Diroximel Fumarate in Patients with Relapsing-Remitting Multiple Sclerosis: NEDA-3 After Re-Baselining in the Phase 3 EVOLVE-MS-1 Study.

INTRODUCTION: Diroximel fumarate (DRF) and dimethyl fumarate (DMF) are orally administered fumarate disease-modifying therapies (DMTs) for multiple sclerosis (MS). The safety, tolerability, and exploratory efficacy of DRF were evaluated in the phase 3 EVOLVE-MS-1 study. No Evidence of Disease Activity (NEDA-3) is a composite efficacy endpoint used in clinical trials for MS defined as no relapse, no 24-week confirmed disability progression (CDP), no new/newly enlarging T2 lesions, and no new gadolinium-enhancing lesions. As NEDA outcomes in studies may be confounded by initial disease activity, the objective of this analysis was to evaluate NEDA-3 in EVOLVE-MS-1 for newly enrolled patients and patients who were re-baselined after approximately 7 weeks. METHODS: Patients entered EVOLVE-MS-1 as either newly enrolled or having completed the 5-week phase 3 EVOLVE-MS-2 study of DRF and DMF. Magnetic Resonance Imaging (MRI) was performed at baseline before each study (approx. 7 weeks apart) and at weeks 48 and 96 in EVOLVE-MS-1. Therefore, patients entering from EVOLVE-MS-2 were re-baselined after approximately 7 weeks. NEDA-3 outcomes on DRF are reported for prior DRF, prior DMF, and de novo patient groups. RESULTS: Of 1057 patients in EVOLVE-MS-1, 239 (22.6%) had rolled over from receiving DRF in EVOLVE-MS-2 ("prior DRF"), 225 (21.3%) had rolled over from receiving DMF in EVOLVE-MS-2 ("prior DMF"), and 593 (56.1%) were newly enrolled ("de novo"). At week 48, Kaplan-Meier estimates of NEDA-3 were 72.3% (prior DRF), 72.1% (prior DMF), and 62.1% (de novo); at week 96, estimates were 50.2% (prior DRF), 48.2% (prior DMF), and 36.5% (de novo). CONCLUSIONS: In EVOLVE-MS-1, after re-baselining at approximately 7 weeks, approximately half of DRF-treated patients achieved NEDA-3 at week 96, compared with 36.5% of patients who were not re-baselined. Re-baselining may be useful for assessing efficacy of DMTs by mitigating the influence of disease activity prior to the onset of efficacy. CLINICAL TRIAL REGISTRATIONS: NCT03093324 (EVOLVE-MS-2); NCT02634307 (EVOLVE-MS-1).

Comparative effectiveness of dimethyl fumarate versus non-specific immunosuppressants: Real-world evidence from MSBase.

Background: The use of non-specific immunosuppressants (NSIS) to treat multiple sclerosis (MS) remains prevalent in certain geographies despite safety concerns, likely due to resource limitations. Objective: To use MSBase registry data to compare real-world outcomes in adults with relapsing-remitting MS (RRMS) treated with dimethyl fumarate (DMF) or NSIS (azathioprine, cyclosporine, cyclophosphamide, methotrexate, mitoxantrone or mycophenolate mofetil) between January 1, 2014 and April 1, 2022. Methods: Treatment outcomes were compared using inverse probability of treatment weighting (IPTW) Cox regression. Outcomes were annualized relapse rates (ARRs), time to discontinuation, time to first relapse (TTFR) and time to 24-week confirmed disability progression (CDP) or 24-week confirmed disability improvement (CDI; in patients with baseline Expanded Disability Status Scale [EDSS] score ≥2). Results: After IPTW, ARR was similar for DMF (0.13) and NSIS (0.16; p = 0.29). There was no difference in TTFR between cohorts (hazard ratio [HR]: 0.98; p = 0.84). The DMF cohort experienced longer times to discontinuation (HR: 0.75; p = 0.001) and CDP (HR: 0.53; p = 0.001), and shorter time to CDI (HR: 1.99; p < 0.008), versus the NSIS cohort. Conclusion: This analysis supports the use of DMF to treat patients with relapsing forms of MS, and may have implications for MS practices in countries where NSIS are commonly used to treat RRMS.

Vaccine response in people with multiple sclerosis treated with fumarates.

People with multiple sclerosis (pwMS) have an increased risk of infection. As disease-modifying therapies (DMTs) and other treatments may interact with the immune system, there may be concerns about vaccine efficacy and safety. Therefore, it is important to evaluate possible interactions between DMTs and vaccines. The fumarates, dimethyl fumarate, diroximel fumarate, and monomethyl fumarate, are approved for the treatment of relapsing multiple sclerosis. This review assesses the evidence on vaccine response in pwMS treated with fumarates, with a particular focus on COVID-19 vaccines. Treatment with fumarates does not appear to result in blunting of humoral responses to vaccination; for COVID-19 vaccines, particularly RNA-based vaccines, evidence indicates antibody responses similar to those of healthy recipients. While data on the effect of fumarates on T-cell responses are limited, they do not indicate any significant blunting. COVID-19 vaccines impart a similar degree of protection against severe COVID-19 infection for pwMS on fumarates as in the general population. Adverse reactions following vaccination are generally consistent with those observed in the wider population; no additional safety signals have emerged in those on fumarates. Additionally, no increase in relapse has been observed in pwMS following vaccination. In pwMS receiving fumarates, vaccination is generally safe and elicits protective immune responses.

