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In two parallel randomized trials in patients with MS, ublituximab resulted in lower relapse rates and fewer brain lesions on MRI than teriflunomide over a period of 96 weeks but did not affect disability.

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.

In a randomized trial, patients who received evobrutinib, an inhibitor of Bruton’s tyrosine kinase, at 75 mg daily had significantly fewer enhancing lesions on MRI during weeks 12 through 24 than those who received placebo. However, there was no significant between-group difference for either a lower or a higher dose of evobrutinib, or in the annualized relapse rate or disability progression at any dose.

In two identical trials involving a total of 1882 patients with multiple sclerosis, the human anti-CD20 monoclonal antibody ofatumumab was associated with a lower annualized relapse rate than the pyrimidine-synthesis inhibitor teriflunomide, as well as fewer lesions on MRI.

Objective Multiple sclerosis (MS) is a multifactorial disease with increasingly complicated management. Our objective is to use on‐demand computational power to address the challenges of dynamically managing MS. Methods A phase 3 clinical trial data (NCT00906399) were used to contextualize the medication efficacy of peg‐interferon beta‐1a vs placebo on patients with relapsing–remitting MS (RRMS). Using a set of reference patients (PORs), selected based on adequate features similar to those of an individual patient, we visualize disease activity by measuring the percentage of relapses, accumulation of new T2 lesions on MRI, and worsening EDSS during the clinical trial. Results We developed MS Vista, a functional prototype of clinical decision support system (CDSS), with a user‐centered design and distributed infrastructure. MS Vista shows the medication efficacy of peginterferon beta‐1a versus placebo for each individual patient with RRMS. In addition, MS Vista initiated the integration of a longitudinal magnetic resonance imaging (MRI) viewer and interactive dual physician‐patient data display to facilitate communication. Interpretation The pioneer use of PORs for each individual patient enables personalized analytics sustaining the dialog between neurologists, patients and caregivers with quantified evidence.

In this randomized trial involving patients with multiple sclerosis, BG-12 (dimethyl fumarate) reduced clinical relapses, disability progression, and MRI lesions. BG-12 treatment resulted in reduced lymphocyte counts and elevated liver aminotransferase levels. Oral BG-12 (dimethyl fumarate) is being investigated for the treatment of multiple sclerosis. Inflammation and oxidative stress are central pathologic factors in multiple sclerosis. 1 , 2 Immune cell activation and infiltration into the central nervous system are thought to result in widespread cellular damage, potentially owing to the dysregulated production and release of reactive oxygen and nitrogen species, such as hydrogen peroxide and peroxynitrite, and proinflammatory stimuli. 3 This combination of toxic factors ultimately results in demyelination and neurodegeneration, causing disease activity and progression of disability. BG-12 has been shown to have beneficial effects in preclinical models of neuroinflammation, neurodegeneration, and toxic . . .

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 . . .

In this trial involving patients with relapsing–remitting multiple sclerosis, BG-12 (dimethyl fumarate) reduced the annualized relapse rate and number of MRI lesions but not disability progression. BG-12 was associated with flushing, diarrhea, and decreased lymphocyte counts. Multiple sclerosis is a chronic demyelinating and neurodegenerative disease of the central nervous system, which is commonly treated with parenteral agents (interferon beta and glatiramer acetate). Oxidative stress and proinflammatory stimuli are important pathologic factors in multiple sclerosis. 1 – 3 Experimental data suggest that BG-12, an oral formulation of dimethyl fumarate, has antiinflammatory and cytoprotective properties that are mediated through activation of the nuclear factor (erythroid-derived 2)–like 2 transcriptional pathway, among others. 3 – 6 Here, we report the results of the Comparator and an Oral Fumarate in Relapsing–Remitting Multiple Sclerosis (CONFIRM) trial, a randomized, multicenter, double-blind, 2-year study evaluating the efficacy and . . .

