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.

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.

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.

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.

Efficacy and Safety Outcomes with Diroximel Fumarate After Switching from Prior Therapies or Continuing on DRF: Results from the Phase 3 EVOLVE-MS-1 Study.

INTRODUCTION: Diroximel fumarate (DRF) is an oral fumarate for relapsing multiple sclerosis (MS) with the same active metabolite as dimethyl fumarate (DMF). DRF has a safety/efficacy profile similar to DMF but with improved gastrointestinal (GI) tolerability and low (< 1%) treatment discontinuation due to GI adverse events (AEs). Efficacy and safety outcomes in patients who switched to DRF from other disease-modifying therapies (DMTs) have not been evaluated. METHODS: EVOLVE-MS-1 is an ongoing, 2-year, open-label, phase 3 study of DRF in adults with relapsing-remitting MS. Patients either entered as newly enrolled to DRF trials, or from the 5-week, randomized, head-to-head, phase 3 EVOLVE-MS-2 study of DRF and DMF. This analysis evaluated safety and GI tolerability in patients continuing on DRF (DRF-rollover) or switching from DMF (DMF-rollover) following EVOLVE-MS-2. Safety and efficacy were evaluated in a subset of newly enrolled patients who had received prior glatiramer acetate (GA; GA/DRF) or interferons (IFN; IFN/DRF) as their most recent DMT, prior to switching to DRF in EVOLVE-MS-1. RESULTS: As of September 1, 2020, 1057 patients were enrolled in EVOLVE-MS-1, including 166, 182, 239, and 225 patients in the GA/DRF, IFN/DRF, DRF-rollover, and DMF-rollover groups, respectively. Treatment discontinuation due to GI AEs was < 1% in all groups. GA/DRF and IFN/DRF patients experienced improvements from baseline in clinical and radiological efficacy outcomes, including significantly reduced annualized relapse rates. Rollover patients had low rates of new or recurrent GI AEs (DRF-rollover, 26.8%/4.2%; DMF-rollover, 27.1%/4.9%). CONCLUSION: After 2 years of DRF exposure, patients with prior GA, IFN, or fumarate treatment had safety outcomes consistent with previous fumarate studies. Efficacy in patients with prior GA or IFN treatment was consistent with previous fumarate studies. The data suggest that transition to DRF from GA, IFN, or DMF is a reasonable treatment strategy, with low rates of discontinuation due to GI AEs. TRIAL REGISTRATION: ClinicalTrials.gov (NCT02634307). INFOGRAPHIC.

A propensity-matched comparison of long-term disability worsening in patients with multiple sclerosis treated with dimethyl fumarate or fingolimod.

BACKGROUND: Although the aggregate of data among patients with multiple sclerosis (MS) have shown similar efficacy between dimethyl fumarate (DMF) and fingolimod (FTY), most studies have not assessed long-term worsening of disability. We compared long-term disability worsening over 5 years, as assessed by the Patient-Determined Disease Steps (PDDS), among participants with MS treated with DMF or FTY. METHODS: We identified individuals in the North American Research Committee on Multiple Sclerosis (NARCOMS) registry who had relapsing-remitting MS (RRMS), residing in the United States (Spring 2011 to Spring 2018), who initiated treatment with DMF (n = 689) or FTY (n = 565) and had ⩾1 year follow-up on index treatment. Participants receiving DMF who were previously treated with FTY and those on FTY previously treated with DMF were excluded. Propensity score matching at baseline was used to match FTY-treated to DMF-treated participants. Time to 6-month confirmed disability worsening (⩾1-point increase on PDDS, sustained for ⩾6 months) was estimated using Cox regression. A sensitivity analysis was conducted to account for differences in the duration of index exposure between DMF and FTY groups. RESULTS: After propensity score matching, 468 DMF-treated participants were matched with 468 FTY-treated participants. Median treatment duration was 3.0 years for DMF and 4.0 years for FTY. At 5 years, 68.3% [95% confidence interval (CI): 62.4-73.5] of DMF-treated participants and 63.3% (95% CI: 59.6-70.1) treated with FTY were free from 6-month confirmed PDDS worsening [hazard ratio (HR) 1.01 (95% CI: 0.79-1.28); p = 0.95]. Results were similar in the sensitivity analysis: 70.5% (95% CI: 61.8-77.6) of DMF-treated participants and 72.7% (95% CI: 65.4-78.6) of FTY-treated participants were free from 6-month confirmed PDDS worsening [HR: 1.04 (95% CI: 0.71-1.51); p = 0.84]. CONCLUSIONS: In participants with MS from the NARCOMS registry, there was no significant difference in confirmed disability (PDDS) worsening over 5 years between those treated with DMF versus FTY.

