Background

Progressive multifocal leukoencephalopathy (PML) is a serious and potentially fatal complication of some multiple sclerosis (MS) disease-modifying therapies, including fingolimod. Precise estimates and risk stratification tools are not available for fingolimod-related PML.

Objectives

To estimate the global risk of PML in MS patients receiving fingolimod, and to investigate the effect of treatment duration and age on the risk of PML.

Methods

The number of PML cases identified from the manufacturer safety database, attributed to fingolimod by expert adjudication (based on criteria published by Berger et al. in 2014) as of 28 February 2020, was compared with the estimated global number of fingolimod-treated patients at risk (overall, by treatment duration, and by assumed age at fingolimod treatment initiation).

Results

It was estimated that approximately 299,600 patients were treated with fingolimod globally as of 28 February 2020, corresponding to >778,900 patient-years (PYs) of exposure. Of the 188 suspected PML cases reported during fingolimod treatment, 37 confirmed cases were clearly attributed to fingolimod through expert adjudication. In 17 cases, PML was attributed to previous natalizumab treatment. The remaining 134 cases either had inadequate information to confirm the diagnosis of PML or were classified as either possible or not PML. The estimated incidence rate was 4.75 (95% confidence interval [CI]: 3.34; 6.55) per 100,000 PYs. The estimated crude incidence was 0.12 (95% CI: 0.09–0.17) per 1,000 patients. The incidence of PML appears to increase with treatment duration and approach a plateau at approximately 0.13 per 1,000 patients during Year 5, after which data were scarce. Incidence of PML appears to increase between 30 and 50 years of age and then stabilize but the exact shape of the relationship with age is uncertain due to wide CIs, underlying assumptions, and other unknown confounding factors. For both treatment duration and age at treatment initiation, the precision of the incidence estimates was low due to the small number of cases.

Conclusions

PML risk associated with fingolimod is low. Although, the estimated risk of fingolimod-associated PML appears to increase with cumulative exposure, the precise pattern of this relationship remains uncertain. There may be an increase in PML risk with increased age at treatment initiation, although the exact pattern of this possible relationship is also uncertain.

Background

B cell depleting therapies are highly effective treatments for multiple sclerosis (MS). B cells are more numerous in active than inactive lesions, and their intrathecal clonal expansion and oligoclonal band production are hallmarks of MS. B cells also present antigens to T cells and secrete inflammatory cytokines. The antigenic specificity of individual B cells in cerebrospinal fluid (CSF) obtained from patients with early MS may help further clarify the role of B cells in MS biology.

Objectives

To determine the viral and autoantigen repertoire of CSF-derived, class-switched B cells from untreated, early MS patients.

Methods

We performed single cell immunoglobulin sequencing on CSF plasma cells, plasmablasts, and class switched memory B cells from 9 untreated patients: five with relapsing remitting MS (RRMS) and four with clinically isolated syndrome (CIS). The interval between the first attack and lumbar puncture ranged from 1 - 222 days (median 67 days). Brain and spinal cord MRIs performed concurrently with lumbar punctures revealed 5/9 patients with gadolinium enhancing lesions.

Using paired heavy and light chain immunoglobulin sequences, we generated 75 monoclonal antibodies (mAbs) and screened them on a suite of unbiased antigen discovery platforms: 1) mouse brain tissue staining, 2) whole human proteome programmable phage display, 3) pan-viral programmable phage display, 4) mouse and human brain immunoprecipitation mass spectrometry.

Results

The mAbs showed diverse antigen specificities. Candidate antigens were primarily ubiquitously expressed, intracellular proteins; however, a minority were macromolecules associated with the plasma membrane and/or enriched in brain tissue. Shared antigenic targets were occasionally identified within subjects but were rarely identified across subjects, with the latter including cytoskeletal proteins. For two mAbs, high-confidence antigens with prima facie relevance to MS were identified: 1) a white matter-restricted lipid species, and 2) an Epstein-Barr virus-interacting host protein.

Conclusions

Using our panel of 75 mAbs derived from plasma cells, plasmablasts, and class-switched memory B cells found in the CSF of early, untreated RRMS/CIS patients, we identified a diverse repertoire of antigenic targets, with a majority comprised of intracellular host proteins.

Background

Neuromyelitis optica (NMO) is a severe demyelinating disease of the central nervous system (CNS) causing irreversible neurological damage. Initial analyses of gut microbiota in NMO, multiple sclerosis and healthy controls (HHC) revealed dysbiosis in the NMO group, suggesting that the gut microbiome may regulate inflammatory responses

Objectives

We hypothesized that gut microbiota from NMO patients may participate and promote inflammatory responses in NMO pathogenesis.

Methods

Wild-type (WT) C57BL/6 germ-free mice were colonized with fecal samples from one untreated NMO patient (n = 10), one household HC (HHC) (n = 9) or vehicle (n = 13) for five weeks and then examined for susceptibility to MOG p35-55-induced experimental autoimmune encephalomyelitis (EAE) for 30 days post immunization. Upon termination of the study, lymphocytes from spleen, lamina propria of small (LP-SI) and large (LP-LI) intestine, mesenteric lymph nodes (MLN), Peyer’s patches (PP), brain, and spinal cord were examined for the expression of IL-17, IFN-γ, Foxp3, CD25, RORγt and Helios.

Results

In comparison to the mean EAE score of the vehicle group (1.9 ± 0.3), severity was greater (p ≤ 0.01) in mice colonized with fecal microbiota from NMO (3.1 ± 0.8) and HHC (2.7 ± 0.7). The mean clinical score of mice colonized with NMO gut microbiota was significantly greater than mice colonized with gut microbiota from HHC or vehicle (p ≤ 0.001). The frequency of CD4⁺Foxp3⁺CD25⁺ cells was decreased in LP-SI, LP-LI, PP and MLN compartments in NMO and HHC compared with vehicle group (p ≤ 0.01). CD4⁺Foxp3⁺Helios⁺ (another regulatory T cell subpopulation) was significantly decreased in MLN and LP-SI of NMO and HHC compared to vehicle group (P ≤ 0.01).

