Evaluating the efficacy and safety of transitioning patients with multiple sclerosis from natalizumab to ocrelizumab (OCTAVE).

INTRODUCTION: Natalizumab is associated with a risk of progressive multifocal leukoencephalopathy (PML) in multiple sclerosis (MS) patients infected with John Cunningham virus (JCV). Ocrelizumab has demonstrated efficacy to treat MS; however, its safety in patients previously treated with natalizumab is unclear. OBJECTIVE: To evaluate the safety and efficacy of ocrelizumab in patients with relapsing MS (RMS) previously treated with natalizumab. METHODS: Clinically and radiographically stable RMS patients, ages 18-65 treated with natalizumab for ⩾ 12 months, were enrolled in the study and initiated ocrelizumab 4-6 weeks after their final dose of natalizumab. Relapse assessment, expanded disability status scale, and brain magnetic resonance imaging (MRI) were performed prior to starting ocrelizumab and at months 3, 6, 9, and 12. RESULTS: Forty-three patients were enrolled, and 41 (95%) completed the study. Two patients had a relapse while on ocrelizumab, one at month 9 and the other at month 12, without changes on brain MRI. Two additional patients had new brain MRI lesions detected at month 3, with no new symptoms. Thirteen serious adverse events (SAEs) were recorded, four of which were considered possibly related to ocrelizumab. CONCLUSION: Overall, our study indicates clinical and MRI stability for most patients transitioning from natalizumab to ocrelizumab. CLINICALTRIALS.GOV IDENTIFIER: NCT03157830.

Quality of life among injectable and oral disease-modifying therapy users in the Pacific Northwest Multiple Sclerosis Registry.

BACKGROUND: Nine oral disease-modifying therapies (DMTs) have been approved for the treatment of multiple sclerosis (MS) in the United States. Few studies have examined self-reported quality of life (QoL) and functional status outcomes among patients who switch to oral medications from injectable MS therapies. This study compares self-reported QoL and disability status between participants switching from injectable to oral DMTs, to those who stay on injectable DMTs continuously for the same time period. METHODS: Longitudinal data were assessed from relapsing MS participants in the Pacific Northwest MS Registry completing a minimum of two surveys between 2012 and 2018 with a maximum of 36 months between surveys. Stayers were defined as those who remained on injectable DMTs continuously from Time 1 to Time 2; switchers were those who switched from injectable to either fingolimod, teriflunomide or dimethyl fumarate during the same time interval. Outcomes of interest were physical and psychological QoL, measured by the Multiple Sclerosis Impact Scale (MSIS-29), and disability, measured by the Patient Determined Disease Steps (PDDS). To analyze the effect of switching to oral DMT on outcomes at Time 2, a one-to-two propensity score matching (PSM) was used to match switchers to stayers. Outcomes at Time 2 were analyzed using paired t-test for QoL scores, and Stuart Maxwell test for PDDS as a categorical variable. RESULTS: Among 2385 participants who returned consecutive yearly surveys, 413 met the inclusion criteria for stayers and 66 for switchers. After one-to-two PSM, 124 stayers were matched to 62 switchers. Paired t-test showed no differences between switchers and stayers for physical (mean difference: - 0.41; [95% confidence interval CI: - 3.3-2.4]; p = 0.78) or psychological (mean difference: - 0.23; [95% CI, - 1.6- 1.1]; p = 0.74) QoL. Additionally, no differences were seen between switchers and stayers in self-reported disability status. CONCLUSIONS: MS registry participants who switched to an oral DMT from injectable showed no significant differences in QoL or self-reported disability status compared to those remaining on injectable DMT continuously in the same time period.

Improved cognitive outcomes in patients with relapsing-remitting multiple sclerosis treated with daclizumab beta: Results from the DECIDE study.

BACKGROUND: Cognitive impairment is common in multiple sclerosis (MS), with cognitive processing speed being the most frequently affected domain. OBJECTIVE: Examine the effects of daclizumab beta versus intramuscular (IM) interferon (IFN) beta-1a on cognitive processing speed as assessed by Symbol Digit Modalities Test (SDMT). METHODS: In DECIDE, patients with relapsing-remitting multiple sclerosis (RRMS) (age: 18-55 years; Expanded Disability Status Scale (EDSS) score 0-5.0) were randomized to daclizumab beta ( n = 919) or IM IFN beta-1a ( n = 922) for 96-144 weeks. SDMT was administered at baseline and at 24-week intervals. RESULTS: At week 96, significantly greater mean improvement from baseline in SDMT was observed with daclizumab beta versus IM IFN beta-1a ( p = 0.0274). Significantly more patients treated with daclizumab beta showed clinically meaningful improvement in SDMT (increase from baseline of ⩾3 points ( p = 0.0153) or ⩾4 points ( p = 0.0366)), and significantly fewer patients showed clinically meaningful worsening (decrease from baseline of ⩾3 points ( p = 0.0103)). Odds representing risk of worsening versus stability or improvement on SDMT were significantly smaller for daclizumab beta ( p = 0.0088 (3-point threshold); p = 0.0267 (4-point threshold)). In patients completing 144 weeks of treatment, the effects of daclizumab beta were generally sustained. CONCLUSION: These results provide evidence for a benefit of daclizumab beta versus IM IFN beta-1a on cognitive processing speed in RRMS. TRIAL REGISTRATION: ClinicalTrials.gov identifier NCT01064401 (Efficacy and Safety of BIIB019 (Daclizumab High Yield Process) Versus Interferon ß 1a in Participants With Relapsing-Remitting Multiple Sclerosis (DECIDE)): https://clinicaltrials.gov/ct2/show/NCT01064401 .