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.

Multiple Sclerosis Patients Treated With Diroximel Fumarate in the Real-World Setting Have High Rates of Persistence and Adherence.

INTRODUCTION: Persistence to multiple sclerosis (MS) disease-modifying therapy is fundamental for maximal treatment outcomes. Diroximel fumarate (DRF) is approved in the USA for relapsing MS. Following oral administration, DRF is metabolized to monomethyl fumarate, the active metabolite of dimethyl fumarate (DMF). DRF showed clinically significant improvements in gastrointestinal (GI) tolerability versus DMF in a head-to-head clinical trial; however, real-world persistence/adherence has not been assessed. We evaluated persistence/adherence in DRF-treated patients in a real-world clinical practice. METHODS: This retrospective analysis of the AcariaHealth Specialty Pharmacy Program included patients initiating DRF from 4 December 2019 through 3 April 2020 and followed until data extraction (31 August 2020). Exclusion criteria included undetermined treatment status (e.g., DRF prescription transfer to a different pharmacy). Endpoints included persistence (overall proportion of patients remaining on DRF), discontinuation rate due to GI adverse events (AEs), and adherence (proportion of days covered [PDC]). GI AEs included GI-related AEs occurring at any time, or any unknown AE without details about the nature of the event if the unknown AE occurred ≤ 90 days after DRF initiation. RESULTS: Overall, 160 patients with MS were included. Median (range) patient age was 51 (20-79) years, 80.6% (129/160) of patients were female, and 16.3% (26/160) had prior DMF treatment. Median (range) treatment duration was 7.6 (0.1-10.4) months. Estimated proportion of patients remaining persistent on DRF treatment at 8 months was 88.6% (95% confidence interval [CI] 82.5-2.7). Overall, 3.8% (6/160) of patients discontinued due to GI AEs. Mean PDC was 91.4% (95% CI 89.1-93.7). In a DMF-to-DRF switch subgroup, 92.3% (24/26) remained persistent on DRF, and 3.8% (1/26) discontinued DRF due to GI AEs. CONCLUSION: This real-world analysis of DRF-treated patients showed high overall persistence, low discontinuation rate due to GI AEs, and high adherence to therapy, aligning with expectations based on DRF clinical trials. Data were consistent in the DMF-to-DRF subgroup. INFOGRAPHIC.

Real-world propensity score comparison of treatment effectiveness of peginterferon beta-1a vs. subcutaneous interferon beta-1a, glatiramer acetate, and teriflunomide in patients with relapsing-remitting multiple sclerosis.

