Novartis may encounter another delay in the path to approval of its next-generation chronic myeloid leukemia therapy Tasigna (nilotinib) if FDA requires that the drug be reviewed by the agency's Oncologic Drugs Advisory Committee later this year.

FDA has said "they may ask us for an ODAC in December, [although] they have not officially asked for that meeting yet," Novartis Oncology President David Epstein said during the firm's Sept. 12 pharma brand and business review.

[Editor's note: Epstein talked extensively about Tasigna during an interview with "The Pink Sheet" DAILY in January (¹ Also see "Novartis Oncology President David Epstein: An Interview With “The Pink Sheet” DAILY (Part 1 of 2)" - Pink Sheet, 19 January, 2007.) .]

The user fee deadline for the selective Bcr-Abl inhibitor had already been delayed by three months to late October to allow FDA to review additional data (² Also see "Novartis To Resubmit Galvus In Mid-2009" - Pink Sheet, 17 July, 2007.).

It is unclear now whether that action date is still accurate, Epstein added. Novartis filed an NDA for Tasigna in November 2006 (³ Also see "Novartis On The Move: Firm Files Tasigna, Aclasta Ahead Of Schedule" - Pink Sheet, 28 November, 2006.).

One area the agency may be seeking advisory panel input on is the risk/benefit profile of Tasigna. In the course of Novartis' clinical studies, 10 sudden deaths occurred in a population of 2,800 patients.

While initially the trial had "liberal entry criteria," following the first six deaths, the company strengthened the criteria to mirror that used by Bristol-Myers Squibb in its study of Sprycel (dasatinib), Epstein said. The revised criteria excluded "patients that have had [a myocardial infarction] within the previous 12 months or patients that had a baseline QTc interval of greater than 450 milliseconds."

The number of deaths declined thereafter, but still, "the total of 10 sudden deaths has raised discussion points with the regulatory agencies as you would expect it would."

Of those cases, five were not related to Tasigna, while in five patients, it was not clear whether the deaths could be linked to the drug.

"We have learned that it's very important that patients who have a history of cardiac disease or patients that are at risk of QTc prolongation not be exposed to the therapy," Epstein noted.

Novartis, however, continues "to be bullish about the eventual approval of this drug with the appropriate labeling to exclude patients who may be at risk," he concluded.

While the risks of the therapy in certain patients may give FDA pause, "the efficacy data is quite good," Epstein maintained.

The firm also is looking to file Tasigna for treatment of gastrointestinal stromal tumors in 2009, according to Novartis' Web site.

In addition to Tasigna, Novartis has been plagued with delays for several other major products.

The company announced in July that a resubmission of its dipeptidyl peptidase-4 agent Galvus (vildagliptin) for type 2 diabetes will be pushed back to 2009, because an additional safety study on patients with renal impairment is expected to take longer than initially anticipated.

In addition, Novartis has encountered many roadblocks in the approval process for its selective COX-2 inhibitor Prexige (lumiracoxib) for the treatment of osteoarthritis symptoms. The company resubmitted the NDA in March after receiving a "not approvable" letter in 2003.

Once optimistic about Prexige's chances, Novartis is now acknowledging approval may be a long shot, in light of the negative environment for COX-2 inhibitors and the recent withdrawal of lumiracoxib in Australia due to two patient deaths.

"I will give you my personal opinion: I don't think we will get an approval," CEO Daniel Vasella stated during the review. The NDA has a Sept. 26 action date.

FDA issued a "not approvable" letter for Merck's COX-2 inhibitor Arcoxia (etoricoxib) for the same indication in April (⁴ Also see "FDA Cold-Cox Merck; Arcoxia “Not Approvable” For Osteoarthritis" - Pink Sheet, 27 April, 2007.).

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

Tasigna Approval May Be Again Delayed To Allow FDA Advisory Cmte. Review – Novartis

More from Archive

More from Pink Sheet