Delivering a blow to Swiss giant Novartis, the US Food and Drug Administration yesterday issued a not approvable letter for its new-generation COX-2 inhibitor Prexige (lumiracoxib) as a once-daily treatment for patients suffering pain from osteoarthritis.

Earlier this month, Novartis’ Chief Executive Daniel Vasella said he feared the firm would not garner US approval for the drug and now these concerns have been confirmed, though in a statement issued today the firm seemed surprised by the non-approvable status, saying it was delivered “despite a clinical trial database…that comprises approximately 40,000 patients and is one of the largest bodies of evidence for any of the drugs in this class.”

The FDA is understandably wary about COX-2s following the 2004 withdrawal of Merck & Co’s blockbuster Vioxx (rofecoxib) and the fallout from the drug class that has occurred since. Indeed, the agency was not immune to criticism during that time as observers weighed in to say its drug approval processes were insufficient in weeding out potentially risky medicines.

But James Shannon, Global Head of Development at Novartis Pharma AG, said the firm continues to believe Prexige can play an important role in treating osteoarthritic pain and it will continue discussions with the FDA.

In the largest clinical study included in the dossier, TARGET, results from more than 18,000 patients showed Prexige cut the incidence of upper gastrointestinal complications by 79% compared to two widely-used non-steroidal anti-inflammatory drugs, ibuprofen and naproxen. Furthermore, it states, Prexige had less impact on blood pressure than either NSAID, with no significant difference in cardiovascular events such as heart attack or stroke.

However, Prexige has also been hit by concerns over liver safety. Prexige is currently approved in more than 50 countries, but has been withdrawn in Australia and placed under restrictions in the European Union amid fears that it may cause serious liver damage. Health Canada is conducting a review of the drug and New Zealand has withdrawn the supply of 200mg and 400mg Prexige tablets.

Still hope for Prexige in limited patient group

At the FDA's request, Novartis submitted clinical data on the liver profile of the proposed 100mg 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 programme. Despite this data, the FDA deemed Prexige not approvable.

There is still perhaps hope for Prexige; the FDA noted in its response that it remained open to exploring its use in patients where Prexige would provide an acceptable benefit-to-risk balance, for example, those with a higher incidence of gastrointestinal complications, including ulcers, people being treated with anticoagulants.