Ariad Pharmaceuticals, Inc announced preliminary clinical data from an ongoing phase-1 clinical trial of its investigational, multi-targeted kinase inhibitor, AP24534, in patients with advanced haematological cancers. The study results provide initial clinical evidence of haematologic, cytogenetic and molecular anti-cancer activity of AP24534 in heavily pretreated patients with resistant and refractory chronic myeloid leukaemia (CML), including those with the T315I mutant variant of the target protein, Bcr-Abl. An abstract describing these data is being submitted for presentation at a major haematology meeting to be held later this year.

Treatment of CML or Philadelphia chromosome positive acute lymphoblastic leukaemia (Ph+ ALL) with Bcr-Abl inhibitors is effective in most patients but frequently results in the emergence of Bcr-Abl mutations that confer drug resistance over time. The T315I mutant of Bcr-Abl currently accounts for approximately 15 to 20 per cent of all drug-resistant cases of CML and Ph+ ALL. First-generation therapies, such as imatinib (Gleevec), and second-generation therapies, such as dasatinib (Sprycel) and nilotinib (Tasigna), are not able to inhibit this mutated protein and, therefore, are not effective against all forms of CML and Ph+ ALL.

Key preliminary findings to date includes: in patients with a variety of Bcr-Abl mutations, haematologic responses, cytogenetic responses, and molecular responses have been observed with AP24534 treatment. Haematologic and cytogenetic responses have also been seen in patients with the T315I mutation, which is resistant to all approved Bcr-Abl inhibitors. Collectively, these data suggest a significant degree of anti-tumour activity of AP24534 in highly resistant CML patients.

In addition, of 23 CML patients in the four highest dosing groups, 19 patients remain on study without disease progression, evidence of control of their disease. Most importantly, of 12 CML patients with the T315I mutation, nine patients remain on study without disease progression, providing further evidence of control of their disease.

For many of the patients in the highest dosing groups, the duration of treatment with AP24534 has been relatively short. In these patients, it is still early for complete-response assessment. Even in spite of this, evidence of significant improvement in multiple blood-cell lineages has been observed.

Preliminary safety assessment shows that AP24534 is well tolerated without dose-limiting toxicity at doses studied to date. The most common drug-related adverse events have been thrombocytopenia (low platelet count) and neutropenia (low white blood cell count), which the Company believes reflects the underlying disease and the extensive pre-treatment of the patients in the trial.

To date, pharmacokinetic data indicate that blood levels predicted preclinically to be associated with complete inhibition of Bcr-Abl mutations have been surpassed. Pharmacodynamic data show evidence that AP24534 is acting mechanistically as designed.

"Especially given that we have not yet reached a maximally tolerated dose, we believe that these preliminary results provide promising evidence of clinical proof-of-concept of AP24534 in patients with drug-resistant and refractory CML and Ph+ ALL, including those with the T315I mutation," said Frank G Haluska, vice president, clinical affairs at Ariad.

Dr Haluska added, "Many of the patients assessed to date have already had objective evidence of anti-tumour activity - haematologic, cytogenetic and molecular responses to AP24534. It is important to underscore the lack of therapeutic options available to the patients included in this study. We expect to complete enrolment in the study and to undertake additional evaluation of the safety and efficacy data in the coming months, leading to a presentation at one of the major haematology meetings later this year. Pending completion of the trial and evaluation of the final results, we believe that the results of this trial could form the basis for a pivotal registration trial of AP24534 starting next year."

CML is characterized by an excessive and unregulated production of white blood cells by the bone marrow due to a genetic abnormality that produces the Bcr-Abl protein.

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