Background:
Dimethyl fumarate (DMF) demonstrated favorable benefit–risk in relapsing-remitting multiple sclerosis (RRMS) patients in phase-III DEFINE and CONFIRM trials, and ENDORSE extension.
...Objective:
The main aim of this study is assessing DMF safety/efficacy up to 13 years in ENDORSE.
Methods:
Randomized patients received DMF 240 mg twice daily or placebo (PBO; Years 0–2), then DMF (Years 3–10; continuous DMF/DMF or PBO/DMF); maximum follow-up (combined studies), 13 years.
Results:
By January 2020, 1736 patients enrolled/dosed in ENDORSE (median follow-up 8.76 years (ENDORSE range: 0.04–10.98) in DEFINE/CONFIRM and ENDORSE); 52% treated in ENDORSE for ⩾6 years. Overall, 551 (32%) patients experienced serious adverse events (mostly multiple sclerosis (MS) relapse or fall; one progressive multifocal leukoencephalopathy); 243 (14%) discontinued treatment due to adverse events (4% gastrointestinal (GI) disorders). Rare opportunistic infections, malignancies, and serious herpes zoster occurred, irrespective of lymphocyte count. For DMF/DMF (n = 501), overall annualized relapse rate (ARR) remained low (0.143 (95% confidence interval (CI), 0.120–0.169)), while for PBO/DMF (n = 249), ARR decreased after initiating DMF and remained low throughout (ARR 0–2 years, 0.330 (95% CI, 0.266–0.408); overall ARR (ENDORSE, 0.151 (95% CI, 0.118–0.194)). Over 10 years, 72% DMF/DMF and 73% PBO/DMF had no 24-week confirmed disability worsening.
Conclusion:
Sustained DMF safety/efficacy was observed in patients followed up to 13 years, supporting DMF’s positive benefit/risk profile for long-term RRMS treatment.
OBJECTIVE:To evaluate 5-year efficacy and safety of alemtuzumab in treatment-naive patients with active relapsing-remitting MS (RRMS) (CARE-MS I; NCT00530348).
METHODS:Alemtuzumab-treated patients ...received treatment courses at baseline and 12 months later; after the core study, they could enter an extension (NCT00930553) with as-needed alemtuzumab retreatment for relapse or MRI activity. Assessments included annualized relapse rate (ARR), 6-month confirmed disability worsening (CDW; ≥1-point Expanded Disability Status Scale EDSS score increase ≥1.5 if baseline EDSS = 0), 6-month confirmed disability improvement (CDI; ≥1-point EDSS decrease baseline score ≥2.0), no evidence of disease activity (NEDA), brain volume loss (BVL), and adverse events (AEs).
RESULTS:Most alemtuzumab-treated patients (95.1%) completing CARE-MS I enrolled in the extension; 68.5% received no additional alemtuzumab treatment. ARR remained low in years 3, 4, and 5 (0.19, 0.14, and 0.15). Over years 0–5, 79.7% were free of 6-month CDW; 33.4% achieved 6-month CDI. Most patients (61.7%, 60.2%, and 62.4%) had NEDA in years 3, 4, and 5. Median yearly BVL improved over years 2–4, remaining low in year 5 (years 1–5−0.59%, −0.25%, −0.19%, −0.15%, and −0.20%). Exposure-adjusted incidence rates of most AEs declined in the extension relative to the core study. Thyroid disorder incidences peaked at year 3 and subsequently declined.
CONCLUSIONS:Based on these data, alemtuzumab provides durable efficacy through 5 years in the absence of continuous treatment, with most patients not receiving additional courses.
CLINICALTRIALS.GOV IDENTIFIER:NCT00530348; NCT00930553.
CLASSIFICATION OF EVIDENCE:This study provides Class III evidence that alemtuzumab durably improves efficacy outcomes and slows BVL in patients with RRMS.This is an open access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivatives License 4.0 (CC BY-NC-ND), which permits downloading and sharing the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal.
