Tuberous Sclerosis Skin Lesions Improved on Everolimus

PRAGUE – Everolimus significantly improved the skin lesions of tuberous sclerosis complex in two phase-III clinical trials, Dr. Sergiusz Jozwiak reported at the annual congress of the European Academy of Dermatology and Venereology.

Tuberous sclerosis is a genetic disorder characterized by the growth of numerous nonmalignant tumors in various organs including the brain, kidneys, heart, and skin.

The most devastating skin lesions associated with tuberous sclerosis complex are facial angiofibromas. Hypopigmented spots are also common, said Dr. Jozwiak, a pediatric neurologist at the Children’s Memorial Health Institute of Warsaw.

In the first study, Examining Everolimus in a Study of Tuberous Sclerosis Complex (EXIST-1), about 100 patients with subependymal giant cell astrocytoma (SEGA) were randomized 2:1 to receive everolimus or placebo. In EXIST-2, approximately 100 patients with renal angiomyolipoma associated with tuberous sclerosis complex or sporadic lymphangioleiomyomatosis were randomized to receive either everolimus or placebo. EXIST-1 participants averaged about 8 years of age; those in EXIST-2 had an average age of 30 years.

Both studies met their primary end points, with favorable effects documented in patients with SEGA and renal angiomyolipoma. This led the Food and Drug Administration to approve everolimus (Afinitor), an oral inhibitor of the mammalian target of rapamycin (mTOR), for the treatment of both conditions.

Dr. Jozwiak reported on the skin lesion response to everolimus, a prespecified secondary end point in EXIST-1 and -2.

Close to 95% of all participants – 224 subjects in the two trials – had skin lesions at baseline. Of those on everolimus, 42% in EXIST-1 and 26% in EXIST-2 had significant improvements in their skin lesions, compared with 11% and 0%, respectively, of those on placebo.

The skin response was partial in all cases as judged on a 7-point scale, but the response, when it occurred, was durable: All patients with a partial response to everolimus maintained that response at last follow-up, ranging from 2 to 20 months. Thus, the median duration of skin response has yet to be determined, Dr. Jozwiak noted.

Mouth ulcers were the most common and troublesome everolimus side effect, seen intermittently in 70% of the patients in the two phase-III trials. The side effect was managed by temporary reductions in dosing or suspension of therapy for a week.

"We were able to reinstitute full-dose therapy in all patients," he said.

There were no other serious treatment-related adverse events. The incidence of infections was similar in the everolimus and placebo arms of the studies.

Everolimus was dosed starting at 4.5 mg/m² per day, with a target trough level of 5-15 ng/mL in EXIST-1. In EXIST-2, which was limited to an adult patient population, the drug was dosed at 10 mg/day.

The EXIST trials were sponsored by Novartis. Dr. Jozwiak is a consultant to the company.

PRAGUE – Everolimus significantly improved the skin lesions of tuberous sclerosis complex in two phase-III clinical trials, Dr. Sergiusz Jozwiak reported at the annual congress of the European Academy of Dermatology and Venereology.

Tuberous sclerosis is a genetic disorder characterized by the growth of numerous nonmalignant tumors in various organs including the brain, kidneys, heart, and skin.

The most devastating skin lesions associated with tuberous sclerosis complex are facial angiofibromas. Hypopigmented spots are also common, said Dr. Jozwiak, a pediatric neurologist at the Children’s Memorial Health Institute of Warsaw.

In the first study, Examining Everolimus in a Study of Tuberous Sclerosis Complex (EXIST-1), about 100 patients with subependymal giant cell astrocytoma (SEGA) were randomized 2:1 to receive everolimus or placebo. In EXIST-2, approximately 100 patients with renal angiomyolipoma associated with tuberous sclerosis complex or sporadic lymphangioleiomyomatosis were randomized to receive either everolimus or placebo. EXIST-1 participants averaged about 8 years of age; those in EXIST-2 had an average age of 30 years.

Both studies met their primary end points, with favorable effects documented in patients with SEGA and renal angiomyolipoma. This led the Food and Drug Administration to approve everolimus (Afinitor), an oral inhibitor of the mammalian target of rapamycin (mTOR), for the treatment of both conditions.