Three-year clinical outcomes of relapsing multiple sclerosis patients treated with dimethyl fumarate in a United States community health center.

BACKGROUND: Following approval of dimethyl fumarate (DMF), we established a registry of relapsing multiple sclerosis (RMS) patients taking DMF at our community MS center. OBJECTIVE: To track DMF patients' tolerability, disease progression, and lymphopenia. METHODS: Patients prescribed DMF for RMS from March 2013 to March 2016 were prospectively enrolled ( N = 412). Baseline data, clinical relapses, magnetic resonance imaging (MRI) activity, discontinuation, and lymphocyte counts were captured through chart review. RESULTS: The mean age of patients starting DMF was 49.4 ± 12.0 years and 70% transitioned from a previous disease-modifying therapy (DMT). Of the patients, 38% discontinued DMF, 76% of whom discontinued due to side effects. Clinical relapse and MRI activity were low. Comparing patients who transitioned from interferon-ß (IFN), glatiramer acetate (GA), or natalizumab (NTZ), patients previously on NTZ had higher rates of relapse than those previously on GA (annualized relapse rate p = 0.039, percent relapse p = 0.021). Grade III lymphopenia developed in 11% of patients. Lymphopenia was associated with older age ( p < 0.001) and longer disease duration ( p < 0.001). CONCLUSION: Given the high rates of lymphopenia and discontinuation, it has become our clinical practice to more closely scrutinize older patients and those with a longer disease duration who are potential candidates for initiating DMF therapy.

Efficacy of daclizumab beta versus intramuscular interferon beta-1a on disability progression across patient demographic and disease activity subgroups in DECIDE.

BACKGROUND: Demonstration of clinical benefits on disability progression measures is an important attribute of effective multiple sclerosis (MS) treatments. OBJECTIVE: Examine efficacy of daclizumab beta versus intramuscular (IM) interferon beta-1a on measures of disability progression in patient subgroups from DECIDE. METHODS: Twenty-four-week confirmed disability progression (CDP), 24-week sustained worsening on a modified Multiple Sclerosis Functional Composite (MSFCS) where 3-Second Paced Auditory Serial Addition Test was replaced by Symbol Digit Modalities Test, and proportion of patients with clinically meaningful worsening in 29-Item Multiple Sclerosis Impact Scale physical impact subscale (MSIS-29 PHYS) score from baseline to week 96 were examined in the overall population and subgroups defined by baseline demographic/disease characteristics. RESULTS: Daclizumab beta significantly reduced risk of 24-week CDP (hazard ratio (HR), 0.73; 95% confidence interval (95% CI), 0.55-0.98), risk of 24-week sustained MSFCS progression (HR, 0.80; 95% CI, 0.67-0.95), and odds of clinically meaningful worsening in MSIS-29 PHYS (odds ratio, 0.76; 95% CI, 0.60-0.95) versus IM interferon beta-1a. Point estimates showed trends favoring daclizumab beta over IM interferon beta-1a across several patient subgroups for all three outcome measures. CONCLUSION: Daclizumab beta showed consistent benefit versus IM interferon beta-1a across measures assessing patient disability/function and across a range of clinical baseline characteristics in patients with relapsing-remitting MS.

MRI utility in the detection of disease activity in clinically stable patients with multiple sclerosis: a retrospective analysis of a community based cohort.

BACKGROUND: Since the application of MRI scanning to the diagnosis and treatment of multiple sclerosis, it has been recognized that only a small fraction of lesions seen on MRI scans produce recognizable symptoms or neurological findings. Because new lesions may occur without clinical detection, the recommendation has been made that MRI scanning be performed on a routine scheduled basis, usually yearly, even in patients who are clinically stable. METHODS: A retrospective chart review study was conducted on MS patients who had MRI scans of the central nervous system between 2009 and 2012 at Providence Multiple Sclerosis Center. Inclusion criteria were patients with relapsing MS who had been treated with interferon beta or glatiramer acetate for 6 months or longer. Information on type, indication, and result of MRI and whether a change in disease modifying therapy occurred as a result of the scan was collected. RESULTS: Of the 436 clinically stable patients who had routine MRI, 16.7 % of subjects had scans revealing new, enlarged or active lesions, yet in only 4.4 % patients was there a change in therapy based upon MRI results. Subjects who had MRI changes were found to be younger (50.15 vs 53.43, p = 0.02) but there was no significant difference in other demographic or clinical characteristics when compared with the subjects who did not have MRI changes. Thirty-six percent of patients with MRI changes did not change DMT due to patient request. CONCLUSIONS: This study provides data on the likelihood of detecting MRI-documented disease activity, in patients demonstrating longer term sustained clinical stability while receiving DMTs. These results may materially assist in the decision whether or not to perform yearly MRI scanning of such patients. The potential clinical impact of the results of routine MRI scanning must be weighed against the consideration of considerable expense of frequent MRI scanning, and the yet unknown adverse impact of retained gadolinium in patients repeatedly receiving this contrast agent. The long-term clinical impact of not changing DMTs in patients in whom MRI changes were observed will be addressed in future studies of this cohort.

