Evaluating the effect of dimethyl fumarate on subclinical biomarkers in a real-world patient cohort.

OBJECTIVE: Evaluate the real-world effect of dimethyl fumarate (DMF) on subclinical biomarkers in patients with relapsing-remitting multiple sclerosis (RRMS) and compare with results from clinical trials. METHODS: Magnetic resonance imaging (MRI) data from 102 RRMS patients were retrospectively collected and processed using icobrain to assess brain atrophy and to assist semi-manual lesion count. RESULTS: Mean (±SD) annualized percent brain volume change in the first 3 years after DMF-initiation were: -0.33 ± 0.68, -0.10 ± 0.60, and - 0.35 ± 0.71%/year, respectively. No new FLAIR lesions were detected in 73.7%, 77.3%, and 73.3% of the patients during years 1, 2, and 3. CONCLUSIONS: Results of this real-world study were consistent with previous DMF phase III clinical trials, supporting the generalizability of the effects observed in clinical trials to the real-world clinical setting.

De-escalation of Disease-Modifying Therapy for People with Multiple Sclerosis Due to Safety Considerations: Characterizing 1-Year Outcomes in 25 People Who Switched from Ocrelizumab to Diroximel Fumarate.

INTRODUCTION: Switching disease-modifying therapy (DMT) may be considered for relapsing-remitting multiple sclerosis (RRMS) if a patient's current therapy is no longer optimal. This was particularly important during the recent COVID-19 pandemic because of considerations around immune deficiency and impaired vaccine response associated with B cell-depleting DMTs. This real-world, single-center study aimed to evaluate change or decline in functional ability and overall disease stability in people with RRMS who were switched from B cell-depleting ocrelizumab (OCRE) to diroximel fumarate (DRF) because of safety concern related to the COVID-19 pandemic. METHODS: Adults with RRMS were included if they had been clinically stable for ≥ 1 year on OCRE. Data collected at baseline and 1 year post switch included relapse rate, magnetic resonance imaging (MRI), blood work for assessment of peripheral immune parameters, the Cognitive Assessment Battery (CAB), optical coherence tomography (OCT), and patient-reported outcomes (PROs). RESULTS: Participants (N = 25) had a mean (SD) age of 52 (9) years, and a mean (SD) duration of 26 (8) months' treatment with OCRE before the switch to DRF. Median washout duration since the last OCRE infusion was 7 months (range 4-18 months). No participants relapsed on DRF during follow-up, and all remained persistent on DRF after 1 year. There were no significant changes in peripheral immune parameters, other than an increase in the percentage of CD19+ cells 1 year after switching (p < 0.05). Similarly, there were no significant changes in CAB, OCT, and PROs. CONCLUSION: These preliminary findings suggest that transition to DRF from OCRE may be an effective treatment option for people with RRMS who are clinically stable but may need to switch for reasons unrelated to effectiveness. Longer follow-up times on larger samples are needed to confirm these observations.

Lymphopenia is Not the Primary Therapeutic Mechanism of Diroximel Fumarate in Relapsing-Remitting Multiple Sclerosis: Subgroup Analyses of the EVOLVE-MS-1 Study.

INTRODUCTION: In EVOLVE-MS-1 (NCT02634307), mean absolute lymphocyte count (ALC) on diroximel fumarate (DRF) declined from baseline by approximately 28% in year 1, then stabilized, similar to ALC decline observed with dimethyl fumarate (DMF). Prior studies reported that clinical efficacy of DMF was not substantially different in patients with and without lymphopenia. METHODS: EVOLVE-MS-1-an open-label, 96-week, phase 3 study-assessed DRF safety and exploratory efficacy in patients with relapsing-remitting multiple sclerosis. This study analyzes efficacy-related outcomes comparing (1) patients with lymphopenia (≥ 1 ALC below lower limit of normal [LLN]) and without (all ALCs ≥ LLN); (2) across quartiles stratified by week 96 ALC decline from baseline: Q1 (≥ 47% decline); Q2 (30% to < 47% decline); Q3 (12% to < 30% decline); Q4 (< 12% decline). RESULTS: Baseline characteristics were similar between patients without (n = 593) and with lymphopenia (n = 452). At week 96, adjusted annualized relapse rate (ARR; 95% confidence interval) was 0.14 (0.11-0.17) without lymphopenia and 0.12 (0.09-0.15) with lymphopenia. Estimated proportions with 12-week confirmed disability progression (CDP12) at week 96 were 10.2% without and 9.3% with lymphopenia. When stratified by quartiles (Q1-Q4), ARR at week 96 was 0.11 (Q1), 0.09 (Q2), 0.13 (Q3), and 0.17 (Q4). Estimated proportions with CDP12 at week 96 were 9.6% (Q1), 10.2% (Q2), 5.7% (Q3), and 10.9% (Q4). At week 96, no evidence of disease activity was achieved by 47.2% (Q1), 47.8% (Q2), 45.4% (Q3), and 37.3% (Q4) of patients. CONCLUSION: In DRF-treated patients in EVOLVE-MS-1, clinical and radiological measurements indicated reduced disease activity regardless of lymphopenia or magnitude of ALC decline from baseline; however, patients who had greater ALC declines appeared to have numerically lower ARR and higher proportions free from relapses and gadolinium-enhancing lesions compared with those with smallest decline. This supports prior evidence that, while lymphopenia may contribute to fumarate efficacy outcomes, it is not the primary mechanism of action. TRIAL REGISTRATION: ClinicalTrials.gov identifier NCT02634307.

