Brain volume increase after discontinuing natalizumab therapy: Evidence for reversible pseudoatrophy.

BACKGROUND: The phenomenon of pseudoatropy after initiation of anti-inflammatory therapy is believed to be reversible, but a rebound in brain volume following cessation of highly-effective therapy has not been reported. OBJECTIVES: To evaluate brain volume change in a treatment interruption study (RESTORE) in which relapsing-remitting multiple sclerosis (RRMS) patients were randomized to switch from natalizumab to placebo, from natalizumab to once-monthly intravenous methylprednisolone (IVMP), or to remain on natalizumab. METHODS: T2 lesion volume (T2LV), baseline normalized brain volumes, and follow-up percent brain volume changes (PBVC) were calculated. Approximate T2 relaxation-time (pT2) was calculated within the brain mask and the T2 lesions to estimate changes in water content. Linear mixed effects models were used to detect differences in T2LV, pT2 in whole brain, pT2 in T2-weighted lesions, and PBVC among the placebo, natalizumab, and IVMP groups. We also estimated contributions of T2LV and pT2 (in whole brain and T2 lesions) to PBVC. RESULTS: T2LV increased in the placebo group (by 0.66 ml/year, p<0.0001) and IVMP (+1.98 ml/year, p = 0.05) groups relative to the natalizumab group. The rates of PBVC were significantly different: -0.239%/year with continued natalizumab and +0.126 %/year after switch to placebo (p = 0.03), while the IVMP group showed brain volume loss (-0.74 %/ year, p = 0.08). pT2 was not statistically different between the groups (p ≥ 0.29) and did not have significant effects on PBVC (p ≥ 0.25). CONCLUSION: The increase in the brain volume in patients witching from natalizumab to placebo is consistent with reversal of so-called pseudoatrophy after starting natalizumab.

Exploratory clinical efficacy and patient-reported outcomes from NOVA: A randomized controlled study of intravenous natalizumab 6-week dosing versus continued 4-week dosing for relapsing-remitting multiple sclerosis.

BACKGROUND: Natalizumab (TYSABRI®) 300 mg administered intravenously every-4-weeks (Q4W) is approved for treatment of relapsing-remitting multiple sclerosis but is associated with increased risk of progressive multifocal leukoencephalopathy (PML). Extended natalizumab dosing intervals of approximately every-6-weeks (Q6W) are associated with a lower risk of PML. Primary and secondary clinical outcomes from the NOVA randomized clinical trial (NCT03689972) suggest that effective disease control is maintained in patients who were stable during treatment with natalizumab Q4W for ≥12 months and who then switched to Q6W dosing. We compared additional exploratory clinical and patient-reported outcomes (PROs) from NOVA to assess the efficacy of Q6W dosing. METHODS: Prespecified exploratory clinical efficacy endpoints in NOVA included change from baseline in Expanded Disability Status Scale (EDSS) score, Timed 25-Foot Walk (T25FW), dominant- and nondominant-hand 9-Hole Peg Test (9HPT), and Symbol Digit Modalities Test (SDMT). Exploratory patient-reported outcome (PRO) efficacy endpoints included change from baseline in the Treatment Satisfaction Questionnaire for Medication (TSQM), Neuro-QoL fatigue questionnaire, Multiple Sclerosis Impact Scale (MSIS-29), EuroQol 5 Dimensions (EQ-5D-5 L) index score, Clinical Global Impression (CGI)-Improvement (patient- and clinician-assessed) and CGI-Severity (clinician-assessed) rating scales. Estimated proportions of patients with confirmed EDSS improvement were based on Kaplan-Meier methods. Estimates of mean treatment differences for Q6W versus Q4W in other outcomes were assessed by least squares mean (LSM) and analyzed using a linear mixed model of repeated measures or ordinal logistic regression (CGI-scale). RESULTS: Exploratory clinical and patient-reported outcomes were assessed in patients who received ≥1 dose of randomly assigned study treatment and had ≥1 postbaseline efficacy assessment (Q6W group, n = 247, and Q4W group, n = 242). Estimated proportions of patients with EDSS improvement at week 72 were similar for Q6W and Q4W groups (11.7% [19/163] vs 10.8% [17/158]; HR 1.02 [95% confidence interval [CI], 0.53-1.98]; P = 0.9501). At week 72, there were no significant differences between Q6W and Q4W groups in LSM change from baseline for T25FW (0.00, P = 0.975), 9HPT (dominant [0.22, P = 0.533] or nondominant [0.09, P = 0.862] hand), or SDMT (-1.03, P = 0.194). Similarly, there were no significant differences between Q6W and Q4W groups in LSM change from baseline for any PRO (TSQM, -1.00, P = 0.410; Neuro-QoL fatigue, 0.52, P = 0.292; MSIS-29 Psychological, 0.67, P = 0.572; MSIS-29 Physical, 0.74, P = 0.429; EQ-5D-5 L, 0.00, P = 0.978). For the EQ-5D-5 L, a higher proportion of Q6W patients than Q4W patients demonstrated worsening (≥0.5 standard deviation increase in the EQ-5D-5 L index score; P = 0.0475). From baseline to week 72 for Q6W versus Q4W, odds ratio (ORs) of LSM change in CGI scores did not show meaningful differences between groups (CGI-Improvement [patient]: OR [95% CI] 1.2 [0.80-1.73]; CGI-Improvement [physician]: 0.8 [0.47-1.36]; CGI-Severity [physician]: 1.0 [0.71-1.54]). CONCLUSIONS: No significant differences were observed in change from baseline to week 72 between natalizumab Q6W and Q4W groups for all exploratory clinical or PRO-related endpoints assessed. For the EQ-5D-5 L, a higher proportion of Q6W than Q4W patients demonstrated worsening.

