Washington Editor

Onyx Pharmaceuticals Inc. and partner Bayer Corp. initiated a pivotal Phase III study in renal cell carcinoma with BAY 43-9006, a cancer candidate considered by some to be one of the most exciting products in development.

BAY 43-9006, also called 9006, is an orally active inhibitor of the enzyme Raf kinase. By inhibiting that enzyme, the companies believe 9006 blocks the Ras/MEK/ERK signaling pathways in cells, a key mediator of tumor cell proliferation.

Phil Nadeau, an analyst with SG Cowen Securities Corp., of New York, said physician consultants believe the 44 percent response and 15 percent partial response rates shown in interim Phase II data of 9006 in renal cell carcinoma is "exciting," and better than certain data produced by Avastin, Genentech Inc.'s candidate for colorectal cancer.

Bill Tanner, managing director at Leerink Swann & Co., of New York, released a prepared statement saying, "9006 represents one of the more exciting agents in development for the treatment of cancer, positioning Onyx as one of the most attractive names in mid-cap biotech."

Onyx's stock (NASDAQ:ONXX) fell $1.48 Monday to close at $23.28. Bayer Corp., of Pittsburgh, is a subsidiary of Leverkusen, Germany-based Bayer AG.

Company officials at Onyx held a conference call Monday to discuss positive Phase II interim data on the open-label part of the trial, and to announce commencement of Phase III work.

"In 12 short months, 9006 has moved from the start of a Phase II trial to beginning a pivotal Phase III with an SPA [Special Protocol Assessment] in place," Hollings Renton, Onyx's chairman and CEO, said during the call. "This rapid progress demonstrates Bayer's capabilities and commitments." (An SPA is an agreement with the FDA on the design and size of clinical trials, which, given positive results, could support a new drug application.)

Renton said the Phase II trials reached the goal of helping the partners identify initial single-agent Phase III indications, and Renal cell carcinoma [RCC] stood out as the obvious choice.

The interim Phase II data for 9006 were presented at the Second International Signal Transduction meeting Saturday in Amsterdam, the Netherlands.

Scott Freeman, vice president of clinical development at Onyx, took conference call listeners through the basics of the Phase II, reminding everyone that the data are early and subject to confirmation.

Nevertheless, the five-center randomized discontinuation study consisted of two 12-week phases. The initial analysis included 41 patients with advanced and progressive RCC who were evaluable after 12 weeks of treatment.

According to the companies, 44 percent had tumor shrinkage of at least 25 percent, and 29 percent had tumors stabilize within 25 percent of pretreatment size. Overall, the companies said, 73 percent did not demonstrate tumor progression by the 12-week evaluation point.

To enter the Phase II, Freeman said patients must have failed at least one prior systemic treatment and had progressive disease on study entry.

Participants in the Phase II with RCC are part of a larger study population totaling 342 patients with advanced refractory progressive solid tumors of multiple types, including RCC, melanoma, colorectal and others, such as pancreas, ovarian and breast.

Julie Wood, vice president, corporate communications and investor relations for Onyx, told BioWorld Today she's not sure when the Phase II will be completed, but said the company expects to have a significant amount of incremental data. It is possible that certain data could be presented at June's American Society of Clinical Oncology annual meeting.

The Phase III study will include 800 people at 100 sites worldwide. Participation is limited to patients with unresectable and/or metastatic disease who have failed a previous systemic therapy.

The primary endpoint is improvement in survival. The study also will assess time-to-disease progression, overall response rate, safety, quality of life and the pharmacokinetics of 9006.

Tanner estimates that the Phase III likely will be fully enrolled by the end of 2004. With a 12-month follow-up, he said, the last patient might be finish observation by the end of 2005, meaning the NDA could be filed in the first half of 2006 with FDA approval in late 2006.

However, he said, the timeline could speed with rapid recruiting and such mechanisms as FDA fast-track designation and accelerated approval.

Whatever the case, initiation of the Phase III means Bayer owes Onyx a $15 million milestone.

Under their arrangement, Onyx is bound to pay 50 percent of development costs. Onyx would share U.S. profits equally, but elsewhere, except Japan, Onyx's share would be less than 50 percent, since Bayer has exclusive rights. In Japan, Bayer will fund product development and Onyx would receive a royalty based on sales.

Aside from the Phase III milestone, the agreement also includes milestone-based, interest-free loan payments, including a $5 million loan that Onyx received in the third quarter of 2002 at the beginning of Phase II trials, a $10 million payment when the companies file for regulatory approval and $10 million upon approval. (See BioWorld Today, June 13, 2003.)

Twice in 2003, Onyx reduced itself, cutting its staff from 95 to 20. The first reduction was in January after the company lost Warner-Lambert Co. as a partner in the development of cancer drug ONYX-015, a modified adenovirus. At that point, the company let go 25 percent of its staff. (See BioWorld Today, Jan. 28, 2003, and Sept. 18, 2003.)

And in June, the company shaved the staff to 20, in an effort to focus on BAY 43-9006. (See BioWorld Today, June 13, 2003.)