Pharmacyclics Completes Trial Of Factor VIIa Inhibitor PCI-27483

Ruzanna Harutyunyan's picture
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Pharmacyclics, Inc. (Nasdaq: PCYC) today announced that the company has completed a Phase 1 clinical trial with PCI-27483, the company's novel, first-in-class small-molecule Factor VIIa inhibitor. The trial was conducted in sixteen (16) healthy volunteers to evaluate the safety and pharmacologic effect of PCI-27483. A single administration of PCI-27483 resulted in a linear dose response in the International Normalized Ratio (INR), a routine laboratory test used to assess the level of anticoagulation (blood-thinning).

"Single doses of PCI-27483 reliably and quickly achieved therapeutic levels of anticoagulation without adverse effects in this initial trial," said James Lowder, M.D., Vice President, Clinical Development for Pharmacyclics. "The ability to achieve precise levels of anticoagulation that can be readily measured differentiates PCI-27483 from other available anticoagulants. The Factor VIIa: tissue factor complex, the pharmacologic target of PCI-27483, has been implicated both in the progression of solid tumors and the increased incidence of venous thromboembolic events observed in many malignancies. Up-regulation of tissue factor expression is observed in pancreatic, lung, and breast cancer, and is associated with a worsened prognosis."

In the recently completed study, PCI-27483 increased the INR with minimal intra-subject variation and a half-life of ten hours. At the highest subcutaneous dose of PCI-27483 evaluated, a mean (+/-standard error) peak INR of 2.72 (+/- 0.24) was achieved one to two hours post-dosing. The trial further established doses of PCI-27483, which upon repeated dosing are expected to maintain the INR in the range of 2.0 to 3.0, the target window for treatment and prevention of thromboembolic events (i.e., formation of blood clots).

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Earlier this year, Pharmacyclics presented data at the 2008 Annual Meeting of the American Association for Cancer Research (AACR) demonstrating that PCI-27483 inhibits tumor growth in an animal model of pancreatic cancer. In previous animal studies, the company has shown that PCI-27483 inhibits the growth of human colorectal tumor cells and murine lung carcinoma cells.

"PCI-27483 is expected to have a dual effect of inhibiting tumor growth and decreasing the incidence of venous thromboembolic events in patients with cancer. We're diligently working to move PCI-27483 through clinical development, as evidenced by our early completion of the Phase 1 trial. We believe that this compound has unique potential for cancer patients," said David Loury, Ph.D., Vice President of Development for Pharmacyclics. "Recent clinical studies have shown that approximately 90% of pancreatic cancers express tissue factor. Accordingly, we are currently preparing for a Phase 1b/2 trial to begin in calendar Q2 '09 to evaluate PCI-27483's effects in patients with pancreatic cancer."

About Factor VII and PCI-27483

Factor VII is a blood protein involved in clotting. Many types of cancer, such as lung, breast, pancreatic, colorectal, gastric and others, express high levels of a cell surface protein known as tissue factor (TF). After binding to TF, Factor VII becomes activated and triggers a host of pathologic processes in the tumor microenvironment that facilitate the growth, invasion and spread of many cancers. Activation of Factor VII (Factor VIIa) by TF also leads to the high incidence of thromboembolic complications seen in cancer patients. PCI-27483 is a novel first-in-class small molecule inhibitor, which selectively targets the Factor VIIa:TF complex. PCI-27483 was developed in a large medicinal chemistry discovery and optimization program, applying high-resolution X-ray structure-based design to the development of candidates of high potency and selectivity for the Factor VIIa:TF complex.

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