Cyclosporine has been the therapeutic mainstay for preventing organ rejection after transplantation for 16 years, but has always been associated with serious adverse effects, including kidney damage and hypertension.
Thus, the transplant paradox: “The very organs that the patients and doctors are trying to save through transplantation are damaged by the drugs that we administer to protect them,” said Dr. Pierre Daloze, head of the transplant unit at Montreal’s Notre Dame Hospital, Centre Hospitalier de l’Université de Montréal.
In Canada, organ donation rates do not satisfy the needs of thousands of recipients waiting for an organ.
The Canadian Organ Replacement Register (CORR) estimates that there are approximately 2,822 Canadians currently on a waiting list for a kidney transplant. This shortage means it is critical for each organ transplant to be successful.
Canadian scientists, including Dr. Daloze, have been using an immunosuppression therapy called Rapamune (sirolimus) that is showing promise for resolving the paradox. Rapamune was approved by Health Canada in 2001 to be used in combination with cyclosporine and corticosteroids for the prevention of organ rejection following renal transplantation.
“Kidney transplantation is a relatively common and successful procedure, but an important consideration is that the drugs patients take in order to prevent rejection can produce side effects that are difficult to tolerate, physically and emotionally,” said Dr. Daloze.
Results from Phase III clinical studies demonstrated that Rapamune, when used in combination with cyclosporine and corticosteroids, reduced acute rejection rates by up to 60 per cent in the first six months compared to control regimens. These studies demonstrated that patients treated with Rapamune experienced a reduction in the incidence of all grades of acute rejection episodes.
Ongoing clinical trials with Rapamune are showing that the withdrawal of cyclosporine is not only possible, but increases the survival rate of kidney grafts. The Rapamune Maintenance Regimen (RMR) study’s one-year results were published in the September 2001 issue of Transplantation and the two-year results were presented at the 10th Congress of the European Society for Organ Transplantation (ESOT) in October 2001.
Five hundred and twenty-five kidney transplant recipients participated in this cyclosporine-elimination trial and results included a reduction in hypertension, renal dysfunction, hyperuricemia and Herpes zoster for those patients on the Rapamune maintenance regimen.
“Rapamune was discovered by Canadian scientists, isolated in Canadian labs and Canadian patients participated in all of the clinical trials,” said Dr. Daloze. “Rapamune is truly a Canadian success story.”More than 30 years ago, the Canadian Geographic scientific expedition scoured the exotic landscape of Easter Island. On this small, remote island in the South Pacific, expedition scientists collected soil samples to be screened for medicinal properties.
Rapamune, its name derived from the native term for Easter Island, Rapa Nui, was initially developed to treat fungal infections. However, Ayerst researchers in Montreal found that while it was a successful anti-fungal agent, the drug produced an unexpected side effect in these patients, suppressing their immune system. As a result, research on its use as an anti-fungal ceased. In the interim, the company’s scientists focused on how the drug could be used to treat cancer. Two studies showed that Rapamune was a cytostatic agent, meaning that it blocked the proliferation of cells without killing them.
“The future for Rapamune appears very bright,” said Dr. Daloze. “Clinical studies are underway for immunosuppression of both heart and liver transplants, and pre-clinical studies have already shown its effectiveness in the treatment of cancer.”