A research collaboration that started in August 2003 came full circle when French company NicOx SA granted Merck & Co. Inc. exclusive worldwide development and marketing rights to nitric oxide-donating drugs for hypertension.

Worth up to $351.4 million for Sophia Antipolis-based NicOx, the deal includes €9.2 million in an up-front payment, as well as up to €279 million (US$340.2 million) in potential milestone payments.

"It really is a very significant agreement for us for a number of reasons," said Damian Marron, NicOx’s vice president of corporate development. "Clearly, one of those is the culmination of about two and a half years of drug research with Merck. It’s a very positive sign for how they view our technology and its capabilities in the cardiovascular arena."

Investors were pleased. The company’s stock (Eurolist:NICOX) soared 27.1 percent, or €1.80 March 21 to close at €8.44. It was the second time this month the shares got a boost. They jumped 79 percent, closing at €6.02, in the first week when NicOx signed a $400 million deal granting New York-based Pfizer Inc. ophthalmic application rights to its technology.

In the deal with Merck, NicOx retains an option to co-promote products to specialist physicians, such as cardiologists, in the U.S. and certain major European countries on a fee-for-detail basis. Merck also will pay the company undisclosed royalties on any sales that result.

"We’ve been quite open publicly that we want to transform ourselves into an integrated company with sales and marketing [capabilities] in the future," Marron said. He added that a cardiovascular sales force in the U.S. would require between 50 and 150 representatives.

"Our aim is to target specialists," he said. "We have to be realistic about what a company of our size can achieve."

Whitehouse Station, N.J.-based Merck and NicOx will focus on nitric oxide-donating derivatives of several major classes of antihypertensive agents to treat high blood pressure, complications of hypertension and other cardiovascular disorders. Merck holds exclusive rights in hypertension and nonexclusive rights for all other cardiovascular indications. Initially, they will work to identify lead candidates for development. Merck will fund and manage all preclinical and clinical development once the lead compounds are selected.

Since beginning their research collaboration, the parties have generated results showing that nitric oxide donation can improve the efficacy of antihypertensive agents in vivo. A prototype compound has demonstrated superiority over a widely used parent reference drug at lowering blood pressure in models of hypertension.

"What we are hoping," Marron said, "is that what we have seen in the animal models we can take through to man."

Current marketed hypertension therapies include beta blockers, ACE inhibitors, diuretics, angiotensin receptor blockers, calcium channel blockers, central alpha receptor agonists, peripheral alpha antagonists and vasodilators. The condition affects about 50 million people in the U.S., and about 1 billion people worldwide. Fewer than half of patients on antihypertensive therapy are able to get their blood pressure under control, NicOx said. They often need a combination of two or more drugs to find a benefit.

A new approach in antihypertensives involves renin inhibitors, but Marron said the data do not appear to "bring anything major in terms of better blood pressure control" to the competitive landscape.

Evidence has suggested that endothelial nitric oxide plays a role in controlling blood pressure when it is released from the lining of blood vessels. It also appears to work with the renin-angiotensin system in controlling vascular tone and kidney function.

When high blood pressure is not controlled, it can lead to an increased risk of heart failure, heart attack, stroke and kidney failure.

Aside from its partnerships with Pfizer and Merck, NicOx is working internally on two compounds, HCT 3012, which is in Phase III development for osteoarthritis; and NCX 4016, which is in Phase II for peripheral arterial obstructive disease. The latter met its primary efficacy endpoint in a Phase IIa study.

While current anti-inflammatory drugs, such as COX-2 inhibitors, are associated with increasing blood pressure problems, NicOx’s HCT 3012 is not and gives that product a competitive edge, Marron said.

"We’ve been able to indicate in our Phase II data that we saw no detrimental effect on blood pressure control, perhaps even a small benefit," he said.

Merck withdrew from the market in 2004 its COX-2 inhibitor, Vioxx, after a study indicated cardiovascular side effects in patients using the painkiller for 18 months or more.

The company’s collaboration with NicOx is "an important validation" of the technology, and a vote of confidence for HCT 3012, said Michele Garufi, NicOx’s chairman and CEO.

Phase III data should be available by the fourth quarter. NicOx expects the program to be complete and ready for regulatory submission in late 2008 or the first half of 2009. Until then, the company plans to find a commercial partner.

"We will partner when the deal is right for NicOx," Marron said. "We have the means to continue development quite comfortably without a partner at this stage."