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Multiple sclerosis (MS) is an autoimmune disease driven by lymphocyte activation against myelin autoantigens in the central nervous system leading to demyelination and neurodegeneration. The deoxyribonucleoside salvage pathway with the rate-limiting enzyme deoxycytidine kinase (dCK) captures extracellular deoxyribonucleosides for use in intracellular deoxyribonucleotide metabolism. Previous studies have shown that deoxyribonucleoside salvage activity is enriched in lymphocytes and required for early lymphocyte development. However, specific roles for the deoxyribonucleoside salvage pathway and dCK in autoimmune diseases such as MS are unknown. Here we demonstrate that dCK activity is necessary for the development of clinical symptoms in the MOG

The monoclonal antibody ublituximab enhances antibody-dependent cellular cytolysis and produces B-cell depletion. Ublituximab is being evaluated for the treatment of relapsing multiple sclerosis.In two identical, phase 3, double-blind, double-dummy trials (ULTIMATE I and II), participants with relapsing multiple sclerosis were randomly assigned in a 1:1 ratio to receive intravenous ublituximab (150 mg on day 1, followed by 450 mg on day 15 and at weeks 24, 48, and 72) and oral placebo or oral teriflunomide (14 mg once daily) and intravenous placebo. The primary end point was the annualized relapse rate. Secondary end points included the number of gadolinium-enhancing lesions on magnetic resonance imaging (MRI) by 96 weeks and worsening of disability.A total of 549 participants were enrolled in the ULTIMATE I trial, and 545 were enrolled in the ULTIMATE II trial; the median follow-up was 95 weeks. In the ULTIMATE I trial, the annualized relapse rate was 0.08 with ublituximab and 0.19 with teriflunomide (rate ratio, 0.41; 95% confidence interval [CI], 0.27 to 0.62; P0.001); in the ULTIMATE II trial, the annualized relapse rate was 0.09 and 0.18, respectively (rate ratio, 0.51; 95% CI, 0.33 to 0.78; P = 0.002). The mean number of gadolinium-enhancing lesions was 0.02 in the ublituximab group and 0.49 in the teriflunomide group (rate ratio, 0.03; 95% CI, 0.02 to 0.06; P0.001) in the ULTIMATE I trial and 0.01 and 0.25, respectively (rate ratio, 0.04; 95% CI, 0.02 to 0.06; P0.001), in the ULTIMATE II trial. In the pooled analysis of the two trials, 5.2% of the participants in the ublituximab group and 5.9% in the teriflunomide group had worsening of disability at 12 weeks (hazard ratio, 0.84; 95% CI, 0.50 to 1.41; P = 0.51). Infusion-related reactions occurred in 47.7% of the participants in the ublituximab group. Serious infections occurred in 5.0% in the ublituximab group and in 2.9% in the teriflunomide group.Among participants with relapsing multiple sclerosis, ublituximab resulted in lower annualized relapse rates and fewer brain lesions on MRI than teriflunomide over a period of 96 weeks but did not result in a significantly lower risk of worsening of disability. Ublituximab was associated with infusion-related reactions. (Funded by TG Therapeutics; ULTIMATE I and II ClinicalTrials.gov numbers, NCT03277261 and NCT03277248.).

Supplementary Figure 2 from Enhanced Immune Recognition of Cryptic Glycan Markers in Human Tumors

Abnormal glycosylation is one of the hallmarks of the cancer cell and is associated with tumor invasion and metastasis. The development of tumor-associated carbohydrate antigen (TACA) vaccines has been problematic due to poor immunogenicity. However, when appropriate targets can be identified, passive immunization with monoclonal antibodies (mAbs) directed against TACAs has been shown to have antitumor activity. Fas ligand (FasL) is a transmembrane protein that induces apoptosis in cells expressing its receptor, Fas. When grafted into mice, FasL-expressing tumor cells break immunologic tolerance to self-antigens and induce antibody-mediated tumor immunity. Here, five IgM mAbs were produced from mice vaccinated with FasL-expressing B16F10 mouse melanoma cells. They recognize various syngeneic and allogeneic murine tumor cell lines. One mAb, TM10, recognizes a range of human tumor cell lines, including melanoma, prostate, and ovarian cancer. It does not bind to untransformed cells. The epitopes recognized by all the mAbs were carbohydrates expressed on proteins. Using carbohydrate microarrays, the antigenic targets of TM10 were found to be high-mannose core structures of N-linked glycans. In normal cells, high-mannose clusters are hidden by extensive saccharide branching but they become exposed in cancer cells as a result of abnormal glycosylation pathways. Vaccination with FasL-expressing tumors therefore enables the immune system to break tolerance to self-antigens, allowing identification of novel TACAs that can form the basis of future humoral anticancer therapy. [Cancer Res 2009;69(5):2018–25]

