FDA Clears Everolimus Tablets for Tuberous Sclerosis Complex

The US Food and Drug Administration (FDA) today announced the approval of everolimus tablets for oral suspension (Afinitor Disperz, Novartis) for the adjunctive treatment of adult and pediatric patients aged 2 years and older with tuberous sclerosis complex (TSC)-associated partial-onset seizures.

It is the first pharmacologic therapy approved in the United States for this indication. TSC, a rare genetic disorder, impacts roughly 1 million patients worldwide and roughly 50,000 in the US. More than 60% of patients with TSC experience seizures that are resistant to anti-epileptic medicines.

"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," Ameet Mallik, the executive vice president of Novartis Oncology US, said in a statement. "This is a welcome advance that reinforces the commitment of Novartis to patients with rare diseases."

The FDA’s decision was made based on data from the 370-patient phase 3 EXIST-2 study, which revealed that the therapy significantly reduced seizure frequency in both everolimus low exposure (LE; 29.3%; 95% CI, 18.8—41.9; P = .003) and high exposure (HE; 39.6%; 95% CI, 35.0—48.7; p<0.001), compared to placebo (15.1%; 95% CI, 9.2–22.8).

Response rates, defined as a ≥50% reduction in seizures were also greater with everolimus LE (28.2%, 95% CI, 20.3—37.3) and HE (40.0%; 95% CI, 31.5–49.0; P <.001) compared with placebo. The most common all-grade adverse events of any cause reported during the core phase at occurring in >15% or more patients in the everolimus LE/HE arms compared with 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%), and pyrexia4 (19.7%/13.8% vs 5.0%).

The therapy inhibits the mammalian target of rapamycin (mTOR), which was shown in animal models to aid mTOR dysregulation prolonged survival, seizure suppression, prevention of the development of new-onset seizures, and prevention of premature death.

The Novartis product, known as Votubia in some countries, has previously been approved for the treatment of certain patients with giant cell astrocytoma and renal angiomyolipoma.

The approval comes on the heels of Novartis’s recent acquisition of AveXis, a gene therapy company currently developing a spinal muscular atrophy therapy, AVXS-101. Novartis Chief Executive Vas Narasimhan said on a conference call with reporters that the company “believe[s] the medicine would have a multi-billion-dollar peak sales potential. We've been regularly scanning and looking for bolt-in acquisition candidates."