Everolimus

Everolimus (RAD-001) is the 40-O-(2-hydroxyethyl) derivative of sirolimus and works similarly to sirolimus as an mTOR (mammalian target of rapamycin) inhibitor.

It is currently used as an immunosuppressant to prevent rejection of organ transplants and treatment of renal cell cancer. Much research has also been conducted on everolimus and other mTOR inhibitors for use in a number of cancers.

It is marketed by Novartis under the tradenames Zortress (USA) and Certican (Europe and other countries) in transplantation medicine, and Afinitor in oncology.

Approvals and indications
Everolimus is approved for various conditions:
 * Advanced kidney cancer (approved in March 2009)
 * Prevention of organ rejection after renal transplant(April 2010)
 * Subependymal giant cell astrocytoma (SEGA) associated with tuberous sclerosis (TS) in patients who are not suitable for surgical intervention (October 2010)
 * Progressive or metastatic pancreatic neuroendocrine tumors not surgically removable (May 2011)

Clinical trials
, Phase III trials are under way in breast cancer, gastric cancer, hepatocellular carcinoma and lymphoma. The use of everolimus in refractory chronic Graft-versus-host disease has been reported in 2012.

Interim phase III trial results in 2011 show that adding Afinitor (everolimus) to exemestane therapy against advanced breast cancer can significantly improve progression-free survival compared with exemestane therapy alone.

Mechanism
In a similar fashion to other mTOR inhibitors its effect is solely on the mTORC1 protein and not on the mTORC2 protein. This can lead to a hyper-activation of the kinase AKT via inhibition on the mTORC1 negative feedback loop while not inhibiting the mTORC2 positive feedback to AKT. This AKT elevation can lead to longer survival in some cell types.?

Role in heart transplantation
Everolimus may have a role in heart transplantation as it has been shown to reduce chronic allograft vasculopathy in such transplants. It also may have a similar role to sirolimus in kidney and other transplants.

Because hypercholesterolemia and hypertriglyceridemia have been reported, monitoring of blood lipid level is recommended.

Use in vascular stents
Everolimus is used in drug-eluting coronary stents as an immunosuppressant to prevent restenosis. Abbott Vascular produces an everolimus-eluting stent called the Xience V. It utilizes the Multi-Link Vision cobalt chromium stent platform and Novartis' everolimus. The product is also currently in use in the United States and as an investigational device in Japan. It is also available under a private-label version called the PROMUS Everolimus-Eluting Coronary Stent System and it is currently available in most major European and Asia-Pacific markets.