On April 10, 2018, the Food and Drug Administration (FDA) approved everolimus tablets for oral suspension (brand name: Afinitor Dispersz, Novartis Pharmaceuticals Corporation) as an adjunctive therapy to treat partial-onset refractory seizures in adults and children over 2 years of age with Tuberous Sclerosis Complex (TSC). Tuberous Sclerosis is a genetic disorder that affects one million people worldwide and is characterized by benign tumors in several organs, epilepsy, behavioral problems and intellectual disability.
FDA’s approval of Afinitor addresses a huge unmet need for TSC patients, since 60 percent of them are unresponsive to the usual anti-epileptic medications.
Extensive preclinical cellular and animal studies conducted by researchers at the Gordon and Mary Cain Pediatric Neurology Research Laboratories located in the Jan and Dan Duncan Neurological Research Institute culminated in the discovery of everolimus, a chemical analog of rapamycin (a.k.a sirolimus), as a potential therapy against refractory epilepsy in TSC patients.
The first study that led the Cain Lab researchers down this path of scientific discovery was published in the Annals of Neurology in 2006. The study led by Drs. Gabriella D’Arcangelo and John Swann, director of the Cain Labs, identified hyperactivation of the mammalian target of rapamycin (mTOR) pathway as the key mechanism underlying abnormal growth of neurons in patients with cortical dysplasia.
Tuberous Sclerosis complex is caused by mutations in TSC1 or TSC2 genes, that hyperactivate the mTOR signaling pathway. mTOR is a kinase protein that regulates many crucial cellular functions and its hyperactivation causes excessive proliferation and growth of neurons, rendering them dysfunctional. Additional changes in neuronal activity and synaptic plasticity causes other abnormalities in brain architecture and functioning.
In 2009, Cain Lab researchers published a follow-up study which demonstrated that administration of rapamycin, an inhibitor of the mTOR kinase and a chemical analog of everolimus, could suppress seizures and neuronal overgrowth in a mouse model of cortical dysplasia.
These promising pre-clinical studies led to an initial pilot clinical trial of 20 patients at Texas Children’s Hospital and Cincinnati Children’s Hospital. This trial was the first successful demonstration of the effectiveness of everolimus in treating seizures in TSC patients and was approved by the FDA in 2010.
Encouraged by these positive results, a much larger international, multicenter clinical trial, called EXIST-3 (EXamining everolimus In a Study of TSC) was undertaken by Novartis Pharmaceuticals Corporation. FDA’s current approval of everolimus for TSC-associated partial-onset epilepsy was based on this study.
EXIST-3 was a randomized and double-blind study that tested the efficacy of everolimus (a.k.a. Afinitor) in reducing the frequency of weekly seizures in 366 TSC patients. The patients had significantly fewer seizures and a small percentage of them exhibited mild side effects such as diarrhea, vomiting and upper respiratory infections.
Many trials have shown everolimus to be safe for human consumption, within the prescribed dosage limits. It has been used extensively as an immunosuppressant during organ transplants to treat renal cell carcinomas and other cancers. In the recent years, it has also been approved for the treatment of TSC-associated giant cell astrocytomas (SEGAs) and TSC-associated renal angiomyolipoma. Last year, the European Union also approved its use as an adjunctive therapy for TSC-associated partial-onset seizures.
For more information on Afinitor, read FDA’s press release.