PARIS — Naproxcinod, an investigational pain reliever being developed for osteoarthritis, resulted in significantly lower blood pressure than did naproxen in a pivotal phase III clinical trial.
This finding holds the key to the drug's seemingly bright future. Conventional NSAIDs such as naproxen, as well as selective cyclooxygenase (COX)-2 inhibitors, are known to affect blood pressure adversely and can counteract the benefits of antihypertensive agents. This hypertensive action is thought to be an important mechanism in the increased cardiovascular risk that has led to across-the-board black box warnings for NSAIDs, study investigator Dr. Brigitte Duquesroix noted at the annual European Congress of Rheumatology.
Naproxcinod is the first in a new class of anti-inflammatory analgesics known as COX-inhibiting nitric oxide donators, said Dr. Duquesroix, director of clinical research at NicOx S.A., in Sophia Antipolis, France.
Naproxcinod has two mechanisms of action: inhibition of both COX-1 and −2 via metabolism to naproxen, plus sustained release of nitric oxide.
Nitric oxide is known to have multiple beneficial cardiovascular effects, including maintenance of vascular endothelial function, antiplatelet activity, and modulation of smooth muscle cell proliferation. It also may have a protective effect in the GI tract.
Dr. Duquesroix reported on 918 patients with knee osteoarthritis seen at 110 U.S. sites. The patients were randomized in a double-blind fashion to 13 weeks of naproxcinod at 375 or 750 mg b.i.d., naproxen 500 mg b.i.d., or placebo. Half of the participants were hypertensive at baseline. Office blood pressure readings were obtained in standardized fashion 2-4 hours after the morning dose.
Over the full 13 weeks, both doses of naproxcinod resulted in lower systolic and diastolic blood pressures, compared with baseline readings and compared with naproxen. At week 13, the naproxcinod 750-mg b.i.d. group had a mean 2.9-mm Hg lower systolic and 1.8-mm Hg lower diastolic blood pressure than did the naproxen 500-mg b.i.d. group. Patients on naproxcinod at 375 mg b.i.d. averaged a 1.8-mm Hg lower systolic and 1.6-mm Hg lower diastolic blood pressure than did naproxen-treated patients.
Analgesic efficacy of naproxcinod at both doses was superior to placebo and was comparable to naproxen based on Western Ontario and McMaster Universities Osteoarthritis Index pain and function scores as well as Patient's Global Assessment of disease status.
GI adverse events were noted in 17% of patients on the 750-mg b.i.d. dose, 13% on the lower dose of naproxcinod, 24% of those on the naproxen 500-mg b.i.d. dose, and 12% on placebo.
Two additional confirmatory pivotal phase III trials are ongoing. One year long clinical trial involves more than 1,000 knee osteoarthritis patients. The other, a 13-week study, features 800 patients with osteoarthritis of the hip. NicOx plans to file for U.S. marketing approval for naproxcinod by mid-2009, Dr. Duquesroix said in an interview.