Background

Disease activity in multiple sclerosis (MS) is highly variable, and there are limited prospective studies on predictors of disease outcomes.

Objectives

The aim of the study is to identify and assess clinical characteristics in MS that predict disease activity and progression.

Methods

The study population consisted of a prospective cohort of 1,008 patients with relapsing-remitting (RR) onset MS enrolled in the CombiRx trial. Cox regression analysis was used to determine hazard ratio (HR) associations between baseline (BL) demographics (age <38 vs. ≥38, sex, race), clinical history (number of relapses in prior year <3 vs. ≥3, disease duration, Expanded Disability Status Scale (EDSS)), and MRI metrics (presence or absence of gadolinium (Gd) and number of T2 lesions), and treatment (glatiramer acetate (GA), interferon-beta 1a (IFN), or combination therapy); with outcomes of time to first new disease activity over 7-years of follow-up including relapse, MRI activity defined by new combined unique active lesion, and disease worsening as defined by confirmed 6-month increase in EDSS.

Results

1,008 participants were randomized, with 959 eligible for assessment of disease worsening and activity on follow-up MRI. Participants were median 38 (range 18, 61) years of age at baseline, 72.7% female, 88.3% Caucasian, 7.1% black/African American, mean 1.2 years since diagnosis, with median 2 relapses in the prior 12 months and median EDSS 2 (IQR 1, 2.5). Risk of relapse was higher in patients younger than 38 at BL vs. older (HR 1.36, 95% CI: 1.12,1.65) and with BL EDSS ≥3.5 vs. <3.5 (HR 1.66, 95% CI: 1.27, 2.14). Presence of Gd+ lesions at baseline was also associated with increased risk of relapse (HR 1.37, 95%CI: 1.14, 1.66). Risk of new MRI activity was higher in younger participants (HR 1.56, 95%CI: 1.34, 1.86) and those taking either single agent arms compared to the combination (GA: HR 1.48, 95%CI 1.22, 1.80; IFN: HR 1.43, 95%CI 1.18, 1.74). Similarly, higher preexisting lesion burden greater than the median lesion count with ≥71 T2 hyperintense lesions vs. <71 (HR 1.50, 95%CI 1.27, 1.78) and presence of BL Gd+ lesions (HR 1.75, 95%CI: 1.49, 2.06) were also associated with a higher risk of developing new MRI activity. Risk of disease worsening was higher for those with BL EDSS < 2 (HR 2.79, 95%CI 2.14, 3.67). There were no associations between sex and disease duration on clinical or radiological disease activity or worsening.

Conclusions

Both clinical and radiological disease activity are predicted by younger age and presence of Gd+ lesions. Additionally, relapses are also predicted by higher EDSS, and there is some protective evidence of the combination therapy in lowering risk of new MRI activity. Only baseline EDSS level was associated with disease worsening.

Background

Ponesimod (PON), an orally active, highly selective and reversible modulator of sphingosine-1-phosphate receptor 1, reduces circulating lymphocytes by sequestration in lymphoid organs. In the phase-3 OPTIMUM study (NCT02425644), PON showed superior efficacy vs teriflunomide (TER) in patients with relapsing multiple sclerosis (RMS).

Objectives

To evaluate prespecified MRI-based endpoints and no evidence of disease activity (NEDA) status in patients with RMS.

Methods

Patients (18-55 years) with RMS (expanded disability status scale scores: 0-5.5) were randomized (1:1) to receive PON 20 mg or TER 14 mg for 108 weeks. MRI endpoints included: percentage change from baseline to week 108 in brain volume (SIENA, Structural Image Evaluation, using Normalization of Atrophy), mean number of new gadolinium-enhancing (Gd+) T1 lesions and volume/count of new/enlarging T2-weighted (T2) lesions. NEDA-3 (absence of confirmed relapse, 12-week confirmed disability accumulation, Gd+T1 and new/enlarging T2 lesions on annual MRIs) and NEDA-4 status (NEDA-3 and no average annual brain volume decrease ≥0.4%) were evaluated from baseline to week 108.