Comparison of switching to 6-week dosing of natalizumab versus continuing with 4-week dosing in patients with relapsing-remitting multiple sclerosis (NOVA): a randomised, controlled, open-label, phase 3b trial.

BACKGROUND: Treatment with natalizumab once every 4 weeks is approved for patients with relapsing-remitting multiple sclerosis, but is associated with a risk of progressive multifocal leukoencephalopathy. Switching to extended-interval dosing is associated with lower progressive multifocal leukoencephalopathy risk, but the efficacy of this approach is unclear. We aimed to assess the safety and efficacy of natalizumab once every 6 weeks compared with once every 4 weeks in patients with relapsing-remitting multiple sclerosis. METHODS: We did a randomised, controlled, open-label, phase 3b trial (NOVA) at 89 multiple sclerosis centres across 11 countries in the Americas, Europe, and Western Pacific. Included participants were aged 18-60 years with relapsing-remitting multiple sclerosis and had been treated with intravenous natalizumab 300 mg once every 4 weeks with no relapses for at least 12 months before randomisation, with no missed doses in the previous 3 months. Participants were randomly assigned (1:1), using a randomisation sequence generated by the study funder and contract personnel with interactive response technology, to switch to natalizumab once every 6 weeks or continue with once every 4 weeks. The centralised MRI reader, independent neurology evaluation committee, site examining neurologists, site backup examining neurologists, and site examining technicians were masked to study group assignments. The primary endpoint was the number of new or newly enlarging T2 hyperintense lesions at week 72, assessed in all participants who received at least one dose of assigned treatment and had at least one postbaseline MRI, relapse, or neurological examination or efficacy assessment. Missing primary endpoint data were handled under prespecified primary and secondary estimands: the primary estimand included all data, regardless of whether participants remained on the assigned treatment; the secondary estimand classed all data obtained after treatment discontinuation or study withdrawal as missing. Safety was assessed in all participants who received at least one dose of study treatment. Study enrolment is closed and an open-label extension study is ongoing. This study is registered with EudraCT, 2018-002145-11, and ClinicalTrials.gov, NCT03689972. FINDINGS: Between Dec 26, 2018, and Aug 30, 2019, 605 patients were assessed for eligibility and 499 were enrolled and assigned to receive natalizumab once every 6 weeks (n=251) or once every 4 weeks (n=248). After prespecified adjustments for missing data, mean numbers of new or newly enlarging T2 hyperintense lesions at week 72 were 0·20 (95% CI 0·07-0·63) in the once every 6 weeks group and 0·05 (0·01-0·22) in the once every 4 weeks group (mean lesion ratio 4·24 [95% CI 0·86-20·85]; p=0·076) under the primary estimand, and 0·31 (95% CI 0·12-0·82) and 0·06 (0·01-0·31; mean lesion ratio 4·93 [95% CI 1·05-23·20]; p=0·044) under the secondary estimand. Two participants in the once every 6 weeks group with extreme new or newly enlarging T2 hyperintense lesion numbers (≥25) contributed most of the excess lesions. Adverse events occurred in 194 (78%) of 250 participants in the once every 6 weeks group and 190 (77%) of 247 in the once every 4 weeks group, and serious adverse events occurred in 17 (7%) and 17 (7%), respectively. No deaths were reported. There was one case of asymptomatic progressive multifocal leukoencephalopathy (without clinical signs) in the once every 6 weeks group, and no cases in the once every 4 weeks group; 6 months after diagnosis, the participant was without increased disability and remained classified as asymptomatic. INTERPRETATION: We found a numerical difference in the mean number of new or newly enlarging T2 hyperintense lesions at week 72 between the once every 6 weeks and once every 4 weeks groups, which reached significance under the secondary estimand, but interpretation of statistical differences (or absence thereof) is limited because disease activity in the once every 4 weeks group was lower than expected. The safety profiles of natalizumab once every 6 weeks and once every 4 weeks were similar. Although this trial was not powered to assess differences in risk of progressive multifocal leukoencephalopathy, the occurrence of the (asymptomatic) case underscores the importance of monitoring and risk factor consideration in all patients receiving natalizumab. FUNDING: Biogen.

Propagating Uncertainty Across Cascaded Medical Imaging Tasks for Improved Deep Learning Inference.

Although deep networks have been shown to perform very well on a variety of medical imaging tasks, inference in the presence of pathology presents several challenges to common models. These challenges impede the integration of deep learning models into real clinical workflows, where the customary process of cascading deterministic outputs from a sequence of image-based inference steps (e.g. registration, segmentation) generally leads to an accumulation of errors that impacts the accuracy of downstream inference tasks. In this paper, we propose that by embedding uncertainty estimates across cascaded inference tasks, performance on the downstream inference tasks should be improved. We demonstrate the effectiveness of the proposed approach in three different clinical contexts: (i) We demonstrate that by propagating T2 weighted lesion segmentation results and their associated uncertainties, subsequent T2 lesion detection performance is improved when evaluated on a proprietary large-scale, multi-site, clinical trial dataset acquired from patients with Multiple Sclerosis. (ii) We show an improvement in brain tumour segmentation performance when the uncertainty map associated with a synthesised missing MR volume is provided as an additional input to a follow-up brain tumour segmentation network, when evaluated on the publicly available BraTS-2018 dataset. (iii) We show that by propagating uncertainties from a voxel-level hippocampus segmentation task, the subsequent regression of the Alzheimer's disease clinical score is improved.

