were evaluated so far (mean age 37 years; 78.2% female; 93.1% RRMS). Most frequent last previous therapy for treated patients was fingolimod, dimethyl fumarate, glatiramer acetate and daclizumab.

For the subsets with valid MSQoL-54 at baseline and month 12 the physical health composite score showed a decrease -0.942 ±14.08 whereas the mental health composite score revealed an increase 0.711 ±17.33 (Change 12 months vs. baseline). None of the differences reached significance.

The number of relapses decreased from 1.0 ±1.09 (Mean ±SD) at baseline to 0.2 ±0.58 (Mean ±SD) at month 12.

Regarding safety, evaluation was performed for the overall study population (N=254). 82 patients experienced at least one AE and 15 patients at least one SAE.

Conclusions

Within the first year of treatment with cladribine tablets in patients with RRMS or SPMS with superimposed relapses there were minimal changes in QoL scores.

We observed a decrease in relapses and the safety results were in line with known safety profile of cladribine tablets.

The NIS is ongoing and patient subset is being followed up.

Abstract

Title

Treatment of cognitive deficits in MS

Background

Despite the high prevalence of cognitive impairment in Multiple Sclerosis (MS) and its tremendous effects on working ability and quality of life, evidence-based and effective treatment strategies are still an unmet need and solutions urgently requested.

Objectives

To provide an overview on the efficacy of pharmacological and non-pharmacological approaches in managing cognitive deficits in MS.

Methods

This part of the teaching course will review and critically discuss whether pharmacological and non-pharmacological treatment options have the potential to treat cognitive impairment in MS.

Results

Overall, patients receiving immunotherapy show better cognitive performance than patients under placebo. Since head-to-head studies are missing no clear statement about superiority can be given. Non-pharmacological treatment strategies (e.g. exercise, cognitive training, cognitive behavioral approaches, meditation) have the potential to support cognitive reserve and self-efficacy which in turn helps to manage cognitive impairment.

Conclusions

Immunotherapies are able to stabilize cognitive performance over time or even to improve cognitive status by targeting on inflammation. From all data available it can be assumed that the earlier we treat, the better the cognitive outcome in the long run.

Non-pharmacological treatment strategies offer the opportunity to improve patients’ self-efficacy and cognitive performance, do not have considerable side-effects, are cost-efficient and therefore highly recommendable in treating MS patients with cognitive problems.

Abstract

Title

Treatment of cognitive deficits in MS

Background

Despite the high prevalence of cognitive impairment in Multiple Sclerosis (MS) and its tremendous effects on working ability and quality of life, evidence-based and effective treatment strategies are still an unmet need and solutions urgently requested.

Objectives

To provide an overview on the efficacy of pharmacological and non-pharmacological approaches in managing cognitive deficits in MS.

Methods

This part of the teaching course will review and critically discuss whether pharmacological and non-pharmacological treatment options have the potential to treat cognitive impairment in MS.

Results

Overall, patients receiving immunotherapy show better cognitive performance than patients under placebo. Since head-to-head studies are missing no clear statement about superiority can be given. Non-pharmacological treatment strategies (e.g. exercise, cognitive training, cognitive behavioral approaches, meditation) have the potential to support cognitive reserve and self-efficacy which in turn helps to manage cognitive impairment.

Conclusions

Immunotherapies are able to stabilize cognitive performance over time or even to improve cognitive status by targeting on inflammation. From all data available it can be assumed that the earlier we treat, the better the cognitive outcome in the long run.

Non-pharmacological treatment strategies offer the opportunity to improve patients’ self-efficacy and cognitive performance, do not have considerable side-effects, are cost-efficient and therefore highly recommendable in treating MS patients with cognitive problems.