NicOx Initiates Clinical Study to Evaluate HCT 3012 Effects on Blood Pressure Vs. Rofecoxib.

SOPHIA ANTIPOLIS, France -- NicOx (Nouveau Marche:NicOx) announces today that it has started a comparative clinical study to evaluate the effects of HCT 3012 and rofecoxib on arterial blood pressure in patients with mild essential hypertension. The aim of the study is to provide definitive proof of data observed in analysis of the OASIS pivotal Phase II trial in patients treated for osteoarthritis (see note 1). This analysis suggested that HCT 3012 decreased systolic blood pressure on average by 3mm Hg, while rofecoxib tended to raise systolic blood pressure by a similar extent (cf. 10 June press release). OASIS results have been accepted by the ACR (American College of Rheumatology) for a presentation at the annual scientific meeting in San Antonio (USA, October 16-21, 2004).

The potentially harmful effects of NSAIDs and coxibs due to a rise in arterial blood pressure are increasingly acknowledged. Even small increases of systolic blood pressure are associated with a significantly greater incidence of cardiovascular events as evidenced by the seventh report of the U.S. Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (see note 2). HCT 3012, through its unique mechanism of action, may potentially counteract the detrimental effects of COX inhibition on blood pressure and may prove to be beneficial in patients with osteoarthritis and concomitant cardiovascular risk factors.

This study will be conducted at the University of Pennsylvania, with Professor Garrett FitzGerald as the Principal Investigator. The trial (see note 3) is a cross-over, randomized, double-blind study in 50 hypertensive patients treated for 6 weeks with each of the trial medications. The primary objective is to assess whether rofecoxib 25 mg qd causes a significant increase in blood pressure compared to HCT 3012 375 mg bid (dose equiactive with rofecoxib 25mg qd). Results are expected in the first quarter of 2005.

Dr. Garrett FitzGerald of the Center for Experimental Therapeutics, University of Pennsylvania, said, "I am delighted to perform this study. HCT 3012 has already been shown to relieve pain in arthritis to a degree comparable with non-steroidal anti-inflammatory drugs. Elevations in blood pressure can complicate treatment with both traditional NSAIDs and newer drugs with greater selectivity for COX-2. Should the mechanism of action of HCT 3012 bypass this problem, it would be a clinically important improvement in the pharmacology of this class of widely-prescribed drugs."

Michele Garufi, Chairman and CEO of NicOx, added, "A broad Phase II programme, in more than 2700 patients, has already demonstrated that HCT 3012 is a potent and safe anti-inflammatory drug. We believe this study will further confirm the unique overall profile of the CINOD class, notably its superior cardiovascular effects. As clinicians become increasingly aware of the cardiovascular risks related to current COX-2 selective therapies, we believe there is a significant need for improved choices for patients at cardiovascular risk, who account for more than 40% of the osteoarthritic population."

NicOx S.A. is an emerging pharmaceutical company involved in the research and development of nitric oxide-donating drugs with superior efficacy and safety profiles in the inflammation, pain and cardiovascular therapeutic areas.

NicOx seeks to commercialize its products through partnerships and co-development agreements where it maintains future marketing rights for specialist products.

NicOx S.A. (Bloomberg: COX:FP, Reuters: NCOX.LN), headquartered in Sophia-Antipolis, France, is a public company listed on the Nouveau Marche of Euronext Paris (segment: Next Economy).

The elements included in this communication may contain forward looking statements subject to certain risks and uncertainties. Actual results of the company may differ materially from those indicated in the forward-looking statements because of different risks factors described in the company's document de reference.

Technical Notes:

(1) Abstract ID # 1859:

AZD3582, a CINOD, differs significantly from Rofecoxib in having a Neutral Effect on Blood Pressure in Patients with Osteoarthritis: Results of a randomized controlled trial 

Thomas Schnitzer(1), Maria Ballabio(2), Erminio Bonizzoni(3). (1)Northwestern University Feinberg School of Medicine, Chicago, IL; (2)NicOx S.A., Sophia Antipolis, France; (3)Institute of Medical Statistics and Biometry, Milan, Italy

Purpose: The relevance of potentially harmful effects of anti-inflammatory drugs (NSAIDs and COXIBs) as a consequence of raising arterial blood pressure is increasingly acknowledged. Novel COX-inhibiting nitric oxide donators (CINODs) have been recently developed to provide a dual mechanism of COX inhibition and controlled nitric oxide release. Through NO release, they may potentially counteract the detrimental effects of COX-inhibition on blood pressure.

Methods: Two randomized, double-blind studies have been conducted to evaluate the efficacy and safety of the first compound of CINOD class, AZD3582 (NO-naproxen), in patients with osteoarthritis. 672 and 543 patients, respectively, with symptomatic knee/hip OA were enrolled and treated with AZD3582 at different doses, naproxen 500mg bid, rofecoxib 25mg qd (R) or placebo for 6 weeks. For cardiovascular safety, systolic blood pressure (SBP) was measured at baseline and at multiple time points throughout the 6 week treatment period.

Results: AZD3582 at doses of 375mg and 750mg bid showed a significantly superior analgesic activity compared to placebo and were equi-efficacious to naproxen and rofecoxib. At 6 weeks, mean supine SBP decreased from baseline with both doses of AZD compared to an increase with R. In the 1st study ANCOVA showed statistically significant LS differences between AZD and rofecoxib: R vs. AZD at 375mg bid: 5.9 mmHg (95%CI 2.3, 9.5); R vs. AZD at 750mg bid: 4.2 (0.69, 7.7). Furthermore, in the subset of patients with hypertension (38.4% of total) changes of SBP were more relevant: R vs. AZD at 375mg bid: 7.5 (1.4, 13.6), p=0.015; R vs. AZD at 750mg bid: 7.2 (1.2, 13.3), p=0.018. Similar findings were observed in the 2nd study. Baseline SBP was 135.5 (1.6) mmHg in AZ 750mg bid and 136.4 (1.6) in R 25mg qd, while 6-week values were, respectively, 133.4 (1.7) and 139.4 (1.7).

Conclusions: These results indicate that equi-analgesic doses of AZD3582 and rofecoxib exert opposite effects on systolic blood pressure after long term treatment, especially in hypertensive patients. Since even small increases of blood pressure are associated with significantly increased frequency of cardiovascular events, AZD3582 may prove to be beneficial in patients with osteoarthritis and concomitant cardiovascular risk factors.

(2) Joint National Committee; JNC 7, JAMA, 2003, 289, 2560-2572(3)

(3) After a screening/run-in of 2-4 weeks, patients will be randomized, in double-blind fashion, to receive either rofecoxib 25 mg qd or HCT 3012 375 mg bid for 6 weeks, followed by 2-week wash-out and, subsequently, by the alternate treatment for a further 6 weeks. The effects of the study treatment of blood pressure will be evaluated through continuous 24 hour BP monitoring at baseline, end of first 6-week treatment, end of 2-week wash-out, and at the end of the second 6-week treatment.