Ambit and Astellas Announce Results From Multiple Quizartinib Presentations at the 53rd Annual Meeting of the American Hematology Society

SAN DIEGO, Dec. 13, 2011 /PRNewswire/ -- Astellas Pharma Inc. (Tokyo: 4503, Astellas) and Ambit Biosciences Corporation announced today that updated results from an interim analysis of a Phase 2 study of quizartinib (formerly AC220) in acute myeloid leukemia (AML) were presented at the 53rd Annual Meeting of the American Society of Hematology (ASH) in San Diego, California.  Data were also presented from two additional posters: one evaluating the pharmacodynamic effects of quizartinib in a pooled analysis from Phase 1 and Phase 2 studies, and another demonstrating that quizartinib enhances the activity of chemotherapy in an in vivo preclinical model of AML harboring the FLT3-ITD mutation.  The findings from those presentations are described below.

"AML is amongst the most challenging hematological malignancies to treat, and very few treatment advances have been made in several decades," said Jorge Cortes, M.D., Internist and Professor, Deputy Chair, Department of Leukemia, Division of Cancer Medicine, The University of Texas M. D. Anderson Cancer Center, Houston, Texas, and primary investigator for the Phase 2 Study.  "A significant portion of AML patients have activating FLT3 mutations, and these patients have a particularly poor prognosis and often relapse or are refractory to current treatment options.  These clinical and preclinical results with quizartinib in FLT3-ITD positive AML are encouraging, and support conduct of further studies of this promising compound both as a monotherapy and in combination with other treatments."

A Phase 2 Open-Label, AC220 Monotherapy Efficacy Study in Patients with Refractory/Relapsed FLT3-ITD Positive Acute Myeloid Leukemia:  Updated Interim Results

The updated clinical response and safety data are from a planned interim analysis of a 62 patient subset from the ongoing Phase 2 multi-center study being conducted in the United States and Europe. Patients included in the analysis were either at least 60 years old and relapsed or refractory to first-line chemotherapy (Cohort 1, N=26), or at least 18 years old and relapsed or refractory to second-line chemotherapy or HSCT (Cohort 2, N=36).  The results from an earlier data cut of this patient subset were presented earlier this year at the European Hematology Association Meeting in London.  The study has now completed enrollment and results for the total study population are expected in 2012.

The co-primary end points of the study are composite complete remission (CRc) rate and complete remission (CR) rate in the first 84 days.  CRc is defined as the sum of complete remission, complete remission with incomplete platelet recovery (CRp), and complete remission with incomplete hematologic recovery (CRi).  In this updated interim analysis on 62 patients there were composite complete response (CRc) rates of 40 percent, 46 percent and 36 percent in all patients, Cohort 1 and Cohort 2, respectively.   The majority of CRc cases were CRi.  Notably, a CRc rate of 55 percent was achieved in patients who were refractory to the prior line of treatment (N=20).  Key secondary end points in the study include duration of remission, rates of partial response, and overall survival.  The median duration of response for patients achieving a CRc was 12.1, 14.3, and 10.1 weeks in all patients, Cohort 1 and Cohort 2, respectively, with patients censored at the time of transplant.  The median overall survival was 25.4, 24.1, and 26.9 weeks for all patients, Cohort 1, and Cohort 2, respectively.  An analysis of survival across all patients demonstrated that patients with a CRc had a 41 percent improved median survival versus non-responders, with durations of 34.1 and 24.2 weeks, respectively.

The most common treatment-related adverse events in the study included nausea, vomiting, fatigue and febrile neutropenia.  Several cases of QTc prolongation were reported early in the study, but most resolved following a dose adjustment, and no Grade 4 cases have been reported in the subset of 62 patients.  One case of Grade 4 QTc prolongation has been observed in the entire study of 333 patients.  Management of other adverse events is also being explored with dose modifications in the ongoing study.

