Lower Annualized Relapse Rate Research Articles

Briumvi: a breakthrough in the treatment of relapsing multiple sclerosis: a review.

Multiple sclerosis (MS) is a chronic systemic autoimmune disorder characterized by plaques of demyelination, autoimmune inflammation, and astrocytic gliosis. The primary cells involved in the pathophysiology of MS are T cells. However, B cells have recently been implicated in the pathophysiology of the disease. Therefore, researchers have been exploring B cell therapy as an alternative treatment option for MS. B cell therapy is based on the targeted depletion of CD20-positive B cells. Rituximab, ocrelizumab, and ofatumumab are anti-CD20 antibodies already approved. Briumvi, the fourth type of anti-CD20 antibody was approved by FDA in December 2022, for the treatment of relapsing types of MS, including relapsing-remitting multiple sclerosis, active secondary progressive multiple sclerosis, and clinically isolated syndromes after the drug was tested in two randomized, double-blind, phase III, ULTIMATE I, and II trials which compared Briumvi (ublituximab) with Aubiago (teriflunomide). Ublituximab was found to have a much lower annual relapse rate in the ULTIMATE II trials than teriflunomide. Briumvi is a chimeric recombinant IgG1 monoclonal antibody directed against human CD20 with potential antineoplastic activity. Its mechanism of action involves several distinct processes that collectively lead to the depletion of B cells and suppression of the immune response. The primary mode of action of Briumvi is its high-affinity binding to CD20. Infusion-related reactions are the most common side effects encountered following intravenous administration of ublituximab.

Efficacy and safety of four-year ofatumumab treatment in relapsing multiple sclerosis: The ALITHIOS open-label extension

Background: Ofatumumab has demonstrated superior efficacy and favorable safety for up to 2.5 years versus teriflunomide in relapsing multiple sclerosis (RMS). Objective: Further characterize efficacy and safety of ofatumumab in RMS. Methods: Efficacy set: patients randomized to ofatumumab/teriflunomide in ASCLEPIOS I/II (core). Safety set: patients who received ⩾ 1 dose of ofatumumab in ASCLEPIOS I/II, APLIOS, APOLITOS (all core), or ALITHIOS (umbrella open-label extension). Patients received continuous ofatumumab or were newly switched from teriflunomide. Data cut-off: 25 September 2021. Results: In the efficacy set (n = 1882), the continuous ofatumumab group had a low annualized relapse rate (ARR 0.05 (95% confidence interval: 0.04–0.07)), low numbers of gadolinium-enhancing (Gd+) T1 lesions (0.01 lesions/scan) and fewer new/enlarging T2 lesions (annualized rate 0.08). Overall, 78.8% met three-parameter “no evidence of disease activity” criteria through 4 years. Switching from teriflunomide led to reduced ARR, risk of confirmed disability worsening (CDW), new/enlarging T2 lesions, Gd+ T1 lesions, and serum neurofilament light chain. In the continuous and newly switched ofatumumab groups, cumulative 3- and 6-month CDW rates remained low. In the safety set (n = 1969), the most frequently reported adverse events were infections and infestations (58.35%). No new safety signals were identified. Conclusion: Ofatumumab has a favorable longer-term benefit–risk profile in RMS. Trial registry: ALITHIOS (NCT03650114): https://clinicaltrials.gov/ct2/show/NCT03650114

Impact of adherence to disease modifying therapies on long-term clinical and economic outcomes in multiple sclerosis: A claims analysis of real-world data.