Results

985/1133 (86.9%) randomized patients completed the study. MRI findings for PON vs TER from baseline to week 108, respectively, were: least square (LS) mean percent change from baseline in brain volume: −0.91% vs −1.25% (difference: 0.34%, 95% CLs: 0.17;0.50, p<0.0001); LS mean difference (PON−TER) in change from baseline in total T2 lesion load: −399.2 mm³ (95% CLs: −651.5;−146.8, p=0.002); mean number of new/enlarging T2 lesions per year: 1.40 vs 3.16 (rate ratio [RR]: 0.44, 95% CLs: 0.36;0.54, p<0.0001); PON vs TER odds ratio (OR [95% CL]) for absence of new/enlarging T2 lesions: 1.71 (1.30;2.25, p=0.0001); mean number of new Gd+T1 lesions per scan: 0.18 vs 0.43 (RR: 0.42, 95% CLs: 0.31;0.56, p<0.0001); PON vs TER (OR [95% CL]) for absence of new Gd+T1 lesions: 2.18 (1.61;2.95, p<0.0001). At week 108, 28.2% (159/564) PON vs 18.3% (102/558) TER patients (OR: 1.70, 95% CLs: 1.27;2.28, p=0.0004) achieved NEDA-3; 15.0% (79/526) PON vs 8.5% (45/532) TER patients (OR: 1.85, 95% CLs: 1.24;2.76, p=0.0026) achieved NEDA-4. The most common reason for not achieving NEDA-3 or NEDA-4 status was presence of new/enlarging T2 lesions.

Conclusions

PON showed benefit vs TER for all MRI outcomes including brain volume loss and a significantly higher proportion of patients achieved NEDA-3 and NEDA-4 status, supporting the effects observed on clinical endpoints.

Background

Serum neurofilament light-chain (sNfL) is associated with disease activity and tissue damage, predicts long-term outcomes, and is reduced by disease-modifying therapies in RRMS patients.

Objectives

In a post hoc analysis, determine sNfL differences from baseline (BL) to 48 months and associations with long-term clinical outcomes in patients treated with intramuscular (IM) interferon (IFN) beta-1a, glatiramer acetate (GA), or both therapies (IFN+GA).

Methods

CombiRx was a placebo (PLB)-controlled double-blind phase 3 trial in treatment-naive RRMS patients randomized to IM IFN beta-1a 30 µg weekly+PLB, GA 20 mg/mL daily+PLB, or IFN+GA treatment for up to 7 years. Samples for biomarker analysis were collected at BL, 6, 12, 36, and 48 months from volunteers for a substudy offered in most sites. Relapses and Expanded Disability Status Scale (EDSS) scores were collected every 3 months. A Simoa Human Neurology 4-Plex A assay analysed sNfL levels. A linear mixed model compared sNfL values over time adjusted for BL EDSS, age, sex and body mass index (BMI). A Cox regression model with the same covariates analysed BL sNfL as a predictor of relapse.

Results

Samples were collected from 159 IFN, 172 GA, and 344 IFN+GA patients. BL characteristics were generally well balanced, including mean age, sex, mean BMI, mean time since symptom and diagnosis onset, and mean EDSS scores. Significant reductions relative to BL in sNfL levels were seen at 6, 12 and 36 months in the IFN, GA, and IFN+GA treatment groups. BL sNfL ≥16 pg/mL significantly predicted relapse within 90 days (hazard ratio [HR]: 2.25, P=0.0041), 180 days (HR: 1.67, P=0.0130) and 1 year from BL (HR: 1.40, P=0.0435), but not over the entire study duration (HR: 1.08, P=0.5596). In patients with BL sNfL ≥16 pg/mL and ≥1 BL gadolinium-enhancing (Gd+) lesion, a significantly higher percentage (16.8%) relapsed within 90 days than in patients with BL sNfL ≥16 pg/mL and no BL Gd+ lesions (9.2%), or BL sNfL <16 pg/mL with (7.3%) or without BL Gd+ lesions (6.7%) (P=0.0051).

Conclusions

Treatment with IFN, GA, and IFN+GA significantly reduced sNfL levels within 6 months and was maintained over 36 months. Results suggest that BL sNfL levels predict relapses within 1 year, and that the combination of lesion activity and sNfL is a stronger predictor of relapse than either one alone.

This analysis was funded by Biogen. Biogen also funded the writing support for this abstract, which was provided by Ashfield Healthcare Communications (Middletown, CT, USA).

Background

A more severe disease course has been reported in African-American (AA) in comparison with Caucasian (CA) MS patients. Sociodemographic differences and limited access to treatment have been often used to explain the different disability profile in the two groups. To date, an objective assessment of disability in AA and potential differences with CA patients is still lacking.