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.

Matching-Adjusted Indirect Comparisons of Diroximel Fumarate, Ponesimod, and Teriflunomide for Relapsing Multiple Sclerosis.

INTRODUCTION: Diroximel fumarate (DRF), ponesimod (PON), and teriflunomide (TERI) are oral disease-modifying therapies approved for the treatment of relapsing multiple sclerosis. No randomized trials have compared DRF versus PON or TERI. OBJECTIVES: The objectives of this analysis were to compare DRF versus PON and DRF versus TERI for clinical and radiological outcomes. METHODS: We used individual patient data from EVOLVE-MS-1, a 2-year, open-label, single-arm, phase III trial of DRF (n = 1057), and aggregated data from OPTIMUM, a 2-year, double-blind, phase III trial comparing PON (n = 567) and TERI (n = 566). To account for cross-trial differences, EVOLVE-MS-1 data were weighted to match OPTIMUM's average baseline characteristics using an unanchored matching-adjusted indirect comparison. We examined the outcomes of annualized relapse rate (ARR), 12-week confirmed disability progression (CDP), 24-week CDP, absence of gadolinium-enhancing (Gd+) T1 lesions, and absence of new/newly enlarging T2 lesions. RESULTS: After weighting, we did not observe strong evidence of differences between DRF and PON for ARR [DRF versus PON incidence rate difference (IRD) -0.02; 95% confidence interval (CI) -0.08, 0.04; incidence rate ratio (IRR) 0.92; 95% CI 0.61, 1.2], 12-week CDP [risk difference (RD) -2.5%; 95% CI -6.3, 1.2; risk ratio (RR) 0.76; 95% CI 0.38, 1.1], 24-week CDP (RD -2.7%; 95% CI -6.0, 0.63; RR 0.68; 95% CI 0.28, 1.0), and absence of new/newly enlarging T2 lesions (RD -2.5%; 95% CI -13, 7.4; RR 0.94; 95% CI 0.70, 1.2). However, a higher proportion of DRF-treated patients were free of Gd+ T1 lesions than PON-treated patients (RD 11%; 95% CI 6.0, 16; RR 1.1; 95% CI 1.06, 1.2). Compared with TERI, DRF showed improved ARR (IRD -0.08; 95% CI -0.15, -0.01; IRR 0.74; 95% CI 0.50, 0.94), 12-week CDP (RD -4.2%; 95% CI -7.9, -0.48; RR 0.67; 95% CI 0.38, 0.90), 24-week CDP (RD -4.3%; 95% CI -7.7, -1.1; RR 0.57; 95% CI 0.26, 0.81), and absence of Gd+ T1 lesions (RD 25%; 95% CI 19, 30; RR 1.4; 95% CI 1.3, 1.5). However, DRF and TERI did not appear to differ significantly with respect to absence of new/newly enlarging T2 lesions when based on comparisons using the overall EVOLVE-MS-1 sample (RD 8.5%; 95% CI -0.93, 18; RR 1.3; 95% CI 0.94, 1.6), or in a sensitivity analysis restricted to newly enrolled EVOLVE-MS-1 patients (RD 2.7%; 95% CI -9.1, 14; RR 1.1; 95% CI 0.68, 1.5). CONCLUSIONS: We did not observe differences between DRF and PON for ARR, CDP, and absence of new/newly enlarging T2 lesions, but there was a higher proportion of patients free of Gd+ T1 lesions among DRF-treated patients than PON-treated patients. DRF had improved efficacy versus TERI for all clinical and radiological outcomes, except for absence of new/newly enlarging T2 lesions. CLINICAL TRIALS REGISTRATION: EVOLVE-MS-1 (ClinicalTrials.gov identifier: NCT02634307); OPTIMUM (ClinicalTrials.gov identifier: NCT02425644).

Real-World Analysis Affirms the High Persistence and Adherence Observed with Diroximel Fumarate in Patients with Multiple Sclerosis.