Conclusions

Our data suggest that NMO fecal microbiota increases EAE susceptibility. Reduction in frequency of T_regs in the gut of mice colonized with NMO fecal material may contribute to EAE exacerbation. Further analysis of microbiota and lymphocyte populations in mice colonized with fecal material from NMO and HHC samples are needed. Results from our ongoing study should provide valuable insight regarding the potential role of gut microbiota in NMO.

Background

People with neurological conditions that impair mobility such as multiple sclerosis (MS) have low levels of physical activity, with walking their primary form of exercise. When the San Francisco Bay Area shelter-in-place order was announced in mid-March 2020 to flatten the curve of SARS-CoV-2 infections, the abrupt closure of gyms, fitness studios, and malls greatly limited options for safe exercise. We leveraged an ongoing study utilizing wearable technology, to understand the impact of the pandemic and the shelter-in-place policy on physical activity in people with MS (PwMS) at-risk for neurological worsening.

Objectives

To test the hypothesis that the average daily step count (STEPS) in people with MS would decrease due to the COVID-19 shelter-in-place order.

Methods

Average daily step count (STEPS) was measured from a large UCSF MS Center cohort of PwMS using a wrist-worn accelerometer (Fitbit Flex2) as previously detailed. STEPS before and after the shelter-in-place were available for 42 participants. Amount, type and frequency of exercise, as well as fatigue (Modified Fatigue Index; MFIS-5) and mental health (Mental Health Inventory; MHI-5) were assessed via questionnaire. The UCSF Institutional Review Board approved the study protocol. Descriptive statistics and pre-post comparisons using Wilcoxon Signed-rank were performed, and figures generated, using R studio.

Results

A decrease in STEPS was observed during the week (p =0.024), and month (p=0.048) after versus before the shelter-in-place order in 42 participants with valid STEPS data during this time period. Individual data showed marked decreased in STEPS the week immediately post shelter-in-place, yet some recovered to near pre shelter-in-place levels. As a group, this rebound was not significant. No significant difference comparing 2019 and 2020 similar epoch STEPS data was observed for these participants.

Conclusions

The data supported the hypothesis that physical activity would be reduced in people with MS due to the COVID-19 activated shelter-in-place. Overall prolongation of reduced activity is troubling, particularly in a population where low activity is already pervasive due to detrimental secondary effects of inactivity. These observations were made possible by the use of remote activity monitoring and aligns with broader efforts to use wearables to track and promote physical activity, augment telehealth, and improve telerehabilitation across populations with chronic neurological disorders.

Background

Multiple Sclerosis (MS) is a complex and heterogeneous disease. Investigating the biological pathways and cell types involved in MS pathophysiology as represented by protein biomarker expression can help inform the development of tools to monitor disease activity, disease progression, identify early evidence of relapse, and monitor treatment response.

Objectives

To develop a blood based multiplex proteomic assay that associates with clinical and radiographic endpoints in patients with MS. These endpoints include the presence of gadolinium-enhanced (Gd+) lesions, Annualized Relapse Rate (ARR) and clinically defined relapse status (active versus stable).

Methods

Serum samples (n=690 in total) from multiple deeply-phenotyped cohorts (ACP, CLIMB and EPIC) were tested in immunoassays for the measurement of 1196 proteins using Proximity Extension Assays (PEA) from Olink^TM and for 215 proteins using xMAP^TM immunoassays from Myriad RBM, Inc. (RBM). Associated radiographic and clinical endpoints at the time of the blood draw were correlated with the protein levels. Twenty-one proteins were selected for inclusion in a custom assay based on their performance in univariate and multivariate statistical models, and replication across independent cohorts. Biological pathway modeling and network analysis were performed to ensure comprehensive representation of MS neurophysiology. Area under the curve (AUC) was selected as the key metric for model performance evaluation.

Results

Multivariate statistical ensembles restricted to the expression levels of the biomarkers selected for the custom assay achieved AUC performance of 0.827 for classification of the presence of Gd+ lesions, 0.802 for classification of clinically defined relapse status, and 0.930 for the classification of patients with Low ARR (≤0.2 relapses) vs High ARR (≥1.0 relapses). A multivariate model utilizing shifts in biomarker expression in longitudinally paired samples achieved the highest observed performance of 0.950 for classification of Gd+ lesion presence. In each case, the multivariate models significantly outperformed (p-value <0.05) the AUC of the highest performing univariate biomarker.

Conclusions

Multivariate models restricted to the 21 selected proteins effectively classified several radiographic and clinical endpoints with stronger performance than any single biomarker. A 21-plex custom assay panel is being developed for further investigation and validation using additional cohorts.

Background

The central vein sign (CVS) is a proposed MRI diagnostic biomarker for multiple sclerosis (MS). Use of gadolinium (Gd) in the CVS literature has been inconsistent, and it is unknown whether Gd improves detection of CVS when using FLAIR*.

Objectives

To determine if, and to what extent, gadolinium injection improves detection of CVS lesions when using FLAIR* imaging.

Methods

A cross-sectional multicenter study recruited adults clinically and/or radiologically suspected of having MS. High-isotropic-resolution, T2*-weighted segmented echo-planar imaging (T2*-EPI) was acquired pre- and post-injection of Gd-based contrast agent at 3T; pre-Gd 3D FLAIR images were also acquired. T2*-EPI and FLAIR images were processed on the QMENTA platform to generate FLAIR* images. FLAIR* pre-Gd and post-Gd scans from this substudy of 30 patients at 5 sites were analyzed. FLAIR images were used to create T2 lesion masks. Subsequently, FLAIR* images were evaluated in a random order. Lesions were categorized as CVS+, CVS-, or excluded based on the North American Imaging in MS (NAIMS) Criteria by two trained raters blinded to clinical data and Gd use. The proportion of CVS+ lesions was calculated for each scan, and differences in CVS detection based on Gd use were assessed by a Wilcoxon rank-sum test. Diagnostic performance was compared against McDonald 2017 Criteria.

