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Aurora Kinase Inhibitor Shows Activity in Chronic Myelogenous Leukemia

Aurora Kinase Inhibitor Shows Activity in Chronic Myelogenous Leukemia

Allison Gandey

December 12, 2006 (Orlando) — A new aurora kinase inhibitor is the first to show clinical activity in a population of treatment-resistant leukemia patients with a poor prognosis. The new Merck and Vertex Pharmaceuticals product, dubbed MK-0457, has been proposed as a targeted approach to address refractory forms of blood cancer.

"We really are focused on disease elimination," lead investigator Francis Giles, MD, from the MD Anderson Cancer Center, in Houston, Texas, told reporters attending the American Society of Hematology 48th Annual Meeting and Exposition. "In regulatory terms, the advantage of the drug is that you are alive. This is an exciting new agent, and there's a great need because there is currently no alternative for these patients."

Patients with refractory chronic myelogenous leukemia often develop resistance to anticancer therapies such as imatinib, dasatinib, and nilotinib. One of the most common mutations that can occur is T3151. The new product is said to address this problem by targeting aurora kinases and BCR-ABL, a gene that when altered promotes uncontrolled cell growth and disease progression in leukemia.

The investigators conducted a phase 1 study in 15 patients with chronic myelogenous leukemia and a history of accelerated or blastic phase disease. Of these, 11 patients carried the T3151 BCR-ABL mutation. Participants received treatment by continuous 5-day intravenous infusions every 2 to 3 weeks for an average of 3 months of therapy to date. The researchers experimented with 8 different doses, ranging from 8 to 40 mg/m2 per hour. They used a standard dose-escalation scheme, with 3 patients per dose level until dose-limiting toxicity, followed by 6 patients per level. Toxicity was defined as a grade 3 or higher nonhematologic adverse event during cycle 1.

Presenting the findings at the meeting, Jamie Freedman, MD, from Merck in Pittsburgh, Pennsylvania, told attendees that the new aurora kinase inhibitor was "very well tolerated in this phase 1 study." Some patients had apparent myelosuppression, which the researchers say is an expected mechanism-based side effect of aurora kinase inhibition. One patient received 15 cycles of therapy and continues to receive treatment.

Patients with T3151 Mutation Responded to Therapy

All 11 patients with the T315I mutation showed clinical signals of antileukemic activity. There was 1 major hematological response, 4 minor, 1 complete cytogenetic response, 2 partial cytogenetic responses, and 1 minimal cytogenetic response. None of the patients without the T315I mutation showed responses.

Investigators are moving forward on new studies of MK-0457. "There will be a pivotal international study of as many centers around the world as we can manage," Dr. Giles said in a news conference. He told Medscape there will be many challenges ahead. "We are looking to initiate distribution for a product with an unknown clinical benefit in a rare subset of leukemia patients." And questions remain about dosing. "If we find that long term all of the dosing levels are safe, it will be difficult to select which to pursue."

Scientists are also investigating whether the product can be offered as an oral tablet. "This is a really exciting area," vice president of the American Society of Hematology, Kenneth Kaushansky, MD, from the University of California, San Diego, told reporters. "Hematology is moving very rapidly from biochemical and molecular study to clinic, and we have the very privileged opportunity of observing these benefits with developments such as this."

ASH 48th Annual Meeting and Exposition: Abstract 163. Presented December 11, 2006.

ARIAD Presents Preclinical Efficacy Data on AP24534, a Novel Oral Kinase Inhibitor for Drug-Resistant CML
ORLANDO, Fla. and CAMBRIDGE, Mass.--(BUSINESS WIRE)--Dec. 10, 2006--ARIAD Pharmaceuticals, Inc. (Nasdaq: ARIA) today announced that its next product candidate, AP24534 - a novel kinase inhibitor discovered by ARIAD scientists - has the potential to treat the major clinically relevant genetic variants of chronic myeloid leukemia (CML), the clear unmet medical need in this hematologic cancer. These preclinical results are being presented today at the American Society of Hematology (ASH) 48th Annual Meeting in Orlando, Florida.

CML is a slowly progressing cancer in which too many white blood cells are made in the bone marrow. In most cases, a genetic abnormality involving the Bcr-Abl protein, a tyrosine kinase encoded by the Philadelphia chromosome, results in constantly activated growth of cancer cells. The disease is most commonly treated with a bone marrow transplant, drug therapy, or a combination of the two - all of which have clinical limitations.

The molecularly targeted drugs - imatinib and nilotinib (Novartis), and dasatinib (Bristol-Myers Squibb) - inhibit the Bcr-Abl protein and are important therapies for patients with CML; however, treatment with these drugs results in mutations of the Bcr-Abl gene, which create substantial drug resistance over time. Dasatinib and nilotinib are effective against some of the clinically relevant mutations but have no effect on the T315I mutant, which now is estimated to account for approximately 25 percent of all drug resistance in CML - representing a key unmet medical need.

"AP24534 showed potent inhibition of the Bcr-Abl-T315I mutant and, in two well-established animal models, demonstrated dose-dependant tumor shrinkage and increased survival," said Tim Clackson, Ph.D., chief scientific officer of ARIAD. "These data support initial clinical evaluation of AP24534 in the treatment of CML patients who no longer respond to other targeted therapies, and we are moving forward with our plans to file an investigational new drug (IND) application for AP24534 in 2H07 in order to initiate clinical trials for our next product candidate."

Data presented today at the ASH meeting demonstrate that AP24534 - an orally active kinase inhibitor - potently inhibits the T315I mutant of Bcr-Abl, as well as the major clinically relevant variants of Bcr-Abl and the naturally occurring, unmutated form of the protein. Daily oral administration of AP24534 to mice bearing xenografts of Bcr-Abl-T315I-expressing cells elicited dose-dependent tumor shrinkage, with complete tumor regression observed at the highest doses. In a separate model, daily oral administration of AP24534 significantly prolonged the survival of mice injected intravenously with Bcr-Abl-T315I-expressing cells. These findings support broad potential applicability of AP24534 in the treatment of CML, particularly in the refractory forms of CML.