HCT 3012 - COX-Inhibiting Nitric Oxide-Donator (CINOD) for Relief of Pain and Inflammation

Developed by French pharmaceutical company NicOx SA, naproxcinod (HCT3012) is the first in a new class of analgesic and anti-inflammatory drugs called COX-inhibiting nitric oxide donators (CINODs). It is indicated for the treatment of acute and chronic nociceptive pain, such as post-operative and arthritic pain.

Naproxcinod (HCT3012) is the company's lead product and is currently in phase III development. Subject to a satisfatory outcome, the company hopes to submit a New Drug Application (NDA) in the first quarter of 2009.

CINODs REPRESENT A NEW CLASS OF ANALGESIC AGENTS

Inhibition of cyclo-oxygenase (COX) enzymes, of which there are two (COX-1 and COX-2), is the basic mode of action of the non-steroidal anti-inflammatory drugs or NSAIDs. Naproxcinod (HCT3012) is an entirely new chemical entity which provides balanced inhibition of COX enzymes while also donating nitric oxide (NO) at sites of inflammation. This mode of action may reduce inflammation, as NO is known to exert a relaxing effect on endothelial cells. Donation of NO may also have a protective effect on the gastrointestinal tract and other organs. Damage to the gastrointestinal tract is a known side effect of conventional NSAID use and is believed to be associated with inhibition of COX-1.

EFFICACY AND SAFETY IN ACUTE AND CHRONIC PAIN

Data showing early evidence of the efficacy and safety of naproxcinod (HCT3012) was first presented in 2002. The drug has now advanced to phase III development, where it is being investigated in three pivotal trials (301, 302, and 303) designed to investigate its efficacy and safety in patients with osteoarthritis. Studies 302 and 303 are now underway following promising results from study 310, in which treatment with naproxcinod (HCT3012) showed superior efficacy to placebo in patients with knee osteoarthritis. It also emerged with a differentiated and potentially beneficial blood pressure profile in comparison with the widely used NSAID naproxen.

While ongoing study 302 will also investigate the safety and efficacy of naproxcinod (HCT3012) in knee osteoarthritis, study 303 is designed to demonstrate its efficacy in relieving the signs and symptoms of osteoarthritis of the hip as well as to provide additional safety data. In this 800-patient trial, patients will be randomized to twice daily naproxcinod 750mg, naproxen 500mg, or placebo.

OASIS STUDY POINTS TO CARDIOVASCULAR SAFETY

Data from the phase II OASIS trial, in which 6-weeks treatment with naproxcinod (HCT3012) proved comparable to the COX-2 specific inhibitor rofecoxib in ameliorating pain in OA patients, also showed no evidence of increases in blood pressure in the naproxcinod (HCT3012) treatment arm. This was in contrast to rofecoxib, which at equi-equivalent doses was associated with a significant increase in systolic blood pressure.

It has been suggested that, via NO release, CINODs may be able to counteract the detrimental effects of COX inhibition on blood pressure. Certainly, concerns have been raised about the cardiovascular safety of COX-2 specific inhibitors. NicOx has recently initiated a new US study to compare the effects of HCT 3012 with rofecoxib on arterial blood pressure in patients with mild hypertension.

MARKETING COMMENTARY

NSAIDs are the cornerstone of analgesia, providing relief from everyday pains such as headache, toothache, muscular aches, mild joint pain and period pain. Although highly effective, they are associated with gastrointestinal side effects and other adverse events. The need for safer NSAIDs has seen the development of second-generation COX-2 specific inhibitors, with improved gastrointestinal safety. CINODs represent third-generation compounds, with potential to provide improved gastrointestinal and cardiovascular safety.

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