Cladribine tablets' potential role as a key example of selective immune reconstitution therapy in multiple sclerosis

Abstract

Multiple sclerosis (MS) is one of the most important, disabling, and prevalent neurological disorders of young adults. It is a chronic inflammatory and neurodegenerative disease when autoreactive B and T cells have downstream effects that result in demyelination and neuronal loss. Anti-inflammatory disease-modifying therapies do have proven efficacy in delaying disease and disability progression in MS. While the progress in MS treatments has already improved the prognosis and quality of patients' lives overall, there are some clear shortcomings and unmet needs in the current MS treatment landscape. The most promising means of MS treatment is selective immune reconstitution therapy (SIRT). This therapy is given in short-duration courses of immunosuppression, producing durable effects on the immune system and preventing nervous tissue loss. This review discusses the mechanisms of action and the data of clinical trials of cladribine tablets as an example of SIRT in MS. The clinical benefits of cladribine tablets in these studies include decreased relapse rate and disability progression with large reductions in lesion activity, and protection against brain volume loss. Whether all of these neurological findings are direct results of lymphocyte depletion, or if there are downstream effects on other, unknown, neurodegenerative processes are yet to be determined, but these clearly point to an interesting area of research.

Keywords: cladribine; multiple sclerosis; selective immune reconstitution; therapy.

Figure 1

Immunopathogenesis of multiple sclerosis and associated immune targets. Abbreviations: APC, antigen presenting cell; HLA, human leukocyte antigen; IFN, interferon; IL, interleukin; MHC, major histocompatibility complex; MMP, matrix metalloproteinase; NO, nitric oxide; ROS, reactive oxygen species; TCR, T-cell receptor; T_h, T helper cell; T_reg, regulatory T cell.

Figure 2

Molecular structure of cladribine Note: Reproduced from the National Center for Biotechnology Information. PubChem Compound Database; CID=20279.

Figure 3

Effects of cladribine tablets 3.5 mg/kg versus placebo in patient subgroups on the RR ratio of cumulative new T1 Gd+ lesions (A) and cumulative active T2 lesions (B). Note: Reproduced from Giovannoni G, Comi G, Montalban X, Hicking C, Dangond F. Benefits of cladribine tablets on magnetic resonance imaging (MRI) outcomes in patients with multiple sclerosis: analysis of pooled double-blind data from the CLARITY and ONWARD studies (Abstract 603; Poster P642). Mult Scler J. 2016;22(3_Suppl):88.⁶⁸ Abbreviations: DMD, disease-modifying drug; EDSS, Expanded Disability Status Scale; Gd+, gadolinium enhancing; HDA, high disease activity (≥2 relapses in previous year regardless of treatment status, or ≥1 relapse in the previous year while on DMD therapy and ≥1 T1 Gd+ lesion or 9 T2 lesions); OR, odds ratio; RR, relative risk; NE, not estimated.