In December 2006, Scientific American distinguished naproxcinod as one of the ten most promising treatments for the world's biggest health threats;[3] however, in 2010 the
U.S. Food and Drug Administration determined that further clinical trials would be needed to obtain approval.[4]
Current situation in pain treatment
Many people are currently relying on traditional NSAIDs and
COX-2 inhibitors (for example
celecoxib) to treat
chronic pain and
inflammation. COX-2 inhibitors have been associated with an increased risk of serious cardiovascular events such as
strokes or
heart attacks.[5] Therefore, there is an unmet need for safer medications. This need is particularly acute among patients with high cardiovascular risk like hypertension which represents 50% of osteoarthritis sufferers.[citation needed]
Indications
Three phase III
clinical trials led by NicOx have shown that naproxcinod was effective to treat pain against knee
osteoarthritis[6][7][8] and hip osteoarthritis.[9] A phase II study showed no significant differences in
efficacy between naproxcinod and the COX-2 inhibitor
rofecoxib in the treatment of pain.[10]
In osteoarthritis, a 750 mg dose is equipotent to 500 mg of naproxen for the treatment of inflammation but with the added benefit of attenuating the cardiovascular effects traditionally associated with NSAIDs.[11]
In July 2010 the FDA decided not to approve naproxcinod.[4]
According to some experts[who?], cardiovascular risks induced by COX-2 inhibitors are caused by increases in blood pressure. Naproxcinod demonstrated in a clinical trial with 916 patients to have a blood pressure profile similar to
placebo.[11] Two phase II randomized controlled trials have shown a decreased systolic blood pressure by 2.1
mmHg after patients took naproxcinod (375 mg or 750 mg twice daily) for six weeks. These effects were especially pronounced in hypertensive populations.[10][12]
Clinical relevance of small increase in blood pressure
During a
U.S. Food and Drug Administration (FDA) COX-2 advisory committee meeting, doctors have underlined the important role of small increase in blood pressure.[13] They cited the CAMELOT trial which has concluded that even a small decrease in systolic blood pressure of 5 mmHg could lead to a reduction of 31% in cardiovascular events.[14] Clinical studies about rofecoxib have shown that this drug increases the systolic blood pressure.[15]
A 2005 analysis shows that a blood pressure decrease of 3.1 mmHG could avoid over 30,000 deaths from stroke and 2,000 deaths from
coronary disease, resulting in more than 449,000
person years of life saved and 1.4 billion
US$ in direct health care cost savings.[16]
Gastrointestinal safety
NSAIDs have also been associated with
gastrointestinal risks such as bleedings. Early studies demonstrated that naproxcinod had a better gastrointestinal profile than naproxen, especially for the
gastroduodenal mucosa,[17][18] but a 2009 review has found only a slight and possibly not clinically relevant reduction of gastrointestinal side-effects.[19][20]
Contraindications and adverse effects
This section needs expansion. You can help by
adding to it. (October 2009)
Similarly to NSAIDs, adverse effects of naproxcinod include gastrointestinal bleedings.[19][20]
Commercialization
Naproxcinod completed a phase III study needed for a
New Drug Application (NDA). As a result, Nicox submitted its project to the FDA in September 2009.[21] In July 2010, the FDA decided not to approve naproxcinod without further clinical trials.[4] Nicox submitted a Marketing Authorization Application (MAA) to the
European Medicines Agency (EMEA) in December 2009.[22] Nicox and Fera Pharmaceuticals announced in November 2015 that they had entered into a license agreement for the development and commercialization of naproxcinod in the United States.[23]
^Baron JA, Sandler RS, Bresalier RS, Lanas A, Morton DG, Riddell R, et al. (November 2008). "Cardiovascular events associated with rofecoxib: final analysis of the APPROVe trial". Lancet. 372 (9651): 1756–1764.
doi:
10.1016/S0140-6736(08)61490-7.
PMID18922570.
S2CID39981292.
^Clinical trial number NCT00542555 for "Analgesic Efficacy and Safety Study of Naproxcinod in Subjects With Osteoarthritis of the Knee" at
ClinicalTrials.gov
^Clinical trial number NCT00504127 for "Efficacy and Safety Study of Naproxcinod in Subjects With Osteoarthritis of the Knee" at
ClinicalTrials.gov
^Clinical trial number NCT00541489 for "Efficacy and Safety Study of Naproxcinod in Subjects With Osteoarthritis of the Hip" at
ClinicalTrials.gov
^
abcWhite WB, Schnitzer TJ, Fleming R, Duquesroix B, Beekman M (September 2009). "Effects of the cyclooxygenase inhibiting nitric oxide donator naproxcinod versus naproxen on systemic blood pressure in patients with osteoarthritis". The American Journal of Cardiology. 104 (6): 840–845.
doi:
10.1016/j.amjcard.2009.05.014.
PMID19733721.
^Wallace JL, Viappiani S, Bolla M (March 2009). "Cyclooxygenase-inhibiting nitric oxide donators for osteoarthritis". Trends in Pharmacological Sciences. 30 (3): 112–117.
doi:
10.1016/j.tips.2009.01.001.
PMID19230986.
^Nissen SE, Tuzcu EM, Libby P, Thompson PD, Ghali M, Garza D, et al. (November 2004). "Effect of antihypertensive agents on cardiovascular events in patients with coronary disease and normal blood pressure: the CAMELOT study: a randomized controlled trial". JAMA. 292 (18): 2217–2225.
doi:
10.1001/jama.292.18.2217.
PMID15536108.
^Whelton A (September 2002). "COX-2-specific inhibitors and the kidney: effect on hypertension and oedema". Journal of Hypertension Supplement. 20 (6): S31–S35.
PMID12683425.
^Wilder-Smith CH, Jonzon B, Fornstedt-Wallin B, Hedman A, Karlsson P (March 2006). "Dose-effect comparisons of the CINOD AZD3582 and naproxen on upper gastrointestinal tract mucosal injury in healthy subjects". Scandinavian Journal of Gastroenterology. 41 (3): 264–273.
doi:
10.1080/00365520510024197.
PMID16497612.
S2CID8025524.