Multiple sclerosis (MS) is a chronic neurodegenerative inflammatory disease that requires long-term commitment to treatment for optimal outcomes. A variety of disease-modifying therapies (DMTs) are now available that reduce relapses and delay disease progression in people with MS. However, adherence remains a significant issue, with a variety of mental, physical, and emotional factors contributing to non-adherence. In a large number of studies, non-adherence has been associated with worse clinical outcomes (relapses and disease severity), a higher economic burden, and loss of work productivity. However, many of these studies were short-term (1-2 years) or cross-sectional studies; thus, more data are needed on the long-term clinical and economic impacts of DMT non-adherence. The objective of this study was to determine the longer-term impact of adherence to DMTs on disease activity and healthcare resource utilization (HCRU) in people with MS. The study hypothesis was that non-adherence to DMTs would be associated long-term with worse clinical outcomes and a higher economic burden. A retrospective administrative claims analysis of the US MarketScan® Commercial database (2011-2017) in individuals (18-65 years) with MS (based on International Classification of Disease coding) was conducted. Adherence was classified by proportion of days covered (PDC) ≥0.8 and non-adherence by PDC <0.8; sensitivity analyses helped further categorize as moderately (PDC ≥0.6-<0.8) or highly (PDC <0.6) non-adherent. Cohorts were matched using propensity score matching. Time to first relapse, annualized relapse rate (ARR), time to use of assistive devices (cane/walker or wheelchair), and annual HCRU (inpatient, emergency room [ER], outpatient, and MRI visits and costs) were compared between cohorts. 10,248 MS cases were identified; 58% met adherence criteria, and 42% met non-adherence criteria. Mean follow-up from diagnosis or first DMT claim was 5.3 years. Adherent individuals had a longer time to first relapse (hazard ratio [HR] 0.83; 95% confidence interval [CI]: 0.77-0.90; p<0.0001), a lower ARR (0.13vs. 0.18, respectively; rate ratio [RR] 0.75 [95% CI: 0.71-0.79]; p<0.0001), and longer lag times to cane/walker use (HR 0.79 [95% CI: 0.66-0.94]; p=0.0067) and wheelchair use (HR 0.68 [95% CI: 0.55-0.83]; p=0.0002) than non-adherent individuals. Adherent individuals had fewer annual inpatient and ER visits and lower total costs than those who were non-adherent (p<0.0001). Sensitivity analyses showed that differences in disease activity and HCRU were generally more pronounced between matched adherent and highly non-adherent pairs than between matched adherent and moderately non-adherent pairs. Significant differences in MS disease activity and HCRU were observed based on adherence to DMTs. Our study underscores the negative impact of non-adherence to DMTs on long-term clinical and economic outcomes in MS.

Clinical feature and disease outcome in patients with myelin oligodendrocyte glycoprotein antibody-associated disorder: a Chinese study

BackgroundTo identify factors associated with relapse risk and disability in myelin oligodendrocyte glycoprotein antibody-associated disorder (MOGAD).MethodBetween 2016 and 2021, 186 patients with MOGAD were included in the study. Factors associated...

Safety and Clinical Efficacy Outcomes From the Long-term Extension Study of Tolebrutinib in Participants With Relapsing Multiple Sclerosis: 2.5-Year Results (S16.010)

Safety and Clinical Efficacy Outcomes From the Long-term Extension Study of Tolebrutinib in Participants With Relapsing Multiple Sclerosis: 2.5-Year Results (S16.010)

MRI, Efficacy, and Safety of Tolebrutinib in Patients with Highly Active Disease (HAD): 2-Year Data from the Phase 2b Long-term Safety (LTS) Study (P6-3.017)

MRI, Efficacy, and Safety of Tolebrutinib in Patients with Highly Active Disease (HAD): 2-Year Data from the Phase 2b Long-term Safety (LTS) Study (P6-3.017)

Comparative effectiveness of cladribine tablets versus other oral disease-modifying treatments for multiple sclerosis: Results from MSBase registry

