Results of preclinical studies evaluating AC220 to be presented at ASH annual meeting

Ambit Biosciences Corporation announced today the presentation of two posters presenting the results of preclinical studies evaluating AC220 at the 51st Annual Meeting of the American Society of Hematology (ASH) in New Orleans. AC220, Ambit's lead product candidate, is a novel, orally available, small molecule that was expressly optimized as a FMS-like tyrosine kinase-3 (FLT3) inhibitor for the treatment of AML. Ambit has completed enrollment of patients in the first-in-human Phase 1 clinical trial in relapsed/refractory AML. A summary of the posters are as follows:

- "AC220, a FLT3 Inhibitor, Increases Survival in Two Genotypically Distinct FLT3 ITD Models of Acute Myeloid Leukemia and Provides Sustained Protection Following Chronic Administration" The study examined the in vivo efficacy of AC220 in limited versus chronic dosing regimens in: (i) an AML disease model dependent on homozygous mutations of the internal tandem duplication (ITD) mutation of FLT3, or FLT3 ITD, (MV4-11 disseminated mouse disease model), and (ii) a separate model that is heterozygous for the FLT3 ITD mutation and whose AML disease progression is believed to be in part driven by genetic mutations unrelated to FLT3 (MOLM-14 disease model) The second model was included to increase the rigor of the preclinical assessment of AC220's in vivo efficacy, as AML is a heterogeneous disease and in a clinical setting is believed to be seldom driven by FLT3 ITD mutations alone. Results of these experiments suggest that AC220 is efficacious in disease models driven by both FLT3 ITD homozygous and heterozygous genotypes. These experiments also concluded that chronic dosing may provide greater disease protection than a limited course of therapy as demonstrated by prolonged survival correlated with delayed disease onset in both disease models. The results of this preclinical study are consistent with observations of AML patients treated with intermittent versus continuous dosing schedules of AC220 in a Phase 1 clinical study. - "AC220, a Potent and Specific FLT3 Inhibitor, Enhances the Cytotoxic Effects of Chemotherapeutic Agents in Cell Culture and in Mouse Tumor Xenograft Models" Patients with FLT3 ITD mutations generally have a poorer prognosis and decreased response to standard chemotherapy treatments compared to patients without the mutation. A series of in vitro cell-based experiments assessed the effects of AC220 dosed in combination with a variety of different chemotherapeutic agents (including cytarabine, decitabine, cladribine, etoposide, and daunorubicin) and in a variety of different dosing schedules. The studies collectively and consistently demonstrated that whether AC220 is dosed prior to, concurrently with, or subsequent to the dosing of the individual chemotherapeutic that it generally provided additive to slightly synergistic effects compared to dosing of either drug alone. These findings were replicated in an in vivo setting with studies evaluating AC220 in combination with cytarabine or decitabine. Not only did these experiments confirm the in vitro findings by evidence of additive effects on reducing tumor burden, significantly extending time-to-endpoint, increasing remission rates, and in some cases achieving cures, but there was also no indication of drug specific antagonism on tumor volume, body weight or WBC counts for any of the dosing schedules. These results support the clinical investigation of AC220 in combination with chemotherapy in AML.

"Combined, these posters present a comprehensive and compelling picture that illustrates the preclinical efficacy of AC220 in a range of AML disease models driven by FLT3 ITD mutations and in combination with a variety of chemotherapy agents commonly used to treat AML," said Wendell Wierenga, PhD, Executive Vice President, Research & Development at Ambit. "Not only do these findings support the continued investigation of AC220 as monotherapy in AML patients that harbor the FLT3 ITD mutation, but these results also provide insights on a range of plausible considerations for the design and conduct of clinical trials that combine the targeted therapy, AC220, with chemotherapy in the treatment of AML patients. We look forward to expanding our clinical program to include such trials in the future."

SOURCE Ambit Biosciences Corporation