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.
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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 Everolimus and Sirolimus.
mTOR inhibitor medicines do a similar job in the body as the TSC1 and TSC2 proteins, controlling how many cells grow and how large they grow. This is the reason the medicines are effective in reducing the size of the tumours in some people with TSC.
Everolimus also has the following names:
- Afinitor (Australia/NZ)
- Votubia
- RAD001
- Zortress
- Certican
Sirolimus is also called:
- Rapamycin (Australia/NZ)
- Rapamune
- RAPA
Everolimus and sirolimus are very similar and have similar side effects. Both can be effective in TSC, however everolimus is more often prescribed as it has been approved by the Australian Therapeutic Goods Administration for use in TSC and is funded by the Pharmaceutical Benefits Scheme (PBS).
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 TSA if you would like help to identify a doctor with this experience.
mTOR inihibitors may reduce the effectiveness of some other medicines, including anti-seizure medications.
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;
- acne.
mTOR inhibitors may affect fertility and should not be taken in pregnancy.
It is usually best practice for people to have all their immunizations up-to-date before starting mTOR inhibitors. Most vaccines can be given safely while patients are taking mTOR inhibitors, however it is always important to check with your doctor.
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.
mTOR inhibitors may interact with many other medicines, including anti-seizure medications and some antibiotics. These interactions may reduce the effectiveness of some medications or can increase the risk of side effects. Always check with your doctor whether new drugs will interact with pre-existing medications and ask whether the levels of medicines should be checked.
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.
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:
https://tsa.org.au/information/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
Afinitor (Everolimus) is part of the pharmaceutical benefits scheme (PBS) and treatment for SEGA falls under this listing. People with TSC in Australia that can obtain medicines under the PBS may be able to obtain this medicine paying only their regular PBS co-payment. You can read more about this decision at tsa.org.au/pbs-listing/
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 listed Aifnitor (Everolimus) for the treatment of SEGAs in TSC. You can read more about this listing at www.pharmac.govt.nz/HMLOnline.php?osq=Everolimus
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: https://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.
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:
https://tsa.org.au/information/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.
Afinitor (Everolimus) is part of the pharmaceutical benefits scheme (PBS) and treatment for renal amgiomyolipoma falls under this listing. People with TSC in Australia that can obtain medicines under the PBS may be able to obtain this medicine paying only their regular PBS co-payment. You can read more about this decision at tsa.org.au/pbs-listing/
In New Zealand, Pharmac have not yet provided general funding for Everolimus for AMLs. Funding for Everolimus or Sirolimus may be available for an individual through a named patient pharmaceutical assessment or a special authority.
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.
What are seizures?
Seizures are experienced by up to 90% of people with TSC. In up to 50% of people with TSC these seizures are not able to be controlled with existing anti-epilepsy medications alone. Read more at: https://tsa.org.au/information/epilepsy/
What other treatments are available for seizures?
Seizures can be treated with anti-epilepsy medications, surgery and diet.
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:
Adjunctive treatment of patients aged 2 years and older with TSC and associated refractory seizures.
Adjunctive means that Everolimus is approved for us in addition to other anti-epilepsy medications.
Afinitor (Everolimus) for seizures has been recommended for inclusion in the pharmaceutical benefits scheme (PBS). After this decision is implemented, people with TSC in Australia that can obtain medicines under the PBS may be able to obtain this medicine through a doctor’s prescription paying only their regular PBS co-payment. We expect this medicine to be included on the PBS by the end of 2018.
What research has been done?
The main clinical trial that investigated the use of Everolimus for seizures is called EXIST-3 (for Examining Everolimus In a Study of TSC).
You can read this study here: www.thelancet.com/journals/lancet/article/PIIS0140-6736(16)31419-2/fulltext
In EXIST-3, Everolimus was shown to be effective at treating patients for whom existing treatment options had failed to control their focal epilepsy. The study reported the number of patients who had at least a 50% reduction in their seizures. The trial found up to 40% of people with TSC taking this medicine had at least a 50% reduction in seizures.
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.
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:
https://tsa.org.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 anaesthetic.
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:
https://tsa.org.au/topicalfaq/
In some hospitals dermatologists have secured hospital funding for this medicine. Tuberous Sclerosis Australia is working towards a long term solution to ensure there is equitable access to this medicine.
In New Zealand, Pharmac has funded this medicine for a small number of children through the named patient pharmaceutical assessment process.
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:
https://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 2015.
