Faculty Bibliography

BACKGROUND:Delayed-release dimethyl fumarate (DMF) has demonstrated robust efficacy in treating patients with relapsing-remitting multiple sclerosis. Decreases in absolute lymphocyte count (ALC) are a well-known pharmacodynamic effect of DMF treatment, but lymphocyte recovery dynamics are not well characterized after discontinuation of DMF. METHODS:Data sources included the Biogen DMF integrated clinical trial data set, a retrospective US chart abstraction study, and data from MSBase. We assessed rate and time course of lymphocyte reconstitution after DMF discontinuation. RESULTS:/L was 12-18 months vs 2-3 months in patients with lymphopenia persisting <6 months. CONCLUSIONS:The majority of patients who discontinued DMF due to lymphopenia experienced ALC reconstitution within 2-4 months following DMF discontinuation. This may help guide clinicians in managing patients who develop lymphopenia during DMF treatment. Prolonged lymphopenia on DMF treatment is associated with slow lymphocyte recovery after DMF discontinuation.

Multiple sclerosis (MS) is a chronic inflammatory and demyelinating disease of the central nervous system. The disease affects more women than men and often is diagnosed during a woman's childbearing years. Typical clinical presentations of the disease are extensive and variable, with symptoms that include dysregulated mood, fatigue, vision problems, weakness, tremor, imbalance, abnormal sensations, bladder dysfunction, and heat sensitivity. If a woman aged 15-50 years experiences these neurologic symptoms in isolation or combination, and the symptoms are not explained by other underlying medical conditions, MS should be suspected. Multiple sclerosis can be divided into four clinical subtypes: 1) relapsing-remitting MS, 2) secondary progressive MS, 3) primary progressive MS, and 4) clinically isolated syndrome. Relapsing-remitting MS at the time of onset is the most common form and accounts for approximately 80% of all cases of MS. Relapsing-remitting MS does not affect life expectancy. However, because of the neurodegenerative and progressive course of the disease, patients accumulate physical and cognitive disabilities over time that result in impaired ability to work, increased financial burden, and slightly increased mortality. A variety of possible risk and prognostic indicators have been identified that may predict the course of disease, particularly the extent of relapses and disability. Multiple sclerosis currently is incurable, but many disease-modifying therapies are available that can reduce the frequency of clinically evident exacerbations and accumulation of disease burden as defined by the number of lesions identified on magnetic resonance imaging. The choice of disease-modifying therapies, contraception use, and treatment of symptoms should be individualized based on age at onset and disease activity and, during pregnancy, the gestational age. Proactive management of MS across the woman's life cycle reduces morbidity, improves maternal and fetal health during pregnancy and the postpartum period, and increases quality-of life-measures for patients and their families.

BACKGROUND:Diroximel fumarate (DRF) is a novel oral fumarate for patients with relapsing-remitting multiple sclerosis (RRMS). DRF and the approved drug dimethyl fumarate yield bioequivalent exposure to the active metabolite monomethyl fumarate; thus, efficacy/safety profiles are expected to be similar. However, DRF's distinct chemical structure may result in a differentiated gastrointestinal (GI) tolerability profile. OBJECTIVE:To report interim safety/efficacy findings from patients in the ongoing EVOLVE-MS-1 study. METHODS:EVOLVE-MS-1 is an ongoing, open-label, 96-week, phase 3 study assessing DRF safety, tolerability, and efficacy in RRMS patients. Primary endpoint is safety and tolerability; efficacy endpoints are exploratory. RESULTS: < 0.0001) and adjusted annualized relapse rate was low (0.16; 95% confidence interval: 0.13-0.20). CONCLUSION:Interim data from EVOLVE-MS-1 suggest DRF is a well-tolerated treatment with a favorable safety/efficacy profile for patients with RRMS.