HAYWARD, Calif., Dec. 11 /PRNewswire-FirstCall/ -- Kosan Biosciences Incorporated today presented results from a dose-escalating Phase 1b clinical trial of its lead Hsp90 inhibitor, tanespimycin (KOS-953) in combination with bortezomib (Velcade(R)), showing a high degree of antitumor activity and tolerability in patients with multiple myeloma who had previously progressed following treatment with multiple conventional therapies. The data were presented by Paul Richardson, M.D., Department of Hematology, Dana Farber Cancer Center in Boston at the American Society of Hematology (ASH) 48th Annual Meeting and Exposition, held in Orlando, Florida. The presentation was entitled, "A Multicenter Phase 1 Clinical Trial of Tanespimycin (KOS-953) + Bortezomib: Encouraging Activity and Manageable Toxicity in Heavily Pre-treated Patients with Relapsed Refractory Multiple Myeloma."
"We are optimistic that tanespimycin represents an important combination treatment for multiple myeloma, for both bortezomib-naïve patients and patients who no longer respond to bortezomib," said Dr. Richardson. "Tanespimycin has demonstrated meaningful anticancer activity and manageable safety when administered in combination with bortezomib in this heavily pretreated patient population. Of particular promise are the data showing that tanespimycin has the potential to enhance effectiveness in bortezomib-sensitive patients, and the data in bortezomib-naïve patients that suggest tanespimycin may enhance the therapeutic response to bortezomib. We look forward to continuing to explore the full potential of this novel compound in larger-scale trials."
"We believe that the safety and activity data for tanespimycin, as well as the pharmacokinetic and mechanistic data, underscore tanespimycin's therapeutic potential and the role of Hsp90 inhibition in the treatment of multiple myeloma," said Robert G. Johnson, Jr., M.D., Ph.D., Kosan's President and Chief Executive Officer. "Tanespimycin has the potential to be the first Hsp90 inhibitor to advance through the clinic and to registration, and could bring important clinical benefit to multiple myeloma patients. Our goal is to initiate a registrational development program for this compound in the first quarter of 2007."
Tanespimycin is the first in a new class of compounds, Hsp90 inhibitors, which work through a novel mechanism of action. Hsp90 is a protein chaperone that binds to several sets of signaling proteins, known as "client proteins." These client proteins include a "who's who" list of cancer-relevant targets such as mutated p53, Bcr-Abl, Raf, ErbB2 and other kinases, as well as steroid hormone receptors, and in multiple myeloma, AKT, IL-6 and IGF-1R. Disruption of the Hsp90-client protein complexes leads to proteasome-mediated degradation of client proteins and cell death.
Phase 1b Clinical Trial Results
The objective of the Phase 1b dose-escalating trial was to define a Phase 2 dose of tanespimycin in combination with bortezomib in patients with relapsed, refractory multiple myeloma, as well as to assess pharmacokinetic and pharmacodynamic parameters. Dose escalation in the trial ranged from 100-340 mg/m2 for tanespimycin, and from 0.7-1.3 mg/m2 for bortezomib. Patients received tanespimycin via one hour infusion two times per week for two weeks out of three weeks, following the bortezomib dose.
Data on 30 patients, with a median of 60 years of age, were reported. Of these 30 patients, 23 received a dose of at least 1.0 mg/m2 of bortezomib and were evaluable for efficacy. All of these patients had received multiple prior chemotherapy regimens (median of 4), and 67% had received bone marrow transplants. Of the 30 patients, 9 (30%) had not seen prior bortezomib, and 5 patients (17%) were bortezomib-refractory (having no response, progressed on or within 60 days of their last dose of a bortezomib-containing regimen). At the time of this data presentation, the first 6 dose cohorts were evaluable (tanespimycin at doses of 100 mg/m2 through 275 mg/m2). Dose escalation continues with assessment of the 340 mg/m2 tanespimycin/1.3 mg/m2 bortezomib cohort ongoing. In this cohort, activity has been observed to date including a partial response in a bortezomib-refractory patient. This dose cohort is still being evaluated and has been expanded to confirm the recommended Phase 2/3 dose.
In patients who received 1.0 mg/m2 of bortezomib or more, the overall response rate (complete, partial and minimal responses) was 57% (13 out of 23 patients), with an overall rate of complete and partial responses of 35% (8 out of 23 patients). Of the 13 responding patients, responses were observed in,
* 5 out of 8 bortezomib-naïve patients (63%); * 6 out of 12 bortezomib-pretreated patients (50%); and * 2 out of 3 bortezomib-refractory patients (67%).
