About quizartinib

We believe that there is a significant unmet need for an approved agent that offers a targeted and effective approach to AML and that can be used either as monotherapy or in combination with chemotherapy or other targeted agents. Patients are waiting for a better tolerated and more convenient therapy which can be used across multiple populations and a variety of settings, including younger and elderly patients, newly diagnosed and relapsed/refractory patients, and patients who have undergone a hematopoietic stem cell transplant, or HSCT.

Quizartinib is a once-daily, orally administered, potent and selective inhibitor of FLT3, a validated target in the treatment of acute myeloid leukemia, or AML. Quizartinib is currently in development for the treatment of relapsed or refractory FLT3-ITD positive and negative AML patients and as a maintenance therapy. Though patients of any age may be FLT3 positive, over 35% of AML patients over age 55 are estimated to harbor a genetic mutation in FLT3, known as the FLT3 internal tandem duplication (FLT3-ITD) mutation. The FLT3-ITD mutation acts like a “power switch” that causes leukemic cells, or blasts, to spread more aggressively and grow back more rapidly following chemotherapy, conferring an especially poor survival outcome. Quizartinib is designed to turn off this switch.

We have conducted studies on the use of quizartinib in more than 500 patients to date, most recently initiating QUANTUM-R, a randomized comparative Phase 3 trial of quizartinib in relapsed/refractory AML patients with the FLT3-ITD mutation. We are also exploring quizartinib in other AML therapeutic settings, irrespective of FLT3-ITD status, including use in newly diagnosed AML patients in combination with chemotherapy, or frontline therapy, followed by continuous single-agent maintenance therapy, as well as maintenance following a hematopoietic stem cell transplantation (HSCT), or bone marrow transplant.

Both the U.S. Food and Drug Administration (FDA) and European Commission have granted orphan drug designation to quizartinib for the treatment of AML.

About AML

AML is the most common type of acute leukemia in adults and is projected to account for approximately 36% of all new leukemia cases in 2014. AML results in uncontrolled growth and accumulation of malignant white blood cells which fail to function normally and interfere with the production of normal blood cells.

According to the American Cancer Society, approximately 18,860 patients will be newly diagnosed with AML in 2014 in the United States and approximately 10,460 are expected to die of the disease in 2014. AML is generally a disease of older people and the median age of a patient at initial diagnosis is 66 years. The five-year survival rate for all AML patients, irrespective of age and FLT3-ITD status, is 23%.

The standard of care for AML has not changed appreciably for decades. Treatment decisions for AML are typically based on the patient’s age (60 years of age being generally referred to as “elderly” and used as a treatment indicator), overall health, cytogenetics and molecular abnormalities such as FLT3-ITD status. These factors determine the aggressiveness of the treatment approach given the high toxicity associated with currently approved treatment options for AML. Importantly, the National Comprehensive Cancer Network recommends participation in clinical trials as a treatment option for all AML patients.

The goal of treatment in AML is to reduce the blasts in the bone marrow to below 5% and return the blood cell counts to normal levels. A bone marrow transplant is generally recognized as the only curative treatment option. Typically, patients who are able to achieve a reduction in bone marrow blasts below 5% are more suitable candidates for transplant and have an improved projected outcome.

FLT3 Kinase in AML

AML is a particularly aggressive and deadly disease and we believe there is a significant unmet need for more effective treatments of AML, particularly for this subset of patients referred to as FLT3-ITD positive. FLT3 is a kinase receptor expressed on hematopoietic progenitor cells (immature blood cells) and plays a critical role in regulating their activation, growth, proliferation, survival and differentiation into mature blood cells. The FLT3-ITD mutation results in the constant ligand-independent activation of FLT3, leading to aggressive proliferation of immature, irregular blasts that lack the ability to differentiate into normal blood cells.

Physicians, as a standard part of diagnosis, routinely test patients for the FLT3-ITD mutation. Patients who are FLT3-ITD positive have a significantly worse prognosis compared to FLT3-ITD negative patients. FLT3-ITD positive patients typically respond to induction chemotherapy; however, they tend to relapse more quickly and at a higher rate, leading to an overall survival rate that is much lower than FLT3-ITD negative patients.

Development of Quizartinib in AML

Given the significant activity we have observed in quizartinib for the treatment of AML, we have pursued a broad development program to evaluate quizartinib in multiple patient populations. We initiated our clinical program in 2007 and to date more than 500 patients have been treated in our Phase 1 and Phase 2/2b clinical trials.

We completed Phase 2 and 2b clinical trials in relapsed/refractory AML patients and results from these trials were reported at the 2012 and 2013 Annual Meeting of the American Society of Hematology, or ASH, the 2013 and 2014 Annual Meeting of the American Society of Clinical Oncology, or ASCO.

These clinical trials demonstrated the following three key clinical benefits of quizartinib:

At multiple doses, quizartinib as a monotherapy demonstrated a high response rate in relapsed/refractory FLT3-ITD positive patients;

A substantial number of patients treated with quizartinib responded to therapy and were bridged to a potentially curative HSCT resulting in better overall survival compared to responders that did not undergo an HSCT; and

Overall survival in FLT3-ITD positive patients treated with quizartinib compared favorably to historical survival data reported for FLT3-ITD positive AML patients.

Based on these results our initial development strategy for quizartinib is to seek approval in relapsed/refractory AML patients with the FLT3-ITD mutation.