Background

Treatment options for pediatric patients with relapsing forms of multiple sclerosis (RMS) are limited. Teriflunomide, approved for adults with RMS in >80 countries, was investigated in pediatric RMS in TERIKIDS (NCT02201108), a 2-year, multicenter, multinational, randomized, double-blind (DB), placebo-controlled, parallel-group phase 3 study.

Objectives

To report the interim results in pediatric patients from the open-label (OL) period of the TERIKIDS study as of 27 November 2019.

Methods

Patients who either completed 96-week DB treatment or qualified for early switch from DB treatment to OL teriflunomide could continue in the OL period until 192 weeks after initial randomization. All patients in the OL period received teriflunomide at a dose based on body weight, equivalent to 14 mg in adults.

Results

In the DB period, teriflunomide reduced risk of relapse (−34%); however, the difference was not statistically significant versus placebo (P=0.29) so TERIKIDS did not meet its primary endpoint. Teriflunomide significantly reduced risk of relapse or high MRI activity (−43%; P=0.041; prespecified sensitivity analysis), number of new/enlarging T2 lesions (−55%; P=0.0006), and number of gadolinium-enhancing lesions (−75%; P<0.0001) relative to placebo. At the cut-off date, 100 (91.7%) patients from the teriflunomide and 52 (91.2%) from the placebo group enrolled in the OL period; 34 patients discontinued, 30 completed, and 88 were ongoing. From DB randomization to week 192, risk of relapse was numerically lower with continuous teriflunomide versus placebo/teriflunomide (hazard ratio [95% CI]: 0.61 [0.38 to 0.98]; P=0.098), as was risk of disability progression sustained for 24 weeks (hazard ratio [95% CI]: 0.552 [0.245 to 1.242]). Number of new/enlarging T2 lesions per MRI scan was reduced with continuous teriflunomide versus placebo/teriflunomide (6.3 vs 13.0; P=0.0006). Incidence of adverse events during the OL period was lower with continuous teriflunomide versus placebo/teriflunomide (68.0% vs 82.7%). Adverse events led to treatment discontinuation during the OL period in 8 patients (increased alanine aminotransferase [n=5], peripheral neuropathy [n=1], pancreatitis [n=2]).

Conclusions

Interim analysis showed that continuous teriflunomide numerically lowered the risk of clinical relapses and 24-week sustained disability progression in pediatric patients compared with delayed initiation of teriflunomide after placebo. Teriflunomide was well tolerated and had a manageable safety profile.

STUDY SUPPORT: Sanofi.

Background

In multiple sclerosis (MS), MRI measures at a whole and regional brain level have proven able to predict future disability, albeit to a limited degree. Their modest prognostic ability may reflect how cognitive and neurological functions are served by distributed networks rather than by single brain regions.

Objectives

We aimed to identify data-driven MRI network-based measures of covarying gray matter (GM) volumes that can predict disability progression.

Methods

We used baseline MRI and longitudinal clinical data from 988 patients with secondary progressive MS (SPMS) from a randomized, double-blind, placebo-controlled, multicenter trial (ASCEND). We applied spatial-ICA to baseline structural GM probability maps to identify co-varying GM regions. We computed correlations between the loading of our ICA components and expanded disability status scale (EDSS), 9 hole peg test (9HPT), and symbol digit modalities test (SDMT) scores. We estimated the progression of the EDSS confirmed at 3 months, 6 months, and 1 year, and respectively the 20% and 10% worsening of 9HPT and SDMT. We used Cox proportional hazard models to determine the prognostic value of our ICA-components and conventional MRI measures (whole and deep GM volumes, and white matter lesion load).

Results

We identified 15 networks of co-varying GM patterns that were clinically relevant. At baseline, SDMT and 9HPT scores correlated more strongly with ICA-components than the conventional MRI measures. The highest correlations were with a mainly basal ganglia component (encompassing the thalamus, caudate, putamen, frontal and temporal lobe). EDSS correlated more closely with an ICA-component involving cerebellum, brainstem, temporal and parietal lobes (r= -0.11, p<0.001). Prognostically, the baseline volume of caudate predicted EDSS progression confirmed at 3 months (HR= 0.81, 95%CI [0.68: 0.98], p<0.05), while some GM network-based measures outperformed conventional MRI measures in predicting SDMT and 9HPT worsening. SDMT progression was predicted by 6 ICA-components (component 8 (HR= 1.26, 95% CI [1.08-1.48], p< 0.005, and component 13 (HR= 1.25, 95% CI [1.07:1.46], p<0.005)). Two ICA-components were predictors of 9HPT worsening (HR=1.30, 95% CI [1.06:1.60], p<0.01; and HR= 1.21, 95%CI [1.01:1.45], p<0.05).

