How is tuberous sclerosis complex (TSC) treated?

Updated: Aug 21, 2018
  • Author: David Neal Franz, MD; Chief Editor: Amy Kao, MD  more...
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Sirolimus (Rapamycin [Rapamune]) is a commercially available immunosuppressant, which forms an inhibitory complex with the immunophilin FKBP12, which binds to and inhibits the ability of mTOR to phosphorylate downstream substrates, such as the S6Ks and 4EBPs. It is marketed as an immunosuppressant, owing to its propensity to inhibit T-cell proliferation, and has been approved for use in this therapeutic setting in the United States since 2001.

Two analogs of sirolimus include everolimus and the prodrug temsirolimus. They act in a similar fashion to sirolimus, although their pharmacokinetics, bioavailability, and adverse effect profiles differ. In clinical trials, common adverse effects include aphthous oral ulcers, hyperlipidemia, thrombocytopenia, acneiform rash, immunosuppression, and impaired wound healing.

Everolimus tablets and tablets for suspension (Afinitor and Afintiro Disperz) are approved in the US for SEGAs associated with tuberous sclerosis that cannot be treated with surgery in adults and children aged 1 year or older. Afinitor is also approved in adults with TSC-associated renal angiomyolipoma, not requiring immediate surgery. In April 2018, the tablets for oral suspension (Afinitor Disperz) were approved for adults and children aged 2 years or older for TSC-associated partial-onset seizures.

Approval of everolimus oral suspension for TSC-associated partial-onset seizures was based on the EXIST-3 (EXamining everolimus In a Study of TSC) trial. Everolimus significantly reduced the frequency of treatment-resistant seizures associated with TSC compared with placebo. The median percentage reduction from baseline in seizure frequency was significantly greater among patients randomized to everolimus oral suspension low exposure (LE 29.3%; p=0.003) and high exposure (HE 39.6%; p< 0.001) compared with placebo (14.9%). Seizure response rate (≥50% reduction) was also greater with everolimus LE (28.2%) and HE (40.0%) (p< 0.001) compared with placebo (15.1%). [5]

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