Title: The need for a closer monitoring of novel drugs in MS: a Siponimod retrospective cohort study (Realhes Study)

Abstract Background Severe cases of lymphopenia have been reported during siponimod clinical trials, which may negatively impact its benefit/risk profile. Objective To evaluate the incidence of lymphopenia during the first 3–6 months of siponimod treatment in clinical practice. Secondary objectives include analyses of factors predisposing to and the clinical relevance of lymphopenia events. Methods In this multicenter retrospective cohort study, collected information from the medical records of 129 patients with MS, from 15 tertiary hospitals in Spain, who initiated treatment with siponimod, were followed-up for at least 3 months and had at least one lymphocyte count evaluation. Results Of the 129 patients, 121 (93.6%) reported lymphopenia events, including 110 (85.3%) with grade ≤ 3 and 11 (8.5%) with grade 4 lymphopenia, higher than those reported in the pivotal clinical trial (73.3% and 3.3% for Grade ≤ 3 and Grade 4 lymphopenia, respectively). Conclusion In this study, the incidence and severity of lymphopenia after starting siponimod treatment were higher than those reported in previous clinical trials. Therefore, our results reinforce the need for closer monitoring of novel MS drugs in clinical practice, as well as larger and longer follow up studies to properly characterize this risk. Trial registration EU PAS Register (http://encepp.eu), identifier #EUPAS45187 (January 17, 2022)