Naproxcinod is NicOx’ lead product, in phase 3 clinical development for the treatment of the signs and symptoms of osteoarthritis. It is a unique nitric oxide-donating anti-inflammatory and the first of the CINOD class (COX-Inhibiting Nitric Oxide Donators).

NicOx aims to develop naproxcinod as a powerful anti-inflammatory agent with no detrimental effects on blood pressure and good gastrointestinal tolerability and safety.

Top-line results from the first phase 3 study were successful. This represents an important step towards NicOx’ goal of making naproxcinod the drug-of-choice for osteoarthritis patients.

Millions of people rely on non steroidal anti-inflammatory drugs (NSAIDs) to treat chronic pain and inflammation relating to a range of conditions, including osteoarthritis. COX-2 selective NSAIDs and also non-selective NSAIDs, have recently been linked to an increased risk of serious cardiovascular events, such as heart attack and stroke, creating a pressing need for new drugs with improved safety profiles. This demand is particularly acute among patients with coexisting cardiovascular risk factors, such as hypertension, who represent around 40% of osteoarthritis sufferers.

In October 2006, NicOx announced top-line results from the first pivotal phase 3 trial for naproxcinod. This study (the 301 trial) randomized 918 patients with osteoarthritis (OA) of the knee at 120 clinical sites in the United States. The results confirmed that naproxcinod is superior to placebo in relieving the signs and symptoms of osteoarthritis. In addition, naproxcinod showed a clear and sustainable effect of lowering blood pressure and had good safety and tolerability.

A month later, NicOx communicated the top-line results of a non-pivotal study, using the Ambulatory Blood Pressure Monitoring (ABPM) technique in 131 hypertensive subjects. This ABPM trial demonstrated a differentiated and favorable 24 hour blood pressure profile for naproxcinod, compared with naproxen, after 2 weeks of treatment.

NicOx believes that naproxcinod will have a significant market potential if its non-negative blood pressure profile in contrast to existing NSAIDs is confirmed. This is based on the fact that the increase in blood pressure seen with existing NSAIDs is viewed as one of the potential factors responsible for the apparent heightened risk of serious cardiovascular events observed with these agents.

However, recent clinical findings have cast significant doubt on the cardiovascular safety of the COX-2 inhibitors (and the whole NSAID class) following their association with an increased risk of serious cardiovascular events, such as heart attack and stroke. These concerns led to the market withdrawal of the COX-2 selective NSAIDs rofecoxib and valdecoxib. An FDA Advisory Committee meeting was held in February 2005 to discuss these issues and the FDA subsequently requested that the labeling of all drugs in the NSAID class should carry a ‘black-box’ warning highlighting the cardiovascular and gastrointestinal risks associated with these products. Additionally, a statement was added to the warnings section of the labels, stressing that all these drugs can lead to onset of new hypertension (high blood pressure) or worsening of pre-existing hypertension and should be used with caution in patients with hypertension.

The phase 3 efficacy program for obtaining regulatory approval for naproxcinod in the United States (US) and Europe consists of the following three pivotal phase 3 studies:

301 study:

The 301 study was the first clinical trial in the phase 3 program for naproxcinod. This study reported top-line results in October 2006 and was a 13-week, double-blind, placebo and naproxen-controlled trial in 918 patients with osteoarthritis of the knee that were enrolled in 120 centers in the United-States. Eligible patients were randomized to one of four treatment groups: naproxcinod 375 mg bid, naproxcinod 750 mg bid, naproxen 500 mg bid or placebo bid.

Both naproxcinod doses (375 mg bid and 750 mg bid) were shown to be superior to placebo on all three co-primary endpoints of the study, with this being highly statistically significant (p<0.001). The three co-primary endpoints were the mean change from baseline at week- 13 in the following scores: the WOMAC™ pain subscale, the WOMAC™ function subscale and patients’ overall rating of disease status. Superiority comparisons versus placebo on these co-primary endpoints conforms with FDA guidance for demonstrating the efficacy of new drugs for treating the signs and symptoms of osteoarthritis.

Naproxcinod showed good overall safety; 46.7% of the patients treated with naproxcinod 750 mg bid and 40.8% on naproxcinod 375 mg bid experienced at least one adverse event, compared to 56.4% on naproxen 500 mg bid and 38.7% on placebo. The number of serious adverse events was low and evenly spread among treatment groups. Blood pressure data for both naproxcinod doses showed a sustained reduction versus baseline and naproxen at all time points (see below). The number of adverse hypotensive events was low across all treatment groups. The 301 study has a long term extension which will provide further safety data.

302 study:

In December 2007, NicOx completed enrollment in the second pivotal phase 3 study for naproxcinod. Initiated in April 2007, the 302 study is a 53-week, randomized, double-blind, efficacy and safety trial in which 1020 patients with osteoarthritis of the knee have been enrolled at 150 clinical sites throughout the United-States. Efficacy results are anticipated in the third quarter of 2008. Patients have been randomized to one of the following treatment groups: naproxcinod 375 mg bid (52 weeks), naproxcinod 750 mg bid (52 weeks), naproxen 500 mg bid (52 weeks) and placebo bid during the first 13 weeks. After 13 weeks, the placebo treated patients are being randomized to either naproxcinod 375 mg bid or naproxcinod 750 mg bid for the remainder of the trial (39 weeks).

