Naproxcinod - Signs and symptoms of Osteoarthritis

		Naproxcinod Signs and symptoms of Osteoarthritis – phase 3 completed


		NicOx' most advanced investigational drug, naproxcinod, has successfully completed a regulatory phase 3 program in patients with osteoarthritis of the knee and hip. Anti-inflammatory agents currently used in the treatment of osteoarthritis (traditional NSAIDs and COX-2 inhibitors) have long been associated with a range of side effects, including gastrointestinal problems. Furthermore, clinical findings continue to cast significant doubt on their cardiovascular safety, including their association with increased blood pressure. Naproxcinod is a unique nitric oxide-donating anti-inflammatory compound and the first CINOD (Cyclooxygenase-Inhibiting Nitric Oxide Donator) in late-phase development. NicOx aims to demonstrate that naproxcinod is an anti-inflammatory agent with no detrimental effect on blood pressure and good gastrointestinal tolerability and safety. NicOx has completed a regulatory phase 3 program for naproxcinod in patients with OA of the knee (the 301 and 302 studies) and hip (the 303 study), with all three studies achieving highly statistically significant results on all three co-primary efficacy endpoints. NicOx plans to submit a New Drug Application (NDA) for naproxcinod to the US Food and Drug Administration (FDA) in mid-2009.



		Traditional NSAIDs and COX-2 inhibitors are widely used for the symptomatic treatment of OA but are associated with a range of side effects, including the tendency to raise blood pressure. (more...) Overview of the phase 3 program. (more...) NicOx intends to differentiate naproxcinod from existing anti-inflammatory agents in terms of blood pressure effect. (more...) Additional ABPM results were consistent with those of previous studies and complete an extensive database describing naproxcinod’s differentiated blood pressure profile.(more...) All three pivotal phase 3 studies for naproxcinod have shown positive efficacy and safety results. (more...) Regulatory interactions & Market launch preparation. (more...) Overview of phase 1 and phase 2 results and data on naproxcinod’s gastrointestinal (GI) safety and tolerability. (more...)



		Traditional NSAIDs and COX-2 inhibitors are widely used for the symptomatic treatment of OA but are associated with a range of side effects, including the tendency to raise blood pressure. Millions of people worldwide rely on traditional Non Steroidal Anti-Inflammatory drugs (NSAIDs) and COX-2 inhibitors to treat chronic pain and inflammation relating to a range of conditions, including osteoarthritis (OA). However, they are associated with a low but significant incidence of serious side effects, such as gastrointestinal and renal complications. COX-2 inhibitors (and to a lesser extent traditional NSAIDs) have also been recently linked to an increased risk of serious cardiovascular events, such as heart attacks and strokes. Due to the sheer number of people taking NSAIDs, providing safer drugs with similar efficacy has been a goal of physicians, patients and the pharmaceutical industry for more than 50 years. The onset of new hypertension (high blood pressure) has been identified as another detrimental effect of traditional NSAIDs and COX-2 inhibitors, as well as the loss of blood pressure control in patients who were previously stably treated with anti-hypertensive agents. These blood pressure effects are of particular concern in the OA population, where approximately 50% of patients also suffer from hypertension. A statement was therefore added to the warnings section of the labels of these drugs, stressing that all COX-2 inhibitors and traditional NSAIDs can lead to onset of new hypertension or worsening of pre-existing hypertension, and should be used with caution in patients with hypertension.
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		Overview of the phase 3 program The phase 3 program was designed to request regulatory approval for naproxcinod in the US and in Europe. As planned, three large pivotal clinical trials have been conducted in this phase 3 program: 301 study: completed in 2006 in 918 patients with osteoarthritis of the knee. 302 study: completed in 2008 in 1020 patients also suffering from osteoarthritis of the knee. 303 study: completed in 2008 in 810 patients with osteoarthritis of the hip. All three studies achieved highly statistically significant results on all three co-primary efficacy endpoints (WOMAC™ pain and function subscales and subject’s overall rating of disease status). Good overall safety and tolerability was also demonstrated by both doses of naproxcinod. NicOx plans to submit a New Drug Application (NDA) for naproxcinod to the US Food and Drug Administration (FDA) in mid-2009. An important issue was the evaluation of naproxcinod’s blood pressure profile, in comparison to traditional NSAIDs and COX 2 inhibitors. As explained above, this could be a key differentiating factor in the anti-inflammatory market, due to the growing recognition that current treatments can raise blood pressure. Both hypertensive and non-hypertensive patients were enrolled in the three phase 3 studies, although patients with uncontrolled hypertension have been excluded. Key efficacy, safety and blood pressure results from these clinical trials are described in detail thereafter.
