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 paediatric 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.

EXIST-3 is a phase III, three-arm, randomized, double-blind, placebo-controlled study of the efficacy and safety of low and high exposure ranges of Afinitor Disperz as adjunctive therapy in patients with treatment-resistant TSC-associated partial-onset seizures, defined as inadequate control of partial-onset seizures 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) who had a diagnosis of TSC per the modified Gomez criteria and experienced = 16 partial-onset seizures during the baseline phase while receiving a stable dose of 1 to 3 concomitant AEDs.

The major efficacy outcome measure was the percentage reduction in seizure frequency from the Baseline phase, during the maintenance period of the core phase. Additional efficacy outcome measures included response rate, defined as at least a 50% reduction in seizure frequency from the baseline phase during the maintenance period of the core phase, and seizure freedom rate during the maintenance period of the core phase.

Efficacy and safety of two trough exposure concentrations of Afinitor Disperz, 3–7 ng/mL (LE) and 9–15 ng/mL (HE) were assessed. Patients in all treatment arms concomitantly received one to three AEDs during the eighteen weeks of study core phase. The youngest patient enrolled was two years of age.

The median number of seizures per week at baseline vs end of core phase was 8.6 vs 6.8 (LE); 9.5 vs 4.9 (HE) and 10.5 vs 8.5 (placebo).The median percentage reduction from baseline in seizure frequency was significantly greater among patients randomized to Afinitor Disperz 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). 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) vs placebo (15.1%, 95% CI 9.2 – 22.8)3. A 25% or greater reduction in seizure frequency was observed in 61 LE patients (52.1%, 95% CI 42.7, 61.5) and 91 HE patients (70%, 95% CI 61.3, 77.7) vs 45 placebo patients (37.8%, 95% CI 29.1, 47.2). The seizure-free rate was 5.1% LE (95% CI 1.9, 10.8) and 3.8% HE (95% CI 1.3, 8.7) vs 0.8% placebo (95% CI 0, 4.6).

The most frequent (=10%) all grade adverse events (AEs), of any cause, reported with Afinitor 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 21 (17.9%) patients in the LE group, 31 (23.8%) patients in the HE group and 13 (10.9%) patients in the placebo group3. The most common Grade 3-4 adverse reactions (incidence = 2%) in the LE/HE groups were stomatitis (3%/4%); pneumonia (1%/2% in HE group), and irregular menstruation (2% HE only). The most common key laboratory abnormality (incidence = 50%) was hypercholesterolemia. The most common Grade 3-4 key laboratory abnormality (incidence = 2%) was neutropenia.

Tuberous sclerosis complex (TSC) is a multi-organ disease with widely variable expression. It may cause non-cancerous tumors to form in vital organs including the brain, kidney, heart, lungs, and skin, as well as resulting disorders such as epilepsy, autism, cognitive impairment, behavioral problems, and psychiatric disorders.

Afinitor (everolimus) (known as Votubia in some countries) is an oral inhibitor of the mTOR pathway. Afinitor Disperz is the first adjunctive treatment approved in the US specifically for adult and pediatric patients aged 2 years and older with tuberous sclerosis complex (TSC)-associated partial-onset seizures. The product is also approved in more than 30 countries, including EU member states, for the treatment of patients with TSC-associated seizures.

Afinitor/Votubia is also approved in more than 95 countries, including the US, EU member states and Japan, for treatment of certain patients with TSC-associated subependymal giant cell astrocytoma (SEGA) and TSC-associated renal angiomyolipoma.