Long-term safety and efficacy of dimethyl fumarate for up to 13 years in patients with relapsing-remitting multiple sclerosis: Final ENDORSE study results.

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.

Assessing the differential sensitivities of wave-CAIPI ViSTa myelin water fraction and magnetization transfer saturation for efficiently quantifying tissue damage in MS.

BACKGROUND: Wave-CAIPI Visualization of Short Transverse relaxation time component (ViSTa) is a recently developed, short-T1-sensitized MRI method for fast quantification of myelin water fraction (MWF) in the human brain. It represents a promising technique for the evaluation of subtle, early signals of demyelination in the cerebral white matter of multiple sclerosis (MS) patients. Currently however, few studies exist that robustly assess the utility of ViSTa MWF measures of myelin compared to more conventional MRI measures of myelin in the brain of MS patients. Moreover, there are no previous studies evaluating the sensitivity of ViSTa MWF for the non-invasive detection of subtle tissue damage in both normal-appearing white matter (NAWM) and white matter lesions of MS patients. As a result, a central purpose of this study was to systematically evaluate the relationship between myelin sensitivity of T1-based ViSTa MWF mapping and a more generally recognized metric, Magnetization Transfer Saturation (MTsat), in healthy control and MS brain white matter. METHODS: ViSTa MWF and MTsat values were evaluated in automatically-classified normal appearing white matter (NAWM), white matter (WM) lesion tissue, cortical gray matter, and deep gray matter of 29 MS patients and 10 healthy controls using 3T MRI. MWF and MT sat were also assessed in a tract-specific manner using the Johns Hopkins University WM atlas. MRI-derived measures of cerebral myelin content were uniquely compared by employing non-normal distribution-specific measures of median, interquartile range and skewness. Separate analyses of variance were applied to test tissue-specific differences in MTsat and ViSTa MWF distribution metrics. Non-parametric tests were utilized when appropriate. All tests were corrected for multiple comparisons using the False Discovery Rate method at the level, α=0.05. RESULTS: Differences in whole NAWM MS tissue damage were detected with a higher effect size when using ViSTa MWF (q = 0.0008; ƞ2 = 0.34) compared to MTsat (q = 0.02; ƞ2= 0.24). We also observed that, as a possible measure of WM pathology, ViSTa-derived NAWM MWF voxel distributions of MS subjects were consistently skewed towards lower MWF values, while MTsat voxel distributions showed reduced skewness values. We further identified tract-specific reductions in mean ViSTa MWF of MS patients compared to controls that were not observed with MTsat. However, MTsat (q = 1.4 × 10-21; ƞ2 = 0.88) displayed higher effect sizes when differentiating NAWM and MS lesion tissue. Using regression analysis at the group level, we identified a linear relationship between MTsat and ViSTa MWF in NAWM (R2 = 0.46; p = 7.8 × 10-4) lesions (R2 = 0.30; p = 0.004), and with all tissue types combined (R2 = 0.71; p = 8.4 × 10-45). The linear relationship was also observed in most of the WM tracts we investigated. ViSTa MWF in NAWM of MS patients correlated with both disease duration (p = 0.02; R2 = 0.27) and WM lesion volume (p = 0.002; R2 = 0.34). CONCLUSION: Because ViSTa MWF and MTsat metrics exhibit differential sensitivities to tissue damage in MS white matter, they can be collected in combination to provide an efficient, comprehensive measure of myelin water and macromolecular pool proton signals. These complementary measures may offer a more sensitive, non-invasive biopsy of early precursor signals in NAWM that occur prior to lesion formation. They may also aid in monitoring the efficacy of remyelination therapies.

Brain volume change after high-dose immunosuppression and autologous hematopoietic cell transplantation for relapsing-remitting multiple sclerosis.

BACKGROUND: Brain volume loss (BVL) is commonly observed after high-dose immunosuppression and autologous hematopoietic cell transplantation (HDIT/HCT) for treatment of multiple sclerosis (MS). To better understand the mechanisms of underlying BVL associated with this treatment, we characterized the time courses of whole-brain (WB), grey-matter (GM) and white-matter (WM) volume loss in relapsing-remitting MS (RRMS) patients who received BEAM-based HDIT/HCT. METHODS: We used Jacobian integration to measure MRI-based WB, GM and WM volume changes up to 5 years after transplant in twenty-four RRMS participants who underwent BEAM-based HDIT/HCT. Using a two-piecewise mixed-effects model, we estimated the short-term (baseline to 1 year) and long-term (beyond 1 year) rates of BVL after HDIT/HCT. We also compared the rates based on the presence of gadolinium-enhancing lesions at baseline, and the maintenance of event-free survival during follow-up. RESULTS: On average, accelerated short-term BVL of -1.37% (SE: 0.21), -0.86% (SE: 0.28) and -2.18% (SE: 0.26) occurred in WB, GM and WM, respectively. Baseline T1-weighted MRI WM lesion volume was a significant predictor in the WB (short-term) and the WM (short-term and long-term). The average rates of BVL after the initial acceleration were -0.22%/y (SE: 0.10), -0.13%/y (SE: 0.11) and -0.36%/y (SE: 0.11) in the WB, GM and WM, respectively. Participants with gadolinium-enhancing lesions at baseline had significantly higher short-term rates of GM (-1.56% vs. -0.27%, p = 0.01) and WB volume loss (-1.94% vs. -0.81%, p = 0.006) at 1 year follow-up as compared to those without gadolinium-enhancing lesions. WM volume loss was not significantly different (-2.59% vs. -1.66%, p = 0.16). Participants who maintained event-free survival had similar rates of BVL compared to those who did not. CONCLUSIONS: BVL may accelerate for months after HDIT/HCT. However, over the long-term, adequate HDIT/HCT may reduce BVL rates to those similar to normal aging at the WB level.

