FDA Approves Pediatric Everolimus for Treatment of SEGA

Roxanne Nelson


August 29, 2012

August 29, 2012 — The US Food and Drug Administration (FDA) announced approval today of a new pediatric dosage form of everolimus for use in very young children with a rare brain tumor.

The new formulation, everolimus tablets for oral suspension (Afinitor Disperz, Novartis), is the first approved pediatric-specific dosage form developed for pediatric tumors, the FDA notes. This new dosage formulation is able to dissolve more rapidly and provides for smaller dose increments, thus allowing for greater dosing flexibility.

The product is indicated for use in the treatment of subependymal giant cell astrocytoma (SEGA).

Everolimus was granted an accelerated approval in 2010 to treat SEGA in patients with tuberous sclerosis complex.

The new formulation is recommended for patients aged 1 year or older with tuberous sclerosis complex who are diagnosed with inoperable SEGA. Before the approval of this new formulation, everolimus was not recommended for use in children younger than 3 years.

The drug label was also updated to include longer-term safety follow-up data.

"Appropriate pediatric dosage forms, such as Afinitor Disperz, help to ensure the safe and effective use of oncology drugs in children," said Richard Pazdur, MD, director of the Office of Oncology Drug Products at the FDA's Center for Drug Evaluation and Research, in a statement. "In addition, today's approval demonstrates the value of further studying a drug to better characterize its benefits and how it should be used in pediatric patients."

Defects in mTOR Pathway

Tuberous sclerosis complex is a rare genetic disorder caused by defects in the TSC1 and TSC2 genes that negatively control the mammalian target of rapamycin (mTOR). It typically causes the growth of benign tumors in many vital organs including the brain, kidneys, heart, eyes, lungs, and skin. SEGAs are considered a major diagnostic feature of the disorder, and can occur in up to 20% of children and adults.

As previously reported by Medscape Medical News, research has shown that inhibitors of the mTOR pathway have a profound effect on the tuberous sclerosis complex, both on the nonmalignant tumors in the brain and skin lesions.

Surgery has thus far been the only option for patients with SEGA, but it is highly invasive, as SEGAs tend to be situated deep in the middle of the brain, near the ventricles. In addition, patients can also have several SEGAs growing bilaterally, which can make surgical resection difficult.

Both everolimus and its pediatric formulation remain under accelerated approval for treatment of SEGA in patients with tuberous sclerosis complex.

When the drug received its accelerated approval for this indication in 2010, the decision was based on data from a single arm study that included 28 pediatric patients and adults.

The manufacturer has now supplied data from the larger and more recent Phase III EXIST-1 trial that included 117 pediatric and adult patients randomly assigned to take everolimus or a placebo daily. The results showed that 35% (27 of 78) receiving everolimus experienced a reduction of 50% or more in the total volume of all their SEGAs, relative to baseline, whereas the placebo group showed no reduction (P < .0001).

Everolimus is manufactured by Novartis, and is a derivative of sirolimus that inhibits mTOR. It has already received FDA approval for a number of other indications including advanced renal cell carcinoma that has progressed after treatment with other cancer therapies (2009); as a treatment for adults with progressive advanced neuroendocrine tumors of pancreatic origin (2011); for adults with tuberous sclerosis complex who have renal angiomyolipomas not requiring immediate surgery (2012); and for use in combination with exemestane (Aromasin, Pfizer) to treat certain postmenopausal women with advanced hormone receptor-positive, HER2-negative breast cancer (2012).


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