Study Results Change the Worldwide Standard of Care for Tuberous Sclerosis
Results from a clinical trial have shown that the drug everolimus can reverse the genetic defect associated with tuberous sclerosis complex (TSC).
The study, EXIST-3, showed that everolimus significantly reduced treatment-resistant seizures associated with TSC when used as an adjunctive therapy.
“What is exciting and significant about this study is that everolimus targets the genetic mutation responsible for TSC, which is the overactivation of mammalian target of rapamycin (mTOR),” says David Franz, MD, founding director of the Tuberous Sclerosis Clinic at Cincinnati Children’s and senior author of the study. “Therefore, everolimus not only treats the seizures, but every other manifestation of the disease, including autism, cognitive impairment, tumors on vital organs and disfiguring skin tumors. What’s more, it has the potential to treat any other disease where the common thread is overactivation of mTOR, such as genetic brain malformations, epilepsy and autism.”
Results confirm patients’ experiences
The Food and Drug Administration (FDA) approved everolimus, a chemotherapy agent, in 2010 to treat children with brain tumors associated with the disease. Since then, Franz and other tuberous sclerosis experts from around the world have been studying its potential to treat other manifestations of TSC in clinical trials.
Kay Rawlings, whose daughter is a patient of Franz’s, is not surprised by the EXIST-3 findings. Her daughter, Cameron, was diagnosed with TSC through fetal ultrasound and began having infantile seizures at about age one. In 2005, when Cameron was three years old, a subependymal giant cell astrocytoma (SEGA) began growing very quickly, causing severe symptoms. “The neurosurgeon at our local hospital wanted to remove it, but the surgical risks were so great that we started researching other options,” says Rawlings. “We flew from Seattle to Cincinnati to see Dr. Franz, and by then the tumor was occupying more than half of Cameron’s cranial cavity.”
Franz prescribed rapamycin (a precursor of everolimus), and Cameron’s tumor began to shrink. Cameron continued taking the drug for several years, then switched to everolimus as an adjunct to the anticonvulsant Lamictal. Today she shows very few signs of TSC. “When we see Dr. Franz at our annual clinic visits, we don’t even discuss the option of surgically removing the SEGA, since it is so small now,” says Rawlings. “Cameron doesn’t have any growths on her organs, including her skin, or any of the behavioral problems that are sometimes associated with TSC. She does have cognitive delays, but continues to show a great capacity for learning.”
Another patient of Franz’s, 10-year-old Jude Chambers, began taking everolimus as part of the EXIST-3 study. Diagnosed with TSC at five months old, Jude experienced intermittent seizure control through drug therapy and a left frontal lobectomy. But he also had SEGAs and extensive tubers on his kidneys. “When Dr. Franz suggested we enroll Jude in the EXIST-3 study in 2014, we were really excited because we knew how much everolimus had helped some other TSC patients,” says Jude’s mother, Jordana. “Since joining that trial, the growths on Jude’s kidneys have shrunk so much that you can hardly see them on scans. We’ve also noticed improvements in his cognitive abilities and his desire to interact socially with other children.”
Based on the results of the EXIST-3 study, the European Medical Association approved everolimus for the adjunctive treatment of seizures associated with TSC in January 2017, and Franz expects FDA approval to take place this year. “What we are learning about everolimus is changing the worldwide standard of care for TSC,” he explains. “We will continue to explore other questions about everolimus, such as whether it can be used with other drugs to reverse the intellectual disability associated with TSC.”
The EXIST-3 study appeared in the Lancet (Sept. 6, 2016). Everolimus is marketed by Novartis, which provided drug and financial support for the study. In addition, several of the study authors are employees of Novartis. The first author of the EXIST-3 study was Jacqueline French, MD, professor of neurology and director of Translational Research & Clinical Trials Epilepsy at NYU Langone’s Comprehensive Epilepsy Center.
