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), and is currently in Phase 2b clinical development.
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 are developing a companion diagnostic test with a partner to identify FLT3-ITD positive patients, and we believe approval of this test will be necessary for the approval of quizartinib.
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.
AML is the most common type of acute leukemia in adults and is projected to account for approximately 29% of all new leukemia cases in 2012. 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 13,780 patients will be newly diagnosed with AML in 2012 in the United States and approximately 10,200 are expected to die of the disease in 2012. 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. This is considered a complete remission, or CR. 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 400 patients have been treated in our Phase 1 and Phase 2 clinical trials. There are currently four ongoing clinical trials with quizartinib. To support a NDA, pending input from regulatory authorities, we plan to initiate a randomized, comparative Phase 3 clinical trial in relapsed/refractory AML patients with the FLT3-ITD mutation in early 2014.
Quizartinib Phase 2 Clinical Trial
A Phase 2 clinical trial of quizartinib in relapsed/refractory AML patients was initiated in November 2009 and completed enrollment in November 2011. Data from our single-arm, 333 patient clinical trial was reported at the American Society of Hematology meeting in December 2012. In the trial, quizartinib demonstrated the ability to significantly reduce the number of blasts in the bone marrow of a substantial number of patients, often for a clinically meaningful duration of time.
Our Phase 2 clinical trial demonstrated the following three key clinical benefits:
- Quizartinib, as a monotherapy, demonstrated a high response rate in relapsed/refractory FLT3-ITD positive patients;
- A substantial number of patients treated with quizartinib were bridged to a potentially curative hematopoietic stem cell transplantation, or an HSCT (commonly referred to as a bone marrow transplant); and
- Overall survival in FLT3-ITD positive patients treated with quizartinib compared favorably to historical survival data reported for both FLT3-ITD positive and negative AML patients.
In addition, nearly one of every five patients treated with quizartinib (irrespective of FLT3-ITD status) remained alive for more than 12 months and such patients are referred to as long term survivors. As of September 2012, approximately half of the long term survivors remained alive and continued to be followed for overall survival.
Based on our clinical trial data and our review of published results from clinical trials of other drug candidates that inhibit FLT3 that are in, or have been in, clinical development for the treatment of AML, we believe that quizartinib has demonstrated superior ability to reduce bone marrow blasts, which we believe is due to quizartinib’s unique combination of potency, selectivity and favorable pharmacokinetics. Quizartinib is currently in a Phase 2b clinical trial to identify the optimal dose for Phase 3 clinical development.
Other Ongoing Clinical Trials for Quizartinib
• Phase 2b Clinical Trial in FLT3-ITD positive relapsed/refractory AML
• Phase 1 Clinical Trial of Quizartinib in Combination with Chemotherapy for Frontline Therapy
• Phase 1 Clinical Trial of Quizartinib as Maintenance Therapy Following an HSCT
• Phase 1 Clinical Trial in Pediatric ALL or AML patients