Safety and efficacy of daclizumab in relapsing-remitting multiple sclerosis: 3-year results from the SELECTED open-label extension study.

BACKGROUND: Daclizumab is a humanized monoclonal antibody against CD25 that modulates interleukin 2 signaling. The SELECT TRILOGY of clinical studies (SELECT/SELECTION/SELECTED) evaluated the safety and efficacy of daclizumab in patients with relapsing-remitting multiple sclerosis (RRMS). We report the long-term safety and efficacy of daclizumab 150 mg subcutaneous every 4 weeks in patients with RRMS in the SELECTED open-label extension study. METHODS: An interim intent-to-treat analysis of all enrolled patients was performed in January 2014 for this ongoing study. RESULTS: The SELECTED study enrolled 90% of patients who completed SELECTION. In the safety and efficacy analysis (N = 410), median treatment time in SELECTED was 25 months (range, <1-45). Adverse events (AEs) were reported in 76% of patients, serious AEs (SAEs) excluding MS relapse in 16%, and treatment discontinuation due to AEs including multiple sclerosis (MS) relapse in 12%. AEs were primarily of mild to moderate severity, and common AEs (≥10%), excluding MS relapse, were nasopharyngitis (12%) and upper respiratory tract infection (12%). Most commonly reported SAEs (in ≥3 patients), excluding MS relapses, were increased serum hepatic enzymes, pneumonia, ulcerative colitis, and urinary tract infection (<1% each). Incidences of AE groups of interest include cutaneous events (28%), cutaneous SAEs (2%), gastrointestinal SAEs (2%), hepatic SAEs, (1%) and malignancies (1%). The incidence of AEs, SAEs, and treatment-related study discontinuations did not increase over time and no deaths were reported. The adjusted annualized relapse rate (95% confidence interval (CI)) analyzed at 6-month intervals was 0.15 (0.10-0.22) for weeks 97-120 and 0.15 (0.10-0.21) for weeks 121-144. In year 3, the adjusted mean (95% CI) number of new/newly enlarging T2 hyperintense lesions was 1.26 (0.93-1.72) and the mean (median) annualized change in brain volume was -0.32% (-0.34%). CONCLUSIONS: The AE incidence did not increase with extension of therapy into year 3 in SELECTED; the safety profile was similar to that previously observed. The clinical efficacy of daclizumab was sustained over the 3 years comprising the SELECT TRILOGY, although potential selection bias cannot be excluded. TRIAL REGISTRATION: Clinicaltrials.gov NCT01051349; first registered January 15, 2010.

Disutility of Cognitive Processing Speed (CPS) Impairment in the Context of Multiple Sclerosis: A Time Trade-Off (TTO) Elicitation Study.

Introduction: Cognitive impairment, especially relating to cognitive processing speed, is a major cause of disability in people with multiple sclerosis (MS). Utility values are quantitative estimates of the quality of life experienced in specific health states and are a key component of cost-effectiveness modelling. However, existing health state utility values in MS typically focus on physical ability and are generally derived using generic (not disease-specific) measures of quality of life. The objective of the current study was to generate health state utility values for levels of cognitive impairment. We used a direct utility elicitation approach called the time trade-off (TTO) methodology. Materials and Methods: Health state descriptions were created following interviews with healthcare professionals, patients, and caregivers in the United States (n=35), and with healthcare professionals in the UK (n=5). Three health states (mild, moderate, and severe impairment) were defined based upon a well-established and validated test for cognitive dysfunction called the Symbol Digit Modalities Test (SDMT) and described using qualitative interview findings. Next, interviews with members of the general public in the UK were conducted to estimate utility values for each health state using the TTO methodology. The procedure was based on the established Measurement and Valuation of Health (MVH) protocol, which generates values on a scale from 0.0 to 1.0. Results: Mean health state utility values were 0.77 ± 0.24 in "mild impairment" (SDMT 43-40), 0.57 ± 0.26 in "moderate impairment" (SDMT 39-32), and 0.34 ± 0.28 in "severe impairment" (SDMT ≤ 31). Discussion: Results indicate that the public perceives that health states of cognitive slowing (as observed in MS) are associated with a substantial reduction in affected individuals' health-related quality of life, quantified using the TTO methodology. Future economic modeling should consider how utility impacts of both cognitive and physical disability can be appropriately incorporated.

Development and validation of a claims-based algorithm to identify patients with Neuromyelitis Optica Spectrum disorder.