Conclusions

Data-driven MRI network-based measures of covarying GM volumes predict disability progression better than volumetric measures of GM and white matter lesion loads. ICA of MRI shows promise as a method that could enrich clinical MS studies with patients more likely to show a treatment response.

Background

White matter (WM) microstructural changes occur in youth with multiple sclerosis (MS) and myelin oligodendrocyte glyoprotein (MOG)-associated disorders. While diffusion tensor imaging has been extensively used to characterize white matter, this method lacks microstructural and pathological specificity. ‘Fixel Based Analysis’ (FBA) statistically estimates changes in diffusion MRI connectivity that is specific to micro and macro-structure. WM damage that leads to less densely packed axons in a fiber bundle causes a decrease in fibre density (FD). If the number of axons is not reduced but occupies less area, then fibre cross-section (FC) will decrease. Last, if the density of axons within a fibre bundle and the area the bundle occupies are reduced, then fibre density and cross-section (FDC) will decrease.

Objectives

To use whole-brain FBA to measure differences in FD, FC, FDC in youth with demyelinating syndromes compared to healthy controls.

Methods

We evaluated group differences in the FBA metrics between 28 typically developing children (17F; age 15.0±2.6y), 19 children with MS (13F; 16.9±1.1y; disease duration (DD)=0.1-11.7y; expanded disability status scale(EDSS):median=1.5,range=0-4.5), and 11 children with MOG (8F;12.1±2.8y; DD=0.5-6.4y;EDSS:m=1.0,r=0-3). Multi-shell diffusion-weighted imaging of the brain was acquired with echo planar imaging on a 3T MRI scanner and was pre-processed to correct for distortions and movement. Whole-brain group FBA was performed on FD, FC and FDC to test differences between groups adjusting for age, sex, total intracranial volume, EDSS and DD (p<0.05, family-wise error (FWE) corrected).

Results

Participants with MS and MOG showed reduced FD, FC and FDC relative to typically developing children (FWE corrected p<0.05). Differences in FD were found within splenium, superior longitudinal fasciculus and optic radiations. MS patients had reduced FDC within the corticospinal tract and cerebellar peduncle compared to MOG patients. In participants with MS and MOG, decreased FD within the brain stem, cerebellar peduncles and corona radiata was associated with increased DD and EDSS.

Conclusions

Our preliminary findings showed that patients with demyelinating disorders display decreased axonal density and fibre bundle size in multiple WM tracts relative to typically developing children, which were related to clinical outcomes (EDSS, DD). These changes were more pronounced in MS compared to MOG participants in selected WM tracts.

Background

Over 2 years in the CARE-MS trials (NCT00530348; NCT00548405), alemtuzumab (12 mg/day; baseline (BL): 5 days; 12 months later: 3 days) significantly improved clinical and MRI outcomes versus subcutaneous interferon beta-1a (SC IFNB-1a) in relapsing-remitting multiple sclerosis patients. Alemtuzumab efficacy was maintained through a 4-year extension study (NCT00930553), wherein patients could receive additional 3-day courses (≥12 months apart, as needed for disease activity) or receive other disease-modifying therapy per investigator’s discretion.

Objectives

To evaluate post hoc the effects of alemtuzumab on brain atrophy over 6 years in CARE-MS patients without relapses and MRI disease activity.

Methods

Analysis included pooled CARE-MS patients with or without disease activity between BL and Year 1 or BL and Year 2. Absence of disease activity was defined as no BL gadolinium (Gd)-enhancing T1 lesions and no clinical relapses or MRI disease activity (new Gd-enhancing or new/enlarging T2 lesions) from Years 0-1 or Years 0-2 (Definition 1). A second definition had the additional criterion of no relapse within 60 days before BL (Definition 2). Brain atrophy was measured by brain parenchymal fraction (BPF); differences in the median annualized percent change in BPF were assessed using ranked ANCOVA adjusted for region and BL BPF.

Results

Compared with SC IFNB-1a, alemtuzumab reduced median annualized percent change in BPF in patients free of disease activity during Years 0-1 (Definition 1: -0.37% vs -0.61%, P=0.006; Definition 2: -0.36% vs -0.54%, P=0.024) or Years 0-2 (Definition 1: -0.27% vs -0.44%, P=0.014; Definition 2: -0.28% vs -0.41%, P=0.045). Median annualized percent change in BPF was reduced with alemtuzumab versus SC IFNB-1a in patients with disease activity in Years 0-1 (-0.61% vs -0.79%, P=0.005) or Years 0-2 (-0.40% vs -0.56%, P<0.0001). Over 6 years, brain volume loss (BVL) was slower in patients without disease activity who initiated alemtuzumab at core study BL (-1.66%) than in those who received SC IFNB-1a in the core studies and initiated alemtuzumab in the extension (-2.05%).

