Quizartinib Summary

Our lead drug candidate, quizartinib, is a once-daily, orally-administered, potent and selective inhibitor of FLT3, a validated target in the treatment of acute myeloid leukemia (AML).

We believe there is a significant unmet need for more effective treatments of AML, particularly for the subset of patients expressing a genetic mutation in FLT3, known as the FLT3 internal tandem duplication (FLT3-ITD) mutation. Over 35% of AML patients over age 55 are estimated to harbor this mutation. We refer to these patients as FLT3-ITD positive. 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 over 480 patients to date. Next, we plan to initiate a randomized comparative Phase 3 trial of quizartinib in relapsed/refractory AML patients with the FLT3-ITD mutation, in the second quarter of 2014. 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.

We believe there is a need for a better tolerated and more convenient therapy which can be used across multiple patient populations and settings, including younger and elder patients, newly diagnosed and relapsed/refractory patients, and patients that have undergone an HSCT.

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 FLT3-ITD status. These prognostic 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 hematopoietic stem cell transplantation (HSCT), or 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 an HSCT and have an improved projected outcome following an HSCT.

Role of the FLT3 Kinase in AML

AML is a particularly aggressive and deadly disease, especially for patients with the FLT3-ITD mutation. 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. Over 35% of AML patients over age 55 are estimated to harbor the FLT3-ITD mutation. 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 harbor the FLT3-ITD mutation are known as FLT3-ITD positive, and 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 with 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 over 480 patients have been treated in our Phase 1 and Phase 2/2b clinical trials.