A drug originally identified by Cain Lab researchers approved by EU for partial-onset seizures in Tuberous Sclerosis patients


A drug initially discovered by the researchers in the Gordon and Mary Cain Foundation for Pediatric Neurology Research at Texas Children’s Hospital to be effective in treating refractory seizures commonly seen in tuberous sclerosis patients is now approved for use in Europe.

Earlier this year, Novartis Pharmaceuticals announced the European Commission (EU) approved Votubia (everolimus) as an adjunctive treatment for patients aged 2 years and older, whose refractory partial-onset seizures are associated with tuberous sclerosis complex (TSC), a rare genetic disorder affecting up to 1 million people worldwide. Approximately 85 percent of individuals with TSC are affected by epilepsy, many of whom have uncontrolled debilitating seizures.

The EU’s approval of Votubia offers a new therapeutic option which addresses a huge unmet need since up to 60 percent of TSC patients become unresponsive to anti-epileptic medications.

Everolimus has been used extensively in humans as an immunosuppressant during organ transplants to treat renal cell carcinomas and other cancers, and to treat subependymal giant cell astrocytomas (SEGAs) associated with TSC.

In 2010, extensive preclinical cellular and animal studies by Cain Lab researchers culminated in the identification of a rapamycin analog, everolimus, as a potential therapy against severe epilepsy in TSC.

Everolimus (Votubia) works by inhibiting the mammalian target of rapamycin (mTOR), a protein that regulates multiple cellular functions. TSC is caused by mutations in the TSC1 or TSC2 genes, resulting in hyperactive signaling of the mTOR pathway which can lead to increased cellular growth and proliferation, neuronal hyper-excitability, abnormalities in cortical architecture and network function and impaired synaptic plasticity.

An initial pilot clinical trial conducted at Texas Children’s and Cincinnati Children’s, and approved by the Food and Drug Administration (FDA), found that most of the severely epileptic children treated with everolimus had significantly fewer seizures. 

Encouraged by those positive results, a much larger international clinical trial, named EXIST-3 (EXamining everolimus In a Study of TSC) was undertaken.

EXIST-3 was a randomized, double-blind, placebo-controlled Phase III trial with the primary aim to test if administration of everolimus significantly reduced the frequency of refractory partial-onset seizures associated with TSC compared to placebo. The EU’s approval of Votubia was based on efficacy and safety data from this pivotal study.

Currently, in the United States, everolimus is approved for other indications and is under consideration by the FDA for TSC-related epileptic seizures.