Conclusions

Brain atrophy was reduced with alemtuzumab compared with SC IFNB-1a in patients without disease activity over 2 years. A slower rate of BVL was maintained through Year 6 in patients without disease activity who received alemtuzumab in the core study compared with SC IFNB-1a, suggesting alemtuzumab may slow neurodegeneration associated with BVL.

STUDY SUPPORT: Sanofi.

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

Studies examining the role of the microbiota in multiple sclerosis (MS) often focus on the gut bacteria; few have considered a potential role of gut mycobiota. Methods for evaluating gut mycobiota are lacking and require systematic evaluation of sequencing protocols, reference databases, and bioinformatics pipelines to properly investigate possible gut mycobiome influences on MS.

Objectives

We set out to evaluate the performance of different sequencing conditions and analytical approaches for characterizing the gut mycobiome in a cohort of healthy individuals and cases with monophasic acquired demyelinating syndrome (mono ADS) or pediatric-onset MS.

Methods

We first assessed a mock-community control pool of known, staggered quantities of 19 defined fungal organisms. We then assessed 201 stool samples obtained from our cohort of 52 healthy individuals, 49 individuals with mono ADS, and 46 participants with pediatric-onset MS. The fungal internal transcribed spacer (ITS) 2 region was sequenced using the Illumina® MiSeq platform. Varying concentrations of PhiX Control v3 Library spike-in were tested to address low-complexity amplicon sequencing. Generated sequences were characterized by the UNITE database—a curated collection of eukaryotic ITS sequences—in conjunction with three distinct fungal sequence analysis pipelines: LotuS, mothur, and PIPITS.

Results

Taxa identified in our mock-community differed across sequencing conditions but were similar between technical replicates. LotuS correctly classified 7 taxa at species-level, 7 taxa at genus-level, whereas 5 remained unclassified. Mothur correctly identified 5 species-level taxa, 11 genus-level taxa, whereas 3 remained unclassified. Lastly, PIPITS correctly identified only 3 species-level taxa, 12 genus-level, while 4 remained unclassified. We successfully generated sequence data for 112 of 147 (76%) individuals (70 females; 42 males). The mean age at stool sample collection was 17.3 (SD 5.1) years. Of the tested sequencing conditions, a spike-in of 50% PhiX produced the highest-quality reads.

Conclusions

The LotuS pipeline best identified fungal taxa in our mock-community, with optimal resolution to species level. Sequencing read quality was optimal when 50% PhiX was used for sequencing ITS2 amplicon libraries of stool samples. Establishment of this validated sequencing pipeline, confirmed using a mock-community with known fungal identities, will aid characterization of gut mycobiomes for our cohort of individuals with/without pediatric-onset MS.

Background

Evobrutinib (EVO) is a highly selective Bruton’s tyrosine kinase inhibitor (BTKI) with a dual mode of action targeting both B cells and myeloid cells, which are known to play a key role in the pathogenesis of autoimmune diseases such as multiple sclerosis (MS). Clinical efficacy of EVO in relapsing MS was shown in a Phase II randomized controlled trial (RCT; NCT02975349) with a significant reduction of T1 Gd-enhancing lesions compared to placebo at Week 24 (the primary endpoint of the study) and continued efficacy through Week 48.

Objectives

To report the long-term efficacy of EVO measured as the annualized relapse rate [ARR]), cumulative probability of and time to qualified relapse (QR, change in neurological symptoms or expanded disability status scale score increase attributed to MS lasting ≥24 hours preceded by a stable or improving neurological status ≥30 days).

Methods

In the 48-week double-blind period (DBP), patients received EVO 25mg once daily (QD), 75mg QD, 75mg BID or placebo (PBO) for the first 24 weeks; all arms continued with the original treatment assignment until 48 weeks, except PBO patients who were switched to EVO 25mg QD. At Week 48, all patients could enter the OLE, where treatment was initially EVO 75mg QD (for a median of ≈48 weeks) before switching to 75mg BID. Long-term efficacy of EVO was assessed at up to 60 weeks of OLE.

Results

Of 213 patients randomized to EVO or PBO, 164 (77%) entered the OLE; of these 148 (90%) completed 108 weeks of treatment. For patients initially receiving PBO or EVO 25mg QD, 75mg QD or 75mg BID in the DBP, ARR (95% CI) was 0.37 (0.21, 0.59), 0.52 (0.33, 0.78), 0.25 (0.12, 0.44) and 0.11 (0.04, 0.25), respectively, at Week 48, and 0.31 (0.21, 0.45), 0.37 (0.25, 0.52), 0.18 (0.10, 0.29) and 0.12 (0.06, 0.22) at Week 108. The cumulative probability of QR in these groups was 0.26 (0.14, 0.38), 0.24 (0.12, 0.36), 0.15 (0.05, 0.25) and 0.08 (0.00, 0.16) at Week 48, and 0.39 (0.25, 0.53), 0.34 (0.20, 0.48), 0.25 (0.12, 0.38) and 0.20 (0.08, 0.31) at Week 96, respectively. The estimated time from randomization by which 20% of patients had a qualified relapse was almost three times longer for patients initiated in the DBP with EVO 75mg BID (827 days [327, not evaluable]) than for patients initiated in the DBP with PBO (281 days [99, 407]) and longer than for patients initiated in the DBP with EVO 25mg QD (166 days [61, 606]) and 75mg QD (530 days [244, 838]). EVO was generally well tolerated, with the safety profile maintained during the 60-week OLE.

