Background

There is a clear need for biomarker development in progressive multiple sclerosis (PMS). Serum neurofilament light (sNFL), and to a lesser extent neurofilament heavy (sNFH), are leading candidates. Whilst sNFL in particular has been examined in relapsing remitting MS, data from PMS are limited and in contrast to immunosuppressive treatments, candidate neuroprotective treatments show a variable effect on these biomarkers [1]. We examine data from the original MS-STAT trial [2].

Objectives

To analyses serum neurofilament data from the MS-STAT trial, assessing cross-sectional and longitudinal sNFL and sNFH and their relationship with MRI and clinical variables.

Methods

Serum samples were acquired at months 0, 6, 12 and 24. sNFL and sNFH were quantified using Single Molecule Array (Simoa). Linear mixed models were used to assess for treatment effects between simvastatin and placebo, and regression, linear mixed and bivariate models to assess association with MRI and clinical variables.

Results

Median baseline sNFL was 14.6pg/ml (IQR 10.8-20.2) and sNFH 64.2pg/ml (23.9-119), rising to 16.0pg/ml (11.9-22.2) and 70.9pg/ml (26.5-123) by 24 months. Higher baseline sNFL was associated with greater subsequent brain atrophy. Similarly, higher sNFL was associated with higher T2 lesion volume (T2LV), and increases in sNFL were associated with increases in T2LV.

High baseline sNFL was associated with worse baseline EDSS (95% CI of coefficient: 0.120 to 0.633), 9-hole peg test (-0.009 to -0.002) and 25 foot walk (-0.515 to -0.019), and a greater deterioration in 25 foot walk from baseline to 2 years (-0.448 to -0.152). There was no evidence of an association between sNFH and these variables.

There was no evidence of a simvastatin treatment effect on either sNFL (95% CI -0.07 to 0.10, p=0.716) or sNFH (95% CI -0.17 to 0.22, p=0.827).

Conclusions

The mode of action of simvastatin in reducing brain atrophy remains to be elucidated, with actions upon vascular comorbidity and intermediate metabolites from cholesterol synthesis pathways as possible candidates [3]. Simvastatin is not immunosuppressive, and in common with other purportedly neuroprotective treatments, there is no evidence from this study that sNFL or sNFH can act as biomarkers of simvastatin treatment. The relationship between sNFL and T2LV supports the hypothesis that in MS, sNFL may act predominantly as a marker of neuroinflammation, even in this typical SPMS cohort.

1. Williams T et al (2020) Neurofilaments in progressive multiple sclerosis: a systematic review. J Neurol.

2. Chataway J et al (2014) Effect of high-dose simvastatin on brain atrophy and disability in secondary progressive multiple sclerosis (MS-STAT): a randomised, placebo-controlled, phase 2 trial. Lancet

3. Palladino R et al (2020) Evaluating the Risk of Macrovascular Events and Mortality among People with Multiple Sclerosis in England. JAMA Neurol

Background

Both induction therapy, like oral cladribine, and B-cell depletion therapy, like rituximab, are highly effective disease modulatory treatments (DMTs) in relapsing multiple sclerosis (MS). The high economic costs of the registered DMTs may limit availability of treatment and strain health budgets worldwide.
Oral cladribine is a recently approved DMT in Europe, while rituximab is used off-label, especially in Norway and Sweden. Large observational studies indicate good tolerance and treatment effects in MS and studies from other diseases indicate a good safety profile. However, to our knowledge, no phase three studies have compared rituximab with any established highly effective DMT. Formal safety data is also lacking for rituximab treatment in MS.

Objectives

To perform a prospective randomized open-label blinded endpoint multicenter non-inferiority study. The primary objective is to test whether rituximab is non-inferior to oral cladribine for treatment of relapsing MS.

Methods

In total 264 MS patients with relapsing MS will be recruited from 11 Norwegian centers and followed for 96 weeks. Inclusion criteria are having a relapsing MS diagnosis, age 18-65 years, at least one clinical relapse or one new T2 lesion on MRI within the last year and willingness to use contraception during the study period. Exclusion criteria are contraindications to either treatment, previous use of either or a similar treatment, or treatment with fingolimod or natalizumab (due to risk of rebound activity) within the last six months. The study participants will be treated with either cladribine or rituximab according to current guidelines.

Results

The primary endpoint is difference in number of new or enlarging T2 lesions between the two groups from rebaseline at 12 weeks to the end of the study at 96 weeks. Furthermore, we will study clinical course, blood samples and MRI biomarkers to provide tools for personalized MS treatment. Finally, the health economic consequences of these treatment options will be evaluated. At the time of abstract submission, 55 patients have been included across three study sites. The Covid19 outbreak unfortunately resulted in a temporary halt in inclusion from March to May 2020, but the study has now been reopened. End of study is estimated to fall 2023.

Conclusions

This study will guide clinicians and patients in future treatment choices for MS. The results will provide valuable knowledge concerning treatment strategies and can potentially have a huge impact on the costs of future MS treatments.

