Nitronaproxen: AZD 3582, HCT 3012, Naproxen Nitroxybutylester, NO-Naproxen

Nitronaproxen [AZD 3582, HCT 3012, naproxen nitroxybutylester, NO-naproxen] is a naproxen derivative with similar anti-inflammatory activity to the parent compound, but with less gastrointestinal toxicity. It is the first of a new class of analgesic and anti-inflammatory drugs known as cyclo-oxygenase-inhibiting nitric oxide donators (CINODs), which are under development by NicOx. The better gastrointestinal tolerability of nitronaproxen appears to be due to its release of nitric oxide (NO) and the consequent maintenance of tissue perfusion and integrity. Nitronaproxen is in phase III clinical development for the treatment of osteoarthritis and is available for licensing. AstraZeneca had been a worldwide licensee for nitronaproxen and other CINODs. However, the results of phase II clinical trials of nitronaproxen did not fulfill AstraZeneca's strategic commercial criteria for further investment and NicOx reacquired rights following AstraZeneca's decision to discontinue its involvement in 2003. NicOx was surprised by AstraZeneca's decision, and remained fully convinced of the potential of nitronaproxen. NicOx is seeking new partners for development of compounds of the CINOD class. Nitronaproxen is in a phase III clinical trial for the treatment of osteoarthritis (OA) of the knee. The 13-week trial completed enrolment of 820 patients from 120 clinical sites in the US in May 2006. The study is designed to confirm that nitronaproxen is superior to placebo and is as effective as naproxen in relieving signs and symptoms of OA. The study will also seek to show that nitronaproxen has no adverse effect on blood pressure. An additional trial has begun that is employing ambulatory blood pressure monitoring to provide a description of the blood pressure effect of nitronaproxen over a 24-hour period in hypertensive subjects. This US trial will enrol approximately 120 volunteers with stable essential hypertension. The volunteers will not have osteoarthritis but will be between the ages of 50 and 75 years (representative of the osteoarthritis population). Results from both trials are expected in the fourth quarter of 2006. The phase II clinical programme for nitronaproxen, which included 2709 patients in five separate clinical studies, showed that the drug is a potent, safe anti-inflammatory agent, with potential for improved cardiovascular safety over NSAIDs and COX-2 selective NSAIDs. An independent advisory board recommended further development of nitronaproxen in the treatment of osteoarthritis in 2004 based on an evaluation of the full results of the phase II clinical programme.A clinical study had begun in September 2004 at the University of Pennsylvania in patients with mild essential hypertension, in which the effects of nitronaproxen and rofecoxib on arterial blood pressure would be compared. However, rofecoxib was withdrawn worldwide on 1 October 2004. It is unclear if the trial was completed. The STAR Multinational Study Group has conducted a phase II gastrointestinal safety and efficacy study of nitronaproxen versus naproxen in 970 patients with osteoarthritis at 80 sites in the following countries: Argentina, Brazil, Hungary, Mexico, Norway, Poland, South Africa and the UK. The study was completed in November 2002. AstraZeneca conducted a randomised, phase II trial evaluating the efficacy and safety of nitronaproxen among 672 subjects with symptomatic knee osteoarthritis. Results have been presented. Certain phase II trial data from 2003 had been somewhat disappointing. However, an underpowered trial and failures and deficiencies in a trial meant that it was not possible to draw conclusions from this data.