BACKGROUND: Multiple disease-modifying therapies (DMTs) have been approved by the U.S. Food & Drug Administration for the treatment of relapsing-remitting multiple sclerosis (RRMS). In separately conducted clinical trials, peginterferon beta-1a, subcutaneous interferon beta-1a (SC IFN beta-1a), glatiramer acetate (GA), and teriflunomide have demonstrated efficacy for reducing relapses. No head-to-head phase III clinical trials have directly compared the treatment efficacy of peginterferon beta-1a with these other DMTs. OBJECTIVES: A propensity score-based comparison was conducted of the treatment effectiveness of peginterferon beta-1a vs. SC IFN beta-1a, GA, and teriflunomide among patients with RRMS identified from a large U.S. administrative healthcare claims database. METHODS: Adult patients (18-65 years of age) who had ≥1 claim for an MS diagnosis between November 2013 and June 2017 and ≥1 claim for peginterferon beta-1a, SC IFN beta-1a, GA, or teriflunomide between November 1, 2014, and March 31, 2017 were identified from the IBM® MarketScan® Commercial database. The index date was the first claim of a patient's DMT initiated. Only patients who had ≥12 months of insurance enrollment pre-index (baseline period) and ≥90 days post-index (variable length follow-up period) were included. Patients were grouped into cohorts according to the index DMT. Patient demographics and clinical characteristics were evaluated. Propensity score matching (PSM) was separately conducted for pairwise comparisons of treatment effectiveness between peginterferon beta-1a and the other DMT cohorts. During the post-index follow-up period, annualized relapse rate (ARR; relapse defined as hospitalization or outpatient visit with subsequent treatment), annualized number and length of inpatient stays, and the number of claims for durable medical equipment were evaluated. RESULTS: With PSM, there were 325 patients (mean age: 46.0 years) in the peginterferon beta-1a cohort compared to 967 (mean age: 46.9 years) in the SC IFN beta-1a cohort; likewise there were 564 patients (mean age: 47.4 years) in the peginterferon beta-1a and 1688 (mean age: 47.6 years) in the GA cohort; and finally there were 584 patients (mean age: 49.1 years) in the peginterferon beta-1a cohort and 1742 (mean age: 49.0 years) in the teriflunomide cohort. During the post-index follow-up period, the ARR did not significantly differ between the peginterferon beta-1a and SC IFN beta-1a cohorts; the ARR was lower among patients treated with peginterferon beta-1a than among those treated with GA (Least squares mean [LSM] estimate: 0.25 vs. 0.31; LSM ratio: 0.809; P=0.027) or teriflunomide (LSM estimate: 0.26 vs. 0.37; LSM ratio: 0.704; P<0.001). The annualized mean number and length of inpatient stays and the mean number of claims for durable medical equipment during the post-index follow-up did not differ between the matched peginterferon beta-1a and GA cohorts nor the peginterferon beta-1a and teriflunomide cohorts. CONCLUSION: In this real-world comparative analysis of patients with similar patient characteristics, treatment with peginterferon beta-1a was associated with lower ARRs than treatment with either GA or teriflunomide; ARRs did not differ among patients treated with SC IFN beta-1a. Also, all other measured secondary outcomes did not differ between study cohorts. These real-world data may help support decision-making in the treatment of patients with RRMS.

A pharmacokinetic and biomarker study of delayed-release dimethyl fumarate in subjects with secondary progressive multiple sclerosis: evaluation of cerebrospinal fluid penetration and the effects on exploratory biomarkers.