Background

Cognitive dysfunction is common in multiple sclerosis (MS) and is particularly prevalent in patients with progressive forms of the disease [1]. Exploring neurofilament associations has clear value in trying to develop treatments for cognition.

Objectives

To perform a post-hoc analysis of the MS-STAT trial [2], assessing serum neurofilament light (sNFL) and heavy (sNFH) as predictive biomarkers of future cognitive performance.

Methods

Serum samples were analysed for sNFL and sNFH using Single Molecule Array (Simoa). Cognition was assessed at months 0, 12 and 24 with a detailed neuropsychometric battery including the Wechsler Abbreviated Scale of Intelligence (WASI) and Brain Injury Rehabilitation Trust Memory and Information Processing Battery (BMIPB), as previously described [3]. Multivariate regression models were used for cross-sectional analysis, and linear mixed models were used to assess the predictive value of dichotomised baseline sNFL and sNFH on changes in cognition. All analyses controlled for the established MRI variables of whole brain volume (WBV) and T2 lesion volume (T2LV) in order to assess the extent to which sNFL and sNFH provided additional prognostic value.

Results

Cross-sectional analyses:

After adjusting for demographics, T2LV and WBV, neither sNFL nor sNFH demonstrated cross-sectional associations with current cognitive performance.

Longitudinal analyses:

Patients with high baseline sNFL experienced significantly greater cognitive decline from 0 to 24 months in WASI full-scale IQ (95% CI of coefficient -0.238 to -0.024), WASI Verbal IQ (-0.281 to -0.011), and in both immediate and delayed BMIPB figure recall (-0.489 to -0.046 and -0.399 to -0.025, respectively). sNFH was not associated with changes in cognitive performance.

Conclusions

Our results demonstrate the prognostic value of sNFL on future changes in cognitive performance in SPMS, assessed through a detailed neuropsychometric battery. sNFL remained significantly associated with future cognitive decline whilst controlling for established MRI biomarkers, suggesting that it may provide additional utility in identifying those who may benefit most from interventions aimed at preventing cognitive decline.

1. Sumowski JF et al (2018) Cognition in multiple sclerosis: State of the field and priorities for the future. Neurology

2. Chataway J et al (2014) Effect of high-dose simvastatin on brain atrophy and disability in secondary progressive multiple sclerosis (MS-STAT): a randomised, placebo-controlled, phase 2 trial. Lancet

3. Chan D et al (2017) Effect of high-dose simvastatin on cognitive, neuropsychiatric, and health-related quality-of-life measures in secondary progressive multiple sclerosis: secondary analyses from the MS-STAT randomised, placebo-controlled trial. Lancet Neurol

Background

Background: Alemtuzumab (ALZ) belongs to the immune reconstitution therapies for relapsing-remitting multiple sclerosis (RRMS). ALZ is used as second or third line treatment in clinical practise, thus the real-world population treated with ALZ is markedly different from the populations in the pivotal trials of ALZ.

Objectives

Objectives: To assess basic characteristics and therapeutic effects on clinical and imaging parameters of disease activity for RRMS patients selected for ALZ.

Methods

Methods: RRMS patients were consecutively included at the MS Centre, Gothenburg. Patients were clinically assessed with Expanded Disability Status Scale (EDSS), occurrence of clinical relapses and with cerebral MRI at baseline, month 12, 24, 36 and 48.

Results

Resluts: 51 (31 females) RRMS patients, mean age and mean disease duration of 35.5 (±7.1) respectively 7.1 (±5.4) years were included. Prior to baseline 6 patients had first line treatment, 38 had second line and 7 were naïve. Reasons to switch to ALZ; break through disease activity despite disease modifying treatment (DMT) (n=23), side effects (n=3), positive JC virus antibody test during natalizumab (n=18), highly active disease from disease onset (n=7). All patients received the first course of ALZ, 50 the second, 14 a third, and 2 a fourth course. At baseline, month 12, 24, 36 and 48 median EDSS was 2 (0-7.5), 1.5 (0-7), 1.5 (0-7.5), 1.5 (0-7.5) and 1.5 (0-7), respectively. At 48 months 34 patients were relapse free, and the annual relapse rate was 0.12. Baseline MRI revealed high lesion load; T2 lesions >20 (n=35), T2 lesions 10-20 (n=12), T2 lesions 1-9 (n=4), 36 patients had no contrast enhancement. Upon follow-up at 12, 24 , 36 and 48 months, 39 patients, 42, 45 and 38 had no new or enlarged T2 lesions respectively, corresponding number with no contrast enhancement was 43, 45, 47, and 40. Mean brain parenchymal fraction at baseline was 0.862 (±0.037, n=43) and was unchanged at follow-up. 23 patients met No Evidence of Disease Activity (NEDA) at 48 months. 9 (18%) patients have switched from ALZ to another DMT (rituximab n=6, autologous hematopoietic stem cell transplantation n=3) due to disease activity.

Conclusions

Conclusions: This real-world population confirms that ALZ as second or third line treatment effectively reduced disease activity. Although most of our patients had previously failed on DMT the proportion of progression free survival (82%) and NEDA (45%) were of similar magnitude as those reported from the pivotal trials CARE-MS I&II.