Background: Effectiveness of cladribine tablets, an oral disease-modifying treatment (DMT) for multiple sclerosis (MS), was established in clinical trials and confirmed with real-world experience. Objectives: Use real-world data to compare treatment patterns and clinical outcomes in people with MS (pwMS) treated with cladribine tablets versus other oral DMTs. Methods: Retrospective treatment comparisons were based on data from the international MSBase registry. Eligible pwMS started treatment with cladribine, fingolimod, dimethyl fumarate, or teriflunomide tablets from 2018 to mid-2021 and were censored at treatment discontinuation/switch, death, loss to follow-up, pregnancy, or study period end. Treatment persistence was evaluated as time to discontinuation/switch; relapse outcomes included time to first relapse and annualized relapse rate (ARR). Results: Cohorts included 633 pwMS receiving cladribine tablets, 1195 receiving fingolimod, 912 receiving dimethyl fumarate, and 735 receiving teriflunomide. Individuals treated with fingolimod, dimethyl fumarate, or teriflunomide switched treatment significantly more quickly than matched cladribine tablet cohorts (adjusted hazard ratio (95% confidence interval): 4.00 (2.54–6.32), 7.04 (4.16–11.93), and 6.52 (3.79–11.22), respectively). Cladribine tablet cohorts had significantly longer time-to-treatment discontinuation, time to first relapse, and lower ARR, compared with other oral DMT cohorts. Conclusion: Cladribine tablets were associated with a significantly greater real-world treatment persistence and more favorable relapse outcomes than all oral DMT comparators.

Ublituximab versus Teriflunomide in Relapsing Multiple Sclerosis

BackgroundThe monoclonal antibody ublituximab enhances antibody-dependent cellular cytolysis and produces B-cell depletion. Ublituximab is being evaluated for the treatment of relapsing multiple sclerosis.MethodsIn 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.ResultsA 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; P<0.001); 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; P<0.001) in the ULTIMATE I trial and 0.01 and 0.25, respectively (rate ratio, 0.04; 95% CI, 0.02 to 0.06; P<0.001), 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.ConclusionsAmong 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.)

Assessing the Risk of Relapse Requiring Corticosteroids After In Vitro Fertilization in Women With Multiple Sclerosis.

Several studies have shown an increased risk of relapse after in vitro fertilization (IVF) in women with multiple sclerosis (MS), especially when a gonadotrophin-releasing hormone (GnRH) agonist stimulation protocol was used. Our objective was to investigate the risk of relapse after IVF in women with MS, overall and according to stimulation protocol (GnRH agonists vs antagonists), using data from the French national health insurance database. This retrospective cohort study included all women with MS who have benefited from IVF between January 1, 2010, and December 31, 2015, in France. Three-month exposed periods after IVF were compared with unexposed periods before IVF, each woman being her own control. Four outcomes were considered: annualized relapse rate (ARR), proportion of IVF with relapse, difference in the number of relapses "after-before," and the delay from IVF to the first relapse. Relapses were identified by an algorithm based on MS-related hospital admissions and the use of corticosteroid therapy. Stimulation protocols and disease-modifying therapies (DMTs) were identified using drug claims. Zero-inflated Poisson regression models adjusted for age at IVF and the presence of DMT were used. A random effect on women was included because women may undergo multiple IVF procedures. Subgroup analyses by stimulation protocol and IVF outcome (pregnancy or failure) were conducted. A total of 225 women accounting for 338 IVF procedures were included (the mean age at the first IVF 34.6 ± 4.5 years; 36% of women underwent at least 2 IVF procedures during the period). No increase in the risk of relapse after IVF was found overall (before vs after IVF: 0.20 vs 0.18 relapse per patient-year; 7.7% vs 7.1% of IVF with women having at least one relapse) and in subgroups. A lower ARR before and after IVF was observed among women who remained treated until IVF. The maintenance of DMT until IVF seemed to be a determining factor in reducing the risk of relapse. Women with MS should be reassured because we did not show an increased risk of relapse requiring the use of corticosteroid therapy after IVF neither with GnRH agonists nor with GnRH antagonists.

Neuromyelitis Optica Spectrum Disorder With Anti-Aquaporin-4 Antibody: Outcome Prediction Models.