Ozanimod in relapsing multiple sclerosis: Pooled safety results from the clinical development program.

BACKGROUND: Ozanimod, an oral sphingosine 1-phosphate receptor 1 and 5 modulator, is approved in multiple countries for the treatment of relapsing multiple sclerosis (RMS). In phase 3 trials, ozanimod was well tolerated and superior to interferon beta-1a 30 µg once-weekly in reducing clinical and radiologic disease activity. The objective of this integrated safety analysis was to evaluate the safety of extended ozanimod exposure in participants with RMS from all clinical trials and compare it with phase 3 trial data. METHODS: We report pooled incidence and study duration‒adjusted incidence rates (IR) of treatment-emergent adverse events (TEAEs) from an interim data cut (January 31, 2019) of RMS participants treated with ozanimod. Data were pooled from a phase 1 pharmacokinetic/pharmacodynamic trial, a placebo-controlled phase 2 trial with dose-blinded extension, 2 large active-controlled phase 3 trials, and an open-label extension (OLE). Results were compared with pooled phase 3 trial data. RESULTS: At the data cutoff, 2631 RMS participants had exposure to ozanimod 0.92 mg (mean 32.0 months) and 2787 had exposure to either ozanimod 0.46 or 0.92 mg (mean 37.1 months). The IRs per 1000 person-years (PY) for any TEAE (772.2) and serious TEAEs (33.2) in the overall population were similar to those in the phase 3 population (896.1 and 31.2, respectively). There were no serious opportunistic infections. There were no second-degree or higher atrioventricular blocks on electrocardiogram. Hepatic enzyme elevations declined over time. Malignancy rates remained low with longer exposure. Pulmonary function tests showed minimal reductions in lung function. Seven ozanimod-treated participants with comorbid risk factors had confirmed macular edema, including 3 in the ongoing OLE. CONCLUSIONS: Safety results in this larger RMS population with greater ozanimod exposure demonstrated no new safety concerns and were consistent with phase 3 trial results.

Neurotoxicity after hematopoietic stem cell transplant in multiple sclerosis.

OBJECTIVE: Accelerated brain volume loss has been noted following immunoablative autologous hematopoietic stem cell transplantation (IAHSCT) for multiple sclerosis. As with other MS treatments, this is often interpreted as 'pseudoatrophy', related to reduced inflammation. Treatment-related neurotoxicity may be contributory. We sought objective evidence of post-IAHSCT toxicity by quantifying levels of Neurofilament Light Chain (sNfL) and Glial Fibrillary Acidic Protein (sGFAP) before and after treatment as markers of neuroaxonal and glial cell damage. METHODS: Sera were collected from 22 MS patients pre- and post-IAHSCT at 3, 6, 9, and 12 months along with 28 noninflammatory controls. sNfL and sGFAP quantification was performed using the SiMoA single-molecule assay. RESULTS: Pre-IAHSCT levels of sNfL and sGFAP were elevated in MS patients compared with controls (geometric mean sNfL 21.8 vs. 6.4 pg/mL, sGFAP 107.4 vs. 50.7 pg/mL, P = 0.0001 for both). Three months after IAHSCT, levels of sNfL and sGFAP increased from baseline by 32.1% and 74.8%, respectively (P = 0.0029 and 0.0004). sNfL increases correlated with total busulfan dose (P = 0.034), EDSS score worsening at 6 months (P = 0.041), and MRI grey matter volume loss at 6 months (P = 0.0023). Subsequent NfL levels reduced to less than baseline (12-month geometric mean 11.3 pg/mL P = 0.0001) but were still higher than controls (P = 0.0001). sGFAP levels reduced more slowly but at 12 months were approaching baseline levels (130.7 pg/mL). INTERPRETATION: There is direct evidence of transient CNS toxicity immediately after IAHSCT which may be chemotherapy mediated and contributes to transient increases in MRI atrophy.

High serum neurofilament light chain normalizes after hematopoietic stem cell transplantation for MS.

Objective: To evaluate neurofilament light chain (NfL) levels in serum and CSF of patients with aggressive MS pre- and post-treatment with immunoablation followed by autologous hematopoietic stem cell transplantation (IAHSCT) and examine associations with clinical and MRI outcomes. Methods: Paired serum and CSF in addition to MRI and clinical measures were collected on 23 patients with MS at baseline and 1 and 3 years post-IAHSCT. An additional 33 sera and CSF pairs were taken from noninflammatory neurologic controls. NfL levels were quantitated using the Simoa platform (Quanterix). Results: Baseline MS NfL levels were significantly elevated relative to controls in serum (p = 0.001) and CSF (p = 0.001). Following IAHSCT, high pretreatment NfL levels significantly reduced in serum (p = 0.0023) and CSF (p = 0.0068) and were not significantly different from controls. Serum and CSF NfL levels highly correlated (r = 0.81, p < 0.0001). Baseline NfL levels were associated with worse pretreatment disease measures (Expanded Disability Status Scale [EDSS], relapses, MRI lesions, and MR spectroscopy (MRS) N-acetylaspartate/creatine). Elevated baseline NfL levels were associated with persistently worse indices of disease burden post-IAHSCT (sustained EDSS progression, cognition, quality of life, T1 and T2 lesion volumes, MRS, and brain atrophy). Conclusion: These data substantiate that serum and CSF NfL levels reflect disease severity and treatment response in patients with MS and may therefore be a useful biomarker. Baseline serum levels associated with markers of pretreatment disease severity and post-treatment outcomes. Classification of evidence: This study provides Class II evidence that for patients with aggressive MS, serum NfL levels are associated with disease severity.

