The FINANCIAL — Novartis on April 20 announced results from a Phase III study showing Afinitor (everolimus), when used as an adjunctive therapy, significantly reduced treatment-resistant seizures associated with tuberous sclerosis complex (TSC) compared to placebo.
Patients in all treatment arms were also taking one to three anti-epileptic drugs (AEDs)[1]. The study, EXIST-3 (EXamining everolimus In a Study of TSC), is being presented during a plenary session at the 68th Annual Meeting of the American Academy of Neurology (AAN) (Abstract #32430, 9:00-11:00 a.m. PST).
“Approximately 85% of individuals with TSC are affected by epilepsy at some point in their lives, yet nearly two-thirds of these patients do not achieve seizure control with available therapies, and may also experience other potentially serious consequences, such as neuropsychological, cognitive, social or learning disabilities,” said Jacqueline A. French, MD, department of neurology, NYU Langone Medical Center and lead investigator of the EXIST-3 trial. “These findings are encouraging as this is the first clinical study demonstrating benefit specifically for TSC patients who suffer from treatment-resistant seizures.”
In the study, 366 patients with TSC and treatment-resistant seizures were randomized to receive targeted concentrations of everolimus titrated to Low Exposure (LE; 3-7 ng/mL; n=117) or High Exposure (HE, 9-15 ng/mL; n =130), or placebo (n=119). The percentage reduction from baseline in seizure frequency was significantly greater among patients randomized to everolimus LE (29.3%, P=0.003; confidence interval [CI]=95%) and HE (39.6%, P<0.001; CI=95%) vs placebo (14.9%; CI=95%). Seizure response rate (>=50% reduction) was also significantly greater with everolimus LE (28.2%, P=0.008; CI=95%) and HE (40.0%, P<0.001; CI=95%) vs placebo (15.1%; CI=95%). The most common (>=20%) adverse events (AEs) reported with everolimus LE/HE vs placebo included stomatitis (28.2%/30.8% vs 3.4%), mouth ulceration (23.9%/21.5% vs 4.2%), and diarrhea (17.1%/21.5% vs 5.0%). Serious AEs reported were 13.7%/13.8% vs 2.5%, according to Novartis.
“There has been a long-standing need to find a treatment option for TSC patients that provides control of treatment-resistant seizures and we are encouraged that data from the EXIST-3 study show everolimus may have this potential,” said Alessandro Riva, MD, Global Head, Novartis Oncology Development and Medical Affairs. “Over the past decade, Novartis has remained committed to the TSC community, improving care for patients and conducting research we hope will bring us closer to addressing some of the most debilitating TSC manifestations.”
Tuberous sclerosis complex is a rare genetic disorder affecting up to one million people worldwide and everolimus is the only approved non-surgical option indicated for treating non-cancerous brain and kidney tumors in certain patients with TSC. EXIST-3 study results show that everolimus is the first adjunctive therapy to achieve clinically significant seizure control in TSC patients and will be the basis for discussion with health authorities worldwide.
Everolimus 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. Pre-clinical research suggests that hyperactive mTOR activity may influence several mechanisms of epileptogenesis, the gradual process by which the brain develops epilepsy.
EXIST-3 study details
EXIST-3 is a Phase III, three-arm, randomized, double-blind, placebo-controlled study of the efficacy and safety of high and low exposure ranges of everolimus as adjunctive therapy in patients with TSC who have treatment-resistant seizures, defined as seizures persisting despite the use of two AEDs. The study enrolled male and female participants (ages 2.2-56.3) with clinically defined TSC, who were on stable doses of one to three AEDs for at least four weeks prior to a two month, pre-randomization, evaluation period.
The primary objective was to assess the effectiveness of adjunctive everolimus as compared to placebo in reducing seizures in patients with TSC who are taking one to three AEDs. Secondary objectives include the percentage of patients free from seizure during the maintenance period and change in seizure frequency.
The most frequent >=10% all grade adverse events (AEs) reported with everolimus LE/HE vs placebo included stomatitis (28.2%/30.8% vs 3.4%), mouth ulceration (23.9%/21.5% vs 4.2%), diarrhea (17.1%/21.5% vs 5.0%), nasopharyngitis (13.7%/16.2% vs 16.0%), upper respiratory tract infection (12.8%/15.4% vs 12.6%), aphthous ulcer (4.3%/14.6% vs 1.7%) pyrexia (fever) (19.7%/13.8% vs 5.0%), vomiting (12.0%/10.0% vs 9.2%), cough (11.1%/10.0% vs 3.4%) and rash (6.0%/10.0% vs 2.5%).
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