Results

The mean participant age was 45 years (SD: 12); 23 (77%) were women. 14 (47%) met McDonald 2017 Criteria for MS, while 16 (53%) did not (“non-MS”). A total of 487 CVS+ lesions and 976 CVS- lesions were evaluated. The percentage of CVS+ lesions post-Gd in the MS group (median 67% [IQR 30%]) was higher than pre-Gd (41% [47%], p<0.001). There was no apparent difference in percentage of CVS+ lesion in the non-MS group (post-Gd: 10% [23%]; pre-Gd: 5% [29%]; p=0.1). In the MS group, 12/14 (86%) had ≥40% CVS+ lesions on post-Gd imaging, whereas only 8/14 (57%) exceeded that threshold on pre-Gd imaging. When evaluating CVS performance using the 40% CVS+ threshold, the sensitivity and specificity of the CVS post-Gd for MS were 86% and 81%, respectively, compared to 54% and 86% pre-Gd.

Conclusions

The detection of the CVS using FLAIR* at 3T is improved when Gd is used. Based on these results, a multicenter prospective CVS diagnostic study, sponsored by NINDS and NAIMS, will use Gd in the study protocol. Future clinical use of the CVS should balance the increased costs and potential risks of Gd use with the risks of misdiagnosis due to missing CVS on non-contrast imaging.

Background

In patients with multiple sclerosis (MS), neurofilament light chain concentration (NfL-c) is increased in blood and cerebrospinal fluid (CSF). Plasma and CSF NfL-c correlate and may serve as a biomarker for neurologic damage and disease activity in relapsing MS (RMS). Ozanimod, a sphingosine 1-phosphate receptor 1 and 5 modulator, reduced annualized relapse rate (ARR) and plasma NfL-c (pNfL-c) vs interferon β-1a (IFN) in phase 3 RMS trials.

Objectives

To expand upon previously reported data showing that baseline (BL) pNfL-c predicts risk of on-treatment relapse, we analyzed the relationship between changes in pNfL-c and on-treatment risk of relapse with ozanimod vs IFN.

Methods

In this exploratory, post hoc analysis, pNfL-c was measured at BL and after 12 and 24 months of treatment with oral ozanimod 0.46 or 0.92 mg/d or intramuscular IFN β-1a 30 µg/wk in the phase 3 SUNBEAM (NCT02294058; ≥12 mo) and RADIANCE (NCT02047734; 24 mo) trials. The effect of treatment on pNfL-c was assessed, as were the relationships between BL pNfL-c and relapse rate and pNfL-c change from BL and ARR. NfL data are reported as median percentage change from BL. Poisson generalized linear models were used to fit the number of relapses as a function of BL pNfL-c and treatment group with an offset for duration. We calculated a predictive model of expected ARR based on median percentage change from BL in pNfL-c.

Results

At end of treatment, median pNfL-c was significantly reduced from BL by 20‒23% (P<0.01) and 23‒27% (P≤0.0001) with ozanimod 0.46 and 0.92 mg, respectively, and by 13‒15% with IFN. Higher BL p-NfL-c was associated with an increase in number of relapses (P<0.0001). Over a 12-month period, participants treated with either dose of ozanimod had significantly fewer relapses than those treated with IFN (P<0.05); the greatest effect was observed with ozanimod 0.92 mg. Further analyses reveal that treatment groups associated with a greater median reduction from BL pNfL-c are also associated with lower ARR. Predictive modeling estimated that a 25% reduction in pNfL-c, similar to that observed with ozanimod 0.92 mg, predicts an ARR (standard error [SE]) of 0.18‒0.23 (0.4); a 13% reduction, which was similar to that observed with IFN, predicts an ARR (SE) of 0.29‒0.37 (0.04).

Conclusions

Our findings further support pNfL-c as a biomarker for RMS disease activity. BL pNfL-c is related to relapse rate, as are changes in pNfL-c during treatment. Ozanimod causes dose-dependent reductions in pNfL-c and ARR compared with IFN.

Background

Pathogenic autoantibodies against aquaporin 4 (AQP4) in neuromyelitis optica spectrum disorder (NMOSD) cause central nervous system injury, with subsequent release of astroglial and neuronal proteins such as glial fibrillary acidic protein (GFAP), neurofilament light chain (NfL), ubiquitin carboxyl-terminal hydrolase L1 (UCH-L1) and Tau into the circulation. N-MOmentum is a randomized, placebo-controlled, double-masked trial of inebilizumab, a B-cell-depleting monoclonal antibody (NCT02200770).

Objectives

Investigate relationships of NfL, UCH-L1, Tau and serum (s)GFAP to disease activity and Expanded Disability Status Scale (EDSS) disability in N-MOmentum trial participants with either AQP4-immunoglobulin G (IgG) seropositive or seronegative NMOSD.

Methods

Serum biomarkers NfL, UCH-L1, Tau and sGFAP were measured using the single molecular array (SIMOA; Quanterix) in 1260 serial and attack-related samples from N-MOmentum participants (n=215) and healthy controls (HC; n=25).

Results

At baseline, biomarkers were elevated in subsets of patients with NMOSD (NfL, 16%; UCH-L1, 6%; Tau, 12%; sGFAP, 29%); NfL and UCH-L1 levels correlated with sGFAP (r=0.53 [p<0.001] and 0.18 [p=0.007]). Baseline elevations were significantly associated with increased attack risk (NfL, hazard ratio [HR] 2.5, p=0.01; UCH-L1, HR 2.8, p=0.039; Tau, HR 2.6, p=0.01; sGFAP, HR 3.03, p<0.001). After controlling for baseline sGFAP in Cox regressions, the other markers were not independently associated with attack risk (all HR <2; p>0.05). In the total cohort, a greater proportion of patients had an attack with placebo than inebilizumab (39% vs 12%). All biomarker levels increased after attacks and median-fold increases from baseline (95% confidence interval) trended higher with placebo than inebilizumab, reaching significance with sGFAP (NfL, 1.49 [0.93–3.37] vs 1.30 [0.84–2.14], p=0.4; UCH-L1, 6.70 [1.59–52.4] vs 1.85 [0.89–23], p=0.12; Tau, 2.19 [0.96–9.46] vs 1.09 [0.40–3.7], p=0.23; sGFAP, 20.2 [4.4–98] vs 1.11 [0.75–24.6], p=0.037). Following attacks, NfL correlated with EDSS score at attack assessments (R=0.55; p<0.001); other biomarkers did not correlate with EDSS score after controlling for NfL levels.