Effect of dimethyl fumarate on lymphocytes in RRMS: Implications for clinical practice.

OBJECTIVE: To assess functional changes in lymphocyte repertoire and subsequent clinical implications during delayed-release dimethyl fumarate (DMF) treatment in patients with multiple sclerosis. METHODS: Using peripheral blood from several clinical trials of DMF, immune cell subsets were quantified using flow cytometry. For some patients, lymphocyte counts were assessed after DMF discontinuation. Incidence of adverse events, including serious and opportunistic infections, was assessed. RESULTS: In DMF-treated patients, absolute lymphocyte counts (ALCs) demonstrated a pattern of decline followed by stabilization, which also was reflected in the global reduction in numbers of circulating functional lymphocyte subsets. The relative frequencies of circulating memory T- and B-cell populations declined and naive cells increased. No increased incidence of serious infection or malignancy was observed for patients treated with DMF, even when stratified by ALC or T-cell subset frequencies. For patients who discontinued DMF due to lymphopenia, ALCs increased after DMF discontinuation; recovery time varied by ALC level at discontinuation. T-cell subsets closely correlated with ALCs in both longitudinal and cross-sectional analyses. CONCLUSIONS: DMF shifted the immunophenotype of circulating lymphocyte subsets. ALCs were closely correlated with CD4+ and CD8+ T-cell counts, indicating that lymphocyte subset monitoring is not required for safety vigilance. No increased risk of serious infection was observed in patients with low T-cell subset counts. Monitoring ALC remains the most effective way of identifying patients at risk of subsequently developing prolonged moderate to severe lymphopenia, a risk factor for progressive multifocal leukoencephalopathy in DMF-treated patients. TRIAL REGISTRATION NUMBERS: EUDRA CT 2015-001973-42, NCT00168701, NCT00420212, NCT00451451, and NCT00835770.

Siponimod versus placebo in secondary progressive multiple sclerosis (EXPAND): a double-blind, randomised, phase 3 study.

BACKGROUND: No treatment has consistently shown efficacy in slowing disability progression in patients with secondary progressive multiple sclerosis (SPMS). We assessed the effect of siponimod, a selective sphingosine 1-phosphate (S1P) receptor1,5 modulator, on disability progression in patients with SPMS. METHODS: This event-driven and exposure-driven, double-blind, phase 3 trial was done at 292 hospital clinics and specialised multiple sclerosis centres in 31 countries. Using interactive response technology to assign numbers linked to treatment arms, patients (age 18-60 years) with SPMS and an Expanded Disability Status Scale score of 3·0-6·5 were randomly assigned (2:1) to once daily oral siponimod 2 mg or placebo for up to 3 years or until the occurrence of a prespecified number of confirmed disability progression (CDP) events. The primary endpoint was time to 3-month CDP. Efficacy was assessed for the full analysis set (ie, all randomly assigned and treated patients); safety was assessed for the safety set. This trial is registered with ClinicalTrials.gov, number NCT01665144. FINDINGS: 1651 patients were randomly assigned between Feb 5, 2013, and June 2, 2015 (1105 to the siponimod group, and 546 to the placebo group). One patient did not sign the consent form, and five patients did not receive study drug, all of whom were in the siponimod group. 1645 patients were included in the analyses (1099 in the siponimod group and 546 in the placebo). At baseline, the mean time since first multiple sclerosis symptoms was 16·8 years (SD 8·3), and the mean time since conversion to SPMS was 3·8 years (SD 3·5); 1055 (64%) patients had not relapsed in the previous 2 years, and 918 (56%) of 1651 needed walking assistance. 903 (82%) patients receiving siponimod and 424 (78%) patients receiving placebo completed the study. 288 (26%) of 1096 patients receiving siponimod and 173 (32%) of 545 patients receiving placebo had 3-month CDP (hazard ratio 0·79, 95% CI 0·65-0·95; relative risk reduction 21%; p=0·013). Adverse events occurred in 975 (89%) of 1099 patients receiving siponimod versus 445 (82%) of 546 patients receiving placebo; serious adverse events were reported for 197 (18%) patients in the siponimod group versus 83 (15%) patients in the placebo group. Lymphopenia, increased liver transaminase concentration, bradycardia and bradyarrhythmia at treatment initiation, macular oedema, hypertension, varicella zoster reactivation, and convulsions occurred more frequently with siponimod than with placebo. Initial dose titration mitigated cardiac first-dose effects. Frequencies of infections, malignancies, and fatalities did not differ between groups. INTERPRETATION: Siponimod reduced the risk of disability progression with a safety profile similar to that of other S1P modulators and is likely to be a useful treatment for SPMS. FUNDING: Novartis Pharma AG.

Two-year results from a phase 2 extension study of oral amiselimod in relapsing multiple sclerosis.

