Insufficient disease inhibition by intrathecal rituximab in progressive multiple sclerosis

Objective Inaccessibility of the inflammation compartmentalized to the central nervous system ( CNS ) may underlie the lack of efficacy of immunomodulatory treatments in progressive multiple sclerosis ( MS ). The double blind combination of R ituximab by I ntra V enous and I ntra T hec A l injection versus placebo in patients with L ow‐ I nflammatory SE condary progressive MS ( RIVITALISE ; NCT 01212094) trial was designed to answer: (1) Whether an induction dose of intravenous and intrathecal rituximab efficiently depletes CNS B cells? and (2) If so, whether this leads to global inhibition of CNS inflammation and slowing of CNS tissue destruction? Methods Patients aged 18–65 years were randomly assigned to rituximab or placebo. Protocol‐stipulated interim analysis quantified the efficacy of B‐cell depletion. Results The efficacy on cerebrospinal fluid ( CSF ) biomarkers failed to reach criteria for continuation of the trial. B‐cell‐related CSF biomarkers ( sCD 21 and B‐cell activating factor) changed only in the active‐treatment arm. While CSF B cells were killed robustly (median −79.71%, P  = 0.0176), B cells in CNS tissue were depleted inadequately (~−10–20%, P  < 0.0001). Consequently, the T‐cell‐specific CSF biomarker sCD 27 decreased slightly (−10.97%, P  = 0.0005), while axonal damage marker, neurofilament light chain did not change. Insufficient saturation of CD 20, lack of lytic complement, and paucity of cytotoxic CD 56 dim NK cells contribute to decreased efficacy of rituximab in the CNS. Interpretation Biomarker studies reliably quantified complementary pharmacodynamic effects of rituximab in the CNS , exposed causes for poor efficacy and determined that RIVITALISE trial would be underpowered to measure efficacy on clinical outcomes. Identified mechanisms for poor efficacy are applicable to all CNS ‐inflammation targeting monoclonal antibodies.