Conclusions

In NMOSD, serum NfL, UCH-L1 and Tau levels were higher than in HC; increased baseline sGFAP levels were associated with greater attack risk. Although sGFAP levels showed the greatest increase following attacks, NfL correlated with attack-related disability.

Background

Clinical trials in acute and chronic neurologic conditions traditionally rely on functional assessments using clinical scales that can be insensitive to treatment response and capture a patient’s function at a single timepoint in a clinical setting. In order to assess the relative sensitivity of real-world activity levels for detection of disease progression and/or treatment response compared with in-clinic assessments, we are using wearable digital biosensors to passively collect activity data in 2 multiple sclerosis (MS) clinical trials.

Objectives

To assess patient biosensor compliance and the potential of real-world digital biosensor data to assess MS disease progression and/or treatment response

Methods

Two randomized, double-blind, placebo-controlled, 52-week Phase 2 clinical trials are currently evaluating the efficacy and safety of elezanumab in subjects with relapsing (RADIUS-R, NCT03737851) or progressive (RADIUS-P, NCT03737812) forms of MS. The primary efficacy assessment is performed in-clinic every 12 weeks. To generate real-world activity data, subjects wore MC10’s BioStamp nPoint® biosensors over 7-day intervals at Baseline and Weeks 24, 36, and 52. The sensors (chest, thigh and calf locations) monitor gait speed, step count and overall activity, including vital signs. Study sites were trained to apply, charge and reapply biosensors by MC10, and site staff trained subjects. Compliance was measured by the percentage of sensor wear days out of the instructed wear days.

Results

As of April 9, 2020, RADIUS-R had enrolled 208 subjects, RADIUS-P had enrolled 123 and 119,00 hours of actigraphy data were collected. Interim compliance rates for subjects completing each interval in RADIUS-R and RADIUS-P respectively were: Baseline (n=188, 101%; n=88, 94%), Week 24 (n=84, 99%; n=21, 86%), Week 36 (n=28, 104%; n=5, 103%), Week 52 (n=4, 79%; n=1, 114%). The average compliance rate across the studies and timepoints was 98%. All treatment-blinded actigraphy data were uploaded to the MC10 cloud for review. The objective at the completion of the studies is to determine differences between treatment groups in relation to clinical endpoints.

Conclusions

To our knowledge, these are the first randomized MS clinical trials to incorporate BioStamp biosensors to capture real-world activity. There was a high level of compliance to-date across study sites for the subjects that have completed one or more 7-day intervals, suggesting use is not overly burdensome.

Background

The N-MOmentum trial of inebilizumab included patients with aquaporin 4-IgG seropositive (AQP4+) or seronegative (AQP4−) neuromyelitis optica spectrum disorder (NMOSD).

Objectives

To report AQP4− participant outcomes in N-MOmentum. .......................................................

Methods

Medical histories and screening data for AQP4− patients were assessed independently by 3 clinical experts before enrollment. Majority decision confirmed diagnoses using the 2006 criteria. Myelin oligodendrocyte glycoprotein-IgG (MOG) serology and annualized attack rates (AARs) were tested post hoc. These observations do not account for bias in estimates of effects on the AAR caused by regression to the mean, introduced by inclusion criteria requiring attacks during the 1 to 2 years before study entry.

Results

Only 18/50 AQP4− patients (36%) were eligible for randomization; 17 were randomized, 4 to placebo (1 MOG+) and 13 to inebilizumab (6 MOG+). Reasons for not enrolling prospective AQP4− NMOSD participants were mainly related to lack of fulfillment of MRI findings required by the 2006 criteria.

Owing to limited patient numbers, we compared the on-study to the pre-study AAR for treated participants to assess treatment effects.

For AQP4− participants (n=17), 40 attacks occurred in 23 patient-years of pre-study follow-up with mean AAR (95% confidence interval) of 1.72 (1.23–2.33). For MOG+ participants (n=7), 16 attacks occurred in 8.3 patient-years of pre-study follow-up with an AAR of 1.93 (1.11–3.14). For double-seronegative participants (n=10), 24 attacks occurred in 15 patient-years of pre-study follow-up with an AAR of 1.60 (1.02–2.38).

After receiving inebilizumab, AARs declined in all groups by the end of the randomized controlled period: AQP4− participants (n=13), 0.09 (0.02–0.26), or 3 attacks in 34.2 patient-years; MOG+ participants (n=6), 0.08 (0.002–0.464), or 1 attack in 12 patient-years; double-seronegative participants (n=7), 0.09 (0.011–0.326), or 2 attacks in 22 patient-years.

The benefit was sustained with longer-term inebilizumab exposure. At 120 days into the open-label period (OLP), during which all participants received inebilizumab, the AAR in AQP4− participants (n=17) remained low (0.069 [0.014–0.202]). No attacks were seen in any AQP4−, MOG+ or double seronegative patient during the OLP.

Conclusions

The N-MOmentum trial provides clinically important insight on the difficulty of correctly diagnosing AQP4− NMOSD and suggests that inebilizumab may have a benefit on AAR in these patients.

Background

Background: Multiple sclerosis (MS) treatment involves disease-modifying therapies (DMTs) and symptom management. There is an unmet need for MS treatments that reverse demyelination and neuronal damage. Elezanumab (formerly ABT-555) is a monoclonal antibody that neutralizes repulsive guidance molecule A (RGMa), a neurite outgrowth inhibitor thought to be involved in MS.

Objectives

Objective: Present the study design and baseline data from 2 studies investigating elezanumab efficacy and safety in patients with progressive MS (PMS) and relapsing MS (RMS).

