Symposia underscore role of Rapamune (Sirolimus) in eliminating Nephrotoxic Immunosuppression in kidney transplant patients ::Sirolimus cited as viable altern


Researchers here on Monday reported that the immunosuppressive agent Rapamune (sirolimus) can be safely and effectively used as the primary drug for maintenance therapy in preventing acute rejection in kidney transplant patients.

Unlike the class of immunosuppressant drugs known as calcineurin inhibitors, which includes the widely used cyclosporine, sirolimus has a mechanism of action that does not produce such adverse effects as kidney damage, high blood pressure or tremor, which are common side effects of cyclosporine.

These findings were presented this week at two symposia during the XVIII International Congress of the Transplantation Society.

"While many patients have indeed benefited from the basic immunosuppressive effects of calcineurin inhibitors, many patients have also suffered from the toxicities that accompany long-term use of these drugs," said symposium panellist Professor Henri Kreis of Hopital Necker, Paris.

"There is a clear need for an alternative therapy to be fully integrated into the immunosuppressive regimen in order to decrease or to eliminate the array of adverse effects caused by calcineurin inhibitors."

Symposium panellist Professor Betram L. Kasiske of Hennepin County Medical Centre in Minneapolis, Minnesota, United States, outlined the various adverse effects caused by calcineurin inhibitors, emphasising that the toxicities produced by these drugs have spurred research efforts aimed at developing an alternative long-term immunosuppression regimen.

He cited the wealth of evidence documenting calcineurin inhibitors' major problem; that is, their propensity for both acute and chronic nephrotoxicity (kidney damage).

He commented further on the equally problematic effect of these drugs' ability to increase cardiovascular risk factors, notably, higher blood pressure. ::Mechanism of Action as it Relates to Toxicity

The primary problem associated with calcineurin inhibitors is nephrotoxicity, which is linked to the mechanism of action employed by this class of immunosuppressants. Calcineurin is an important enzyme in the body's normal immune response system, but calcineurin inhibition also alters the way certain genes are expressed, thereby setting in motion the chain of events that causes nephrotoxicity.

Alternatively, the mechanism of action for Rapamune is to inhibit the activation of TOR (target of rapamycin), a newly discovered class of intracellular synthetic proteins central to the immune response system.

"The unique mechanism of action employed by sirolimus is the basis for its superior safety profile, " said Professor Kasiske.

"Because it does not inhibit calcineurin, sirolimus does not harm kidney function or increase blood pressure." ::Eliminating Nephrotoxicity

Use of sirolimus as a base therapy, instead of cyclosporine, is possible because both patient survival and acute rejection rates were similar among sirolimus-treated patients and cyclosporine-treated patients, according to data reviewed at the symposia by Professor Henri Kreis.

Professor Kreis's findings confirm that sirolimus is as effective as cyclosporine for the prevention of acute rejection and does not cause the associated nephrotoxicity and tremor. The ability of sirolimus to be equally protective at preventing organ rejection, while preserving sound kidney function, make it an attractive alternative to calcineurin inhibitors. ::Optimising Sirolimus

Earlier studies showed that when sirolimus was used in combination with cyclosporine, both the rate and severity of acute rejection episodes were reduced. Additionally, data from a Phase II study demonstrated that treatment with sirolimus allowed for reduced dosing of cyclosporine, meaning less exposure to its toxicities. These findings were discussed by Barry D. Kahan, MD, PhD, of the University of Texas Medical School in Houston, Texas, United States.

Dr. Kahan also reviewed Phase III trials that evaluated the effect of adding sirolimus to cyclosporine and steroid regimens, compared to adding azathioprine or placebo to cyclosporine and steroids. Only 12.0 per cent of the patients treated with the sirolimus-based regimen of 5mg/day and 16.9 per cent of the 2mg/day group experienced acute rejection episodes, compared to 24 per cent of patients treated with azathioprine, cyclosporine and steroids.

"The ability of sirolimus to act synergistically with cyclosporine, reducing acute rejection and decreasing the dosing levels of cyclosporine, means we are likely to observe improved long-term organ survival and achieve superior outcomes for patients due to the reduced risk of nephrotoxicity," commented Dr. Kahan. ::Sirolimus as Primary Maintenance Therapy

Sirolimus-based immunosuppression eliminates the major concern of nephrotoxicity. The results of two studies suggesting that sirolimus can be used instead of cyclosporine as primary maintenance therapy were presented at the symposia by Jose M. Morales, MD, of Hospital 12 de Octubre in Madrid, Spain.

Dr. Morales reviewed data documenting comparable rejection rates and patient survival rates in kidney transplant recipients who were randomised to receive either sirolimus or cyclosporine, both agents given in combination with azathioprine and steroids (prednisone).

While rates of acute rejection and patient survival were almost identical, patients treated with the sirolimus-based regimen had markedly better kidney function and lower blood pressure. Like all immunosuppressants, Rapamune has side effects, the most important of which is hyperlipidemia. However, unlike kidney damage, hyperlipidemia is treatable with standard and widely used drugs. Hyperlipidemia is a multifactorial event common to transplant recipients treated with standard cyclosporine and corticosteroids. One added possible benefit of sirolimus is that is it has not been shown to increase blood pressure.

Rapamune (sirolimus) oral solution received marketing approval from the United States Food and Drug Administration (FDA) in September 1999 for the prevention of acute kidney transplant rejection. It has also been approved in Argentina, Brazil, Columbia, Mexico, and Venezuela, and registration is pending in Canada, Switzerland, Australia, Chile and South Africa.

Rapamune's application with the European Medicines Evaluation Agency (EMEA) recently received a negative opinion from the Committee for Proprietary Medicinal Products (CPMP), but is under appeal. A tablet formulation received FDA approval on 25 August, 2000. Contact: Gina Volkaert of Ogilvy PR/Brussels, +32-2545-6722

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