INTRODUCTION: No validated algorithm exists to identify patients with neuromyelitis optica spectrum disorder (NMOSD) in healthcare claims data. We developed and tested the performance of a healthcare claims-based algorithm to identify patients with NMOSD. METHODS: Using medical record data of 101 adults with NMOSD, multiple sclerosis (MS), or myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD), we tested the sensitivity and specificity of claims-based algorithms developed through interviews with neurologists. We tested the best-performing algorithm's face validity using 2016-2019 data from IBM MarketScan Commercial and Medicare Supplemental databases. Demographics and clinical characteristics were reported. RESULTS: Algorithm inclusion criteria were age ≥ 18 years and (≥1 NMO diagnosis [or ≥ 1 transverse myelitis (TM) and ≥ 1 optic neuritis (ON) diagnosis] and ≥ 1 NMOSD drug) or (≥2 NMO diagnoses ≥90 days apart). Exclusion criteria were MS diagnosis or use of MS-specific drug after last NMO diagnosis or NMOSD drug; sarcoidosis diagnosis after last NMO diagnosis; or use of ≥1 immune checkpoint inhibitor. In medical record billing data of 50 patients with NMOSD, 30 with MS, and 21 with MOGAD, the algorithm had 82.0% sensitivity and 70.6% specificity. When applied to healthcare claims data, demographic and clinical features of the identified cohort were similar to known demographics of NMOSD. CONCLUSIONS: This clinically derived algorithm performed well in medical records. When tested in healthcare claims, demographics and clinical characteristics were consistent with previous clinical findings. This algorithm will enable a more accurate estimation of NMOSD disease burden using insurance claims datasets.

Efficacy of Ofatumumab and Teriflunomide in Patients With Relapsing MS From Racial/Ethnic Minority Groups: ASCLEPIOS I/II Subgroup Analyses.

BACKGROUND AND OBJECTIVES: Race and ethnicity may influence the efficacy of disease-modifying therapies in patients with multiple sclerosis (MS). Incidence of MS in ethnically diverse groups may be higher; however, these populations are under-represented in MS trials. This post hoc analysis compared the proportion of patients achieving 3-parameter no evidence of disease activity (NEDA-3) with ofatumumab vs teriflunomide in participants with relapsing MS (RMS) enrolled in the ASCLEPIOS I/II trials by race/ethnicity subgroup. METHODS: ASCLEPIOS I/II were identical, double-blind, double-dummy, active-controlled, multicenter, phase 3 trials. Participants were randomized (1:1) to receive ofatumumab 20 mg every 4 weeks or teriflunomide 14 mg once daily for up to 30 months. Pooled data were used to determine the efficacy/safety of ofatumumab vs teriflunomide in participants who self-identified as non-Hispanic Black, non-Hispanic Asian, Hispanic/Latino, or non-Hispanic White. Participants who did not self-identify into one of these groups were classified as other/unknown. RESULTS: Of the 1,882 participants, 64 (3.4%) self-identified as non-Hispanic Black, 71 (3.8%) as non-Hispanic Asian, 145 (7.7%) as Hispanic/Latino, and 1,538 (81.7%) as non-Hispanic White. Baseline participant demographics/characteristics were largely balanced across subgroups, aside from minor variations in sex, disease duration, and MRI lesions. From months 0 to 24, the proportion of ofatumumab vs teriflunomide-treated patients achieving NEDA-3 (odds ratio [95% CI]) was as follows: non-Hispanic Black, 33.3% vs 3.4% (15.9 [1.67-151.71; p = 0.0162]); non-Hispanic Asian, 42.9% vs 21.9% (3.18 [0.95-10.59; p = 0.06]); Hispanic/Latino, 36.6% vs 18.6% (3.21 [1.32-7.79; p = 0.01]); and non-Hispanic White, 37.4% vs 16.6% (3.57 [2.73-4.67; p < 0.0001]). Rates of AEs were generally similar between treatment groups and across race/ethnicity subgroups; no new or unexpected safety signals were identified. DISCUSSION: Ofatumumab was associated with greater proportions of NEDA-3 achievement than teriflunomide across race/ethnicity subgroups in the ASCLEPIOS trials. Within each treatment group, the proportion of patients achieving NEDA-3 from months 0 to 24 was similar across the subgroups and overall pooled population. Both ofatumumab and teriflunomide were well tolerated. Future MS trials should include ethnically diverse groups to better inform treatment decisions and improve real-world patient outcomes. TRIAL REGISTRATION INFORMATION: ClinicalTrials.gov: NCT02792218 (clinicaltrials.gov/ct2/show/NCT02792218), NCT02792231 (clinicaltrials.gov/ct2/show/NCT02792231). Submission date: June 2, 2016. First enrollment: August 26, 2016. CLASSIFICATION OF EVIDENCE: This study provides Class II evidence that among patients aged 18-55 years with RMS, the improvement in NEDA-3 with ofatumumab was comparably better than with teriflunomide among patients self-identified as non-Hispanic Black, non-Hispanic Asian, non-Hispanic White, Hispanic/Latino, and other/unknown.

