Providing leverage for a small-molecule program targeted at heart failure, Cytokinetics Inc. is collaborating with Amgen Inc. in a deal potentially worth $725 million.

The companies will work to discover, develop and commercialize small-molecule drugs that activate cardiac muscle contractility, and Thousand Oaks, Calif.-based Amgen has taken an option to participate in future development and commercialization of the program's lead candidate, CK-1827452.

Immediate money to Cytokinetics, of South San Francisco, includes $42 million in an up-front license and technology access fee, as well $33 million in proceeds from the sale of about 3.5 million shares to Amgen at $9.47 each. Contingent payments consist of a $50 million fee if Amgen exercises its option to develop CK-1827452, and up to $600 million in development and commercialization milestone payments for the product and others that come out of the program.

Robert Blum, Cytokinetics' president, said the deal is a significant catalyst for the heart failure program and the company's overall business.

"I'd say that this is transformative in many ways for our company because it affords us certain financial latitudes," he told BioWorld Today, "as we continue to build our pipeline not only in heart failure, but also for other research and development activities under way here."

If a product reaches the market, Cytokinetics is eligible for escalating royalties that increase as sales climb. It also could increase its royalty rate even higher by choosing to share in the Phase III development costs, earning a right to co-promote products in North America. If that happens, the company expects to play a large role in commercialization activities at institutional care facilities.

It has been a goal for the company to retain a commercial presence with its products, said the company's co-founder and CEO James Sabry.

Considering congestive heart failure affects about 5 million people in the U.S. and that 30 percent to 40 percent of discharged patients either die or are readmitted after treatment, the market potential for a new therapy would be large. In 2001, heart failure drugs brought in about $2.7 billion, and that figure is expected to grow to $4 billion by 2011, according to Cytokinetics.

"Ironically, there's relatively few new mechanistic approaches and new drugs being discovered or developed," Blum said.

While current drugs treat only symptoms and effects of the disease, Cytokinetics' program is "a totally novel mechanism for treating heart failure," Sabry said, explaining that it targets the underlying cellular mechanisms responsible for the disease.

CK-1827452 activates cardiac myosin, the cytoskeletal motor protein in the cardiac muscle cell that converts chemical energy into the mechanical force that results in cardiac contraction. The product currently is in Phase I trials, but is slated to enter an international Phase II program early in 2007.

Amgen will make its decision on whether to exercise the option to develop CK-1827452 once it meets certain criteria in Phase IIa trials, expected to occur within the next one to two years, Blum said. Cytokinetics can develop the product on its own, ending the research collaboration, if Amgen declines to take the option.

The Phase II program "will involve multiple Phase IIa clinical trials in different subpopulations of patients with heart failure and comorbidities," Blum said. Specifically, it will evaluate the safety and efficacy of the product in patients with stable heart failure, ischemic heart disease, impaired renal function, acutely decompensated heart failure, and those with chronic heart failure who are at an increased risk for death and hospital admission.

As CK-1827452 progresses through the clinic, Cytokinetics and Amgen will work to identify and characterize other activators of cardiac myosin as backup or follow-on compounds. Cytokinetics will conduct all development activities until Amgen decides whether to exercise its option.

The collaboration between the two companies is worldwide, excluding Japan, where Cytokinetics is seeking a separate partnership.

Cytokinetics chose Amgen as a partner because it shared a philosophy in which both companies are "focused on innovative products, new mechanism approaches," Blum said, later adding that "they're not a company that employs a fast-follower strategy. They are a company that takes risks and enjoys rewards from taking those risks."

Aside from its cardiovascular program, Cytokinetics has three programs in oncology, including ispinesib (SB-715992), which is in Phase II for breast cancer and various other cancers; SB-743921, which is in Phase I/II for non-Hodgkin's lymphoma; and GSK-923295, which is expected to enter Phase I studies in 2007.

All three products are part of a collaboration with London-based GlaxoSmithKline plc, originally signed in June 2001. The alliance is focused on therapies that target KSP - kinesin spindle protein - and other cytoskeletal proteins involved in cell proliferation.

Cytokinetics' stock (NASDAQ:CYTK) rose 11.5 percent, or 86 cents on Wednesday, to close at $8.34, while Amgen's stock (NASDAQ:AMGN) was up 9 cents, to close at $68.40.