Everolimus

Everolimus is approved for various conditions:

• Advanced kidney cancer (US FDA approved in March 2009)[3]
• Prevention of organ rejection after renal transplant(US FDA April 2010)[4]
• Subependymal giant cell astrocytoma (SEGA) associated with tuberous sclerosis (TS) in patients who are not suitable for surgical intervention (US FDA October 2010)[5]
• Progressive or metastatic pancreatic neuroendocrine tumors not surgically removable (May 2011)[6]
• Breast cancer in post-menopausal women with advanced hormone-receptor positive, HER2-negative type cancer, in conjunction with exemestane (US FDA July 2012)[7]
• 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).[8]
• Tuberous sclerosis complex-associated partial-onset seizures for adult and pediatric patients aged 2 years and older. (US FDA April 2018).[9]

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."[10] 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.[11]

As of October 2010, Phase III trials are under way in gastric cancer, hepatocellular carcinoma, and lymphoma.[12] The experimental use of everolimus in refractory chronic graft-versus-host disease was reported in 2012.[13]

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.[14]

A study published in 2012 shows that everolimus sensitivity varies between patients depending on their tumor genomes.[15] A group of patients with advanced metastasic bladder carcinoma (NCT00805129) [16] 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.

Compared with the parent compound rapamycin, everolimus is more selective for the mTORC1 protein complex, with little impact on the mTORC2 complex.[17] 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.[17]

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.[18]

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.[18]

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.".[8]

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.[19]

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.,[20] 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.[21] Recently published report by Thorat et al showed a positive impact on hepatocellular carcinoma (HCC) when everolimus was used as primary immunosuppression starting as early as first week after living donor liver transplantation (LDLT) surgery.[22] In their retrospective and prospective analysis at China Medical University Hospital in Taiwan, the study cohort (n=66) was divided in two groups depending upon the postoperative immunosuppression. Group A: HCC patients that received Everolimus + Tacrolimus based immunosuppressive regimen (n=37). Group B: HCC patients that received standard Tacrolimus based immunosuppressive regimen without everolimus (n=29). The target trough level for EVR was 3 to 5 ng/ml while for TAC it was 8–10 ng/ml. The 1-year, 3-year and 4-year overall survival achieved for Group A patients (Everolimus group) was 94.95%, 86.48% and 86.48%, respectively while for Group B patients it was 82.75%, 68.96%, and 62.06%, respectively (p=0.0217). The first 12-month report of ongoing Everolimus multicenter prospective trial in LDLT (H2307 trial), Jeng LB et al have shown a 0% recurrence of HCC in everolimus group at 12 months.[23] Jeng LB concluded that an early introduction of everolimus + reduced tacrolimus was non-inferior to standard tacrolimus in terms of efficacy and renal function at 12 months, with HCC recurrence only in tacrolimus control patients.

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 Elite and Synergy.

Inhibition of mTOR, the molecular target of everolimus, extends the lifespan of model organisms including mice,[24] 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.[25] Everolimus treatment of mice results in reduced metabolic side effects compared to sirolimus.[17]

• Discovery and development of mTOR inhibitors

• Sedrani R, Cottens S, Kallen J, Schuler W (August 1998). "Chemical modification of rapamycin: the discovery of SDZ RAD". Transplantation Proceedings. 30 (5): 2192–4. doi:10.1016/S0041-1345(98)00587-9. PMID 9723437.

• "Everolimus". Drug Information Portal. U.S. National Library of Medicine.