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ARIAD Pharmaceuticals, Inc. (NASDAQ: ARIA) today announced updated molecular response data from its Phase 1 and pivotal Phase 2 trials of ponatinib, its investigational BCR-ABL inhibitor, in heavily pretreated patients with resistant or intolerant chronic myeloid leukemia (CML) or Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL). The studies now show that 51 percent of chronic-phase CML patients in the Phase 1 trial achieved a major molecular response (MMR) with a median follow-up of 30 months, and 34 percent of chronic-phase patients achieved MMR in the PACE trial with a median follow-up of 15 months.
These data are being featured today at 6:00 p.m. in two poster presentations at the 54th Annual Meeting of the American Society of Hematology (ASH) being held in Atlanta, Georgia.
Molecular response is a measurement of blood levels of the transcript product of the BCR-ABL oncogene. MMR is defined as a value less than or equal to 0.1% on the accepted International Scale. All patient samples were evaluated for molecular response at a single central laboratory (Molecular MD) using a standardized assay. MMR is a secondary efficacy endpoint for chronic-phase CML patients in ARIAD’s Phase 1 and pivotal Phase 2 PACE trials of ponatinib.
Phase 1 Trial MMR Rates in Chronic-Phase CML Patients
The ongoing Phase 1 dose-escalation study of ponatinib enrolled 81 patients with resistant or refractory hematologic cancers, including 43 patients with chronic-phase CML. Sixty-one percent of the chronic-phase CML patients in this study had failed at least three prior tyrosine kinase inhibitors (TKI).
With a median follow-up of 30 months, 51 percent (22 of 43) of patients with chronic-phase CML enrolled in the study achieved MMR, including 75 percent (9 of 12) who had the T315I mutation, which is the most common mutation among resistant patients.
The median time to MMR was 5.6 months, and the median duration of MMR in chronic-phase CML has not yet been reached. At the time of analysis, 21 of 22 patients who achieved MMR remained in the study and continued to receive ponatinib.
Molecular response rates increased over time with nine percent (4 of 43) of chronic-phase CML patients achieving MMR by 3 months and 51 percent (22 of 43) achieving MMR overall. Patients continued to achieve MMRs after 12 months of follow-up.
Thirty-three percent (14 of 43) of chronic-phase CML patients achieved MR4 (4-log reduction in BCR-ABL transcripts).
The most common non-hematologic treatment-related adverse events in all patients in this trial included rash (42%), arthralgia (20%), increased lipase (20%), fatigue (19%) and dry skin (19%), with the majority of these being grades 1 or 2 in severity. The most common hematologic treatment-related adverse events included thrombocytopenia (34%), neutropenia (14%) and anemia (12%), with thrombocytopenia and neutropenia being primarily grades 3 or 4 in severity.
PACE Trial MMR Rates in Chronic-Phase CML Patients
The ongoing pivotal Phase 2 PACE trial enrolled 449 patients with chronic myeloid leukemia (CML) or Philadelphia-positive acute lymphoblastic leukemia (Ph+ ALL), who are resistant or intolerant to dasatinib or nilotinib or who have the T315I mutation.
With a median follow up of 15 months, 34 percent (91 of 267) of chronic-phase CML patients achieved MMR; the reported prior MMR rate to their most recent TKI was three percent.
Fifteen percent (39 of 267) of patients achieved a 4.5-log reduction of BCR-ABL transcripts (MR4.5).
Fifty-three percent (10 of 19) of chronic-phase patients who failed only one prior approved TKI achieved MMR with ponatinib.
The median time to MMR among responders was 6 months. MMR was durable with 81 percent of patients estimated to remain in MMR at 12 months (by Kaplan-Meier analysis). Median duration of MMR among chronic-phase CML patients has not yet been reached.
The most common non-hematologic treatment-emergent adverse events in all patients in the PACE trial included rash (38%), abdominal pain (38%), headache (35%), dry skin (35%), and constipation (34%), with the majority of these being grades 1 or 2 in severity.
The most common hematologic treatment-emergent adverse events were thrombocytopenia (42%), neutropenia (24%), and anemia (20%), which were primarily grades 3 or 4 in severity.
Pancreatitis and pneumonia were the most common non-hematologic treatment-emergent serious adverse events (5% each), followed by abdominal pain (4%), myocardial infarction (3%), congestive heart failure (3%), atrial fibrillation (3%), and pyrexia (3%). The most common hematologic serious adverse events were anemia, febrile neutropenia, and thrombocytopenia (3% each).
Internally discovered at ARIAD, ponatinib is an investigational BCR-ABL inhibitor that also selectively inhibits certain other tyrosine kinases in preclinical studies, including FLT3, RET, KIT, and the members of the FGFR, PDGFR and VEGFR families of kinases.