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BACKGROUND: Pregnancy is a common consideration for people with multiple sclerosis (pwMS); MS onset is typically between 20 and 45 years of age, during potential child-bearing years. Pregnancy and postpartum care are a significant factor influencing disease-modifying therapy (DMT) selection for many pwMS. To date, few DMTs are considered safe to continue during pregnancy and real-world treatment patterns before, during, and after pregnancy remain uncharacterized. Evolving guidance is needed regarding how to optimize management of the pregnancy and postpartum periods considering the changing DMT landscape. This analysis in two large claims databases describes DMT utilization for the treatment of MS before, during, and after pregnancy and relapse patterns during pregnancy and postpartum. METHODS: In this retrospective, observational study, the US MarketScan Commercial and Medicaid claims database was assessed for female patients aged 18-55 years with ≥1 insurance claim submitted under the diagnosis code of MS from 01 January 2016-30 April 2021 and continuous enrollment eligibility from ≥6 months prior to pregnancy date (preconception) through 6 months of follow-up following delivery (postpartum period). Comorbid conditions were examined preconception and postpartum, including anxiety and depression. Moderate/severe relapse was defined as MS-related hospitalization, or an outpatient visit and one claim within 7 days of the visit with steroids or total plasma exchange. RESULTS: A total of 944 patients (mean [standard deviation] age, 32.4 [5.0] years) were eligible; 688 (73%) were commercially insured and 256 (27%) received Medicaid. Compared with commercially-insured patients, use of DMTs was lower among Medicaid patients at 6 months preconception (25.4% vs 40.4%; p < 0.001), with similar patterns observed both during pregnancy and postpartum. Overall, prevalence of DMT use declined sharply during pregnancy, from 36.3% of patients in the 6 months preconception to 17.9%, 5.3%, and 5.8% in trimesters 1, 2 and 3, respectively. Postpartum DMT utilization increased to 20.9% at 0-3 months and 24.4% at 4-6 months. Of all patients in the preconception period, the most frequently used DMTs were glatiramer acetate (14.3%), dimethyl fumarate (6.0%), interferon (5.2%), and natalizumab (4.9%). Due to small sample size, information was limited for anti-CD20s and alemtuzumab. The proportion of patients with any moderate/severe relapse declined over pregnancy (preconception, n = 82 [8.7%]; pregnancy, n = 25 [2.6%]), but increased postpartum (n = 94 [10.0%]). Of the 889 patients who stopped DMT during pregnancy, the risk of postpartum relapses was lower in the patients who resumed DMT postpartum (10/192) than in patients who did not (76/697) (5.2% vs 10.9%; odds ratio, 0.455 [95% confidence interval 0.216-0.860], p = 0.018). Cases of postpartum depression and anxiety were significantly lower in commercially-insured patients vs Medicaid patients (postpartum depression, 13.7% vs 27.0%, p < 0.01; postpartum anxiety, 16.3% vs 30.5%, p < 0.01). CONCLUSION: DMT utilization declined sharply during pregnancy; it gradually increased postpartum but remained below pre-pregnancy use. The proportion of pwMS experiencing a moderate/severe relapse and number of relapses declined over pregnancy but increased postpartum. Reinitiation of DMT during the postpartum period was associated with lower risk of relapses, supporting a role for early reinitiation of DMT postpartum. STUDY SUPPORTED BY: Biogen.
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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.
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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).
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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.