The combination of tanespimycin and bortezomib was generally well- tolerated. Common toxicities, which were manageable and reversible, included fatigue, diarrhea, constipation, thrombocytopenia and nausea (mild-to-moderate severity). While no maximal tolerated dose has been reached, dose-limiting toxicities observed in single patients consisted of reversible hepatotoxicity and a single episode of pancreatitis that resolved. There was no cardiovascular toxicity and no Cremophor hypersensitivity observed. Importantly, the rate of peripheral neuropathy was low (peripheral neuropathy is a common toxicity of bortezomib).
Plasma pharmacokinetic analysis (with tanespimycin administered with and without bortezomib) showed that bortezomib did not affect the PK of tanespimycin. Induction of Hsp70 (a biomarker of Hsp90 inhibition) was demonstrated in peripheral blood leukocytes and maintained across the 3-4 day dosing interval, suggesting a durable pharmacologic effect of tanespimycin. In addition, there was an increased loss of total and phosphoAKT, especially pronounced at the 275 mg/m2 tanespimycin level. AKT is a sensitive client protein to Hsp90 inhibition. Evaluation of bone marrow cells demonstrated selective apoptosis of the myeloma cells without apoptosis of normal cells. Correspondingly, there was a decrease in level of two Hsp90 client proteins, IGF-1 receptor and IL-6 receptor.
Registration Program of Tanespimycin Planned
While data collection of the Phase 1b clinical trial continues, Kosan's current plans are to initiate the registrational development program for tanespimycin in the first quarter of 2007 after completion of ongoing discussions with US and European Health Authorities. One planned trial will test tanespimycin plus bortezomib in patients with relapsed refractory disease. Another planned trial will compare tanespimycin plus bortezomib versus bortezomib alone in a first-relapsed patient population. Kosan has been granted orphan status for tanespimycin in multiple myeloma in both the US and Europe.
About Kosan
Kosan Biosciences is a biotechnology company advancing two new classes of anticancer agents through clinical development - Hsp90 (heat shock protein 90) inhibitors and epothilones. Kosan is leveraging its proprietary discovery platform to generate a pipeline of potentially significant product candidates, primarily in the area of oncology.
Hsp90 inhibitors have a novel mechanism of action targeting multiple pathways involved in cancer cell growth and survival. Kosan's proprietary formulation of tanespimycin (KOS-953) is currently in Phase 1 and 2 clinical trials, primarily for multiple myeloma in combination with Velcade(R) (bortezomib) and HER2-positive metastatic breast cancer in combination with Herceptin(R) (trastuzumab). In addition, intravenous and oral formulations of Kosan's second-generation Hsp90 inhibitor, alvespimycin (KOS-1022), are being evaluated in Phase 1 clinical trials.
Epothilones inhibit cell division with a mechanism of action similar to taxanes, one of the most successful classes of anti-tumor agents. KOS-862 is currently being studied in a Phase 2 single-agent clinical trial in patients with HER2-positive metastatic breast cancer, as well as a Phase 2 combination trial with Herceptin(R). KOS-1584, a second candidate designed to improve pharmacokinetics, is in Phase 1 clinical trials in patients with solid tumors. Kosan's epothilone program is partnered with Roche through a global development and commercialization agreement.
For additional information on Kosan Biosciences, please visit the company's website at http://www.kosan.com.
This press release contains forward-looking statements within the meaning of the "safe harbor" provisions of the Private Securities Litigation Reform Act of 1995 (the "Act"). Such forward-looking statements include but are not limited to statements relating to the further development and potential safety, efficacy and registration of tanespimycin (KOS-953), and Kosan's development plans with respect to tanespimycin, including but not limited to Kosan's plans with respect to initiations of clinical trials for tanespimycin and the timing thereof. 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, risks related to the clinical advancement of Kosan's product candidates, including the risk that clinical trials may not demonstrate safety and efficacy sufficient to obtain the requisite regulatory approvals or to result in a marketable product; risks related to Kosan's and its collaborators' ability to timely commence and complete clinical trials; 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, 2006 and other periodic filings with the SEC. Kosan does not undertake any obligation to update forward-looking statements.
Velcade(R) (bortezomib) is a registered trademark of Millennium Pharmaceuticals, Inc.
Herceptin(R) (trastuzumab) is a registered trademark of Genentech, Inc.
Kosan Biosciences IncorporatedCONTACT: Gary S. Titus, Chief Financial Officer, +1-510-731-5373,titus@kosan.com; or Jane Green, +1-510-731-5335 (office), +1-415-652-4819(mobile), green@kosan.com, both of Kosan
Web site: http://www.kosan.com/