BackgroundRecognizing the predictors of disease relapses in patients with anti-aquaporin-4 antibody (AQP4-ab)-positive neuromyelitis optica spectrum disorder (NMOSD) is essential for individualized treatment strategy. We aimed to identify the factors that predicted relapses among patients with AQP4-ab-positive NMOSD, develop outcome prediction models, and validate them in a multicenter validation cohort.MethodsBetween January 2015 and December 2020, 820 patients with NMOSD were registered at Huashan Hospital. We retrospectively reviewed their medical records, and included 358 AQP4-ab-positive patients with 1135 treatment episodes. Univariate and multivariate analyses were used to explore the predictors of relapse, severe visual or motor disability during follow-up. A model predicting the 1- and 2-year relapse-free probability was developed and validated in an external validation cohort of 92 patients with 213 treatment episodes.ResultsLower serum AQP4-ab titer (< 1:100), higher Expanded Disability Status Scale (EDSS) score at onset (≥ 2.5), and use of intravenous methylprednisolone (IVMP) at the first attack predicted an overall lower annualized relapse rate. Older age (> 48 years), optic neuritis at onset, and higher onset EDSS score (≥ 2.5) significantly increased the risk for blindness, while IVMP at the first attack and maintenance therapy reduced the risk for blindness. Myelitis at onset increased the possibility of motor disability (EDSS ≥ 6.0), severe motor disability or death (EDSS ≥ 8.0), while maintenance therapy reduced these possibilities. Anderson and Gill model identified that the risk factors predicting recurrent relapses under certain treatment status were female gender, high AQP4-ab titer (≥ 1:100), previous attack under same therapy, lower EDSS score at treatment initiation (< 2.5), and no maintenance therapy or oral prednisone lasting less than 6 months. A nomogram using the above factors showed good discrimination and calibration abilities. The concordance indexes in the primary and validation cohort were 0.66 and 0.65, respectively.ConclusionThis study reports the demographic, clinical and therapeutic predictors of relapse, and severe visual or motor disability in NMOSD. Early identification of patients at risk of unfavorable outcomes is of paramount importance to inform treatment decisions.

Treatment response, risk of relapse and clinical characteristics of Taiwanese patients with neuromyelitis optica spectrum disorder

The long-term disease course and efficacy of maintenance therapies have rarely been investigated in Asian patients with neuromyelitis optica spectrum disorder (NMOSD). Medical records of patients fulfilling the 2015 International Consensus Diagnostic Criteria for NMOSD at three medical centers in Taiwan were systematically analyzed. Linear regression analysis was performed to investigate factors related to annualized relapse rate (ARR); survival analysis was used to estimate the relapse-free intervals among therapies. A total of 557 relapses affecting 648 regions (202 optic neuritis, 352 acute myelitis, and 94 brain syndromes) in 204 patients were analyzed during a follow-up period of 69.5 months (range, 1-420). Up to 36.1% of myelitis-onset patients and 24.0% of optic neuritis-onset patients exhibited a limited form disease, defined as having one or more relapses confined to the same region. The median ARR was significantly lower in patients with limited form disease than those with relapses involving multiple regions (0.30 vs. 0.47, respectively). An older age at disease onset was associated with a lower ARR (p=0.023). Kaplan-Meier analysis showed that the estimated time (months) to next relapse was longest in rituximab-treatment group (58.0±13.2), followed by immunosuppressant (48.5±4.8) or prednisone (29.6±4.6) groups, and shortest in those without maintenance therapy (27.6±4.2) (p=8.1×10-7). Limited form disease and older age at disease onset are associated with a lower relapse rate in NMOSD. Compared to no maintenance therapy, rituximab and immunosuppressant significantly reduce the relapse risks.

The Dimethyl Fumarate Experience: A Handy Drug With Broad Clinical Utility.

