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Everolimus known also as Certican or RAD-001 is produced by Novartis (with the proposed brand name Afinitor).

A substance that is being studied in the treatment of cancer. It belongs to the families of drugs called immunosuppressive agents and antiangiogenesis agents.

A derivative of the natural macrocyclic lactone sirolimus with immunosuppressant and anti-angiogenic properties.

In cells, everolimus binds to the immunophilin FK Binding Protein-12 (FKBP-12) to generate an immunosuppressive complex that binds to and inhibits the activation of the mammalian Target of Rapamycin (mTOR), a key regulatory kinase.

Inhibition of mTOR activation results in the inhibition of T lymphocyte activation and proliferation associated with antigen and cytokine (IL-2, IL-4, and IL-15) stimulation and the inhibition of antibody production

N I C E appraisal

Everolimus was referred to N I C E for the second line treatment of metastatic kidney cancer ( mRCC)in November 2008. For further information on the N I C E submission please see the N I C E website http://www.nice.org.uk/Guidance/TA/WaveCRS1/48


Mechanism of Action

Everolimus (Certican), a rapamycin analogue, previously known as RAD (40-0-[2-hydroxyethyl]-rapamycin, is a novel macrolide with potent immunosuppressive and antiproliferative properties. Everolimus blocks growth factor-driven transduction signals in the T-cell response to alloantigen and proliferation of both hematopoietic and nonhematopoietic cells. Following stimulation of the interleukin (IL)-2 receptor on the activated T cell, everolimus inhibits p70 S6 kinase (involved in the cellular proliferation signal), thereby arresting the cell cycle at the G1 to S phase. Although these inhibitory activities occur later in the T-cell cycle than do those of the CIs, they are complementary and provide a rationale for the addition of everolimus to cyclosporine (CsA)-based immunosuppression.[1] This combination has the potential to reduce acute rejection and calcineurin toxicity, and favors long-term graft survival.

Clinical Trials

Following preclinical renal transplant studies that showed that everolimus prevented rejection and improved survival,[2] prevented smooth muscle cell proliferation,[3] and reduced CsA nephrotoxicity[4] in cynomolgus monkey kidney allografts, 3 pivotal clinical trials in de novo renal transplant recipients were conducted: (1) B201 (European),[5] (2) B251 (United States and Brazil),[6] and (3) B156 (European).[7] Two of these studies (B201, B251) compared the efficacy equivalence and safety of everolimus to mycophenolate mofetil (CellCept, mycophenolate mofetil [MMF]), and the third study (B156) examined the effect of everolimus in a CsA-reduction regimen. The study designs and methods of these trials are outlined in Tables 1 and 2.

Results of B201. 

In this study powered for equivalent efficacy, the 12-month rates of graft loss, patient death, loss to follow-up, and acute rejection were not statistically different among the 3 treatment groups: everolimus 1.5 mg/day, everolimus 3 mg/day, and MMF.[5] Biopsy-proven acute rejection was 23.2% and 19.7% in patients treated with everolimus 1.5 mg/day and 3 mg/day, respectively, and 24% in patients treated with MMF. However, elevations in serum lipid levels were most pronounced in the group that received everolimus 3 mg/day, and serum creatinine levels were significantly higher (P < .05) in MMF-treated patients compared with everolimus-treated patients (both groups).

Results of B251. 

Similar to the B201 study results, this phase 3 trial (also powered for equivalent efficacy) showed good efficacy with regard to graft loss, patient death, and loss to follow-up in all treatment groups.[6] Biopsy-proven acute rejection rates were not significantly different: 19% (everolimus 1.5mg/day), 22% (everolimus 3.0 mg/day), and 24% (MMF 2g/day). Furthermore, acute rejection episodes requiring antibody therapy were statistically less frequent in everolimus-treated (1.5 mg/day) patients compared with MMF-treated patients. The everolimus-treated patients had higher mean serum cholesterol and triglyceride levels than the MMF-treated patients, although all patients had increased levels that peaked at 2 months and responded to lipid-lowering therapy. A higher incidence of patients with elevated serum creatinine was observed in the everolimus groups compared with the MMF group.

