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

Durable Clinical Responses Observed With Monotherapy Treatment; Registration Study Planned

San Francisco : December 9, 2008 – Ambit Biosciences today 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 (nausea, diarrhea, vomiting), 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.”

The study also measured the impact of AC220 in an ex vivo plasma inhibitory activity (PIA) assay, which assessed the impact of AC220 levels in patient plasma samples on FLT3 phosphorylation in cell lines expressing the FLT3 kinase. Plasma from patients completely inhibited FLT3 phosphorylation in FLT3-ITD and wild-type cell lines at the 12 mg and 60 mg doses, respectively. This result characterizes AC220 as not only the most potent and selective FLT3 inhibitor tested to date using the PIA assay, but it is the first compound to completely suppress FLT3 phosphorylation ex vivo at doses that are easily achievable and sustainable in the clinic. This makes AC220 a suitable compound with which to test the hypothesis that complete and sustained inhibition of FLT3 activity will lead to clinical benefit in AML patients, particularly those expressing the FLT3-ITD mutation.

“We are pleased with the response data and tolerability profile observed to date in the ongoing trial for AC220,” said Wendell Wierenga, Ph.D., Executive Vice President of R&D; at Ambit. “With these data, we are planning to further investigate AC220 as a monotherapy treatment, as well as in combination with other therapies for AML. We are also conducting additional studies to evaluate the potential utility of AC220 in other oncology indications, as well as in autoimmune disease.”

Study Design

The study is a first-in-human Phase 1 clinical trial for relapsed or refractory AML patients or untreated patients unlikely to benefit from chemotherapy. FLT3 status was not an inclusion criterion. The study has a standard 3+3 dose escalation design with 50% dose increments. AC220 was administered orally once a day for 14 days followed by a 14 day rest period (1 cycle) in the first ten cohorts, starting with a dose of 12 mg in the first cohort to 450mg in the 10th cohort. More recently, patients were being dosed on a continuous dosing regimen starting at 200 mg/day for 28 days (1 cycle), in an effort to inhibit FLT3 phosphorylation as much as possible. The continuous dose regimen was recently escalated to 300mg/day. Patients are allowed to receive further cycles if they are perceived to have clinical benefit. Bone marrow aspirates and bone marrow biopsies were taken to determine the clinical response.

Preclinical Data

In addition to the clinical data, Ambit presented preclinical data on AC220. Using its kinase profiling technology to determine how selectively AC220 interacted with more than 400 different human kinases, it was found that besides FLT3, AC220 binds only four other and related kinases with an affinity within 10-fold of that for FLT3. In addition, AC220 was shown to strongly inhibit the autophosphorylation of the ITD mutant form of FLT3, a major driver of AML.

About Acute Myeloid Leukemia (AML)

Acute myeloid leukemia is a form of blood cancer. According to the American Cancer Society, approximately 13,000 new cases of AML will be diagnosed in the United States in 2008. The median age of a patient with AML is about 67 years old. Standard treatment for patients 60 years or older with AML includes systemic combination chemotherapy. The median survival for patients receiving induction chemotherapy, which is associated with high mortality, is 6-11 months, with shorter survival for patients over the age of 60 years. The five-year survival rate for AML is less than 15 percent due to refractory and relapsed disease associated with standard treatments. According to a report from Decision Resources, the U.S. AML market is expected to more than double by 2015.

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, inflammatory disease, and other indications. Ambit employs a novel kinase profiling technology named KINOMEscan™ to screen compounds against large numbers of human kinases. Ambit’s lead compound, AC220, is in clinical development for the treatment of AML and other indications. Ambit plans to commence in 2009 several clinical studies with AC220, including a registration study in AML. Ambit’s clinical pipeline also includes AC480, an oral panHER inhibitor that was in-licensed from BMS as part of an ongoing collaboration. Ambit is conducting Phase 2 studies with AC480 in patients with solid tumor cancers. Additionally, Ambit has an advancing pool of preclinical candidates targeting BRAF (in collaboration with Cephalon), JAK2, Aurora, and CSF1R. Through its KINOMEscan Division, Ambit markets its technology as a profiling service. For more information, visit