INTRODUCTION: Adherence to disease-modifying therapies is key for achieving optimal outcomes in multiple sclerosis (MS). Diroximel fumarate (DRF) is an oral fumarate approved for treatment of relapsing forms of MS. It has the same pharmacologically active metabolite as dimethyl fumarate (DMF) and similar efficacy and safety profiles, but with demonstrated fewer gastrointestinal (GI) related adverse events (AEs). There are limited data characterizing persistence and adherence to DRF in the real world. METHODS: This retrospective analysis of the AcariaHealth Specialty Pharmacy Program included patients with MS initiating DRF from 1 December 2019 to 30 January 2021. This analysis evaluated persistence, measured as proportion of patients remaining on therapy; discontinuation rate due to GI AEs; and adherence measured by proportion of days covered (PDC). RESULTS: Overall, 1143 patients were included; 433 (37.9%) patients had been treated with prior DMF and switched to DRF. Persistence was high in both groups: the estimated proportion of patients remaining on DRF at 16 months was 82.3% [95% confidence internal (CI) 77.2-86.3%], and 90.1% (95% CI 82.2-94.6%) in the DMF to DRF group. Fifty-two (4.5%) patients overall and 15 (3.5%) in the DMF switch subgroup discontinued DRF due to GI AEs. Mean PDC was 90.8% (95% CI 89.2-92.5%), and 85.4% (95% CI 83.3-87.4%) of patients achieved PDC ≥ 80% in the overall population. In the DMF to DRF group, mean PDC was 90.7% (95% CI 88.0-93.5%), and 84.8% (95% CI 81.4-88.1%) of patients achieved PDC ≥ 80%. CONCLUSION: In this analysis of  > 1000 patients treated with DRF in real-world clinical practice, overall persistence at 16 months was high, treatment discontinuation due to GI AEs was low, and patients were highly adherent to therapy. Of 433 patients who switched from DMF to DRF, most (> 90%) were able to tolerate and persist on DRF after switching. Graphical abstract available for this article.

Magnetic Resonance Phase Alterations in Multiple Sclerosis Patients with Short and Long Disease Duration.

OBJECTIVE: The analysis of the MR phase provides additional information on the tissue microstructure. In multiple sclerosis (MS) lesions phase alterations may reflect different stages of inflammatory activity. Here we investigated lesion morphology in MS patients with short and long disease duration on T2* weighted, phase, magnitude and susceptibility weighted imaging (SWI) at 7 Tesla (T). METHODS: 17 MS or clinically isolated syndrome patients with short (<60 months) and 11 with long (>60 months) disease duration underwent 7 T MRI. Lesions were subsequently analyzed side-by-side with regard to morphology and visibility on T2* weighted, SWI, magnitude and SWI-filtered phase images. RESULTS: 126 of 192 T2* weighted lesions (65.6%) were characterized by a phase alteration pattern, and hence could be differentiated on phase images. In detail, a significantly reduced proportion of lesions showing phase alterations was detectable in patients with longer disease duration (mean±SD 51 ± 37%, range 0-100%) compared to patients with short disease duration (mean ± SD 90 ± 19.5%, range 50-100%, p = 0.003). CONCLUSION: This cross-sectional study identified different patterns of phase changes in lesions of MS patients with short and long standing disease. Longitudinal studies are warranted to prove that MR phase imaging is useful in determining the activity and the developmental stage of individual MS plaques.

Identical lesion morphology in primary progressive and relapsing-remitting MS--an ultrahigh field MRI study.

Potential differences between primary progressive (PP) and relapsing-remitting (RR) multiple sclerosis (MS) have been controversially discussed. In this study, we compared lesion morphology and distribution in patients with PPMS and RRMS (nine in each group) using 7 T MRI. We found that gray and white matter lesions in PPMS and RRMS patients did not differ in their respective morphological characteristics (e.g., perivascular p = 0.863, hypointense rim p = 0.796, cortical lesion count p = 0.436). Although limited by a small sample size, our study results suggest that PPMS and RRMS, despite differences in disease course and clinical characteristics, exhibit identical lesion morphology under ultrahigh field MRI.

Periventricular venous density in multiple sclerosis is inversely associated with T2 lesion count: a 7 Tesla MRI study.

BACKGROUND: Damage to venules in multiple sclerosis was first described decades ago. Today, ultrahigh magnetic field strength T2*-weighted magnetic resonance imaging (MRI) techniques depict very small cerebral veins in vivo with great anatomical detail. OBJECTIVE: We aimed to investigate alterations of periventricular small blood vessel appearance in relation to T2 lesion count and distribution in multiple sclerosis and clinically isolated syndrome in comparison with healthy control subjects at 7 Tesla MRI. METHODS: We investigated 38 patients (including 16 with early multiple sclerosis and seven with clinically isolated syndrome) and 22 matched healthy controls at 7 Tesla. The protocol included T2*-weighted Fast Low Angle Shot, and T2-weighted Turbo Inversion Recovery Magnitude sequences. We quantified periventricular venous density by a novel region-of-interest-based algorithm, expressing the ratio of 'veins per region-of-interest' as well as of 'periventricular vascular area'. RESULTS: Our study revealed significantly decreased venous density in multiple sclerosis patients compared with healthy controls. Venous alterations were already detectable in clinically isolated syndrome and early multiple sclerosis, although to a smaller extent. Venous density correlated inversely with periventricular and whole-brain T2 lesion count. Furthermore, we found no indication for cerebral venous congestion in multiple sclerosis. CONCLUSION: High spatially resolving anatomical T2*-weighted MRI revealed vascular alterations in early stages of multiple sclerosis, presumably as a part of widespread haemodynamic and metabolic alterations.