Objectives: The aim of this study was to characterize multiple sclerosis (MS) patients exposed to dimethyl fumarate (DMF) and to evaluate the predictors of therapeutic response. In addition, the study offers a picture of how DMF use has changed over the past few years in naive or switcher patients.Methods: In this observational monocentric study, we examined the prescription flow of DMF in MS patients categorized as naive or switchers (for safety/tolerability, ineffectiveness, and de-escalation strategy) from 2015 to 2019. Clinical and magnetic resonance imaging data of DMF-treated patients were analyzed, and NEDA-3 status at 24 months was evaluated by the three assessment components (absence of clinical relapses, no Expanded Disability Status Scale progression, no radiological activity). Determinants of therapeutic response were also evaluated using regression analysis.Results: The sample included 595 MS patients exposed to DMF categorized as naive (158; 26.5%) and switchers for reasons of safety/tolerability (198; 33.3%), inefficacy (175; 29.4%), and de-escalation strategy (64; 10.8%). A 15% increase in DMF use in naive and horizontal shift groups was observed in the last 3 years of observation, whereas there was a drop, with prescription passed from ~20% to <5%, as an exit strategy from second-line therapies. NEDA-3 status was calculated for 340 patients after 24 months of DMF treatment and achieved in 188 (55.3%) of these. Analyzing the predictors of DMF response, we observed that lower annualized relapse rate (ARR) in 2 years pretreatment [hazard ratio (HR) = 0.49, p = 0.001] and being naive patients (HR = 1.38, p = 0.035) were associated with achievement of NEDA-3. Analogously, ARR in 2 years pretreatment affected the NEDA-3 achievement at 24 months in patients of the de-escalation group (HR = 0.07, p = 0.041), also indicating an effect related to the DMF initiation within 3 months (HR = 1.24, p = 0.029).Conclusion: Our findings confirm DMF as a handy drug with broad clinical utility, with greater benefits for naive patients and horizontal switchers. Additionally, an increase in the flow of DMF prescriptions in these two groups of patients was also observed in our cohort.

Concentration of evobrutinib, a BTK inhibitor, in cerebrospinal fluid during treatment of patients with relapsing multiple sclerosis in a phase 2 study

Background Evobrutinib, a highly selective Bruton's tyrosine kinase (BTK) inhibitor, demonstrated a low annualized relapse rate (75mg twice-daily: 0.11, 95%CI 0.04–0.25) in a phase 2 randomized controlled trial in patients with relapsing multiple sclerosis (RMS; NCT02975349). This was maintained in an open-label extension (OLE) through 108 weeks (0.12, 95%CI 0.06–0.22; 75mg once-daily for ∼48 weeks, then 75mg twice-daily). Evobrutinib concentrations in the brain achieved high BTK occupancy in an experimental autoimmune encephalomyelitis model. We investigated evobrutinib distribution into cerebrospinal fluid (CSF) in patients with RMS. Methods Plasma and CSF samples were collected 2–3 hours post-dose from phase 2 OLE patients (75mg twice-daily for >1 year, including ≥6 days uninterrupted dosing before sampling) and evobrutinib concentrations measured. Plasma protein binding was measured ex vivo in sub-study participant samples to determine free plasma evobrutinib concentrations. Results Nine patients from one center were enrolled: 89% female, median age 50.5 years and median disease duration 6.9 years (at phase 2 study baseline); all had stable RMS. In plasma, mean total evobrutinib concentration (95%CI) was 115.0 (71.8–184.3) ng/mL and free evobrutinib concentration was 5.5 ng/mL. Evobrutinib was quantifiable in the CSF of all patients; the geometric mean concentration in CSF was 3.21 (2.27–4.55) ng/mL; 58% of the free plasma concentration. Conclusion Evobrutinib administered at an efficacious, steady-state dose was detected in the CSF of patients with RMS at concentrations consistent with free plasma concentrations. Therefore, evobrutinib may inhibit BTK-expressing cells, including B cells and microglia, in the central nervous system.

PND1 IMPACT of EARLY Disease Modifying Therapy (DMT) Treatment Initiation and Use of High-Efficacy (HET) on Clinical and Health Outcomes in Patients with Multiple Sclerosis (MS)

