ARIAD’s second oncology product candidate, AP24534, is an internally discovered novel oral multi-targeted kinase inhibitor that we believe has broad potential applications in cancer. AP24534 is currently being evaluated in a Phase 1 clinical study for the treatment of patients with hematological (blood-based) cancers. Read Recent Press Release on AP24534.
In preclinical studies, AP24534 demonstrated efficacy and oral dosing flexibility in animal models of chronic myeloid leukemia (CML), including forms of CML caused by clinically relevant variants of the target protein, Bcr-Abl. Significantly, AP24534 potently inhibited a specific mutant, T315I, which is resistant to all currently available drugs. Additional preclinical studies demonstrated that AP24534 also inhibits Flt3, a target associated with acute myeloid leukemia (AML).
Preclinical studies also demonstrated that AP24534 potently inhibited additional targets that control the process of angiogenesis, or blood vessel growth, including the receptors for vascular endothelial growth factors (VEGFRs), fibroblast growth factors (FGFRs), and angiopoietin (Tie2). Inhibiting angiogenesis is a clinically validated approach to treating multiple solid tumors.
Additional preclinical studies indicate that AP24534 should be well tolerated at anticipated therapeutic dose levels in cancer patients. We believe the results of our preclinical testing support the broad potential of AP24534 in patients with leukemias as well as solid tumors.
AP24534 clinical trials
We have initiated a Phase 1 clinical trial to evaluate oral AP24534 in patients with refractory hematological cancers, including patients with CML and AML. This multi-center, sequential dose-escalation study is designed to determine the safety and tolerability of oral AP24534, as well as its pharmacokinetics (behavior of the drug in patients) and its pharmacodynamics (the effects of the drug on patients’ cells). Since all participants will have well-characterized malignancies, the trial will provide us with initial information describing AP24534’s anti-tumor activity. We plan to explore the potential of AP24534 in specific solid tumors through additional clinical studies.
Leukemia and other hematological cancers
Leukemia is a blood-based cancer characterized by the abnormal proliferation and accumulation of immature, functionless blood cells in the blood and marrow, which impede the development and function of normal blood cells. If untreated, the cancerous blood cells overwhelm the bone marrow, enter the bloodstream and eventually invade other parts of the body, such as the lymph nodes, spleen, liver and central nervous system.
According to the Leukemia and Lymphoma Society, an estimated 44,240 new cases of leukemia were diagnosed in the United States in 2007, approximately 21,790 people died from the disease, and more than 218,000 people in the U.S. were either living with, or in remission from leukemia. The incidence of hematological cancers, such as leukemias, lymphomas and myelomas, is among the fastest-growing cancers due to the aging population. While most cases occur in older adults (more than half are diagnosed in adults over age 67), leukemia also causes more deaths than any other cancer among children and adults under the age of 20.*
Chronic myeloid leukemia (CML)
CML is characterized by an excessive and unregulated production of white blood cells by the bone marrow due to a genetic abnormality involving the Bcr-Abl protein. After a slow, chronic phase of production of too many white blood cells, CML typically evolves to more aggressive phases (i.e., “accelerated” phase or “blast crisis”). Treatment with Bcr-Abl inhibitors is initially effective but frequently results in the emergence of Bcr-Abl mutations that confer drug resistance. The T315I mutant of Bcr-Abl currently accounts for 15-20 percent of all drug resistance in CML. First-generation therapies for CML, such as imatinib, and second-generation therapies for CML, such as dasatinib and nilotinib, are not able to inhibit this mutated protein and thus are not effective against all forms of CML—indicating a key unmet medical need.
Acute myeloid leukemia (AML)
AML is a fast-growing cancer in which too many abnormal and immature white blood cells are rapidly made in the bone marrow and interfere with the production of normal blood cells. Flt3 is a validated target for AML. Mutation of the Flt3 protein, which is responsible for the proliferation of normal blood cells, is the most common genetic abnormality related to AML, present in approximately one-third of all AML patients and associated with adverse prognoses. The most common Flt3 mutation, the so-called internal tandem duplication, is linked to a particularly poor disease prognosis and is expected to be particularly susceptible to Flt3 inhibition. There are no Flt3 inhibitors currently approved for the treatment of AML.
Angiogenesis and solid tumors
Malignant tumors cannot grow beyond a certain size without essential nutrients and oxygen. Angiogenesis is a key process in tumor growth and spread in which tumors provoke the growth of new blood vessels to the tumor from pre-existing vessels; these new blood vessels provide the tumor with oxygen and nutrients, allowing these cells to grow, invade nearby tissue and spread to other parts of the body. To induce angiogenesis, tumors secrete various growth factors, such as VEGF, which send chemical signals to existing blood vessels to stimulate the growth of new blood vessels.
Currently available angiogenesis inhibitors are designed to stop the effects of the protein VEGF on tumors, interfering with the development of new blood vessels and blocking the supply of oxygen and nutrients that the tumor needs to grow and spread. However, studies have shown that resistance to VEGF inhibitors is associated with higher expression of additional growth factors, in particular members of the FGF and angiopoietin families. Simultaneous inhibition of VEGFR, FGFR, and the angiopoietin 1 receptor (Tie2) is expected to provide more potent inhibition of angiogenesis that is less prone to resistance than blocking VEGF alone.
