A. Bar-Or
Center for Neuroinflammation and Experimental Therapeutics, Perelman School of Medicine, University of Pennsylvania NeurologyAuthor Of 5 Presentations
FC02.05 - Safety and Efficacy in Patients Treated With Dimethyl Fumarate and Followed For 13 Years: Final Results of ENDORSE
Abstract
Background
DMF is a well-established therapy for relapsing forms of multiple sclerosis (RMS); data from ENDORSE, an extension to phase 3 studies DEFINE and CONFIRM, has enabled >10 years follow-up.
Objectives
We report safety/efficacy of DMF in patients with RMS treated with DMF and followed for 13 years in ENDORSE (NCT00835770) (2 years DEFINE/CONFIRM, and >10 years ENDORSE).
Methods
Incidence of serious AEs (SAEs), discontinuations due to AEs, annualized relapse rate (ARR) and Expanded Disability Status Scale (EDSS) score were assessed. Patients were treated with DMF 240 mg BID: placebo (PBO)/DMF (PBO, years 0–2 /DMF, years 3–10) or continuously (DMF/DMF). Efficacy outcomes were assessed in patients up to 10 years due to sample size considerations. For lymphocyte analysis, data from first DMF exposure were analysed for patients in DEFINE/CONFIRM/ENDORSE.
Results
At 23 January 2020, 1736 patients enrolled/received ≥1 dose DMF. Of 1736 patients, 760 completed. Patients were followed for a median (min,max) of 6.76(0.04,10.98) years in ENDORSE, and 2 years in DEFINE/CONFIRM. Overall, 551 (32%) patients experienced SAEs; most were MS relapse and fall. There was one case of PML in this study. There was no increased incidence of other infections or serious infections. Sixteen percent (n=282) patients discontinued due to AEs; 2% relapse, 2% disease progression, and 4% GI disorders. ALC decreased over the first 48 weeks, and then remained generally stable for the majority of the study. The proportion of patients with other AEs of special interest (including opportunistic infection, malignancy, and serious herpes zoster) was similar regardless of ALC. For patients continuously treated (n=501), overall ARR remained low (0.141[95% CI, 0.119,0.167]), while for PBO/DMF patients (n=249) ARR decreased after initiating DMF (ARR 0–2 years, 0.330[95% CI, 0.266,0.408]; ARR overall, 0.149[95% CI, 0.116,0.190]). Overall, 60% of DMF/DMF and 66% of PBO/DMF patients remained relapse-free; 20% and 17% of patients had 1 relapse, respectively. Walking abilities were maintained throughout the study; the number of patients with EDSS scores ≤3.5 was 413/479(86%) DMF/DMF (179/217[82%] PBO/DMF) at Year 2, and 173/226(77%) DMF/DMF (67/90[74%] PBO/DMF) at Year 10. Seventy-two percent and 73% of DMF/DMF and PBO/DMF patients, respectively, had no 24-week confirmed disability progression over 10 years.
Conclusions
These safety and efficacy data in patients followed for 13 years, support DMF as a long-term option for patients with RMS.
FC03.05 - Reduced thalamic atrophy in patients initiating earlier versus delayed ocrelizumab therapy: results from the OLE of OPERA I/II and ORATORIO
Abstract
Background
In multiple sclerosis (MS), thalamic integrity is affected both directly by demyelination, neuronal loss and increasing iron concentration, and indirectly by remote gray and white matter lesions affecting neural projections into and out of the thalamus. Thalamic atrophy may therefore reflect a large fraction of MS-related brain damage and thus represent a useful marker of overall damage and therapeutic efficacy.
Objectives
To assess the efficacy of ocrelizumab (OCR) in patients switching to or maintaining OCR therapy on thalamic atrophy in patients with relapsing MS (RMS) and primary progressive MS (PPMS), participating in the OPERA I/II (NCT01247324/NCT01412333) and ORATORIO (NCT01194570) Phase III trials, respectively.
Methods
At the end of the double-blind controlled treatment period in OPERA I/II, patients entered the open‑label extension (OLE), and either continued to receive OCR (OCR-OCR) or switched from interferon β-1a (IFN β-1a) to OCR (IFN β-1a-OCR). In ORATORIO, patients entered the OLE ~3–9 months after the double-blind period cut-off and either continued OCR (OCR-OCR) or switched from placebo (PBO) to OCR (PBO-OCR). Changes in thalamic volume from the core trial baseline were computed using Jacobian integration and analyzed using a mixed-effect repeated measurement model, adjusted for baseline volume, age, baseline gadolinium-enhancing lesions (presence/absence), baseline T2 lesion volume, region (US vs rest of the world), Expanded Disability Status Scale category (<4, ≥4), week, treatment, treatment and time interaction, and treatment and baseline volume interaction.
Results
In the OLE of OPERA I/II, changes (%) in thalamic volume from baseline at OLE Week 46, 94, 142, 190, and 238, were: –2.88/–2.12 (p<0.001), –3.31/–2.36 (p<0.001), –3.61/–2.78 (p<0.001), –3.68/–3.03 (p<0.001), and –4.07/–3.41 (p<0.001), for IFN β-1a-OCR/OCR-OCR patients, respectively. During the OLE of ORATORIO, changes in thalamic volume at OLE Day 1, Week 48, 96, and 144, were: –3.46/–2.44 (p<0.001), –3.93/–2.61 (p<0.001), –4.30/–3.25 (p<0.001), and –4.86/–3.62 (p<0.001), for PBO-OCR/OCR-OCR patients, respectively.
