By Lisa Seachrist
SILVER SPRING, Md. — An FDA advisory panel endorsed Monsanto Co.'s new non-steroidal anti-inflammatory drug (NSAID) Celebrex to treat the signs and symptoms of arthritis without serious gastrointestinal (GI) side effects.
The Arthritis Advisory Committee voted unanimously to recommend that the agency approve Celebrex (celecoxib) for the treatment of osteoarthritis and rheumatoid arthritis. In addition, the panel recommended that the drug's label indicate that the drug is less likely to cause ulcers and interfere with platelet aggregation than other NSAIDs.
"Most of us believe that this drug has gone a long way to establishing this a COX-2 selective agent," said panel Chairman Steven Abramson, who is also chairman of rheumatology and medicine at the Hospital for Joint Diseases, in New York. "I am very impressed with the clinical data."
Philip Needleman, co-president at G.D. Searle, the pharmaceutical division of St. Louis-based Monsanto, and chief scientist at Monsanto, said staffers are "pretty satisfied with the outcome. This is the acceptance of the notion that this is the beginning of the era of smart drugs."
Celebrex Stops Prostaglandin-Making Enzyme
Prostaglandins cause the pain associated with inflammation. Normally, these ubiquitous substances carry out "housekeeping" duties all over the body. When disease or trauma triggers inflammation, the body produces a flood a prostaglandins.
All NSAIDs ease pain and inflammation by inhibiting the enzymes (cyclooxygenases) that create prostaglandins from the fatty acid arachidonic acid. Unfortunately, in blocking the production of prostaglandins, NSAIDs as a class can lead to stomach ulceration and perforation.
Currently approved NSAIDs indiscriminately block both cyclooxygenase-1 (COX-1) and cyclooxygenase-2 (COX-2). Present in most human tissues, COX-1 is vital to protecting the GI system and maintaining normal platelet count. COX-2 is turned on by inflammatory cells, and is present in the brain, kidney and female reproductive tract.
Monsanto developed the COX-2 inhibiting Celebrex with the idea that blocking COX-1can lead to GI ulceration and bleeding, inhibition of platelet aggregation and dangerous interactions with other drugs. As a result, the company is requesting that, in approving Celebrex, the agency drop for this product the gastrointestinal warning that is standard for the label of NSAIDs.
Such a label would give the drug a huge advantage in the marketplace, where upper GI complications from NSAID use currently result in 107,000 hospitalizations and 16,500 deaths each year in the U.S.
Searle presented data from clinical trials representing more than 11,000 patients. The company focused on its Phase III trials in North America in both osteoarthritis and rheumatoid arthritis.
In those studies, the company showed that Celebrex was as effective in treating arthritis as several other NSAIDs including naproxen sodium, ibuprofen and diclofenac. In addition, Celebrex also proved compatible with two medications commonly prescribed to arthritis patients: methotrexate for the treatment of rheumatoid arthritis; and warfarin, a blood thinner prescribed for concomitant cardiovascular conditions such as blood clots.
Searle also presented data showing there was a significant decrease in ulcers that could be detected with endoscopy, compared to other NSAIDs. Ten percent of placebo patients had ulcers on endoscopy, compared to 11 percent of patients receiving Celebrex. Thirty-three percent of patients on the other NSAIDs, however, had such ulcers.
"We are talking about rational drug design that spares the COX-1 function, resulting in fewer side effects," said Needleman.
The agency, however, took issue with the company's claim that Celebrex had fewer GI side effects, noting that fewer ulcers identified with an endoscope may not necessarily translate into less gastric ulceration and perforation. The agency also noted that the studies of Celebrex were insufficiently powered to determine whether the drug was safer than commonly used NSAIDs.
"The data aren't adequate to determine an annual event rate," said Lawrence Goldkind, medical officer with FDA's division of gastrointestinal and coagulation drugs. "We would recommend a Phase IV study to assess that claim."
Panel Recommends Revising GI Effects Warning
The panel recommended that the agency put the GI information generated by the sponsor in the label. Panel members were unwilling to completely lift the GI warnings that accompany the label for all NSAIDs, because patients are still at risk for ulcer when using Celebrex; however, they recommended the agency seriously alter the warning.
"My view is that the agency should look at the words in the warning and see which apply for this drug," said panel member Daniel Lovell, a pediatric rheumatologist at Children's Hospital Medical Center, in Cincinnati. "A lot of the wording in that warning is not accurate, in light of the data we have for this drug."
The company and the FDA agreed that Celebrex had renal toxicities similar to those found in all NSAIDs, indicating that renal complications may be the result of COX-2 inhibition.
The agency also had questions about whether Celebrex should be labeled for pain management. The committee didn't specifically make recommendations for that indication, but it did indicate that studies of dental pain and osteoarthritis pain make a strong case for such a label. In addition, because Celebrex has no effect on platelets, the committee recommended that the agency remove warnings about using low-dose aspirin in combination with the drug.
Should the FDA approve Celebrex, G.D. Searle and Pfizer Inc. of New York, will commercialize the product in the U.S. and develop the drug elsewhere in the world except in Japan, where Searle will develop the drug with Yamanouchi Pharmaceutical Corp. Ltd., of Tokyo. The agency usually chooses to follow the advice of its advisory panels, but is not bound to do so.
The agency has a statutory obligation to deliver an action letter to the company by the end of December. Monsanto's stock (NYSE:MTC) closed Tuesday at $43.50, down $1.812. *