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Discovery and development of clofarabine: a nucleoside analogue for treating cancer

Nature Reviews Drug Discovery volume 5, pages 855–863 (2006)Cite this article

Key Points

  • Acute leukaemia is the most common paediatric cancer, with acute lymphoblastic leukaemia (ALL) and acute myelogenous leukaemia (AML) being the two most common types.

  • Despite the progress that has been made in the treatment of paediatric leukaemias and the high overall survival rate, a major need still exists for alternative therapies that are not cross-resistant to other cytotoxic agents and do not have overlapping toxicities with currently available drugs.

  • Clofarabine was discovered through a programme searching for new nucleoside anticancer drugs in which novel analogues of existing agents cladribine and fludarabine were iteratively designed, synthesis and screened with a view to addressing known deficiencies of the prior agents.

  • Following entry into cells, clofarabine is phosphorylated in a stepwise manner by cytosolic kinases to the nucleotide analogues, clofarabine 5′-mono-, di-, and triphosphate, with clofarabine triphosphate being the active form.

  • Once the triphosphate moiety is formed, the anticancer activity of clofarabine is believed to be due to three mechanisms: potent competition with dATP for DNA polymerase α and ε, which then incorporate clofarabine-monophosphate into internal and terminal DNA sites, impairing DNA elongation and/or repair; potent inhibition of ribonucleotide reductase, limiting DNA synthesis; and induction of apoptosis.

  • Preclinical models showed that clofarabine has a broad spectrum of antitumour activity in preclinical models of leukaemia and solid tumour malignancies and that its mechanism of activity was different from that of other nucleoside analogues, such as fludarabine and cladribine.

  • Based on the promising data seen in Phase I studies in paediatric patients with hematologic malignancies, interest by investigators and physicians, and positive feedback by the FDA, development for paediatric patients with ALL and AML was prioritized.

  • On the basis of Phase II studies, clofarabine became the first new drug approved by the FDA for the treatment of paediatric acute leukaemia in over a decade and was recently approved in the European Union for the same indication.

Abstract

The treatment of acute leukaemias, which are the most common paediatric cancers, has improved considerably in recent decades, with complete response rates approaching ∼90% in some cases. However, there remains a major need for treatments for patients who do not achieve or maintain complete remission, for whom the prognosis is very poor. In this article, we describe the challenges involved in the discovery and development of clofarabine, a second-generation nucleoside analogue that received accelerated approval from the US FDA at the end of 2004 for the treatment of paediatric patients 1–21 years old with relapsed or refractory acute lymphoblastic leukaemia after at least two prior regimens. It is the first such drug to be approved for paediatric leukaemia in more than a decade, and the first to receive approval for paediatric use before adult use.

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Figure 1: Structure of clofarabine and related nucleoside analogues.
Figure 2: Schematic of clofarabine mechanism of action.

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Acknowledgements

Drug development is a team effort. Clofarabine could not have been developed without the help of numerous unnamed, but dedicated, individuals. The authors would like to specifically thank B. Bauta, M. Bernstein, S. Schmid, B. Waud and B. Parker for their help in the preparation of this manuscript.

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Authors and Affiliations

  1. Genzyme, 4545 Horizon Hill Boulevard, San Antonio, 78229, Texas, USA

    Peter L. Bonate, Larry Arthaud, William R. Cantrell Jr., Katherine Stephenson & Steve Weitman

  2. Southern Research Institute, 2000 Ninth Avenue South, Birmingham, 35205, Alabama, USA

    John A. Secrist III

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Correspondence to Peter L. Bonate.

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Competing interests

P.L.B., L.A., W.J.C. and K.S. are employees of Genzyme, the manufacturer of clofarabine. S.W. is a previous employee of Genzyme and current consultant to Genzyme. J.A.S. is an employee of Southern Research Institute, an organization that has received funding from Genzyme.

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Glossary

Complete response

The disappearance of all signs of cancer in response to treatment, but not necessarily a sign that the patient has been cured. Also called a complete remission51.

