National Horizon Scanning Centre

Everolimus (Certican) for

prophylaxis of organ rejection in
renal or cardiac transplantation

August 2008

This technology summary is based on information available at the time of research

and a limited literature search. It is not intended to be a definitive statement on the safety, efficacy or
effectiveness of the health technology covered and should not be used for commercial purposes.

The National Horizon Scanning Centre Research Programme is part of the

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Everolimus (Certican) for prophylaxis of organ rejection in renal

or cardiac transplantation
Target group
Prophylaxis of organ rejection for allogeneic renal or cardiac transplant: adults at low
and moderate immunological risk.

Technology description
Everolimus (RAD-001; Certican), a proliferation signal inhibitor (of the mammalian
target of rapamycin [mTOR] protein), is an oral immunosuppressant that targets the
primary causes of progressive allograft dysfunction (also known as chronic rejection)
following organ transplantation. It is anticipated that everolimus will be used in
combination with ciclosporin and corticosteroids, and as a substitute for sirolimus,
azathioprine or mycophenolic acid. Everolimus is administered at 1.5-3.0mg daily, with
dose adjustment to achieve defined trough blood levels.

Everolimus is in phase III clinical trials within a drug-eluting stent for coronary artery
restenosis, as prophylaxis of liver transplant rejection, and for renal cancer and
neuroendocrine tumours.

Innovation and/or advantages

Everolimus is first drug in its class for both renal and cardiac transplant recipients.
Everolimus may improve long-term patient and graft survival, with potentially fewer side
effects than sirolimus, azathioprine or mycophenolic acid.

Developer
Novartis Pharmaceuticals UK Ltd.

Availability, launch or marketing dates, and licensing plans:

Everolimus is available in some EU countries (under mutual recognition process) for the
prevention of organ rejection in heart and kidney transplantation, but is not currently
available in the UK.

NHS or Government priority area:

This topic is relevant to the:
National Service Framework for renal services: part one - dialysis and transplantation
(2004).
National Service Framework for coronary heart disease (2000).

Relevant guidance
Renal transplantation:
NICE technology appraisal. The clinical effectiveness and cost effectiveness of
immuno-suppressive therapy for renal transplantation in adults. 2004 1 .
NICE clinical guideline in development. Kidney disease: Early identification and
management of adults with chronic kidney disease in primary and secondary care.
Expected September 2008 2 .
UK Renal Association. Clinical Practice Guidelines: assessment for renal
transplantation. 2008 3 .

Cardiac transplantation:
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NICE clinical guideline. Chronic heart failure management of chronic heart failure
in adults in primary and secondary care. Issued July 2003. Guideline warrants a partial
update after March 2008 review 4 .
SIGN. Chronic heart failure. 2007 5 .

Clinical need and burden of disease

Kidney transplantation is the renal replacement therapy of choice for patients with
chronic kidney disease stage 5, who are considered to be fit for major surgery and for
chronic immunosuppression3,6 . Patients who undergo renal transplantation are required to
receive life-long (or at least long-term) treatment with immunosuppressive drugs. When
selecting these treatments, the risk of immunologically mediated graft failure for any
donorrecipient pair needs to be balanced against the drugs side effects for the recipient.
The ultimate aim of treatment is to prolong patient and graft survival1,7 .

In 2001, there were around 13,900 patients receiving immunosuppression after kidney
transplantation in England and Wales. In 2001, about 1,500 new renal transplants were
performed in England and Wales, with about 21% of organs coming from live donors.
Over 90% of these transplants were performed in people aged 18 years. The median age
of all adults receiving a kidney transplant in 2001 was 49 years. There is a 710% annual
increase in the UK dialysis population, and the number of people needing a transplant is
expected to rise over the next decade1.

There were 162 heart transplants in the UK between 1st April 2006 and 31st March 2007 8 .
Although there are no randomised studies of transplantation in patients with heart failure
owing to the intrinsic practical limitations in this field, observational data demonstrate an
improved quality of life after transplantation, with a 7080% survival at five years. Long-
term prognosis is limited by the side effects of immunosuppression, such as hypertension,
malignancy, renal failure and infection, and the development of graft vascular disease3.

