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Everolimus for autosomal dominant polycystic kidney disease with renal impairment

Source agency:

NHSC

Date of Submission:

20/10/2009

Date of Printing:

05/02/2012

Disclaimer:

This report is work in progress and should not be used for external distribution without permission from the originating agency. Users should be aware that reports are based on information available at the time of research and often on a limited literature search.

Technology, Company & Licensing

Technology name:

Everolimus

Technology - description:

Everolimus (RAD-001) is an orally active inhibitor of the mammalian target of rapamycin (mTOR) protein, which inhibits the proliferation of renal tubular epithelial cells and reduces the rate of cyst growth and expansion. Everolimus is administered orally at an initial dose of 2.5mg twice daily followed by therapeutic dose monitoring (TDM) to 3-8ng/ml and is intended to be used in addition to current therapy.

Company or developer:

Novartis Pharmaceuticals UK Ltd.

Reason for database entry:

Potentially new technology for autosomal dominant polycystic kidney disease with renal impairment.

Technology - stage in early warning process:

Assessment complete

Technology - stage of development:

Investigational - phase III

Licensing, reimbursement and other approval:

In phase III trials.

Technology - type(s):

Drug

Technology - use(s):

Therapeutic

Patient Indication & Setting

Patient indications:

• Autosomal dominant polycystic kidney disease with renal impairment (chronic kidney disease stage II and III).

Disease description and associated mortality and morbidity:

Autosomal dominant polycystic kidney disease (ADPKD) is a common inherited disorder, characterised by the progressive increase in the number and size of bilateral renal cysts, which results in enlargement of the kidneys to 3-4 times their normal size. This is accompanied by the development of renal impairment and eventual chronic kidney disease (CKD) in the majority of affected individuals. Disease progression in ADPKD is highly variable, with symptoms usually appearing between the ages of 30 and 60 years (1,2). Mutations in the PKD1 gene encoding polycystin 1 are responsible for 85% of cases of ADPKD, whilst mutations on the PKD2 gene encoding polycystin 2 (a less severe phenotype) cause the remaining 15% . Patients may experience complications such as hypertension, haematuria, liver and pancreatic cysts (75% by 50 years of age), intracranial aneurisms, kidney stones and urinary tract infections (2).

Approximately 50% of patients will have end-stage renal disease by 60 years of age (8), but one third will reach 70 years with some preservation of renal function (9).

Number of Patients:

ADPKD is one of the most common hereditary disorders, with a prevalence of between 1 in 400 and 1 in 1,000 (6) (approximately 13,500-54,100 people in England and Wales). In 2007 the incidence rate of polycystic kidney disease (PKD) as the primary cause of renal disease was 6.5 per million in England and 7.4 per million in Wales (approximately 354 people in England and Wales) and accounted for 12.7% of new renal transplants in the UK (7).

Technology - specialities(s):

Renal disease & urology

Technology - setting(s):

Community and primary care, General hospital and ambulatory care

Setting - further information:

 

Impact

Alternative and/or complementary technology:

Additive or complementary technology

Current Technology:

There are currently no pharmacological or other therapies that have been shown to prevent renal cyst formation. Current therapies used in ADPKD, including dialysis and transplantation, aim to control symptoms and associated complications of renal disease.

Health Impact:

Reduction in associated morbidity or improved quality of life for patients and/or carers .

Diffusion:

-

Cost, infrastructure and economic consequences:

The cost of everolimus for ADPKD is currently unknown.

Ethical, social, legal, political and cultural impact:

-

Evidence & Policy

Clinical evidence and safety:

Trial: NCT00414440; ADPKD; everolimus vs placebo; phase III.
Sponsor: Novartis Pharmaceuticals.
Status: Ongoing.
Source of information: Trial registry (10).
Location: Germany.
Design: Randomised, double-blind, controlled.
Participants and schedule: n=400; adults 18-65 years; ADPKD; CKD stage II/III.
Randomised to everolimus 2.5mg twice daily plus TDM 3-8ng/ml or placebo for 2 years.
Follow-up : 2 year follow up.
Primary outcome: Mean total kidney volume.
Secondary outcomes: Mean cyst and parenchyma volume; renal function; incidence of newly developing end stage renal disease (ESRD); blood pressure.
Expected reporting date : Study started Dec 2006 with expected date of final analysis Q2 2010.

Economic evaluation:

-

Ongoing research:

-

Ongoing or planned HTA:

-

Web link:

http://www.nhsc-healthhorizons.org.uk/outputs/specialties/

References and sources:

1) NHS Choices. Autosomal dominant polycystic kidney disease. http://www.nhs.uk/Conditions/Autosomal dominant-polycystic-kidney-disease/Pages/Symptoms.aspx Accessed 28 August 2009.
2) Torres VE, Harris PC, Pirson Y. Autosomal dominant polycystic kidney disease. Lancet 2007;369:1287-1301.
3) National Institute for Health and Clinical Excellence. Chronic kidney disease: early identification and management of chronic kidney disease in adults in primary and secondary care. Clinical Guideline CG73. London: NICE; September 2008.
4) Tal MW, Tompson C. Clinical practice guidelines for the care of patients with chronic kidney disease. UK Renal Association. 2007. http://www.renal.org/pages/media/download_gallery/CKDfinalMar07.pdf. Accessed 02 September 2009.
5) Scottish Intercollegiate Guidelines Network. Diagnosis and management of chronic kidney disease. Clinical Guideline 108. Edinburgh: SIGN; 2008.
6) National Genetics Education and Development Centre. Adult Polycystic Kidney Disease (APKD). NHS. http://www.geneticseducation.nhs.uk/learning/conditions.asp?id=2 Accessed 02 September 2009.
7) UK Renal Registry. ESRD incident rates in 2007 in the UK: national and centre-specific analyses – chapter 3. http://www.renalreg.com/Report-Area/Report%202008/Chapter03.pdf Accessed 15 September 2008.
8) Harris PC, Torres VE. Polycystic kidney disease, autosomal dominant. Gene Tests at NCBI. http://www.ncbi.nlm.nih.gov/bookshelf/br.fcgi?book=gene&part=pkd-ad Accessed 28 August 2009.
9) The Polycystic Kidney Disease Charity. Autosomal dominant polycystic kidney disease – information booklet for patients, their families and carers. http://www.pkdcharity.co.uk/ADPKD%20Infomation%20Booklet%20March%202007%20v3.pdf Accessed 28 August 2009.
10) ClinicalTrials.gov. Efficacy, safety and tolerability of everolimus in preventing end-stage renal disease in patients with autosomal dominant polycystic kidney disease. http://www.clinicaltrials.gov/ct2/show/NCT00414440?term=NCT00414440&rank=1 Accessed 28 August 2009.

Notes: