Novartis Pharmaceuticals AG (BASEL, Switzerland) announced that it has received a "not approvable" letter from the US FDA for its COX-2 inhibitor Prexige® (lumiracoxib) as a once-daily treatment for patients suffering from pain due to osteoarthritis. Although the rejection by the US FDA of Novartis' drug application was widely expected, the company intends to continue discussions with the FDA as it still believes that lumiracoxib has fewer side effects than other nonsteroidal anti-inflammatory drugs (NSAIDs) and that it remains an important therapy for appropriate patients with osteoarthritic pain.

The FDA's response came despite a clinical trial database for lumiracoxib that comprises approximately 40,000 patients and is one of the largest bodies of evidence for any drug in this class. In particular, results of the TARGET study involving more than 18,000 patients showed lumiracoxib reduced the incidence of serious upper gastrointestinal complications by 79% compared with two widely-used NSAIDs, naproxen and ibuprofen, in patients not taking aspirin. TARGET also showed lumiracoxib was associated with significantly smaller increases in blood pressure than naproxen and ibuprofen, with no significant difference in cardiovascular events such as heart attack or stroke.
 
At the FDA's request, Novartis submitted clinical data on the liver profile of the proposed Prexige 100 mg once-daily dose studied over 12 months of therapy. The results showed 0.85% of patients had elevations of the liver enzymes aspartate aminotransferase (AST) and alanine aminotransferase (ALT) of greater than "three times the upper limit of normal," which is similar to levels observed with currently available NSAIDs. There were also no cases of jaundice or hepatic failure on Prexige 100 mg once-daily dosing in the clinical development program. Despite these data, the FDA deemed the drug not approvable.
 
The FDA noted in its response that it remained open to exploring the use of this medicine in patients for whom Prexige would provide an acceptable benefit-to-risk balance. This group could include patients with a higher incidence of gastrointestinal complications, including those suffering from ulcers or being treated with anticoagulants.
 
Novartis had to withdraw all doses (100 mg, 200 mg, and 400 mg tablets) of lumiracoxib from the Australian market in August following at least eight reports of serious liver side effects including the death of two patients and the need for liver transplants in at least two other patients, believed to be caused by lumiracoxib. Australia was one of the first countries to approve lumiracoxib, prior to studies demonstrating that the 100 mg dose is as effective as the higher doses but with fewer side effects.

Novartis intends to continue to introduce lumiracoxib in Europe where it received marketing approval in November 2006, but has notified physicians that the drug should not be used in those with liver disease or those at risk with respect to their clinical histories or other prescribed medicines taken. Prexige is sold in more than 50 countries, where only the 100 mg dose is marketed, accounting for over 7 million prescriptions. An alternative trade name for this medicine has been submitted to the US FDA approval.

—A. Techman