The two doses of naproxcinod will be compared to placebo on the three co-primary efficacy endpoints which are the same as those used in the two other pivotal phase 3 studies . A secondary endpoint of the trial will compare the efficacy of naproxcinod and naproxen at 26 weeks. The general safety and tolerability of naproxcinod will be assessed until week-52 and the trial has a 1-week post-treatment safety period..

303 study:

In June 2007, NicOx initiated the third and final pivotal phase 3 trial in NicOx' planned clinical development program for naproxcinod. The 303 study is a 13-week, double-blind, placebo and naproxen controlled trial in patients with osteoarthritis of the hip. This efficacy and safety clinical trial is expected to enroll approximately 800 patients at around 100 clinical centers in the United States, Canada and Europe and efficacy results are anticipated by the end of 2008. Eligible patients will be randomized to three arms: naproxcinod 750 mg bid, placebo bid and naproxen 500 mg bid.
Three co-primary endpoints will compare the efficacy of naproxcinod to placebo, based on the mean change between baseline and week 13 in the following scores: the WOMACTM pain subscale, the WOMACTM function subscale and the subject's overall rating of disease status. In addition, other variables will be measured in order to assess the general safety and tolerability of naproxcinod.

In addition to confirming the efficacy of naproxcinod, the phase 3 program is designed to show that it has no detrimental effect on blood pressure, in contrast to naproxen, a currently marketed NSAID. Patients' blood pressure was and will be measured during each of the phase 3 trials by using controlled office blood pressure measurements (OBPMs) during each visit to the treatment center. NicOx plans to conduct a predefined statistical analysis of the pooled blood pressure data from these three studies (including the completed 301 study and the currently running 302 and 303 studies).

Both hypertensive and non-hypertensive patients were enrolled in the 301 study and the blood pressure effect of naproxcinod was compared to both naproxen and placebo on a number of blood pressure endpoints. In the overall patient population, a key blood pressure endpoint was based on the difference between the systolic blood pressure measurements at baseline and the mean of the measurements at week 2, 6 and 13. A number of other endpoints were based on the change in systolic and diastolic blood pressure from baseline, as well as the number of patients who initiated treatment with antihypertensive medication. A top-line analysis of these blood pressure endpoints demonstrated that both naproxcinod 750 mg bid and 375 mg bid had no detrimental effects on blood pressure and decreased systolic and diastolic blood pressure, versus baseline and compared to naproxen. Naproxcinod's beneficial blood pressure profile was sustained until the 13-week time point. At week-13, the results showed a difference in systolic blood pressure from baseline, corrected for placebo, of approximately -0.5 mm Hg for naproxcinod 375 mg bid, -1 mm Hg for naproxcinod 750 mg bid and +2 mm Hg for naproxen. In terms of diastolic blood pressure, the differences from baseline, corrected for placebo, were approximately -1 mm Hg for naproxcinod 375 mg bid, -1.5 mm Hg for naproxcinod 750 mg bid and +0.5 mm Hg for naproxen.

Blood pressure related assessments that are being made in the hypertensive subpopulation include the number of patients who needed to switch or increase the dose of their ongoing antihypertensive treatment, in addition to the number of patients whose classification of hypertension changed from adequate to borderline or uncontrolled. There were also a number of endpoints based on changes in systolic and diastolic blood pressure from baseline.

Various blood pressure endpoints will compare the different treatments in terms of the mean change from baseline in systolic and diastolic blood pressure at a range of time points. Additional blood pressure endpoints will also assess the appearance of new hypertension or worsening of pre-existing hypertension.

NicOx designed the ABPM study to provide complementary blood pressure data to the phase 3 program for naproxcinod by using the Ambulatory Blood pressure Monitoring (ABPM) technique. This involves using a portable device to independently measure and record subject’s blood pressure at frequent intervals over a 24-hour period. Top-line results from this trial showed a differentiated and favorable 24 hour blood pressure profile for naproxcinod, compared to naproxen, after 2 weeks of treatment in hypertensive subjects.

The ABPM trial was a pharmacodynamic, double blind, cross-over study, where 131 volunteer subjects with stable essential hypertension were enrolled at 15 active clinical centers in the United States. These subjects were between the age of 50 and 75, in order to be representative of the osteoarthritis population. They were randomized to one of two groups: around half were administered with 750 mg of naproxcinod, twice-daily, for 14-days, followed by 500 mg of naproxen, twice-daily, for 14 days and the other half received the compounds in the opposite order. Placebo was administered during wash-out periods.

