FDA's "complete response" letter to NicOx for its nonsteroidal anti-inflammatory drug naproxcinod underscores the difficulty of developing NSAIDs in the post- Vioxx era. Not only will the firm need to do additional safety studies, but it still needs to show the clinical benefit of what it hopes will be naproxcinod's key market differentiator.

The product had suffered an overwhelmingly negative advisory committee vote, so FDA's letter, announced July 22 (two days before the user fee deadline), was not a genuine surprise, and might even be welcome at the company because it offers goalposts to aim for as NicOx contemplates the next steps for the product.

The agency recommended one or more long-term controlled studies to assess the drug's cardiovascular and gastrointestinal safety, according to a NicOx statement.

"Additional studies to demonstrate a clinically-meaningful therapeutic benefit attributable to the nitric oxide donation were also requested," the company said. That request might suggest that FDA is open to the possibility of advantageous side effect labeling. The firm noted that "no clinical efficacy studies were requested."

Naproxcinod was developed to address gastropathy and elevated blood pressure, two side effects associated with other NSAID products. After naproxcinod is taken orally, it is hydrolyzed into naproxen and nitric oxide. The nitric oxide is thought to stimulate GI protective factors in the body and fight the rise of blood pressure caused by NSAIDs.

The additional studies would address the problems that FDA reviewers had with the original application. In briefing documents, the agency said the company did not adequately prove it addressed the GI and blood pressure NSAID side effects and recommended neither claim be included in the product label if it was approved (Also see "NicOx Takes It In The Gut: FDA Not Accepting Naproxcinod Claims On Blood Pressure Or GI Safety" - Pink Sheet, 11 May, 2010.).

FDA reviewers concluded the data indicated naproxcinod was effective in osteoarthritis versus placebo, but did not support the claim naproxcinod was not inferior to the NSAID naproxen (Roche's Naprosyn and others).

The company also withdrew a proposed claim naproxcinod could significantly decrease ulcers just before the advisory committee meeting began after FDA determined the company's studies did not use an acceptable endpoint.

Optimism Evident At Advisory Committee

While FDA's Drug Safety and Risk Management and Arthritis Advisory Committees clearly voted against recommending approval of naproxcinod on May 12, members were not totally against the drug. But they did indicate they wanted more data.

Committee members, who voted 16-1-1 against approval, were offering encouragement and appeared to recognize the drug has promise. They said they recognized its effectiveness against placebo, but there was not enough evidence to support claims it reduced NSAID side effects (Also see "Naproxcinod Effective But Safety Concerns Remain, Advisory Committee Says" - Pink Sheet, 12 May, 2010.).

"Although there is enthusiasm about the concept, and I would love for it to be true, I don't believe that sponsor demonstrated that it is true," David Blumenthal, Cleveland Veterans Affairs Medical Center, said during the meeting.

Clinicians on the panel were unsure whether they would prescribe it, given the evidence presented. And without a GI tolerability or blood pressure benefit claim, it would be difficult for naproxcinod to develop a market niche.

NicOx did not conduct an outcome study for its naproxcinod application, as usually is required with novel NSAIDs. It instead submitted a non-inferiority trial against naproxen, three GI tolerability studies and three blood pressure studies. FDA asked for outcome studies, but could not require them (Also see "Naproxcinod Approval Not Likely Without New Trials, But Which Trials Unclear" - Pink Sheet, 17 May, 2010.).

EMA Approval In Trouble?

NicOx said it will discuss the "complete response" letter and next steps with FDA as soon as possible.

The drug still is under review by the European Medicines Agency. The application was submitted in December 2009 and an approval decision is expected in the first quarter of 2011, according to a Piper Jaffray analyst note.

"We believe investors are unlikely to afford the stock greater value until they see European naproxcinod approval, which given the FDA's stance, may be riskier than usual," analysts said in the note.

-Derrick Gingery (d.gingery@elsevier.com)

Naproxcinod Must Show More Data On Both Safety And Therapeutic Benefit After "Complete Response" Letter

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