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		NicOx intends to differentiate naproxcinod from existing anti-inflammatory agents in terms of blood pressure effect As explained above, there is a clear unmet medical need for a novel anti-inflammatory agent with no detrimental impact on blood pressure. COX-2 inhibitors and traditional non-steroidal anti-inflammatory drugs (NSAIDs), such as naproxen, are widely used for the symptomatic treatment of OA but can lead to the onset of new episodes of high blood pressure or worsening of pre-existing hypertension. Naproxcinod is metabolized to yield naproxen as well as a nitric oxide-donating moiety, and endothelial nitric oxide is believed to play an important role in controlling blood pressure. NicOx’ technology may therefore endow naproxcinod with an improved blood pressure profile and blood pressure measurements were performed during the phase 3 program to explore this possibility. Blood pressure assessments in the phase 3 program Patients' blood pressure was measured during each of the phase 3 trials by using controlled Office Blood Pressure Measurements (OBPMs), collected in a rigorous and standardized manner during each visit to the treatment centers, at baseline and at weeks 2, 6 and 13⁽¹⁾. The blood pressure data from the 301, 302 and 303 studies (2,734 patients) was then pooled and analyzed according to a prospectively designed statistical plan (the 304 analysis, see detailed results below)⁽²⁾. The objective of this pooled analysis was to evaluate the profile of naproxcinod 375 mg bid and 750 mg bid on blood pressure in a large OA population up to and including 13 weeks, compared to placebo and naproxen 500 mg bid. The pooled blood pressure analysis showed that naproxcinod 750 mg bid lowered SBP and DBP compared to naproxen with high statistical significance (p<0.001) Top-line results of the 304 analysis were announced in a press release dated December 17, 2008. Both doses of naproxcinod showed a significant reduction in systolic and diastolic blood pressure (SBP and DBP) compared to naproxen 500 mg bid over the whole 13 week period (p<0.001 for naproxcinod 750 mg bid and p<0.05 for naproxcinod 375 mg bid). As depicted on the chart below, naproxcinod 750 mg bid lowered SBP by 2.2 mmHg (p<0.001) and DBP by 1.2 mmHg (p<0.001) compared to naproxen 500 mg bid, in terms of the mean change between baseline and the average over weeks 2, 6 and 13. Naproxcinod 375 mg bid lowered SBP by 1.2 mmHg (p<0.05) and DBP by 0.8 mmHg (p<0.05) compared to naproxen, in terms of the mean change between baseline and the average over weeks 2, 6 and 13. Both doses of naproxcinod showed a similar blood pressure profile to placebo, as indicated by one-sided 95% confidence intervals CIs. In contrast, naproxen 500 mg bid raised SBP by 2.0 mmHg (p<0.001) compared to placebo, in terms of the mean change between baseline and the average over weeks 2, 6 and 13. A significantly lower proportion of patients on naproxcinod experienced an increase in SBP of 5 mmHg or more, compared to naproxen Over the whole 13 week period of the 304 pooled analysis, the proportion of patients whose SBP increased by 5 mmHg or more was higher for naproxen 500 mg bid, as compared to naproxcinod 750 mg bid (p<0.001), naproxcinod 375 mg bid (p=0.013) and placebo (p<0.001). Both naproxcinod doses showed a similar blood pressure profile to placebo Both doses of naproxcinod (375 and 750 mg bid) were similar to placebo in the 304 analysis, as indicated by one-sided 95% CIs. In contrast, naproxen 500 mg bid raised SBP compared to placebo (p<0.001). Further analyses are ongoing and NicOx plans to disclose more detailed results at leading medical conferences and in peer reviewed scientific publications during 2009 and 2010. ⁽¹⁾ OBPMs were performed by a health care professional during a patient’s visit to the treatment center using a standard technique and equipment (i.e. a sphygmomanometer) with the patient in the sitting position. They were performed in the morning and the time between intake of study-drug and measurement of OBPM was between 2 and 4 hours. Three measurements were taken at each visit, using standard American Heart Association (AHA) and Joint National Committee (JNC) 7 criteria (Pickering 2005, Chobanian 2003). Further initiatives were taken to best control the OBPMs. For example, they were performed after 5 minutes of rest, with a one minute interval between each reading, and it was specified that the patients should remain quiet, without conversation during the measurements. It was also specified that the same arm should be used for the OBPMs at all visits, with a cuff appropriate to the arm size. (return) ⁽²⁾ The statistical analysis plan pre-specified the calculation of 95% confidence intervals (CIs) and the statistical methods used to make these comparisons. The calculation of p values was not planned, although they have been included above for illustrative purposes. (return)