Existing comparators and treatments

After kidney transplantation, NICE currently recommends the use of basiliximab or
daclizumab with a combination of other drugs including calcineurin inhibitors (CNIs) for
induction treatment. CNIs are also recommended for use in maintenance therapy1.

Immunosuppressive agents approved for solid organ transplantation, used in

combinations and/or sequences include1,9 :
Anti-proliferative agents such as azathioprine and mycophenolate mofetil
CNIs such as ciclosporin and tacrolimus
TOR inhibitors such as sirolimus
Antilymphocyte globulins (polyclonal and monoclonal)
Steroids

Efficacy and safety

Trial name Everolimus versus mycophenolate Everolimus versus mycophenolate mofetil;

mofetil; de novo kidney transplant; phase de novo kidney transplant; phase III 11 .
III 10 .
Sponsor Yale University School of Medicine. Institute of Clinical and Experimental
Medicine.
Status Published Published
Location US Prague
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Design Randomised, controlled, double blind. Randomised, controlled, double blind.

Participants n=196; adults; de novo kidney transplant. n=588; adults; de novo renal allograft
in trial Randomised to everolimus 1.5mg or transplant.
3.0mg daily or mycophenolate mofetil 2g Randomised to everolimus 1.5mg or 3.0mg
daily; plus full dose of ciclosporin and daily or mycophenolate mofetil 2g daily;
steroids. plus ciclosporin and steroids.
Follow-up 36 months. 36 months.
Primary Efficacy failure (biopsy acute rejection, Efficacy failure (biopsy acute rejection,
outcome graft loss, survival, loss to follow-up). graft loss, survival, loss to follow-up).
Key results Primary efficacy failure with everolimus Everolimus 1.5mg, 3.0mg and
1.5mg 33.7%; everolimus 3.0mg 34.0% mycophenolate mofetil: graft loss occurred
and mycophenolate mofetil 31.1% in 7.2%, 16.7% and 10.7% respectively
(p=0.810). (p=0.0048 for everolimus 1.5mg vs 3.0mg).
Efficacy failure occurred in 33.0%, 38.9%
and 37.2% of patients respectively (p=0.455
overall).
Adverse - Diarrhoea, lymphocele, peripheral oedema
effects and hyperlipidemia were more common
with everolimus, whereas viral infections
were more common with mycophenolate
mofetil.

Trial code NCT00251004 12 ; CRAD001A2309: de NCT00658320 13 : de novo kidney

novo kidney transplant; phase III. transplant; phase III.
Sponsor Novartis Novartis
Status Ongoing Ongoing
Location USA, Canada, Europe (including UK). Japan
Design Randomised, controlled. Randomised, controlled.
Participants n=825; adults; de novo kidney transplant. n=120; adults; de novo kidney transplant.
in trial Randomised to: Randomised to:
Mycophenolate mofetil 1.44g and Everolimus 1.5mg/kg daily starting dose
ciclosporin with steroids, or everolimus and ciclosporin with steroids, or
0.75mg starting dose (target range 3-8 mycophenolate mofetil 2g daily and
ng/ml) with reduced dose ciclosporin, or ciclosporin with steroids.
everolimus 1.5mg starting dose (target
range for everolimus 6-12ng/ml) with
reduced dose ciclosporin.
Follow-up 24 months. 12 months.
Primary Treated biopsy acute rejection, graft loss, Graft loss, survival.
outcome survival.
Secondary Renal function by glomerular filtration Safety.
outcomes rate (GFR); chronic allograft nephropathy;
infections.
Expected Study started 2006. Completion date Study started Feb 2008. Estimated
reporting confidential. completion date Aug 2010.
date

Trial code CRAD001A253: de novo heart transplant; everolimus vs azathioprine; phase III 14,15 .
Status Published
Design Randomised, double blind, controlled.
Participants n=634; adults; de novo heart transplant.
in trial Randomised to everolimus 1.5mg or 3.0 mg or azathioprine. All in combination with
ciclosporin, corticosteroids and statins.
Follow-up 6, 12, 24 months and open label extension through 48 months
Primary Composite of death, graft loss or re-transplantation, loss to follow-up, biopsy-proved
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outcome acute rejection grade 3A or rejection with haemodynamic compromise.

