Everolimus is the 40-O-(2-hydroxyethyl) derivative of sirolimus

Sirolimus

Sirolimus , also known as rapamycin, is an immunosuppressant drug used to prevent rejection in organ transplantation; it is especially useful in kidney transplants. A macrolide, sirolimus was first discovered as a product of the bacterium Streptomyces hygroscopicus in a soil sample from Easter...

 and works similarly to sirolimus as an mTOR (mammalian target of rapamycin

Mammalian target of rapamycin

The mammalian target of rapamycin also known as mechanistic target of rapamycin or FK506 binding protein 12-rapamycin associated protein 1 is a protein which in humans is encoded by the FRAP1 gene...

) inhibitor.

It is currently used as an immunosuppressant

Immunosuppression

Immunosuppression involves an act that reduces the activation or efficacy of the immune system. Some portions of the immune system itself have immuno-suppressive effects on other parts of the immune system, and immunosuppression may occur as an adverse reaction to treatment of other...

 to prevent rejection

Transplant rejection

Transplant rejection occurs when transplanted tissue is rejected by the recipient's immune system, which destroys the transplanted tissue. Transplant rejection can be lessened by determining the molecular similitude between donor and recipient and by use of immunosuppressant drugs after...

 of organ transplant

Organ transplant

Organ transplantation is the moving of an organ from one body to another or from a donor site on the patient's own body, for the purpose of replacing the recipient's damaged or absent organ. The emerging field of regenerative medicine is allowing scientists and engineers to create organs to be...

s 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

Novartis

Novartis International AG is a multinational pharmaceutical company based in Basel, Switzerland, ranking number three in sales among the world-wide industry...

 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

Breast cancer

Breast cancer is cancer originating from breast tissue, most commonly from the inner lining of milk ducts or the lobules that supply the ducts with milk. Cancers originating from ducts are known as ductal carcinomas; those originating from lobules are known as lobular carcinomas...

, gastric cancer, hepatocellular carcinoma

Hepatocellular carcinoma

Hepatocellular carcinoma is the most common type of liver cancer. Most cases of HCC are secondary to either a viral hepatitide infection or cirrhosis .Compared to other cancers, HCC is quite a rare tumor in the United States...

 and lymphoma

Lymphoma

Lymphoma is a cancer in the lymphatic cells of the immune system. Typically, lymphomas present as a solid tumor of lymphoid cells. Treatment might involve chemotherapy and in some cases radiotherapy and/or bone marrow transplantation, and can be curable depending on the histology, type, and stage...

.

Interim phase III trial results in 2011 show that adding Afinitor (everolimus) to exemestane

Exemestane

Exemestane is a drug used to treat breast cancer. It is a member of the class of drugs known as aromatase inhibitors. Some breast cancers require estrogen to grow. Those cancers have estrogen receptors , and are called ER-positive. They may also be called estrogen-responsive,...

 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

AKT

Akt, also known as Protein Kinase B , is a serine/threonine protein kinase that plays a key role in multiple cellular processes such as glucose metabolism, cell proliferation, apoptosis, transcription and cell migration.-Family members:...

 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

Drug-eluting stent

A drug-eluting stent ' is a peripheral or coronary stent placed into narrowed, diseased peripheral or coronary arteries that slowly releases a drug to block cell proliferation. This prevents fibrosis that, together with clots , could otherwise block the stented artery, a process called restenosis...

 as an immunosuppressant to prevent restenosis

Restenosis

Restenosis literally means the reoccurrence of stenosis, a narrowing of a blood vessel, leading to restricted blood flow. Restenosis usually pertains to an artery or other large blood vessel that has become narrowed, received treatment to clear the blockage and subsequently become renarrowed...

. 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 an investigational device in the United States and 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.