In conventional non-quantitative magnetic resonance imaging, image contrast is consistent within images, but absolute intensity can vary arbitrarily between scans. For quantitative analysis of ...intensity data, images are typically normalized to a consistent reference. The most convenient reference is a tissue that is always present in the image, and is unlikely to be affected by pathological processes. In multiple sclerosis neuroimaging, both the white and gray matter are affected, so normalization techniques that depend on brain tissue may introduce bias or remove biological changes of interest. We introduce a complementary procedure, image “calibration,” the goal of which is to remove technical intensity artifacts while preserving biological differences. We demonstrate a deep learning approach to segmenting fat from within the orbit of the eyes on T1-weighted images at 1.5 and 3 T to use as a reference tissue, and use it to calibrate 1018 scans from 256 participants in a study of pediatric-onset multiple sclerosis. The machine segmentations agreed with the adjudicating expert (DF) segmentations better than did those of other expert humans, and calibration resulted in better agreement with semi-quantitative magnetization transfer ratio imaging than did normalization with the WhiteStripe1 algorithm. We suggest that our method addresses two key priorities in the field: (1) it provides a robust option for serial calibration of conventional scans, allowing comparison of disease change in persons imaged at multiple time points in their disease; and (ii) the technique is fast, as the deep learning segmentation takes only 0.5 s/scan, which is feasible for both large and small datasets.
•Deep learning model for segmenting orbital fat from T1-weighted MRI.•Segmentation performs as well as expert human raters.•Orbital fat segmentations used to produce “calibrated” images with longitudinally consistent contrast.•Comparison of scan calibration to WhiteStripe, a scan normalization technique.
Tolebrutinib is an oral, CNS-penetrant, irreversible inhibitor of Bruton’s tyrosine kinase, an enzyme expressed in B lymphocytes and myeloid cells including microglia, which are major drivers of ...inflammation in multiple sclerosis. We aimed to determine the dose-response relationship between tolebrutinib and the reduction in new active brain MRI lesions in patients with relapsing multiple sclerosis.
We did a 16-week, phase 2b, randomised, double-blind, placebo-controlled, crossover, dose-finding trial at 40 centres (academic sites, specialty clinics, and general neurology centres) in ten countries in Europe and North America. Eligible participants were adults aged 18–55 years with diagnosed relapsing multiple sclerosis (either relapsing-remitting or relapsing secondary progressive multiple sclerosis), and one or more of the following criteria: at least one relapse within the previous year, at least two relapses within the previous 2 years, or at least one active gadolinium-enhancing brain lesion in the 6 months before screening. Exclusion criteria included a diagnosis of primary progressive multiple sclerosis or a diagnosis of secondary progressive multiple sclerosis without relapse. We used a two-step randomisation process to randomly assign eligible participants (1:1) to two cohorts, then further randomly assign participants in each cohort (1:1:1:1) to four tolebrutinib dose groups (5, 15, 30, and 60 mg administered once daily as an oral tablet). Cohort 1 received tolebrutinib for 12 weeks, then matched placebo (ie, identical looking tablets) for 4 weeks; cohort 2 received 4 weeks of placebo followed by 12 weeks of tolebrutinib. Participants and investigators were masked for dose and tolebrutinib-placebo administration sequence; investigators, study team members, and study participants did not have access to unmasked data. MRI scans were done at screening and every 4 weeks over 16 weeks. The primary efficacy endpoint was the number of new gadolinium-enhancing lesions detected on the scan done after 12 weeks of tolebrutinib treatment (assessed at week 12 for cohort 1 and week 16 for cohort 2), relative to the scan done 4 weeks previously, and compared with the lesions accumulated during 4 weeks of placebo run-in period in cohort 2. Efficacy data were analysed in a modified intention-to-treat population, using a two-step multiple comparison procedure with modelling analysis. Safety was assessed for all participants who received at least one dose of study drug. This trial is registered with ClinicalTrials.gov (NCT03889639), EudraCT (2018-003927-12), and WHO (U1111-1220-0572), and has been completed.
