No Early Effect of Intrathecal Rituximab in Progressive Multiple Sclerosis (EFFRITE Clinical Trial)

Abstract

Background. The progressive phase of multiple sclerosis (MS) is characterized by an intrathecal (IT) compartmentalization of inflammation, involving B-cells within meningeal follicles, and resisting all the available immunosuppressive treatments. A new therapeutic paradigm may be to target this inflammation by injecting immunosuppressive drugs inside the central nervous system compartment. Methods. We designed a single-center, open-label, randomized, controlled, phase II study designed to evaluate the safety and efficacy of IT rituximab in progressive MS (EFFRITE trial; ClinicalTrial Registration NCT02545959). Patients were randomized into three arms (1 : 1 : 1): control group, IT rituximab (20 mg, IT) group, and intravenous+IT (IV+IT) group. The main outcome was a change in levels of CSF biomarkers of inflammation (osteopontin). Secondary outcomes were changes in levels of CSF biomarkers of axonal loss (neurofilament light chain) and clinical and MRI changes. Results. Ten patients were included (2 : 4 : 4). No adverse event occurred. OPN level remained stable in CSF at each time point, whereas NFL had slightly decreased (-8.7%) at day 21 ( p = 0.02 ). Clinical parameters remained stable and leptomeningeal enhancements remained unchanged. Conclusion. Clinical outcome and biomarkers of inflammation were not dramatically modified after IT injection of rituximab, probably due to its limited efficiency in CSF. Drug issues for future studies are discussed.

Acting centrally or peripherally: A renewed interest in the central nervous system penetration of disease-modifying drugs in multiple sclerosis

“…There is no compelling biological explanation presented in the literature providing a rationale as to why rituximab may be able to cross the BBB whereas other monoclonal antibodies are seemingly restricted to the periphery, and it may be that detection of low levels of rituximab in the CNS is confounded by the methods used in the studies reported to date (Petereit and Rubbert-Roth, 2009;Hagens et al, 2018). Moreover, recent clinical studies of intrathecally administered rituximab in patients with progressive MS have reported that treatment does not halt disease progression (Bergman et al, 2021(Bergman et al, , 2018Bonnan et al, 2021).…”

What Have Failed, Interrupted, and Withdrawn Antibody Therapies in Multiple Sclerosis Taught Us?

“…Intrathecal rituximab resulted in a significant and sustained reduction in circulating B cells, but only a transient drop in CSF B cells and unchanged brain imaging outcomes during the 24-week follow-up period [ 181 ]. In the open-label phase II trial EFFRITE (NCT02545959), 10 patients were randomized into control group ( n = 2), intrathecal rituximab group (20 mg) ( n = 4), or intravenous (375 mg/m 2 ) plus intrathecal (20 mg) rituximab group ( n = 4) [ 182 ]. Patients received the therapy once and clinical, blood, MRI, and CSF assessments at several points in time during the one-year follow-up.…”

“…Clinical parameters remained stable and leptomeningeal enhancements remained unchanged. Soluble CD21 (sCD21), which is a marker of B-cell pool, was decreased in serum but not in CSF after rituximab [ 182 ].…”

“…As other mAbs, rituximab does not pass readily across the BBB, and its CSF concentration has been estimated to reach only 0.1% of that in serum after intravenous administration [ 189 ]. Under the assumption that the compartmentalization of inflammation behind a relatively intact BBB in progressive MS prevents access through current DMTs [ 190 ], intrathecal administration of rituximab was evaluated in several clinical trials in patients with progressive MS [ 180 – 182 ]. The low efficacy of intrathecal administration of rituximab in previous trials might be attributed to low bioavailability (CSF rituximab levels of 2% of serum values) [ 180 ].…”

“…Whether the intrathecal dose chosen was too low or if complex mechanisms like internalization of the antibody-CD20 complex also play a role in the reduced ability of rituximab to deplete B cells remains elusive [ 191 ]. Insufficient complement and effector cells for CDD and ADCC might further explain the poor CNS efficacy of rituximab in progressive MS [ 180 , 182 , 186 ]. Moreover, a significant efflux of intrathecally administered rituximab into systemic circulation and an inadequate dispersion of rituximab in CSF were observed [ 180 , 182 ].…”