BACKGROUND: Biomarkers are a useful and reliable measure of disease activity in many fields of medicine. Axonal and glial biomarkers in multiple sclerosis (MS) are being applied more often as technology is improving and becoming increasingly reliable. Nonclinical studies have shown dimethyl fumarate (DMF) to have cytoprotective and anti-inflammatory effects. The purpose of this study is to explore the pharmacokinetics (PK) of DMF (by measuring MMF, the active compound) in serum and cerebrospinal fluid (CSF) as well as relevant biomarker data for patients with secondary progressive MS (pwSPMS) and whether there is objective evidence for neuroprotection in pwSPMS treated with DMF. METHODS: Sixteen pwSPMS had serum and cerebrospinal fluid (CSF) evaluation for PK studies levels of MMF at various time points after ingestion of DMF. The CSF biomarkers neurofilament light chain (NfL), glial fibrillary acidic protein (GFAP), ubiquitin carboxyo-terminal hydrolase isozyme L1 (UCH-L1) and total tau (T-tau) were measured at baseline, week 6 and week 28 after initiating DMF with a starting dose of 120 mg twice daily for 4 weeks, followed by a maintenance dose of 240 mg twice daily. Clinical correlation of these patients with EDSS and MRI at these same time periods were made with the biomarkers. Four normal human volunteers had CSF studies for biomarkers at baseline. RESULTS: PK data showed CSF MMF concentration 11% of plasma with Tmax of plasma at 5 hr and Tmax of CSF at 7 hr. Biomarker data showed that CS NfL and to a lesser extent, GFAP, but not UCH-L1 nor T-tau showed relevant changes with clinical data. Some pwSPMS receiving DMF showed clinical improvements in Expanded Disability Status Scale (EDSS). Biomarker changes, but not MRI, correlated with clinical measures in this group of pwSPMS over the observation period. CONCLUSIONS: PK data showed that the Tmax of CSF MMF peaked only 2 hours later than that of plasma with 11% measured in the CSF so that MMF readily crossed the blood brain barrier allowing potential direct penetration into the brain. NfL CSF levels, and to a lesser extent, GFAP CSF levels, showed correlation to disease activity in pwSPMS . These data suggest that DMF may have some benefit in reducing disease activity in pwSPMS if studied for a longer duration and larger well-controlled studies are warranted. DMF was reasonably well tolerated but 3 of the 16 patients did discontinue DMF at 6 weeks due to persistent side effects. NfL appeared to be more clinically relevant biomarker than brain MRI in this this group during the 28-week study period.

Dimethyl fumarate treatment shifts the immune environment toward an anti-inflammatory cell profile while maintaining protective humoral immunity.

BACKGROUND: Delayed-release dimethyl fumarate (DMF) demonstrates sustained efficacy and safety for relapsing forms of MS. Absolute lymphocyte count (ALC) is reduced initially, then stabilizes on treatment. OBJECTIVE: PROCLAIM, a 96-week, prospective, open-label, phase 3b study, assessed lymphocyte subsets and immunoglobulin (Ig) levels during 48 and 96 weeks (W) of DMF treatment. METHODS: Patients received 240 mg DMF BID. Endpoints: lymphocyte subset count changes (primary); Ig isotypes and ALC changes (secondary); adverse events and relationship between ALC changes and ARR/EDSS (exploratory); and neurofilament assessment (ad hoc). RESULTS: Of 218 patients enrolled, 158 (72%) completed the study. Median ALC decreased 39% from baseline to W96 (BL-W96), stabilizing above the lower limit of normal (baseline: 1.82 × 109/L; W48: 1.06 × 109/L; W96: 1.05 × 109/L). CD4 + and CD8 + T cells correlated highly with ALC from BL-W96 (p < 0.001). Relative to total T cells, naive CD4 + and CD8 + T cells increased, whereas CD4 + and CD8 + central and effector memory T cells decreased. Total IgA, IgG, IgM, and IgG1-4 subclass levels remained stable. Adverse event rates were similar across ALC subgroups. ARR, EDSS, and neurofilament were not correlated with ALCs. CONCLUSION: Lymphocyte decreases with DMF were maintained over treatment, yet immunoglobulins remained stable. No increase in infection incidence was observed in patients with or without lymphopenia. SUPPORT: Biogen.

Characterizing Long-term Disability Progression and Employment in NARCOMS Registry Participants with Multiple Sclerosis Taking Dimethyl Fumarate.

