Science Editor

The conversion of chronic myeloid leukemia from a likely death sentence to a chronically manageable disease by imatinib (Gleevec, Novartis Inc.) has been "one of the great breakthroughs" of modern oncology, Timothy Clackson told BioWorld Today. Gleevec has brought the 2009 Lasker Award to its discoverer Brian Druker, and years or decades of life to many of the patients taking it.

But mutations in the BCR-ABL kinase that Gleevec targets eventually render the drug ineffective for a significant subset of patients. Many mutations in the ABL kinase leave BCR-ABL sensitive to second-line agents dasatinib (Sprycel, Bristol-Myers Squibb) and nilotinib (Tasigna, Novartis). But at least one mutation, a point mutation known as T315I, confers resistance to the second-line agents as well. For that reason, a so-called pan inhibitor, which would be effective against both BCR-ABL and known mutations, is high on the wish list of CML drug developers and patients alike.

In the Nov. 3, 2009, issue of Cancer Cell, Clackson, who is senior vice president and chief scientific officer of Cambridge, Mass-based Ariad Pharmaceuticals, Druker and their colleagues reported preclinical data on such a pan-BCR-ABL inhibitor: AP24534, a compound that appears to be effective at preventing such mutations from forming in the first place if it is given early enough, as well as inhibiting mutations that already have formed.

The change that confers drug resistance on BCR-ABL is, in one sense, small. Like most ABL mutations that confer resistance, T315I are point mutations, though some double mutations also have been reported. But in the case of T315I, the resulting amino acid change "puts a big bump in the middle of the binding site" for all three agents, Clackson said.

AP24534 is "very much [the result of] a structure-based drug design approach," Clackson said. His team first determined the crystal structure of the mutant, and devised "various ways of making a drug that would more or less slide by the bump and still bind."

AP24534, the result of those attempts, is not active against aurora kinases, which have been the target of other third-line inhibitors in development, including VX-680/mk-0457, whose clinical development was halted in 2007 due to toxicity issues. Clackson said that whether those issues were related to the fact that mk-0457 inhibits aurora kinases is unknown. But the data, he added, do show that AP24534 is "clearly completely different from . . . other agents" in its target profile.

In animal studies as well as cell culture assays, including a screen specifically designed to predict whether and how resistance might emerge, AP24534 was active against both BCR-ABL and the mutations that occur most frequently in the clinic. And it appears to do so, Clackson stressed, "at concentrations which are fairly modest, and which we now know are clinically achievable."

Clackson is referring to a currently ongoing Phase I trial of AP24534 that enrolled heavily pretreated patients with resistant and refractory CML. In an update provided in late July, when 32 patients had been treated in six dosing groups, the company reported that study results showed initial evidence of hematologic, cytogenetic and molecular anticancer activity. Clackson said the next update is planned for the American Society of Hematology annual meeting in December.

So far, as is typical in clinical development, AP24534 is being tested in late-stage patients. But Clackson pointed out that if AP24534 is indeed able to prevent resistance, it would have the potential to be what he termed a "last-generation inhibitor," a drug that, at least until a true cure comes along, can eradicate the CML stem cells that are insensitive to kinase inhibition, and which could be all that is needed to keep CML at bay permanently.

"You could imagine moving up the line as clinical development proceeds," he said. "All of the biology implies that if you could prevent the emergence of resistance, you would get better outcomes."