Novartis Afinitor Phase III trial on tuberous sclerosis meets primary endpoint

Novartis Pharmaceuticals Corporation ("Novartis") announced today Phase III trial results that showed more than one-third of patients taking Afinitor® (everolimus) tablets experienced a 50% or greater reduction in the size of their subependymal giant cell astrocytomas (SEGAs), non-cancerous brain tumors associated with tuberous sclerosis complex (TSC). This study, the largest prospective clinical trial to date in this patient population, is being presented on Saturday, July 9 at the International TSC Research Conference in Washington, D.C.

Currently, Afinitor is approved in the US for the following indication: to treat patients with SEGA associated with tuberous sclerosis who require therapeutic intervention but are not candidates for curative surgical intervention. The effectiveness of everolimus is based on an analysis of change in SEGA volume. Additionally, the indication states, clinical benefit such as improvement in disease-related symptoms or increase in overall survival has not been shown.

Tuberous sclerosis complex affects approximately 25,000 to 40,000 people in the US and one to two million people worldwide, and is associated with a variety of resulting disorders including seizures, swelling in the brain (hydrocephalus), developmental delays and skin lesions. Also known as tuberous sclerosis (TS), TSC is a genetic disorder that may cause non-cancerous tumors to form in vital organs and can affect many different parts of the body, most commonly the brain and kidney. Signs and symptoms of TSC vary depending on which system and which organs are involved. SEGAs occur in up to 20% of patients with TSC. In countries where everolimus is not approved, brain surgery is the only treatment option for patients with growing SEGAs.

The 117-patient, randomized, placebo-controlled Phase III EXIST-1 (EXamining everolimus In a Study of TSC) trial met its primary endpoint of SEGA response rate, with 35% of patients (27 of 78) receiving everolimus experiencing a 50% or greater reduction in SEGA volume (sum of volumes of all target SEGAs) relative to baseline versus 0% of patients (0 of 39) on placebo (p<0.0001).

"This study, which included SEGA patients from infancy to adulthood, provides compelling evidence of the impact of everolimus in reducing SEGA size with a tolerability profile consistent with the previous everolimus trial in this treatment setting," said Dr. Sergiusz Jozwiak, a lead EXIST-1 investigator and Professor, Department of Child Neurology, The Children's Memorial Health Institute, Warsaw, Poland. "This is very good news for patients and caregivers in many countries who currently may face brain surgery as the only treatment option for growing SEGAs."

Everolimus targets mTOR, a protein that acts as an important regulator of tumor cell division, blood vessel growth and cell metabolism. Tuberous sclerosis complex is caused by defects in the TSC1 and/or TSC2 genes. When these genes are defective, mTOR activity is increased, which can cause uncontrolled tumor cell growth and proliferation, blood vessel growth and altered cellular metabolism, leading to the formation of non-cancerous tumors throughout the body, including the brain. By inhibiting mTOR activity in this signaling pathway, everolimus may reduce cell proliferation, blood vessel growth and glucose uptake related to SEGA associated with TSC.

"The positive results seen in the Phase III trial point to the important role of everolimus and mTOR inhibition in SEGA associated with TSC," said Herve Hoppenot, President, Novartis Oncology. "This outcome is welcome news as we continue our research efforts to fully understand the potential of this important treatment option across the wide range of disorders associated with TSC."

The Phase III study supports the findings of the Phase II study used for registration in several countries. The extension phase of the Phase II study, which is also being presented at the conference, provides data to support the treatment of patients with SEGA associated with TSC for a duration of up to three years.