Everolimus Treats Underlying Cause of Tuberous Sclerosis Seizures

MedicalResearch.com Interview with:

Jacqueline French, MD Professor, Department of Neurology Director Translational Research& Clinical Trials Epilepsy NYU Langone Medical Center

Dr. Jacqueline French

Jacqueline French, MD
Professor, Department of Neurology
Director Translational Research& Clinical Trials Epilepsy
NYU Langone Medical Center 

MedicalResearch.com: What is the background for this study?

Dr. French:  Tuberous sclerosis complex (TSC) is a disease associated with abnormal cell growth, caused by dysfunction of the TSC1 or TSC2 genes and dysruption of the MTOR pathway, which leads to cortical malformations, neuronal hyperexcitability, and seizures. Seizures in patients with TSC often start within the first year of life, and tend not to respond to traditional treatments. Everolimus is a marketed drug that has been used to treat other manifestations of TSC (including giant cell tumors of the brain, renal angiomyolipomas, and angiofibromas of the skin).

This study was a placebo-controlled add-on study of everolimus for the treatment of refractory seizures in children and adults with epilepsy.Following an 8-week baseline phase, patients aged 2-65 years (stratified by age) with TSC and refractory seizures on 1-3 antiepileptic drugs were randomized to EVE LT or HT Cmin target ranges or placebo, and treated in an 18 week Core Phase (6-wk titration + 12-wk maintenance). Primary endpoints were change from baseline in average weekly frequency of TSC-seizures (seizures not previously shown to be generalized in onset by EEG), expressed as response rate (≥50% reduction [RR]), and percentage reduction.

MedicalResearch.com: What are the main findings?

Dr. French:  Overall, 366 patients were randomized to EVE LT (n=117), HT (n=130), or placebo (n=119). The median percentage reduction in TSC-seizures was significantly greater with EVE LT (29.3%, P=0.003) and HT (39.6%, P<0.001) vs placebo (14.9%). RR was also significantly greater with EVE LT (28.2%, P=0.008) and HT (40%, P<0.001) vs placebo (15.1%). The most frequent ≥10% all grade adverse events (AEs) reported with EVE LT/HT vs placebo included stomatitis (28.2%/30.8% vs 3.4%), diarrhea (17.1%/21.5% vs 5%), mouth ulceration (23.9%/21.5% vs 4.2%), nasopharyngitis (13.7%/16.2% vs 16%), upper respiratory tract infection (12.8%/15.4% vs 12.6%), aphthous ulcer (4.3%/14.6% vs 1.7%), and pyrexia (19.7%/13.8% vs 5%). Discontinuations due to AEs (5.1%/3.1% vs 1.7%) were low.

MedicalResearch.com: What should clinicians and patients take away from your report?

Dr. French:  They should take away that this is the first epilepsy treatment that addresses the underlying defect that causes seizures. In other words, this treatment is not a “one size fits all” general seizure treatment-It is addressing the root problem.

This provides a therapy for patients with Tuberous sclerosis complex that treats multiple aspects of their disease, not only one-It can treat SEGA (Giant cell tumor), renal angiomyolipoma, angiofibroma as well.

MedicalResearch.com: What recommendations do you have for future research as a result of this study?

Dr. French:  The long-term extension study is ongoing-Since everolimus impacts the underlying pathophysiology in Tuberous sclerosis complex (MTOR overactivation), it is possible that longer treatment will provide greater benefit. We also need to understand what long-term tolerability will be.

It is possible that other epilepsies will also respond to Everolimus-For example, epilepsy due to cortical dysplasia may also relate to an over-activation of the M-tor pathway.

MedicalResearch.com: Thank you for your contribution to the MedicalResearch.com community.


Abstract, EXIST-3 (French, J, et al.  EXamining everolimus In a Study of TSC), presented during a plenary session at the 68th Annual Meeting of the American Academy of Neurology (AAN) (Abstract #32430, April 2016).

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Last Updated on May 2, 2016 by Marie Benz MD FAAD