Conclusions
In the OLE, patients with RMS and PPMS who were initially randomized to ocrelizumab experienced less thalamic volume loss compared with those initiating ocrelizumab later.
PS07.04 - Fibre-specific white matter differences in children with pediatric acquired demyelinating syndromes compared to healthy children
Abstract
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.
PS10.03 - Functional survey of the pediatric multiple sclerosis microbiome
Abstract
Background
Metagenomic sequencing reveals the functional potential of the gut microbiome, and may explain how the gut microbiome influences pediatric-onset multiple sclerosis (MS) risk.
Objectives
To examine the gut microbiome functional potential by metagenomic analysis of stool samples from pediatric MS cases and controls using a case-control design.
Methods
Persons ≤21 years old enrolled in the Canadian Pediatric Demyelinating Disease Network who provided a stool sample and were not exposed to antibiotics or corticosteroids 30 days prior were included for study. All MS cases met McDonald criteria, had symptom onset <18 years of age and had either no prior disease-modifying drug (DMD) exposure or were exposed to beta-interferon or glatiramer acetate only. Twenty MS cases were matched to 20 non-affected controls by sex, age (± 3 years), stool consistency (Bristol Stool Scale, BSS) and, when possible, by race. Shotgun metagenomic reads were generated using the Illumina NextSeq platform and assembled using MEGAHIT. Metabolic pathway analysis was used to compare the gut microbiome between cases and controls, as well as cases by DMD status (DMD naïve vs DMD exposed MS cases vs controls). Gene ontology classifications were used to assess α-diversity and differential abundance analyses (based on the negative binomial distribution) reported as age-adjusted log-fold change (LFC) in relative abundance, 95% confidence intervals (CI), and false discovery rate adjusted p-values.
Results
The MS cases were aged 13.6 mean years at symptom onset. On average, MS cases and controls were 16.1 and 15.4 years old at the time of stool collection and 80% of each group were girls. MS cases and controls were similar for body mass index (median: 22.8 and 21.0, respectively), stool consistency (BSS types 1-2: n=4, types 3-5: n=16, for both MS and controls) and race (Caucasian: 11 and 9, respectively). Eight MS cases were DMD naïve. Richness of gene ontology classifications did not differ by disease status or DMD status (all p>0.4). However, differential analysis of metabolic pathways indicated that the relative abundance of tryptophan degradation (via the kynurenine pathway; LFC 13; 95%CI: 8–19; p<0.0005) and cresol degradation (LFC 19; 95%CI: 13–25; p<0.0001) pathways were enriched for MS cases vs controls. Differences by DMD status were also observed, e.g., choline biosynthesis was enriched in DMD exposed vs naïve MS cases (LFC 21; 95%CI: 12–29; p<0.0001).
Conclusions
We observed differences in the functional potential of the gut microbiome of young individuals with MS relative to controls at various metabolic pathways, including enrichment of pathways related to tryptophan and metabolism of industrial chemicals. DMD exposure affected findings, with enrichment of pathways involved in promoting CNS remyelination (e.g., choline).
YI01.02 - BTK inhibition results in preferential reduction of pro-inflammatory B-cell responses through modulation of B-cell metabolism
Abstract
Background
Results of B-cell depleting therapies have underscored important antibody-independent functions of B cells in multiple sclerosis (MS) pathogenesis. Bruton’s Tyrosine Kinase (BTK) is a key down-stream signaling molecule of the B cell receptor, and BTK inhibitors (BTKi) have been used for treating various B-cell malignancies. BTKi are now being pursued as a ‘next generation’ non-depleting approach to B-cell targeting in MS. However, the contributions of BTK to MS-relevant functional B-cell responses, and the impact of BTKi on such responses, remain largely unknown.
Objectives
We would like to assess the impact of BTK inhibition on MS implicated B-cell functions and explore underlying mechanisms.
Methods
We applied a series of functional assays and RNA sequencing to human B cells, isolated from peripheral blood of healthy individuals or MS patients, as well as from human tonsils, to study influence of BTKi on B-cell survival, activation, proliferation, antibody production, antigen presenting functions, cytokine production and metabolism.
Results
As expected, BTKi strongly decreased B-cell activation with minimal effects on B cell survival. BTKi also significantly limited the induction of co-stimulatory molecules (CD80, CD86) expression on activated B cells, which in turn resulted in a decreased capacity of the B cells to support both polyclonal as well as antigen-specific T-cell activation. Interestingly, BTKi treatment preferentially reduced pro-inflammatory B-cell cytokine (GM-CSF, TNFα and IL-6) secretion with only marginal influence on B-cell IL-10 production, resulting in a decreased capacity of the B cells to promote myeloid cell pro-inflammatory responses. Unbiased transcriptomic analysis of either vehicle- or BTKi-treated B cells suggested that BTKi could limit metabolism-related pathways, and subsequent seahorse analyzer experiments confirmed that BTKi decreased B-cell mitochondrial respiration and glycolysis. Metabolic manipulation further revealed that the level of mitochondrial respiration could control the balance between pro- and anti-inflammatory B cell responses.
Conclusions
BTKi preferentially limits pro-inflammatory B-cell responses that are implicated in MS pathophysiology. Our study also reveals a fundamental role for metabolism in regulating B-cell functions, and points to a novel therapeutic strategy targeting the balance between pro- and anti-inflammatory responses of B cells through modulation of their energy-utilization pathways.