Effects of baseline age and disease duration on the efficacy and safety of siponimod in patients with active SPMS: Post hoc analyses from the EXPAND study.

BACKGROUND: Older age and longer disease duration (DD) may impact the effectiveness of disease-modifying therapies in patients with multiple sclerosis (MS). Siponimod is a sphingosine 1-phosphate receptor modulator approved for the treatment of active secondary progressive MS (SPMS) in many countries. The pivotal phase 3 EXPAND study examined siponimod versus placebo in a broad SPMS population with both active and non-active disease. In this population, siponimod demonstrated significant efficacy, including a reduction in the risk of 3-month confirmed disability progression (3mCDP) and 6-month confirmed disability progression (6mCDP). Benefits of siponimod were also observed across age and DD subgroups in the overall EXPAND population. Herein we sought to assess the clinical impact of siponimod across age and disease duration subgroups, specifically in participants with active SPMS. METHODS: This study is a post hoc analysis of a subgroup of EXPAND participants with active SPMS (≥ 1 relapse in the 2 years before the study and/or ≥ 1 T1 gadolinium-enhancing magnetic resonance imaging lesion at baseline) receiving oral siponimod (2 mg/day) or placebo during EXPAND. Data were analyzed for participant subgroups stratified by age at baseline (primary cut-off: < 45 year ≥ 45 years; and secondary cut-off: < 50 years or ≥ 50 years) and by DD at baseline (< 16 years or ≥ 16 years). Efficacy endpoints were 3mCDP and 6mCDP. Safety assessments included adverse events (AEs), serious AEs, and AEs leading to treatment discontinuation. RESULTS: Data from 779 participants with active SPMS were analyzed. All age and DD subgroups had 31-38% (3mCDP) and 27-43% (6mCDP) risk reductions with siponimod versus placebo. Compared with placebo, siponimod significantly reduced the risk of 3mCDP in participants aged ≥ 45 years (hazard ratio [HR]: 0.68; 95% confidence interval [CI]: 0.48-0.97), < 50 years (HR: 0.69; 95% CI: 0.49-0.98), ≥ 50 years (HR: 0.62; 95% CI: 0.40-0.96), and in participants with < 16 years DD (HR: 0.68; 95% CI: 0.47-0.98). The risk of 6mCDP was significantly reduced with siponimod versus placebo for participants aged < 45 years (HR: 0.60; 95% CI: 0.38-0.96), ≥ 45 years (HR: 0.67; 95% CI: 0.45-0.99), < 50 years (HR: 0.62; 95% CI: 0.43-0.90), and in participants with < 16 years DD (HR: 0.57; 95% CI: 0.38-0.87). Increasing age or longer MS duration did not appear to increase the risk of AEs, with an observed safety profile that remained consistent with the overall active SPMS and overall SPMS populations in EXPAND. CONCLUSIONS: In participants with active SPMS, treatment with siponimod demonstrated a statistically significant reduction in the risk of 3mCDP and 6mCDP compared with placebo. Although not every outcome reached statistical significance in the subgroup analyses (possibly a consequence of small sample sizes), benefits of siponimod were seen across a spectrum of ages and DD. Siponimod was generally well tolerated by participants with active SPMS, regardless of baseline age and DD, and AE profiles were broadly similar to those observed in the overall EXPAND population.

Real-World Safety and Effectiveness After 5 Years of Dimethyl Fumarate Treatment in Black and Hispanic Patients with Multiple Sclerosis in ESTEEM.

INTRODUCTION: Multiple sclerosis (MS) clinical trials have included low numbers of patients from racial and ethnic minority populations; therefore, it is uncertain whether differences exist in response to disease-modifying therapies. We evaluated the real-world safety and effectiveness of dimethyl fumarate (DMF) treatment over 5 years in four patient cohorts: Black, non-Black, Hispanic, and non-Hispanic people with relapsing-remitting MS. METHODS: ESTEEM is an ongoing, 5-year, multinational, prospective study evaluating the long-term safety and effectiveness of DMF in people with MS. The analysis included patients newly prescribed DMF in routine practice at 393 sites globally. RESULTS: Overall, 5251 patients were analyzed (220 Black, 5031 non-Black; 105 Hispanic, 5146 non-Hispanic). Median (min-max) months of follow-up was 32 (0-72) for Black, 29 (1-77) for Hispanic, and 41 (0-85) for both the non-Black and non-Hispanic populations. In total, 39 (18%) Black and 29 (28%) Hispanic patients reported adverse events leading to treatment discontinuation versus 1126 (22%) non-Black and 1136 (22%) non-Hispanic patients; gastrointestinal disorders were the most common in all subgroups. Median lymphocyte counts decreased by 37% in Black, 40% in non-Black, 10% in Hispanic, and 39% in non-Hispanic patients in the first year, then remained stable and above the lower limit of normal in most patients. Annualized relapse rates (ARRs) (95% confidence intervals) up to 5 years were 0.054 (0.038-0.078) for Black, 0.077 (0.072-0.081) for non-Black, 0.069 (0.043-0.112) for Hispanic, and 0.076 (0.072-0.081) for non-Hispanic populations, representing reductions of 91-92% compared with ARR 12 months before study entry (all p < 0.0001). CONCLUSION: The safety profile of DMF in these subgroups was consistent with the overall ESTEEM population. Relapse rates remained low in Black and Hispanic patients, and consistent with non-Black and non-Hispanic patients. These data demonstrate a comparable real-world treatment benefit of DMF in Black and Hispanic patients. TRIAL REGISTRATION: ClinicalTrials.gov identifier NCT02047097.

