Ambit Biosciences Presents Data on its Targeted Cancer Therapeutic AC220 for Acute Myeloid Leukemia

Ambit Biosciences has announced preliminary data from a clinical trial evaluating the company’s lead compound, AC220, as an oral monotherapy treatment for patients with acute myeloid leukemia. In this ongoing, open-label, dose escalation study, durable clinical responses have been observed in patients treated with AC220.

Furthermore, AC220 has been well-tolerated and is dose proportional at all doses tested. These clinical results, together with a review of the clinical pharmacokinetics and preclinical in vitro and in vivo pharmacology for AC220, were presented today at the 50th Annual Meeting of the American Society of Hematology (ASH) in San Francisco, California.

Based on the data generated from this ongoing clinical trial, Ambit met with the US Food and Drug Administration (FDA) to review a strategy for conducting a registration study of AC220 as a monotherapy treatment in elderly AML patients. Ambit will be communicating with FDA in the coming months to finalize design of the study, which Ambit plans to initiate in the first half of 2009.

“The clinical data we have generated to date for AC220 represent a potential major advancement for the treatment of AML and an important validation of Ambit’s KINOMEscan™ profiling and drug optimization technology,” said Scott Salka, CEO of Ambit. “The target therapeutic profile that we created for AC220 using KINOMEscan™ appears to be playing out in the clinic, and we are hopeful that additional clinical data will continue to show the positive patient response that we’ve seen thus far. We are pleased to have the opportunity to advance this promising drug into a study intended for registration.”

AC220 is a novel 2nd generation class III receptor tyrosine kinase inhibitor with potent in vitro and in vivo activity in FLT3-dependent tumors. Activating mutations in the FLT3 kinase are present in approximately 25-40% of patients with acute myeloid leukemia (AML), and these patients have a significantly worse prognosis than those with the wild type form of FLT3.

While several small molecule compounds have been evaluated in the clinic as FLT3 inhibitors, none were originally developed with the intention of inhibiting FLT3. In contrast, AC220 has been explicitly optimized and developed by Ambit as a selective FLT3 inhibitor, and the compound possesses a unique combination of high potency, selectivity, bioavailability, and pharmacokinetic properties compatible with once a day oral dosing.

The clinical trial is a first-in-human Phase 1 study with relapsed or refractory AML patients, or previously untreated AML patients unlikely to benefit from chemotherapy, to evaluate the safety, tolerability, pharmacokinetics, and preliminary evidence of efficacy of AC220. Current results from the trial showed an overall response rate of 30% (16 out of 54 patients), including one complete remission (CR), two complete remissions with incomplete platelet recovery (CRp), two complete remissions with incomplete blood count recovery (CRi), and 11 partial remissions (PR).

Given the poor prognosis associated with activating mutations of FLT3 kinase, the FLT3 genotype of patients was analyzed and it was found that 13 patients had a specific mutation of FLT3 called the internal tandem duplication (ITD) mutation. There was a 46% remission rate (6 out of 13) for patients with the ITD mutation, including one CR, two CRi, and three PR.

In those patients who responded to AC220, the median duration for response was 14 weeks, with one patient exhibiting a clinical response for 41 weeks. The overall median survival for all patients was 20 weeks.

AC220 has been well tolerated in doses ranging from 12 to 450 mg, and a maximum tolerated dose (MTD) has yet to be identified. Drug-related side effects included gastrointestinal-related events, fever, peripheral edema, anorexia, headache, and fatigue, and most of these have been Grade = 2.

“The patients who enrolled in this trial had a median of three separate rounds of prior treatment, representing a heavily pre-treated population. Yet, we are seeing responses for nearly one out of three patients, which is very encouraging,” noted Jorge Cortes, M.D., professor of medicine and deputy chair of the Department of Leukemia at MD Anderson Cancer Center and principal investigator for the clinical study.

“The fact that we are seeing these responses for significant durations of time, and in a monotherapy trial where optimal dosing has not yet been determined is really exciting; we were not expecting to see this kind of data in what was originally designed to be a safety study.”