Humoral immune response after Ad26.COV2.S vaccination in patients with multiple sclerosis treated with natalizumab.

The immunomodulatory effects of disease-modifying therapies for multiple sclerosis might affect the immune response to vaccines for severe acute respiratory syndrome coronavirus 2. We analyzed the severe acute respiratory syndrome coronavirus 2-specific antibody response and lymphocyte profile before and after Ad26.COV2.S (Johnson & Johnson) vaccination in natalizumab-treated patients with multiple sclerosis. There was a 72-fold increase in mean anti-severe acute respiratory syndrome coronavirus 2 spike immunoglobulin G levels 4 weeks after vaccination and a 137-fold increase after 6 months. Other immune signals were within normal ranges. Natalizumab-treated patients with multiple sclerosis had a robust immune response to Ad26.COV2.S vaccine, and other immune signals were not significantly affected.

Whole blood miRNAs in relapsing MS patients treated with dimethyl fumarate in the phase 4 TREMEND trial.

We investigated the impact of dimethyl fumarate (DMF), an oral therapy for relapsing multiple sclerosis (MS), on blood microRNA (miRNA) signatures and neurofilament light (NFL) levels. DMF normalized miR-660-5p and modulated various miRNAs associated with the NF-kB pathway. These alterations reached a peak 4-7 months after treatment. Notably, particular miRNAs correlated with high or low NFL levels, implying their potential role as markers of treatment efficacy. Our findings broaden the understanding of DMF's immunomodulatory effects and may aid in predicting treatment responses.

Efficacy of Dimethyl Fumarate in Young Adults with Relapsing-Remitting Multiple Sclerosis: Analysis of the DEFINE, CONFIRM, and ENDORSE Studies.

INTRODUCTION: Dimethyl fumarate (DMF) showed favorable benefit-risk in patients with relapsing-remitting multiple sclerosis (MS) in phase 3 DEFINE and CONFIRM trials and in the ENDORSE extension study. Disease activity can differ in younger patients with MS compared with the overall population. METHODS: Randomized patients received DMF 240 mg twice daily or placebo (PBO; years 0-2 DEFINE/CONFIRM), then DMF (years 3-10; continuous DMF/DMF or PBO/DMF; ENDORSE); maximum follow-up (combined studies) was 13 years. This integrated post hoc analysis evaluated safety and efficacy of DMF in a subgroup of young adults aged 18-29 years. RESULTS: Of 1736 patients enrolled in ENDORSE, 125 were young adults, 86 treated continuously with DMF (DMF/DMF) and 39 received delayed DMF (PBO/DMF) in DEFINE/CONFIRM. Most (n = 116 [93%]) young adults completed DMF treatment in DEFINE/CONFIRM. Median (range) follow-up time in ENDORSE was 6.5 (2.0-10.0) years. Young adults entering ENDORSE who had been treated with DMF in DEFINE/CONFIRM had a model-based Annualized Relapse Rate (ARR; 95% CI) of 0.24 (0.16-0.35) vs. 0.56 (0.35-0.88) in PBO patients. ARR remained low in ENDORSE: 0.07 (0.01-0.47) at years 9-10 (DMF/DMF group). At year 10 of ENDORSE, EDSS scores were low in young adults: DMF/DMF, 1.9 (1.4); PBO/DMF, 2.4 (1.6). At ~ 7 years, the proportion of young adults with no confirmed disability progresion was 81% for DMF/DMF and 72% for PBO/DMF. Patient-reported outcomes (PROs) (SF-36 and EQ-5D) generally remained stable during ENDORSE. The most common adverse events (AEs) in young adults during ENDORSE were MS relapse (n = 53 [42%]). Most AEs were mild (n = 20 [23.3%], n = 7 [17.9%]) to moderate (n = 45 [52.3%], n = 23 [59.0%]) in the DMF/DMF and PBO/DMF groups, respectively. The most common serious AE (SAE) was MS relapse (n = 19 [15%]). CONCLUSION: The data support a favorable benefit-risk profile of DMF in young adults, as evidenced by well-characterized safety, sustained efficacy, and stable PROs. CLINICAL TRIAL INFORMATION: Clinical trials.gov, DEFINE (NCT00420212), CONFIRM (NCT00451451), and ENDORSE (NCT00835770).

