Another Go At Certican: Novartis Transplant Agent To Go To Advisory Committee

Dec. 7 meeting marks the third review cycle for the transplant indication for everolimus, which previously received two "approvable" letters.

Novartis has another chance to bring everolimus to market in the U.S. for its originally proposed setting - prevention of transplant rejection - with a new set of clinical data and a narrower indication. FDA's Cardiovascular and Renal Drugs Advisory Committee will assess the merits of this application, the panel's second review of the agent on Dec. 7.

Novartis' earlier attempts to gain approval for the proliferation inhibitor as a transplant agent met with "approvable" letters from FDA. The first came in October 2003; the second, in August 2004, requested further study on use in combination with lower cyclosporine doses. Instead of conducting that study, Novartis did an extension of a heart transplant study.

Based on concerns over safety more than efficacy, the Cardio-Renal advisory committee recommended against approval in November 2005. The panel determined in a split 7-6 vote that there was not sufficient information available to conclude that the sponsor's proposed regimen had been demonstrated as safe and effective in heart transplantation, and called for further short-term studies with lower doses of cyclosporine that would better clarify renal safety (Also see "Novartis Certican Short-Term Renal Safety Study Suggested By Panel" - Pink Sheet, 21 Nov, 2005.).

The company had better luck, however, getting the same molecule cleared in other settings. FDA's oncology office approved everolimus as Afinitor in March (Also see "Afinitor Wins FDA Nod For Kidney Cancer" - Pink Sheet, 30 Mar, 2009.). Everolimus also is cleared by the device center as the drug in Abbott's drug-eluting stent Xcience .

Everolimus is marketed for transplant use as Certican in 60 markets around the world, Novartis points out.

In this go round, Novartis is shifting focus to a new everolimus indication - prevention of rejection of transplanted kidneys only - and leaving aside the previously rejected heart transplant claim.

In the kidney transplant setting, Novartis conducted additional clinical trials as well as long-term follow-up of earlier pivotal trials.

But the company has not yet given up on gaining approval for use with heart transplant. Novartis has continued on with a robust clinical trial program in the transplant setting, testing everolimus in settings like heart, kidney, liver and lung transplantation against/with a variety of immunosuppressive agents.

Trials versus different drugs may address some of the 2005 advisory panel's concerns that everolimus didn't shown enough of an efficacy advantage against other therapies to treat heart transplant patients.

The firm is still recruiting patients into a major trial of the efficacy and safety of everolimus and reduced cyclosporine in recipients of heart transplants, initiated after the initial advisory committee recommendation. Data are expected in 2011.

Novartis also is pursing a raft of additional indications. The drug is an inhibitor of the mammalian target of rapamycin, like Wyeth's Torisel (temsirolimus), which was the first mTOR agent approved for renal cancer. The anti-cell proliferation effects of the mechanism of action mean the target is valuable for both prevention of transplant rejection and to treat tumors.

-Mary Jo Laffler ([email protected])