Methods

Methods: RADIUS-R (NCT03737851) and RADIUS-P (NCT03737812) are 2 ongoing, 52-week, proof-of-concept, RAndomized, Double-blind, placebo-controlled, multIple-dose phase 2 stUdies investigating efficacy and safety of elezanumab added to Standard of care in patients with RMS and PMS, respectively. RADIUS-R includes patients with relapsing-remitting MS (RRMS; no relapse 6 months before screening), or active secondary-progressive MS (SPMS; relapse 6 to 24 months before screening). RADIUS-P includes patients with primary-progressive MS (PPMS) or non-active SPMS (no relapses 24 months before screening). Patients in both studies were randomized 1:1:1 to receive 1 of 2 doses of elezanumab or placebo intravenously every 4 weeks through week 48. The primary endpoint for both studies is mean overall response score (ORS; based on Expanded Disability Status Scale [EDSS], Timed 25-Foot Walk [T25FW], and 9-hole Peg Test [9HPT]-dominant and nondominant) at week 52.

Results

Results: Overall, 208 patients enrolled in RADIUS-R and 123 in RADIUS-P. In RADIUS-R, 199 (96%) patients were diagnosed with RRMS, while 9 (4%) were diagnosed with SPMS. In RADIUS-P, 59 (48%) patients were diagnosed with PPMS, and 63 (52%) were diagnosed with SPMS. Baseline mean (SD) age was 45.7 (8.4) years (RADIUS-R) and 52.6 (7.0) years (RADIUS-P). Overall, 66% of RADIUS-R and 48% of RADIUS-P patients were women. Mean (SD) ORS components for RADIUS-R were: T25FW, 7.3 (4.0); 9HPT-dominant, 28.0 (22.5); and 9HPT-nondominant, 30.0 (23.5); EDSS (median [range]), 3.5 (1.0, 6.5). ORS components for RADIUS-P were: T25FW, 12.5 (11.2); 9HPT-dominant, 31.4 (27.6); and 9HPT-nondominant, 38.1 (37.3); EDSS, 6.0 (2.0, 7.0). Most patients used concomitant DMTs (RADIUS-R, 75%; RADIUS-P, 69%), most commonly ocrelizumab (RADIUS-R, 45%; RADIUS-P, 59%).

Conclusions

Conclusion: RADIUS-R and RADIUS-P are ongoing phase 2 studies investigating safety and efficacy of elezanumab as a remyelination agent.

Background

FLUENT investigated immune cell subset changes in the innate and adaptive immune systems during fingolimod therapy, and their associations with efficacy and safety outcomes.

Objectives

To report changes in immune cell profile, efficacy and safety of fingolimod 0.5 mg/day in adults with relapsing multiple sclerosis (RMS).

Methods

In FLUENT (NCT03257358), a prospective, 12 month, phase 4, multicenter, nonrandomized, open-label study, patients were stratified as fingolimod naive (Cohort 1) or previously treated with fingolimod 0.5 mg/day continuously for ≥2 years (Cohort 2). Primary outcome was change from Baseline to Month 12 in immune cell subsets. Secondary outcomes included Patient Determined Disease Steps (PDDS), anti-John Cunningham virus (anti-JCV) antibody status, serum neurofilament light chain (NfL) concentration, and adverse events (AEs) incidence. Data were analyzed from all patients completing Month 12 follow-up.

Results

165 patients enrolled in Cohort 1; 217 in Cohort 2. Proportionally more patients in Cohort 1 than Cohort 2 relapsed in the year before baseline. At Baseline, patients in Cohort 1 had proportionally more naive and central memory CD4+ and CD8+ T cells and memory B cells, and proportionally fewer effector memory CD4+ and CD8+ T cells and regulatory B cells, than those in Cohort 2. At Month 12, between-cohort differences in the proportions of these lymphocyte types/subtypes were much reduced or negligible. Levels were essentially unchanged in Cohort 2, indicating reductions in naive T cells and increases in effector memory T cells and regulatory B cells in Cohort 1. Mean baseline PDDS scores were low (Cohort 1, 1.7; Cohort 2, 1.8), and changed little by Month 12. Median change from Baseline in anti-JCV antibody index was small in both cohorts. Proportions of patients with positive JCV serology remained stable at Month 12 (61% and 67% in Cohorts 1 and 2 vs 57% and 65% at Baseline). Mean serum NfL level was higher in Cohort 1 than Cohort 2 at Baseline (12.2 vs 9.6 pg/mL); levels were similar at Month 12 (8.7 vs 9.8 pg/mL), having reduced substantially in Cohort 1. Proportionally more patients in Cohort 1 than in Cohort 2 had treatment-emergent AEs (54.6% vs 44.2%), and discontinued study treatment (12.3% vs 5.5%); 5.5% of patients in each cohort reported serious AEs.

Conclusions

These data expand our knowledge of changes in immune cell profiles over time in patients with RMS treated with fingolimod in the short or long term.

Background

Ozanimod, an oral sphingosine 1-phosphate receptor 1 and 5 modulator, is approved in the US and EU for the treatment of relapsing forms of multiple sclerosis (RMS).

Objectives

To characterize the long-term safety and efficacy of ozanimod in participants with RMS in an ongoing open-label extension (OLE) trial.

Methods

Participants with RMS who completed a phase 1, 2, or 3 ozanimod clinical trial were eligible to enroll in DAYBREAK (NCT02576717), where they received ozanimod 0.92 mg/d (equivalent to ozanimod HCl 1 mg). The primary objective was to evaluate safety in the overall population; treatment-emergent adverse events (TEAE) were monitored. Efficacy was evaluated with annualized relapse rate (ARR), calculated via negative binomial regression and pooled for all parent-trial treatment groups. Number of new/enlarging T2 and gadolinium-enhancing (GdE) MRI brain lesions were reported for the subset of participants who entered the OLE from an active-controlled phase 3 trial.

