Clinical Experience with Dimethyl Fumarate and Natalizumab in Pregnant Women with Multiple Sclerosis: A Four-Patient Case Series.

Interferon ß and glatiramer acetate are the disease-modifying drugs (DMDs) considered relatively safe for use in pregnant women with multiple sclerosis (MS); however, the safety profile of dimethyl fumarate (DMF) and natalizumab (NTZ) in this population remains inconclusive. Here, we present four cases of pregnant women with MS who were treated with DMF and NTZ (n = 2 patients, each) during their pregnancy and discuss our observations with the use of these drugs and the clinical courses of the patients. We retrospectively examined relapse of MS during pregnancy and after delivery; duration of exposure to DMDs; maternal, fetal, and neonatal adverse events; breastfeeding; and timing of resumption of DMDs. The two patients treated with DMF discontinued treatment 5 or 6 weeks after the discovery of pregnancy. DMF was resumed 1 week postpartum, and mixed breastfeeding was initiated. Brain magnetic resonance imaging in one patient 9 months after delivery revealed a new lesion; however, it was not classified as a clinical relapse. In two patients treated with NTZ, the dosing interval was extended to 6 weeks after the discovery of pregnancy. One patient discontinued NTZ at 30 weeks and the other at 25 weeks of gestation, as a slight restriction in fetal growth was observed owing to hyperemesis gravidarum. Both patients opted for formula feeding, and no relapse was observed within 1 year postpartum. Additionally, no abnormalities were observed in any of the patients during the perinatal period, and their development was normal. Investigation of drug safety in pregnant and parturient women primarily relies on registries, postmarketing surveillance, and case reports due to ethical limitations on conducting randomized controlled trials. Our findings demonstrated that DMF and NTZ were not contraindicated during pregnancy or the perinatal period in women with MS; nevertheless, vigilant monitoring is essential to ensure the safety of these drugs.

Efficacy and Safety of the Natural Killer T Cell-Stimulatory Glycolipid OCH-NCNP1 for Patients With Relapsing Multiple Sclerosis: Protocol for a Randomized Placebo-Controlled Clinical Trial.

BACKGROUND: Multiple sclerosis (MS) is an autoimmune inflammatory disease of the central nervous system that causes myelin sheath damage and axonal degeneration. The glycolipid (2S, 3S, 4R)-1-O-(α-d-galactosyl)-2-tetracosanoylamino-1,3,4-nonaetriol (OCH-NCNP1 or OCH) exerts an immunoregulatory action that suppresses T helper (Th)1 cell-mediated immune responses through natural killer T cell activation, selective interleukin-4 production, and Th2 bias induction in human CD4-positive natural killer T cells. OBJECTIVE: This trial aims to investigate the efficacy and safety of the immunomodulator OCH in patients with relapsing MS through 24-week repeated administration. METHODS: This protocol describes a double-blind, multicenter, placebo-controlled, randomized phase II clinical trial that was initiated in September 2019. The participants were randomly assigned to either a placebo control group or an OCH-NCNP1 group and the investigational drug (3.0 mg) was orally administered once weekly for the 24-week duration. Major inclusion criteria are as follows: patients had been diagnosed with relapsing MS (relapsing-remitting and/or secondary progressive MS) based on the revised McDonald criteria or were diagnosed with MS by an attending physician as noted in their medical records; patients with at least two medically confirmed clinical exacerbations within 24 months prior to consent or one exacerbation within 12 months prior to consent; patients with at least one lesion suspected to be MS on screening magnetic resonance imaging (MRI); and patients with 7 points or less in the Expanded Disability Status Scale during screening. Major exclusion criteria are as follows: diagnosis of neuromyelitis optica and one of optic neuritis, acute myelitis, and satisfying at least two of the following three items: (1) spinal cord MRI lesion extending across at least three vertebral bodies, (2) no brain MRI lesions during onset (at least four cerebral white matter lesions or three lesions, one of which is around the lateral ventricle), and (3) neuromyelitis optica-immunoglobulin G or antiaquaporin-4 antibody-positive. Outcome measures include the primary outcome of MRI changes (the percentage of subjects with new or newly expanded lesions at 24 weeks on T2-weighted MRI) and the secondary outcomes annual relapse rate (number of recurrences per year), relapse-free period (time to recurrence), sustained reduction in disability (SRD) occurrence rate, period until SRD (time to SRD occurrence), no evidence of disease activity, and exploratory biomarkers from phase I trials (such as gene expression, cell frequency, and intestinal and oral microbiome). RESULTS: We plan to enroll 30 patients in the full analysis set. Enrollment was closed in June 2021 and the study analysis was completed in March 2023. CONCLUSIONS: This randomized controlled trial will determine whether OCH-NCNP1 is effective and safe in patients with MS as well as provide evidence for the potential of OCH-NCNP1 as a therapeutic agent for MS. TRIAL REGISTRATION: ClinicalTrials.gov NCT04211740; https://clinicaltrials.gov/study/NCT04211740. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): DERR1-10.2196/46709.