Approval Of Novartis' Everolimus Could Mean mTOR Inhibitor Class REMS

The likely approval of Novartis' everolimus for prevention of kidney transplant rejection could bring with it safety labeling updates and Risk Evaluation and Mitigation Strategies for all drugs in the mTOR inhibitor class.

FDA's Cardiovascular and Renal Drugs Advisory Committee voted 11-1 to recommend approval of everolimus for use to prevent rejection in kidney transplantation at a Dec. 7 meeting (¹ (Also see "Panel Recommends Novartis' Kidney Transplant Drug Certican" - Pink Sheet, 7 Dec, 2009.)). The panel agreed that a REMS is necessary for the drug - and Novartis has already voluntarily submitted one to FDA - but stressed that everolimus' safety profile is similar to, and not any worse than, those of other drugs in the mTOR inhibitor class, including Pfizer's Rapamune (sirolimus) and Torisel (temsirolimus).

The safety issues of primary concern include proteinuria, lipid elevations and wound-healing complications. If approved according to the panel's recommendations, everolimus would be the first transplant medication with a REMS, and could set a new safety monitoring standard for the field.

"I felt that, yes, there is some concern about some of the cardiovascular issues, but I have a hard time getting out of my mind this class of mTOR inhibitors and how different or similar this one is to sirolimus - and I didn't feel like it is very different at all," said panel member Robert Dupuis, University of North Carolina. "I voted for REMS because I think we need to emphasize this aspect of cardiovascular outcomes to a greater degree than we do, particularly in the transplant community."

Due to consensus on this point, FDA Division of Special Pathogen Transplant Products Director Renata Albrecht asked the panel whether it was worth revisiting the safety labeling for the mTOR class.

"I think it's definitely something that should be studied for this class," said committee member Volker Nickeleit, University of North Carolina - especially in light of the growing body of data shedding light on the importance and potential benefits of mTOR inhibition.

Committee member Elaine Morrato, University of Colorado, agreed with the importance of studying safety across the entire class. "Some of these are questions that would be for the mTOR class, not just this drug," she said. "So conceptualization of this might be an observational study or a registry type trial - to think of it maybe a bit more broadly. It may be challenging working with different sponsors ... but some of these seem to be class-based kinds of questions."

Everolimus Worked With Less Immunosuppression

The favorable vote for everolimus came four years after the same committee voted against the agent for use in heart transplantation (² (Also see "Novartis Certican Short-Term Renal Safety Study Suggested By Panel" - Pink Sheet, 21 Nov, 2005.)).

It was taking that earlier committee's advice the provided the selling point for the current committee: Novartis went back and studied several doses of everolimus with lower doses of cyclosporine, finding the drug to be non-inferior to the firm's own Myfortic (mycophenolic acid) - a benefit proven without the risk of concomitant use of high doses of the immunosuppressant cyclosporine.

Novartis' proposed treatment regimen is to start patients on 1.5 mg everolimus per day, then to adjust the dose to reach a target trough concentration of 3-8 ng/mL. Everolimus would be taken concurrently with 100 to 200 ng/mL cyclosporine for the first month, 75 to 150 ng/mL for the second and third months, 50 to 100 ng/mL for the fourth and fifth months, and 25-50 ng/mL for month six and beyond. The firm said those levels of cyclosporine are 50 percent to 60 percent lower than those traditionally used.

"I think what is being given to you today is awfully novel, in that I never would have thought 50 ng/mL as a trough level of cyclosporine has all that much efficacy at all," said Novartis consultant Stuart Flechner, Cleveland Clinic. "So I reflect here that the combination with the mTOR inhibitor is permitting such low levels of cyclosporine with maintenance of efficacy that it is a huge advantage."

Further, he said, "one would contemplate that over time, the negative impact of the calcineurin inhibitor [cyclosporine] on the kidney is less. Has that been proven? No. Do we have five- to 10-year data? No. But I think one would assume keeping doses at such a low level is going to be beneficial to kidney function."

Committee member Richard Mann, University of Medicine and Dentistry of New Jersey, also was impressed by how low the cyclosporine levels were in the study. "I would never have felt comfortable keeping a patient on levels of cyclosporine ... of 25 to 50 [ng/mL] that are being used in this study. ... I would say that I agree that we have not used calcineurin inhibitor levels anywhere near this low ... it looks at what we can do in terms of minimizing calcineurin inhibitor long-term toxicity."

Could REMS Control Off-Label Use?

But acting panel chair Emil Paganini, Critical Care Nephrology Consulting, pointed out that demonstration of benefit with the lower doses of cyclosporine would make off-label use of everolimus an attractive treatment option for patients older and sicker than the sponsor's proposed patient population: low-to-moderate immunological risk patients.

Other panel members confirmed the inevitability of off-label use, which they said is high already with Rapamune.

Novartis' proposed REMS - which includes a Medication Guide, user surveys, a communication plan, and program evaluation tools - would not likely control for off-label use, and the committee had many suggestions to improve the plan.

"I would really discourage off-label," Paganini said. "But if you're going to do off-label ... there should be some sort of method to capture all of that data, so that we can analyze the off-label use and see in fact ... if someone who is a little bit more tenuous is helped by this drug or hurt by this drug."

Several members suggested long-term studies to evaluate cardiovascular risk, greater clarity in labeling of dose titration recommendations, and very specific recommendations as to what the sponsor and FDA mean in terms of "routine" testing for drug levels, lipids and proteins.

Panel member Morrato suggested a more proactive approach to the REMS, with evaluation of the program occurring sooner than the sponsor's proposed 18 months post-launch (a standard timeframe for REMS).

"Much of the REMS is focused on written material - labeling, medication guide, pamphlet, kits, etc. - and we know that written materials in and of themselves are not always very efficient in actually increasing awareness," she said. Paganini agreed, adding that "I would even go so far as to say that anybody that is going to prescribe this product should take some sort of computer course. ...some sort of quick, one-hour computer thing about the drug."

Morrato also suggested the company rely more on objective measurement than patient-reporting by looking at electronic medical records to determine the frequency of lipid and blood examination. Paganini agreed, noting that practice patterns likely will change if everolimus is introduced, and should be monitored.

- Jamie Hammon ( ³ [email protected] )