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

Abstract

With the recent approval of cladribine tablets, siponimod and ozanimod, there has been a renewed interest into the extent to which these current generation disease-modifying therapies (DMTs) are able to cross into the central nervous system (CNS), and how this penetration of the blood-brain barrier (BBB) may influence their ability to treat multiple sclerosis (MS). The integrity of the CNS is maintained by the BBB, blood-cerebrospinal fluid barrier, and the arachnoid barrier, which all play an important role in preserving the immunological environment and homeostasis within the CNS. The integrity of the BBB decreases during the course of MS, with a putative temporal relationship to disease worsening. Furthermore, it is currently considered that progression of the disease is mediated mainly by resident cells of the CNS. The existing literature provides evidence to show that some of the current generation DMTs for MS are able to penetrate the CNS and potentially exert direct effects on CNS-resident cells, in particular the CNS-penetrating prodrugs cladribine and fingolimod, and other sphingosine-1 phosphate receptor modulators; siponimod and ozanimod. Other current generation DMTs appear to be restricted to the periphery due to their high molecular weight or physicochemical properties. As more effective brain penetrant therapies are developed for the treatment of MS, there is a need to understand whether the potential for direct effects within the CNS are of significance, and whether this brings additional benefits over and above treatment effects mediated in the periphery. In turn, this will require an improved understanding of the structure and function of the BBB, the role it plays in MS and subsequent treatments. This narrative review summarizes the data supporting the biological plausibility of a potential benefit from therapeutic molecules entering the CNS, and discusses the potential significance in the current and future treatment of MS.