Clofarabine.

Abstract

Clofarabine [Clofarex] is a purine nucleoside in development with Bio-envision, the Southern Research Institute and ILEX Oncology as an anticancer agent. Clofarabine's nucleoside structure is such that both the purine and ribose rings are halogenated, which allows it to inhibit DNA synthesis at two critical junctures: DNA polymerase I and RNA reductase. An intravenous infusion and an oral formulation are undergoing clinical development. Clofarabine was originated by the Southern Research Institute. In August 1998 Bioenvision signed a co-development agreement with the Southern Research Institute, under which it obtained the right to manufacture, market and distribute clofarabine worldwide, except Japan and Southeast Asia. In addition, the company appears to have licensed rights from the Institute that cover the development and marketing of other purine nucleoside analogues that have relevance in the treatment of leukaemia and lymphoma. Bioenvision will pay royalties to the Southern Research Institute for sales of clofarabine. Bioenvision extended its option in May 2004 to manufacture, market and distribute clofarabine in Japan and Southeast Asia, and is seeking a co-marketing partner to convert the option into a license agreement following the terms agreed upon between Bioenvision and the Southern Research Institute. Bioenvision and ILEX Products (a wholly owned subsidiary of ILEX Oncology) signed an agreement in February 2004 that converted ILEX's option (agreed in March 2001) to market and distribute clofarabine in the US and Canada. As part of the deal, Bioenvision received a $US3.5 million payment from ILEX in December 2003. In March 2004, Genzyme Corporation announced that it had signed a merger agreement with ILEX Oncology under which ILEX shareholders will receive shares of Genzyme common stock valued at approximately $US1 billion in equity value. Genzyme's business combination with ILEX is expected to be completed by the middle of 2004, Genzyme will, therefore, acquire a considerable boost to its product portfolio. Bioenvision obtained the exclusive option from the Southern Research Institute in September 2003 to manufacture, market and distribute clofarabine in Japan and Southeast Asia. Bioenvision stated it was actively seeking a co-marketing partner to convert this option into a license. Bioenvision announced in June 2003 that it had formed two separate agreements with Ferro Pfanstiehl Laboratories. The agreements cover worldwide development and supply of clofarabine, excluding the US and Canada. Ferro Pfanstiehl has more than 25 years of experience in potent compound manufacturing. The US FDA granted clofarabine fast-track designation for the treatment of refractory or relapsed acute lymphoblastic leukaemia in children in September 2003. Clofarabine has also been granted orphan drug status by the US FDA for the treatment of adult and paediatric patients with acute lymphocytic leukaemia (ALL) or acute myeloid leukaemia (AML). In December 2001, clofarabine was granted orphan drug status in the EU for the treatment of adult and paediatric patients with ALL. A single-agent phase II study has been completed in patients with acute leukaemia and myelodysplastic syndromes. Results of a phase II study of clofarabine in the treatment of acute myelogenous leukaemia in older adults who are not considered suitable for intensive chemotherapy have been very positive, with a 64% response rate in these patients being reported. In May 2004, Bioenvision announced that it had decided to stop enrollment at 25 evaluable patients (initially anticipated to be approximately 37 patients) because of the encouraging interim results. It said the trial would conclude earlier than expected and be completed by the end of June 2004. The pivotal trial will enroll approximately 65 patients with AML considered unsuitable for intensive chemotherapy. Bioenvision currently has phase II trials ongoing in adult and paediatric patients with acute leukaemia and chronic lymphocytic leukaemia (CLL). In addition, Bioenvision-sponsored phase I/II clinical trials of clofarabine in patients with CLL and non-Hodgkin's lymphoma are underway in Europe. In July 2002, ILEX began two US multicentre, open-label, phase II trials in children with relapsed or refractory AML or ALL. Children enrolled in the studies receive an intravenous infusion of clofarabine over 2 hours for five consecutive days every 2-6 weeks. In June 2003, at the 39th Annual Meeting of the American Society of Clinical Oncology (ASCO-2003), an overall response rate of 28% was reported for clofarabine therapy in heavily pretreated children with acute leukaemia. In September 2003, a multicentre European phase II trial (BIOV-111) was initiated in children with relapsed/refractory ALL. In December 2003, the first of 65 patients received treatment. As part of the global development programme, Bioenvision and ILEX are also conducting a phase II study in adult patients with AML. The companies are planning to investigate the potential use of clofarabine in combination with DNA-damaging agents, because clofarabine has been shown to inhibit DNA repair and may, therefore, potentiate the effects of DNA damaging drugs. A phase I/II trial of clofarabine in combination with cytarabine (Ara-C) in adult patients with first relapse AML, ALL, CML blast crisis and myelodysplastic syndrome was initiated at the University of Texas MD Anderson Cancer Centre in October 2002. Clofarabine has completed US phase I trials, and has reported favourable results in patients with leukaemia and solid tumours, including breast, colorectal and prostate cancers. A phase I/II trial in patients with solid tumours was initiated in July 2002. In addition, ILEX said it intended to develop an oral formulation of clofarabine for the treatment of colorectal cancer.