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		Additional ABPM results were consistent with those of previous studies and complete an extensive database describing naproxcinod’s differentiated blood pressure profile. Two additional phase 1 studies in osteoarthritis patients with controlled hypertension were planned, the 111 and 112 studies. These trials were designed to assess the 24-hour blood pressure profile of naproxcinod, in comparison to ibuprofen and naproxen, 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. These studies were expected to provide complementary data to the phase 3 program, where OBPMs were taken during patients’ visits to the treatment centers. Top-line results from the 111 dose-escalating study Positive top-line results from the first of these ABPM studies, the 111 study, were announced in November 2008. In this study, 118 osteoarthritis patients with controlled hypertension were randomized to receive naproxcinod or naproxen, with escalating doses every three weeks. The trial included three doses of naproxcinod (375 mg bid, 750 mg bid and a supra-therapeutic dose of 1125 mg bid), which were compared to naproxen (250, 500 and 750 mg bid). 24-hour blood pressure monitoring was conducted at baseline and at the end of each three-week dose escalation (i.e. at the end of week 3, 6 and 9), using an FDA validated, ABPM device. The primary objective of the study was to characterize the 24-hour arterial blood pressure profile of the three doses of naproxcinod, as measured by ABPM after each dose, compared to naproxen. At all time points, naproxcinod showed a decrease in the mean 24-hour SBP and DBP from baseline in contrast to naproxen. In terms of the overall treatment effect, as an average over week 3, 6 and 9, naproxen raised SBP by 1.5 mmHg from baseline, while naproxcinod lowered it by 2.3 mmHg, resulting in a difference between the two treatments of 3.8 mmHg (p=0.011) in favor of naproxcinod (see chart below). The three doses of naproxcinod showed good general safety and tolerability. In the naproxcinod arm 32 patients (54.2%) experienced one or more adverse events, compared to 38 patients (64.4%) in the naproxen arm. There were no serious adverse events in the naproxcinod arm. NicOx plans to provide further details of the results at a leading cardiology conference in 2009. Top-line results from the 112 parallel arms study Positive results from the 112 clinical pharmacology study in 299 patients with osteoarthritis (OA) and hypertension were announced in December 2008. The 112 study was designed to characterize the 24 hour blood pressure profile of naproxcinod in comparison to the two most widely used NSAIDs. Patients were randomized to receive naproxcinod 375 mg bid, naproxcinod 750 mg bid, naproxen 250 mg bid, naproxen 500 mg bid, or ibuprofen 600 mg tid (three times daily) for 13 weeks. The study was not designed to show statistical significance between the treatment arms but rather aimed to explore the 24-hour blood pressure profile of the two naproxcinod doses, in comparison to different NSAIDs. No formal sample size computations were performed in the 112 protocol. The 24-hour blood pressure monitoring was conducted at baseline and at week 13 using a validated ABPM device. The primary parameter was the mean 24-hour ambulatory SBP as measured by ABPM at week 13. Compared to naproxen 500 mg bid, naproxcinod 750 mg bid lowered SBP by 2.7 mmHg and DBP by 1.4 mmHg, in terms of the mean change from baseline at week 13. Naproxcinod 375 mg bid decreased SBP by 1.1 mmHg and DBP by 0.8 mmHg compared to naproxen 250 mg bid. Naproxcinod 750 mg bid showed a 3.8 mmHg decrease in SBP and a 0.7 mmHg decrease in DBP compared to ibuprofen 600 mg tid, in terms of the mean change from baseline at week 13. Naproxcinod 375 mg bid showed a reduction in SBP of 4.2 mmHg and a reduction in DBP of 1.7 mmHg, compared to ibuprofen 600 mg tid (see chart below). Naproxcinod 375 mg bid was the treatment with the lowest percentage of patients experiencing at least one adverse event. There were no treatment-related serious adverse events in the study. Far more patients in the ibuprofen arm discontinued due to an adverse event compared to the other treatments. The 112 results were consistent with those of previous studies and complete an extensive database describing naproxcinod’s differentiated blood pressure profile. Further analyses on the 111 and 112 studies will form the basis of presentations at leading medical conferences and peer reviewed scientific publications during 2009 and 2010. Results from the 104 study The data from the 111 and 112 studies complement the results of a pilot 2-week ABPM study with naproxcinod compared to naproxen in hypertensive volunteers (the 104 study), which were presented at the American Heart Association (AHA) in November 2008. The study showed an encouraging differentiation in the blood pressure curves for naproxcinod compared to naproxen when viewed over 24 hours. A further post hoc analysis, which was accepted by the American Heart Association scientific panel, compared the mean 24-hour systolic blood pressure (SBP) as measured by ABPM in the two groups (i.e. naproxcinod vs. naproxen), at the end of the 2 weeks of active treatment. The mean 24-hour SBP showed a difference of 2.4 mmHg (standard error 0.87 mmHg) in favor of naproxcinod as compared to naproxen (p=0.007) after 2 weeks of treatment. Interestingly, for the daytime measurements (the 8 hours following the morning dose), the mean 8-hour SBP showed a difference of 4.4 mmHg (standard error 0.98 mmHg) in favor of naproxcinod as compared to naproxen (p<0.0001) after 2 weeks of treatment (see chart below). The number of adverse events was low across both active treatment periods.
