Studies Show ABT-263 and ABT-869 to be Promising in Targeting Cancer Cells'
ABBOTT PARK, Ill., May 15 /PRNewswire-FirstCall/ -- Abbott scientists will highlight the latest clinical trial data of several investigative compounds in the company's oncology pipeline at this year's American Society of Clinical Oncology (ASCO) Annual Meeting, scheduled for May 30 in Chicago. The presentations include ABT-263, a Bcl-2 family protein antagonist, and ABT-869, an oral small molecule that provides simultaneously potent and specific inhibition of the VEGFR and PDGFR families. Both compounds were discovered by Abbott scientists and are being co-developed by Abbott and Genentech. The company's meeting abstracts are available online today at http://www.asco.org.
By targeting a key survival mechanism of cancer cells, Abbott scientists identified ABT-263 as a potent inhibitor of Bcl-2 family proteins. The Bcl-2 family proteins regulate apoptosis (programmed cell death), the natural process by which damaged or unwanted cells die and are cleared from the body. When this process is defective, damaged cells can continue to divide, leading to the formation and growth of tumors. Preclinical studies showed promising activity against chronic lymphocytic leukemia (CLL), lymphomas and small cell lung cancer -- Phase I/II trials are currently underway in these diseases.
Additionally, Abbott scientists are targeting another vital characteristic of cancer cells with ABT-869. In early studies, data have shown that ABT-869 inhibits a distinct set of kinases that are involved in angiogenesis, a process by which tumors gain access to new blood vessels. Inhibition of these kinases may suppress tumor growth by cutting off tumor blood supply. ABT-869 is currently being tested against several tumor types in Phase II clinical trials.
"Researchers from around the world have requested to study Abbott's
Bcl-2 family protein inhibitors, which is an indication of the potential
value that ABT-263 might bring to the cancer research field," said John
Leonard, M.D., senior vice president, Pharmaceuticals, Research and
Development, Abbott. "We have built an early stage pipeline that targets
the processes that cancers need to survive and we're looking forward to
advancing our work in this area."
Presentation highlights include:
-- A Phase I Study Evaluating the Safety, Pharmacokinetics, and Efficacy
of ABT-263 in Subjects With Refractory or Relapsed Lymphoid
-- Reduction in Platelet Counts as a Mechanistic Biomarker and Guide for
Adaptive Dose-escalation in Phase I Studies of the Bcl-2 Family
-- Dynamic Contrast Enhanced MRI (DCE MRI) for Assessment of Effects of
Anti-Angiogenic Therapy: Comparison of the Transfer Constant (Ktrans)
to Blood Flow and Permeability Derived by a Distributed Parameter
-- Relationship of Dose of ABT-869 on Biomarkers of Angiogenesis and
Their Correlation With Pharmacodynamic (PD) Outcome
Study Background and Results
Thirty patients with refractory or relapsed lymphoid malignancies have been enrolled in an ongoing Phase I study evaluating safety, pharmacokinetics and efficacy. Subjects received ABT-263 orally once daily for 14 consecutive days followed by seven days off drug in each cycle of therapy. Results showed that ABT-263 had an acceptable side-effect profile at the seven-dose (10, 20, 40, 80, 160, 225 and 315 mg) cohort levels and showed evidence of anti-tumor activity. Researchers observed 99 percent and 36 percent tumor reduction in two patients with bulky chronic lymphocytic leukemia (CLL). Another patient with bulky CLL/small lymphocytic lymphoma (SLL) experienced a 75 percent reduction and a patient with follicular lymphoma experienced a 20 percent tumor reduction. Lastly, a patient with NK/T cell lymphoma had a 75 percent reduction in tumor measurements. Adverse events included two Grade 3 dose- limiting toxicities (upper respiratory infection (URI) and elevated liver enzymes) and five cases of Grade 3 thrombocytopenia (low-platelet count) without any sign of bleeding.
Reductions in platelet counts were analyzed in the three ongoing Phase I trials as a biomarker of Bcl-2 family protein inhibition. Subjects received doses ranging from 10 mg to 315 mg. The study data demonstrate that ABT-263 induces a transient decrease in circulating platelets via inhibition of Bcl- XL, without decreasing platelet production, confirming on-target activity. At 315 mg, researchers observed a 69 percent reduction in mean platelets from baseline values. Typically, platelet nadir occurred on days three to five with recovery during continued dosing. Tumor regression was observed in six patients, with three patients showing more than 50 percent tumor shrinkage. Adverse events included three dose-limiting toxicities, one Grade 3 URI at 160 mg, one Grade 3 alanine aminotransferase (ALT) elevation at 315 mg and one fatal respiratory failure at 10 mg. Updated information will be presented at the ASCO Annual Meeting.
