As with all information published on this site, this page is intended to provide basic information about Tuberous Sclerosis Complex (TSC). It is not intended to, and it should not, constitute medical or other advice. Readers are warned not to take any action without first seeking medical advice.

What is an mTOR inhibitor?

In an individual with TSC, their cells are unable to produce either the protein called TSC1 or the protein called TSC2. These proteins play an important role in controlling how many cells grow and how large they grow. Without the proteins, tumours can form.

The term mTOR inhibitor refers to a group of medicines. The generic (official) names for the two main medicines are Sirolimus and Everolimus.

mTOR inhibitor medicines seem to do a similar job in the body as the TSC1 and TSC2 proteins, controlling how many cells grow and how large they grow. Scientists think this is the reason the medicines are effective in reducing the size of the tumours in some people with TSC.

Sirolimus is also called:

  • Rapamycin (Australia/NZ)
  • Rapamune
  • RAPA

Everolimus also has the following names:

  • Afinitor (Australia/NZ)
  • Votubia
  • RAD001
  • Zortress
  • Certican
The importance of TSC experts in using these medicines

mTOR inhibitors should be prescribed by a doctor experienced in their use in TSC. Your doctor may benefit from talking to another doctor who has this experience. You can contact ATSS if you would like help to identify a doctor with this experience.

Side effects of mTOR inhibitors

mTOR inihibitors may reduce the effectiveness of some other medicines, including anti-seizure medications. mTOR inhibitors may affect fertility and should not be taken in pregnancy.

Side effects of mTOR inhibitors can include:

  • mouth sores (oral ulcerations);
  • reduced resistance to infection;
  • shortness of breath, cough and fever;
  • amenorrhea (periods stopping temporarily).
  • delayed healing of wounds
  • high cholesterol levels

Doctors use blood tests to monitor side effects. This may include checking the kidney, liver, immune system, cholesterol and blood sugars. Blood tests also check levels of the medicine in the blood which determines whether the dose is correct.

Research is ongoing and may identify long term side effects that are not yet known. So far researchers have been re-assured by finding only relatively minor side effects in the majority of people taking the medicine. However, as with all new treatments, doctors and patients need to remain vigilant.

mTOR inhibitors for SEGAs

What is a SEGA?

SEGA stands for subependymal giant cell astrocytoma. A SEGA is a benign tumour of the brain that occurs in about 15% of people with TSC. You can read more about SEGAs here:

http://tsa.thedesignweb.com.au/i-need-to-know-more/signs/brain/

What other treatments are available for SEGAs?

When a SEGA is found to be large or growing rapidly, surgery is the main treatment option.

What approvals have been given for the use of mTOR inhibitors?

In Australia, the Therapeutic Goods Administration (TGA) have approved the use of Afinitor (Everolimus) as follows:

For the treatment of subependymal giant cell astrocytoma (SEGA) associated with tuberous sclerosis (TS), who require therapeutic intervention but are not candidates for curative surgical resection

The Australian Federal Minister for Health, the Hon Peter Dutton, recently announced that the cost of Everolimus for Tuberous Sclerosis will be subsidised by the government through the pharmaceutical benefits scheme (PBS). You can read more about this decision here: http://tsa.thedesignweb.com.au/2013/10/pbs-listing/ and http://tsa.thedesignweb.com.au/2013/05/pbac-everolimus/

In New Zealand, Medsafe have approved the use of Afinitor (Everolimus) as follows:

Subependymal giant cell astrocytoma (SEGA) associated with tuberous sclerosis complex (TSC) who require therapeutic intervention but are not amenable to surgery.

Pharmac, who make decisions on which medicine the New Zealand government will subsidise, have not yet considered a general listing for Aifnitor (Everolimus) in TSC.

What research has been done?

The main clinical trial that investigated the use of Everolimus for SEGAs is called EXIST-1 (for Examining Everolimus In a Study of TSC).

You can read the abstract for this study here: http://www.thelancet.com/journals/lancet/article/PIIS0140-6736%2812%2961134-9/abstract

In EXIST-1, Everolimus was shown to be effective at treating patients with SEGA by shrinking the volume of the primary (main) brain tumours. The main brain tumours shrank by half in approximately 30% of patients and by about a third in around 70% of patients.

Who should I speak to about this?

Consult your neurologist to find out more about this medicine and to discuss how this information applies to your individual circumstances.

mTOR inhibitors for Kidney Angiomyolipomas (AMLs)

What is an AML?

Angiomyolipomas (AMLs) are a benign tumour in the kidneys made up of blood vessels (angio), muscle (myo) and fat (lipo). They occur in about 80% of people with TSC. You can read more about AMLs here:

http://tsa.thedesignweb.com.au/i-need-to-know-more/signs/kidneys/

What other treatments are available for AMLs?

Angiomyolipomas (AMLs) are usually only treated if they are very large or if there has been bleeding. Treatment options include embolisation and surgery.

What approvals have been given for the use of mTOR inhibitors?

In Australia, the Therapeutic Goods Administration (TGA) have approved the use of Afinitor (Everolimus) as follows:

Patients with tuberous sclerosis complex (TSC) who have renal angiomyolipoma not requiring immediate surgery.