Conclusions

With EVO 75mg BID, the efficacy (ARR, 0.11) at Week 48 was maintained at 108 weeks. Probability of and time to QR highlighted that, despite switching to EVO 75mg QD/BID in OLE, patients initiated in the DBP on EVO 25mg QD, 75mg QD or PBO did not achieve the same level of efficacy of those initiated in the DBP on 75mg BID. The maximum efficacy observed at the 75mg BID dose correlated with optimal BTK occupancy achieved with BID dosing.

Background

Diroximel fumarate (DRF) is a novel oral fumarate approved in the United States for relapsing forms of multiple sclerosis (MS). DRF undergoes pre-systemic hydrolysis to monomethyl fumarate (MMF), the same pharmacologically active metabolite as dimethyl fumarate (DMF). DRF 462 mg and DMF 240 mg produce bioequivalent exposure of MMF and are expected to have similar efficacy and safety profiles. In DMF-treated patients, annual rates of brain volume loss over 6 years ranged from -0.19 to -0.37, approaching rates observed in healthy adults (-0.1% to -0.3%).

Objectives

To report percent brain volume change (PBVC) and impact on disability in patients from EVOLVE-MS-1 who have received DRF treatment for up to 2 years.

Methods

EVOLVE-MS-1 (NCT02634307) is an ongoing, open-label, phase 3 study to assess the long-term safety, tolerability, and efficacy of DRF 462 mg over 96 weeks in adults with relapsing-remitting MS. Normalized brain volume was assessed at baseline and used to calculate PBVC at Weeks 48 and 96. Confirmed Disability progression (CDP) was measured using the Expanded Disability Status Scale (≥1.5-, ≥1.0-, or ≥0.5-point increase from a baseline score of 0, 1.0-5.5, or 6.0, respectively), with changes sustained for 12 weeks. Estimated proportion of patients with CDP was calculated by the Kaplan-Meier method. No evidence of disease activity (NEDA)-3 was defined as no relapses, no 12-week CDP, and no new/enlarging T2 or new gadolinium-enhancing lesions. This post hoc analysis was conducted in a subgroup of patients who had brain volume scan measurements at baseline, Week 48, and Week 96. The Week 48 and Week 96 visits occurred within an analysis window of ±12 weeks.

Results

As of 2 July 2019, a total of 1051 patients were enrolled in EVOLVE-MS-1 and 365 patients were included in this analysis. Median (range) exposure was 96 (75-100) weeks. Mean (SD) PBVC was -0.36 (0.60) from baseline to Week 48 and -0.35 (0.55) from Week 48 to Week 96. Estimated proportion of patients who were free of CDP was 94.3% at Week 48 and 90.7% at Week 96. The proportion of patients with NEDA-3 at Week 48 and Week 96 was 44.7% (163/365) and 25.2% (91/361), respectively.

Conclusions

Interim findings from the ongoing EVOLVE-MS-1 study demonstrate that yearly PBVC in DRF-treated patients approached the rate observed in healthy adults and was consistent with previous studies of DMF. Most patients remained free of CDP at 2 years.

Supported by: Biogen

Background

In a Phase II randomized study (NCT02975349) in patients with relapsing MS, evobrutinib (EVO) 75 mg twice-daily (BID) reduced total T1 Gd+ lesions (primary endpoint) and annualized relapse rate (ARR) over 24 weeks versus placebo, with efficacy maintained through Week 108. EVO was generally well tolerated.

Objectives

To describe the safety profile of EVO in the long-term treatment of MS by reporting detailed safety data from the study’s open-label extension (OLE) over 60 weeks.

Methods

In the 48-week double-blind period (DBP), patients received EVO 25 mg once-daily (QD) or 75 mg QD, 75 mg BID, or placebo for the first 24 weeks. All arms continued with the original treatment assignment until 48 weeks, except placebo patients who were switched to EVO 25 mg QD. At Week 48, all patients could enter the OLE, where treatment was initially EVO 75 mg QD (for a median of ~48 weeks) before switching to 75 mg BID. Safety was assessed throughout the OLE by the nature, severity, and occurrence of treatment emergent adverse events (TEAEs) by NCI-CTCAE v4.03 criteria, as well as vital signs, ECGs, and clinical laboratory safety parameters.