Twenty-four patients from a completed Phase I trial (ABT-869), which studied three dose levels of ABT-869, were evaluated to compare two different measures of angiogenesis using functional imaging -- the distributed parameter (DP) model and the transfer constant (Ktrans) model. DP is a dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) model that enables derivation of blood flow and capillary permeability-surface area product (PS). Tests indicated that time over threshold could be an important predictor of efficacy, and results demonstrated that an appropriate value for the plasma concentration threshold could be 0.08 ug/mL, with time above threshold value of 3.5 hours. In seven out of 20 cases (35 percent), DP-PS correctly predicted the eventual outcome. These results seem to indicate that PS derived from DP model showed better correlation with drug exposure and could predict patient outcome better than Ktrans.
In a separate analysis, the effects of ABT-869 on biomarkers of angiogenesis were evaluated. Correlations of dose and pharmacokinetics of ABT-869, with serum biomarkers, tumor DCE-MRI tracer kinetics, proteinuria and hypertension were assessed. Results appeared to indicate that ABT-869 induced dose-dependent changes in serum biomarkers are consistent with anti-angiogenic activity. However, these serum biomarkers had limited value in predicting safety, i.e., proteinuria or hypertension. The utility of tumor flow and permeability changes on DCE-MRI in predicting proteinuria should be further examined. Updated information will be presented at the ASCO Annual Meeting.
Background on Abbott's Oncology Pipeline
Bcl-2 Family Protein Inhibitors (ABT-263)
Researchers have been interested in the Bcl-2 family of proteins since their role in preventing apoptosis -- the natural process by which damaged or unwanted cells die and are cleared from the body -- was proven more than a decade ago. Discovered by Abbott scientists, ABT-263 restores programmed cell death, a natural mechanism for the elimination of cancerous cells, by inhibiting the function of Bcl-2 proteins.
Bcl-2 proteins play a central role in regulating apoptosis, as well as tumor formation, tumor growth and resistance to treatment. Pioneering work in structural biology at Abbott established how the Bcl-2 family proteins interact with one another, leading researchers to develop a novel compound that causes cancer cells to self-destruct.
ABT-263 is in Phase I/II clinical trials for lymphomas and solid tumors, including small cell lung cancer. Preclinical data has shown that Abbott's Bcl-2 family protein inhibitors bind to Bcl-2 proteins, restoring cell death to cancerous cells. Additionally, the compounds were found to enhance the effects of chemotherapy and radiation used to treat other types of cancer, such as non-small cell lung cancer.
Kinase Inhibitors (ABT-869)
Many oncology researchers are currently developing agents that target kinases, a class of enzymes that are often overly activated in cancer cells. Inhibition of the appropriate kinases can suppress tumor growth by cutting off its blood supply.
Discovered by Abbott scientists, ABT-869 is an oral small molecule that provides simultaneously potent and specific inhibition of the VEGFR and PDGFR families that is in Phase I clinical trials for solid tumors and selected hematologic malignancies such as leukemia. Phase II trials for several tumor types began this year.
PARP Inhibitors (ABT-888)
DNA damaging agents remain some of the most successful treatments for cancer. The enzyme Poly(ADP-ribose)polymerase (abbreviated PARP) can help repair DNA damage caused by these agents used to treat cancer and render them ineffective. As PARP activity is often increased in cancer cells, it provides these cells with a survival mechanism.
ABT-888 is an oral PARP-inhibitor developed by Abbott researchers to prevent DNA repair in cancer cells and increase the effectiveness of common cancer therapies such as radiation and alkylating agents.
ABT-888 completed a Phase 0 trial for patients with refractory solid tumors and lymphoid malignancies, and has entered several Phase I trials. Preclinical data indicates ABT-888 has improved the effectiveness of radiation and many types of chemotherapy in animal models of cancer.
About Abbott Oncology
Abbott Oncology is committed to the discovery and development of innovative cancer treatments that enable patients to live longer and healthier lives. Abbott's oncology research is focused on developing more targeted, less toxic therapies than are currently available to improve the quality of life for some patients living with cancer.
Abbott (NYSE: ABT) is a global, broad-based health care company devoted to the discovery, development, manufacture and marketing of pharmaceuticals and medical products, including nutritionals, devices and diagnostics. The company employs more than 68,000 people and markets its products in more than 130 countries.
Abbott's news releases and other information are available on the
company's Web site at http://www.abbott.com.
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