A decision to withdraw Novartis' Prexige (lumiracoxib) in Australia after two patients died from serious liver injury following treatment with the drug is likely to impact the outcome of FDA's decision on a pending NDA for the COX-2 inhibitor.

The Australian Therapeutic Goods Administration issued an announcement Aug. 10 recalling Prexige because of serious liver side effects. The TGA said it has received eight reports of serious hepatic adverse reactions associated with lumiracoxib, including two deaths and two patients requiring liver transplants. All of the reports have come since March 2007, with six of the cases reported in the last six weeks, the agency said. As a result, TGA acted to withdraw the drug Aug. 10.

"Although there is limited data on the natural history of the hepatic side effects of lumiracoxib, the pre-registration clinical trial data suggested that if a patient developed elevated liver function tests while on the drug, they were likely to normalize their biochemistry when the lumiracoxib was ceased," the agency stated. "However, in the eight serious Australia reports studied, some patients have not improved on cessation of the medicine due to the severity of the hepatic injury."

Patients are advised to cease taking the medication immediately and be assessed for liver damage by a physician.

Novartis issued a statement Aug. 11, pointing out that serious liver side effects have been reported rarely for all COX-2 inhibitors and traditional non-steroidal anti-inflammatory drugs. The company estimated that approximately 60,000 patients have been treated with Prexige in Australia, and that the majority of patients have received the 200 mg formula.

In the U.S., Novartis' is seeking approval of a lower, 100 mg dose of Prexige, similar to the dosage approved in Europe and Canada. The company has been anticipating FDA action on the NDA later this year after the agency informed the company that it would not convene an Arthritis Drugs Advisory Committee meeting to review the application (¹ Also see "Prexige Review Will Not Include FDA Arthritis Drugs Advisory Committee" - Pink Sheet, 15 June, 2007.).

Much of the spotlight around COX-2's has focused on cardiovascular risks, not liver concerns, especially after FDA's April rejection of Merck's Vioxx follow-on Arcoxia (etoricoxib) for osteoarthritis due to increased cardiovascular risks (² Also see "FDA Cold-Cox Merck; Arcoxia “Not Approvable” For Osteoarthritis" - Pink Sheet, 27 April, 2007.).

Nonetheless, the latest concerns do not come without some initial warning. FDA deemed Prexige "not approvable" in 2003 primarily due to liver toxicity issues. Since Novartis' original NDA submission, the company completed an 18,000-patient trial, TARGET. The company has maintained that Prexige is a different kind of COX-2 with a shorter plasma half life. It was approved for the treatment of osteoarthritis symptoms in Europe and Canada in 2006.

In an Aug. 13 note, A.G. Edwards analyst Joseph Tooley noted that, "While this is a setback for [Novartis] and patients who depend on the COX-2 inhibitor for critical pain management, this will not dramatically affect [Novartis'] long-term prospects." Prexige posted $33 million in 2006 sales. Tooley said he estimated that sales would reach $125 million in 2007, excluding U.S. revenues.

Novartis, however, has been more bullish on lumiracoxib, with Pharmaceuticals CEO Thomas Ebeling predicting in January that the drug would reach blockbuster status (³ Also see "Novartis Bullish About Prexige; Anticipates Blockbuster Potential" - Pink Sheet, 18 January, 2007.).

- Jessica Merrill (j.merrill@elsevier.com)

Novartis Withdraws Prexige In Australia Ahead Of FDA Decision Due To Deaths

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