Everolimus

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Everolimus
Everolimus.svg
Everolimus ball-and-stick.png
Clinical data
License data
Pregnancy
category
  • US: D (Evidence of risk)
Routes of
administration
By mouth
ATC code
Legal status
Legal status
  • In general: ℞ (Prescription only)
Pharmacokinetic data
Biological half-life ~30 hours[1]
Identifiers
Synonyms 42-O-(2-hydroxyethyl)rapamycin
CAS Number
PubChem CID
DrugBank
ChemSpider
UNII
KEGG
ChEMBL
ECHA InfoCard 100.149.896
Chemical and physical data
Formula C53H83NO14
Molar mass 958.224 g/mol
3D model (JSmol)
 NYesY (what is this?)  (verify)

Everolimus (INN) (/ˌɛvəˈrləməs/) (earlier code name RAD001) is the 40-O-(2-hydroxyethyl) derivative of sirolimus and works similarly to sirolimus as an inhibitor of mammalian target of rapamycin (mTOR).

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

It is marketed by Novartis under the trade names Zortress (USA) and Certican (Europe and other countries) in transplantation medicine, and as Afinitor (general tumours) and Votubia (tumours as a result of TSC) in oncology. Everolimus is also available from Biocon, with the brand name Evertor.

Approvals and indications[edit]

Everolimus is approved for various conditions:

  • Advanced kidney cancer (US FDA approved in March 2009)[2]
  • Prevention of organ rejection after renal transplant(US FDA April 2010)[3]
  • Subependymal giant cell astrocytoma (SEGA) associated with tuberous sclerosis (TS) in patients who are not suitable for surgical intervention (US FDA October 2010)[4]
  • Progressive or metastatic pancreatic neuroendocrine tumors not surgically removable (May 2011)[5]
  • Breast cancer in post-menopausal women with advanced hormone-receptor positive, HER2-negative type cancer, in conjunction with exemestane (US FDA July 2012)[6]
  • Prevention of organ rejection after liver transplant(Feb 2013)
  • Progressive, well-differentiated non-functional, neuroendocrine tumors (NET) of gastrointestinal (GI) or lung origin with unresectable, locally advanced or metastatic disease (US FDA February 2016).[7]

UK National Health Service[edit]

NHS England has been criticised for delays in deciding on a policy for the prescription of Everolimus in the treatment of Tuberous Sclerosis. 20 doctors addressed a letter to the board in support of the charity Tuberous Scelerosis Association saying " around 32 patients with critical need, whose doctors believe everolimus treatment is their best or only option, have no hope of access to funding. Most have been waiting many months. Approximately half of these patients are at imminent risk of a catastrophic event (renal bleed or kidney failure) with a high risk of preventable death."[8] In May 2015 it was reported that Luke Henry and Stephanie Rudwick, the parents of a child suffering from Tuberous Sclerosis were trying to sell their home in Brighton to raise £30,000 to pay for treatment for their daughter Bethany who has tumours on her brain, kidneys and liver and suffers from up to 50 epileptic fits a day.[9]

Clinical trials[edit]

As of October 2010, Phase III trials are under way in gastric cancer, hepatocellular carcinoma, and lymphoma.[10] The use of everolimus in refractory chronic graft-versus-host disease was reported in 2012.[11]

Interim phase III trial results in 2011 showed that adding Afinitor (everolimus) to exemestane therapy against advanced breast cancer can significantly improve progression-free survival compared with exemestane therapy alone.[12]

A study published in 2012 shows that everolimus sensitivity varies between patients depending on their tumor genomes.[13] A group of patients with advanced metastasic bladder carcinoma (NCT00805129) [14] treated with everolimus revealed a single patient who had a complete response to everolimus treatment for 26 months. The researchers sequenced the genome of this patient and compared it to different reference genomes and to other patients' genomes. They found that mutations in TSC1 led to a lengthened duration of response to everolimus and to an increase in the time to cancer recurrence. The mutated TSC1 apparently had made these tumors vulnerable to treatment with everolimus.

Mechanism[edit]

Compared with the parent compound rapamycin, Everolimus is more selective for the mTORC1 protein complex, with little impact on the mTORC2 complex.[15] 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. Thus, Everolimus has important effects on cell growth, cell proliferation and cell survival.