Supplementary Figure 1 from Enhanced Immune Recognition of Cryptic Glycan Markers in Human Tumors

SummaryMultiple sclerosis (MS) is an autoimmune disease associated with inflammatory demyelination in the central nervous system (CNS). Autologous hematopoietic cell transplantation (HCT) is under investigation as a promising therapy for treatment-refractory MS. Here we identify a reactive myeloid state in chronic experimental autoimmune encephalitis (EAE) mice and MS patients that is surprisingly associated with neuroprotection and immune suppression. HCT in EAE mice leads to an enhancement of this myeloid state, as well as clinical improvement, reduction of demyelinated lesions, suppression of cytotoxic T cells, and amelioration of reactive astrogliosis reflected in reduced expression of EAE- associated gene signatures in oligodendrocytes and astrocytes. Further enhancement of myeloid cell incorporation into the CNS following a modified HCT protocol results in an even more consistent therapeutic effect corroborated by additional amplification of HCT-induced transcriptional changes, underlining myeloid-derived beneficial effects in the chronic phase of EAE. Replacement or manipulation of CNS myeloid cells thus represents an intriguing therapeutic direction for inflammatory demyelinating disease.

Multiple sclerosis (MS) is a heterogenous autoimmune disease in which autoreactive lymphocytes attack the myelin sheath of the central nervous system. B lymphocytes in the cerebrospinal fluid (CSF) of patients with MS contribute to inflammation and secrete oligoclonal immunoglobulins1,2. Epstein-Barr virus (EBV) infection has been epidemiologically linked to MS, but its pathological role remains unclear3. Here we demonstrate high-affinity molecular mimicry between the EBV transcription factor EBV nuclear antigen 1 (EBNA1) and the central nervous system protein glial cell adhesion molecule (GlialCAM) and provide structural and in vivo functional evidence for its relevance. A cross-reactive CSF-derived antibody was initially identified by single-cell sequencing of the paired-chain Bcell repertoire of MS blood and CSF, followed by protein microarray-based testing of recombinantly expressed CSF-derived antibodies against MS-associated viruses. Sequence analysis, affinity measurements and the crystal structure of the EBNA1-peptide epitope in complex with the autoreactive Fab fragment enabled tracking of the development of the naive EBNA1-restricted antibody to a mature EBNA1-GlialCAM cross-reactive antibody. Molecular mimicry is facilitated by a post-translational modification of GlialCAM. EBNA1 immunization exacerbates disease in a mouse model of MS, and anti-EBNA1 and anti-GlialCAM antibodies are prevalent in patients with MS. Our results provide a mechanistic link for the association between MS and EBV and could guide the development of new MS therapies.

FOXP3+regulatory T cells (Treg) depend on exogenous IL-2 for their survival and function, but circulating levels of IL-2 are low, making it unclear how Treg access this critical resourcein vivo. Here, we show that Treg use heparanase (HPSE) to access IL-2 sequestered by heparan sulfate (HS) within the extracellular matrix (ECM) of inflamed central nervous system tissue. HPSE expression distinguishes human and murine Treg from conventional T cells and is regulated by the availability of IL-2. HPSE-/-Treg have impaired stability and functionin vivo, including the experimental autoimmune encephalomyelitis (EAE) mouse model of multiple sclerosis. Conversely, endowing Treg with HPSE enhances their ability to access HS-sequestered IL-2 and their tolerogenic functionin vivo. Together, these data identify novel roles for HPSE and the ECM in immune tolerance, providing new avenues for improving Treg-based therapy of autoimmunity.One-Sentence SummaryRegulatory T cells use heparanase to strip IL-2 bound to extracellular matrix within inflamed tissues, thereby supporting their homeostasis and function.

Multiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system (CNS). Astrocytes are the most abundant glial cells in the CNS, and their dysfunction contributes to the pathogenesis of MS and its animal model, experimental autoimmune encephalomyelitis (EAE). Recent advances highlight the pivotal role of cellular metabolism in programming immune responses. However, the underlying immunometabolic mechanisms that drive astrocyte pathogenicity remain elusive. Nicotinamide adenine dinucleotide (NAD

20 yr ago, a tribute appeared in this journal on the 70th anniversary of an animal model of disseminated encephalomyelitis, abbreviated EAE for experimental autoimmune encephalomyelitis. “Observations on Attempts to Produce Disseminated Encephalomyelitis in Monkeys” appeared in the Journal of Experimental Medicine on February 21, 1933. Rivers and colleagues were trying to understand what caused neurological reactions to viral infections like smallpox, vaccinia, and measles, and what triggered rare instances of encephalomyelitis to smallpox vaccines. The animal model known as EAE continues to display its remarkable utility. Recent research, since the 70th-anniversary tribute, helps explain how Epstein–Barr virus triggers multiple sclerosis via molecular mimicry to a protein known as GlialCAM. Proteins with multiple domains similar to GlialCAM, tenascin, neuregulin, contactin, and protease kinase C inhibitors are present in the poxvirus family. These observations take us a full circle back to Rivers’ first paper on EAE, 90 yr ago.

Vitamin D is a steroid hormone that has been widely studied as a potential therapy for multiple sclerosis and other inflammatory disorders. Pre-clinical studies have implicated vitamin D in the transcription of thousands of genes, but its influence may vary by cell type. A handful of clinical studies have failed to identify an in vivo gene expression signature when using bulk analysis of all peripheral immune cells. We hypothesized that vitamin D’s gene signature would vary by immune cell type, requiring the analysis of distinct cell types. Multiple sclerosis patients (n = 18) were given high-dose vitamin D (10,400 IU/day) for six months as part of a prospective clinical trial (NCT01024777). We collected peripheral blood mononuclear cells from participants at baseline and again after six months of treatment. We used flow cytometry to isolate three immune cell types (CD4+ T-cells, CD19+ B-cells, CD14+ monocytes) for RNA microarray analysis and compared the expression profiles between baseline and six months. We identified distinct sets of differentially expressed genes and enriched pathways between baseline and six months for each cell type. Vitamin D’s in vivo gene expression profile in the immune system likely differs by cell type. Future clinical studies should consider techniques that allow for a similar cell-type resolution.

Larry Steinman divides his time between the neurology clinic and the lab where his team helped develop the first antibody therapy for multiple sclerosis. In this interview with Neuron, he talks about his family and upbringing, his team strategy as a principal investigator, and his long trajectory in translational medicine.

Multiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system (CNS). Astrocytes are the most abundant glial cells in the CNS, and their dysfunction contributes to the pathogenesis of MS and its animal model, experimental autoimmune encephalomyelitis (EAE). Recent advances highlight the pivotal role of cellular metabolism in programming immune responses. However, the underlying immunometabolic mechanisms that drive astrocyte pathogenicity remain elusive. Nicotinamide adenine dinucleotide (NAD + ) is a vital coenzyme involved in cellular redox reactions and a substrate for NAD + -dependent enzymes. Cellular NAD + levels are dynamically controlled by synthesis and degradation, and dysregulation of this balance has been associated with inflammation and disease. Here, we demonstrate that cell-autonomous generation of NAD + via the salvage pathway regulates astrocyte immune function. Inhibition of nicotinamide phosphoribosyltransferase (NAMPT), a key enzyme in the salvage pathway, results in depletion of NAD + , inhibits oxidative phosphorylation, and limits astrocyte inflammatory potential. We identified CD38 as the main NADase up-regulated in reactive mouse and human astrocytes in models of neuroinflammation and MS. Genetic or pharmacological blockade of astrocyte CD38 activity augmented NAD + levels, suppressed proinflammatory transcriptional reprogramming, impaired chemotactic potential to inflammatory monocytes, and ameliorated EAE. We found that CD38 activity is mediated via calcineurin/NFAT signaling in mouse and human reactive astrocytes. Thus, NAMPT–NAD + –CD38 circuitry in astrocytes controls their ability to meet their energy demands and drives the expression of proinflammatory transcriptional modules, contributing to CNS pathology in EAE and, potentially, MS. Our results identify candidate therapeutic targets in MS.