Results

In total, 2639 participants completed the parent trials; this interim analysis (data cut 20 December 2019) included 2494 participants with mean (range) ozanimod exposure of 35.4 (0.03–50.2) months in the OLE. Adjusted ARR in the OLE was 0.112 (95% confidence interval, 0.093‒0.135). At months 24 and 36, 79% and 75% of participants, respectively, were relapse free in the OLE. Three- and 6-month confirmed disability progression was observed in 10.8% and 8.6% of participants in the OLE, respectively. Mean number of new/enlarging T2 lesions per scan at 24 months was similar, regardless of parent-trial treatment group (range, 1.57–1.90), as were mean number of GdE lesions at month 24 (range, 0.2 ‒0.4). In the OLE, 2039 participants (81.8%) had any TEAE, 236 (9.5%) had a serious TEAE (SAE), and 56 (2.2%) discontinued due to a TEAE. Similar rates of TEAEs and SAEs occurred when assessed by parent-trial treatment group. The most common TEAEs were nasopharyngitis (17.9%), headache (14%), upper respiratory tract infection (9.9%), and lymphopenia (9.6%). TEAEs were generally similar to parent trial observations. There were no serious opportunistic infections. Exposure-adjusted incidence rates of TEAEs and SAEs have decreased over time.

Conclusions

In DAYBREAK, ozanimod was associated with low ARR and low new/enlarging T2 and GdE lesion counts over time. Most participants were relapse free and did not experience disability progression. Ozanimod was generally well tolerated and no new safety concerns emerged with long-term use.

Background

Magnetic resonance imaging (MRI) findings in patients with neuromyelitis optica spectrum disorder (NMOSD) have not previously been studied with data from a prospective, randomized controlled study. During N-MOmentum, longitudinal MRIs were performed systematically.

Objectives

To characterize MRI findings in patients with NMOSD in the N-MOmentum study of inebilizumab. .....................

Methods

MRIs of the spinal cord, optic nerve and brain were performed at baseline, within 8 days of an NMOSD attack and at the end of the randomized controlled period (RCP; month 6.5). MRIs were read centrally by two independent, blinded-to-treatment neuroradiologists for new gadolinium-enhancing (Gd)-T1 enhancement events. Attacks were adjudicated by an expert committee.

Results

Complete MRI data were available for 192 (83%) of 230 participants, 42 of whom had an adjudicated attack (22 myelitis, 14 optic neuritis, 6 multi-domain). The remaining 38 patients did not have valid post-baseline MRI scans available for analysis. Inter-rater agreement between the two neuroradiologists for gadolinium-enhancing lesions was 98% for brain, 95% for spinal cord and 90% for optic nerve.

At the time of acute adjudicated NMOSD attacks, new Gd-T1 MRI enhancement corresponding to the affected clinical domain was present in 19/22 myelitis attacks (86%) and 11/14 optic neuritis attacks (79%). At the time of acute optic neuritis attacks, asymptomatic, new Gd-T1 enhancement was simultaneously observed in 4/14 spinal cord MRIs (29%) and 1/14 brain MRIs (7%). At the time of acute myelitis attacks, asymptomatic, new Gd-T1 enhancement was simultaneously observed in 6/22 optic nerve MRIs (27%) and 3/22 brain MRIs (14%).

In the 150 participants without an adjudicated attack, new Gd-T1 MRI enhancements compared with baseline readings were observed in the brain, spinal cord and optic nerve in 3%, 18% and 51% of patients at the end of the RCP, respectively.

Conclusions

At the time of attack, MRI enhancements were highly correlated to the clinical presentations. However, asymptomatic Gd-T1 enhancements were detected outside the symptomatic attack domain in about one-third of cases. Furthermore, subclinical Gd-T1 enhancements were observed in many patients who did not experience clinically overt attacks. Subclinical blood–brain barrier breakdown, particularly in the optic nerve, may be a frequent phenomenon in patients with active NMOSD.

Background

Background: The envelope protein of the human endogenous retrovirus type W (HERV-W ENV) is expressed in chronic active MS lesions. Preclinical models have shown that HERV-W ENV activates microglia, prevents maturation of oligodendrocyte precursor cells, and leads to neuronal death. Following the effects of a B-cell depleting, anti-inflammatory therapy, rituximab (RTX), with temelimab (TML), a humanized, IgG4-κ monoclonal antibody against HERV-W ENV represents a novel therapeutic approach against neurodegenerative features of MS.

Objectives

Objective: To present safety preclinical results on the interaction of RTX and TML, and the trial design of the ProTEct-MS study.

Methods

Design/Methods: Interactions between RTX and TML were studied in vitro in high density-peripheral blood mononuclear cells (PBMCs) and ex-vivo in a whole blood loop system from fresh human blood.

ProTEct-MS is a randomized, double-blind, placebo controlled, parallel group study. Enrolment commenced in 2020/6 and will be completed in 2020/12. Patients with RMS (2017 McDonald criteria) (N=40) being previously treated for ³12 months with RTX are randomized (1:1:1:1) to monthly iv TML (18, 36 or 54mg/kg) and placebo for 48 weeks.

Eligibility criteria: age 18-55 yrs, Expanded Disability Status Scale (EDSS) of 2.5-5.5 at screening; clinical worsening in ³1 neurological domain as assessed by EDSS, 6MWT or T25FW, or cognitive functioning as assessed by SDMT over the last year.

Primary objective: assessment of safety and tolerability of TML

Secondary outcome measures: MRI: change of brain atrophy, lesion volume and magnetization transfer ratio

Results

Results: Co-administration of TML with RTX was overall comparable to vehicle for all blood parameters assessed including cytokine levels of all five donors tested in both in vitro and ex-vivo assays. Co-administration of TML with RTX did not affect the functionality profile of either compound. By September 2020, 25% of patients are expected to be randomized, providing baseline clinical and MRI characteristics.

Conclusions

Conclusions: Preclinical safety experiments of the drug combination showed no evidence against the use of TML following RTX in humans. ProTEct-MS study patients represent a RMS cohort with progression in absence of relapse activity (PIRA,) i.e. whose present clinical condition is stable under RTX therapy, enabling TML's effects on attenuating mechanisms of progression to be measured without interference by acute inflammatory activity.

