FIRST THERAPY FOR TUBEROUS SCLEROSIS APPROVED BY FDA

November 2, 2010 ( UPDATED November 3, 2010 ) — The US Food and Drug Administration (FDA) has granted accelerated approval for everolimus (Afinitor tablets; Novartis Pharmaceuticals, Inc) as the first medication for children and adults with subependymal giant cell astrocytoma (SEGA) who require therapeutic intervention but are not candidates for curative surgical resection.

SEGAs are slow-growing, benign brain tumors that occur in up to 20% of patients with tuberous sclerosis, a genetic disorder that affects about 25,000 to 40,000 people in the United States.

"Patients with this disease currently have limited treatment options beyond surgical intervention," explained Richard Pazdur, MD, director of the Office of Oncology Drug Products in the FDA's Center for Drug Evaluation and Research, in an agency news release. "It is important for research to continue in rare diseases where patients have few or no existing drug treatment options."

The accelerated approval program allows FDA approval of treatments for serious diseases with an unmet medical need, based on an endpoint reasonably expected to predict clinical benefit. As a result, patients have earlier access to the drug while additional long-term safety and efficacy data are still being collected.

In this instance, FDA approval was based on a priority review of data from an open-label, single-arm clinical study of everolimus (n = 28) showing that almost one third (9; 32%) of patients achieved more than 50% shrinkage of their largest SEGA tumor at 6 months. Of 4 patients whose tumors returned after surgery, 3 met the endpoint of a 50% or greater reduction in tumor volume.

Overall duration of response ranged from about 3 months to 2.5 years (median, 266 days). Although SEGAs did not resolve completely, new tumors did not occur during treatment.

Adverse events reported in 30% or more of SEGA study patients included mouth sores, upper respiratory tract infections, sinusitis, middle ear infections, and fever. Common laboratory test abnormalities included elevated liver enzymes, creatinine and glucose, as well as hyperlipidemia, leukopenia, anemia, and thrombocytopenia.

The data from this 28-patient study, which led to approval of the new indication, have just been published in the New England Journal of Medicine (2010;363:1801-1811). Lead author Darcy Krueger, MD, PhD, and colleagues from the Cincinnati Children's Hospital conclude that everolimus therapy was associated with a "marked reduction" in the volume of SEGAs and seizure frequency and that "it may offer a potential alternative to neurosurgical resection in some cases." However, they add that long-term studies are needed.

According to the company news release, an international phase 3 randomized, placebo-controlled study (EXamining everolimus In a Study of Tuberous sclerosis complex; EXIST-1) is currently underway to further explore the benefits of everolimus therapy for SEGAs associated with tuberous sclerosis; endpoints include SEGA response, seizure rate, and skin lesion response rate.

As reported by Medscape Medical News, everolimus previously was approved by the FDA for the treatment of advanced renal cell carcinoma refractory to sunitinib or sorafenib therapy. Marketed as Zortress (Novartis), it is also indicated for use with low-dose cyclosporine, basiliximab, and corticosteroids to prevent organ rejection in adult kidney transplant patients at low to moderate immunologic risk.

The SEGA indication for everolimus is currently being evaluated for approval in the European Union and Switzerland.