Results of B156. 

An analysis of 12-month data from this study showed that the rates of biopsy-proven acute rejection, graft loss, and patient death were significantly lower (P = .013) in patients treated with lower-dose Neoral compared with patients receiving the full dose.[7] Increased serum cholesterol and triglyceride levels were observed in both groups, although levels were higher in the full-dose Neoral group. The mean and median serum creatinine levels were higher in the full-dose Neoral group, although this difference did not reach statistical significance. Subsequently, an analysis of the data from 10 patients in the full-dose Neoral dose group and 12 in the reduced-dose Neoral group was conducted.[8] Glomerular filtration rate (GFR) was measured at weeks 4 and 12 and months 6 and 12. Overall, there was a 25% to 30% improvement in GFR in the reduced-dose group, which was most pronounced at 12 months.


Everolimus has a 2-hour time to maximal concentration (Cmax) with dose proportionality (ie, the higher the dose, the higher the serum concentration) as well as excellent correlation between the trough level and the area under the blood concentration-time curve (AUC).[9] The therapeutic window for everolimus as assessed in phase 2 dose-finding studies and the phase 3 trials already discussed appears to have a lower limit of 3 ng/mL and an upper limit of 15 ng/mL.

Cost-Effectiveness of Newer Agents

Immunosuppressive regimens that include everolimus and/or basiliximab (Simulect) are potentially cost-effective.[10] Data from 5 randomized studies including 1296 de novo kidney transplant recipients were analyzed using an economic model. A baseline strategy of CsA (Neoral) plus corticosteroids was compared to 4 strategies that added basiliximab, MMF, and/or everolimus to the regimen:

  • Basiliximab, CsA, corticosteroids
  • Basiliximab, azathioprine (AZA), CsA, corticosteroids
  • Basiliximab, MMF, CsA, corticosteroids
  • Basiliximab, everolimus, CsA, corticosteroids

All strategies that included basiliximab and/or everolimus resulted in lower cost and better outcome than the baseline strategy in the first year following kidney transplantation. Regimens that included everolimus were associated with the lowest incidence of acute rejection and the lowest cost of treatment. However, no cost was applied for everolimus as this drug was not yet on the market.


Everolimus has equivalent efficacy to MMF for the prevention of acute renal allograft rejection. This comes at a price, however, due to the fact that everolimus negatively affects renal function and serum lipid levels. Serum creatinine levels are higher in patients treated with everolimus plus CsA than in those treated with MMF plus CsA. The situation is not improved significantly by reducing the CsA dose. Furthermore, everolimus contributes to hyperlipidemias caused by CsA and corticosteroids. Although everolimus allows for a dose reduction of CsA and therefore might reduce overall cost of care, the cost of everolimus has yet to be established and more than likely will increase the cost of care during the first posttransplant year, without improving significantly the incidence of acute rejection compared with MMF.

Media Releases

Huliq (KC) 27-May-08

Novartis (KC) 19-May-08


MedicalNewsToday (KC) 16-Sep-08

PharmaTimes (KC) 09-Sep-08

Cancer Consultants (KC) 23-Jul-08

  • Everolimus Improves Progression-free Survival in Renal Cell Cancer

Reuters (KC) 17-May-08

Interactive Investor (KC) 28-Feb-08

MedPage (KC) 28-Feb-08

Novartis Press Release 28-Feb-08

  • Everolimus (RAD001) significantly extends progression-free survival in advanced kidney cancer patients after failure of other targeted therapy

Reuters (KC) 28-Feb-08

PharmaTimes (KC) 28-Feb-08

GE&B News(KC) 27-Feb-08

  • Everolimus (RAD001) Significantly Extends Progression-Free Survival in Advanced Kidney Cancer Patients After Failure of Other Targeted Therapy


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