BACKGROUND: Amiselimod, an oral selective sphingosine-1-phosphate 1 receptor modulator, suppressed disease activity dose-dependently without clinically relevant bradyarrhythmia in a 24-week phase 2, placebo-controlled study in relapsing-remitting multiple sclerosis. OBJECTIVE: To assess safety and efficacy of amiselimod over 96 weeks. METHODS: After completing the core study, patients on amiselimod continued at the same dose, whereas those on placebo were randomised 1:1:1 to amiselimod 0.1, 0.2 or 0.4 mg for another 72 weeks. Most patients receiving 0.1 mg were re-randomised to 0.2 or 0.4 mg upon availability of the core study results. RESULTS: Of 415 patients randomised in the core study, 367 (88.4%) entered and 322 (77.6%) completed the extension. One or more adverse events were reported in 303 (82.6%) of 367 patients: 'headache', 'lymphocyte count decreased', 'nasopharyngitis' and 'MS relapse' were most common (14.7%-16.9%). No serious opportunistic infection, macular oedema or malignancy was reported and no bradyarrhythmia of clinical concern was observed by Holter or 12-lead electrocardiogram. The dose-dependent effect of amiselimod on clinical and magnetic resonance imaging-related outcomes from the core study was sustained in those continuing on amiselimod and similarly observed after switching to active drug. CONCLUSION: For up to 2 years of treatment, amiselimod was well tolerated and dose-dependently effective in controlling disease activity.

Impact of immunoablation and autologous hematopoietic stem cell transplantation on gray and white matter atrophy in multiple sclerosis.

BACKGROUND: Immunoablation and autologous hematopoietic stem cell transplantation (IA/aHSCT) halts relapses, white matter (WM) lesion formation, and pathological whole-brain (WB) atrophy in multiple sclerosis (MS) patients. Whether the latter was due to effects on gray matter (GM) or WM warranted further exploration. OBJECTIVE: To model GM and WM volume changes after IA/aHSCT to further understand the effects seen on WB atrophy. METHODS: GM and WM volume changes were calculated from serial baseline and follow-up magnetic resonance imaging (MRI) ranging from 1.5 to 10.5 years in 19 MS patients treated with IA/aHSCT. A mixed-effects model with two predictors (total busulfan dose and baseline T1-weighted WM lesion volume "T1LV") characterized the time-courses after IA/aHSCT. RESULTS: Accelerated short-term atrophy of 2.1% and 3.2% occurred in GM and WM, respectively, on average. Both busulfan dose and T1LV were significant predictors of WM atrophy, whereas only busulfan was a significant predictor of GM atrophy. Compared to baseline, a significant reduction in GM atrophy, not WM atrophy, was found. The average rates of long-term GM and WM atrophy were -0.18%/year (standard error (SE): 0.083) and -0.07%/year (SE: 0.14), respectively. CONCLUSION: Chemotherapy-related toxicity affected both GM and WM. WM was further affected by focal T1-weighted lesion-related pathologies. Long-term rates of GM and WM atrophy were comparable to those of normal-aging.

High-dose immunosuppressive therapy and autologous HCT for relapsing-remitting MS.

OBJECTIVE: To evaluate the safety, efficacy, and durability of multiple sclerosis (MS) disease stabilization after high-dose immunosuppressive therapy (HDIT) and autologous hematopoietic cell transplantation (HCT). METHODS: High-Dose Immunosuppression and Autologous Transplantation for Multiple Sclerosis (HALT-MS) is a phase II clinical trial of HDIT/HCT for patients with relapsing-remitting (RR) MS who experienced relapses with disability progression (Expanded Disability Status Scale [EDSS] 3.0-5.5) while on MS disease-modifying therapy. The primary endpoint was event-free survival (EFS), defined as survival without death or disease activity from any one of: disability progression, relapse, or new lesions on MRI. Participants were evaluated through 5 years posttransplant. Toxicities were reported using the National Cancer Institute Common Terminology Criteria for Adverse Events (AE). RESULTS: Twenty-five participants were evaluated for transplant and 24 participants underwent HDIT/HCT. Median follow-up was 62 months (range 12-72). EFS was 69.2% (90% confidence interval [CI] 50.2-82.1). Progression-free survival, clinical relapse-free survival, and MRI activity-free survival were 91.3% (90% CI 74.7%-97.2%), 86.9% (90% CI 69.5%-94.7%), and 86.3% (90% CI 68.1%-94.5%), respectively. AE due to HDIT/HCT were consistent with expected toxicities and there were no significant late neurologic adverse effects noted. Improvements were noted in neurologic disability with a median change in EDSS of -0.5 (interquartile range -1.5 to 0.0; p = 0.001) among participants who survived and completed the study. CONCLUSION: HDIT/HCT without maintenance therapy was effective for inducing long-term sustained remissions of active RRMS at 5 years. CLINICALTRIALSGOV IDENTIFIER: NCT00288626. CLASSIFICATION OF EVIDENCE: This study provides Class IV evidence that participants with RRMS experienced sustained remissions with toxicities as expected from HDIT/HCT.

Ocrelizumab versus Interferon Beta-1a in Relapsing Multiple Sclerosis.

