ARIAD Pharmaceuticals, Inc. (NASDAQ: ARIA) today announced updated clinical data from an ongoing Phase 1 study of its investigational pan-BCR-ABL inhibitor, AP24534, in patients with resistant and refractory chronic myeloid leukemia (CML). The data confirm strong clinical evidence of hematologic, cytogenetic and molecular anti-leukemia activity of AP24534, a multi-targeted kinase inhibitor, in heavily pretreated patients with CML, including those with the T315I mutation of the target protein, BCR-ABL. The data are being presented this afternoon at the 46th Annual Meeting of the American Society of Clinical Oncology (ASCO) being held in Chicago, IL.
“These are remarkable results that now suggest that responses to AP24534 are persistent and include molecular responses in heavily pretreated patients with resistant leukemia”
Data on fifty-seven patients in seven dosing cohorts (2, 4, 8, 15, 30, 45 and 60 mg administered orally once daily) are being reported at ASCO. Fifty-three of the patients have resistant and refractory CML or Philadelphia-chromosome positive (Ph+) acute lymphoblastic leukemia (ALL). Ninety-four percent of these 53 patients have been treated with, and were resistant to, at least two of the available first-line and second-line tyrosine kinase inhibitors for CML. Sixty-six percent of the patients were pretreated with three or more prior tyrosine kinase inhibitors, including imatinib (Gleevec®), dasatinib (Sprycel®), and nilotinib (Tasigna®) and investigational agents.
"The updated findings from this study confirm in a larger number of patients, that AP24534 continues to be well-tolerated and produce beneficial and durable anti-leukemia activity in patients who have failed prior tyrosine kinase inhibitor therapy for CML, including patients with the T315I mutation for which there are no currently available treatments," stated Moshe Talpaz, M.D., Associate Director of Translational Research and Associate Chief of Hematologic Malignancies, Trotman Professor of Leukemia Research, University of Michigan Medical Center, and study investigator. "We are highly encouraged by the documentation of efficacy at the molecular level and the anti-leukemic activity that looks to be durable. Pending completion of further clinical trials, AP24534 represents a potential significant advance for CML patients who have become resistant to currently available therapies and who are in great need of new treatment options."
Updated results from the open-label, dose-escalating study presented at ASCO include:
- AP24534 was well tolerated at therapeutic dose levels including the newly evaluated 45 mg/day dose. This dose cohort was initiated in December 2009. With the exception of the DLTs of elevated amylase and lipase and grade 2 pancreatitis observed at 60 mg, the safety profile is similar when doses equal to or greater than 30 mg/day (the dose associated with sustained blood levels above the target inhibitory concentration) are compared with all doses in the trial.
- Of the 57 patients treated with AP24534, thirty-seven patients (65 percent) currently remain on study. At doses equal to or greater than 30 mg/day, 25 of 33 patients (76 percent) continue to be treated with AP24534.
- With this update, molecular responses have begun to emerge. Of 32 resistant chronic phase CML patients evaluated at least once since baseline, 8 achieved a major molecular response (MMR), some of them after only 2 months of treatment with AP24534. Four of these MMRs were seen in patients with the T315I mutation; 4 others were seen in patients with other mutations. These observations are consistent with the pre-clinical profile of AP24534 as a pan-BCR-ABL inhibitor.
- With longer follow-up now available, responses appear to be durable. Out of 12 major cytogenetic responses (MCyR) in patients with chronic phase CML, 11 remain on therapy without progression after an average of almost a year on treatment (327 days). Nine of the 12 patients had cytogenetic response confirmed with at least a second assessment after three months. Only one patient experienced CML progression after having achieved a MCyR and this was in a patient enrolled in the sub-therapeutic 4 mg dose cohort.
- Of 26 chronic phase CML patients evaluable for cytogenetic response across all dose levels, 46 percent (12 of 26) experienced a MCyR, with 31 percent (8 of 26) a complete cytogenetic responses (CCyR). In patients treated at dose levels equal to or greater than 30 mg/day, the MCyR rate in chronic phase patients is 58 percent (7 of 12). Three of twelve evaluable patients with accelerated phase, blast phase or Ph+ ALL experienced a MCyR (including one CCyR).
- A complete hematologic response (CHR) was observed in 85 percent (22 of 26) of chronic phase CML patients evaluable for hematologic response (16 patients entered the study with a baseline CHR). A major hematologic response was observed in five of twelve (42 percent) evaluable patients with accelerated phase, blast phase or Ph+ ALL.
- Anti-leukemic activity was seen in patients with resistant BCR-ABL mutations. Of the 21 CML patients with the T315I mutation in the study, 57 percent (12 of 21) have chronic phase disease. Nine of these patients are currently evaluable for response: eight (89 percent) have achieved a CHR and six (67 percent) have experienced a MCyR (including CCyR in 5 patients).
"These are remarkable results that now suggest that responses to AP24534 are persistent and include molecular responses in heavily pretreated patients with resistant leukemia," said Frank G. Haluska, M.D., Ph.D., vice president, clinical affairs at ARIAD. "With a larger number of patients and longer term follow-up, the response rates continue to be highly encouraging, and the clinical benefit from AP24534 appears to be durable. The data provide evidence that AP24534 is well tolerated at therapeutic dose levels and constitute the foundation for our pivotal trial to begin in the second half of this year."
ARIAD Pharmaceuticals, Inc.