COVID-19 Vaccine Response in People with Multiple Sclerosis Treated with Dimethyl Fumarate, Diroximel Fumarate, Natalizumab, Ocrelizumab, or Interferon Beta Therapy.

BACKGROUND: Some multiple sclerosis (MS) disease-modifying therapies (DMTs) impair responses to vaccines, emphasizing the importance of understanding COVID-19 vaccine immune responses in people with MS (PwMS) receiving different DMTs. METHODS: This prospective, open-label observational study enrolled 45 participants treated with natalizumab (n = 12), ocrelizumab (n = 16), fumarates (dimethyl fumarate or diroximel fumarate, n = 11), or interferon beta (n = 6); ages 18-65 years inclusive; stable on DMT for at least 6 months. Responder rates, anti-SARS-CoV-2 spike receptor-binding domain IgG (anti-RBD) geometric mean titers (GMTs), antigen-specific T cells, and vaccination-related adverse events were evaluated at baseline and 8, 24, 36, and 48 weeks after first mRNA-1273 (Moderna) dose. RESULTS: At 8 weeks post vaccination, all natalizumab-, fumarate-, and interferon beta-treated participants generated detectable anti-RBD IgG titers, compared to only 25% of the ocrelizumab cohort. At 24 and 36 weeks post vaccination, natalizumab-, fumarate-, and interferon beta-treated participants continued to demonstrate detectable anti-RBD IgG titers, whereas participants receiving ocrelizumab did not. Anti-RBD GMTs decreased 81.5% between 8 and 24 weeks post vaccination for the non-ocrelizumab-treated participants, with no significant difference between groups. At 36 weeks post vaccination, ocrelizumab-treated participants had higher proportions of spike-specific T cells compared to other treatment groups. Vaccine-associated side effects were highest in the ocrelizumab arm for most symptoms. CONCLUSIONS: These results suggest that humoral response to mRNA-1273 COVID-19 vaccine is preserved and similar in PwMS treated with natalizumab, fumarate, and interferon beta, but muted with ocrelizumab. All DMTs had preserved T cell response, including the ocrelizumab cohort, which also had a greater risk of vaccine-related side effects.

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.

Dimethyl fumarate is associated with lower rates of infection and lower infection-related healthcare costs when compared with ocrelizumab.

BACKGROUND: Infections in people with multiple sclerosis (PwMS) may have a detrimental effect on disease progression, risk of hospitalization, and healthcare resource utilization (HRU). The infection risk and HRU costs may vary between disease-modifying therapies (DMTs); however, the individual risks and differences associated with DMTs are not well characterized. Some DMTs may increase the risk for infections in PwMS; however, previous studies have reported an intact humoral immune response in dimethyl fumarate (DMF)-treated patients. The objective was to compare infection-related HRU and healthcare costs (HCCs) between PwMS treated with DMF or ocrelizumab (OCR). METHODS: Eligible patients were identified from the Optum US claims database between April 2017 and September 2020 (DMF n = 1429; OCR n = 3170). Patients were followed from index date to first occurrence of: (1) end of study, (2) end of insurance eligibility, (3) discontinuation of index DMT, or (4) switch from index DMT to another DMT. Outcomes were annualized rate of infection encounters (defined as infection encounters [n] during follow-up window / days followed [n] × 365); annualized infection-related HCCs (defined as aggregated costs of infection encounters during follow-up window / days followed [n] × 365); location-specific infections, and overall infection-related events. Propensity score matching (PSM) 1:1 method was used; PS was calculated via logistic regression for probability of DMF treatment conditional on demographics and comorbidities. Mean differences (MD) were reported for infection encounter measures. RESULTS: After PSM, DMF and OCR cohorts (n = 1094 in each cohort) were balanced based on baseline characteristics (standardized MD of adjusted baseline characteristics <0.1). Mean (standard deviation) follow-up was 296 (244) days for DMF patients and 297 (243) for OCR patients. DMF patients experienced lower annualized rates of overall infection encounters vs OCR patients (MD -0.51 [95% confidence interval (CI): -0.92 to -0.11], p = 0.01). When stratified by type of infection encounter, DMF patients experienced significantly lower annualized rates of outpatient (MD [95% CI]: -0.44 [-0.80 to -0.08], p = 0.02) and inpatient/hospitalization infection encounters (-0.08 [-0.14 to -0.02], p<0.01) vs OCR patients. A trend towards a shorter duration of infection-related hospitalization in the DMF vs the OCR group was observed (MD [95% CI]: -2.20 [-4.73 to 0.26] days, p = 0.08). The most common infection types in both DMT groups were urinary tract infections, sepsis, and pneumonia. DMF patients experienced lower annualized infection-related HCCs (MD [95% CI]: -$3642 [-$6380 to -$904], p < 0.01) vs OCR patients, which were driven largely by infection-related hospitalization costs (-$3639 [-$6019 to -$1259], p < 0.01). CONCLUSION: DMF-treated patients PS-matched with OCR patients experienced lower annualized rates of infection encounters and lower infection-related HCCs.