Between May 14, 2019, and Jan 2, 2020, we enrolled and randomly assigned 130 participants to tolebrutinib: 33 to 5 mg, 32 to 15 mg, 33 to 30 mg, and 32 to 60 mg. 129 (99%) completed the treatment regimen and 126 were included in the primary analysis. At treatment week 12, there was a dose-dependent reduction in the number of new gadolinium-enhancing lesions (mean SD lesions per patient: placebo, 1·03 2·50; 5 mg, 1·39 3·20; 15 mg, 0·77 1·48; 30 mg, 0·76 3·31; 60 mg, 0·13 0·43; p=0·03). One serious adverse event was reported (one patient in the 60 mg group was admitted to hospital because of a multiple sclerosis relapse). The most common non-serious adverse event during tolebrutinib treatment was headache (in one 3% of 33 in the 5 mg group; three 9% of 32 in the 15 mg group; one 3% of 33 in the 30 mg group; and four 13% of 32 in the 60 mg group). No safety-related discontinuations or treatment-related deaths occurred.
12 weeks of tolebrutinib treatment led to a dose-dependent reduction in new gadolinium-enhancing lesions, the 60 mg dose being the most efficacious, and the drug was well tolerated. Reduction of acute inflammation, combined with the potential to modulate the immune response within the CNS, provides a scientific rationale to pursue phase 3 clinical trials of tolebrutinib in patients with relapsing and progressive forms of multiple sclerosis.
Sanofi.
Summary Background Patients with multiple sclerosis, a chronic inflammatory demyelinating disease of the central nervous system with autoimmune pathogenesis, have shown partial response to a number ...of immunomodulating treatments, but the search for more effective, safe, and convenient therapeutic options continues. Amiselimod is an oral selective modulator of sphingosine 1-phosphate 1 (S1P1 ) receptor, which is being developed for the treatment of various autoimmune-mediated diseases. We assessed the safety and efficacy of amiselimod in patients with relapsing– remitting multiple sclerosis. Methods In this double-blind phase 2 trial, patients aged 18–60 years with active relapsing–remitting multiple sclerosis from 84 centres in Europe and Canada were randomly assigned (1:1:1:1) with an interactive web-response system to receive once daily oral amiselimod 0·1 mg, 0·2 mg, 0·4 mg, or placebo for 24 weeks. All study personnel, site personnel, investigators, and patients were masked to the treatment assignment during the study. The primary endpoint was the total number of gadolinium-enhanced T1-weighted lesions on monthly brain MRI scans from weeks 8 to 24. Analysis was done on the predefined evaluable population (all randomised patients who did not have any major protocol deviations, completed 24 weeks of treatment as planned, and had at least three valid post-dose MRI scans). This trial is registered with ClinicalTrials.gov , number NCT01742052. Findings Between Jan 31, 2013, and Dec 24, 2013, 536 patients were screened and 415 patients randomly assigned to amiselimod 0·1 mg (n=105), 0·2 mg (n=103), 0·4 mg (n=104), or placebo (n=103). The median total number of gadolinium-enhanced T1-weighted lesions from weeks 8 to 24 did not differ between the amiselimod 0·1 mg and placebo groups (median 1·6 lesions range 0–132 in the placebo group vs 2·0 0–105 in the 0·1 mg group median difference 0·0, 95% CI −1·0 to 0·0, p=0·7517), but was significantly lower in the two higher amiselimod dose groups than in the placebo group (0·0 lesions range 0–35 in the 0·2 mg group median difference vs placebo −1·0, 95% CI −1·0 to 0·0, p=0·0021 and 0·0 range 0–30 in the 0·4 mg group –1·0, −1·2 to 0·0, p=0·0003). The estimated incident rate ratio compared with placebo was dose-dependently decreased with amiselimod (0·1 mg 0·53 95% CI 0·33–0·85; p=0·0079, 0·2 mg 0·39 95% CI 0·24–0·63; p=0·0001, and 0·4 mg 0·23 95% CI 0·14–0·38; p<0·0001). The incidence of treatment-emergent adverse events, including infections and cardiac disorders, were similar in the amiselimod treatment groups (59 56% of 105 patients in the 0·1 mg group, 69 67% of 103 in the 0·2 mg group, and 58 56% of 104 in the 0·4 mg group) to the incidence in the placebo group (66 64% of 103 patients); the most common treatment-emergent adverse events were headache (ten 10%, ten 10%, and ten 10% vs four 4%) and nasopharyngitis (nine 9%, seven 7%, ten 10% vs eight 8%). No serious treatment-emergent adverse event was reported for more than one patient in any group and no clinically significant heart rate reduction was observed at any amiselimod dose. Interpretation Amiselimod 0·2 mg and 0·4 mg significantly reduced the total number of gadolinium-enhanced T1-weighted lesions. The safety and efficacy profiles of amiselimod suggest that this S1P1 receptor modulator is a new potential treatment in multiple sclerosis and potentially other immune-mediated inflammatory diseases and deserves further investigation. Funding Mitsubishi Tanabe Pharma Corporation.
