Kosan Biosciences Incorporated said Tanespimycin in Myeloma Evaluation or TIME-1 pivotal phase III trial for tanespimycin as a potential treatment for multiple myeloma is open for enrolment. TIME-1 is a pivotal phase III trial comparing tanespimycin in combination with bortezomib (Velcade) with bortezomib alone in patients following a single prior course of treatment (first-relapse).

Kosan has completed both a Special Protocol Assessment with the US Food and Drug Administration and a Scientific Advice process with the Committee for Medicinal Products for Human Use of the centralized European Medicines Agency, thus, providing what the company believes is a validated path to registration in many major world markets for the TIME-1 trial. TIME-1 is the most advanced Hsp90 inhibitor clinical program in the industry, underscoring the company's leadership in this new class of anticancer therapies.

The TIME registration program is designed to include two trials: a pivotal phase III trial (TIME-1) and a smaller supportive trial. The TIME-1 trial is proceeding on track and remains the foundation of the company's registration strategy. The TIME-2 trial, recently opened for patients who have failed numerous (at least three) prior myeloma therapies, will be closed and replaced with an alternative supportive trial. TIME-2 had been designed to support TIME-1 for full approval as well as to provide a potential strategy for pursuing accelerated approval based on a demonstration of clinically important activity in highly relapsed-refractory patients who have no other proven therapeutic options. Based on accumulating clinical data, Kosan believes that this highly relapsed-refractory patient population represents an increasingly difficult efficacy hurdle, and that adjusting the design of the supportive trial to include a less heavily pretreated patient population that is more likely to respond will increase the probability of clinical success in the TIME program. Kosan is confident that an alternative supportive trial can be completed within the timeframe of the TIME-1 trial and will not affect the timeline for conclusion of the TIME registration program.

"The opening of our TIME-1 pivotal trial is a major milestone for Kosan as tanespimycin represents a potentially important new treatment option for patients with multiple myeloma," said Robert G. Johnson, Jr., M.D., Ph.D., president and chief executive officer, Kosan. "We are confident that by making this adjustment now in our TIME program, we will accomplish three major objectives: with a different supportive trial design, we will make TIME a better and stronger registration program; we will preserve a reasonable and timely pathway to regulatory approval; and, by focusing on patients with less advanced disease who have been less heavily pretreated, we will increase the probability of success in our new supportive TIME trial. The successful completion of TIME-1 remains the foundation of our registration strategy."

The TIME-1 trial is an open-label, randomised, multi-centre, international trial that will enrol approximately 470 patients with first-relapse disease. The trial will compare two groups: patients treated with bortezomib plus tanespimycin and patients treated with bortezomib alone. Tanespimycin will be administered in a one-hour infusion twice weekly every three weeks at a dose of 340 mg/m2 and all patients will receive standard doses of bortezomib (1.3 mg/m2). The TIME clinical program will utilize Kosan's improved, proprietary, injectable suspension formulation of tanespimycin. TIME-1 is designed with a primary endpoint of progression-free survival (PFS), and there are several predefined secondary endpoints. TIME-1 is powered to show a 2.75 month PFS benefit in the tanespimycin plus bortezomib group compared to the bortezomib alone group.

The TIME-2 supportive trial, that was originally designed to enrol approximately 130 patients, will be closed and replaced with a new supportive trial in patients with less advanced disease.


Kosan's TIME registration program is the company's most advanced program in its clinical portfolio and tanespimycin is the most advanced Hsp90 inhibitor in clinical development. Tanespimycin has demonstrated high tolerability and antitumour activity in patients with multiple myeloma as monotherapy and in combination with Velcade. Data from an ongoing Phase 1b trial suggest that the combination with Velcade has greater activity in patients who have received fewer prior regimens than those who were more heavily pretreated. A recent analysis of the phase 1b data comparing patients who had three or fewer prior regimens with patients who received four or more prior regimens supports the conclusion that less heavily pretreated patients were more likely to demonstrate an objective response than patients with four or more prior regimens. The data showed that 60 per cent of the patients with three or fewer prior regimens had objective responses while only 22 per cent of the patients with four or more prior regimens had a response. Data from the phase 1b trial also suggest that the combination may exert a neuroprotective effect.

In addition to the activity and tolerability of the tanespimycin combination in multiple myeloma, tanespimycin has also demonstrated potent antitumor activity and a high level of tolerability in patients with HER2-positive metastatic breast cancer. Data from an ongoing phase II trial of tanespimycin plus trastuzumab (Herceptin) were recently presented at the 2007 San Antonio Breast Cancer Symposium showing a 55 per cent clinical benefit in patients who had failed trastuzumab therapy prior to entering the trial.

Kosan's second-generation Hsp90 inhibitor, alvespimycin, has demonstrated encouraging antitumor activity (42 per cent clinical benefit) and tolerability combined with trastuzumab in a phase I clinical trial in patients with refractory HER2-positive metastatic breast cancer, and in patients with refractory ovarian cancer who were progressing on standard chemotherapy. Kosan has expanded this phase I trial to include the combination of alvespimycin plus trastuzumab and paclitaxel (Taxol). In the first quarter 2008, Kosan plans to initiate a phase II trial of alvespimycin as monotherapy in patients with HER2-positive metastatic breast cancer who have not previously been treated with trastuzumab.

Kosan's lead epothilone clinical candidate, KOS-1584, has demonstrated promising antitumor activity and tolerability in patients with solid tumours, including non-small cell lung, ovarian and pancreatic cancers. Kosan plans to initiate a Phase 2 trial of KOS-1584 in non-small cell lung cancer in the first quarter of 2008.

In addition to its lead programs in Hsp90 inhibition and epothilones, Kosan's motilin agonist, KOS-2187, licensed to Pfizer, is progressing in a phase 1 trial as a potential treatment for gastroesophageal reflux disease (GERD) and other gastrointestinal disorders. In 2008, Kosan plans to file investigational new drug (IND) applications for its next-generation epothilone, KOS-1803, and its novel nuclear export inhibitor, KOS-2464.