To explore the impact of early DMT treatment initiation and use of HET on clinical and health outcomes in patients with MS. A targeted literature review was conducted using Embase (including Medline) to identify studies published from January 2006-March 2020. Search terms included clinical-outcomes: annualized relapse rate (ARR), disability progression, magnetic resonance imaging (MRI) outcomes; and health-related outcomes: quality of life (QoL), work-productivity, therapy persistence, and healthcare resource utilization (HCRU). Among the screened studies, 69 were included in this review (50 observational studies, 18 clinical trials, and 1 systematic review; 35 US/Canadian, 20 global, 12 European, and 2 Australian studies). ARR and disease progression were the most common outcomes in the included studies. Inhibition of MS disability, slower disease progression, lower ARR, improved persistence/adherence, cost-savings, and decrease in HCRU were achieved if a DMT was initiated early following diagnosis. Definition of HET varied across studies; while most studies identified infused DMTs as HET, some studies also included fingolimod as HET. Use of HET was associated with improvements in QoL, work productivity, therapy persistence, and reduction in hospitalizations. Of 4 studies which evaluated early initiation of HET (E-HET), all favored the induction vs escalation approach. Overall, several studies found that E-HET in the MS disease process produced greater efficacy in reducing relapse rate, MRI-activity, brain atrophy, and long-term disease progression. However, no studies were identified that addressed the effect of E-HET on health-related outcomes. Emerging evidence suggests that initiating E-HET in MS leads to better clinical outcomes while HET use is associated with improved health-related outcomes. However, a need exists to better understand the humanistic and economic benefits of initiating E-HET in the MS disease course and in standardizing the definition of HET to better inform treatment decision-making for patients and providers.

Anti-MOG antibody–associated disorders: differences in clinical profiles and prognosis in Japan and Germany

BackgroundNeurological disorders with IgG antibodies against myelin-oligodendrocyte glycoprotein (MOG-IgG) have been increasingly recognised as a new type of neuroinflammatory disorder.ObjectiveThe study aimed to identify regional and ethnic differences in clinical...

Natalizumab is associated with early improvement of working ability in relapsing-remitting multiple sclerosis patients: WANT observational study results.

The Work Ability in Natalizumab-Treated MS Patients (WANT) study assessed work ability, quality of life, and cognitive processing speed during natalizumab treatment. WANT was a 1-year, prospective, multicenter observational study conducted in Italy. Inclusion criteria included relapsing-remitting multiple sclerosis (MS), natalizumab treatment, full-time worker status, and loss of working hours due to MS as measured by the Work Productivity and Activity Impairment Questionnaire for MS (WPAI:MS). The primary endpoint was change in WPAI:MS domain scores after 1 year on natalizumab. Secondary endpoints included change in annualized relapse rate (ARR), Multiple Sclerosis Impact Scale (MSIS-29) score, and Symbol Digit Modalities Test (SDMT) score. At enrollment, the 91 patients had a mean age of 38.3 (standard deviation [SD], 9.0) years and a mean ARR of 1.5 (SD, 0.8). After 1 year, improvements were observed in all WPAI:MS domains, with significant reductions in Absenteeism (-4.2 [SD, 26.0], p = 0.0190) and Work Productivity Loss (-7.2 [SD, 28.6]; p = 0.0456). These changes were accompanied by a low ARR (0.1), and 87.9% of patients were relapse free. Significant improvement was observed in MSIS-29 physical and psychological domains (reductions of 2.8 [SD, 11.6; p = 0.0295] and 6.3 [SD, 15.6; p = 0.0007], respectively) and SDMT score (increase of 2.4 [SD, 7.9; p = 0.0006]). Adverse events were reported in 32 of 104 patients (30.8%). The reductions in Absenteeism and Work Productivity Loss and the improved physical and psychological functioning reported after 1 year of natalizumab treatment in real-world settings extend our understanding of natalizumab's effects on patient-centric and health economics outcomes.

