[8][9] Cladribine, sold under the brand name Mavenclad, is used for the treatment of adults with highly active forms of relapsing-remitting multiple sclerosis.
[10] Cladribine is a purine analogue that selectively targets and suppresses lymphocytes implicated in the underlying pathogenesis of multiple sclerosis and B-cell leukaemia.
[13] Cladribine is used as a first- and second-line treatment for symptomatic hairy cell leukemia and for B-cell chronic lymphocytic leukaemia, and is administered by intravenous or subcutaneous infusion.
[17] In 2019, cladribine tablets were approved by the FDA for the treatment of relapsing forms of multiple sclerosis, to include relapsing-remitting disease and active secondary progressive disease, in adult patients who have had an inadequate response to, or are unable to tolerate, an alternate drug indicated for the treatment of multiple sclerosis.
[17][18] Cladribine may cause foetal harm when administered to a pregnant woman and is listed by the FDA as pregnancy category D; safety and efficacy in children has not been established.
DCK is the rate-limiting enzyme for conversion of the cladribine prodrug into its active triphosphate form, leading to the selective depletion of dividing and non-dividing T and B lymphocytes.
Carson then synthesised cladribine, and through clinical research at Scripps starting in the 1980s, Beutler tested it as intravenous infusion and found it was especially useful to treat hairy cell leukemia.
No pharmaceutical companies were interested in selling the drug because hairy cell leukemia was an orphan disease, so Beutler's lab synthesised and packaged it and supplied it to the hospital pharmacy; the laboratory also developed a test to monitor blood levels.
[14] In the mid-1990s, Beutler, in collaboration with Jack Sipe, a neurologist at Scripps Institute, ran several clinical trials exploring the utility of cladribine in multiple sclerosis, based on the drug's immunosuppressive effects.
[28] Ivax acquired the rights for oral administration of cladribine to treat multiple sclerosis from Scripps in 2000,[29] and partnered with Serono in 2002.
[33] An oral formulation of the drug with cyclodextrin was developed[34]: 16 by Ivax and Serono, and then Merck KGaA conducted clinical trials.
[35] The ratio of benefit to harm was not clear to regulators, and further studies were requested to address concerns related to severe lymphopenia and cancer cases observed during pivotal trials.
[34]: 54–55 Clinical studies of multiple sclerosis were still ongoing at the time of the rejections, and Merck KGaA committed to completing them.
[36] Based on the supporting data from the completed clinical trials that confirmed no increased risk of cancer, Merck announced it would again seek regulatory approval.
[38] On 22 June 2017, the EMA's Committee for Medicinal Products for Human Use (CHMP) adopted a positive opinion, recommending the granting of a marketing authorisation for the treatment of relapsing forms of multiple sclerosis.
[46] Clinical improvements can be observed at Week 24 of treatment,[46][47][48] and benefits may be sustained up to 4 years, beyond the 2-year dosing period and recovery of total lymphocytes.
[44][49][50] Post-hoc analyses of clinical trial data showed that 89% of patients remained free from disability progression two years after treatment.
[53] Furthermore, treatment with cladribine tablets has been shown to significantly reduce the rate of brain atrophy in patients with highly active relapsing-remitting multiple sclerosis.
[10] However, in up to 10 years of follow-up of patients receiving cladribine tablets for multiple sclerosis, no cases of progressive multifocal leukoencephalopathy have been observed; baseline MRI must be performed prior to initiating treatment.
Compared with a matched reference population from the Global Cancer Observatory database, cladribine tablets had no increased risk of malignancy in long-term real-world evidence data.