Susceptibility and severity of COVID-19 infection vary widely. Prior exposure to endemic coronaviruses, common in young children, may protect against SARS-CoV-2. We evaluated risk of severe COVID-19 among adults with and without exposure to young children in a large, integrated healthcare system. Adults with children 0–5 years were matched 1:1 to adults with children 6–11 years, 12–18 years, and those without children based upon a COVID-19 propensity score and risk factors for severe COVID-19. COVID-19 infections, hospitalizations, and need for intensive care unit (ICU) were assessed in 3,126,427 adults, of whom 24% (N = 743,814) had children 18 years or younger, and 8.8% (N = 274,316) had a youngest child 0–5 years. After 1:1 matching, propensity for COVID-19 infection and risk factors for severe COVID-19 were well balanced between groups. Rates of COVID-19 infection were slightly higher for adults with exposure to older children (incident risk ratio, 1.09, 95% confidence interval, [1.05–1.12] and IRR 1.09 [1.05–1.13] for adults with children 6–11 and 12–18, respectively), compared to those with children 0–5 years, although no difference in rates of COVID-19 illness requiring hospitalization or ICU admission was observed. However, adults without exposure to children had lower rates of COVID-19 infection (IRR 0.85, [0.83–0.87]) but significantly higher rates of COVID-19 hospitalization (IRR 1.49, [1.29–1.73]) and hospitalization requiring ICU admission (IRR 1.76, [1.19–2.58]) compared to those with children aged 0–5. In a large, real-world population, exposure to young children was associated with less severe COVID-19 illness. Endemic coronavirus cross-immunity may play a role in protection against severe COVID-19.

A woman presented at age 18 years with partial myelitis and diplopia and experienced multiple subsequent relapses. Her MRI demonstrated T2 abnormalities characteristic of multiple sclerosis (MS) (white matter ovoid lesions and Dawson fingers), and CSF demonstrated an elevated IgG index and oligoclonal bands restricted to the CSF. Diagnosed with clinically definite relapsing-remitting MS, she was treated with various MS disease-modifying therapies and eventually began experiencing secondary progression. At age 57 years, she developed an acute longitudinally extensive transverse myelitis and was found to have AQP4 antibodies by cell-based assay. Our analysis of the clinical course, radiographic findings, molecular diagnostic methods, and treatment response characteristics support the hypothesis that our patient most likely had 2 CNS inflammatory disorders: MS, which manifested as a teenager, and neuromyelitis optica spectrum disorder, which evolved in her sixth decade of life. This case emphasizes a key principle in neurology practice, which is to reconsider whether the original working diagnosis remains tenable, especially when confronted with evidence (clinical and/or paraclinical) that raises the possibility of a distinctively different disorder.

Immunotherapy approaches focusing on T cells have provided breakthroughs in treating solid tumors. However, there remains an opportunity to drive anticancer immune responses via other cell types, particularly myeloid cells. ATRC-101 was identified via a target-agnostic process evaluating antibodies produced by the plasmablast population of B cells in a patient with non-small cell lung cancer experiencing an antitumor immune response during treatment with checkpoint inhibitor therapy. Here, we describe the target, antitumor activity in preclinical models, and data supporting a mechanism of action of ATRC-101. Immunohistochemistry studies demonstrated tumor-selective binding of ATRC-101 to multiple nonautologous tumor tissues. In biochemical analyses, ATRC-101 appears to target an extracellular, tumor-specific ribonucleoprotein (RNP) complex. In syngeneic murine models, ATRC-101 demonstrated robust antitumor activity and evidence of immune memory following rechallenge of cured mice with fresh tumor cells. ATRC-101 increased the relative abundance of conventional dendritic cell (cDC) type 1 cells in the blood within 24 h of dosing, increased CD8+ T cells and natural killer cells in blood and tumor over time, decreased cDC type 2 cells in the blood, and decreased monocytic myeloid-derived suppressor cells in the tumor. Cellular stress, including that induced by chemotherapy, increased the amount of ATRC-101 target in tumor cells, and ATRC-101 combined with doxorubicin enhanced efficacy compared with either agent alone. Taken together, these data demonstrate that ATRC-101 drives tumor destruction in preclinical models by targeting a tumor-specific RNP complex leading to activation of innate and adaptive immune responses.