In this phase 2 trial involving 104 patients with relapsing–remitting multiple sclerosis, patients who received rituximab on days 1 and 15 had fewer gadolinium-enhancing lesions on magnetic resonance ...imaging and fewer relapses during 48 weeks of follow-up than patients who received placebo. Rituximab was associated with more adverse events within 24 hours after the first infusion. The study was too small and short to assess uncommon adverse events or long-term safety.
Patients with relapsing–remitting multiple sclerosis who received rituximab on days 1 and 15 had fewer gadolinium-enhancing lesions on MRI and fewer relapses during 48 weeks of follow-up than patients who received placebo.
Multiple sclerosis, the prototypical inflammatory demyelinating disease of the central nervous system, is second only to trauma as a cause of acquired neurologic disability in young adults.
1
Multiple sclerosis usually begins as a relapsing, episodic disorder (relapsing–remitting multiple sclerosis), evolving into a chronic neurodegenerative condition characterized by progressive neurologic disability.
2
The traditional view of the pathophysiology of multiple sclerosis has held that inflammation is principally mediated by CD4+ type 1 helper T cells. Therapies (e.g., interferon beta and glatiramer acetate) developed on the basis of this theory decrease the relapse rate by approximately one third
3
,
4
but do not fully . . .
Objective
To define changes in phenotype and functional responses of reconstituting T cells in patients with aggressive multiple sclerosis (MS) treated with ablative chemotherapy and autologous ...hematopoietic stem cell transplantation (HSCT).
Methods
Clinical and brain magnetic resonance imaging measures of disease activity were monitored serially in patients participating in the Canadian MS HSCT Study. Reconstitution kinetics of immune‐cell subsets were determined by flow cytometry, whereas thymic function was assessed using T‐cell receptor excision circle analyses as well as flow cytometry measurements of CD31+ recent thymic emigrants (RTEs). Functional assays were performed to track central nervous system–autoreactive antigen‐specific T‐cell responses, and the relative capacity to generate Th1, Th17, or Th1/17 T‐cell responses.
Results
Complete abrogation of new clinical relapses and new focal inflammatory brain lesions throughout the 2 years of immune monitoring following treatment was associated with sustained decrease in naive T cells, in spite of restoration of both thymic function and release of RTEs during reconstitution. Re‐emergence as well as in vivo expansion of autoreactive T cells to multiple myelin targets was evident in all patients studied. The reconstituted myelin‐specific T cells exhibited the same Th1 and Th2 responses as preablation myelin‐reactive T cells. In contrast, the post‐therapy T‐cell repertoire exhibited a significantly diminished capacity for Th17 responses.
