Cladribine: An Investigational Immunomodulatory Agent for Multiple Sclerosis

Brousil, J; Roberts, Russel J.; Schlein, Amanda L

doi:10.1345/aph.1h037

Cited by 41 publications

(31 citation statements)

References 32 publications

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“…The possibility to reveal unrecognised myelodysplastic disorders as a consequence of CdA marrow suppression cannot be underestimated. A Phase III trial with the oral formulation is in progress in > 1200 MS patients with the RR type [70].…”

Section: Antimetabolite Immunosuppressants 221 Cladribinementioning

confidence: 99%

Compared benefit of approved and experimental immunosuppressive therapeutic approaches in multiple sclerosis

Gonsette¹

2007

Expert Opinion on Pharmacotherapy

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An important amount has been learnt about the mechanisms of action, efficacy and long-term toxicities of mitoxantrone. Importantly, recent observations strongly suggest that early administration of potent immunosuppressants (mitoxantrone and alemtuzumab) is definitely more effective than approved immunomodulators to delay or even reverse disability progression. Given the cardiotoxicity of mitoxantrone, restricting exposure to the drug to 2 or 3 years, the benefits and risks of immunosuppressants previously used as off-label treatments (cyclophosphamide and cladribine) have been revisited, and the potential efficacy in multiple sclerosis of recent immunosuppressants used in other autoimmune diseases, organ transplantation and cancer therapy has received increasing attention. Those immunosuppressants comprise monoclonal antibodies targeting B cells, lymphocytes and monocytes, IL-2 receptor and alpha4 integrin, as well as new molecules (pixantrone and isoxazole derivatives) and a new generation of immunosuppressants (fingolimod), which modulate lymphocyte re-circulation. This review addresses the most recent data concerning the efficacy and safety of mitoxantrone and of new experimental therapies that are presently in progress.

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Section: Antimetabolite Immunosuppressants 221 Cladribinementioning

confidence: 99%

Compared benefit of approved and experimental immunosuppressive therapeutic approaches in multiple sclerosis

Gonsette¹

2007

Expert Opinion on Pharmacotherapy

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“…This small molecule was designed rationally after recognition of the selective vulnerability of lymphocytes in an inherited disorder of adenosine deaminase deficiency [35,36]. Carson and colleagues discovered that the lymphopenia observed in this disorder was caused by the accumulation of deoxyadenosine nucleotides within lymphocytes [37].…”

Section: Cladribinementioning

confidence: 99%

“…Compared with other cell types, lymphocytes have high levels of deoxycytidine kinase but low levels of 5 0 -nucleotidase and so are particularly unable to effectively metabolize cladribine [39]. The accumulation of cladribine nucleotides disrupts DNA synthesis and repair and ultimately leads to sustained reduction in lymphocytes [36].…”

Section: Mechanism Of Action Of Cladribinementioning

confidence: 99%

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Development of oral cladribine for the treatment of multiple sclerosis

et al. 2009

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Multiple sclerosis (MS) is a chronic immune-mediated disorder of the CNS in which autoreactive CD4+ and CD8+ T lymphocytes, B lymphocytes, antibodies, macrophages and cytokines synergize to attack myelin sheaths and injure underlying axons. Current disease-modifying drugs (DMDs) for MS require regular and frequent parenteral administration and are associated with limited long-term treatment adherence. Of all the potential new oral MS agents in development, cladribine is the only therapy with the potential for short-course dosing. Cladribine is an immunosuppressant that offers targeted, sustained regulation of the immune system and that has a well-characterized safety profile, derived from more than 15 years of use of the parenteral formulation in oncology indications and MS. This paper discusses the need for new MS therapies to improve treatment adherence, and reviews the mechanism of action, existing efficacy and safety data, and the clinical development of oral cladribine. The need for continuous risk monitoring for all new potent immunoactive drugs under development is emphasized. Preliminary results of the 96-week, double-blind, randomized, placebo-controlled, multicenter CLARITY (CLAdRIbine Tablets Treating MS OrallY) study are encouraging and provide the first complete phase III data on an oral DMD for MS.

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“…[72][73][74] However, a double-blind, placebo-controlled phase III study of subcutaneously administered cladribine in 159 patients with secondary and primary progressive MS unexpectedly failed to exhibit significant clinical and MRI benefits after one year. 75 As cladribine also exists in an oral formulation and as pilot trials also have provided encouraging data, 76 a large randomized, double-blind, placebocontrolled phase III trial, including 1,290 patients with active inflammatory relapsing-remitting MS has recently been initiated.…”

Section: Cladribinementioning

confidence: 99%

Immunosuppressive Agents in Multiple Sclerosis

2007

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Summary:Immunosuppressive agents have been used in multiple sclerosis (MS) for decades. The approval of several immunomodulatory agents against MS beginning in the 1990s, whose putative mechanisms of action appeared "more MSspecific," curtailed the importance of immunosuppressants, which made them treatment options of second choice. However, with the recent approval of mitoxantrone for treatment of patients with active forms of relapsing-remitting or secondary progressive MS and with a number of oral immunosuppressive agents being assessed in phase II and III clinical trials, a "renaissance" of this type of agents is currently occurring. This review provides an outline of the most important clinical studies and discusses relevant side effects of the major immunosuppressants (i.e., mitoxantrone, azathioprine, cyclophosphamide, methotrexate, mycophenolate mofetil, cladribine, and sirolimus/temsirolimus). The current knowledge of the putative mechanisms of action of these compounds is discussed.

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Cladribine: An Investigational Immunomodulatory Agent for Multiple Sclerosis

Abstract: While data do not support its use as a first-line MS treatment, cladribine may be a promising agent for refractory patients with secondary progressive MS. Further studies are warranted.

Cited by 41 publications

References 32 publications

Compared benefit of approved and experimental immunosuppressive therapeutic approaches in multiple sclerosis

Compared benefit of approved and experimental immunosuppressive therapeutic approaches in multiple sclerosis

Development of oral cladribine for the treatment of multiple sclerosis

Immunosuppressive Agents in Multiple Sclerosis

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