BACKGROUND: Delayed-release dimethyl fumarate (DMF) is effective in relapsing-remitting multiple sclerosis (RRMS), but long-term effects of DMF on disability and disease progression in clinical settings are unknown. We evaluated disability and employment outcomes in persons with RRMS treated with DMF for up to 5 years. METHODS: This longitudinal study included US North American Research Committee on Multiple Sclerosis (NARCOMS) Registry participants with RRMS reporting DMF initiation in fall 2013 through spring 2018 with 1 year or more of follow-up. Time to 6-month confirmed disability progression (≥1-point increase in Patient-Determined Disease Steps [PDDS] score) and change in employment status were evaluated using Kaplan-Meier analysis. Participants were censored at last follow-up or at DMF discontinuation, whichever came first. RESULTS: During the study, 725 US participants with RRMS had at least 1 year of DMF follow-up data, of whom most were female and White. At year 5, 69.9% (95% CI, 65.4%-73.9%) of these participants were free from 6-month confirmed disability progression, and 84.7% (95% CI, 78.6%-89.2%) were free from conversion to secondary progressive MS. Of 116 participants with data at baseline and year 5, most had stable or improved PDDS and Performance Scales scores over 5 years. Of 322 participants 62 years and younger and employed at the index survey, 66.0% (95% CI, 57.6%-73.1%) were free from a negative change in employment type over 5 years. CONCLUSIONS: Most US NARCOMS Registry participants treated up to 5 years with DMF remained free from 6-month confirmed disability progression and conversion to secondary progressive MS and had stable disability and employment status. These results support the long-term stability of disability and work-related outcomes with disease-modifying therapy.

Effectiveness of Dimethyl Fumarate in Patients With Relapsing Multiple Sclerosis Switching After Suboptimal Response to Glatiramer Acetate, Including Patients With Early Multiple Sclerosis: Subgroup Analysis of RESPOND.

INTRODUCTION: This post hoc subset analysis of RESPOND evaluated the effectiveness of dimethyl fumarate (DMF) 240 mg twice daily in patients with relapsing multiple sclerosis (RMS) after suboptimal response to glatiramer acetate (GA; "first switch" patients), including patients with early MS ("early MS switch" patients). METHODS: Patients had discontinued GA due to suboptimal response and initiated DMF treatment within 60 days after enrollment. Relapse data were collected from medical records. First switch patients had had one prior approved MS therapy (GA) before initiating DMF treatment. Early MS switch patients were first switch patients with baseline Patient-Reported Expanded Disability Status Scale (PR-EDSS) score ≤ 3.5, ≤ 1 relapses in the past 1 year, or both. RESULTS: Among first switch patients (n = 231), the annualized relapse rate (ARR) was 0.48 (95% confidence interval [CI] 0.40-0.58) for 12 months before DMF initiation and 0.11 (95% CI 0.06-0.18) for 12 months after DMF initiation, a 78% decrease in ARR. Among early MS switch patients with baseline PR-EDSS score ≤ 3.5 (n = 120), ≤ 1 relapses in the prior year (n = 219), or both (n = 114), the ARRs (95% CIs) for 12 months before DMF initiation were 0.47 (0.37-0.59), 0.37 (0.32-0.44), and 0.39 (0.31-0.49), respectively; values for 12 months after DMF initiation were 0.06 (0.02-0.19), 0.09 (0.05-0.17), and 0.06 (0.02-0.20), respectively, an 87, 75, and 83% decrease in ARR. The proportion of patients relapse-free 12 months after DMF initiation versus 12 months before were 94 versus 59% in first switch patients, and 97 versus 58%, 94 versus 63%, and 97 versus 61% in early MS switch patients in the PR-EDSS score ≤ 3.5, ≤ 1 relapses in the prior year, or PR-EDSS score ≤ 3.5 and ≤ 1 relapses subgroups, respectively. After 12 months of DMF treatment, most patient-reported outcomes scores showed significant improvement. CONCLUSIONS: DMF may be an effective treatment option in first switch and early MS switch patients with RMS who experience a suboptimal response to GA. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT01903291.

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

INTRODUCTION: Compared 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. METHODS: ESTEEM 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. RESULTS: Overall, 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. CONCLUSIONS: Relapse 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.