ATLANTA, Dec. 12 /PRNewswire-FirstCall/ -- Kosan Biosciences Incorporated (Nasdaq: KOSN - News) today reported interim results from two clinical trials of KOS-953, Kosan's proprietary formulation of the Hsp90 inhibitor 17-AAG, in two oral presentations at the 47th Annual Meeting of the American Society of Hematology (ASH) in Atlanta, GA. Data from a Phase I single-agent clinical trial and a Phase Ib combination trial of KOS-953 co-administered with bortezomib (Velcade®) demonstrated early signs of anticancer activity and tolerability in patients with relapsed-refractory multiple myeloma.
"We are very encouraged by these interim clinical results that indicate the potential of KOS-953 in the treatment of multiple myeloma and further validate heat shock protein 90 as an anticancer target," said Dr. Kenneth Anderson, Director, Jerome Lipper Multiple Myeloma Center at the Dana-Farber Cancer Institute, and Kraft Family Professor of Medicine, Harvard Medical School.
"In both studies, KOS-953 exhibited meaningful clinical benefit among heavily pre-treated patients, with manageable side effects. The response rates and time on study in the combination trial are particularly promising and the dose escalation is still on-going."
KOS-953 Phase Ib Combination Trial with Bortezomib (Velcade)
Interim results of the Phase Ib combination trial of KOS-953 co-administered with bortezomib (BZ) in patients with relapsed-refractory multiple myeloma included data from 18 previously treated patients (median number of 4 prior therapies), 78% of whom were BZ-refractory and 67% percent of whom had failed transplantation. Of the 16 evaluable patients, 9 responses were observed (56%): 2 near Complete Responses (nCR) and 7 minor responses (MR), with 3 additional patients (19%) with stable disease (SD) of greater than 3 cycles. Asher Chanan-Khan, M.D., Department of Medicine, Roswell Park Cancer Institute, Buffalo, New York, presented these data.
The ongoing trial is a dose-escalation study designed to define the recommended Phase II dose of KOS-953 and BZ, and to evaluate the pharmacokinetics and biological activity of the two drugs in combination. Drugs were administered (BZ preceding KOS-953) on the approved BZ schedule. Toxicity was primarily mild-to-moderate fatigue and gastrointestinal symptoms. One episode of dose-limiting toxicity (Grade 4 elevated liver function test) was observed. No additive toxicity has been observed and no cardiovascular toxicity was noted. BZ did not influence the pharmacokinetics of KOS-953 and KOS-953 did not interfere with the proteasomal inhibition of BZ. Dose escalation continues in an effort to define the optimal Phase II doses of the combination.
KOS-953 Phase I Single Agent Trial
Paul G. Richardson, M.D., Department of Medical Oncology/Hematologic Malignancies, Dana-Farber Cancer Institute, Boston, presented updated results of the Phase I single-agent trial of KOS-953 in patients with relapsed-refractory multiple myeloma. The presentation included data from 19 evaluable patients, all of whom had advanced disease (median number of five prior regimens, 41% having also failed transplantation). Clinical benefit, including minor response (one patient), and stable disease of greater than 3 cycles (eleven patients) was observed in 63% of evaluable patients. Bone marrow aspirates collected following treatment showed an increase in apoptosis of myeloma cells, while the peripheral blood cells showed the typical reactive induction of Hsp70, a stress response to biologically active doses of an Hsp90 inhibitor.
The ongoing Phase I trial is a dose-escalation study designed to determine the maximum tolerated dose, safety profile, pharmacokinetics and pharmacodynamics of KOS-953. In the trial, KOS-953 was administered at escalating dose levels on a twice-weekly schedule every three weeks and successfully reached a current dose level of 340 mg/m2. Two episodes of dose-limiting toxicity (Grade 3-4 elevated liver function tests) were observed. Other side effects were manageable and included fatigue, gastrointestinal events, liver function abnormalities, myalgias and rash. No cardiovascular toxicity was noted. Assessment at a higher dose level is planned in an effort to define the recommended dose for possible future trials.
In both the Phase I monotherapy and Phase Ib combination clinical trials, pharmacokinetics of KOS-953 were linear with respect to exposure and maximum plasma concentrations over the dose range tested.