A randomized clinical trial of autologous T-cell therapy in multiple sclerosis: subset analysis and implications for trial design.

BACKGROUND: Tovaxin is an autologous T-cell immunotherapy under investigation for the treatment of MS. The product consists of in vitro expanded myelin-reactive T-cells manufactured against up to six immunodominant peptides derived from three myelin antigens. METHODS: A Phase 2b placebo controlled study (TERMS) was conducted in 150 subjects to gather safety and efficacy data in relapsing-remitting MS and clinically isolated syndrome subjects. RESULTS: Tovaxin had a favorable safety profile. Although no statistically significant clinical or radiological benefit of Tovaxin immunotherapy was identified in the modified intent-to-treat population, a prospective analysis of subjects with more active disease favored Tovaxin in terms of annualized relapse rate (ARR) and disability progression. An analysis also found a possible legacy effect of prior disease-modifying treatment (DMT) which may have contributed to a lowered ARR in the placebo group. DMT-naïve subjects treated with Tovaxin had a lower ARR compared to the placebo group, particularly in those with active baseline disease (ARR ≥ 1, ARR>1). However, clinical benefit was not was accompanied by a treatment-dependent improvement in MRI measures. CONCLUSIONS: Previous DMT exposure may reduce effect size and study power. Limiting subject selection to DMT-treatment-naïve individuals may be a reasonable approach to phase 2 or proof-of-concept studies of limited duration.

The Two Sides of Siponimod: Evidence for Brain and Immune Mechanisms in Multiple Sclerosis.

Siponimod is a selective sphingosine 1-phosphate receptor subtype 1 (S1P1) and 5 (S1P5) modulator approved in the United States and the European Union as an oral treatment for adults with relapsing forms of multiple sclerosis (RMS), including active secondary progressive multiple sclerosis (SPMS). Preclinical and clinical studies provide support for a dual mechanism of action of siponimod, targeting peripherally mediated inflammation and exerting direct central effects. As an S1P1 receptor modulator, siponimod reduces lymphocyte egress from lymph nodes, thus inhibiting their migration from the periphery to the central nervous system. As a result of its peripheral immunomodulatory effects, siponimod reduces both magnetic resonance imaging (MRI) lesion (gadolinium-enhancing and new/enlarging T2 hyperintense) and relapse activity compared with placebo. Independent of these effects, siponimod can penetrate the blood-brain barrier and, by binding to S1P1 and S1P5 receptors on a variety of brain cells, including astrocytes, oligodendrocytes, neurons, and microglia, exert effects to modulate neural inflammation and neurodegeneration. Clinical data in patients with SPMS have shown that, compared with placebo, siponimod treatment is associated with reductions in levels of neurofilament light chain (a marker of neuroaxonal damage) and thalamic and cortical gray matter atrophy, with smaller reductions in MRI magnetization transfer ratio and reduced confirmed disability progression. This review examines the preclinical and clinical data supporting the dual mechanism of action of siponimod in RMS.

Safety of Fingolimod in Patients with Multiple Sclerosis Switched from Natalizumab: Results from TRANSITION-A 2-Year, Multicenter, Observational, Cohort Study.

Multiple sclerosis (MS) patients receiving natalizumab and who are at risk of developing progressive multifocal leukoencephalopathy (PML) often switch to other high-efficacy disease-modifying therapies including fingolimod as a risk mitigation strategy, which could impact treatment safety and effectiveness. The TRANSITION study aimed to evaluate the safety of fingolimod over two years in patients with MS after switching from natalizumab in a real-world setting. The safety and effectiveness were assessed by monitoring serious and other adverse events (SAEs, AEs). We assessed effectiveness by recording relapses, Expanded Disability Status Scale (EDSS) scores, and MRI activity. Of 637 patients enrolled, 505 completed the study (mean age, 42 years). Overall, 72.8% and 12.7% experienced AEs and SAEs respectively. The most common AEs were fatigue, headache, and urinary tract infection; no cases of PML were observed. Fingolimod treatment resulted in low disease activity. Patients with ≤8 weeks washout period had a markedly lower risk of relapses (4.5%) than those with >8 weeks (51.4%). In patients switching from natalizumab to fingolimod, no new safety signals with overall low relapse activity were observed in patients with washout latencies of ≤8 weeks before fingolimod initiation. Fingolimod was found to be safe and effective in patients transitioning from natalizumab.

Advancing Care and Outcomes for African American Patients With Multiple Sclerosis.

