Washington Editor

Onyx Pharmaceuticals Inc. and Bayer Pharmaceuticals Corp. plan to file for FDA approval of BAY 43-9006, which has been renamed sorafenib, based on interim Phase IIII data from a study in advanced kidney cancer patients.

"The progress announced today represents a clinical milestone in the development of targeted cancer therapy for patients with kidney cancer," Onyx Chairman, President and CEO Hollings Renton said during a conference call. "This is the first randomized study demonstrating that an oral targeted agent significantly delays disease progression in patients with advanced renal cancer."

That news generated investor excitement, as shares in Onyx (NASDAQ:ONXX) traded in double-digit percentages during premarket hours before settling at $33.25 as the market closed Monday, a gain of 45 cents.

The partners expect to prepare a new drug application for possible accelerated approval following a review of the pivotal study's safety and efficacy data by an independent data monitoring committee, which concluded that the trial has met its surrogate endpoint. The statistically significant findings revealed longer progression-free survival in patients treated with the investigational drug compared to placebo.

The decision to file for approval based on interim Phase III data was made six months after the companies said they would not file for approval based solely on Phase II findings. That news caused Emeryville, Calif.-based Onyx's stock to lose $13.47 in a fall to $27.34, a year after the partners trumpeted interim Phase II data. (See BioWorld Today, Oct. 28, 2003, and Oct. 26, 2004.)

Nevertheless, as previously agreed to with the FDA, Onyx and Bayer will continue the pivotal study to its primary endpoint of overall survival. The multinational, placebo-controlled trial recently completed enrollment of more than 800 patients. Entry criteria included clear-cell histology and a failure of one prior systemic treatment within eight months of beginning the trial.

In addition to survival, it was designed to evaluate disease progression, overall response rate and safety. The study began late in 2003 under the FDA's special protocol assessment process, and patients whose disease progressed while on the drug can continue the treatment as the drug might slow the rate of their progression.

"Subsequent to preparing and submitting a new drug application, and assuming a favorable review by the FDA," said Leonard Post, Onyx's senior vice president of research and development, "we could commercially launch sorafenib in 2006."

The partners are in a first-to-market race with New York-based Pfizer Inc.'s SU011248 (Sutent). A European filing for sorafenib likely would follow the coming FDA submission, and include full Phase III data.

Sorafenib operates by way of multiple mechanisms and exhibits both anti-proliferative and anti-angiogenic properties. Preclinical models demonstrated its inhibition of tumor cell proliferation by targeting the RAF/MEK/ERK signaling pathway at the level of the RAF kinase. The drug also exerted an anti-angiogenic effect by targeting the receptor tyrosine kinases VEGFR-2 and PDGFR and their associated signaling cascades. In addition, sorafenib also inhibited other tyrosine kinases, including FLT-3 and c-KIT.

It has been named a fast-track product by the FDA.

To advance the product, Onyx in 2003 significantly pared its operations to focus solely on co-developing sorafenib. The company laid off most of its staff and assigned its remaining employees to work with Bayer on the compound. (See BioWorld Today, June 13, 2003.)

Earlier this month, Onyx and Bayer, of West Haven, Conn., began testing sorafenib in a Phase III study of liver cancer patients. More than 500 patients will be randomized per the design of the trial, which will measure differences in survival, time to symptom progression and time to tumor progression compared to placebo. Other plans are being drawn up for a pivotal trial of the drug in combination with chemotherapy for metastatic melanoma. (See BioWorld Today, March 9, 2005.)

In two months, the partners intend to report the kidney cancer trial's findings at the American Society of Clinical Oncology meeting in Orlando, Fla.