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		All three pivotal phase 3 studies for naproxcinod have shown positive efficacy and safety results. Below are presented the efficacy and safety results of the three pivotal phase 3 studies. The 303 study met its co-primary endpoints in hip OA patients. The 303 study was completed in November 2008, it was a 13-week, double-blind, placebo and naproxen controlled trial in 810 patients with OA of the hip, who had been enrolled at 120 clinical centers in the United States, Canada and Europe. Eligible patients had a diagnosis of primary osteoarthritis of the hip of at least three months in duration and were randomized on a 2:2:1 basis to receive respectively: Naproxcinod 750 mg bid Placebo bid Naproxen 500 mg bid. Efficacy: At week-13, naproxcinod 750 mg bid has been compared to placebo on three standard co-primary endpoints used to demonstrate the efficacy of drugs for treating the signs and symptoms of osteoarthritis⁽¹⁾: WOMAC™ pain subscale, WOMAC™ function subscale, Subject’s overall rating of disease status. WOMAC™ is a standard knee and hip osteoarthritis index assessing the three dimensions of pain, disability and joint stiffness using a battery of 24 questions. The results demonstrated that naproxcinod was superior to placebo with high statistical significance (p<0.001) on all three of these co-primary endpoints. No statistical comparison was made between naproxen 500 mg bid and the other two arms on the efficacy endpoints, due to the 2:2:1 randomization in the study, although numerical data show that naproxcinod 750 mg bid behaved in a similar fashion to naproxen 500 mg bid on these efficacy scores. Safety: Naproxcinod 750 mg bid showed good overall safety and tolerability in the 303 study. The percentage of patients who experienced one or more GI adverse events was the same for placebo and naproxcinod 750 mg bid at 15.5%, compared to 19.2% for naproxen 500 mg bid. In terms of the percentage of patients who experienced at least one adverse event overall, this was lower for naproxcinod 750 mg than naproxen 500 mg bid. There was not a single serious cardiovascular or serious GI adverse event in the naproxcinod arm during the 13 weeks of the 303 study, in contrast to the placebo and naproxen 500 mg bid arms. Naproxcinod 750 mg bid showed a similar blood pressure profile to placebo, supporting earlier findings suggesting its non-detrimental effect on blood pressure. The 302 study met its co-primary endpoints in knee-OA patients. The 302 study, which was completed in September 2008, recruited 1020 patients with osteoarthritis of the knee of at least 3 months duration at 150 clinical sites throughout the United States. The 302 study was a 53 week, double blind trial, in which patients were 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) Placebo bid during the first 13 weeks. After 13 weeks, the placebo treated patients were randomized to either naproxcinod 375 mg bid or naproxcinod 750 mg bid for the remainder of the trial (39 weeks). Efficacy: At week-13, the two doses of naproxcinod (750 mg and 375 mg bid) have been compared to placebo on the same three standard co-primary endpoints as in the 303 study (see above). Both doses of naproxcinod were shown to be superior to placebo on all these three co-primary endpoints with high statistical significance (p<0.001). A secondary endpoint of the trial was to compare the efficacy of naproxcinod and naproxen at 26 weeks⁽²⁾. At week-13 and 26, naproxcinod 750 mg bid comfortably met the secondary endpoint of being statistically non-inferior to naproxen 500 mg bid, in terms of the mean change from baseline in the WOMAC™ pain and function subscales. Although not a pre-specified secondary endpoint of the study, a post hoc analysis showed that naproxcinod 375 mg bid was also statistically non inferior to naproxen 500 mg bid at week-26 on these two parameters. Safety: There were no safety concerns relating to naproxcinod treatment up to week-26 in the 302 study and all the active treatment arms were similar to placebo in terms of the percentage of patients with one or more adverse event at week-13. At week-26, the percentage of patients with one or more adverse event was similar for each of the study drugs. The number of serious adverse events was low and evenly distributed among the treatment groups. Overall, the results of the 302 study suggest that naproxcinod has a non-detrimental effect on blood pressure. Detailed efficacy results from the 301 study Efficacy: The 301 study was the first clinical trial in the phase 3 program for naproxcinod. It 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 who 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. The same three co-primary efficacy endpoints as the 302 and 303 study were met with high statistical significance (p<0.001). Safety: 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, confirming