Development of oral cladribine for the treatment of multiple sclerosis

Abstract

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.

Managing MS in a changing treatment landscape

“…As expected for a drug with preferentially lymphotoxic effects, myelosuppression is the major dose-limiting effect, and leukopenia, neutropenia and thrombocytopenia may occur. Infections have been reported in patients who have pre-existing immune system disorders [122].…”

Oral drugs in multiple sclerosis therapy: an overview and a critical appraisal

“…Several CTs demonstrated very significant effectiveness and safety of cladribine in the cure of hairy-cell leukemia, and the control of many other lymphoid malignancies (see in review, [136],). Cladribine was also extensively tested in selected autoimmune disorders, most notably in MS, with evidence of efficacy, tolerability and acceptable side effects/toxicity [137]. In January 2005, Serono and IVAX announced plans to initiate a Phase III study of oral cladribine (previously administered via parenteral or subcutaneous) (Mylinax, Serono and IVAX) in MS. Tablets were taken in two cycles per year, each lasting a few days.…”

“…The safety profile of cladribine before MS has been assessed in several autoimmune disorders and the parenteral formulation of cladribine is used as a first-line treatment for hairy cell leukemia [137].…”

Aktuelles zur MS-Therapie: Orale Therapeutika

“…2,1 mg pro kg eine Reduktion akuter gadoliniumaufnehmender MS-Läsionen erzielt. Eine weitere placebokontrollierte, doppelblinde, monozentrische Studie untersuchte über 18 Monate in einer Phase-II-Studie die Wirkung von Cladribin auf schubförmige MS-Patienten (Übersicht in [8] …”