Background

Ozanimod is a sphingosine 1-phosphate receptor 1 and 5 modulator that blocks the capacity of lymphocytes to egress from lymphoid tissue, reducing the number of lymphocytes in peripheral blood. The mechanism by which ozanimod exerts therapeutic effects in multiple sclerosis is unknown, but may involve reduction of lymphocyte migration into the central nervous system.

Objectives

To characterize the phenotype of circulating leukocytes in relapsing multiple sclerosis (RMS) in participants treated with ozanimod.

Methods

In a phase 1, open-label, pharmacokinetic/pharmacodynamic study, 24 participants with RMS were randomized to oral ozanimod 0.46 (n=13) or 0.92 mg/d (n=11) [equivalent to ozanimod HCl 0.5 or 1 mg] for ~12 weeks, including an initial 7-d dose escalation (0.23 mg/d x 4d + 0.46 mg/d x 3d). Key exclusion criteria were active infection, history of chronic infections or immunodeficiency, recent live vaccination, previous lymphocyte-depleting or immunosuppressant therapy, and absolute lymphocyte count <1.0 × 10⁹/L. Exploratory analyses used flow cytometry to characterize proportional changes from baseline in leukocyte subsets on days 28, 56, and 85 in total peripheral blood mononuclear cells (PBMC) and total T cells. Proportional change from baseline is reported using descriptive statistics.

Results

Ozanimod was associated with dose-dependent decreases in absolute numbers of CD4+ and CD8+ T cells. Within the PBMC population, ozanimod was associated with a minimal increase in the proportion of CD8+ TEMRA cells (ozanimod 0.92 mg only) and no change in CD8+ effector memory T (TEM) cells. A decrease in the proportion of CD4+ and CD8+ naive and central memory T (TCM) cells and CD4+ TEM cells was evident. Within the total T cell population, ozanimod was associated with an increase in the proportion of CD4+ TEM cells (ozanimod 0.92 mg only) and CD8+ TEM and TEMRA cells. A decrease in the proportion of CD4+ naive (ozanimod 0.92 mg only) and CD8+ naive cells was observed; CD4+ and CD8+ TCM cells were minimally affected. Changes from baseline were more pronounced with ozanimod 0.92 mg than with ozanimod 0.46 mg.

Conclusions

During ozanimod treatment, the relative frequencies of circulating cell types within total PBMCs and within the remaining T cell population were altered. These shifts in circulating leukocyte proportions support the hypothesis that although ozanimod inhibits trafficking of some subsets of lymphocytes, the remaining circulating cells are still poised to provide immune surveillance.

Background

The central vein sign (CVS) is a proposed diagnostic biomarker for MS that can be identified using FLAIR*. The robustness of 3T FLAIR*, with and without the injection of gadolinium contrast agent (Gd), for imaging the CVS in a multicenter setting has not yet been demonstrated.

Objectives

To assess the conspicuity of the CVS on 3T FLAIR* imaging acquired across different sites with and without the injection of Gd.

Methods

A cross-sectional multicenter study recruited adults with a clinical and/or radiological suspicion of having MS from 10 sites within the North American Imaging in MS (NAIMS) Cooperative. High-isotropic-resolution T2*-weighted segmented echo-planar imaging (T2*-EPI) was acquired at 3T, pre- and post-injection of Gd, along with 3D FLAIR on different scanner brands and models. T2*-EPI and FLAIR images were processed on an online imaging platform (QMENTA) to generate FLAIR* images. To objectively assess the conspicuity of the CVS inside MS lesions, lesions and veins were segmented automatically and used to compute lesion-to-vein contrast-to-noise ratio (CNR) measures. ANOVA was used to compare CNR values across sites with post-hoc Tukey Honest Significant Difference testing. Multiple testing between sites was considered by controlling the false discovery rate. One-sided paired t-testing was used to compare the overall lesion-to-vein CNR values between pre- and post-Gd FLAIR*.

Results

Seventy-eight patients from nine sites were included in the analysis; one site was excluded due to low enrollment. The overall mean(coefficient of variation, CV) lesion-to-vein CNR values across the nine sites were 0.35(14%) and 0.37(12%) for pre- and post-Gd FLAIR*, respectively. Excluding an additional site that used an unharmonized FLAIR acquisition, the resulting mean(CV) CNR values were 0.36(12%) for pre-Gd and 0.37(11%) for post-Gd FLAIR*. Across most sites, there was a significant improvement in lesion-to-vein CNR measures for post-Gd compared to pre-Gd FLAIR* [mean difference = 0.011, p < 0.001, 95% CI: (0.008,0.015)].

Conclusions

Lesion-to-vein CNR measures across sites are in line with values first published for 3T FLAIR* and demonstrate the robustness of 3T FLAIR* for imaging the CVS in a multicenter setting. Moreover, there was an increase in vein conspicuity with improvement in CNR on post-Gd FLAIR*. Based on these results, a prospective multicenter NAIMS CVS diagnostic study, sponsored by NINDS, will use 3T FLAIR* imaging with Gd in the study protocol.

Background

The gut microbiota is emerging as a critical regulator of immune responses and appears to play an important role in MS. The International Multiple Sclerosis Microbiome study (iMSMS) is a global collaboration aimed at elucidating the role of commensal gut bacteria in MS by acquiring and analyzing samples from 2000 patients and 2000 household healthy controls.

Objectives

The iMSMS focuses on identifying the microbes, genes and pathways that are involved in MS pathogenesis and on investigating how the microbiome changes response to treatment.

Methods

A total of 576 case and household healthy control pairs were recruited from 7 centers located in the US (West and East coasts), Europe and South America. Stool samples were collected and evaluated by both 16S and shallow whole metagenome shotgun sequencing. Univariate and multivariate linear regression analyses were conducted to understand patterns of variation on gut microbiome.