Results

Of 213 patients who received EVO during the double-blind period, 164 (77%) entered the OLE (safety analysis population) and 148 (90%) completed 60 weeks of treatment. Overall, 107 (65.2%) patients had a treatment emergent adverse event (TEAE), the majority of which were mild (47.6%) or moderate (36.0%), and none led to death. TEAEs were balanced across previous DBP treatment groups; the most frequent TEAEs over the OLE period, including the dose-switch, were nasopharyngitis (7.9%, Grade 2 or less), increased lipase (7.9%, Grade 3 or less), upper respiratory tract infection (6.1%, Grade 2 or less), and urinary tract infection (4.9%, Grade 2 or less); analysis of TEAEs by exposure-adjusted incidence rate showed no evidence of an increase after patients switched to 75 mg BID. Thirteen patients (7.9%) reported a serious TEAE, most frequently related to infections (6 patients, not treatment-related). Five patients (3.0%) had a TEAE during the OLE that led to treatment withdrawal, of which 3 were considered related to treatment (nausea, increased lipase, and increased lipase and amylase). The incidence of overall infections in the OLE was similar to that observed in the DBP. Transient elevated liver aminotransferases reported in the 48-week DBP were not observed in the OLE after prolonged treatment or after the switch to 75 mg BID. No adverse ECG findings were noted across all evobrutinib groups. There was also no apparent effect of EVO dose received in the DBP on safety parameters in the OLE.

Conclusions

In a 60 week OLE period of a Phase II study, the safety of EVO was similar to that seen in the DBP. Overall, long-term EVO treatment was generally well tolerated in patients with relapsing MS.

Background

Previous studies have described extensive microstructural brain tissue abnormalities in pediatric MS patients. However, available techniques do not distinguish the extent to which such abnormalities are due to axonal loss or demyelination. Further, little is known about microstructural brain tissue changes in MOG-associated disorders (MOGad).

Objectives

To apply a combined analysis of magnetization transfer saturation (MT_sat) and multi-shell diffusion-weighted imaging (DWI) with computation of myelin and axonal volume fractions (MVF and AVF) and imaging g-ratio (the ratio between inner and outer diameter of the myelin sheath); to investigate the specific relationship between these metrics in the corpus callosum (CC) and within brain white matter lesions (WML) of pediatric MS and MOGad.

Methods

We acquired standardized 3T brain MRI in 26 healthy controls (HC) (58% females (F), mean age [years (y) (range)] 15y (9-19)); 16 MS (69% F, 17y (14-18), disease duration (DD) 3y (1-7), time from last relapse (TLR) 2y (0-6)); and 11 MOGad (72% F, 12y (8-18), DD 3y (0-6), TLR 1y (0-3), 8/11 relapsing). WML and CC were segmented according to establishes procedures. DWI processing was performed with FSL and DMIPy; MT_sat, MVF, AVF, and g-ratio were computed using the Jargon data management system. We used general linear models to model average MVF, AVF, and g-ratio in the CC and WML of each group, including the factors age, DD, and the interaction term group*DD. Models including sex were tested, and all exhibited lower AIC.

Results

Relative to HC, MS showed decreased CC MVF (-0.018/y, p=0.0304) and AVF (-0.0069/y; p=0.053) and corresponding increased CC g-ratio (0.0084/y, p=0.059) with increased DD. Relative to HC, MOGad showed decreased CC MVF (-0.017/y, p=0.0304) and AVF (-0.0081/y, p=0.014) with increased DD, without significant CC g-ratio changes. Both MS and MOGad showed decreased average WML MVF compared to HC WM (-0.19, p<10^-8; and -0.2, p<10^-8). MOGad also showed decreased average WML AVF (-0.067, p=0.0048) compared to HC. Average WML g-ratio was higher in MS than MOGad (0.17, p=0.0102), but not significantly different from HC in either group. WML MVF, AVF, and g-ratio did not change significantly with DD in MS or MOGad compared to HC.

Conclusions

Both pediatric MS and MOGad exhibited MRI correlates of axonal loss and demyelination in the CC and WML. Our measures of axonal loss in MOGad reinforces recent work warning of potentially long-term impacts on the brain from non-MS demyelinating pathologies.

Background

Background: Diffusely abnormal white matter (DAWM) regions have been found to transform over time into focal white matter lesions (FWML) and to associate with progression in secondary progressive MS (SPMS). However, few studies have assessed changes of DAWM and FWML over time in relapsing-remitting MS (RRMS). Hence, we compared volumetric changes of DAWM and FWML over time as well as the transformation of DAWM into FWML (DAWM-to-FWML) in RRMS and SPMS.

Objectives

Objectives: 1) To automatically segment FWML and DAWM and characterize the longitudinal evolution of FWML, DAWM and FWML/DAWM Ratio in RRMS vs. SPMS. 2) To compare the volume of DAWM (at each visit) that transforms into FWML in the last MRI scan.