The emergence of SARS-CoV-2 triggering the COVID-19 pandemic ranks as arguably the greatest medical emergency of the last century. COVID-19 has highlighted health disparities both within and between countries and will leave a lasting impact on global society. Nonetheless, substantial investment in life sciences over recent decades has facilitated a rapid scientific response with innovations in viral characterization, testing, and sequencing. Perhaps most remarkably, this permitted the development of highly effective vaccines, which are being distributed globally at unprecedented speed. In contrast, drug treatments for the established disease have delivered limited benefits so far. Innovative and rapid approaches in the design and execution of large-scale clinical trials and repurposing of existing drugs have saved many lives; however, many more remain at risk. In this review we describe challenges and unmet needs, discuss existing therapeutics, and address future opportunities. Consideration is given to factors that have hindered drug development in order to support planning for the next pandemic challenge and to allow rapid and cost-effective development of new therapeutics with equitable delivery.

Immunotherapies for multiple sclerosis (MS) significantly decrease the risk of new relapses. However, the chronic compartmentalized inflammation and neurodegeneration that define progressive MS are not prevented by these therapies and so significant damage to the brain and spinal cord and resulting disability ensues. Hence, the possibility of combining current immunotherapies with neuroprotective, remyelinating or regenerative therapies should be pursued.This article sheds light on neuroprotective, remyelination and neurorepair strategies for MS, the numerous mechanisms for therapeutic targeting and the new candidates for combination therapies. We searched PubMed for articles with the terms, 'neuroprotection', remyelination' or 'regeneration' and 'therapies' or 'drugs' and 'Multiple Sclerosis'.An enriched understanding of the neurobiology and molecular changes that are activated by inflammatory CNS damage will provide new opportunities for the identification of neuroprotective, remyelinating and regenerative therapies. Success will depend on the improvement of CNS drug delivery, the identification of new predictive biomarkers, the optimization of clinical trials by assessment of the damage to the visual pathway and the testing of novel therapies in acute optic neuritis.

ObjectiveVitamin D status has been linked to risk of inflammatory brain lesions. We sought to assess the safety and pharmacokinetics of oral vitamin D dosing regimens in boys with X-linked adrenoleukodystrophy (ALD).MethodsIn this open-label, multi-center, phase I study, we enrolled 21 ALD males without brain lesions, aged 1.5 to 25 years to oral vitamin D supplementation for 12 months. Our primary outcome was attainment of plasma 25-hydroxyvitamin D levels in target range (40-80ng/ml) at 6 and 12 months. Secondary outcomes included safety and glutathione levels in brain and blood. Participants were initially assigned to a fixed dosing regimen starting at 2,000 IU daily, regardless of weight. Following a mid-study safety assessment, we modified the dosing regimen so all subsequent participants were assigned to a weight-stratified dosing regimen starting as low as 1,000 IU daily.ResultsBetween October 2016 and June 2019, we recruited 21 participants (n=12 fixed dose; n=9 weight-stratified) with a median age and weight of 6.7 years and 20 kilograms. Most participants achieved target plasma vitamin D levels at 6 and 12 months regardless of dosing regimen. In the fixed dose regimen, 6 of 12 participants had asymptomatic elevation in urine calcium:creatinine or plasma 25-hydroxyvitamin D; no laboratory deviations occurred with the weight-stratified regimen. Glutathione levels increased between baseline and 12 months in the brain but not in the blood.ConclusionsOur weight-stratified vitamin D dosing regimen was well-tolerated and achieved target 25-hydroxyvitamin D levels in most participants. Brain glutathione levels increased over the 12-month trial period.Clinicaltrials.gov identifierNCT02595489Classification of EvidenceThis study provides Class II evidence that a weight-stratified dosing regimen of vitamin D supplementation is safe, well-tolerated, and effective at achieving moderately high vitamin D levels in boys with ALD.Sources of fundingNIH/NINDS K23NS087151

