NicOx Plunges 21% on FDA Rejection of Arthritis Drug
By Donna Young
Adhering to the advice of a May panel of rheumatologists and drug safety experts, the FDA has refused to approve NicOx SA's experimental osteoarthritis drug naproxcinod until more studies are completed, which sent the French drugmaker's stock into a tailspin Thursday.
Shares of Sophia Antipolis, France-based NicOx (EPA:COX) plummeted 21 percent Thursday, or €0.60, to close at €2.24 (US$2.90).
The FDA rejection was not much of a surprise, given that the agency tends to follow the advice of its outside advisers. Panelists at a joint meeting of the agency's Arthritis and Drug Safety and Risk Management Advisory Committees in May voted 16 to 1, with one abstention, against approval of naproxcinod as a treatment to relieve the signs and symptoms of osteoarthritis. (See BioWorld Today, May 13, 2010.)
Although naproxcinod has been studied in 35 completed trials, including three Phase III studies in osteoarthritis of the knee or hip, the FDA permitted NicOx to forgo conducting any long-term safety outcome trials and instead use naproxen data for that purpose.
But the lack of such a requirement left the FDA's panelists at the May meeting edgy. That uneasiness apparently grabbed the attention of regulators, who said in a complete response letter that NicOx must conduct one or more long-term controlled studies to assess the cardiovascular and gastrointestinal safety of naproxcinod.
The company provided no timeline for the completion of those trials, and told BioWorld Today that it would "review appropriate options once the details of any potential future studies are clarified with the FDA."
NicOx developed naproxcinod, a cyclooxygenase-inhibiting nitric oxide-donating compound, with the aim of being a less toxic nonsteroidal anti-inflammatory drug (NSAID) than naproxen, which is sold as a prescription and over-the-counter medicine under various brand names, with the most well-known being Naprosyn and Aleve. Naproxcinod essentially is a mixture of naproxen and nitric oxide.
NicOx has contended that naproxcinod's nitric oxide effect mitigates the potential increase in blood pressure associated with NSAIDs. But FDA scientists said a consistent effect on systolic and diastolic blood pressure in the naproxcinod studies was mainly present at peak and the effect through the dosing interval was variable, leaving the potential impact on cardiac outcomes unclear. (See BioWorld Today, May 11, 2010.)
NicOx Thursday said regulators also called for additional studies to demonstrate a "clinically meaningful therapeutic benefit" of naproxcinod's nitric oxide donation, but the company declined to acknowledge whether those trials were optional or a requirement, simply stating that the FDA had "recommended" the studies.
NicOx initially had sought to include in naproxcinod's labeling claims about gastrointestinal advantages of the drug, but company President Elizabeth Robinson in May said the firm was dropping those assertions after FDA documents made it clear that the duration of the company's studies and endpoints may not be adequate to back up those claims.
About 50 percent of chronic NSAID users are at risk of gastrointestinal ulcers, and developing an effective product that comes without those adverse effects has been difficult.
Currently marketed NSAIDs carry strong warnings about the increased risk of gastrointestinal bleeding.
Chapel Hill, N.C.-based Pozen Inc. and its partner London-based AstraZeneca plc, on the other hand, won the FDA's OK in April for their combination naproxen-esomeprazole arthritis drug Vimovo after those companies' data showed that patients experienced significantly fewer endoscopic gastric ulcers compared with those receiving enteric-coated naproxen. (See BioWorld Today, May 3, 2010.)
Northbrook, Ill.-based Horizon Pharma Inc. also is developing a naproxen combination product, HZN-602, with the intent of improving the drug's gastrointestinal safety profile, while maintaining its ability to reduce pain and inflammation.
HZN-602 is a fixed-dose of immediate-release naproxen with a high dose of famotidine, an H2 antagonist.
One advantage for NicOx is that the FDA is not seeking any additional clinical efficacy studies. The agency earlier had acknowledged that all three of the company's Phase III trials in its application achieved statistical significance in demonstrating that naproxcinod at twice-daily dosages of 375 mg and 750 mg was more effective than placebo in treating osteoarthritis. But the FDA's advisers in May concluded that the company's data were insufficient to determine whether the drug was as effective as naproxen.
NicOx Thursday said it plans to discuss the complete response letter and potential next steps as early as possible with the FDA. The company emphasized that it "remains well funded," with cash, cash equivalents and financial instruments of €138.5 million at the end of March.
"NicOx has no long-term debt and is constantly reviewing all aspects of its cost base to ensure careful conservation of its funds," the company said in a statement.
NicOx told BioWorld Today it could not offer detailed guidance on additional cash needs until it has "evaluated the needs for further naproxcinod studies."
Naproxcinod's marketing authorization application in Europe, which was submitted December 2009, remains under review, with analysts' predictions for a decision from regulators there by the first quarter of next year.
Published July 23, 2010