Insufficient disease inhibition by intrathecal rituximab in progressive multiple sclerosis

Abstract

ObjectiveInaccessibility 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 Rituximab by IntraVenous and IntraThecAl injection versus placebo in patients with Low‐Inflammatory SEcondary progressive MS (RIVITALISE; NCT01212094) 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?MethodsPatients aged 18–65 years were randomly assigned to rituximab or placebo. Protocol‐stipulated interim analysis quantified the efficacy of B‐cell depletion.ResultsThe efficacy on cerebrospinal fluid (CSF) biomarkers failed to reach criteria for continuation of the trial. B‐cell‐related CSF biomarkers (sCD21 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 sCD27 decreased slightly (−10.97%, P = 0.0005), while axonal damage marker, neurofilament light chain did not change. Insufficient saturation of CD20, lack of lytic complement, and paucity of cytotoxic CD56dim NK cells contribute to decreased efficacy of rituximab in the CNS.InterpretationBiomarker 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.

Pharmacodynamic effects of daclizumab in the intrathecal compartment

“…The current study demonstrates that approximately 0.1% of systemically administered daclizumab reaches the intrathecal compartment, consistent with other monoclonal antibodies such as rituximab 17, 18. The observed rise in serum and CSF IL‐2 levels provides evidence for the ability of daclizumab to inhibit consumption of IL‐2 by activated T cells14 in both systemic and intrathecal compartments.…”

Targeting B cells in relapsing–remitting multiple sclerosis: from pathophysiology to optimal clinical management

“…The authors demonstrated that higher rituximab concentrations paradoxically decreased the rituximab concentration on the surface of B cells, due to facilitated internalization of CD20/ rituximab complexes in vitro [Komori et al 2016]. Therefore, the 200 mg dose was considered sufficient to saturate CD20 leading to long-lasting depletion of B cells from peripheral circulation [Komori et al 2016]. However, greater surface binding does not mean more-efficient depletion and the study did not investigate B-cell depletion in vivo for the different rituximab dosages to allow definite conclusions.…”

“…rituximab on day 1 and day 15 with intrathecally administered rituximab. The authors demonstrated that higher rituximab concentrations paradoxically decreased the rituximab concentration on the surface of B cells, due to facilitated internalization of CD20/ rituximab complexes in vitro [Komori et al 2016]. Therefore, the 200 mg dose was considered sufficient to saturate CD20 leading to long-lasting depletion of B cells from peripheral circulation [Komori et al 2016].…”

“…Apart from the usage as monotherapy, rituximab was also tested as add-on therapy (4-weekly doses of 375 mg/m 2 , added on to IFNs or glatiramer acetate) in patients with RRMS demonstrating an additional reduction of Gd-enhanced brain lesions [Naismith et al 2010]. The RIVITALISE trial [ClinicalTrials.gov identifier: NCT01212094] evaluated the efficacy of intrathecally administered rituximab compared with placebo in SPMS following the hypothesis of compartmentalized inflammation in the progressive phase of MS. 2% of serum concentrations were measured in the CSF representing a 20-fold increase in bioavailability of serum values achievable without intrathecal dosing [Komori et al 2016]. However, the trial was prematurely terminated due to not meeting efficacy endpoints during the interim analysis.…”

The future of multiple sclerosis treatments

“…In patients using rituximab for other indications, PML cases have rarely been reported [70]. Although rituximab rapidly and consistently decreases the numbers of peripheral CD20+ and CD19+ cells [71], a small phase II trial of intrathecal rituximab was terminated early because of low efficacy on the CSF biomarkers [72]. Rituximab induced an incomplete and transient depletion of B cells in the CSF, whilst the effects on peripheral B cells were complete and lasting.…”