EVEROLIMUS USEFUL FOR TUBEROUS SCLEROSIS

July 13, 2001 — New data confirm previous findings and show that inhibitors of the mTOR pathway have a profound effect on tuberous sclerosis complex (TSC) — on both the tuber-shaped nonmalignant tumors in the brain and on troublesome skin lesions.
"It shows that we are on the right track," Stephen Roberts, PhD, chief scientific officer at the Tuberous Sclerosis Alliance (TSA), told Medscape Medical News. The effects of these drugs are profound, which suggests that mTOR is a key pathway, he said.
However, the drugs are not curative, which suggests that there are other pathways involved, he noted. In addition, it is not clear if these drugs have an impact on the neurologic aspects of the disease, such as seizures and learning disabilities, he said.
Dr. Roberts was commenting on new data presented last week at the Summit on Drug Discovery in TSC and Related Disorders in Washington, DC. The meeting drew 200 participants from 19 countries, and was organized and funded by the TSA.
TSC affects about 50,000 people in the United States and an estimated 1 million worldwide, explained Kari Luther Rosbeck, TSA's chief executive officer. The disorder stems from defects in the TSC1 and/or TSC2 genes, and results in the formation of nonmalignant tumors throughout the body, including in vital organs such as the brain, kidney, liver, and lungs.
Symptoms tend to vary with the severity of the disease, but often appear in infancy, presenting as seizures or neurologic problems (including autism) as a result of the tuber-shaped growths in the brain. Hence, neurologists are often the first point of contact and are involved in the management of these patients, Ms. Rosbeck noted. However, skin lesions are also common, and may be the presenting feature, so dermatologists and primary care physicians might be the initial contact. Oncologists become involved in the care of these patients only when the tumors become malignant, which does happen, such as when the growths in the kidney transform into renal cell carcinoma.
The defects in the TSC1/2 genes responsible for TSC activate the mTOR pathway, so a logical approach to developing drug therapy for this disease has focused on mTOR inhibitors, such as everolimus (Afinitor, Novartis).
New data from a phase 3 trial of 117 patients confirmed this drug's activity in reducing the volume of nonmalignant tumors in the brain, known as subependymal giant cell astrocytomas (SEGAs). Everolimus has been approved for this indication in some countries on the basis of the efficacy shown in an earlier phase 2 trial of 28 patients. In the United States, this was an accelerated approval granted (in October 2010) on the basis that a confirmatory phase 3 study would be conducted, which is the study reported at the Washington meeting.
Everolimus is also approved for use in renal cell carcinoma after the failure of other agents, and is marketed at different doses under a different brand name (Zortress) for the prevention of organ rejection after transplantation.
The phase 3 study — the largest prospective trial ever conducted in this disorder — found that 35% of patients (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).
The results provide "compelling evidence of the impact of everolimus in reducing SEGA size," said lead investigator Sergiusz Jozwiak, MD, professor of child neurology at the Children's Memorial Health Institute in Warsaw, Poland. "This is very good news for patients...who currently may face brain surgery as the only treatment option for growing SEGAs," he said in a statement.
Brain surgery has, until recently, been the only option for these patients, but it is highly invasive because the SEGAs are situated deep in the middle of the brain, near the ventricles, explained Dr. Roberts. Patients can have several SEGAs growing bilaterally, which makes "surgery very difficult, and it can be life-threatening," Ms. Rosbeck added. However, if SEGAs continue to grow, that can also be life-threatening.
Other results from this phase 3 study showed that everolimus had an impact on skin lesions and, in a subset of 44 patients, reduced the volume of angiomyolipomas, the nonmalignant tumors in the kidney.
Sirolimus/Rapamycin for Skin Lesions
It was reported at the meeting that another drug in the same class, sirolimus (also known as rapamycin), shows efficacy in TSC. Sirolimus (Rapamune, Pfizer) is marketed as an immunosuppressant following organ transplantation; the drug is also used on cardiovascular drug-eluting stents. It was reported at the meeting that a new topical formulation of the drug has been shown to be effective against the skin lesions, known as facial angiofibromas, that develop in TSC patients.
The study of the topical formulation, led by Mary Kay Koenig, MD, from the University of Texas Medical School in Houston, was conducted in 30 patients with TSC, and the product was developed by the academic pharmacy at that institution. Among patients who used the topical product, 73% reported a reduction in the appearance of facial angiofibromas, compared with 38% in the placebo group. Some patients reported a slight discomfort on initial application (skin burning, itching), but only 2 discontinued treatment, and monthly blood sampling showed that no drug was absorbed.
Dr. Koenig and colleagues conclude that the topical product can "safely decrease the appearance of facial angiofibromas in patients with TSC." Other treatments that have been used for this symptom include curettage, cryosurgery, dermabrasion, shave excisions, and laser therapy. Although the "majority of these treatments are initially effective, they are uncomfortable and, over time, the lesions occur," the researchers noted.
A larger multicenter study of this topical product is now planned, Ms. Rosbeck said.
The small study reported at the meeting was "proof of concept," and the results are convincing, very consistent, and very encouraging, added Dr. Roberts. "The skin lesions can be the most important symptom for the individual, because they are outwardly visible and affect their quality of life every day," he explained.
"These lesions can be raised, red, and completely disfiguring," added Ms. Rosbeck, "and individuals can have hundreds of thousands of them on their face."