Objectives

Here, we characterized sociodemographic, motor and neuropsychological features of AA and CA patients with multiple sclerosis.

Methods

Fifty-seven AA patients (43F, mean age 37.84 ± 10.54 yrs, mean disease duration 5.64 ± 5.74 yrs, median EDSS 2, EDSS range 0-6.5), 37 AA healthy controls (HC) (25F, mean age 35.97 ± 12.44 yrs), 50 CA patients (36F, mean age 39.02 ± 10.83 yrs, mean disease duration 5.90 ± 5.94 yrs, median EDSS 1.5, EDSS range 0-6) and 28 CA HC (17F, mean age 35.57 ± 11.77 yrs) were prospectively enrolled. In all subjects, an extensive neuropsychological and sensory-motor evaluation was performed. The sensory-motor evaluation included 9-hole peg test (9-HPT), grooved pegboard test (GPT), finger tapping test (FTT), 25-foot walk test (25-FWT), 2-minutes walk test (2-MWT), evaluation of segmental strength, grip strength, vibration sensitivity (VS) and standing balance (theta score from NIH toolbox). The neuropsychological evaluation included Symbol Digit Modalities Test (SDMT), California Verbal Learning Test-II (CVLT), Brief Visuospatial Memory Test–Revised (BVMT), Stroop Color and Word Test (SCVT), Controlled Oral Word Association Test (COWAT) and a multitasking attention-memory test (MAMT). Each patient’s group was compared with a race-matched HC group via ANCOVA analysis, accounting for age, gender, years of education and socioeconomic status expressed as yearly income (9 categories with 1 = less than $5,000 and 9 = $100,000+). In the comparison of cognitive performance, years of education, premorbid intelligence estimated with the Wechsler Test of Adult Reading (WTAR) and depressive symptoms evaluated via Beck Inventory were also included as covariates of no interest.

Results

AA and CA patients did not differ in age, gender, disease duration, while they did differ in total years of education (p<0.001) and yearly income (p=0.001). When compared to their matched HC group, AA and CA patients showed similar deficits in information processing speed, ambulation, manual dexterity, sensitivity and balance (p ranging from 0.029 to <0.001). While CA showed an additional impairment of verbal memory (p=0.009), AA patients showed additional involvement of verbal fluency (p=0.005), multitasking capability (p=0.024), motor speed and coordination (p=0.048) and grip strenght (p=0.041).

Conclusions

Even when accounting for sociodemographic features, AA patients show more severe and widespread disability than CA patients with MS.

Background

Ponesimod (PON) is a sphingosine-1-phosphate receptor 1 modulator. Activation of these receptors on cardiomyocytes during treatment initiation cause transient effects on heart rate (HR) and antrioventicular (AV) conduction. The OPTIMUM phase 3 study assessed efficacy, safety, and tolerability of PON and teriflunomide (TER) in relapsing multiple sclerosis.

Objectives

We report on the cardiac safety profile of ponesimod versus teriflunomide in the phase 3 OPTIMUM study (NCT02425644).

Methods

Patients (18-55 years) were randomized 1:1 to PON (20 mg) or TER (14 mg) for 108 weeks. For PON, a gradual 14-day up-titration starting with 2 mg was implemented to address 1^st-dose cardiac effects. Cardiac safety was assessed by blood pressure (BP) and 12-lead ECG measurements. Cardiac treatment-emergent adverse events (TEAEs), major adverse cardiovascular (CV) events (MACE; defined as CV death, non-fatal myocardial infarction [MI], and non-fatal stroke), and TEAEs of special interest (AESIs) are reported.