BACKGROUND: B cells influence the pathogenesis of multiple sclerosis. Ocrelizumab is a humanized monoclonal antibody that selectively depletes CD20+ B cells. METHODS: In two identical phase 3 trials, we randomly assigned 821 and 835 patients with relapsing multiple sclerosis to receive intravenous ocrelizumab at a dose of 600 mg every 24 weeks or subcutaneous interferon beta-1a at a dose of 44 µg three times weekly for 96 weeks. The primary end point was the annualized relapse rate. RESULTS: The annualized relapse rate was lower with ocrelizumab than with interferon beta-1a in trial 1 (0.16 vs. 0.29; 46% lower rate with ocrelizumab; P<0.001) and in trial 2 (0.16 vs. 0.29; 47% lower rate; P<0.001). In prespecified pooled analyses, the percentage of patients with disability progression confirmed at 12 weeks was significantly lower with ocrelizumab than with interferon beta-1a (9.1% vs. 13.6%; hazard ratio, 0.60; 95% confidence interval [CI], 0.45 to 0.81; P<0.001), as was the percentage of patients with disability progression confirmed at 24 weeks (6.9% vs. 10.5%; hazard ratio, 0.60; 95% CI, 0.43 to 0.84; P=0.003). The mean number of gadolinium-enhancing lesions per T1-weighted magnetic resonance scan was 0.02 with ocrelizumab versus 0.29 with interferon beta-1a in trial 1 (94% lower number of lesions with ocrelizumab, P<0.001) and 0.02 versus 0.42 in trial 2 (95% lower number of lesions, P<0.001). The change in the Multiple Sclerosis Functional Composite score (a composite measure of walking speed, upper-limb movements, and cognition; for this z score, negative values indicate worsening and positive values indicate improvement) significantly favored ocrelizumab over interferon beta-1a in trial 2 (0.28 vs. 0.17, P=0.004) but not in trial 1 (0.21 vs. 0.17, P=0.33). Infusion-related reactions occurred in 34.3% of the patients treated with ocrelizumab. Serious infection occurred in 1.3% of the patients treated with ocrelizumab and in 2.9% of those treated with interferon beta-1a. Neoplasms occurred in 0.5% of the patients treated with ocrelizumab and in 0.2% of those treated with interferon beta-1a. CONCLUSIONS: Among patients with relapsing multiple sclerosis, ocrelizumab was associated with lower rates of disease activity and progression than interferon beta-1a over a period of 96 weeks. Larger and longer studies of the safety of ocrelizumab are required. (Funded by F. Hoffmann-La Roche; OPERA I and II ClinicalTrials.gov numbers, NCT01247324 and NCT01412333 , respectively.).

Ocrelizumab versus Placebo in Primary Progressive Multiple Sclerosis.

BACKGROUND: An evolving understanding of the immunopathogenesis of multiple sclerosis suggests that depleting B cells could be useful for treatment. We studied ocrelizumab, a humanized monoclonal antibody that selectively depletes CD20-expressing B cells, in the primary progressive form of the disease. METHODS: In this phase 3 trial, we randomly assigned 732 patients with primary progressive multiple sclerosis in a 2:1 ratio to receive intravenous ocrelizumab (600 mg) or placebo every 24 weeks for at least 120 weeks and until a prespecified number of confirmed disability progression events had occurred. The primary end point was the percentage of patients with disability progression confirmed at 12 weeks in a time-to-event analysis. RESULTS: The percentage of patients with 12-week confirmed disability progression was 32.9% with ocrelizumab versus 39.3% with placebo (hazard ratio, 0.76; 95% confidence interval [CI], 0.59 to 0.98; P=0.03). The percentage of patients with 24-week confirmed disability progression was 29.6% with ocrelizumab versus 35.7% with placebo (hazard ratio, 0.75; 95% CI, 0.58 to 0.98; P=0.04). By week 120, performance on the timed 25-foot walk worsened by 38.9% with ocrelizumab versus 55.1% with placebo (P=0.04); the total volume of brain lesions on T2-weighted magnetic resonance imaging (MRI) decreased by 3.4% with ocrelizumab and increased by 7.4% with placebo (P<0.001); and the percentage of brain-volume loss was 0.90% with ocrelizumab versus 1.09% with placebo (P=0.02). There was no significant difference in the change in the Physical Component Summary score of the 36-Item Short-Form Health Survey. Infusion-related reactions, upper respiratory tract infections, and oral herpes infections were more frequent with ocrelizumab than with placebo. Neoplasms occurred in 2.3% of patients who received ocrelizumab and in 0.8% of patients who received placebo; there was no clinically significant difference between groups in the rates of serious adverse events and serious infections. CONCLUSIONS: Among patients with primary progressive multiple sclerosis, ocrelizumab was associated with lower rates of clinical and MRI progression than placebo. Extended observation is required to determine the long-term safety and efficacy of ocrelizumab. (Funded by F. Hoffmann-La Roche; ORATORIO ClinicalTrials.gov number, NCT01194570 .).

Brain atrophy after bone marrow transplantation for treatment of multiple sclerosis.

BACKGROUND: A cohort of patients with poor-prognosis multiple sclerosis (MS) underwent chemotherapy-based immune ablation followed by immune reconstitution with an autologous hematopoietic stem cell transplant (IA/aHSCT). This eliminated new focal inflammatory activity, but resulted in early acceleration of brain atrophy. OBJECTIVE: We modeled the time course of whole-brain volume in 19 patients to identify the baseline predictors of atrophy and to estimate the average rate of atrophy after IA/aHSCT. METHODS: Percentage whole-brain volume changes were calculated between the baseline and follow-up magnetic resonance imaging (MRI; mean duration: 5 years). A mixed-effects model was applied using two predictors: total busulfan dose and baseline volume of T1-weighted white-matter lesions. RESULTS: Treatment was followed by accelerated whole-brain volume loss averaging 3.3%. Both the busulfan dose and the baseline lesion volume were significant predictors. The atrophy slowed progressively over approximately 2.5 years. There was no evidence that resolution of edema contributed to volume loss. The mean rate of long-term atrophy was -0.23% per year, consistent with the rate expected from normal aging. CONCLUSION: Following IA/aHSCT, MS patients showed accelerated whole-brain atrophy that was likely associated with treatment-related toxicity and degeneration of "committed" tissues. Atrophy eventually slowed to that expected from normal aging, suggesting that stopping inflammatory activity in MS can reduce secondary degeneration and atrophy.

Immunoablation and autologous haemopoietic stem-cell transplantation for aggressive multiple sclerosis: a multicentre single-group phase 2 trial.

