Cladribine

Cladribine is used for as a first and second-line treatment for symptomatic hairy cell leukemia and for B-cell chronic lymphocytic leukemia and is administered by intravenous or subcutaneous infusion.[5][7]

Since 2017, cladribine is approved as an oral formulation (10 mg tablet) for the treatment of RRMS in Europe, UAE, Argentina, Chile, Canada and Australia. Marketing authorization for RRMS and SPMS in the US was obtained in March 2019.[8]

Some investigators have used the parenteral formulation orally to treat patients with HCL. It is important to note that approximately 40% of oral cladribine is bioavailable orally. It used, often in combination with other cytotoxic agents, to treat various kinds of histiocytosis, including Erdheim–Chester disease[9] and Langerhans cell histiocytosis,[10]

Cladribine can cause fetal 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.[7]

Injectable cladribine suppresses the body's ability to make new lymphocytes, natural killer cells and neutrophils (called myelosuppression); data from HCL studies showed that about 70% of people taking the drug had fewer white blood cells and about 30% developed infections and some of those progressed to septic shock; about 40% of people taking the drug had fewer red blood cells and became severely anemic; and about 10% of people had too few platelets.[7]

At the dosage used to treat HCL in two clinical trials, 16% of people had rashes and 22% had nausea, the nausea generally did not lead to vomiting.[7]

In comparison, in MS, cladribine is associated with a 6% rate of severe lymphocyte suppression (lymphopenia) (levels lower than 50% of normal). Other common side effects include headache (75%), sore throat (56%), common cold-like illness (42%) and nausea (39%)[11]

As a purine analogue, it is taken up into rapidly proliferating cells like lymphocytes to be incorporated into DNA synthesis. Unlike adenosine, cladribine has a chlorine molecule at position 2, which renders it partially resistant to breakdown by adenosine deaminase (ADA). In cells it is phosphorylated into its toxic form, deoxyadenosine triphosphate, by the enzyme deoxycytidine kinase (DCK). This molecule is then incorporated into the DNA synthesis pathway, where it causes strand breakage. This is followed by the activation of transcription factor p53, the release of cytochrome c from mitochondria and eventual programmed cell death (apoptosis).[12] This process occurs over approximately 2 months, with a peak level of cell depletion 4–8 weeks after treatment[13]

Within the lymphocyte pool, cladribine targets B cells more than T cells. Both HCL and B-cell chronic lymphocytic leukaemia are types of B cell blood cancers. In MS, its effectiveness may be due to its ability to effectively deplete B cells, in particular memory B cells[14] In the pivotal phase 3 clinical trial of oral cladribine in MS, CLARITY, cladribine selectively depleted 80% of peripheral B cells, compared to only 40-50% of total T cells.[15] More recently, cladribine has been shown to induce long term, selective suppression of certain subtypes of B cells, especially memory B cells.[16]

Another family of enzymes, the 5´nucleotidase (5NCT) family, is also capable of dephosphorylating cladribine, making it inactive. The most important subtype of this group appears to be 5NCT1A, which is cytosolically active and specific for purine analogues. When DCK gene expression is expressed as a ratio with 5NCT1A, the cells with the highest ratios are B cells, especially germinal centre and naive B cells.[16] This again helps to explain which B cells are more vulnerable to cladribine-mediated apoptosis.

Although cladribine is selective for B cells, the long term suppression of memory B cells, which may contribute to its effect in MS, is not explained by gene or protein expression. Instead, cladribine appears to deplete the entire B cell department. However, while naive B cells rapidly move from lymphoid organs, the memory B cell pool repopulates very slowly from the bone marrow.

Ernest Beutler and Dennis A. Carson had studied adenosine deaminase deficiency and recognized that because the lack of adenosine deaminase led to the destruction of B cell lymphocytes, a drug designed to inhibit adenosine deaminase might be useful in lymphomas. Carson then synthesized 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 (HCL). No pharmaceutical companies were interested in selling the drug because HCL was an orphan disease, so Beutler's lab synthesized and packaged it and supplied it to the hospital pharmacy; the lab also developed a test to monitor blood levels. This was the first treatment that led to prolonged remission of HCL, which was previously untreatable.[17]^:14–15

In February 1991 Scripps began a collaboration with Johnson & Johnson to bring intravenous cladribine to market and by December of that year J&J had filed an NDA; cladrabine was approved by the FDA in 1993 for HCL as an orphan drug,[18] and was approved in Europe later that year.[19]^:2

The subcutaneous formulation was developed in Switzerland in the early 1990s and it was commercialized by Lipomed GmbH in the 2000s.[19]^:2[20]

In the mid-1990s Beutler, in collaboration with Jack Sipe, a neurologist at Scripps, ran several clinical trials exploring the utility of cladribine in multiple sclerosis, based on the drug's immunosuppressive effects. Sipe's insight into MS, and Beutler's interest in MS due to his sister's having had it, led a very productive collaboration.[17]^:17[21] Ortho-Clinical, a subsidiary of J&J, filed an NDA for cladribine for MS in 1997 but withdrew it in the late 1990s after discussion with the FDA proved that more clinical data would be needed.[22][23]

Ivax acquired the rights for oral administration of cladribine to treat MS from Scripps in 2000,[24] and partnered with Serono in 2002.[23] Ivax was acquired by Teva in 2006,[25][26] and Merck KGaA acquired control of Serono's drug business in 2006.[27]

An oral formulation of the drug with cyclodextrin was developed[28]^:16 and Ivax and Serono, and then Merck KGaA conducted several clinical studies. Merck KGaA submitted an application to the European Medicines Agency in 2009, which was rejected in 2010, and an appeal was denied in 2011.[28]^:4–5 Likewise Merck KGaA's NDA with the FDA rejected in 2011.[29] The concerns were that several cases of cancer had arisen, and the ratio of benefit to harm was not clear to regulators.[28]^:54–55 The failures with the FDA and the EMA were a blow to Merck KGaA and were one of a series of events that led to a reorganization, layoffs, and closing the Swiss facility where Serono had arisen.[30][31] However, several MS clinical trials were still ongoing at the time of the rejections, and Merck KGaA committed to completing them.[29] A meta-analysis of data from clinical trials showed that cladiribine did not increase the risk of cancer at the doses used in the clinical trials.[32]

In 2015 Merck KGaA announced it would again seek regulatory approval with data from the completed clinical trials in hand,[30] and in 2016 the EMA accepted its application for review.[33] On June 22, 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.[34]

Finally, after all these problems it was approved in Europe on August 2017 for highly active RRMS.[35]

Cladribine has been studied as part of a multi-drug chemotherapy regimen for drug-resistant T-cell prolymphocytic leukemia.[41]