NicOx announced the top-line results from the ABPM trial in December 2006, which showed a 2 mmHg difference in both the average systolic and diastolic blood pressure in favor of naproxcinod, in terms of the mean change from baseline as measured by ABPM. This difference did not reach statistical significance for systolic blood pressure, the primary endpoint of the trial (p=0.101). However statistical significance was achieved for diastolic blood pressure, which was an important secondary endpoint (p=0.007). The study also showed a clear and positive differentiation in the blood pressure curves for naproxcinod compared to naproxen when viewed over 24 hours. The analysis of additional secondary endpoints is currently ongoing. The number of adverse events was low across both active treatment periods.

These top-line results are consistent with what was observed after 2 weeks of treatment in the 301 study. The OBPMs taken during the first pivotal phase 3 study showed a reduction in systolic and diastolic blood pressure versus baseline and naproxen. This effect was sustained over the full 13 weeks of the study, although the maximal difference for systolic blood pressure was only reached at the 6 and 13 week time points.

In addition to the recent cardiovascular safety concerns surrounding the NSAID class, these products have long been associated with gastrointestinal side effects, ranging in severity from gastric discomfort to potentially life threatening bleeding. NicOx intends to confirm the good gastrointestinal tolerability and safety profile of naproxcinod, as part of its plans to establish this product as the drug of choice for the treatment of signs and symptoms of osteoarthritis.

Based on interactions with the Food and Drug Administration (FDA), NicOx believes that its global clinical development program outlined above, is adequate to satisfy current requirements in the United States with regards to demonstrating the efficacy and safety of naproxcinod for treating the signs and symptoms of osteoarthritis.

In the context of the recent concerns regarding the cardiovascular safety of the NSAID class, the FDA has examined the non-clinical, pharmacokinetic and clinical data concerning naproxcinod and COX inhibition that was submitted by NicOx. The US authority provided feedback in November 2006 and notified NicOx that a large clinical cardiovascular outcomes study would not be required for naproxcinod at the time of New Drug Application (NDA) submission. Thus, based on the information available at this time, NicOx’ clinical development program is expected to provide a security database adequate for NDA submission.

The FDA’s feedback on the safety database requirements from naproxcinod is consistent with scientific advice received from the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMEA) in October 2006. The European authority stated that it agrees with NicOx’ pre-approval safety database proposal for naproxcinod, which does not include a long-term cardiovascular safety study. The CHMP also commented on the design of NicOx’ phase 3 clinical program for naproxcinod, in terms of demonstrating the product’s efficacy and assessing its blood pressure effect compared to existing anti-inflammatory agents.

Currently, NicOx expects to  file a New Drug  Application  (NDA)  in  the US for naproxcinod in mid-2009.

In a successful phase 2 program, involving 5 separate clinical trials and a total of 2709 patients, naproxcinod demonstrated equal efficacy to existing NSAID and COX-2 inhibitors (rofecoxib and naproxen were used as comparators in the trials). Significantly, naproxcinod also appeared to show no unwanted increase in blood pressure, in contrast to the comparator drugs, especially in hypertensive patients. The results also indicated that naproxcinod has an improved gastro-intestinal safety profile compared to naproxen.

On December 15, 2005, the full results of the OASIS phase 2 trial for naproxcinod were published in the journal Arthritis Care and Research: T.J. Schnitzer et al., Volume 53, Issue 6, page 827-837. The OASIS trial demonstrated that naproxcinod 375 mg and 750 mg bid were superior to placebo (p<0.001) and non-inferior to rofecoxib 25 mg per day (p<0.001) in treating the signs and symptoms of osteoarthritis of the knee, as measured by the difference between the baseline WOMAC™ pain subscale scores and the mean at 4 and 6 weeks. Although naproxen 500 mg bid was not formally tested for efficacy, both doses of naproxcinod appeared to be as effective as naproxen in reducing the WOMAC™ pain subscale score. Mean systolic blood pressure was also lower in the naproxcinod treatment groups at the end of 6 weeks, compared to baseline, in contrast to no change with placebo and an increase with rofecoxib and naproxen.

In February 2003, NicOx announced the results of STAR, a phase 2 trial for naproxcinod, which indicated that naproxcinod has an improved gastro-intestinal safety profile compared to naproxen. Naproxcinod showed an advantage compared to naproxen on the primary endpoint of the trial (the incidence of patients with at least one gastro-intestinal ulcer of 3mm or greater), although this did not reach statistical significance (p=0.07). There was a lower than predicted rate of gastro-intestinal ulcers in the naproxen group (14% vs. 20-25%) compared to the protocol statistical plan, suggesting that the phase 2 study may have been under-powered to reach the primary endpoint.

In a number of secondary endpoints related to the frequency of gastro-duodenal ulcers and erosions and stomach ulcers and erosions. Naproxcinod also revealed a statistically significant reduction in scoring systems that express the severity of the gastro-duodenal damage (Lanza’s scores 3 and 4) and a statistically significant reduction of dyspeptic symptoms (reflux and abdominal pain), compared to naproxen.

The study also showed that naproxcinod has equivalent efficacy to naproxen in relieving the pain associated with osteoarthritis on all three WOMAC™ subscales of pain, stiffness and function. Naproxcinod was well tolerated overall and did not produce significant changes in blood pressure.