Results

Of 1131 patients who received treatment (PON: n=565, TER: n=566), baseline mean HR was 70.6 bpm (PON), 70.3 bpm (TER), range 45-126 bmp. Cardiac TEAEs leading to treatment discontinuation occurred in 1 (0.2%) patient on PON (cardiomyopathy) and 2 (0.4%) patients on TER (1 atrial fibrillation, 1 coronary artery insufficiency). No MACE were reported on PON; 3 MACE occurred on TER. HR and rhythm AESIs were reported in 29 (5.1%) PON patients vs. 24 (4.2%) TER patients. Incidence of HR and rhythm AESIs on Day 1 in the PON group (2 mg) was 2.1%, and included bradycardia (HR<50bpm) in 0.7% and 1^st degree AV block in 0.5%; vs. 0.4% in TER. Max mean reduction in HR from pre- to post-dose on Day 1 was observed at 2h post-dose for PON at -8.7bpm compared with -1.7bpm for TER. On Day 1, 3 patients on PON had post-dose asymptomatic HR≤40bpm, all had pre-treatment HR<55bpm. On Day 1, new ECG findings of sinus bradycardia was 20.0% in patients at risk for symptomatic bradyarrhythmia, compared to 3.0% (all asymptomatic) in patients who were not at-risk. The up-titration was not associated with clinically significant bradyarrhythmia events; none were serious or leading to discontinuation of treatment, no 2^nd degree or higher AV blocks were reported.

Conclusions

In the 2-year OPTIMUM study, PON treatment was not associated with an increased risk for major CV events such as MI, stroke, or CV death compared to TER. The up-titration regimen successfully mitigates 1^st-dose effects and supports removing the requirement for 1^st-dose cardiac monitoring in patients without risk factors of symptomatic bradycardia.

Background

OPTIMUM was a multicenter, double-blind, active-comparator phase 3 superiority trial that assessed efficacy, safety, and tolerability of ponesimod 20 mg (PON) vs teriflunomide 14 mg (TER) in patients with relapsing multiple sclerosis (RMS). The primary endpoint of annualized relapse rate was met demonstrating PON’s superiority vs TER.

Objectives

To assess treatment effect on disability progression using time to worsening of timed 25-foot walk (T25FW), 9-Hole Peg Test (9HPT), Symbol Digit Modalities Test (SDMT), Paced Auditory Serial Addition Test [PASAT-3] , Expanded Disability Status Scale (EDSS) and composites of these endpoints.

Methods

OPTIMUM enrolled patients with RMS (EDSS:0-5.5), randomized (1:1) to daily PON or TER for 108 weeks. Change in MS functional composite (MSFC) Z-score (mean of T25FW, 9HPT, PASAT-3 Z-scores), and SDMT from baseline to Week 108 was assessed using Mixed-Effect Model Repeated Measures. Analyses of time to first confirmed (12-week) disability event were conducted post-hoc; disability was defined as 4-point worsening in SDMT, 20% worsening in T25FW or 9HPT, in addition to EDSS (as defined for the secondary endpoint).

Results

Of 1133 patients (PON=567, TER=566), 86.9% completed study. Changes from baseline in overall MSFC Z‑score: 0.02 PON vs −0.039 TER (mean difference, 0.059; p=0.047); for the 3 individual components of MSFC Z-score, mean differences (p-values) were: T25FW, 0.20 sec (p=0.37); 9HPT, –0.93 sec (p<0.0001); PASAT-3, 0.55 number correct (p=0.16). The PON vs TER worsening events up to EOS were, respectively: confirmed 20% worsening in T25FW, 9.2% vs 13.1% (hazard ratio [HR]:0.70; p=0.045); 4-point worsening in SDMT, 22.1% vs 26.4% (HR:0.82; p=0.12)], composite EDSS/SDMT, 26.3% vs 32.7% (HR:0.80; p=0.045)]; composite EDSS/9HPT/T25FW, 18.2% vs 24.0% (HR:0.76; p=0.035); numerical differences in favour of PON in time to confirmed worsening in 9HPT and SDMT assessed individually were not statistically significant.

Conclusions

Measures of worsening of impairment and disability in this exploratory analysis indicated benefits for PON vs TER. Composite endpoints provide more power to statistical assessments owing to greater number of events analyzed, making them particularly useful in RMS trials.

Background

Dimethyl fumarate (DMF) and ocrelizumab are two effective immunomodulators for multiple sclerosis (MS). Identifying overlapping mechanisms of action between the drugs may elucidate common pathways in preventing disease activity.

Objectives

In this study we analyzed cytokine and immune-profiling data to evaluate the similarities and differences between these two disease-modifying therapies in MS.

Methods

Plasma and PBMCs from MS patients were collected at baseline, 3 months and 6 months after treatment with DMF (n=16) and ocrelizumab (n=13). Immunophenotyping was performed with mass cytometry (CyTOF) and analyzed with gating based on cell surface markers. Cytokine analysis from plasma was performed with Olink assays and analyzed with linear mixed effects models.

