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, including various forms of leukemia, a blood-based cancer. AP24534 is a potent inhibitor of Bcr-Abl, a target associated with drug-resistant chronic myeloid leukemia (CML). Our preclinical studies showed that AP24534 demonstrated efficacy and oral dosing flexibility in animal models of CML, including forms of CML caused by clinically relevant variants of the target protein, Bcr-Abl. Specifically, 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).
In addition, AP24534 has demonstrated in preclinical studies potent inhibition of additional targets that control the process of angiogenesis, or blood vessel growth, including the receptors for vascular endothelial growth factors, or VEGFRs, fibroblast growth factors, or FGFRs, and angiopoietin, or Tie2. Inhibiting angiogenesis is a clinically validated approach to treating multiple solid tumors. Based on AP24534’s differentiated and unique profile, we believe these findings support the broad potential of the drug not only in drug-resistant CML, but also in other hematological cancers, such as AML, and various solid tumors.
We have completed extensive preclinical studies of AP24534, including efficacy and safety assessment studies, which we believe indicate that the drug candidate should be well tolerated at anticipated therapeutic dose levels in cancer patients. We plan to initiate two Phase 1 trials of AP24534 in 2008. The first, to begin in the first half of 2008, will evaluate oral AP24534 in drug-resistant and refractory chronic myeloid leukemia and other hematologic malignancies. Later in 2008, the second trial is expected to evaluate oral AP24534 in patients with solid tumors.
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 over 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.
* Source: Leukemia, Lymphoma, Myeloma, Facts 2007-2008.