Interpretation
Our results indicate that diminished Th17 and Th1/17 responses, rather than Th1 responses, are particularly relevant to the abrogation of new relapsing disease activity observed in this cohort of patients with aggressive MS following chemoablation and HSCT. ANN NEUROL 2013;73:341–354
Diffusely abnormal white matter (DAWM), characterised by biochemical changes of myelin in the absence of frank demyelination, has been associated with clinical progression in secondary progressive MS ...(SPMS). However, little is known about changes of DAWM over time and their relation to focal white matter lesions (FWML). The objectives of this work were: 1) To characterize the longitudinal evolution of FWML, DAWM, and DAWM that transforms into FWML, and 2) To determine whether gadolinium enhancement, known to be associated with the development of new FWML, is also related to DAWM voxels that transform into FWML. Our data included 4220 MRI scans of 689 SPMS participants, followed for 156 weeks and 2677 scans of 686 RRMS participants, followed for 96 weeks. FWML and DAWM were segmented using a previously validated, automatic thresholding technique based on normalized T2 intensity values. Using longitudinally registered images, DAWM voxels at each visit that transformed into FWML on the last MRI scan as well as their overlap with gadolinium enhancing lesion masks were identified. Our results showed that the average yearly rate of conversion of DAWM-to-FWML was 1.27 cc for SPMS and 0.80 cc for RRMS. FWML in SPMS participants significantly increased (t = 3.9; p = 0.0001) while DAWM significantly decreased (t = -4.3 p < 0.0001) and the ratio FWML:DAWM increased (t = 12.7; p < 0.00001). RRMS participants also showed an increase in the FWML:DAWM Ratio (t = 6.9; p < 0.00001) but without a significant change of the individual volumes. Gadolinium enhancement was associated with 7.3% and 18.7% of focal New T2 lesion formation in the infrequent scans of the RRMS and SPMS cohorts, respectively. In comparison, only 0.1% and 0.0% of DAWM-to-FWML voxels overlapped with gadolinium enhancement. We conclude that DAWM transforms into FWML over time, in both RRMS and SPMS. DAWM appears to represent a form of pre-lesional pathology that contributes to T2 lesion volume increase over time, independent of new focal inflammation and gadolinium enhancement.
We demonstrate a new technique to quantify longitudinal changes in magnetization transfer ratio (MTR) magnetic resonance imaging (MRI). These changes are indicative of demyelination and ...remyelination. This technique comprises a definition of ΔMTR lesions, which are identified directly from the MTR images, and an automatic procedure for segmenting these lesions. We used this technique to analyze MTR changes in lesions of subjects with rapidly progressing multiple sclerosis before and after treatment with immunoablation and autologous stem cell transplant. Subjects who experienced clinical improvement after treatment showed significantly improved MTR recovery in lesions that were recovering during treatment (p<0.0001) while those who were clinically stable after treatment showed significantly poorer MTR recovery (p=0.002). The statistical power of this technique to detect treatment effects on MTR recovery was shown to be considerably better than previous methods. These results suggest that longitudinal measurements of MTR in ΔMTR lesions may be an important technique for the assessment of treatment effects on remyelination in clinical trials.
White matter plasticity likely plays a critical role in supporting cognitive development. However, few studies have used the imaging methods specific to white matter tissue structure or experimental ...designs sensitive to change in white matter necessary to elucidate these relations. Here we briefly review novel imaging approaches that provide more specific information regarding white matter microstructure. Furthermore, we highlight recent studies that provide greater clarity regarding the relations between changes in white matter and cognition maturation in both healthy children and adolescents and those with white matter insult. Finally, we examine the hypothesis that white matter is linked to cognitive function via its impact on neural synchronization. We test this hypothesis in a population of children and adolescents with recurrent demyelinating syndromes. Specifically, we evaluate group differences in white matter microstructure within the optic radiation; and neural phase synchrony in visual cortex during a visual task between 25 patients and 28 typically developing age‐matched controls. Children and adolescents with demyelinating syndromes show evidence of myelin and axonal compromise and this compromise predicts reduced phase synchrony during a visual task compared to typically developing controls. We investigate one plausible mechanism at play in this relationship using a computational model of gamma generation in early visual cortical areas. Overall, our findings show a fundamental connection between white matter microstructure and neural synchronization that may be critical for cognitive processing. In the future, longitudinal or interventional studies can build upon our knowledge of these exciting relations between white matter, neural communication, and cognition.
Main Points
New imaging tools can characterize white matter plasticity and cognitive development.
White matter maturation predicts cognitive development.
In pediatric demyelinating disorders, white matter compromise predicts disrupted neural communication.
PDF