Additionally, mTORC2 is believed to play an important role in glucose metabolism and the immune system, suggesting that selective inhibition of mTORC1 by drugs such as Everolimus could achieve many of the benefits of rapamycin without the associated glucose intolerance and immunosuppression.[15]

TSC1 and TSC2, the genes involved in tuberous sclerosis, act as tumor suppressor genes by regulating mTORC1 activity. Thus, either the loss or inactivation of one of these genes lead to the activation of mTORC1.[16]

Everolimus binds to its protein receptor FKBP12, which directly interacts with mTORC1, inhibiting its downstream signaling. As a consequence, mRNAs that code for proteins implicated in the cell cycle and in the glycolysis process are impaired or altered, and tumor growth is inhibited.[16]

Adverse reactions[edit]

A trial using 10 mg/day in patients with NETs of GI or lung origin reported "Everolimus was discontinued for adverse reactions in 29% of patients and dose reduction or delay was required in 70% of everolimus-treated patients. Serious adverse reactions occurred in 42% of everolimus-treated patients and included 3 fatal events (cardiac failure, respiratory failure, and septic shock). The most common adverse reactions (incidence greater than or equal to 30%) were stomatitis, infections, diarrhea, peripheral edema, fatigue and rash. The most common blood abnormalities found (incidence greater than or equal to 50%) were anemia, hypercholesterolemia, lymphopenia, elevated aspartate transaminase (AST) and fasting hyperglycemia.".[7]

Role in heart transplantation[edit]

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.[17]

Role in liver transplantation[edit]

Although, sirolimus had generated fears over use of m-TOR inhibitors in liver transplantation recipients, due to possible early hepatic artery thrombosis and graft loss, use of everolimus in the setting of liver transplantation is promising. Jeng et al.,[18] in their study of 43 patients, concluded the safety of everolimus in the early phase after living donor liver transplantation. In their study, no hepatic artery thrombosis or wound infection was noted. Also, a possible role of everolimus in reducing the recurrence of hepatocellular carcinoma after liver transplantation was correlated. A target trough level of 3 ng/mL at 3 months was shown to be beneficial in recipients with pre-transplant renal dysfunction. In their study, 6 of 9 renal failure patients showed significant recovery of renal function, whereas 3 showed further deterioration, one of whom required hemodialysis.[19]

Use in vascular stents[edit]

Everolimus is used in drug-eluting coronary stents as an immunosuppressant to prevent restenosis. Abbott Vascular produce an everolimus-eluting stent (EES) called Xience Alpine. It utilizes the Multi-Link Vision cobalt chromium stent platform and Novartis' everolimus. The product is widely available globally including USA, Europe, and APAC countries. Boston Scientific also market EESes, recent offerings being Promus Premiere and Synergy.

Use in aging[edit]

Inhibition of mTOR, the molecular target of Everolimus, extends the lifespan of model organisms including mice,[20] and mTOR inhibition has been suggested as an anti-aging therapy. Everolimus was used in a recent clinical trial by Novartis, and short-term treatment was shown to enhance the response to the influenza vaccine in the elderly, possible by reversing immunosenescence.[21] Everolimus treatment of mice results in reduced metabolic side effects compared to sirolimus.[15]

See also[edit]

References[edit]

