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The Gene genie

Imatinib has helped many patients with CML, but alone it is unlikely to provide a cure

Over the last five years, imatinib (Gleevec/Glivec) has become the gold standard treatment for chronic myeloid leukaemia (CML), a malignant bone marrow cancer that affects one to two individuals in every 100,000.

Although it is a relatively rare disease, gross sales of imatinib were $2.17bn for 2005, which is one of the reasons why two large pharmaceutical firms, Novartis Pharmaceuticals and Bristol-Myers Squibb (BMS), are rapidly developing next-generation therapeutics to combat CML.

Another reason is that many patients who, initially, respond well to imatinib therapy end up developing resistance to the drug and relapsing. When this happens, these patients have few, if any, suitable alternative treatment options.

It is estimated that in 2006 there will be about 4,500 new cases of CML in the US and that about 600 patients will die of the disease.

Root cause of CML
CML arises when stem cells in the bone marrow develop a genetic defect, causing them to produce excessive numbers of white blood cells of the myeloid lineage. The genetic defect responsible for this is the BCR-ABL gene, created when the ABL gene on chromosome 9 is translocated and fused to the BCR gene on chromosome 22. This fusion gene encodes the BCR-ABL protein, an aberrant tyrosine kinase that drives proliferation, differentiation and survival of the leukaemic cells.

CML progresses from a typically benign chronic-phase, which lasts three to five years, to an accelerated-phase, and then a blast-crisis, as the leukaemic stem cells acquire additional genetic abnormalities.

Imatinib is a potent inhibitor of BCR-ABL tyrosine kinase. Its clinical activity is highest in newly-diagnosed patients with CML in chronic-phase, with 98 per cent of these patients achieving normal blood counts. However, while the disease is well-controlled, it is not eradicated and recurs in most patients if imatinib therapy is discontinued.

This is a major concern because the leukaemic progenitor cells that persist can develop mutations in the BCR-ABL gene that enable them to become resistant to imatinib. This is evidenced by the 16 per cent of chronic-phase CML patients that develop drug resistance to imatinib after 3.5 years of treatment.

The mutations can reduce the sensitivity of the BCR-ABL protein to imatinib, or stabilise BCR-ABL in an active conformation that imatinib cannot bind. Hence, Novartis and BMS are developing a new generation of more potent tyrosine kinase inhibitors that are less susceptible to the most common mechanisms of resistance.

Sidestepping resistance
Novartis, developer and manufacturer of imatinib, is working on nilotinib (AMN-107, Tarsigna), a structural derivative of the compound.

This orally administered compound has demonstrated activity against 32 mutant forms of BCR-ABL. It has 20- to 50-fold increased potency relative to imatinib, in imatinib-sensitive cell lines, and has three to seven times the activity in imatinib-resistant cell lines.

A registrational phase II trial of nilotinib is underway in imatinib-resistant patients with CML and, in June 2006, a global phase III study was launched that gives patients expanded access to nilotinib until it becomes commercially available. Novartis plans to file for approval in the EU and US in late 2006.

BMS is developing a compound that is structurally unrelated to imatinib, called dasatinib (BMS-354825). This agent was originally synthesised as an SRC-family inhibitor, however, it was also found to inhibit BCR-ABL.

SRC is tyrosine kinase whose over-expression has been reported to confer resistance to imatinib. Dasatinib is 325-fold more potent than imatinib, in imatinib-sensitive cells, and has demonstrated activity against 18 imatinib-resistant BCR-ABL mutants.

The compound is capable of binding to BCR-ABL regardless of its conformation, unlike imatinib and nilotinib which can only bind to the inactive form of the protein.

BMS completed a New Drug Application (NDA) for dasatinib in December 2005 after phase II trials were finalised. The US Food and Drug Administration is now reviewing the NDA under Accelerated Approval status and a decision on the application is expected before the end of 2006.

Despite dasatinib and nilotinib having impressive response rates in patients with chronic-phase, imatinib-resistant CML, responses in patients with accelerated-phase and blast-phase CML are lower and relapses are common.

Alternative approaches
One of the reasons behind this is that neither agent is effective against the BCR-ABL mutation, known as T315I, which is found in approximately 15 per cent of patients who acquire resistance to imatinib therapy. Therapeutics directed against this mutation represent the next major frontier in the treatment of CML.

One such compound is Vertex and Merck & Co`s VX-680, an Aurora kinase inhibitor that also inhibits multiple other kinases, including BCR-ABL. It has demonstrated preclinical activity against T315I-mutated BCR-ABL and phase I studies in haematologic malignancies, including CML, have been initiated.

An immunomodulatory approach to eradicating CML includes cancer vaccine CMLVAX100 (ABLVAX), which is currently under development with Breakthough Therapeutics.

The BCR-ABL fusion creates a unique sequence of amino acids expressed only in leukaemic cells, and is thus a potential tumour-specific antigen. CMLVAX100 contains five short peptides derived from the fusion region that are designed to elicit a T-cell mediated immune response against cells with the BCR-ABL gene.

Phase II trials in patients with CML who have not achieved total molecular remission with imatinib are complete.

In June 2006, ChemGenex launched a multinational phase II/III clinical trial of homoharringtonine (Ceflatonin) in patients with chronic, accelerated or blast-phase CML with the T315I mutation.

An alkaloid derived from an evergreen tree, homoharringtonine up-regulates the expression of genes linked with apoptosis in myeloid cells. It was promising in a phase II trial of imatinib-resistant CML patients. Ongoing trials are exploring its efficacy in patients with the T315I mutation.

Imatinib has been a wonder drug, but whether new agents can eliminate the earliest progenitor cells and, thus, all evidence of disease, is still to be determined.

The author
Pipeline is written by Ben Benson-Cooper, of Adis International, using information derived from Adis Clinical Trials Insight and R&D Insight. For more information on Adis services, contact Camille Scot-Smith on 020 7981 0733

2nd September 2008

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