Preliminary results were presented at a 2014 TSC conference in the United States. You can view this presentation here:
tsa.org.au/resources/research-updates-tsc-world-conference-video
A number of case reports suggest that Sirolimus may be effective if applied directly to the skin. Some of these studies include:
- Tu, J., et al., Topical rapamycin for angiofibromas in paediatric patients with tuberous sclerosis: follow up of a pilot study and promising future directions. Australas J Dermatol, 2014. 55(1): p. 63-9.
- R. S. Foster, L. J. Bint, A. R. Halbert. Topical 0.1% rapamycin for angiofibromas in paediatric patients with tuberous sclerosis: a pilot study of four patients. Australas J Dermatol 2012; 53: 52-56.
- A. K. Haemel, A. L. O’Brian, J. M. Teng. Topical rapamycin: a novel approach to facial angiofibromas in tuberous sclerosis. Arch Dermatol 2010; 146: 715-718.
- M. K. Koenig, A. A. Hebert, J. Roberson et al. Topical rapamycin therapy to alleviate the cutaneous manifestations of tuberous sclerosis complex: a double-blind, randomized, controlled trial to evaluate the safety and efficacy of topically applied rapamycin. Drugs R D 2012; 12: 121-126.
- M. M. Mutizwa, D. R. Berk, M. J. Anadkat. Treatment of facial angiofibromas with topical application of oral rapamycin solution (1mgmL(-1) ) in two patients with tuberous sclerosis. Br J Dermatol 2011; 165: 922-923.
- R. Salido, G. Garnacho-Saucedo, I. Cuevas-Asencio et al. Sustained clinical effectiveness and favorable safety profile of topical sirolimus for tuberous sclerosis – associated facial angiofibroma. J Eur Acad Dermatol Venereol 2012; 26: 1315-1318.
- M. Wataya-Kaneda, M. Tanaka, A. Nakamura, S. Matsumoto, I. Katayama. A topical combination of rapamycin and tacrolimus for the treatment of angiofibroma due to tuberous sclerosis complex (TSC): a pilot study of nine Japanese patients with TSC of different disease severity. Br J Dermatol 2011; 165: 912-916.
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.
What is LAM?
Lymphangioleiomyomatosis (LAM) is a lung disease that affects almost exclusively women, usually between the onset of puberty and menopause. When a person has LAM, an unusual type of muscle cell is found in their lungs, airways, and blood and lymph vessels. Over time, these muscle cells destroy the lungs and make it difficult for oxygen to get across the wall of the airway and into the blood cells. This prevents the lungs from providing oxygen to the rest of the body.
You can read more about LAM at:
https://tsa.org.au/information/lungs/
What other treatments are available for LAM?
Most treatments for LAM are aimed at easing symptoms and preventing complications. The main treatments are:
- Medicines to improve air flow in the lungs and reduce wheezing;
- Oxygen therapy;
- Procedures to remove fluid from the chest or abdomen and stop it from building up again;
- Lung transplantation.
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 LAM. In the USA the Food and Drug Administration (FDA) approved Sirolimus for the treatment of LAM in 2015.
Despite the lack of formal approval in Australia, some respiratory specialist doctors will consider prescribing an mTOR inhibitor to treat LAM. This is called “off-label” use. In this situation a hospital may provide funding for the medication.
What research has been done?
The main clinical trial into the use of Sirolimus for LAM is called the MILES trial. In the Miles trial, sirolimus stabilised lung function and was associated with a reduction in symptoms and improvement in quality of life for women with LAM.
Who should I speak to about this?
Consult your lung physician to discuss how this information applies to your individual circumstances.
What research has been done?
Studies into mTOR inhibitors for cognition and autism found no benefits when participants were assessed using standardised testing methods. However many patients and family members who use these medicines for other signs and symptoms have reported improvements to alertness, social interactions and the ability to focus on tasks.
Reports have been published of individuals or small groups of people with TSC being treated with these medicines for:
- cardiac rhabdomyomas
- liver angiomyolipomas
- retinal hamartomas
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.
Help us provide high quality TSC information
We rely on the generosity of donors and fundraisers to publish these information pages and keep them up to date. Please support our work if you can so we can continue to provide life changing information and support to families like Harrison’s. Donate now.
Last updated: November 2022
Reviewed by:Dr Sean Kennedy, Paediatric Nephrologist, Sydney Children’s Hospital
References:
- European Medicines Agency. EPAR Summary for the Public: Votubia (Everolmius). viewed 1st August, 2013. https://www.ema.europa.eu/ema/index.jsp?curl=pages/medicines/human/medicines/002311/human_med_001484.jsp
- 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.
- 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.
- McCormack, F.X., et al., Efficacy and safety of sirolimus in lymphangioleiomyomatosis. The New England Journal of Medicine, 2011. 364: p. 1595-1606.