NicOx's HCT 3012 Shows Equivalent Efficacy to Rofecoxib Without Any Increase of Systolic Blood Pressure in Osteoarthritis Patients
SOPHIA ANTIPOLIS, France, June 10 /PRNewswire-FirstCall/ -- NicOx S.A. (Nouveau Marche: NICOX) today presented Phase II clinical results (Abstract #OP 0016 - see note 1) on its lead CINOD compound, HCT 3012 (ex AZD3582), at the EULAR (European League Against Rheumatism) Annual Congress taking place from 9-12 June in Berlin, Germany. The results demonstrate that after six weeks' treatment with HCT 3012 osteoarthritis patients experienced pain relief equivalent to rofecoxib. At equi-analgesic doses, patients treated with rofecoxib experienced an increase in systolic blood pressure (SBP), an effect particularly evident in hypertensive patients). In contrast HCT 3012 showed no statistical difference in SBP compared to placebo. The differences in SBP between the HCT 3012 and rofecoxib treatment groups were statistically significant.
Clinical data were generated during the OASIS trial, a randomized, double-blind study conducted to evaluate the efficacy and safety of the first compound in the CINOD class, HCT 3012. Cardiovascular safety was assessed through SBP measurement at baseline and at multiple time points throughout the six-week treatment period.
HCT 3012 (750 mg bid and 375 mg bid) was shown to be effective in the WOMAC pain subscale and the majority of subjects and investigators rated the overall treatment, disease status and response therapy at six weeks as good or very good. The study was conducted vs. placebo, naproxen 500 mg bid, and a fully active dose of rofecoxib (25 mg qd).
Professor Thomas Schnitzer, Assistant Dean for Clinical Research at Northwestern University (Chicago, USA), commented: "The relevance of potentially harmful effects of NSAIDs and coxibs due to an increase in arterial blood pressure is increasingly acknowledged. Even small increases of blood pressure are associated with a significantly increased incidence of cardiovascular events. In that respect, CINODs, through NO release, 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."
Michele Garufi, Chairman and CEO of NicOx, added: "These results support the therapeutic value of the new CINOD class. The European Committee for Human Medicinal Products has recently recommended changes to Cox-2 labeling to strengthen cardiovascular warnings. We believe NicOx's CINOD class could offer patients a potent and safe anti-inflammatory alternative, with a superior CV safety profile. With this aim, we are pursuing further targeted Phase II studies with HCT 3012 and we are planning to start in the near future a clinical study in the US to assess the beneficial effects on systolic blood pressure observed with HCT 3012 compared to Cox-2s in hypertensive patients. At the same time, NicOx, together with its clinical advisory board, is finalising a Phase III development plan for HCT 3012 which is planned to commence in 2005."
Note to Editors:
Note 1: Abstract OP0016 "A Phase II study of the efficacy and safety of AZD3582, A CINOD, in subjects with Osteoarthritis of the knee"
Thomas J. Schnitzer(1), Alan J. Kivitz(2), Robert S. Lipetz(3), Nick Sanders(4), Angela Hee(4)
* (1)NCCR, Northwestern University Feinberg School of Medicine, Chicago, IL, (2)Altoona Center for Clinical Research, Duncansville, PA, (3)Encompass Clinical Research, Spring Valley, CA, (4)AstraZeneca LP, Wilmington, DE, United States
Background: New treatments for symptomatic osteoarthritis (OA) need to demonstrate better efficacy or greater safety than current drugs. In general, coxibs have provided an improved GI safety profile compared to NSAIDs but remain associated with important renal and cardiovascular side effects. CINODs, cox-inhibiting nitric-oxide (NO) donators, were developed to provide the benefits of NO generation, which in the preclinical setting are associated with GI protection from NSAID-induced GI damage, improved renal safety, and enhancement of analgesic efficacy.
Objectives: The primary objective was to find the doses of AZD3582 (AZD; 125, 275 and 750 mg bid) that were non-inferior in analgesic efficacy to rofecoxib 25 mg qd in subjects with knee OA. Additionally, analgesic efficacy of AZD was compared to naproxen, 500 mg bid, and placebo, and overall safety and tolerability of AZD assessed.
Methods: 672 subjects with symptomatic knee OA (ACR criteria) meeting inclusion criteria which include flare were randomized to one of 6 groups: placebo, AZD 125 mg bid, AZD 375 mg bid, AZD 750 mg bid, rofecoxib 25 mg qd and naproxen 500 mg bid and evaluated after 1, 2, 4 and 6 weeks for efficacy (WOMAC subscales, global assessments) and safety (BP, ECG, lab and AE monitoring). The primary endpoint was the within subject difference in WOMAC pain subscale from baseline to the average value at 4 and 6 weeks. An efficacy analysis was based on 645 subjects who provided post-baseline WOMAC assessments.
Results: AZD 375 mg bid and AZD 750 mg bid groups demonstrated statistically significantly greater pain relief, -12 mm (-18,-6) and -13 mm (-19,-7), respectively, than placebo and similar to that observed with rofecoxib and naproxen. AZD 375 mg and 750 mg bid groups were non-inferior in analgesic efficacy compared to rofecoxib, -2 mm (-8,+4)and -3 mm (-9,+3) respectively, with a predefined non-inferiority margin of 10 mm. AZD 125 mg bid was similar to placebo. Findings for WOMAC pain (at all points), stiffness, function and total score; and overall rating of treatment by subjects and investigators supported the conclusions drawn for the primary variable. General safety and tolerability were similar in all active treatment groups; however, at 6 weeks there was a decrease in mean supine systolic BP in the AZD 375 mg and AZD 750 mg dosage groups (-4 mm Hg and -2 mm Hg, respectively) compared to an increase of 2 mm Hg in the rofecoxib group and an increase of 1 mm Hg in the naproxen group. Similar trends with these agents were observed for mean supine diastolic BP.
Table:
LS Mean Change from baseline in WOMAC pain score (mm)
in the mean of Week 4 and Week 6
Group N Baseline Mean Change: LS Mean 95% CI
Placebo 104 66 -25 (-30,-21)
AZD3582 125 mg bid 105 67 -26 (-30,-22)
AZD3582 375mg bid 107 66 -38 (-42,-34)
AZD3582 750mg bid 114 67 -38 (-43,-35)
Rofecoxib 25mg qd 98 65 -36 (-40,-31)
Naproxen 500mg bid 117 65 -37 (-41,-33)
Conclusion: AZD 375 mg bid and 750 mg bid were superior to placebo and non-inferior to rofecoxib 25 mg qd in WOMAC pain subscale score. Mean systolic and diastolic BP was reduced at week 6 in the AZD 375 mg bid and 750 mg bid groups compared to an increase in subjects treated with rofecoxib 25 mg qd. AZD is an effective analgesic agent in OA that may be associated with a favorable cardiorenal profile.
Support: AstraZeneca LP
NicOx S.A. (Bloomberg: COX:FP, Reuters: NCOX.LN), 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, headquartered in Sophia-Antipolis, France, is a public company listed on the Nouveau Marche of Euronext Paris (segment: Next Economy).
nicox.com
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