Novartis plans to resubmit Prexige (lumiracoxib) in the U.S. in the first half of 2007 after the oral COX-2 inhibitor was approved in the European Union and Canada for osteoarthritis symptoms, the company said Nov. 7.

"FDA requested additional data, and we are working closely with them to complete the data required for resubmission," Novartis told "The Pink Sheet" DAILY. "FDA has confirmed that no additional cardiovascular studies are required before resubmission."

In 2004, Novartis pushed back the projected timeline for resubmitting the NDA from 2006 to 2007, shortly after Merck's Vioxx (rofecoxib) was withdrawn from the market due to cardiovascular adverse events. At the time, the company said it expected that FDA could request additional CV data on pipeline COX-2 candidates (¹ Also see "Prexige 2007 Filing Target Assumes FDA Will Request Additional CV Data" - Pink Sheet, 21 October, 2004.).

FDA deemed Prexige "not approvable" in 2003, primarily because of liver toxicity concerns. Since Novartis submitted the NDA, however, the drug maker has completed additional studies, including the 18,000-patient trial, TARGET (The Therapeutic Arthritis Research & Gastrointestinal Event Trial).

Novartis received notification of European approval of Prexige for the symptomatic relief of knee and hip osteoarthritis from the EU's Mutual Recognition Program Nov. 1, the firm said. The company plans to roll out Prexige in Europe during 2007 and 2008. The launch will likely start in Germany, but will ultimately depend on national processes, Novartis said. The drug has been approved in the U.K. since December 2005.

In Canada, Prexige has been approved for signs and symptoms of osteoarthritis of the knee in adults. As part of that approval, the company agreed to conduct a postmarketing study of 20,000 Canadian patients for a two-year period, providing "regular updates" to Health Canada.

The oral selective COX-2 inhibitor will be available in both Europe and Canada in 100 mg tablets dosed once daily. In clinical testing, Prexige has been shown to offer similar pain relief to Pfizer's Celebrex ( celexocib), while demonstrating a superior gastrointestinal safety profile to traditional non-steroidal anti-inflammatory drugs.

The European and Canadian approvals were based on data from clinical trials involving more than 34,000 patients, including TARGET.

TARGET, the largest published one-year study of gastrointestinal safety outcomes in osteoarthritis patients to date, was published in The Lancet in 2004. The trial showed that Prexige had approximately one-third the rate of gastrointestinal side effects compared to the NSAID naproxen (² Also see "Prexige TARGET Study: Not Quite A Bull's-Eye For Novartis" - Pink Sheet, 19 August, 2004.).

The study also found no significant difference in the composite cardiovascular endpoint between Prexige and naproxen, although four (0.11%) patients in the naproxen arm had a myocardial infarction compared to 10 (0.28%) in the Prexige arm.

Dosing in the trial was significantly higher than the 100 mg once daily dosing approved in the EU and Canada. In TARGET, patients were treated with 400 mg Prexige, 800 mg ibuprofen three times daily or 500 mg naproxen twice daily.

EU action on Prexige was delayed because Novartis withdrew its application in 2004 pending outcome of the European Medicines Evaluation Agency's completion of a safety review of the COX-2 inhibitor class (³ Also see "EMEA To Get To Heart Of COX-2 Inhibitor Safety Issues At Feb. 14-17 Meeting" - Pink Sheet, 20 January, 2005.).

Merck is also seeking approval of its Vioxx follow-on Arcoxia (etoricoxib), which is "approvable" at FDA. The company recently released positive preliminary results from a long-term CV safety trial, MEDAL, showing that Arcoxia was non-inferior to diclofenac with regard to the primary endpoint of confirmed thrombotic events (⁴ Also see "Merck’s Vioxx Successor Arcoxia May Be Closer To Market" - Pink Sheet, 23 August, 2006.).

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

Novartis Will Resubmit COX-2 Inhibitor In The U.S. In 2007

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