Detection of Phosphorylated and Total FLT3 and STAT5 in Whole Blood;

Modulation by Quizartinib (AC220) from Phase I and II Trials in AML

The pharmacodynamic effects of quizartinib treatment in AML patients was assessed using whole blood samples from patients enrolled in a previously performed Phase 1 study, and from the 62 patient subset in the Phase 2 study described above.  Proprietary and customized immunoassays were developed, optimized and validated at Ambit to detect both total (t) and phosphorylated (p) levels of FLT3, as well as the downstream signaling protein STAT5.  Blood samples were examined prior to treatment with quizartinib on Day 1 of treatment and again after either 8 or 15 days of treatment, depending upon study. 

Results from this assay demonstrated that following administration of quizartinib there was a profound, immediate and sustained pharmacodynamic effect in inhibiting both FLT3 and the subsequent downstream phosphorylation of the biologically important signaling protein, STAT5.  A mean pFLT3 inhibition of 80 percent was observed within 24-hours of the first dose, and there was a strong correlation with inhibiting phosphorylation of STAT5 (p < 0.007).  These findings support the linkage between FLT3 activation and downstream STAT5 activation, and demonstrate the ability of quizartinib to inhibit both of these important signaling molecules that are involved in the pathology of FLT3-ITD positive AML.  Results at later time points showed that approximately one half (47 percent) of evaluable patients had nearly complete inhibition (>90 percent) of tFLT3 levels by the end of the first week of dosing.  Total FLT3 levels, as well as quizartinib-driven decreases in these levels correlated significantly with patients' peripheral blast counts and reductions in peripheral blast counts, respectively.  These findings suggest that the Ambit-developed assay can effectively track effects of drug administration on peripheral disease burden, and that further exploration is merited to determine the potential clinical utility in the future disease management of AML. 

Quizartinib (AC220), a Potent and Specific FLT3 Inhibitor, Enhances the Activity of Combined Cytarabine and Daunorubicin Chemotherapy in a FLT3-ITD Model of AML

Induction chemotherapy with a combination of cytarabine and an anthracycline (e.g. daunorubicin) is the first-line standard of care in the clinical management of AML patients.  To investigate the potential role of quizartinib in this setting, a series of three in vivo preclinical studies were performed using a solid tumor bearing mouse model with a leukemic cell line harboring the FLT3-ITD mutation (MV4-11).  The effect of quizartinib and standard chemotherapy alone and in combination with one another were assessed and compared.  Study 1 explored the effects of a low dose of quizartinib alone (1 mg/kg), cycles of cytarabine (Ara-C) alone (60 mg/kg), and in combination.  Study 2 explored the effects of a low dose of quizartinib alone (0.5 mg/kg), cycles of Ara-C + daunorubicin (DNR) (80 mg/kg and1 mg/kg, respectively) as a regimen alone, and in combination.  Study 3 explored the effects of a high dose of quizartinib alone (10 mg/kg), cycles of Ara-C + DNR (80 mg/kg and 1 mg/kg, respectively) as a regimen alone, and in combination.  In all studies, multiple quizartinib dosing schedules were evaluated, including both the episodic dosing of quizartinib in 7-day cycles between chemotherapy, and continuous dosing of quizartinib layered on top of chemotherapy.  Effect of the different treatments was measured by effects on tumor growth delay, tumor burden, tumor regression levels over time.

The results of these preclinical studies demonstrated that both low and high doses of quizartinib can be safely combined with the Ara-C + DNR chemotherapy regimen, and that there was no antagonism between the treatments, regardless of schedule or dose.  Dosing quizartinib in combination with Ara-C, or in combination with Ara-C + DNR, resulted in improved effect on tumor burden, tumor growth delay and tumor regression versus dosing either agent or regimen alone.  Continuous dosing of quizartinib layered on top of chemotherapy produced the best results.  In Study 3, the combination of continuous quizartinib and Ara-C + DNR lead to rapid and complete regression which was sustained for a longer period of time versus any other treatment arm.  For episodic dosing, high dose quizartinib post Ara-C had improved results compared to initiating quizartinib post DNR.  Supported by these findings, a Phase 1 clinical study has recently been initiated to evaluate the combination of quizartinib and standard induction and consolidation chemotherapy in newly diagnosed AML patients.