BACKGROUND: Strong immunosuppression, including chemotherapy and immune-depleting antibodies followed by autologous haemopoietic stem-cell transplantation (aHSCT), has been used to treat patients with multiple sclerosis, improving control of relapsing disease. We addressed whether near-complete immunoablation followed by immune cell depleted aHSCT would result in long-term control of multiple sclerosis. METHODS: We did this phase 2 single-arm trial at three hospitals in Canada. We enrolled patients with multiple sclerosis, aged 18-50 years with poor prognosis, ongoing disease activity, and an Expanded Disability Status Scale of 3.0-6.0. Autologous CD34 selected haemopoietic stem-cell grafts were collected after mobilisation with cyclophosphamide and filgrastim. Immunoablation with busulfan, cyclophosphamide, and rabbit anti-thymocyte globulin was followed by aHSCT. The primary outcome was multiple sclerosis activity-free survival (events were clinical relapse, appearance of a new or Gd-enhancing lesion on MRI, and sustained progression of Expanded Disability Status Scale score). This study was registered at ClinicalTrials.gov, NCT01099930. FINDINGS: Between diagnosis and aHSCT, 24 patients had 167 clinical relapses over 140 patient-years with 188 Gd-enhancing lesions on 48 pre-aHSCT MRI scans. Median follow-up was 6.7 years (range 3.9-12.7). The primary outcome, multiple sclerosis activity-free survival at 3 years after transplantation was 69.6% (95% CI 46.6-84.2). With up to 13 years of follow-up after aHSCT, no relapses occurred and no Gd enhancing lesions or new T2 lesions were seen on 314 MRI sequential scans. The rate of brain atrophy decreased to that expected for healthy controls. One of 24 patients died of transplantation-related complications. 35% of patients had a sustained improvement in their Expanded Disability Status Scale score. INTERPRETATION: We describe the first treatment to fully halt all detectable CNS inflammatory activity in patients with multiple sclerosis for a prolonged period in the absence of any ongoing disease-modifying drugs. Furthermore, many of the patients had substantial recovery of neurological function despite their disease's aggressive nature. FUNDING: Multiple Sclerosis Scientific Research Foundation.

Safety and efficacy of the selective sphingosine 1-phosphate receptor modulator ozanimod in relapsing multiple sclerosis (RADIANCE): a randomised, placebo-controlled, phase 2 trial.

BACKGROUND: Modulation of sphingosine 1-phosphate (S1P) receptors in a non-selective manner decreases disease activity in patients with multiple sclerosis but has potential safety concerns. We assessed the safety and efficacy of the oral selective S1P receptor modulator ozanimod in patients with relapsing multiple sclerosis. METHODS: RADIANCE is a combined phase 2/3 trial. Patients with relapsing multiple sclerosis were recruited from 55 academic and private multiple sclerosis clinics in 13 countries across Europe and the USA. Eligible participants were aged 18-55 years, had an Expanded Disability Status Scale (EDSS) score of 0-5·0, and had either one or more relapses in the previous 12 months, or one or more relapses in the past 24 months and one or more gadolinium-enhancing lesions on MRI in the previous 12 months before screening. Participants were assigned by a computer-generated randomisation sequence in a 1:1:1 ratio to ozanimod (0·5 mg or 1 mg) or matching placebo once daily for 24 weeks by an independent, unmasked, statistical team. Trial participants, study site personnel, MRI assessors, steering committee members, and the study statistician were masked to treatment assignment. To attenuate first-dose cardiac effects, ozanimod was up-titrated from 0·25 mg to 0·5 mg or 1 mg over 8 days. The primary endpoint was the cumulative number of total gadolinium-enhancing MRI lesions measured by an independent MRI analysis centre at weeks 12-24 after treatment initiation. Analysis was by intention to treat. Here, we report results from the 24-week phase 2 trial. This trial is registered with ClinicalTrials.gov, number NCT01628393. The 2-year phase 3 trial is ongoing. FINDINGS: The first patient was randomised on Oct 18, 2012, and the final visit of the last randomised patient was on May 11, 2014. The intention-to-treat and safety population consisted of 258 participants, 88 were assigned placebo, 87 ozanimod 0·5 mg, and 83 ozanimod 1 mg; 252 (98%) patients completed the assigned treatment. The mean cumulative number of gadolinium-enhancing lesions at weeks 12-24 was 11·1 (SD 29·9) with placebo compared with 1·5 (3·7) with ozanimod 0·5 mg (odds ratio 0·16, 95% CI 0·08-0·30; p<0·0001) and 1·5 (3·4) with ozanimod 1 mg (odds ratio 0·11, 95% CI 0·06-0·21; p<0·0001). Three serious adverse events unrelated to treatment were reported in patients assigned ozanimod 0·5 mg: optic neuritis, somatoform autonomic dysfunction, and cervical squamous metaplasia (HPV-related). No serious infectious or cardiac adverse events were reported, and no cases of macular oedema arose. The most common adverse events in the ozanimod 0·5 mg and 1 mg groups compared with placebo were nasopharyngitis (11 and five vs 12), headache (five and three vs eight), and urinary-tract infections (six and two vs two). The maximum reduction in mean heart rate by Holter monitoring during the first 6 h in ozanimod-treated participants was less than 2 beats per min (bpm) compared with baseline, with no patient having a minimum hourly heart rate less than 45 bpm. Electrocardiograms and 24-h Holter monitoring showed no increased incidence of atrioventricular block or sinus pause with ozanimod. INTERPRETATION: Ozanimod significantly reduced MRI lesion activity in participants with relapsing multiple sclerosis, with a favourable safety profile over a period of 24 weeks. These findings warrant phase 3 trials, which are ongoing. FUNDING: Receptos, Inc.