By Lisa Seachrist

Washington Editor

The FDA has OK'd Onyx Pharmaceuticals Inc.'s Phase III pivotal trial design of its replicating virus therapy product, ONYX-015, in recurrent head and neck cancer.

Even though Onyx is still searching for a marketing and development partner, the Richmond, Calif.-based company intends to initiate the study in the fourth quarter of this year or early 2000 with or without a partner.

"We are in talks with potential partners," said Hollings Renton, president and CEO of Onyx. "We intend to complete a partnership agreement by the fourth quarter of this year, which would coincide with the start of the clinical trial. I'm optimistic about it."

Renton noted the company has about $20 million in cash, its approximate annual burn rate. "In order to fund a pivotal trial fully we will need a partnership or a financing," he said.

The pivotal trial plan to which the agency agreed is a randomized two-arm study of ONYX-015 in patients with recurrent head and neck tumors. ONYX-015 is an adenovirus that has been genetically engineered so it no longer inactivates the p53 tumor suppressor gene in normal cells. It is designed to replicate in and kill tumor cells deficient in p53 activity.

Loss of p53 function is the most common genetic abnormality in cancer. More than 50 percent of human cancers have this defect. Because chemotherapy often relies on an active p53 protein, ONYX-015 provides another avenue for destroying cancer.

Similar to the Phase II study of ONYX-015 that produced strong positive results, the Phase III study agreed upon will employ a treatment arm comprised of infusions of standard chemotherapy (5-fluorouracil and cisplatin) and ONYX-015 directly injected into tumors of the head and neck, and a control arm of chemotherapy alone. Patients who see their cancer progress on the chemotherapy-alone arm will be eligible to be treated with ONYX-015 and chemotherapy.

"The FDA has been very supportive all along of our efforts," Renton said.

The Phase III study will include 180 evaluable patients and 40 centers in the United States and Europe. The primary endpoint for the study will be progression-free survival and durable tumor responses. Secondary endpoints will include quality-of-life measurements and overall survival.

In the U.S., annual incidence of head and neck cancer is estimated by the American Cancer Society at 41,400 cases with 12,300 associated deaths. First-line therapy for localized head and neck cancer is typically surgery and adjuvant radiation. However, tumors recur in approximately one-third of patients following first-line therapy, at which point the cancer is considered incurable. Median survival for these patients with chemotherapy is approximately six months.

In addition to the lead indication of recurrent head and neck cancer, the company is testing the oncolytic virus in early Phase II studies in pancreatic cancer and colorectal cancer that has metastasized to the liver. ONYX also is exploring ONYX-015's use in preventing the preneoplastic conditions of Barrett's esophagus and oral leukoplakia from turning into cancer.

"The long-term goal is to move this product from an injectable product to an infusion," Renton said. "We just didn't want to jump in. We wanted to make sure we are doing this in a logical fashion. Non-small-cell lung cancer will be the lead indication in an infusible product."

Renton said the next step for the product would be to include anticancer genes in the virus, generating a second mechanism killing tumor cells.

"There's been a lot of attention for ONYX-015," Renton said. "But, this is really a platform for creating anticancer therapies, not just a product."

Onyx's stock (NASDAQ:ONXX) closed Tuesday at $8.875, up 6 cents a share.