Novartis has received a "not approvable" letter from FDA for its COX-2 inhibitor Prexige (lumiracoxib) for osteoarthritic pain, the firm announced Sept. 27.

The outcome of the review is not unexpected; during a Sept. 12 business review, CEO Daniel Vasella told analysts, "I don't think we will get an approval" (¹ Also see "Tasigna Approval May Be Again Delayed To Allow FDA Advisory Cmte. Review – Novartis" - Pink Sheet, 12 September, 2007.).

The company had resubmitted the NDA in March after receiving a "not approvable" letter in 2003.

Novartis is not completely abandoning hope that Prexige could be approved for specific populations, however.

"Now that we have the FDA's decision, we will start the discussions with them as soon as possible to seek to agree on a path forward, including as to the nature (size, duration, etc.) of the studies that may be required" to gain approval, Novartis told "The Pink Sheet" DAILY.

"FDA noted in its response that it remained open to exploring the use of this medicine in patients where Prexige would provide an acceptable benefit-to-risk balance," the company pointed out in a same-day statement.

"This group could include patients with a higher incidence of gastrointestinal complications, including those suffering from ulcers or being treated with anticoagulants."

While the company would not specify the FDA's reasons for deeming the drug not approvable, the agency had requested that Novartis submit clinical data on the liver profile of the proposed 100 mg once-daily dose studied over 12 months of therapy.

Prexige was withdrawn recently in Australia after two patients died from serious liver injury following treatment. The Australian Therapeutic Goods Administration said it has received eight reports of serious hepatic adverse reactions associated with lumiracoxib, including two deaths and two patients requiring liver transplants (² Also see "Novartis Withdraws Prexige In Australia Ahead Of FDA Decision Due To Deaths" - Pink Sheet, 13 August, 2007.).

FDA's decision "came despite a clinical trial database for Prexige that comprises approximately 40,000 patients and is one of the largest bodies of evidence for any drug in this class," Novartis asserted.

Results of the 18,000-patient Therapeutic Arthritis Research and Gastrointestinal Event Trial (TARGET) demonstrated less than one percent of patients had elevations of the liver enzymes aspartate aminotransferase and alanine aminotransferase greater than three times the upper limit of normal, "which is similar to levels observed with currently available NSAIDs."

There were no cases of jaundice or hepatic failure on Prexige 100 mg once-daily dosing in the clinical development program, the company said.

TARGET additionally showed Prexige 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, Novartis noted.

FDA cited concerns with cardiovascular safety when it issued a "not approvable" letter for Merck's COX-2 inhibitor Arcoxia (etoricoxib) for the same indication in April (³ Also see "FDA Cold-Cox Merck; Arcoxia “Not Approvable” For Osteoarthritis" - Pink Sheet, 27 April, 2007.).

-Brooke McManus (b.mcmanus@elsevier.com)

No Big Surprise For Novartis: Prexige Is “Not Approvable” At FDA

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