Background
Multiple myeloma is a cancer that affects the plasma cells, a type of immune cell that produces antibodies to help fight infection and disease. KOS-953 is a novel formulation of 17-AAG, an Hsp90 inhibitor. In vitro and in vivo studies showed that inhibition of Hsp90 by KOS-953 leads to protein degradation and apoptosis of multiple myeloma cells. By blocking Hsp90 function, KOS-953 markedly enhances the sensitivity of multiple myeloma cells to bortezomib (Mitsiades et al 2005, Blood Epub 18 October 2005).
In addition to the KOS-953 single-agent and combination studies in multiple myeloma reported on today, the original formulation of 17-AAG is being evaluated in multiple Phase I, Phase Ib and Phase II clinical trials in a variety of tumor types. These trials are sponsored by the National Cancer Institute (NCI) under a Cooperative Research and Development Agreement (CRADA) between Kosan and the NCI Cancer Therapy Evaluation Program (CTEP). In 2004, Kosan obtained orphan drug designation for 17-AAG from both the U.S. Food and Drug Administration (FDA) and the European Medicines Agency (EMEA) for the treatment of multiple myeloma as well as another hematologic cancer, chronic myelogenous leukemia.
About Hsp90 Inhibitors
17-AAG is an analog of the polyketide geldanamycin that inhibits Hsp90 (heat shock protein 90), a protein found in high levels in tumor cells. Hsp90 is a molecular "chaperone" which maintains the stability of numerous "client proteins" implicated in tumor growth and metastasis, including protein kinases and transcription factors. By blocking the activity of Hsp90, Kosan's geldanamycin analogs lead to the disruption of the Hsp90-client protein complexes and the degradation of the client proteins. By targeting multiple growth-signaling pathways involved in cancer, these compounds may have potential use in a variety of tumor types, both as single agents and in combination with other signal transduction inhibitors and cytotoxic drugs.
About Kosan
Kosan Biosciences is advancing two new classes of anticancer agents through clinical development. Kosan's most advanced compound, KOS-862 (Epothilone D), is in Phase II and Phase Ib clinical trials in breast cancer, and a follow-on compound, KOS-1584, is in Phase I clinical trials. These programs are partnered with Roche through a global development and commercialization agreement. Kosan is also developing Hsp90 (heat shock protein 90) inhibitors in collaboration with the National Cancer Institute (NCI), including 17-AAG, a first generation geldanamycin analog. Kosan's proprietary formulation of 17-AAG, KOS-953, is in Phase I and Phase II clinical trials for multiple myeloma and HER2 metastatic breast cancer. In addition, a second-generation geldanamycin analog, KOS-1022 (DMAG), is currently in Phase I clinical trials, in collaboration with the NCI. Kosan has generated a pipeline of additional product candidates for gastrointestinal motility, infectious diseases and cancer based on its proprietary technologies for discovering, developing and manufacturing polyketide analogs. Polyketides are an important class of natural products that have yielded numerous pharmaceuticals for the treatment of cancer, infectious diseases, high cholesterol, transplant rejection and other diseases. For additional information on Kosan Biosciences, please visit the Company's website at www.kosan.com.
This press release contains "forward-looking" statements, including statements with respect to the further development and potential safety and efficacy of KOS-953 in the treatment of cancer. Any statements contained in this press release that are not statements of historical fact may be deemed to be forward-looking statements. There are a number of important factors that could cause the results of Kosan to differ materially from those indicated by these forward-looking statements, including, among others, the risk that the U.S. Food and Drug Administration may require changes to the protocols and informed consents for clinical trials of KOS-953, which changes may have a material adverse effect on the timing of, and Kosan's ability to conduct, those clinical trials, risks related to the clinical advancement of KOS-953, including the risk that clinical trials for this product candidate may not demonstrate safety and efficacy sufficient to obtain the requisite regulatory approvals or to result in a marketable product, risks related to the possible determination that an earlier-stage compound, such as KOS-1022, will be more appropriate for commercial development than KOS-953, risks related to the potential for others to develop products containing or based on 17-AAG, risks related to Kosan's dependence on the NCI for the development of its Hsp90 inhibitors and other risks detailed from time to time in the Company's SEC reports, including its Quarterly Report on Form 10-Q for the quarter ended September 30, 2005 and other periodic filings with the SEC. Kosan does not undertake any obligation to update forward-looking statements.
NOTE: Velcade® is a registered trademark of Millennium Pharmaceuticals, Inc.
Source: Kosan Biosciences Incorporated