Multiple sclerosis (MS) has historically been underdiagnosed and undertreated among African Americans. Recent evidence suggests that African Americans with MS have a different clinical presentation, increased disease incidence and burden, and worse long-term outcomes vs their White counterparts. Due to limited data available for African Americans in MS clinical trials, it is difficult to make informed, generalizable conclusions about the natural history, prognosis, and therapeutic response in this population. In this narrative review, we highlight the nature and magnitude of the health disparities experienced by African Americans with MS and underscore the pressing need to increase knowledge about and understanding of MS disease manifestations in this group. In addition, we describe the mission and objectives of the recently established National African Americans with Multiple Sclerosis Registry, which is intended to be a platform to advance the care of African Americans with MS and address health disparities they may experience.

Comparative Efficacy and Safety of Ozanimod and Dimethyl Fumarate for Relapsing-Remitting Multiple Sclerosis Using Matching-Adjusted Indirect Comparison.

BACKGROUND: Patients with multiple sclerosis (MS) experience relapses and sustained disability progression. Since 2004, the number of disease-modifying therapies (DMTs) for MS has grown substantially. As a result, patients, healthcare providers, and insurers are increasingly interested in comparative efficacy and safety evaluations to distinguish between treatment options, but head-to-head studies between DMTs are limited. OBJECTIVE: The aim of the current study was to compare efficacy and safety outcomes with the DMTs ozanimod and dimethyl fumarate (DMF) using a matching-adjusted indirect comparison (MAIC) to adjust for cross-trial differences in study design and population. METHODS: A systematic literature review was performed to identify clinical studies evaluating the efficacy and safety of ozanimod compared with DMF. Individual patient-level data (IPD) for ozanimod were obtained from the SUNBEAM and RADIANCE Part B trials, and aggregate-level patient data (APD) for DMF were obtained from CONFIRM and DEFINE. A MAIC is used to weight IPD to APD based on important baseline patient characteristics considered to be effect modifiers or prognostic factors in order to balance the covariate distribution to establish more homogenous trial populations. Once trial populations are determined to be sufficiently homogenous, outcomes of interest are estimated and used to generate treatment effects between the weighted IPD and APD. We used MAIC methodology to compare efficacy and safety outcomes of interest between ozanimod 1.0 mg once daily (OD) and DMF 240 mg twice daily (BID), including confirmed disability progression (CDP) at 3 and 6 months, annualized relapse rate (ARR), proportion of patients relapsed, overall adverse events (AEs), serious AEs (SAEs), and discontinuations due to AEs. RESULTS: After matching patient data, baseline patient characteristics were balanced between patients receiving ozanimod and those receiving DMF. Compared with DMF, ozanimod demonstrated significantly improved CDP at 3 months (hazard ratio 0.67; 95% confidence interval [CI] 0.53-0.86), ARR (rate ratio [RR] 0.80; 95% CI 0.67-0.97), proportion of patients relapsed (odds ratio [OR] 0.66; 95% CI 0.52-0.83), overall AEs (OR 0.11; 95% CI 0.08-0.16), SAEs (OR 0.27; 95% CI 0.19-0.39), and discontinuations (OR 0.11; 95% CI 0.07-0.17). CDP at 6 months did not differ significantly between the two agents (RR 0.89; 95% CI 0.62-1.26). CONCLUSIONS: After adjustment of baseline patient characteristics, the MAIC demonstrated that the efficacy and safety of ozanimod 1.0 mg OD was superior to that of DMF 240 mg BID. Although a MAIC is less likely to produce biased estimates than a naïve or a standard indirect treatment comparison via a common comparator, limitations include potential confounding due to unobserved and thus unaccounted for baseline differences.

Ozanimod and dimethyl fumarate (DMF) are disease-modifying therapies used to treat relapsing-remitting multiple sclerosis (MS). Comparative efficacy and safety evaluation is important to key patients, healthcare providers, and health insurers; however, head-to-head studies between MS therapies are limited. In this analysis, we used an indirect treatment comparison method, specifically a matching-adjusted indirect comparison (MAIC), to compare results of clinical trials of ozanimod and DMF. In this MAIC, findings suggested that ozanimod was associated with greater reductions of relapses, a lowered risk of disability progression at 3 months, and improved safety outcomes compared with DMF. Although MAICs were conducted while adjusting for important treatment-effect modifiers and/or prognostic factors, the possibility of confounding as a result of unobserved baseline differences remains. Such an issue can be resolved only by conducting a head-to-head treatment comparison in a randomized clinical trial.

Clinical outcomes of patients with multiple sclerosis treated with ocrelizumab in a US community MS center: an observational study.

