April 26, 2012 — The US Food and Drug Administration (FDA) has approved everolimus (Afinitor, Novartis) for the treatment of renal angiomyolipomas not requiring immediate surgery in patients with tuberous sclerosis complex. This marks the first drug to receive approval specifically for this indication.

EVEROLIMUS APPROVED FOR ANGIOMYOLIPOMAS DUE TO TS

"This approval underscores the FDA's commitment to the development of drugs for rare diseases with significant unmet medical needs," said Richard Pazdur, MD, director of the Office of Hematology and Oncology Products in the FDA's Center for Drug Evaluation and Research, in a statement.

"It also represents another example of where an understanding of a disease's underlying biology can lead to more selective drug development," he added.

Everolimus, which targets the mammalian target of rapamycin (mTOR), has already been approved for patients with advanced renal cell carcinoma after treatment with sunitinib (Sutent, Pfizer) or sorafenib (Nexavar, Bayer Health Care) has failed.

Last year, the FDA also approved its use in the treatment of advanced pancreatic neuroendocrine tumors (pNETs).

Everolimus is also marketed under another trade name, Zortress, under which it is used to prevent organ rejection in some adult kidney transplant recipients.

In 2009, the FDA granted orphan drug designation to everolimus for patients with subependymal giant cell astrocytoma that is associated with tuberous sclerosis, as well as renal angiomyolipomas. As previously reported by Medscape Medical News, growing research demonstrates that inhibitors of the mTOR pathway appear to have a profound effect on tuberous sclerosis complex.

The accelerated approval of everolimus for this indication was based on the results of the phase 3 EXIST-2 (EXamining everolimus In a Study of TSC) study, a double-blind, placebo-controlled clinical trial of 118 patients. The study showed that 42% of patients (33 of 79) in the everolimus group experienced a substantial reduction in tumor size that persisted, on average, more than 5 months. This was compared with 0% of patients (0 of 39) receiving placebo (P < .0001).

All of the patients had tumors in both kidneys, and approximately 40% had undergone treatment to control bleeding from the tumors.

"For the first time, a large placebo-controlled study has focused specifically on angiomyolipomas in TSC patients, an area with clear unmet need," said John Bissler, MD, lead author of the EXIST-2 trial and Clark D. West Endowed Chair of Nephrology at Cincinnati Children's Hospital Medical Center, Ohio, in a news release.

"In addition to the tumor reduction seen with everolimus in this trial, significant improvement in skin lesions including facial angiofibromas was observed, which can be a key concern for people living with TSC," he said.

Tuberous sclerosis complex affects about 50,000 people in the United States and an estimated 1 million people worldwide, and stems from defects in the TSC1 and/or TSC2 genes. This leads to the formation of nonmalignant tumors throughout the body, including in vital organs such as the brain, kidney, liver, and lungs.

The defects in the TSC1/2 genes responsible for the disease activate the mTOR pathway, hence the focus on therapy involving mTOR inhibitors, such as everolimus

The most common adverse effects observed with everolimus were sore mouth, nausea or vomiting, skin problems (acne or eczema), cough, headache, diarrhea, abdominal pain, joint pains, swelling of legs or arms, and upper respiratory tract infection. In addition, 15% of female patients reported missing 1 or more menstrual periods during the study period.