Diroximel Fumarate as a Novel Oral Immunomodulating Therapy for Relapsing Forms of Multiple Sclerosis: A Review on the Emerging Data.

Multiple sclerosis (MS) is a chronic inflammatory, demyelinating and neurodegenerative disorder of the central nervous system. Disease-modifying drugs (DMDs) and subsequent adherence are crucial for preventing reversible episodes of neurological dysfunction and delayed onset of progressive accumulation of irreversible deficits. Yet, side effects may limit their usage in clinical practice. Gastrointestinal (GI) side effects are a significant limitation of the use of dimethyl fumarate (DMF), the most frequently prescribed oral DMD in MS worldwide. Diroximel fumarate (DRF) is a second-generation oral fumaric acid ester (FAE) that was developed as a formulation with better GI tolerability. The improved tolerability is assumed to be related to a lower synthesis of gut-irritating methanol. Other explanations for DRF's lower extent of GI irritation include a more modest off-target activity due to its chemical structure. The superior GI tolerability of DRF compared to DMF could be proven in clinical trials and lead to approval of DRF for the treatment of relapsing forms of MS/relapsing-remitting MS (United States Food and Drug Administration and European Medicines Agency, respectively). Here, we summarize the mode of action of oral FAE and compare the chemical and physiological characteristics of DMF and DRF. Moreover, we discuss the adverse effects of FAE and introduce the emerging preclinical and trial data leading to the approval of DRF in MS. This article additionally reviews our current understanding of coronavirus disease 2019 (COVID-19) and the efficacy of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) vaccination in people treated with FAE.

Temporal Trendsin Humoral and Cellular Immune Responsesto SARS-CoV-2 mRNA Vaccines Among Multiple Sclerosis Patients TreatedWith Natalizumab, Ocrelizumab or Fumarates

Objective: To examine the temporal trends of humoral and cell-mediated immune responses to SARS-CoV-2 mRNA vaccines among multiple sclerosis (MS) patients on different immunomodulatory therapies. Background: The impact of various MS medications on the immune responses to SARS-CoV-2 vaccine is of acute interest to patients and clinicians. Design/Methods: 22 MS patients treated with ocrelizumab (OCR, n=9), natalizumab (NTZ, n=8), fumarates (FUM, n=5;diroximel fumarate, 3 and dimethyl fumarate, 2) received BNT162b2 (Pfizer, n=15) or mRNA-1273 (Moderna, n=7) vaccines. Blood samples were collected before and after each of the two vaccine doses, and 2 months after second vaccine dose. AntiSARS-CoV-2 spike protein titers were measured using quantitative assay (Labcorp). Antibody neutralization was measured with a lentivirus-based pseudovirus particle expressing the D614 spike protein (Labcorp-Monogram Biosciences). T-cell reactivity was determined by measuring interferon-gamma and interleukin-2 in response to stimulation with SARS-CoV-2 peptides. Results: All patients in NTZ and FUM cohorts, but only 22% (2/9) of OCR cohort developed anti-spike and neutralizing antibodies. The highest titers were measured after the second vaccine dose, without significant difference between the NTZ and FUM cohorts in anti-spike IgG (69.7+/-55.1 vs 56.0+/-36.7 arbitrary units/ml) or neutralizing ID50 (1513+/-1317 vs 942+/ -566). Two months after the second vaccine, the antibody titers and neutralizing ID50 decreased by 72% and 79% in NTZ cohort, respectively, and by 45% and 49% in FUM cohort. T-cell reactivity was observed in all cohorts as early as 7 days after the first vaccine, and further increased following the second vaccine. Conclusions: Patients on NTZ and FUM mounted robust antibody responses to SARS-CoV-2 mRNA vaccines, in contrast to OCR-treated patients. T-cell responses were comparable among all three treatment cohorts. Two months after the second vaccine, the serological responses decreased by 45-79%. These findings may inform the optimal timing of additional vaccine doses for MS patients.