New treatments for multiple sclerosis (MS) focused on B cells have created an atmosphere of excitement in the MS community. B cells are now known to play a major role in disease, demonstrated by the highly impactful effect of a B cell-depleting antibody on controlling MS. The idea that a virus may play a role in the development of MS has a long history and is supported mostly by studies demonstrating a link between B cell-tropic Epstein–Barr virus (EBV) and disease onset. Efforts to develop antiviral strategies for treating MS are underway. Although gaps remain in our understanding of the etiology of MS, the role, if any, of viruses in propagating pathogenic immune responses deserves attention., Highlights Clinical studies show that depletion of B cells reduces disease burden in both relapsing-remitting and progressive multiple sclerosis (MS) patients. B cell-tropic viruses may trigger aberrant immune responses in MS in genetically susceptible individuals owing, in part, to a failure in viral surveillance and clearance. The most compelling data supporting an etiologic role for viral involvement in MS have emerged for Epstein–Barr virus (EBV). Targeting mechanisms by which EBV is thought to participate in MS pathogenesis provides an opportunity for new drug development in MS.

Background and purposeWe investigated plasma neurofilament light chain concentration (pNfL) as a biomarker for neuroaxonal damage and disease activity using data from Phase 3 trials of ozanimod in relapsing multiple sclerosis (RMS).MethodspNfL was measured before and after ozanimod 0.46mg or 0.92mg daily or interferon β-1a 30µg weekly in the randomized, double-blind SUNBEAM and RADIANCE trials. In these post hoc analyses, we investigated relationships between pNfL (at baseline and median percentage change from baseline to Month 12 [SUNBEAM] or 24 [RADIANCE]) and clinical and magnetic resonance imaging outcomes.ResultsMedian (Q1, Q3) baseline pNfL, available in 1244 of 1346 SUNBEAM participants, was 14.70 (10.16, 23.26) pg/ml and in 1109 of 1313 RADIANCE participants was 13.35 (9.42, 20.41) pg/ml. Baseline gadolinium-enhancing (GdE) and T2 lesion counts increased and brain volume decreased with increasing baseline pNfL. Baseline pNfL was higher in those with versus without on-treatment relapse. Median percentage reduction in pNfL at 12months in SUNBEAM (n=1238) and 24months in RADIANCE (n=1088) was greater for ozanimod (20%-27%) than interferon β-1a (13%-16%; p&nbsp

Infection with Epstein-Barr virus is the trigger for the development of multiple sclerosis

Summary Background Ozanimod is a sphingosine 1-phosphate receptor modulator, which selectively binds to sphingosine 1-phosphate receptor subtypes 1 and 5 with high affinity. In the RADIANCE phase 2 study in participants with relapsing multiple sclerosis, ozanimod was associated with better efficacy than placebo on MRI measures and was well tolerated. The RADIANCE phase 3 study aimed to confirm the safety and efficacy of ozanimod versus interferon beta-1a in individuals with relapsing multiple sclerosis. Methods We did a 24-month, multicentre, double-blind, double-dummy phase 3 trial in participants with relapsing multiple sclerosis at 147 medical centres and clinical practices in 21 countries. Participants were aged 18–55 years, had multiple sclerosis according to 2010 McDonald criteria, a relapsing clinical course, brain MRI lesions consistent with multiple sclerosis, an expanded disability status scale score of 0·0–5·0, and either at least one relapse within 12 months before screening or at least one relapse within 24 months before screening plus at least one gadolinium-enhancing lesion within the 12 months before randomisation. Participants were randomly assigned (1:1:1) via an interactive voice response system to daily oral ozanimod 1·0 mg or 0·5 mg or weekly intramuscular interferon beta-1a 30 μg. Participants, investigators, and study staff were masked to treatment allocation. The primary endpoint was annualised relapse rate (ARR) over 24 months. The primary analysis was done in the intention-to-treat population of all participants who received study drug and safety was assessed in all randomly assigned participants who received study drug, grouped by highest dose of ozanimod received. This trial is registered at ClinicalTrials.gov , NCT02047734 , and EudraCT, 2012-002714-40. Findings Between Dec 27, 2013, and March 31, 2015, we screened 1695 participants, of which 375 did not meet inclusion criteria. 1320 participants were enrolled and randomly assigned to a group, of whom 1313 received study drug (433 assigned to ozanimod 1·0 mg, 439 assigned to ozanimod 0·5 mg, and 441 assigned to interferon beta-1a) and 1138 (86·7%) completed 24 months of treatment. Adjusted ARRs were 0·17 (95% CI 0·14–0·21) with ozanimod 1·0 mg, 0·22 (0·18–0·26) with ozanimod 0·5 mg, and 0·28 (0·23–0·32) with interferon beta-1a, with rate ratios versus interferon beta-1a of 0·62 (95% CI 0·51–0·77; p Interpretation In this 24-month phase 3 study in participants with relapsing multiple sclerosis, ozanimod was well tolerated and associated with a significantly lower rate of clinical relapses than intramuscular interferon beta-1a. These findings show the potential of ozanimod as an effective oral therapy for individuals with relapsing multiple sclerosis. Funding Celgene International II.