Acute leukaemia

A rapidly progressing cancer that starts in the blood-forming tissue, such as the bone marrow, in which too many immature white blood cells (WBCs) are formed. When the WBCs are lymphocytes the disease is known as acute lymphocytic or lymphoblastic leukaemia (ALL) and when the WBCs do not refer to lymphocytes the disease is referred to as acute myelogenous or non-lymphocytic leukaemia (AML)51.

Blasts

Blast cells are immature precursors of lymphocytes (lymphoblasts) or granulocytes (myeloblasts) that do not normally appear in peripheral blood. Acute leukaemia is often indicated by the presence of peripheral blood blast cells.

Nucleoside

An organic compound consisting of a sugar, usually ribose or deoxyribose, linked to a heterocyclic nitrogenous base, particularly a purine or pyrimidine, especially a compound obtained by hydrolysis of a nucleic acid.

Nucleotide

The structural unit of nucleic acids, such as DNA or RNA, a nucleotide consists of a nucleoside and a (poly)phosphate group. A nucleotide that lacks a phosphate group is called a nucleoside.

V max

The maximum initial velocity of an enzyme-catalysed reaction.

IC50

The concentration of a substance that results in a 50% effect on some measure of biochemical function or substance–target binding interaction.

C max

The maximum concentration of drug in systemic circulation that is attained after dosing.

Palmoplantar erythrodysthesia

A cutaneous drug reaction manifesting in painful edematous erythema on the palms of the hands and soles of the feet.

Mucositis

Sore and inflamed mouth.

Grade

The grade of an adverse event ranges from 1–5, usually, and is an ordinal measure of the degree of severity. The higher the grade, the more severe the adverse event. Grades 1 and 2 are generally mild severity, whereas Grades 3 and 4 adverse events are usually thought to be dose-limiting. A grade of 5 relates to death. A common guideline for toxicity grading is the National Cancer Institute's Common Terminology Criteria for Adverse Events.

Serious adverse events

A serious adverse event, which has nothing to do with the severity of the adverse event (see Grade), is any adverse event that results in death, is life-threatening, requires or prolongs hospitalization, causes disability, results in a congenital abnormality, or requires intervention to prevent permanent impairment or damage.

Balanced clearance

Clearance is a proportionality constant between the concentration of drug in the body and its rate of removal from the body. A secondary definition is the volume of blood cleared by the drug per unit time. Balanced clearance refers to when there is balance between competing mechanisms of elimination, for example, the drug is cleared equally by the liver and kidneys.

Fast-track designation

The FDA assigns fast-track status to expedite review of new drugs used to treat serious or life-threatening conditions or which demonstrate the potential to address an unmet medical need.

Orphan drug designation

Orphan drug designation requires that the patient population affected is less than 200,000 per year and there is no reasonable expectation to recover the cost of developing the drug from sales in the United States. The advantages to obtaining such status are that sponsors of drugs granted orphan drug status do not have to pay FDA user fees for review of the application; the Internal Revenue Service grants up to a 50% tax credit to recoup expenses related to the development of the drug along with other tax-related incentives; and the FDA grants 7 years of marketing exclusivity for the drug.

Accelerated approval

Accelerated approval, also sometimes referred to as Subpart H, must be applied for after fast-track designation is approved. A drug can receive fast-track designation yet not gain accelerated approval. Traditional approval must demonstrate an effect on a clinically meaningful endpoint; in the case of cancer therapeutics, the 'gold standard' is survival. Under accelerated approval, a drug's approval might be based on a surrogate endpoint that is reasonably likely to be predictive of clinical benefit. When accelerated approval is granted, the sponsor is required to perform post-approval confirmatory studies.

Stable disease

Cancer that is neither decreasing nor increasing in extent or severity51.

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Bonate, P., Arthaud, L., Cantrell, W. et al. Discovery and development of clofarabine: a nucleoside analogue for treating cancer. Nat Rev Drug Discov 5, 855–863 (2006). https://doi.org/10.1038/nrd2055

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