  1. ^ R.N Formica Jra; K.M Lorberb; A.L Friedmanb; M.J Biaa; F Lakkisa; J.D Smitha; M.I Lorber (March 2004). "The evolving experience using everolimus in clinical transplantation". Transplantation Proceedings. 36 (2): S495–S499. doi:10.1016/j.transproceed.2004.01.015. 
  2. ^ "Afinitor approved in US as first treatment for patients with advanced kidney cancer after failure of either sunitinib or sorafenib" (Press release). Novartis. 2009-03-30. Retrieved April 6, 2009. 
  3. ^ "Novartis receives US FDA approval for Zortress (everolimus) to prevent organ rejection in adult kidney transplant recipients" (Press release). Novartis. 2010-04-22. Retrieved April 26, 2010. 
  4. ^ "Novartis’ Afinitor Cleared by FDA for Treating SEGA Tumors in Tuberous Sclerosis". 1 Nov 2010. 
  5. ^ http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm254350.htm
  6. ^ "US FDA approves Novartis drug Afinitor for breast cancer". Reuters. 20 Jul 2012. 
  7. ^ a b Everolimus (Afinitor). Feb 2016
  8. ^ Lintern, Shaun (14 April 2015). "Policy delays risk 'preventable deaths', doctors warn NHS England". Health Service Journal. Retrieved 20 April 2015. 
  9. ^ "Couple forced to sell home after NHS refuse to fund daughter's treatment for rare illness". Daily Express. 11 May 2015. Retrieved 12 May 2015. 
  10. ^ http://www.genengnews.com/gen-news-highlights/novartis-afinitor-cleared-by-fda-for-treating-sega-tumors-in-tuberous-sclerosis/81244159/
  11. ^ Lutz M, Kapp M, Grigoleit GU, Stuhler G, Einsele H, Mielke S (April 2012). "Salvage therapy with everolimus improves quality of life in patients with refractory chronic graft-versus-host disease" (PDF). Bone Marrow Transplant. 47 (S1): S410–S411. 
  12. ^ "Positive Trial Data Leads Novartis to Plan Breast Cancer Filing for Afinitor by Year End". 2011. 
  13. ^ Iyer, G; Hanrahan, AJ; Milowsky, MI; Al-Ahmadie, H; Scott, SN; Janakiraman, M; Pirun, M; Sander, C; Socci, ND; Ostrovnaya, I; Viale, A; Heguy, A; Peng, L; Chan, TA; Bochner, B; Bajorin, DF; Berger, MF; Taylor, BS; Solit, DB (2012). "Genome sequencing identifies a basis for everolimus sensitivity". Science. 338: 221. PMC 3633467Freely accessible. PMID 22923433. doi:10.1126/science.1226344. 
  14. ^ [1]
  15. ^ a b c Arriola Apelo, Sebastian I.; Neuman, Joshua C.; Baar, Emma L.; Syed, Faizan A.; Cummings, Nicole E.; Brar, Harpreet K.; Pumper, Cassidy P.; Kimple, Michelle E.; Lamming, Dudley W. (2015-10-13). "Alternative rapamycin treatment regimens mitigate the impact of rapamycin on glucose homeostasis and the immune system". Aging Cell. 15: 28–38. ISSN 1474-9726. PMC 4717280Freely accessible. PMID 26463117. doi:10.1111/acel.12405. 
  16. ^ a b [2]
  17. ^ Eisen HJ, Tuzcu EM, Dorent R, et al. (August 2003). "Everolimus for the prevention of allograft rejection and vasculopathy in cardiac-transplant recipients". N. Engl. J. Med. 349 (9): 847–58. PMID 12944570. doi:10.1056/NEJMoa022171. 
  18. ^ Jeng LB; Thorat A; Hsieh YY; et al. (April 2014). "Experience of using everolimus in the early stage of living donor liver transplantation.". Transpl Proc. 46 (3): 744–48. PMID 24767339. doi:10.1016/j.transproceed.2013.11.068. 
  19. ^ Jeng L, Thorat A, Yang H, Yeh C-C, Chen T-H, Hsu S-C. Impact of Everolimus On the Hepatocellular Carcinoma Recurrence After Living Donor Liver Transplantation When Used in Early Stage: A Single Center Prospective Study [abstract]. Am J Transplant. 2015; 15 (suppl 3). http://www.atcmeetingabstracts.com/abstract/impact-of-everolimus-on-the-hepatocellular-carcinoma-recurrence-after-living-donor-liver-transplantation-when-used-in-early-stage-a-single-center-prospective-study/. Accessed September 1, 2015.
  20. ^ Harrison, David E.; Strong, Randy; Sharp, Zelton Dave; Nelson, James F.; Astle, Clinton M.; Flurkey, Kevin; Nadon, Nancy L.; Wilkinson, J. Erby; Frenkel, Krystyna (2009-07-16). "Rapamycin fed late in life extends lifespan in genetically heterogeneous mice". Nature. 460 (7253): 392–395. ISSN 1476-4687. PMC 2786175Freely accessible. PMID 19587680. doi:10.1038/nature08221. 
  21. ^ Mannick, Joan B.; Del Giudice, Giuseppe; Lattanzi, Maria; Valiante, Nicholas M.; Praestgaard, Jens; Huang, Baisong; Lonetto, Michael A.; Maecker, Holden T.; Kovarik, John (2014-12-24). "mTOR inhibition improves immune function in the elderly". Science Translational Medicine. 6 (268): 268ra179. ISSN 1946-6242. PMID 25540326. doi:10.1126/scitranslmed.3009892. 

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