Results

DMF reduced both effector T and memory B cell populations while increasing CD56bright natural killer (NK) cells. Ocrelizumab exerted its main immunomodulatory effect by reducing the frequency of all B cells and increasing frequency of NK cells. At 6 months, naïve B-cells began to reconstitute; however, memory B cells remain depleted. DMF treatment was associated with a significant reduction of plasma cytokines involved in inflammatory pathways, such as IL-6 and IL-12 signaling in MS and Dectin-1 signaling. In addition, DMF lowered plasma cytokines that are dysregulated in psoriasis and involved in allograft rejection pathways. Ocrelizumab treatment led to the upregulation of neurotropic proteins in the plasma of MS patients, including proteins involved in NAD biosynthesis and tryptophan metabolism.

Conclusions

Our high-dimensional immunophenotyping results suggest that DMF and ocrelizumab both increase NK cells in addition to affecting different immune cell populations and cytokine pathways to exert their effects in MS patients. Detecting similarities between the mechanisms of the two drugs may contribute to identifying more specific therapeutic targets.

Background

Depression and anxiety have increased prevalence in multiple sclerosis (MS). There are limited studies on associations of depression and anxiety with MS disease characteristics.

Objectives

The aim of the study is to identify and quantify associations of depression and anxiety with MS disease activity and disability.

Methods

The study population included a prospective cohort of 1008 treatment-naïve participants with relapsing-remitting (RR) MS enrolled in the CombiRx trial. Entrance criteria included at least 2 relapses in the prior 2 years. Covariate adjusted linear regression analyses were conducted to determine associations and adjusted R-squared (R2) between baseline scores on three components of the Multiple Sclerosis Quality of Life Index (MSQLI): the Mental Health Inventory (MHI), Depression Subscale (MHD), and Anxiety Subscale (MHA), where lower scores indicated more severe symptoms on each component of the MSQLI subscale; with outcomes of baseline MS disease characteristics including Expanded Disability Status Scale (EDSS) and total MRI lesion volume (T1+T2). Kruskal-Wallace comparison was used to assess prior relapse frequency (0, 1-2, and 3 or more in prior 12 months) and median MSQLI measures.

Results

Lower EDSS scores were associated with higher MHI scores (β = -0.31, R² = 0.1274, p <0.0001), higher MHA scores (β = -0.21, R² = 0.1060, p <0.0001), and higher MHD (β = -0.22, R² = 0.1096, p <0.0001), when adjusted for age and sex at baseline. Baseline MHA score was modestly associated with relapse frequency (p =0.043), with a median rank MHA score of 5 for 0 relapses, 4.6 for 1-2 relapses, and 4.6 for ≥3 relapses. Components of the MSQLI were not associated with MRI lesion volume.

Conclusions

Depression and anxiety in MS are associated with increased baseline EDSS disability. Of the three measures, only anxiety was associated with higher baseline relapse frequency. A follow-up analysis is planned to examine associations of depression and anxiety on longitudinal MS disease outcomes in the trial cohort.

Abstract

Progressive MS represents the major unmet therapeutic need in MS, today. Our understanding od progressive MS, as a part of the full spectrum of MS, has expanded considerably. In order to better treat progressive MS we must understand how this phase of the disease develops and how to recognize the progressive course. In this teaching course we will review the definitions of progressive MS and how this is a subset of worsening MS, what the role of inflammation plays, how progression interacts with MS disease activity and how all this could lead to better therapies.

Abstract

Progressive MS represents the major unmet therapeutic need in MS, today. Our understanding od progressive MS, as a part of the full spectrum of MS, has expanded considerably. In order to better treat progressive MS we must understand how this phase of the disease develops and how to recognize the progressive course. In this teaching course we will review the definitions of progressive MS and how this is a subset of worsening MS, what the role of inflammation plays, how progression interacts with MS disease activity and how all this could lead to better therapies.

Abstract

Progressive MS represents the major unmet therapeutic need in MS, today. Our understanding od progressive MS, as a part of the full spectrum of MS, has expanded considerably. In order to better treat progressive MS we must understand how this phase of the disease develops and how to recognize the progressive course. In this teaching course we will review the definitions of progressive MS and how this is a subset of worsening MS, what the role of inflammation plays, how progression interacts with MS disease activity and how all this could lead to better therapies.