Abstract and Introduction
Abstract
Cladribine, a synthetic deoxyadenosine analog, is an oral immunomodulatory agent that produces targeted, sustained reduction of T and B lymphocytes. This mechanism of action provides the rationale for use in relapsing–remitting multiple sclerosis (MS) in a short-course annual dosing regimen. Based on the results of a pivotal Phase III study, therapy with cladribine tablets has the potential to become a licensed oral disease-modifying medication for relapsing forms of MS. This article will review the key points regarding MS and its pathogenesis, and discuss current unmet treatment needs. In particular the review provides an overview of emerging potential new oral MS therapies with a focus on the mechanism of action, chemistry, pharmacokinetics, pharmacodynamics, clinical efficacy and safety of cladribine tablets. Assessments and conclusions will include a speculative 5-year outlook.
Introduction
Multiple sclerosis (MS) is a chronic, immune-mediated disorder of the CNS, which is characterized by inflammation, demyelination, axonal degeneration and episodic neurological symptoms that frequently transform into progressive neurodegeneration. It is the most common cause of nontraumatic neurological disability in young adults. Research from a number of groups has shown that MS lesions on brain magnetic resonance imaging (MRI) may be present in patients before the first symptoms emerge, but once diagnosed, long-term treatment is essential to stabilize the patient's condition, prevent breakthrough disease and delay the onset or progression of disability over its subsequent life-long course.
Multiple sclerosis is associated with dynamic, unpredictable episodes of exacerbation with inflammatory demyelination that result in plaque-like lesions visualized by MRI of the CNS that may correlate relatively poorly with clinical attacks, and variable degrees of transient, persistent or progressive neurodegeneration. The heterogeneous nature of MS contributes to difficulties in predicting the outcome of treatment for a significant number of patients, and is also reflected in variable responsiveness between individuals to MS treatments. This may account for the observation that currently available disease-modifying drugs (DMDs) are not completely effective in all patients. For example, the proportion of relapsing–remitting MS (RRMS) patients not adequately responding to disease-modifying therapy has been reported to range from 7 to 49%, depending on the criteria used; and methods to define incomplete responses or breakthrough MS disease have recently been evaluated. Therefore, there is a significant unmet need for additional MS therapies, with improved efficacy and novel mechanisms of action, suitable for treatment both in early and later stages of the disease.
The increased understanding and appreciation of the role of inflammation in the development of early MS has led to improved diagnostic criteria and increased early intervention with DMDs, which target immune processes. T and B lymphocytes are both thought to play an important role in the complex immunopathology of MS, including the production of inflammatory cytokines and antibodies directed against CNS components. The influx of activated, myelin autoreactive T cells into the CNS is a critical step in an acute inflammatory demyelinating response that gives rise to symptoms and clinical relapses in MS. Both CD4 and CD8 T cells are present in MS lesions, and several histopathologic subtypes of MS. CD4 T cells play a key role in the regulation of the events associated with the inflammatory cascade, while CD8 cells are involved in the destruction of target cells expressing specific antigens. In addition, activated myelin autoreactive T cells have been shown in the blood and cerebrospinal fluid of MS patients, while only nonactivated autoreactive cells have been detected in 'healthy' individuals. There is mounting evidence to suggest that B cells are also implicated in the inflammatory response and development of demyelinating lesions in MS. High numbers of chronically activated B cells and unique oligoclonal immunoglobulin G bands are present in the cerebrospinal fluid of patients with MS, correlating with the rate of disease progression. B cells may facilitate the pathogenesis of MS through the production of autoreactive antibodies, and through antigen-presenting and cytokine-secreting roles, leading to abnormal T-cell and macrophage activation, thereby perpetuating CNS inflammation, demyelination and neurodegeneration.
Given the significant involvement of lymphocytes in the pathogenesis of MS, the targeted reduction of T- and B-cell populations represents a novel strategy to reduce and control MS activity. The actions of some of the agents currently in development are directed at these core components of MS immunopathology. Here, the data are reviewed for cladribine, an immunomodulatory therapy with preferential lymphocyte-reducing activity, recently developed in tablet form for a short-course, annual oral dosing regimen in patients with MS.