Ozanimod, a sphingosine 1-phosphate receptor modulator, selectively binds to receptor subtypes 1 and 5 with high affinity. The RADIANCE phase 2 study showed that ozanimod had better efficacy than placebo on MRI measures, with a favourable safety profile, in participants with relapsing multiple sclerosis. The SUNBEAM study aimed to assess the safety and efficacy of ozanimod versus intramuscular interferon beta-1a in participants with relapsing multiple sclerosis.SUNBEAM was a randomised, double-blind, double-dummy, active-controlled phase 3 trial done at 152 academic medical centres and clinical practices in 20 countries. We enrolled participants aged 18-55 years with relapsing multiple sclerosis, baseline expanded disability status scale (EDSS) score of 0·0-5·0, and either at least one relapse within the 12 months before screening or at least one relapse within 24 months plus at least one gadolinium-enhancing lesion within 12 months before screening. Participants were randomly assigned 1:1:1 by a blocked algorithm stratified by country and baseline EDSS score to at least 12 months treatment of either once-daily oral ozanimod 1·0 mg or 0·5 mg or weekly intramuscular interferon beta-1a 30 μg. Participants, investigators, and study staff were masked to treatment assignment. The primary endpoint was annualised relapse rate (ARR) during the treatment period and was assessed in the intention-to-treat population. Safety was assessed in all participants according to the highest dose of ozanimod received. This trial is registered at ClinicalTrials.gov, number NCT02294058 and EudraCT, number 2014-002320-27.Between Dec 18, 2014, and Nov 12, 2015, 1346 participants were enrolled and randomly assigned to ozanimod 1·0 mg (n=447), ozanimod 0·5 mg (n=451), or interferon beta-1a (n=448). 91 (6·8%) participants discontinued the study drug (29 in the ozanimod 1·0 mg group; 26 in the ozanimod 0·5 mg group; and 36 in the interferon beta-1a group). Adjusted ARRs were 0·35 (0·28-0·44) for interferon beta-1a, 0·18 (95% CI 0·14-0·24) for ozanimod 1·0 mg (rate ratio [RR] of 0·52 [0·41-0·66] vs interferon beta-1a; p0·0001), and 0·24 (0·19-0·31) for ozanimod 0·5 mg (RR 0·69 [0·55-0·86] vs interferon beta-1a; p=0·0013). Few ozanimod-treated participants discontinued treatment because of adverse events (13 [2·9%] who received ozanimod 1·0 mg; seven [1·5%] who received ozanimod 0·5 mg; and 16 [3·6%] who received interferon beta-1a). No first-dose, clinically significant bradycardia or second-degree or third-degree atrioventricular block was reported. The incidence of serious adverse events was low and similar across treatment groups (13 [2·9%] participants who received ozanimod 1·0 mg; 16 [3·5%] who received ozanimod 0·5 mg; and 11 [2·5%] who received interferon beta-1a). No serious opportunistic infections occurred in ozanimod-treated participants.In participants with relapsing multiple sclerosis treated for at least 12 months, ozanimod was well tolerated and demonstrated a significantly lower relapse rate than interferon beta-1a. These findings provide support for ozanimod as an oral therapy for individuals with relapsing multiple sclerosis.Celgene International II.