Anticanceractivity of IPI-504 in Preclinical Studies

Novel Compound Shown to be a Potent Inhibitor of Hsp90 and Synergistically Cytotoxic with Bortezomib in Models of Multiple Myeloma

Infinity Pharmaceuticals, Inc. announced today positive preclinical data on the company's novel investigational compound IPI-504, a potent inhibitor of Heat Shock Protein 90 (Hsp90). Results demonstrate that IPI-504 significantly reduces tumor burden in several animal models of cancer, including multiple myeloma, breast, lung, and prostate cancer. Furthermore, a key clinical benefit of the compound relative to other Hsp90 inhibitors currently being developed is its proposed administration to patients using a simple water-based formulation. This data was presented during the 96th Annual Meeting of the American Association for Cancer Research (AACR) held in Anaheim, California. The initiation of a Phase I clinical study of IPI-504 is planned for the first half of 2005.

IPI-504 is an innovative and proprietary small molecule compound specifically designed to attack a cancer cell's machinery for maintaining protein homeostasis, the process by which cells continue the orderly formation and destruction of proteins. Hsp90 helps proteins to fold into their correct three-dimensional shape to properly perform their function. Cancer cells are preferentially reliant on Hsp90 activity for proper protein homeostasis because they endure genetic and cellular stresses that alter their normal protein balance. Research shows that inhibition of Hsp90 forces cancer cells to "commit suicide" through a process of programmed cell death or apoptosis.

"IPI-504 demonstrates Infinity's ability to discover and develop proprietary compounds for the treatment of cancer, an area of tremendous unmet medical need," said Julian Adams, Ph.D., Chief Scientific Officer, Infinity. "Protein homeostasis is a very promising and exciting area of focus for cancer research. By focusing on creating a compound that targets this cellular mechanism, we were also able to design IPI-504 to exhibit several advantageous traits -- it binds tightly to Hsp90, shows selective tumor tissue retention at active concentrations for 48 hours, and demonstrates excellent water solubility, enabling a key drug delivery advantage as a simple i.v. infusion."

Study Findings

Infinity's presentation, entitled "Antitumor activity of a novel, water-soluble Hsp90 inhibitor IPI-504 in multiple myeloma" (Abstract #6160) discussed data from in vitro and in vivo studies of Infinity's lead investigational anticancer agent. These studies demonstrate that IPI-504 binds to Hsp90 more tightly than 17-AAG (Ki = 28 nM for IPI-504 vs. 67 nM for 17-AAG) in vitro. In addition, IPI-504 showed potent cellular activity against multiple myeloma, including bortezomib-resistant cells. When used in combination with bortezomib, IPI-504 provided synergistic benefits in its effect on multiple myeloma cells at concentrations significantly lower than their individual IC50s. When examined in vivo, IPI-504 demonstrated a 71% reduction in tumor volume relative to control in the RPMI-8226 human xenograft model of multiple myeloma. It was also found to decrease serum lambda chain concentrations (similar to M protein in the human disease), enabling monitoring of disease burden with a surrogate marker. In an orthotopic model of human myeloma, IPI-504 significantly prolonged the survival of mice relative to the control. This preclinical research was conducted by Infinity researchers in collaboration with investigators at the Dana-Farber Cancer Institute led by Kenneth C. Anderson M.D., Chief, Division of Hematologic Neoplasia.