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

ROME, Aug 29 (PROTEXT) - Researchers here on Monday reportedthat the immunosuppressive agent Rapamune (sirolimus) can besafely and effectively used as the primary drug for maintenancetherapy in preventing acute rejection in kidney transplantpatients.

Unlike the class of immunosuppressant drugs known ascalcineurin inhibitors, which includes the widely usedcyclosporine, sirolimus has a mechanism of action that does notproduce such adverse effects as kidney damage, high bloodpressure or tremor, which are common side effects ofcyclosporine.

These findings were presented this week at two symposiaduring the XVIII International Congress of the TransplantationSociety.

"While many patients have indeed benefited from the basicimmunosuppressive effects of calcineurin inhibitors, manypatients have also suffered from the toxicities that accompanylong-term use of these drugs," said symposium panellist ProfessorHenri Kreis of Hopital Necker, Paris.

"There is a clear need for an alternative therapy to be fullyintegrated into the immunosuppressive regimen in order todecrease or to eliminate the array of adverse effects caused bycalcineurin inhibitors."

Symposium panellist Professor Betram L. Kasiske of HennepinCounty Medical Centre in Minneapolis, Minnesota, United States,outlined the various adverse effects caused by calcineurininhibitors, emphasising that the toxicities produced by thesedrugs have spurred research efforts aimed at developingan alternative long-term immunosuppression regimen.

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

He commented further on the equally problematic effect ofthese 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 isnephrotoxicity, which is linked to the mechanism of actionemployed by this class of immunosuppressants. Calcineurin is animportant enzyme in the body's normal immune response system, butcalcineurin inhibition also alters the way certain genes areexpressed, thereby setting in motion the chain ofevents that causes nephrotoxicity.

Alternatively, the mechanism of action for Rapamune is toinhibit the activation of TOR (target of rapamycin), a newlydiscovered class of intracellular synthetic proteins central tothe immune response system.

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

"Because it does not inhibit calcineurin, sirolimus does notharm 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 rejectionrates were similar among sirolimus-treated patients andcyclosporine-treated patients, according to data reviewed at thesymposia by Professor Henri Kreis.

Professor Kreis's findings confirm that sirolimus is aseffective as cyclosporine for the prevention of acute rejectionand does not cause the associated nephrotoxicity and tremor. Theability of sirolimus to be equally protective at preventing organrejection, while preserving sound kidney function, make it anattractive alternative to calcineurin inhibitors.::Optimising Sirolimus

Earlier studies showed that when sirolimus was used incombination with cyclosporine, both the rate and severity ofacute rejection episodes were reduced. Additionally, data from aPhase II study demonstrated that treatment with sirolimus allowedfor reduced dosing of cyclosporine, meaning less exposure to itstoxicities. These findings were discussed by BarryD. Kahan, MD, PhD, of the University of Texas Medical School inHouston, Texas, United States.

Dr. Kahan also reviewed Phase III trials that evaluated theeffect of adding sirolimus to cyclosporine and steroid regimens,compared to adding azathioprine or placebo to cyclosporine andsteroids. Only 12.0 per cent of the patients treated with thesirolimus-based regimen of 5mg/day and 16.9 per cent of the2mg/day group experienced acute rejection episodes, compared to24 per cent of patients treated with azathioprine, cyclosporineand steroids.

"The ability of sirolimus to act synergistically withcyclosporine, reducing acute rejection and decreasing the dosinglevels of cyclosporine, means we are likely to observe improvedlong-term organ survival and achieve superior outcomes forpatients due to the reduced risk of nephrotoxicity," commentedDr. Kahan.::Sirolimus as Primary Maintenance Therapy

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

Dr. Morales reviewed data documenting comparablerejection rates and patient survival rates in kidney transplantrecipients who were randomised to receive either sirolimus orcyclosporine, both agents given in combination with azathioprineand steroids (prednisone).

While rates of acute rejection and patient survival werealmost identical, patients treated with the sirolimus-basedregimen had markedly better kidney function and lower bloodpressure. Like all immunosuppressants, Rapamune has sideeffects, the most important of which is hyperlipidemia.However, unlike kidney damage, hyperlipidemia is treatable withstandard and widely used drugs. Hyperlipidemia is amultifactorial event common to transplant recipients treated withstandard cyclosporine and corticosteroids. One added possiblebenefit of sirolimus is that is it has not been shownto increase blood pressure.

Rapamune (sirolimus) oral solution received marketingapproval from the United States Food and Drug Administration(FDA) in September 1999 for the prevention of acute kidneytransplant rejection. It has also been approved in Argentina,Brazil, Columbia, Mexico, and Venezuela, and registrationis pending in Canada, Switzerland, Australia, Chile and SouthAfrica.

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

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