Naproxcinod Explained

Naproxcinod (nitronaproxen) is a nonsteroidal anti-inflammatory drug (NSAID) developed by the French pharmaceutical company NicOx. It is a derivative of naproxen with a nitroxybutyl ester to allow it to also act as a nitric oxide (NO) donor. This second mechanism of action makes naproxcinod the first in a new class of drugs, the cyclooxygenase inhibiting nitric oxide donators (CINODs), that are hoped to produce similar analgesic efficacy to traditional NSAIDs, but with less gastrointestinal and cardiovascular side effects.[1] [2]

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.

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.[4] 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.

Indications

Three phase III clinical trials led by NicOx have shown that naproxcinod was effective to treat pain against knee osteoarthritis[5] and hip osteoarthritis. A phase II study showed no significant differences in efficacy between naproxcinod and the COX-2 inhibitor rofecoxib in the treatment of pain.[6]

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.[7]

In July 2010 the FDA decided not to approve naproxcinod.[8]

Mechanism of action

Naproxcinoid is metabolized to naproxen and a nitric oxide donating moiety. NO has various cardiovascular effects, including vasodilatory and platelet-inhibitory actions as well as the inhibition of vascular smooth muscle proliferation that serves to maintain normal vascular tone.

Safety profile

Blood pressure profile

According to some experts, 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. 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.[9]

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.[10] 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.[11] Clinical studies about rofecoxib have shown that this drug increases the systolic blood pressure.[12]

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.[13]

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,[14] [15] but a 2009 review has found only a slight and possibly not clinically relevant reduction of gastrointestinal side-effects.[16] [17]

Contraindications and adverse effects

Similarly to NSAIDs, adverse effects of naproxcinod include gastrointestinal bleedings.

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.[18] In July 2010, the FDA decided not to approve naproxcinod without further clinical trials. Nicox submitted a Marketing Authorization Application (MAA) to the European Medicines Agency (EMEA) in December 2009.[19] 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.[20]

See also

Notes and References

  1. Ellis JL, Augustyniak ME, Cochran ED, Earl RA, Garvey DS, Gordon LJ, Janero DR, Khanapure SP, Letts LG, Melim TL, Murty MG, Schwalb DJ, Shumway MJ, Selig WM, Trocha AM, Young DV, Zemtseva IS . 6 . NMI-1182, a gastro-protective cyclo-oxygenase-inhibiting nitric oxide donor . Inflammopharmacology . 12 . 5–6 . 521–534 . 2005 . 16259719 . 10.1163/156856005774382661 . 3231846 .
  2. Cirino G, Distrutti E, Wallace JL . Nitric oxide and inflammation . Inflammation & Allergy - Drug Targets. 5 . 2 . 115–119 . April 2006 . 16613570 . 10.2174/187152806776383143 . 10.1.1.628.532 .
  3. http://www.sciam.com/article.cfm?id=special-report-10-promisi, Special Report: 10 Promising Treatments for World's Biggest Health Threats, By Charles Q. Choi. 2006
  4. Baron JA, Sandler RS, Bresalier RS, Lanas A, Morton DG, Riddell R, Iverson ER, Demets DL . 6 . Cardiovascular events associated with rofecoxib: final analysis of the APPROVe trial . Lancet . 372 . 9651 . 1756–1764 . November 2008 . 18922570 . 10.1016/S0140-6736(08)61490-7 . 39981292 .
  5. News: NicOx Announces Top-Line Results From Naproxcinod 52-Week 301 Safety Extension. 24 July 2008. 2 February 2010.
  6. Karlsson J, Pivodic A, Aguirre D, Schnitzer TJ . Efficacy, safety, and tolerability of the cyclooxygenase-inhibiting nitric oxide donator naproxcinod in treating osteoarthritis of the hip or knee . The Journal of Rheumatology . 36 . 6 . 1290–1297 . June 2009 . 19411388 . 10.3899/jrheum.081011 . free .
  7. White WB, Schnitzer TJ, Fleming R, Duquesroix B, Beekman M . 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 . September 2009 . 19733721 . 10.1016/j.amjcard.2009.05.014 .
  8. http://www.genengnews.com/gen-news-highlights/nicox-shares-plummet-as-fda-says-osteoarthritis-drug-not-ready-for-approval/81243699/ NicOx Shares Plummet as FDA Says Osteoarthritis Drug Not Ready for Approval
  9. Wallace JL, Viappiani S, Bolla M . Cyclooxygenase-inhibiting nitric oxide donators for osteoarthritis . Trends in Pharmacological Sciences . 30 . 3 . 112–117 . March 2009 . 19230986 . 10.1016/j.tips.2009.01.001 .
  10. Web site: Analysis of FDA COX-2 Advisory Committee Meeting. 2005. 21.
  11. Nissen SE, Tuzcu EM, Libby P, Thompson PD, Ghali M, Garza D, Berman L, Shi H, Buebendorf E, Topol EJ . 6 . 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 . November 2004 . 15536108 . 10.1001/jama.292.18.2217 .
  12. Whelton A . COX-2-specific inhibitors and the kidney: effect on hypertension and oedema . Journal of Hypertension Supplement . 20 . 6 . S31–S35 . September 2002 . 12683425 .
  13. Grover SA, Coupal L, Zowall H . Treating osteoarthritis with cyclooxygenase-2-specific inhibitors: what are the benefits of avoiding blood pressure destabilization? . Hypertension . 45 . 1 . 92–97 . January 2005 . 15545508 . 10.1161/01.HYP.0000149684.01903.b8 . 19825259 . 10.1.1.576.8621 .
  14. Wilder-Smith CH, Jonzon B, Fornstedt-Wallin B, Hedman A, Karlsson P . 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 . March 2006 . 16497612 . 10.1080/00365520510024197 . 8025524 .
  15. Hawkey CJ, Jones JI, Atherton CT, Skelly MM, Bebb JR, Fagerholm U, Jonzon B, Karlsson P, Bjarnason IT . 6 . Gastrointestinal safety of AZD3582, a cyclooxygenase inhibiting nitric oxide donator: proof of concept study in humans . Gut . 52 . 11 . 1537–1542 . November 2003 . 14570719 . 1773862 . 10.1136/gut.52.11.1537 .
  16. Geusens P . Naproxcinod, a new cyclooxygenase-inhibiting nitric oxide donator (CINOD) . Expert Opinion on Biological Therapy . 9 . 5 . 649–657 . May 2009 . 19392579 . 10.1517/14712590902926071 . 70711735 .
  17. Schubert-Zsilavecz, M, Wurglics, M, Neue Arzneimittel 2010
  18. News: NicOx submits naproxcinod application to FDA. Reuters. 25 September 2009. 3 February 2010 . Michelson M .
  19. News: MAA for naproxcinod submitted to EMEA through centralized procedure. NewsMedical.net. 22 December 2009. 2 February 2010.
  20. Web site: Fera Pharmaceuticals - Press Releases. www.ferapharma.com. 2016-04-20.

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