Methods

Methods: The data included 4220 MRI scans of 689 SPMS participants, followed for 156 weeks, scanned at screening, weeks 24, 48, 72, 96, 108, and 156; and 2677 scans of 686 RRMS participants, followed for 96 weeks, scanned at screening, weeks 24, 48 and 96. FWML and DAWM were automatically segmented using a previously-validated, automated, 2-weighted-intensity thresholding technique. DAWM voxels at screening, weeks 24, 48, 72, 96, and 108 that transformed into FWML at the last MRI scan (w96 for RRMS, and w156 for SPMS) were identified.

Results

Results: Over time, SPMS participants showed volumes of FWML that significantly increased (t=2.5; p=0.01) along with a significant decrease of DAWM (t=-4.1; p<0.0001), and a significant Ratio increase (t=10.5; p<0.00001). RRMS participants only showed a significant increase in the Ratio (t=6.9; p<0.00001). Interestingly, the voxels of DAWM that transformed into FWML at the last visit significantly changed as disease duration progressed in both RRMS and SPMS, but in different directions, increasing in RRMS (t=3.8; p<0.001) and decreasing in SPMS (t=-12.2; p<0.00001).

Conclusions

Conclusions: A significant volume of DAWM transformed into FWML over time in both RR and SPMS. However, the volume of DAWM that experienced this transformation increased over time in RRMS, explaining why we do not see significant changes of the overall DAWM volumes at each visit. Conversely, the volume of DAWM-to-FWML transformation decreases progressively at each visit in SPMS, reflecting a decrease in the remaining portion of DAWM still available to transform into FWML. The finding that the transformation of DAWM-to-FWML accelerates with time in RRMS, but decelerates in SPMS, could suggest differences in the mechanisms underlying this transformation in RR and SPMS.

Background

Background: Diffusely abnormal white matter (DAWM) is associated with decreased axonal and myelin density, fibrillary gliosis, and inflammatory cell activation on histopathology, and has been linked to progression in secondary progressive MS (SPMS). However, few studies have focused on assessing DAWM in primary progressive MS exclusively. Hence, we aimed to characterize the longitudinal evolution of DAWM and its relationship with focal white matter lesions (FWML) and confirmed disability progression (CDP) in a PPMS population.

Objectives

Objectives: 1) To automatically segment and characterize the longitudinal evolution of FWML and DAWM in PPMS. 2) To assess associations of voxels of DAWM that transform into FWML at last visit with CDP (CDP=sustained increase in EDSS that persisted for 24 weeks).

Methods

Methods: The data included 1753 MRI scans of 376 PPMS participants, followed for 122 weeks, scanned at screening, weeks 06, 48, 96, and 122. FWML and DAWM were automatically segmented using a previously validated automated 2-weighted-intensity thresholding technique. All gadolinium enhancing and new white matter lesion voxels were excluded from the FWML mask, to capture the chronic component of FWML. DAWM voxels at screening, weeks 06, 48 and 96 that transformed into FWML at the last MRI scan (w122) were segmented.

Results

Results: As disease duration increased, PPMS participants showed volumes of chronic FWML that significantly increased (t=7.3; p<0.0001) but no significant changes in DAWM volumes. The voxels of DAWM in subsequent scans that transformed to FWML at the last visit significantly decreased as disease duration progressed (t=-8.8; p<0.0001) and were not significantly associated with CDP.

Conclusions

Conclusions: DAWM voxels show a dynamic transformation into FWML over time, with volumes of DAWM-to-FWML transformation in PPMS decreasing progressively as disease duration increases. These dynamic changes are similar to those observed in SPMS. However, unlike SPMS, where previous studies have shown an association between DAWM-to-FWML transformation and CDP, this group of PPMS participants did not show such an association. This finding would suggest that other factors, other than DAWM evolution, might have a stronger weight in disease progression in PPMS, compared to SPMS.

Background

Multiple sclerosis (MS) and MOG-associated disorders (MOGad) are characterized by hyperintense white matter (WM) lesions on T₂/FLAIR MRI. Conventional imaging is sensitive but does not inform on the specific pathological substrate. Magnetization transfer saturation provides a good myelin measure, and multishell diffusion is sensitive to the axon + myelin assembly. Together, these can be modelled to estimate myelin volume fraction (MVF), axonal volume fraction (AVF) and imaging g-ratio.

Objectives

To quantify gradients of damage to axons and myelin in lesions and surrouding normal appearing white matter, in pediatric MS and MOGad.

