May 18, 2004 (Boston) — The experimental immunosuppressant drug everolimus can be safely administered and appears to be effective in preventing rejection in de novo liver transplants, according to a research presented here Monday.

Gary A. Levy, MD, FRCP, director of the Multi Organ Transplant Program at Toronto General Hospital in Ontario, presented results from his center at the 2004 annual meeting of the American Transplant Congress, the joint meeting of the American Society of Transplant Surgeons and the American Society of Transplantation.

Dr.Levy presented results from a 12-month randomized controlled, double-blind trial, plus a 24-month open-label extension. In the study, 119 liver transplant patients were randomized to one of three doses of everolimus (1 mg, 2 mg, or 4 mg daily) plus cyclosporine and steroids or to placebo plus cyclosporine and steroids.

At 12 months, the drop-out rates were higher for patients taking everolimus — from 57% to 64% — than for placebo (43%), and about half of the discontinuations were for adverse events.

Of the patients eligible to continue in the open-label extension, 10 taking 1 mg, 8 taking 2 mg, and 2 taking 4 mg everolimus choose to do so, for a completion rate of 91% at the 1-mg dose, 72.7% at the 2-mg dose, and 33.3% at the 4-mg dose.

There was a trend toward more thrombocytopenia, greater hypercholesterolemia (7%, 10%, and 10% for the 1 mg, 2 mg, and 4 mg doses, respectively, compared with 3% for placebo), and worsened renal function at 12 and 36 months for the everolimus patients. Renal dysfunction ranged from 10% to 21% in the everolimus groups compared with 7% in the placebo group.

However, when analyzed for platelet count, most patients were within the normal range, suggesting that the trend might not be clinically significant except at the higher 4 mg dose, Dr. Levy told Medscape.

"At all doses it is safe, but there is a trend towards more adverse events at the higher dose," he said, noting that there were also dose-related effects on creatinine clearance.

There was also a trend toward a lower incidence of death and rejection in the higher dose groups, but Dr. Levy said that the 2-mg dose would might likely be the one pursued for marketing, as it appears to have the appropriate balance of safety and efficacy.

After 36 months, graft survival ranged from 80% to 96% in the everolimus groups.

Dr. Levy said that Toronto General and the other sites were in the beginning stage of planning phase III trials in liver transplantation.

In viewing Dr. Levy's paper, James Trotter, MD, an assistant professor of medicine at the University of Colorado Health Sciences Center in Denver, said that he and other surgeons were looking forward to the availability of everolimus. He said he was not surprised by the results, and expected it to be a relatively safe and effective therapy.

"This class of drug is probably the best out there," he said.

Dr. Levy said everolimus would likely be used initially in combination with other calcineurin inhibitors, but it could eventually be used as a stand-alone therapy for maintenance.

ATC 2004: Abstract 756. Presented May 17, 2004.

Reviewed by Gary D. Vogin, MD