Depletion of B lymphocytes is associated with suppression of inflammatory activity in multiple sclerosis. We aimed to assess the safety and efficacy of atacicept, a recombinant fusion protein that suppresses B-cell function and antibody production. In this placebo-controlled, double-blind, 36-week, phase 2 trial (ATAMS) in Australia, Canada, Europe, and the USA, patients aged 18–60 years with relapsing multiple sclerosis were randomly assigned via an interactive voice response system in a 1:1:1:1 ratio, stratified by geographical region, to receive weekly subcutaneous injections with atacicept (25, 75, or 150 mg) or placebo. Both patients and study personnel were masked to treatment assignment. The primary endpoint was the change in mean number of gadolinium-enhancing lesions on T1-weighted MRI per patient per scan between weeks 12 and 36. Efficacy endpoints were analysed in the intention-to-treat population. Patients who completed week 36 were eligible to participate in a long-term extension study (ATAMS EXT), consisting of a double-blind phase followed by an open-label phase, for a total study time of up to 5 years. The study was terminated early after the independent data and safety monitoring board noted an increased annualised relapse rate with atacicept. The protocol was subsequently amended to include a 60-week safety follow-up, to allow treatment with approved multiple sclerosis drugs, and to change the primary endpoint to gadolinium-enhancing T1 lesions per scan during the entire double-blind period of ATAMS. Both the trial and the extension are registered with ClinicalTrials.gov, numbers NCT00642902 (ATAMS) and NCT00853762 (ATAMS EXT). Between April 23, 2008, and early study termination on Sept 11, 2009, 255 patients were randomly assigned: 63 to placebo, 63 to atacicept 25 mg, 64 to 75 mg, and 65 to 150 mg. 90 (35%) patients completed the week 36 treatment visit, 26 (10%) discontinued before study termination (including one who dropped out before receiving study treatment), and 139 (55%) discontinued because of study termination. During the double-blind period of ATAMS, annualised relapse rates were higher in the atacicept groups than in the placebo group (atacicept 25 mg, 0·86, 95% CI 0·43–1·74; 75 mg, 0·79, 0·40–1·58; 150 mg, 0·98, 0·52–1·81; placebo, 0·38, 0·17–0·87). Mean numbers of gadolinium-enhancing T1 lesions per scan were similar in all groups (25 mg, 2·26, 0·97–5·27; 75 mg, 2·30, 1·08–4·92; 150 mg, 2·49, 1·18–5·27; placebo, 3·07, 1·40–6·77). Seven patients (one taking placebo and six atacicept) discontinued treatment because of adverse events. One death occurred in the placebo group. During the safety follow-up, immunoglobulin concentrations and B-cell counts returned towards predose values and annualised relapse rates in the atacicept groups decreased until they were similar to that of the placebo group Increased clinical disease activity associated with atacicept suggests that the role of B cells and humoral immunity in multiple sclerosis is complex. For studies that explore therapeutic immunomodulation in multiple sclerosis, rigorous monitoring for negative effects on clinical and MRI outcomes is warranted. Merck Serono (Merck KGaA) and EMD Serono (Merck KGaA).

In this trial, teriflunomide reduced annualized relapse rates and disability progression over 108 weeks of treatment in patients with relapsing MS, although diarrhea, nausea, hair thinning, and abnormalities in alanine aminotransferase levels were reported. Teriflunomide, the active metabolite of leflunomide, is being investigated as a new oral disease-modifying therapy for relapsing forms of multiple sclerosis. 1 Although the two drugs are related in structure, teriflunomide has a distinct profile. 2 It reversibly inhibits dihydroorotate dehydrogenase, a key mitochondrial enzyme involved in new pyrimidine synthesis for DNA replication. Consequently, the drug reduces T- and B-cell activation, proliferation, and function in response to autoantigens. However, teriflunomide preserves the replication and function of slowly dividing cells that use exogenous supplies of pyrimidine nucleotides through the so-called salvage pathway. 3 – 5 Teriflunomide has been shown to delay the onset of disease, . . .