Methods

15 MS [67% females (F), mean (range) age [years (y)]: 17y (14-18), disease duration (DD) 3y (0-6), time from last relapse (TLR) 2y (0-6)] and 7 MOGad [86% F, 13y (8-18), DD 3y (0-6), TLR 1y (0-3), 6/7 relapsing] participants received 3T brain MRI. MVF, AVF and g-ratio were computed according to established procedures. T₂ lesions were segmented according to standardized pipelines and WM masks by multi-atlas segmentation. Euclidean distance transforms labelled voxels in normal-appearing WM with the distance to the nearest lesion voxel, and voxels inside lesions with the distance to the nearest non-lesional WM voxel. Mean MVF, AVF and g-ratio were computed on each isodistant surface. Data were modeled using linear mixed models with distance, diagnosis, and their interaction. Knots were used at 0 and 2mm distance.

Results

MVF decreased towards the center of lesions (MOGad: -0.03/mm; MS: -0.05/mm; p values (ps)<0.002; difference n.s.) as did AVF (MOGad: -0.03/mm; MS: -0.01/mm; ps<0.0002; difference p=0.02); this graded damage extended to 2mm outside lesions. Beyond this, AVF continued to increase (MOGad: 0.001/mm; MS: 0.0003/mm; ps<10^-6; difference p<10^-6). Inside lesions, g-ratio increased towards the center in MS (0.03/mm, p<10^-6) and decreased in MOGad (p=0.15; MOGad-MS difference p<10^-4). G-ratio rose with distance outside lesions (MOGad: 0.001/mm; MS: 0.0004/mm; ps<10^-4; difference p<10^-5). AVF and g-ratio were similar between groups (within 2%) at 20mm from lesions; MVF was higher in MS (14%, p=0.08).

Conclusions

MS and MOGad showed myelin and axonal loss of decreasing severity with distance from lesion center, and this damage extended outside visible lesions. However, MOGad exhibited more severe axonal loss within and near lesions. The corresponding decreasing g-ratio relative to MS may indicate preferential loss of small axons in MS, or relatively better remyelination in MOGad.

Background

The gut microbiota may influence multiple sclerosis (MS) onset. Pediatric MS offers the opportunity to examine pathological processes close to risk acquisition.

Objectives

To examine the gut microbiota from stool samples of persons with pediatric onset MS, or monophasic acquired demyelinating syndromes (ADS) and unaffected controls in a case-control study.

Methods

Persons ≤21 years old with symptom onset <18 years of age with either MS (McDonald criteria) or ADS were eligible, as were unaffected controls with no known neurological or immune-mediated condition (migraine, asthma/allergies were permissible) were enrolled via the Canadian Pediatric Demyelinating Disease Network. Stools were collected between Nov/2015–Mar/2018, shipped on ice, and stored at -80°C. The 16S ribosomal RNA gene (V4 region) was amplified from extracted DNA and sequenced via the Illumina MiSeq platform. Amplicon sequence variants were used to compare the gut microbiota by disease status (MS/ADS/controls). The MS cases were also compared by disease-modifying drug (DMD) status (exposed/naïve). Negative binomial regression was used for genus-level analyses, with rate ratios adjusted (aRR) for age and sex.

Results

Of the 32/41/36 included MS/ADS/control participants, 24/23/21 were girls, averaging age 16.5/13.8/15.1 years at stool sample, respectively. The MS/ADS cases were 14.0/6.9 years at symptom onset. The 3 groups (MS/ADS/controls) were relatively similar for: body mass index (median: 22.8/19.7/19.9), presence of constipation (number of participants with a Bristol Stool Scale score of 1 or 2=8/9/7) and diet (% caloric intake for fat (median)=34/35/34 and for fibre (median)=9/10/11 g/day). Nine MS cases (28%) were DMD naïve. Gut microbiota diversity (alpha and beta) did not differ by disease (MS/ADS/controls), or DMD status (all p>0.1), while taxa-level findings did. For example, relative abundance of the Proteobacteria, Sutterella was depleted for MS cases vs controls and MS vs ADS cases (aRR:0.13;95%CI:0.03–0.59 and 0.21;95%CI:0.05–0.98), but did not differ for the ADS cases vs controls or by DMD status for the MS cases (all p>0.1). Several of the butyrate-producing genera within the Clostridia class (Firmicutes phylum) —Ruminococcaceae UCG−003, Lachnospiraceae UCG−008 and UCG−004—exhibited similar patterns.

Conclusions

Gut microbiota diversity was similar for individuals with pediatric MS relative to either monophasic ADS or unaffected controls. However, at the taxa-level, differences were observed which differentiated the MS cases from the monophasic ADS cases and controls.

Background

Over 2 years in the CARE-MS trials (NCT00530348; NCT00548405), alemtuzumab (12 mg/day; baseline (BL): 5 days; 12 months later: 3 days) significantly improved clinical and MRI outcomes versus subcutaneous interferon beta-1a (SC IFNB-1a) in relapsing-remitting multiple sclerosis patients. Alemtuzumab efficacy was maintained through a 4-year extension study (NCT00930553), wherein patients could receive additional 3-day courses (≥12 months apart, as needed for disease activity) or receive other disease-modifying therapy per investigator’s discretion.

