Ambit Biosciences announced today that the company presented data from its ongoing Phase I clinical evaluation of AC220, a small-molecule class III receptor tyrosine kinase (RTK) inhibitor for the treatment of acute myeloid leukemia (AML). Data were presented in a poster titled, "AC220 Preclinical Profile and Early Human Experience in Relapsed or Refractory Acute Myeloid Leukemia," at the 49thAmerican Society of Hematology (ASH) Annual Meeting and Exposition on Saturday, December 8 at 5:30 p.m. Eastern.
"This is the first clinical data we have presented in a peer-reviewed forum," said Scott Salka, CEO of Ambit. "As such, it represents a significant milestone for us. We are especially proud that we have been able to successfully evolve our business model from focusing primarily on our technology platform to concentrating on becoming a drug discovery and development company."
The Phase I trial is a multi-center, open-label, sequential dose-escalation study that will enroll 20-40 patients with relapsed or refractory AML. The preliminary clinical data was based on an AC220 oral solution administered once daily for 14 days followed by a 14 day rest period or immediate continuous dosing. The first two cohorts were reported on: one at 12 mg/day and the other at 18 mg/day. Dose proportional increases in exposure were seen. Based on 11 patients, no hematological toxicity was observed, and the compound was well absorbed and tolerated. Non-leukemia-related adverse events were mild and included gastrointestinal disorders, cough, decreased appetite and dysgeusia. All patients achieved steady plasma levels of the drug within 8-14 days. At the 18 mg dose, trough levels of the drug (free fraction) were several fold greater than the concentration of the compound needed to inhibit the activity of its target, FLT3 kinase, by 50 percent.
With regard to hematological changes, 3 patients in the 18 mg/day cohort demonstrated improvements. One patient, who remains on AC220, demonstrated a greater than 50 percent reduction in bone marrow blasts, and one patient demonstrated major platelet-associated hematologic improvement.
"We have had strong success in leveraging our kinase screening technology to generate drug candidates, and this Phase I data helps validate our drug discovery approach," said Wendell Wierenga, Ph.D., executive vice president of R&D for Ambit. "Our kinase screening technology allowed us to optimize AC220 and gave us data on the compound that helped us shape its clinical potential. We are exceptionally pleased with both the preclinical and early clinical data that we have so far seen."
In vitro data shows that AC220 has highly selective affinity for several class III RTKs including FLT3, KIT, CSF1R/FMS, RET and PDGFR. AML patients with mutations in FLT3 mutations have a significantly worse prognosis than patients with wild-type FLT3, suggesting that FLT3 is a driver of the disease. In the MV4;11 human leukemia cell line, which harbors a FLT3-ITD mutation, AC220 demonstrated subnanomolar potency, and the compound inhibits FLT3 autophosphorylation and proliferation of MV4;11.
With respect to preclinical models of efficacy, in a mouse solid tumor xenograft of a cell line derived from an AML patient, AC220 inhibited tumor growth at 1 mg/kg dosage and caused tumor regression at 3 mg/kg.
"While this data is early stage, preliminary results are encouraging, and we are accelerating enrollment for this clinical trial based on patient response," noted Jorge Cortes, M.D., professor of medicine and deputy chair in the department of leukemia at The University of Texas, MD Anderson Cancer Center and principal investigator in this study. "I am hopeful that AC220 will offer physicians an additional weapon in their arsenal to combat this devastating disease."
About Ambit Biosciences
Ambit Biosciences is a privately-held biopharmaceutical company engaged in the discovery and development of small molecule kinase inhibitors for the treatment of cancer. The company also markets the industry's most comprehensive kinase profiling service through its KinomeScan Division. KinomeScan is a proprietary technology designed to screen small molecule libraries against large numbers of human kinases. Ambit has multiple drug candidates in pre-clinical and clinical development, including AC220, a selective class III receptor tyrosine kinase inhibitor currently in Phase I for treatment of acute myeloid leukemia. The company has partnerships with Roche, Bristol-Myers Squibb, GlaxoSmithKline, Cephalon, and other leading organizations. For more information, please visit www.ambitbio.com.