BACKGROUND: To monitor long-term outcomes of ocrelizumab treatment. OBJECTIVE: To evaluate safety and treatment outcomes of ocrelizumab in a community-based multiple sclerosis (MS) population. METHODS: Adult patients with MS prescribed ocrelizumab were eligible. Chart reviews were conducted at the start of ocrelizumab treatment and every 6 months thereafter. RESULTS: Of the 355 patients enrolled, 71.9% were female; mean (SD) age was 51.8 (12.5) years; 78.3% had relapsing MS (RMS). Median baseline Expanded Disability Status Scale (EDSS) (IQR) was 3.0 (2.0-4.0) for RMS, 6.5 (6.0-7.5) for secondary progressive MS, and 6.5 (6.0-7.0) for primary progressive MS. Respiratory infections occurred in 40.1% and urinary tract infections in 33.1% of patients. There was no difference in the percentage of infections among patients <55 (68.5%, n=122), and those ≥55 of age (67.5%, n=104) (p=0.94). Twenty-five hospitalisations were due to infections; 69.2% of these patients were ≥55 with a mean EDSS of 5.7 (±1.86). Four patients have died. Serum IgM and IgG levels did not predict infection risk. Annualised relapse rate was 0.34 for the patients with RMS in the preceding 2 years and 0.09 in patients who received ≥2 ocrelizumab 600 mg courses. The first on-treatment MRI was stable in 262 (90.0%) patients, 6.9% had new T2 lesions, 2.7% had enlarging T2 lesions and 1.4% had gadolinium-enhancing lesions. Median EDSS at 12 months was unchanged. CONCLUSION: Ocrelizumab effectively controlled relapse risk and disability worsening. Although only 12.1% of patients have discontinued ocrelizumab, infections resulting in hospitalisation are a concern, especially in older and disabled patients.

Matching-adjusted indirect treatment comparison of ozanimod versus teriflunomide for relapsing multiple sclerosis.

BACKGROUND: A growing number of immunomodulating disease-modifying therapies are available for treatment of relapsing multiple sclerosis (RMS). In the absence of randomized head-to-head trials, matching-adjusted indirect comparisons (MAICs) can be used to adjust for cross-trial differences and evaluate the comparative efficacy and safety of these agents. We used MAIC methodology to indirectly compare key outcomes with ozanimod (OZM) and teriflunomide (TERI) in the treatment of RMS. METHODS: A systematic literature review was conducted to identify clinical trials evaluating the efficacy and safety of OZM vs TERI. Given the absence of head-to-head trials of OZM vs TERI, we used a matching-adjusted indirect comparison to adjust for potential treatment effect modifiers and prognostic factors while assessing confirmed disability progression (CDP), relapse, and safety outcomes. Individual patient data for OZM (SUNBEAM and RADIANCE Part B trials) and aggregate level data for TERI (ASCLEPIOS I/II, TOWER, OPTIMUM, and TEMSO trials) were used to evaluate the following outcomes: annualized relapse rate (ARR), proportion of patients relapsed, CDP at 3 and 6 months, overall adverse events (AEs), serious AEs (SAEs), and discontinuations due to AEs. RESULTS: After matching, baseline patient characteristics were balanced between OZM and TERI. Compared with TERI, OZM demonstrated significant improvements in ARR (rate ratio: 0.73; 95% CI: 0.62-0.84), proportion of patients relapsed (odds ratio [OR]: 0.56; 95% CI: 0.44-0.70), overall AEs (OR: 0.35; 95% CI: 0.29-0.43), SAEs (OR: 0.53; 95% CI: 0.37-0.77), and discontinuations due to AEs (OR: 0.14; 95% CI: 0.09-0.21). OZM demonstrated statistically significant improvements in CDP at 3 months (hazard ratio [HR]: 0.78; 95% CI: 0.66-0.92) but nonsignificant differences at 6 months (HR: 0.78; 95% CI: 0.60-1.01) compared with TERI. CONCLUSION: In this indirect treatment comparison of patients with RMS, OZM appeared to have an improved benefit-risk profile over TERI.

Interferons and Multiple Sclerosis: Lessons from 25 Years of Clinical and Real-World Experience with Intramuscular Interferon Beta-1a (Avonex).

Recombinant interferon (IFN) ß-1b was approved by the US Food and Drug Administration as the first disease-modifying therapy (DMT) for multiple sclerosis (MS) in 1993. Since that time, clinical trials and real-world observational studies have demonstrated the effectiveness of IFN therapies. The pivotal intramuscular IFN ß-1a phase III trial published in 1996 was the first to demonstrate that a DMT could reduce accumulation of sustained disability in MS. Patient adherence to treatment is higher with intramuscular IFN ß-1a, given once weekly, than with subcutaneous formulations requiring multiple injections per week. Moreover, subcutaneous IFN ß-1a is associated with an increased incidence of injection-site reactions and neutralizing antibodies compared with intramuscular administration. In recent years, revisions to MS diagnostic criteria have improved clinicians' ability to identify patients with MS and have promoted the use of magnetic resonance imaging (MRI) for diagnosis and disease monitoring. MRI studies show that treatment with IFN ß-1a, relative to placebo, reduces T2 and gadolinium-enhancing lesions and gray matter atrophy. Since the approval of intramuscular IFN ß-1a, a number of high-efficacy therapies have been approved for MS, though the benefit of these high-efficacy therapies should be balanced against the increased risk of serious adverse events associated with their long-term use. For some subpopulations of patients, including pregnant women, the safety profile of IFN ß formulations may provide a particular benefit. In addition, the antiviral properties of IFNs may indicate potential therapeutic opportunities for IFN ß in reducing the risk of viral infections such as COVID-19.