Dr. Jozwiak reported on the skin lesion response to everolimus, a prespecified secondary end point in EXIST-1 and -2.

Close to 95% of all participants – 224 subjects in the two trials – had skin lesions at baseline. Of those on everolimus, 42% in EXIST-1 and 26% in EXIST-2 had significant improvements in their skin lesions, compared with 11% and 0%, respectively, of those on placebo.

The skin response was partial in all cases as judged on a 7-point scale, but the response, when it occurred, was durable: All patients with a partial response to everolimus maintained that response at last follow-up, ranging from 2 to 20 months. Thus, the median duration of skin response has yet to be determined, Dr. Jozwiak noted.

Mouth ulcers were the most common and troublesome everolimus side effect, seen intermittently in 70% of the patients in the two phase-III trials. The side effect was managed by temporary reductions in dosing or suspension of therapy for a week.

"We were able to reinstitute full-dose therapy in all patients," he said.

There were no other serious treatment-related adverse events. The incidence of infections was similar in the everolimus and placebo arms of the studies.

Everolimus was dosed starting at 4.5 mg/m² per day, with a target trough level of 5-15 ng/mL in EXIST-1. In EXIST-2, which was limited to an adult patient population, the drug was dosed at 10 mg/day.

The EXIST trials were sponsored by Novartis. Dr. Jozwiak is a consultant to the company.

PRAGUE – Everolimus significantly improved the skin lesions of tuberous sclerosis complex in two phase-III clinical trials, Dr. Sergiusz Jozwiak reported at the annual congress of the European Academy of Dermatology and Venereology.

Tuberous sclerosis is a genetic disorder characterized by the growth of numerous nonmalignant tumors in various organs including the brain, kidneys, heart, and skin.

The most devastating skin lesions associated with tuberous sclerosis complex are facial angiofibromas. Hypopigmented spots are also common, said Dr. Jozwiak, a pediatric neurologist at the Children’s Memorial Health Institute of Warsaw.

In the first study, Examining Everolimus in a Study of Tuberous Sclerosis Complex (EXIST-1), about 100 patients with subependymal giant cell astrocytoma (SEGA) were randomized 2:1 to receive everolimus or placebo. In EXIST-2, approximately 100 patients with renal angiomyolipoma associated with tuberous sclerosis complex or sporadic lymphangioleiomyomatosis were randomized to receive either everolimus or placebo. EXIST-1 participants averaged about 8 years of age; those in EXIST-2 had an average age of 30 years.

Both studies met their primary end points, with favorable effects documented in patients with SEGA and renal angiomyolipoma. This led the Food and Drug Administration to approve everolimus (Afinitor), an oral inhibitor of the mammalian target of rapamycin (mTOR), for the treatment of both conditions.

Dr. Jozwiak reported on the skin lesion response to everolimus, a prespecified secondary end point in EXIST-1 and -2.

Close to 95% of all participants – 224 subjects in the two trials – had skin lesions at baseline. Of those on everolimus, 42% in EXIST-1 and 26% in EXIST-2 had significant improvements in their skin lesions, compared with 11% and 0%, respectively, of those on placebo.

The skin response was partial in all cases as judged on a 7-point scale, but the response, when it occurred, was durable: All patients with a partial response to everolimus maintained that response at last follow-up, ranging from 2 to 20 months. Thus, the median duration of skin response has yet to be determined, Dr. Jozwiak noted.

Mouth ulcers were the most common and troublesome everolimus side effect, seen intermittently in 70% of the patients in the two phase-III trials. The side effect was managed by temporary reductions in dosing or suspension of therapy for a week.

"We were able to reinstitute full-dose therapy in all patients," he said.

There were no other serious treatment-related adverse events. The incidence of infections was similar in the everolimus and placebo arms of the studies.

Everolimus was dosed starting at 4.5 mg/m² per day, with a target trough level of 5-15 ng/mL in EXIST-1. In EXIST-2, which was limited to an adult patient population, the drug was dosed at 10 mg/day.

The EXIST trials were sponsored by Novartis. Dr. Jozwiak is a consultant to the company.