The Australian Federal Minister for Health, the Hon Peter Dutton, recently announced that the cost of Everolimus for Tuberous Sclerosis will be subsidised by the government through the pharmaceutical benefits scheme (PBS). You can read more about this decision here: http://tsa.thedesignweb.com.au/2013/10/pbs-listing/ and http://tsa.thedesignweb.com.au/2013/05/pbac-everolimus/

In New Zealand, ATSS expects that will consider applications during the second half of 2013.

What research has been done?

The main clinical trial into the use of Everolimus for Kidney AMLs is called EXIST-2 (for Examining Everolimus In a Study of TSC).

In EXIST-2 Everolimus was found to be effective in reducing the size of the kidney AMLs. Of the patients who took Everolimus, 97% showed stabilisation or some shrinkage of their AMLs. In 80% of patients their AMLs shrank by more than 30% after 48 weeks of treatment.

Who should I speak to about this?

Consult your nephrologist or renal physician to find out more about this medicine and discuss how this information applies to your individual circumstances.

mTOR inhibitors for Facial Angiofibomas

What are facial angiofibromas?

Facial angiofibromas are overgrowths of normal skin cells made up of blood vessels (angio) and fibrous tissue (fibroma). They occur in the majority of people over five years of age with TSC. You can read more about facial angiofibromas here:

http://tsa.thedesignweb.com.au/signs-and-symptoms/skin/

What other treatments are available for facial angiofibromas?

Surgical treatments for facial angiofibomas usually involve the use of a laser such as a vascular or CO2 laser. All laser treatments are uncomfortable and will require either local or general anesthetic.

What approvals have been given for the use of mTOR inhibitors?

There have been no approvals in Australia or New Zealand for mTOR inhibitors to be used to treat facial angiofibromas. Neither the U.S. Food and Drug Administration (FDA) or the European Medicines Agency has approved mTOR inhibitors to be used to treat facial angiofibromas.

Despite the lack of formal approval, some doctors will consider prescribing an mTOR inhibitor to treat facial angiofibromas. This is called “off-label” use. You can read more about this here:

http://tsa.thedesignweb.com.au/2012/11/topicalfaq/

What research has been done?

The first clinical trial into the use of mTOR inhibitors to treat facial angiofibomas is called the Treatment Trial (its full name is Topical Rapamycin to Erase Angiofibromas in TSC – Multicenter Evaluation of a Novel Therapy). You can read more about this trial here:

http://www.clinicaltrials.gov/ct2/show/NCT01526356

There is one Australian centre participating in this trial, and it is fully recruited. The first publication from the Treatment Trial is expected in late 2014.

A number of case reports suggest that Sirolimus may be effective if applied directly to the skin. Some of these studies include:

In addition, the clinical trials investigating mTOR inhibitor use for SEGAs (EXIST-1) and kidney AMLs (EXIST-2) found some evidence of improvements in facial angiofibromas in patients taking an mTOR inhibitor.

Who should I speak to about this?

Consult your dermatologist to find out more about this medicine and discuss how this information applies to your individual circumstances.

mTOR inhibitors for other signs and symptoms of TSC

What research has been done?

There are a number of studies that are complete or in progress for these signs and symptoms of TSC:

In addition, the clinical trials investigating mTOR inhibitor use for SEGAs (EXIST-1) and kidney AMLs (EXIST-2) found some evidence of improvements in epilepsy and neurocognition in patients taking an mTOR inhibitor.

Despite the lack of formal evidence of effectiveness and no approvals for use, some doctors will consider prescribing an mTOR inhibitor to treat other signs and symptoms of TSC. This is called “off-label” use.

Who should I speak to about this?

Consult your doctor to find out more about this medicine and discuss how this information applies to your individual circumstances.

 

About this article

Prepared by: Clare Stuart, The Australasian Tuberous Sclerosis Society

Reviewed by: Dr John Lawson, Paediatric Neurologist, Sydney Children’s Hospital, Dr Sean Kennedy, Paediatric Nephrologist, Sydney Children’s Hospital, Dr Orli Wargon, Dermatologist, Sydney Children’s Hospital

TSC Family review provided by Kate Norris and Anthony Crosby.

References:

  1. European Medicines Agency. EPAR Summary for the Public: Votubia (Everolmius). viewed 1st August, 2013. http://www.ema.europa.eu/ema/index.jsp?curl=pages/medicines/human/medicines/002311/human_med_001484.jsp
  2. Franz, D.N., et al., Efficacy and safety of everolimus for subependymal giant cell astrocytomas associated with tuberous sclerosis complex (EXIST-1): a multicentre, randomised, placebo-controlled phase 3 trial. Lancet, 2013. 381(9861): p. 125-32.
  3. Bissler, J.J., et al., Everolimus for angiomyolipoma associated with tuberous sclerosis complex or sporadic lymphangioleiomyomatosis (EXIST-2): a multicentre, randomised, double-blind, placebo-controlled trial. Lancet, 2013. 381(9869): p. 817-24.