Key results 6 month primary efficacy for azathioprine, everolimus 3.0mg and everolimus 1.5mg:
46.7%, 27.0% (p=<0.001) and 36.4% (p=0.03) respectively. 12 months: 52.8%, 32.2%
(p=<0.001) and 41.6% (p=0.02). 24 months: 57.5%, 36.0% (p<0.001) and 45.9%
(p=0.016) respectively. Graft loss and death were similar between groups. Incidence of
multiple episodes of rejection of at least grade 3A: 14.0%, 6.6% (p=0.02) and 8.1%
(p=0.06). At 12 months rejection of at least grade 3A were: 45.8%, 21.3% (p<0.001) and
30.6% (p<0.001).
Adverse Most frequent reasons for premature discontinuation were: renal disorders, infections,
effects leukopenia, gastrointestinal disorders, neurological disorders, anaemia and
thrombocytopenia.

Trial code NCT00150046; CRAD001A2411: de novo heart NCT00300274 18 ; CRAD001A2310:

transplant; phase IIIb 16,17 . de novo heart transplant; phase III.
Sponsor Novartis Novartis
Status Completed; published abstract. Ongoing
Location Germany, Spain, Italy and France. US, UK and Germany.
Design Randomised, controlled. Randomised, controlled.
Participants n=176; adults 18-65 years; de novo heart n=630; adults 18-70 years; de novo
in trial transplant. heart transplant.
Randomised to everolimus (target range 3-8 Randomised to everolimus and
ng/ml) and reduced exposure ciclosporin or reduced ciclosporin or 3g
mycophenolate mofetil 1.5g with standard mycophenolate mofetil with
exposure ciclosporin. All in combination with ciclosporin.
corticosteroids.
Follow-up 12 months. 24 months.
Primary Composite of death, graft loss, loss to follow-up, Treated biopsy confirmed acute
outcome biopsy-proved acute rejection grade 3A or rejection, graft loss, survival.
rejection or rejection with haemodynamic
compromise.
Secondary Renal function. Renal function by GFR.
outcomes
Key results Incidence of acute rejection grade 3A 22.8% for -
everolimus vs. 29.8% for mycophenolate
mofetil. Incidence of composite efficacy failure
32.6% vs. 41.7% respectively (everolimus
statistically non-inferior). Renal function
6928mL/min and 7230mL/min for everolimus
and mycophenolate mofetil respectively and
change of renal function were clinically
comparable but not statistically different.
Creatinine clearance remained stable after 1
month with everolimus, but declined with
mycophenolate mofetil.
Expected - Study started Dec 2005. Completion
reporting date unknown.
date
Adverse Discontinuation due to adverse effects were -
effects similar between trial arms.

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Estimated cost and cost impact

The cost of everolimus has not been determined for this indication. The costs of other
immunosuppressive treatments are a :

Drug Estimated cost per dose Estimated cost per course or

28 days
Basiliximab (SC) 842.40 per 20mg dose 1,684.80 per course
Daclizumab (IV) 671.00 per dose 3,355.00 per course
Tacrolimus (oral) 19.00-26.50 (0.2-0.3mg/kg per 532.00-742.00 per 28 days
day)
Mycophenolate 7.00 (2g per day) 196.00 per 28 days
mofetil (oral)
Sirolimus (oral) 18.00 (6mg loading dose) to 168.00 per 28 days
6.00 (2mg per day).

Potential or intended impact speculative

Patients
; Reduced morbidity Reduced mortality or increased ; Improved quality of life for
survival patients and/or carers
Quicker, earlier or more accurate Other: None identified
diagnosis or identification of
disease

Services
Increased use Service reorganisation required Staff or training required

; Decreased use: improves graft Other: None identified

survival.

Costs
Increased unit cost compared to Increased costs: more patients Increased costs: capital
alternative coming for treatment investment needed
New costs: Savings: ; Other: unsure of relative cost.

References
1
National Institute of Health and Clinical Excellence. The clinical effectiveness and cost effectiveness of
immuno-suppressive therapy for renal transplantation. NICE technology appraisal TA85. September 2004.
2
National Institute of Health and Clinical Excellence. Kidney disease: Early identification and management of
adults with chronic kidney disease in primary and secondary care. NICE clinical guideline in development.
Expected September 2008 (12th wave).
3
UK Renal Association. Clinical Practice Guidelines: assessment for renal transplantation. March 2008.
Available at: http://www.renal.org/guidelines/print/transplantationguidelinesFINALApril08.pdf (accessed
11.8.08).
4
National Institute of Health and Clinical Excellence. Chronic heart failure management of chronic heart
failure in adults in primary and secondary care. Clinical Guideline CG5. 2003 (review date February 2008)
5
Scottish Intercollegiate Guidelines Network (SIGN). Chronic heart failure. 2007. Available at:
www.sign.ac.uk/pdf/pat95.pdf (accessed 13.8.08).

a
British National Formulary. No. 55 March 2008. For an average 67.5kg adult.
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6
Webster AC, Lee VW, Chapman JR et al. Target of rapamycin inhibitors (TOR-I; sirolimus and everolimus) for
primary immunosuppression in kidney transplant recipients. Available at: http://www.cochrane.org
/reviews/en/ab004290.html (accessed 13.8.08).
7
Woodroffe R, Yao GL, Meads C. Clinical and cost effectiveness of newer immunosuppressive regimens in
renal transplantation: a systematic review and modelling study. Health Technology Assessment 2005; 9: 21.
Available at: http://www.ncchta.org/execsumm/summ921.shtml (accessed 11.8.08).
8
UK Transplant Organisation. Transplant activity in the UK. Available at: https://www.uktransplant
.org.uk/ukt/statistics/transplant_activity_report/current_activity_reports/ukt/transplant_activity_uk_2006-
2007.pdf. (accessed 12.8.08).
9
Taylor AL, Watson CJ, Bradley JA. Immunosuppressive agents in solid organ transplantation: mechanisms of
action and therapeutic efficacy. Critical Reviews in Oncology and Haematology. 2005;56(1):23-46.
10
Lorber MI, Mulgaonkar S, Butt KM et al. Everolimus versus mycophenolate mofetil in the prevention of
rejection in de novo renal transplant recipients: a 3-year randomised, multicenter, phase III study.
Transplantation. 2005; 80(2):244-52.
11
Vitko S, Margreiter R, Weimar W et al. Three year efficacy and safety results from a study of everolimus
versus mycophenolate mofetil in de novo renal transplant patients. American Journal of Transplantation.
2005;5(10):2521-30.
12
Clinical trials. Efficacy and safety study of everolimus plus cyclosporine and mycophenolic acid plus
cyclosporine in kidney transplants. Available at: http://clinicaltrials.gov/ct2/show/NCT00251004 (accessed
12.8.08).
13
Clinical trials. Concentration controlled everolimus with reduced dose Neoral versus mycophenolate mofetil
with standard dose Neoral in de novo renal transplant adult recipients treated with basiliximab and
corticosteroids. Available at: http://clinicaltrials.gov/ct2/show/NCT00658320?term=NCT006
58320&rank=1(accessed 12.8.08).
14
Vigano M, Tuzcu M, Benza R et al. Prevention of acute rejection and allograft vasculopathy by everolimus in
cardiac transplant recipients: a 24 month analysis. Journal of Heart and Lung Transplant. 2007; 26(6): 584-92.
15
Eisen HJ, Tuzcu M, Dorent R et al. Everolimus for the prevention of allograft rejection and vasculopathy in
cardiac transplant recipients. The New England Journal of Medicine. 2003; 349(9): 847-858.
16
Clinical trials. Efficacy and safety of everolimus in de novo heart transplant recipients. Available at:
http://clinicaltrials.gov/ct2/show/NCT00150046 (accessed 13.8.08).
17
Lehmkuhl H, Livi U, Arizon J et al. Results of a multicenter, randomised trial of everolimus with reduced
exposure cyclosporine versus MMF and standard exposure cyclosporine in de novo cardiac transplant
recipients. The Journal of Heart and Lung Transplantation. 2008; 27(2) Suppl S65.
18
Clinical trials. Efficacy and safety of everolimus in recipients of heart transplants to prevent acute and chronic
rejection. Available at: http://clinicaltrials.gov/ct2/show/NCT00300274?term= NCT00300274&rank=1
(accessed 12.8.08).

The National Institute for Health Research National Horizon Scanning Centre Research
Programme is funded by the Department of Health.
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NHS, the NIHR or the Department of Health

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