About Quizartinib

Quizartinib, formerly known as AC220, is being developed in collaboration between Ambit Biosciences and Astellas Pharma Inc. and is a novel, potent, highly selective, orally bioavailable FMS-like tyrosine kinase-3 (FLT3) inhibitor.  Quizartinib is currently under evaluation in a Phase 2 clinical trial as monotherapy treatment for adult and elderly patients with relapsed/refractory AML that have an internal tandem duplication (ITD) mutation in the FLT3 gene.

About Acute Myeloid Leukemia

Acute myeloid leukemia (AML) is a form of blood cancer.  According to the American Cancer Society, approximately 13,000 adults were newly diagnosed with AML in 2009 in the United States with approximately 9,000 expected to die of the disease in that year.  AML is generally a disease of older people and is uncommon before the age of 40.  The average age of a patient with AML is 67 and median survival for these patients is less than six months.  The five-year survival rate for all AML patients is less than 15 percent. According to a report from Decision Resources, the U.S. AML market is expected to more than double by 2015.

About the Ambit Biosciences/Astellas Pharma Inc. Collaboration

In December 2009, Ambit Biosciences and Astellas Pharma Inc. entered into a global strategic partnership agreement to jointly research, develop and commercialize FLT3 kinase inhibitors in multiple indications, including the lead investigational compound, quizartinib.  The companies are presently evaluating quizartinib in a Phase 2 clinical trial in relapsed and refractory AML patients that have the internal tandem duplication (ITD) mutation in the FLT3 gene.  The companies are also collaborating on a comprehensive development program to explore the utility of quizartinib in other AML patient subpopulations.  Additionally, the companies are collaborating on a research and development program for additional FLT3 inhibitors for a variety of oncology and non-oncology indications.  The companies share equal responsibility and expenses for the development of products in the U.S. and Europe, while Astellas has sole responsibility in the rest of the world.  Astellas will be responsible for implementation of commercialization activities worldwide.  Ambit received a $40 million up-front payment upon entering into the collaboration agreement, and is eligible to receive up to $350 million in development milestone payments, undisclosed sales milestones, and tiered, double-digit royalties on global revenues.  Ambit also has an option to co-promote products in the U.S. where Astellas and Ambit share equally all profits and losses generated from U.S. sales.

About Ambit Biosciences

Ambit Biosciences is a privately held biopharmaceutical company engaged in the development of a robust pipeline of small molecule kinase inhibitors for the treatment of cancer, inflammatory disease and other indications.  Ambit's lead compound, quizartinib (AC220), is a novel, potent, highly selective, orally bioavailable FMS-like tyrosine kinase-3 (FLT3) inhibitor, and is currently under clinical investigation in patients with relapsed or refractory AML.  Ambit is developing quizartinib in collaboration with Astellas Pharma Inc. as part of a worldwide agreement to jointly develop and commercialize FLT3 kinase inhibitors in oncology and non-oncology indications.  In addition to quizartinib, Ambit's clinical pipeline includes AC430, an oral JAK2 inhibitor, and AC480, a pan-HER inhibitor. Ambit also has a preclinical candidate, CEP-32496, and a BRAF inhibitor licensed to Cephalon.  For more information, visit www.ambitbio.com.

About Astellas

Astellas Pharma Inc., located in Tokyo, Japan, is a pharmaceutical company dedicated to improving the health of people around the world through provision of innovative and reliable pharmaceuticals. Astellas has approximately 16,800 employees worldwide. The organization is committed to becoming a global category leader in Urology, Immunology including Transplantation and Infectious Diseases, Oncology, Neuroscience, and DM complications and Metabolic Diseases. For more information on Astellas Pharma Inc., please visit our website at www.astellas.com/en.

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SOURCE Ambit Biosciences