Ofatumumab versus Teriflunomide in Multiple Sclerosis

BackgroundOfatumumab, a subcutaneous anti-CD20 monoclonal antibody, selectively depletes B cells. Teriflunomide, an oral inhibitor of pyrimidine synthesis, reduces T-cell and B-cell activation. The relative effects of these two drugs in patients with multiple sclerosis are not known.MethodsIn two double-blind, double-dummy, phase 3 trials, we randomly assigned patients with relapsing multiple sclerosis to receive subcutaneous ofatumumab (20 mg every 4 weeks after 20-mg loading doses at days 1, 7, and 14) or oral teriflunomide (14 mg daily) for up to 30 months. The primary end point was the annualized relapse rate. Secondary end points included disability worsening confirmed at 3 months or 6 months, disability improvement confirmed at 6 months, the number of gadolinium-enhancing lesions per T1-weighted magnetic resonance imaging (MRI) scan, the annualized rate of new or enlarging lesions on T2-weighted MRI, serum neurofilament light chain levels at month 3, and change in brain volume.ResultsOverall, 946 patients were assigned to receive ofatumumab and 936 to receive teriflunomide; the median follow-up was 1.6 years. The annualized relapse rates in the ofatumumab and teriflunomide groups were 0.11 and 0.22, respectively, in trial 1 (difference, −0.11; 95% confidence interval [CI], −0.16 to −0.06; P<0.001) and 0.10 and 0.25 in trial 2 (difference, −0.15; 95% CI, −0.20 to −0.09; P<0.001). In the pooled trials, the percentage of patients with disability worsening confirmed at 3 months was 10.9% with ofatumumab and 15.0% with teriflunomide (hazard ratio, 0.66; P=0.002); the percentage with disability worsening confirmed at 6 months was 8.1% and 12.0%, respectively (hazard ratio, 0.68; P=0.01); and the percentage with disability improvement confirmed at 6 months was 11.0% and 8.1% (hazard ratio, 1.35; P=0.09). The number of gadolinium-enhancing lesions per T1-weighted MRI scan, the annualized rate of lesions on T2-weighted MRI, and serum neurofilament light chain levels, but not the change in brain volume, were in the same direction as the primary end point. Injection-related reactions occurred in 20.2% in the ofatumumab group and in 15.0% in the teriflunomide group (placebo injections). Serious infections occurred in 2.5% and 1.8% of the patients in the respective groups.ConclusionsAmong patients with multiple sclerosis, ofatumumab was associated with lower annualized relapse rates than teriflunomide. (Funded by Novartis; ASCLEPIOS I and II ClinicalTrials.gov numbers, NCT02792218 and NCT02792231.)

Real-World Safety and Effectiveness of Dimethyl Fumarate in Hispanic or Latino Patients with Multiple Sclerosis: 3-Year Results from ESTEEM.

IntroductionCompared with the non-Hispanic/non-Latino population, Hispanic/Latino patients with multiple sclerosis (MS) are reported to exhibit greater disease severity. Geographical location and genetics play a role in differences observed across Hispanic/Latino subpopulations. We evaluated real-world safety and effectiveness of dimethyl fumarate (DMF) on MS disease activity in Hispanic/Latino patients.MethodsESTEEM is an ongoing, 5-year, multinational, prospective study evaluating long-term safety and effectiveness of DMF in patients with MS. This interim analysis included patients newly prescribed DMF in routine practice at 394 sites globally.ResultsOverall, 4986 non-Hispanic/non-Latino and 98 Hispanic/Latino patients were analyzed; median (range) follow-up was 18 (2–37) months. Unadjusted annualized relapse rates (ARRs) for 12 months before DMF initiation versus 36 months post DMF initiation, respectively, were: non-Hispanic/non-Latino patients, 0.82 (95% CI 0.80–0.84) versus 0.10 (95% CI 0.09–0.10), 88% lower ARR (P < 0.0001); Hispanic/Latino patients, 0.80 (95% CI 0.65–1.00) versus 0.09 (95% CI 0.06–0.14), 89% lower ARR (P < 0.0001). In total, 28 (29%) Hispanic/Latino patients reported adverse events leading to treatment discontinuation; gastrointestinal (GI) disorders (n = 10, 10%) were the most common, consistent with the non-Hispanic/non-Latino population (8%). Median lymphocyte counts decreased by approximately 24% in the first year (vs 36% decrease in non-Hispanic/non-Latino patients) then remained stable and above the lower limit of normal in most patients.ConclusionsRelapse rates remained low in Hispanic/Latino patients, consistent with non-Hispanic/non-Latino patients. The safety profile of DMF in Hispanic/Latino patients was consistent with safety findings from the non-Hispanic/non-Latino ESTEEM population, demonstrating the real-world treatment benefit of DMF in the Hispanic/Latino patient cohort.

Real-World Safety and Effectiveness of Dimethyl Fumarate in Black or African American Patients with Multiple Sclerosis: 3-Year Results from ESTEEM.

