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 PatientsThe 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.
- 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).