ARIAD discontinues Phase III EPIC trial of Iclusig in patients with newly diagnosed CML
CAMBRIDGE, Mass.—ARIAD Pharmaceuticals Inc. announced Oct 18 that it is discontinuing the Phase III EPIC (Evaluation of Ponatinib versus Imatinib in Chronic Myeloid Leukemia) trial of Iclusig (ponatinib) in patients with newly diagnosed chronic myeloid leukemia. According to ARIAD, it and the U.S. Food and Drug Administration mutually agreed that the trial should be terminated because arterial thrombotic events were observed in patients treated with Iclusig.
“This decision was made in the interest of patient safety based on a recent assessment of data in the clinical trial,” noted ARIAD in the news release about the decision, with Dr. Timothy P. Clackson, president of research and development and chief scientific officer at ARIAD, adding: "Our decision to stop the EPIC trial at this time is based on our current evaluation of the safety data in the trial since it was placed on partial clinical hold last week. We believe that this is in the best interests of patient safety and the overall development of Iclusig."
Share prices for ARIAD dropped quickly on the news, falling from a high of $4.48 per share at the end of day Oct. 17, the day before the announcement, to $2.68 per share by the end of day Oct. 18.
Patients in the EPIC trial are being removed from treatment and will be transferred to the care of their physician. ARIAD announced in early September that 50 percent of patients, or approximately 264 patients, had been enrolled in the EPIC trial by that time. Final enrollment was to be 307 patients.
The EPIC trial was a randomized, two-arm, multicenter trial that sought to compare the efficacy of ponatinib with that of imatinib in adult patients with newly diagnosed chronic myeloid leukemia (CML) in the chronic phase. The trial was being conducted at approximately 150 investigational sites in more than 20 countries. Patients in the trial had to be at least 18 years of age and diagnosed with CML within six months prior to enrollment. Approximately 500 patients were to be randomized 1:1 to the standard dose of ponatinib (45 mg given orally once daily) or imatinib (400 mg given orally once daily). Increasing the imatinib dose to 600 mg or 800 mg per day was permitted. The primary endpoint of the trial was major molecular response at 12 months of treatment.
Iclusig is commercially available in the U.S. and EU for patients with resistant or intolerant CML and Philadelphia-chromosome positive acute lymphoblastic leukemia (Ph+ ALL). ARIAD says that it continues to work with health authorities to make appropriate changes to the Iclusig product labeling to reflect the recently announced safety findings from the pivotal PACE trial that was the basis of its marketing approvals.
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. After a chronic phase of production of too many white blood cells, CML typically evolves to the more aggressive phases referred to as accelerated phase or blast crisis. Ph+ ALL is a subtype of acute lymphoblastic leukemia that carries the Ph+ chromosome that produces BCR-ABL. It has a more aggressive course than CML and is often treated with a combination of chemotherapy and tyrosine kinase inhibitors (TKIs). The BCR-ABL protein is expressed in both of these diseases.
Iclusig is a kinase inhibitor, with its primary target being BCR-ABL. Iclusig was designed using ARIAD's computational and structure-based drug design platform specifically to inhibit the activity of BCR-ABL. Iclusig targets not only native BCR-ABL but also its isoforms that carry mutations that confer resistance to treatment, including the T315I mutation, a common mutation which has been associated with resistance to other approved TKIs.