Background

Recent US estimates suggest that the prevalence of multiple sclerosis (MS) is nearly 3 times higher in women, many of childbearing age. Oral delayed-release dimethyl fumarate (DMF) has demonstrated a favorable benefit-risk profile in trials and post-marketing surveillance. DMF should be used in pregnant women with MS only if the potential benefit justifies the potential risk to the fetus.

Objectives

To provide pregnancy outcomes and DMF exposure data as of 08 April 2020 in women with MS treated with DMF in an ongoing prospective international registry (NCT01911767, TecGistry).

Methods

Women exposed to DMF from the first day of their last menstrual period before conception or during pregnancy were evaluated. Data were obtained at enrolment, 6−7 months of gestation, 4 weeks after estimated due date, and 4, 12 and 52 weeks after birth. As reported previously, outcomes included live births, pregnancy loss, ectopic/molar pregnancies, birth defects and anomalies, and infant or maternal death after delivery. Gestational weight was classified by percentile (<10^th, 10^th−90^th, >90^th) based on standardized growth charts.

Results

As of 08 April 2020, 345 patients were enrolled, with a median age of 32 years. Median gestational week at first exposure to DMF was 1 (range: 0, 13) and at enrollment was 9 (0, 39.3). Median (range) duration of fetal DMF exposure duration was 5 (0, 40) weeks. Among discontinuations, one was due to a serious AE. Of the known outcomes, 277 were live births (122 with 52 weeks of follow-up), 19 fetal losses including 1 molar and 1 ectopic pregnancy resulting in spontaneous abortions. One neonatal death and no maternal deaths were reported. Of 274 infants of known gestational age, 249 (91%) were full term, and 25 (9%) premature (<37 weeks). Gestational weight data were available for 232 infants, of whom 26 (11%) were small, 190 (82%) appropriate, and 16 (7%) large. Overall, 8 infants had adjudicator-confirmed birth defects, including ventricular septal defect, congenital hydronephrosis, ureteral duplication, pyloric stenosis, transposition of the great vessels, unilateral developmental dysplasia of the hip, and 1 premature infant with multiple birth defects.

Conclusions

The pregnancy outcome frequencies observed in this updated analysis were consistent with previous reports and did not exceed those seen in the MS and general populations. No additional safety signals were identified.

Supported by: Biogen

Background

In clinical studies, delayed-release dimethyl fumarate (DMF) demonstrated a favorable benefit–risk profile in patients with relapsing-remitting multiple sclerosis (MS). Real-world studies enable characterization of risks that may only emerge with long-term exposure in clinical practice. ESTEEM (NCT02047097) is an ongoing 5-year study characterizing long-term safety and effectiveness of routinely prescribed DMF in MS patients.

Objectives

To report 5-year safety and effectiveness in patients with multiple sclerosis (MS) treated with DMF under routine care.

Methods

Patients treated with DMF were recruited from ~380 sites. The primary objective was to determine incidence, type, and pattern of serious adverse events (SAEs), and AEs leading to discontinuation. Secondary objectives included assessment of DMF effectiveness on annualized relapse rate (ARR) and patient-reported outcomes (PROs).

Results

On April 3, 2019, 5084 patients had ≥1 dose of DMF and qualified for analysis. Mean (SD) age was 40.0 (11.2) years at enrollment, and 74% were female. In total, 1506 patients were treated for >24–48 months, and 441 were treated for >48 months. Two hundred and forty-five patients (4.8%) experienced SAEs; infections (n=64; 1.3%) and nervous system disorders (n=35; <1%) were most common. There were 1676 (33.0%) permanent treatment discontinuations: 965 (19.0%) due to AEs (most commonly: gastrointestinal AEs [395, 7.8%] and occurrence of lymphopenia [125, 2.5%]) and 260 (5.1%) due to insufficient efficacy. Overall ARR over the period of up to 5 years (0.09; 95% CI: 0.09–0.10) was significantly lower than in the year prior to baseline (0.82, 95% CI: 0.80–0.84), representing an 88.6% risk reduction [95% CI: 87.7–89.4 P<0.0001]). At 54 months, the Kaplan-Meier estimated probability of patients without relapse was 71.1% (n=4286). PROs were generally stable from baseline to Year 5.

Conclusions

Results from the ongoing study with up to 5 years follow-up reveal no new safety concerns emerging from real-world use of DMF. DMF demonstrated beneficial therapeutic effects for those patients that remained on treatment up to 5 years.