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FDA Approves Everolimus for Tuberous Sclerosis Based on Six-Month Open Label Trial

Talan, Jamie

doi: 10.1097/01.NT.0000392762.42435.f0
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Investigators reported that everolimus reduced the volume of subependymal giant-cell astrocytomas in nearly all of 28 patients with tuberous sclerosis patients in an open-label trial.

The US FDA has granted accelerated approval of a kidney cancer drug, everolimus (Afinitor), for treating the benign subependymal giant-cell astrocytomas (SEGAs) associated with tuberous sclerosis complex, a rare, genetic disease that causes tumors to grow in the brain and on other vital organs such as the kidneys, heart, eyes, lungs, and skin. Other symptoms include seizures, developmental delay, behavioral problems, skin abnormalities, and lung and kidney disease.

The accelerated approval, granted Oct. 29, was based on data from a six-month open-label trial, which tested the safety and efficacy of the experimental therapy in reducing the volume of SEGAs. Novartis, which provided the study drug, sponsored the study, which was reported Nov. 4 in the New England Journal of Medicine.

Virtually all of the patients — ages 3 to 34, but mostly children under 18 — showed a decrease in the size of their brain tumors and none had to have surgery, the standard protocol, following the drug treatment, the senior study author David Neal Franz, MD, director of the Tuberous Sclerosis Clinic and professor of pediatrics and neurology at Cincinnati Children's Hospital and the University of Cincinnati, told Neurology Today. This is the first targeted drug therapy for this disorder.

Among their findings, the investigators reported that everolimus reduced SEGA volume by 30 percent in 21 (78 percent) of 28 patients; and by at least 50 percent in nine patients (32 percent) in the first six months of treatment. After the six months, patients were given the option of continuing treatment; most continued with the treatment for a median of 21.5 months.

The study authors noted that SEGAs, which develop in 5- to 20-percent of those with tuberous sclerosis complex, are benign, but they recommend that patients have regular monitoring with serial neuroimaging every one to three years so that these tumors can be caught early. They are generally deep in the brain and the hydrocephalus that can develop threatens intracranial pressure.

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Tuberous sclerosis complex is caused by mutations on either of two genes, TSC1 and TSC2, which encode for the proteins hamartin and tuberin respectively; the proteins encoded by the two genes form a tumor-suppressor complex that limits the activation of the mammalian target of rapamycin (mTOR) complex 1, the authors explained in the study. “When either TSC1 or TSC2 is deficient, mTOR complex is upregulated, leading to abnormal cellular growth, proliferation, and protein synthesis,” the authors wrote. Everolimus inhibits mTOR complex, correcting the specific molecular defect causing the tuberous sclerosis complex, they added.

As a secondary outcome, the investigators also measured the effect of everolimus on seizure frequency. They had EEG recordings from 16 patients before and after six months on the drug and nine of them experienced decreases in their seizures.

At the end of the study, the data were presented to FDA officials who agreed that it should be fast-tracked into the approval system. “We are thrilled,” said Dr. Franz. “Young people with tuberous sclerosis who develop astrocytomas may not only avoid surgery but this medicine also reduces another serious problem, seizures, and improves other problems inherent in this disease (tumors in other parts of the body.)”

Among adverse effects, about 30 percent of the patients reported mouth sores, upper respiratory tract infections, sinusitis, middle ear infections, or fever during the six-month study period. The drug is an immunosuppressant that is used in transplantation and Dr. Franz said that such side effects were not surprising. These transient symptoms did not stop patients from completing the study.

Following the accelerated approval of the drug, Novartis is required to continue with long-term follow-up and the testing of the drug in a larger randomized placebo-controlled trial, said Dr. Franz, who will be involved in these studies.

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“These findings are very important,” said Joyce Y Wu, MD, director of the Tuberous Sclerosis Complex (TSC) Clinic and associate professor at the Mattel Children's Hospital at the University of California-Los Angeles. “There was no medical treatment for this disease prior to this FDA approval, and its use could help us avoid brain surgery for these patients.”

“What's more,” she added, “the phase 2 findings suggest that other aspects of tuberous sclerosis improved with this medication, epilepsy and the facial angiofibromas (facial tumors) and that led to improved quality of life for these young patients.” She said that the reductions in tumor volume and epilepsy suggest that this medicine could have benefits for non-TSC patients as well.”



Elizabeth Anne Thiele, MD, PhD, director of the Herscot Center for Tuberous Sclerosis Complex and director of the pediatric epilepsy program at Massachusetts General Hospital, said that studies with this drug and with rapamycin, which also works on the mTOR pathway, suggests that there is a rapid tumor regrowth after these drugs are discontinued and that patients may have to remain on the drugs for years.



“We are hopeful that we will be able to identify drugs that not only reduce the size of the tumors but will also either kill abnormal cells or prevent regrowth,” said Dr. Thiele.

The Cincinnati researchers are now conducting a long-term efficacy and safety study.

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Krueger DA, Care MM, Franz DN, et al. Everolimus for subependymal giant-cell astrocytomas in tuberous sclerosis. N Engl J Med 2010;363(19):1801-1811.
    Krueger DA, Franz DN. Current management of tuberous sclerosis complex. Paediatr Drugs 2008; 10(5):299-313.
      ©2010 American Academy of Neurology