New era drug gives hope to Gleevec resistant leukaemia sufferers

Apr 19 2005

Gleevec, a drug regarded by many as having "wonder drug" capabilities in the treatment of chronic myelogenous leukaemia (CML) and other cancers, has been revealed as having shortcomings in that some patients have undergone a relapse after building a resistance to the drug. For others with the advanced stage of the disease, the drug has failed to produce durable remissions.

Now however, scientists have discovered that a molecular understanding of resistance has rapidly led to a new generation of drugs that might prove even more effective than Gleevec.

Two new studies report that a new compound, known as AMN107, may one day offer a more potent alternative for treating patients with acquired Gleevec resistance and others with advanced CML.

In its original conception Gleevec works in CML patients by selectively deactivating Bcr-Abl, the abnormal tyrosine kinase protein that triggers rapid growth of leukemic cells and was hailed as the first approved drug to directly inhibit the activity of an enzyme known to cause uncontrolled cell growth, and it has been highly successful for many patients.

But scientists soon recognized that some patients develop mutations in the Bcr-Abl protein that drastically reduces Gleevec's effectiveness.

To overcome this resistance to Gleevec, scientists are designing new compounds and AMN107 is one such drug produced by Novartis Pharmaceuticals in Basel, Switzerland in collaboration with investigators at the Dana Farber Cancer Institute.

Basically AMN107 retains half the chemical makeup of Gleevec, while the other half was designed to create a tighter link to Bcr-Abl, thus increasing potency and potentially overcoming resistance due to mutations in Bcr-Abl.

Scientists at the Oregon Health and Science University in Portland compared the potency of the new compound against Gleevec using a panel of cell lines expressing 16 different Gleevec-resistant, mutant versions of Bcr-Abl and their results showed that AMN107 was at least 20 times more potent than Gleevec against most of the resistant mutants.

Thomas O'Hare, a research specialist in Gleevec pioneer Brian Druker's laboratory at the Oregon Health and Science University Cancer Institute says the results show that 15 of the 16 mutants were sensitive to AMN107, while one mutant remained insensitive and would require a different, as yet undiscovered, inhibitor. The results were equally impressive when the other leading drug in this field, a Bristol-Myers Squibb compound called BMS-354825, was also investigated. The team say that the data indicates that AMN107 is a highly active Bcr-Abl inhibitor that may have clinical utility in patients with Gleevec-refractory CML which is great news for patients. They believe that having several safe and effective drugs available is the key to controlling acquired drug resistance in CML.

Study leader, Francis Giles, M.D., a professor of medicine at the University of Texas M. D. Anderson Cancer Centre say AMN107 appears to effectively rescue patients with chronic myeloid leukaemia (CML) who did not respond to targeted therapy with Gleevec, more than 70 percent of advanced CML patients in an international study have shown a response to the drug, AMN107, and patients with the early form of the disease have responded at a rate of more than 90 percent.

Giles says "If you can take a pill and rescue people who failed the current standard of care, that is remarkable, the drug is very safe, and we are seeing a response that improves daily."

The response rate in over 100 patients enrolled in the clinical trial to date continues to improve, as doses are rapidly increased. The first patients began treatment at 50 milligrams, but now all are taking 400 milligrams twice a day "and we have certainly not reached a dose-limiting toxicity," Giles says that the "vast majority" of CML patients do very well on Gleevec, and that AMN107 was designed to treat the 10 percent of patients who do not respond, either because of a known mutation that Gleevec does not treat, or because the cancer has advanced to the point where other mutations in the cancer arise.

They are about to launch a series of studies testing use of AMN107 as the first therapy used by CML patients, whether they have the early chronic stage, advanced "accelerated" and terminal "blast" stages of the disease to see how AMN107 can fit into the treatment picture. They expect that patients will benefit from both agents.

Giles says the research represents a new era of medical treatment where the integration between preclinical researchers and clinical oncologists is seamless.

The study is being funded by Novartis, which manufacturers both AMN107 and Gleevec. Giles presented first results of the therapy in a fewer number of patients last December at the annual meeting of the American Society of Haematology.

The study, which includes researchers and patients at the University of Frankfurt in Germany, is still ongoing.