Objectives

To evaluate post hoc the effects of alemtuzumab on brain atrophy over 6 years in CARE-MS patients without relapses and MRI disease activity.

Methods

Analysis included pooled CARE-MS patients with or without disease activity between BL and Year 1 or BL and Year 2. Absence of disease activity was defined as no BL gadolinium (Gd)-enhancing T1 lesions and no clinical relapses or MRI disease activity (new Gd-enhancing or new/enlarging T2 lesions) from Years 0-1 or Years 0-2 (Definition 1). A second definition had the additional criterion of no relapse within 60 days before BL (Definition 2). Brain atrophy was measured by brain parenchymal fraction (BPF); differences in the median annualized percent change in BPF were assessed using ranked ANCOVA adjusted for region and BL BPF.

Results

Compared with SC IFNB-1a, alemtuzumab reduced median annualized percent change in BPF in patients free of disease activity during Years 0-1 (Definition 1: -0.37% vs -0.61%, P=0.006; Definition 2: -0.36% vs -0.54%, P=0.024) or Years 0-2 (Definition 1: -0.27% vs -0.44%, P=0.014; Definition 2: -0.28% vs -0.41%, P=0.045). Median annualized percent change in BPF was reduced with alemtuzumab versus SC IFNB-1a in patients with disease activity in Years 0-1 (-0.61% vs -0.79%, P=0.005) or Years 0-2 (-0.40% vs -0.56%, P<0.0001). Over 6 years, brain volume loss (BVL) was slower in patients without disease activity who initiated alemtuzumab at core study BL (-1.66%) than in those who received SC IFNB-1a in the core studies and initiated alemtuzumab in the extension (-2.05%).

Conclusions

Brain atrophy was reduced with alemtuzumab compared with SC IFNB-1a in patients without disease activity over 2 years. A slower rate of BVL was maintained through Year 6 in patients without disease activity who received alemtuzumab in the core study compared with SC IFNB-1a, suggesting alemtuzumab may slow neurodegeneration associated with BVL.

STUDY SUPPORT: Sanofi.

Background

Diroximel fumarate (DRF) is a novel oral fumarate approved in the United States for relapsing forms of multiple sclerosis (MS). DRF undergoes pre-systemic hydrolysis to monomethyl fumarate (MMF), the same pharmacologically active metabolite as dimethyl fumarate (DMF). DRF 462 mg and DMF 240 mg produce bioequivalent exposure of MMF and are expected to have similar efficacy and safety profiles. In DMF-treated patients, annual rates of brain volume loss over 6 years ranged from -0.19 to -0.37, approaching rates observed in healthy adults (-0.1% to -0.3%).

Objectives

To report percent brain volume change (PBVC) and impact on disability in patients from EVOLVE-MS-1 who have received DRF treatment for up to 2 years.

Methods

EVOLVE-MS-1 (NCT02634307) is an ongoing, open-label, phase 3 study to assess the long-term safety, tolerability, and efficacy of DRF 462 mg over 96 weeks in adults with relapsing-remitting MS. Normalized brain volume was assessed at baseline and used to calculate PBVC at Weeks 48 and 96. Confirmed Disability progression (CDP) was measured using the Expanded Disability Status Scale (≥1.5-, ≥1.0-, or ≥0.5-point increase from a baseline score of 0, 1.0-5.5, or 6.0, respectively), with changes sustained for 12 weeks. Estimated proportion of patients with CDP was calculated by the Kaplan-Meier method. No evidence of disease activity (NEDA)-3 was defined as no relapses, no 12-week CDP, and no new/enlarging T2 or new gadolinium-enhancing lesions. This post hoc analysis was conducted in a subgroup of patients who had brain volume scan measurements at baseline, Week 48, and Week 96. The Week 48 and Week 96 visits occurred within an analysis window of ±12 weeks.

Results

As of 2 July 2019, a total of 1051 patients were enrolled in EVOLVE-MS-1 and 365 patients were included in this analysis. Median (range) exposure was 96 (75-100) weeks. Mean (SD) PBVC was -0.36 (0.60) from baseline to Week 48 and -0.35 (0.55) from Week 48 to Week 96. Estimated proportion of patients who were free of CDP was 94.3% at Week 48 and 90.7% at Week 96. The proportion of patients with NEDA-3 at Week 48 and Week 96 was 44.7% (163/365) and 25.2% (91/361), respectively.

Conclusions

Interim findings from the ongoing EVOLVE-MS-1 study demonstrate that yearly PBVC in DRF-treated patients approached the rate observed in healthy adults and was consistent with previous studies of DMF. Most patients remained free of CDP at 2 years.

Supported by: Biogen