earlier published clinical data. This was confirmed by a safety extension study run for an additional 52 week period. No unexpected safety finding was revealed, and good overall long term safety was observed. In addition, the results showed that the patients’ mean blood pressure was stable for 52 weeks following the completion of the 301 study, suggesting that naproxcinod does not increase blood pressure over time. ⁽¹⁾Superiority comparisons versus placebo on three co-primary efficacy endpoints (WOMAC™ pain subscale, WOMAC™ function subscale and subject’s overall rating of disease status) in two well designed, well controlled trials conform to FDA guidance for demonstrating the efficacy of new drugs for the treatment of the signs and symptoms of osteoarthritis. (return) ⁽²⁾Non-inferiority comparisons to existing products are required by the European Medicines Agency (EMEA) for demonstrating the efficacy of new drugs. (return)
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		Regulatory interactions & Market launch preparation 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 concerns regarding the cardiovascular safety of the NSAID class, the FDA has examined the non-clinical, pharmacokinetic and clinical data for naproxcinod 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 for 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. In December 2008, NicOx announced the signature of an agreement with the fine chemical company DSM, for the commercial manufacturing and supply of naproxcinod drug substance (or active pharmaceutical ingredient, API). The aim of this agreement is to secure commercial supplies of an appropriate scale to ensure the successful commercial launch of naproxcinod. As per the agreement, NicOx envisages the first deliveries of significant quantities of commercial material being made from the fourth quarter of 2009 onwards. In September 2008, NicOx announced it has signed an exclusive agreement with Capsugel, the leading producer of two-piece capsules, for the commercial manufacturing and global supply of naproxcinod capsules. The aim of this agreement is to ensure sufficient supplies of naproxcinod capsules to underpin its successful commercial launch. This is all part of NicOx’ strategy to maximize the commercial potential and economic value of naproxcinod, as NicOx owns the global development and marketing rights to this compound. Going forward, NicOx will be looking for co-commercialization partnerships for naproxcinod, with NicOx retaining certain commercialization rights in the US and selected EU markets, in order to fully exploit the drug’s commercial and strategic value and to aid the Company’s planned transition to a fully integrated pharmaceutical business. Currently, NicOx expects to file a New Drug Application (NDA) in the US for naproxcinod in mid 2009.
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		Overview of phase 1 and phase 2 results A successful phase 2 program, involving five separate clinical trials and a total of 2709 patients, has been completed for naproxcinod. On December 15, 2005, the full results of the OASIS phase 2 trial for naproxcinod were published in the Journal of Arthritis Care and Research (T.J. Schnitzer et al. (2005) 53:6, 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 the COX-2 inhibitor rofecoxib 25 mg qd (once 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 of weeks 4 and 6. 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. Naproxcinod’s gastrointestinal (GI) safety In addition to the recent cardiovascular safety concerns surrounding the traditional NSAID class, these products have long been associated with gastrointestinal side effects, ranging in severity from gastric discomfort to potentially life-threatening bleeding. In February 2003, NicOx announced the results of STAR, a phase 2 trial, in which naproxcinod showed an advantage compared to naproxen on the primary endpoint (the incidence of patients with at least one gastrointestinal ulcer of 3 mm or greater), although this did not reach statistical significance (p=0.07) (see chart below). In the STAR trial, a number of secondary endpoints related to the frequency of gastro-duodenal ulcers and erosions and stomach ulcers and erosions were also measured, and were favorable for naproxcinod. 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. Naproxcinod was well tolerated overall and did not produce significant changes in blood pressure. An endoscopic phase 1 study had previously shown a statistically significant decrease in the gastroduodenal toxicity for naproxcinod 750 mg bid compared to naproxen 500 mg bid (p<0.05), as well as for naproxcinod 375 mg bid compared to naproxen 500 mg bid (p<0.05), in terms of the mean number of erosions and ulcers after 12 days of treatment (cross-over study with 25 healthy volunteers per group, see chart below).
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