Novartis announced that the European Commission has approved Votubia (everolimus) dispersible tablets as an adjunctive treatment for patients aged two years and older whose refractory partial-onset seizures, with or without secondary generalization, are associated with tuberous sclerosis complex (TSC). Votubia is now the first approved pharmacologic therapy in all 28 member states of the European Union (EU), plus Iceland and Norway, specifically for the treatment of refractory partial-onset seizures associated with TSC.
“With this latest approval of Votubia in the EU, patients with TSC suffering from refractory partial-onset seizures – one of the most debilitating manifestations of TSC – now have a new therapeutic option to address a critical unmet need,” said Bruno Strigini, CEO, Novartis Oncology. “This is a welcome advance and an important milestone in our ongoing commitment to improving care for this patient community.”
The EU approval of Votubia was based on efficacy and safety data from a pivotal Phase III study (EXIST-3: EXamining everolimus In a Study of TSC), which found that when used as an adjunctive therapy, Votubia significantly reduced the frequency of refractory partial-onset seizures associated with TSC compared to placebo. Efficacy and safety of two trough exposure concentrations of Votubia, 3-7 ng/mL (low exposure) and 9-15 ng/mL (high exposure) were assessed. Patients in all treatment arms concomitantly received one to three anti-epileptic drugs (AEDs) during the eighteen weeks of study core phase. The youngest patient enrolled was two years of age. Seizure response rate (>=50% reduction) was significantly greater with Votubia low exposure (LE) (28.2%, 95% confidence interval [CI] 20.3 – 37.3; p=0.008) and high exposure (HE) (40.0%, 95% CI 31.5 – 49.0; p<0.001) vs placebo (15.1%, 95% CI 9.2 – 22.8). The median percentage reduction from baseline in seizure frequency was also significantly greater among patients randomized to Votubia LE (29.3%, 95% CI 18.8 – 41.9; p=0.003) and HE (39.6%, 95% CI 35.0 – 48.7; p<0.001) vs placebo (14.9%, 95% CI 0.1 – 21.7). The most common all-grade adverse events (AEs) of any cause reported during the core phase at frequencies >=15% in Votubia LE/HE arms included stomatitis, diarrhea, nasopharyngitis, upper respiratory tract infection, and pyrexia.
Tuberous sclerosis complex is a rare genetic disorder affecting up to one million people worldwide. Approximately 85% of individuals with TSC are affected by epilepsy, and uncontrolled seizures associated with TSC can be debilitating for patients. Votubia is the only approved non-surgical option indicated for treating non-cancerous brain and kidney tumors in certain patients with TSC. EXIST-3 is the first Phase III study to demonstrate the significant benefit of adjunctive Votubia in the treatment of refractory partial-onset seizures in patients with TSC[2],[5]. These data may be used to support regulatory filings in other countries.
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[6],[7]. Pre-clinical research suggests that hyperactive mTOR activity may influence several mechanisms of epileptogenesis, the gradual process by which the brain develops epilepsy in TSC[8].
About EXIST-3 (EXamining everolimus In a Study of TSC)
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 Votubia as adjunctive therapy in patients with TSC who have refractory partial-onset seizures, defined as seizures persisting despite the use of two or more sequential regimens of single or combined anti-epileptic drugs (AEDs). The study enrolled male and female participants (ages 2.2 – 56.3 years) 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[2],[3].
The primary objective was to assess the effectiveness of adjunctive Votubia as compared to placebo in reducing refractory partial-onset seizures in patients with TSC. Secondary objectives included the percentage of patients free from seizure during the maintenance period, change in seizure frequency, and safety.
The most frequent (>=10%) all grade adverse events (AEs), of any cause, reported with Votubia LE/HE vs placebo included stomatitis (54.7%/63.8% vs 9.2%), 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%), 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%). Grade 3 or 4 AEs occurred in 13 (10.9%) patients in the placebo group, 21 (17.9%) patients in the LE group, and 31 (23.8%) patients in the HE group[3].
Filed Under: Drug Discovery
