By Frances Bishopp

Staff Writer

In a period of 10 days, NitroMed Inc., which develops products that produce therapeutic benefit through the delivery of nitric oxide to specific tissues and organs, entered into major collaborations with two Johnson & Johnson subsidiaries, Ortho Pharmaceutical Corp. and Cordis Corp.

The agreements are the first corporate collaborations for the Boston-based company, which was founded in 1993. On the Ortho alliance, NitroMed will collaborate with R.W. Johnson Pharmaceutical Research Institute (PRI), of Raritan, N.J., which is the research and development division of Ortho Pharmaceuticals.

Financial details of the deals were not disclosed.

Under the terms of the Ortho agreement, PRI, NitroMed and Ortho will develop a new generation of nonsteroidal anti-inflammatory drugs (NSAIDs) with an improved safety profile. The agreement stipulates that payments to NitroMed include an equity investment by the Johnson & Johnson Development Corp., of New Brunswick, N.J., licensing fees and sponsored research.

NitroMed will also receive additional research funds, milestone payments and royalties on products that proceed to market.

PRI, NitroMed and Ortho, of New Brunswick, N.J., will develop NSAID products which combine known NSAID compounds with nitric oxide (NO) donors to reduce the gastric toxicity associated with chronic use of NSAIDs. PRI will be responsible for clinical development and Ortho and affiliates will receive exclusive worldwide rights to market any development products. The agreement applies to both prescription and over-the-counter products.

NitroMed and Cordis, of Warren, N.J., will develop products for the treatment of cardiovascular disorders, initially focusing on coronary artery restenosis, using NitroMed's NO-based technology.

Under this agreement, funding by Cordis to NitroMed includes an equity investment, sponsored research, licensing fees, milestones and royalties.

Cordis and NitroMed will collaborate on coronary stents coated with NO donor groups to reduce restenosis following coronary angioplasty. Cordis has the exclusive worldwide rights to clinical development and marketing of any products resulting from the collaboration.

Nitric oxide, since its discovery 10 years ago as a signaling molecule, has demonstrated a broad range of biological functions, such as platelet inhibition, myocardial contractility, control of vascular tone and inhibition of vascular smooth muscle proliferation.

NO also governs protection of gastric mucosa, relaxation of the penile cavernosal smooth muscle underlying erectile response and signaling in the nervous system.

In the body, nitrogen monoxide functions in a number of reactive redox forms that act locally to influence specific biological processes.

While gaseous or uncharged forms of nitrogen monoxide regulate critical NO-mediated functions, they can also have deleterious effects when improperly controlled, including the unwanted killing of cells and induction of hypotension.

The challenge in development of NO-based pharmaceuticals has been to harness the activity of NO in a manner that enables efficient, targeted therapeutic impact without the toxic effects.

Manuel Worcel, president and CEO of NitroMed, explained that NitroMed's technology addresses this problem through the development of compounds designed to deliver other NO forms, in particular, positively charged nitrosonium ions (NO+), which have potent biological effects and a prolonged duration of action with a favorable safety profile.

The critical and unique feature of the company's technology, Worcel said, is the use of specifically designed small-molecule NO donors that deliver NO+ directly to key regulatory proteins in certain physiologic pathways.

Also, the NitroMed technology engineers NO+ to be delivered to defined targets, which avoid formation of toxic NO intermediates and address the challenge of NO's limited molecular specificity, while maintaining beneficial biological activity.

NitroMed, PRI and Ortho will work to develop oral NSAID drugs that contain NO molecules which, when delivered locally, stimulate physiologic pathways and protect gastrointestinal (GI) mucosa against NSAID-induced damage. Chronic use of NSAIDs can lead to life-threatening GI ulceration and hemorrhage.

NitroMed is pursuing two approaches to this problem: synthesis of several new chemical entities consisting of existing approved NSAIDs linked to NO donor groups (NO-NSAIDs) and co-administration of NSAIDs formulated with NO donor molecules.

NitroMed and Cordis will work to resolve restenosis by developing proteins and polymers containing NO donor groups to locally stimulate critical cardioprotective pathways.

NitroMed has demonstrated in animal models that a single application of NO-albumin at the time of vascular intervention inhibits restenosis, as do stents coated with NO-albumin, which significantly reduces the incidence of restenosis in stent-implanted carotid arteries.

"We reduce the risk of restenosis in animal models by 50 percent," Worcel said.

NitroMed also has development programs in myocardial infarction, male erectile dysfunction, asthma, pulmonary hypertension and stroke. *