IntroductionBlack or African American (black/AA) patients with multiple sclerosis (MS) are reported to exhibit greater disease severity compared with non-black or non-AA patients. Whether differences exist in response to MS disease-modifying therapies remains uncertain, as MS clinical trials have included low numbers of non-white patients. We evaluated real-world safety and effectiveness of dimethyl fumarate (DMF) on MS disease activity in black/AA patients.MethodsESTEEM is an ongoing, 5-year, multinational, prospective study evaluating long-term safety and effectiveness of DMF in patients with MS. This interim analysis included patients newly prescribed DMF in routine practice at 394 sites globally.ResultsOverall, 4897 non-black/non-AA and 187 black/AA patients were analyzed; median (range) follow-up 18 (2–37) months. Unadjusted annualized relapse rates (ARRs) for 12 months before DMF initiation versus 36 months post DMF initiation, respectively, were: non-black/non-AA patients, 0.83 (95% CI 0.80–0.85) versus 0.10 (95% CI 0.09–0.10), 88% lower ARR (P < 0.0001); black/AA patients, 0.68 (95% CI 0.58–0.80) versus 0.07 (95% CI 0.05–0.10), 90% lower ARR (P < 0.0001). In total, 35 (19%) black/AA patients reported adverse events leading to treatment discontinuation; gastrointestinal disorders were most common (7%), consistent with non-black/non-AA patients (8%). Median lymphocyte counts decreased by 22% in the first year (vs 36% in non-black/non-AA patients), then remained stable and above lower limit of normal in most patients.ConclusionsRelapse rates remained low in black/AA patients, consistent with non-black/non-AA patients. The safety profile of DMF in black/AA patients was consistent with that in the non-black/non-AA ESTEEM population, although lymphocyte decrease was less pronounced in black/AA patients.

Long-Term Effect of Immediate Versus Delayed Fingolimod Treatment in Young Adult Patients with Relapsing-Remitting Multiple Sclerosis: Pooled Analysis from the FREEDOMS/FREEDOMSII Trials.

IntroductionFingolimod has demonstrated clinical and MRI benefits versus placebo/interferon β-1a in young adults with multiple sclerosis (MS). Here we report the long-term effects of fingolimod 0.5 mg on clinical and MRI outcomes in young adults with MS aged ≤ 30 years followed up for up to 8 years (96 months).MethodsThis post hoc analysis of pooled FREEDOMS/FREEDOMS II studies included patients who either received fingolimod 0.5 mg from randomization (immediate; N = 163) or switched from placebo to fingolimod at month (M) 24 (delayed; N = 147). The 6-month confirmed disability improvement [6m-CDI: based on Expanded Disability Status Scale (EDSS)], 6m-CDI-plus (6m-CDI+; EDSS, 9-Hole Peg Test, Timed 25-Foot Walk Test), 6-month confirmed disability progression (6m-CDP), time to EDSS score ≥ 4, annualized relapse rates (ARRs), new/newly enlarging T2 (neT2) lesions, and annual rate of brain volume loss (BVL) were analyzed from baseline to M24, M48, and M96. Cox regression and negative binomial regression models were used to analyze measured outcomes.ResultsAt baseline, more than two-thirds of young adult patients were treatment naïve, had more than two relapses in the previous 2 years, and EDSS score < 2. From M0 to M96, a significantly higher proportion of young adult patients in the immediate group (vs. delayed group) achieved 6m-CDI (58.2% vs. 30.5%, p = 0.0206) and 6m-CDI+ (70.6% vs. 42.3%, p = 0.0149); significantly fewer patients reached 6m-CDP (20.1% vs. 34.7%, p = 0.0058) and EDSS ≥ 4 (24.1% vs. 34.1%, p = 0.0041). Up to M96, young adults in the immediate versus delayed group had lower ARRs (0.16 vs. 0.38, p < 0.0001) and a higher proportion of patients were free of neT2 lesions at M48 (31.0% vs. 5.0%, p = 0.0011).ConclusionIn young adult patients with MS, immediate versus delayed fingolimod treatment was associated with improved disease outcomes and greater long-term benefits in both disease activity and disability progression.FundingNovartis Pharma AG.