Results

This is the largest MS microbiome study reported to date. Our results showed a statistically significant difference of beta diversity between MS and healthy controls for the first time in MS. Intriguingly, multiple species of Akkermansia, including the known mucin-degrading bacterium Akkermansia muciniphila, were significantly enriched in untreated MS patients after adjusting for confounding factors, but the difference was not detected in treated MS group versus control. Ruminococcus torques and Eisenbergiella tayi were also among the top significantly enriched bacteria in MS. Inversely, a main butyrate producer, Faecalibacterium prausnitzii, was significantly decreased in the untreated MS group. Functional pathways of L-tryptophan biosynthesis and L-threonine biosynthesis were slightly increased in untreated MS patients, while 5-aminoimidazole ribonucleotide biosynthesis I was increased in the treated group.

Conclusions

Our large household-controlled study allowed us to identify modest but statistically robust MS-associated changes in bacterial composition and functions. It provides the foundation for all future studies of the gut microbiota in MS. The strain-level genomic variation and microbiome-derived molecules need to be further explored for understanding microbial adaptation and pathogenicity.

Background

In persons with multiple sclerosis (MS), the Expanded Disability Status Scale (EDSS) is the criterion standard for assessing disability, but its in-person nature constrains patient participation in research and clinical assessments.

Objectives

To develop and validate a scalable, electronic, unsupervised patient-reported EDSS (ePR-EDSS) that would capture MS-related disability across the spectrum of severity.

Methods

We enrolled 136 adult MS patients, split into a preliminary testing Cohort 1 (n=50), and a validation Cohort 2 (n=86), which was evenly distributed across EDSS groups. Each patient completed an ePR-EDSS either immediately before or after a MS clinician’s Neurostatus EDSS (NS-EDSS) evaluation. The final ePR-EDSS version includes 23 questions, takes between 7-12 minutes to complete (based on time measured for Cohort 2 participants), and can be accessed at https://openmsbioscreen.ucsf.edu/predss/about.

Results

In Cohort 2, mean age was 50.6 years (range 26-80) and median EDSS was 3.5 (IQR 1.5, 5.5). The ePR-EDSS and EDSS agreed within 1-point for 86% of examinations; kappa for agreement within 1-point was 0.85 (p<0.001). The correlation coefficient between the two measures was 0.91 (<0.001). For individual functional systems, complete agreement was highest for the brainstem score (55.8%) and lowest for the sensory score (31.4%). In sensitivity analyses adjusted for NS-EDSS, the absolute difference between ePR-EDSS and NS-EDSS was not significantly related to age, sex, disease duration, years of education, or the timepoint at which the ePR-EDSS tool was assessed (before/after neurological exam).

Conclusions

The ePR-EDSS is unique compared to other published tools - it can be accessed and performed by the patient without any supervision, is freely and openly available, has built-in logic to calculate functional system and total scores, and is validated over a wide NS-EDSS range. It demonstrated high correlation with NS-EDSS, with good agreement even at lower EDSS levels. For clinical care, the ePR-EDSS could enable the longitudinal monitoring of a patient’s disability. For research, it provides a valid and rapid measure across the entire spectrum of disability and permits broader participation with fewer in-person assessments.

Background

Background: Multiple sclerosis (MS) treatment involves disease-modifying therapies (DMTs) and symptom management. There is an unmet need for MS treatments that reverse demyelination and neuronal damage. Elezanumab (formerly ABT-555) is a monoclonal antibody that neutralizes repulsive guidance molecule A (RGMa), a neurite outgrowth inhibitor thought to be involved in MS.

Objectives

Objective: Present the study design and baseline data from 2 studies investigating elezanumab efficacy and safety in patients with progressive MS (PMS) and relapsing MS (RMS).

Methods

Methods: RADIUS-R (NCT03737851) and RADIUS-P (NCT03737812) are 2 ongoing, 52-week, proof-of-concept, RAndomized, Double-blind, placebo-controlled, multIple-dose phase 2 stUdies investigating efficacy and safety of elezanumab added to Standard of care in patients with RMS and PMS, respectively. RADIUS-R includes patients with relapsing-remitting MS (RRMS; no relapse 6 months before screening), or active secondary-progressive MS (SPMS; relapse 6 to 24 months before screening). RADIUS-P includes patients with primary-progressive MS (PPMS) or non-active SPMS (no relapses 24 months before screening). Patients in both studies were randomized 1:1:1 to receive 1 of 2 doses of elezanumab or placebo intravenously every 4 weeks through week 48. The primary endpoint for both studies is mean overall response score (ORS; based on Expanded Disability Status Scale [EDSS], Timed 25-Foot Walk [T25FW], and 9-hole Peg Test [9HPT]-dominant and nondominant) at week 52.

Results

Results: Overall, 208 patients enrolled in RADIUS-R and 123 in RADIUS-P. In RADIUS-R, 199 (96%) patients were diagnosed with RRMS, while 9 (4%) were diagnosed with SPMS. In RADIUS-P, 59 (48%) patients were diagnosed with PPMS, and 63 (52%) were diagnosed with SPMS. Baseline mean (SD) age was 45.7 (8.4) years (RADIUS-R) and 52.6 (7.0) years (RADIUS-P). Overall, 66% of RADIUS-R and 48% of RADIUS-P patients were women. Mean (SD) ORS components for RADIUS-R were: T25FW, 7.3 (4.0); 9HPT-dominant, 28.0 (22.5); and 9HPT-nondominant, 30.0 (23.5); EDSS (median [range]), 3.5 (1.0, 6.5). ORS components for RADIUS-P were: T25FW, 12.5 (11.2); 9HPT-dominant, 31.4 (27.6); and 9HPT-nondominant, 38.1 (37.3); EDSS, 6.0 (2.0, 7.0). Most patients used concomitant DMTs (RADIUS-R, 75%; RADIUS-P, 69%), most commonly ocrelizumab (RADIUS-R, 45%; RADIUS-P, 59%).

Conclusions

Conclusion: RADIUS-R and RADIUS-P are ongoing phase 2 studies investigating safety and efficacy of elezanumab as a remyelination agent.