Novartis drug Afinitor DISPERZ receives FDA approval to treat TSC-associated partial-onset seizures

Novartis announced that the US Food and Drug Administration (FDA) has approved Afinitor DISPERZ (everolimus tablets for oral suspension), for the adjunctive treatment of adult and pediatric patients aged two years and older with tuberous sclerosis complex (TSC)-associated partial-onset seizures. Afinitor DISPERZ is now the first approved pharmacologic therapy in the US specifically indicated for the treatment of this condition.

TSC 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. More than 60% of TSC patients who experience seizures stop responding to available anti-epileptic therapies. EXIST-3 is the first Phase III study to demonstrate the significant benefit of adjunctive Afinitor DISPERZ in the treatment of patients with TSC-associated partial-onset seizures. Furthermore, Afinitor is the only approved non-surgical option indicated for treating TSC-associated non-cancerous brain tumors (subependymal giant cell astrocytoma, or SEGA) and TSC-associated kidney tumors (renal angiomyolipoma).

“We are pleased that this latest approval for Afinitor DISPERZ in the US will make an important difference to patients with tuberous sclerosis complex who experience partial-onset seizures, one of the most debilitating manifestations of TSC,” said Ameet Mallik, Executive Vice President, Novartis Oncology US. “This is a welcome advance that reinforces the commitment of Novartis to patients with rare diseases.”

The FDA approval of Afinitor DISPERZ 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, Afinitor DISPERZ significantly reduced the frequency of treatment-resistant seizures associated with TSC compared to placebo. The median percentage reduction from baseline in seizure frequency was significantly greater among patients randomized to Afinitor DISPERZ low exposure (LE; 29.3%, 95% CI 18.8, 41.9; p=0.003) and high exposure (HE; 39.6%, 95% CI 35.0, 48.7; p<0.001) vs placebo (14.9%, 95% CI 0.1, 21.7). Seizure response rate (≥50% reduction) was also greater with Afinitor LE (28.2%, 95% confidence interval [CI] 20.3, 37.3) and HE (40.0%, 95% CI 31.5, 49.0; p<0.001) vs placebo (15.1%, 95% CI 9.2, 22.8). The most common all-grade adverse events of any cause reported during the core phase at frequencies > 15% in the Afinitor DISPERZ LE/HE arms included stomatitis, diarrhea, nasopharyngitis, upper respiratory tract infection, and pyrexia.

Afinitor works by inhibiting the mammalian target of rapamycin (mTOR), a protein that regulates multiple cellular functions. In TSC, inactivating mutations in either the TSC1 or the TSC2 gene lead to hamartoma formation throughout the body as well as seizures and epileptogenesis. Overactivation of mTOR results in neuronal dysplasia, aberrant axonogenesis and dendrite formation, increased excitatory synaptic currents, reduced myelination, and disruption of the cortical laminar structure causing abnormalities in neuronal development and function. Treatment with an mTOR inhibitor in animal models of mTOR dysregulation in the brain resulted in prolonged survival, seizure suppression, prevention of the development of new-onset seizures, and prevention of premature death.