Novartis announced results from a phase III study showing Afinitor (everolimus), when used as an adjunctive therapy, significantly reduced treatment-resistant seizures associated with tuberous sclerosis complex (TSC) compared to placebo. Patients in all treatment arms were also taking one to three anti-epileptic drugs (AEDs). The study, EXIST-3 (EXamining everolimus In a Study of TSC), is being presented during a plenary session at the 68th Annual Meeting of the American Academy of Neurology (AAN).

"Approximately 85 per cent of individuals with TSC are affected by epilepsy at some point in their lives, yet nearly two-thirds of these patients do not achieve seizure control with available therapies, and may also experience other potentially serious consequences, such as neuropsychological, cognitive, social or learning disabilities," said Jacqueline A. French, MD, department of neurology, NYU Langone Medical Center and lead investigator of the EXIST-3 trial. "These findings are encouraging as this is the first clinical study demonstrating benefit specifically for TSC patients who suffer from treatment-resistant seizures."

In the study, 366 patients with TSC and treatment-resistant seizures were randomized to receive targeted concentrations of everolimus titrated to Low Exposure (LE; 3-7 ng/ml; n=117) or High Exposure (HE, 9-15 ng/ml; n =130), or placebo (n=119). The percentage reduction from baseline in seizure frequency was significantly greater among patients randomized to everolimus LE (29.3 per cent, P=0.003; confidence interval [CI]=95 per cent) and HE (39.6 per cent, P<0.001; CI=95 per cent) vs placebo (14.9 per cent; CI=95 per cent). Seizure response rate (>=50 per cent reduction) was also significantly greater with everolimus LE (28.2 per cent, P=0.008; CI=95 per cent) and HE (40.0 per cent, P<0.001; CI=95 per cent) vs placebo (15.1 per cent; CI=95 per cent). The most common (>=20 per cent) adverse events (AEs) reported with everolimus LE/HE vs placebo included stomatitis (28.2 per cent/30.8 per cent vs 3.4 per cent), mouth ulceration (23.9 per cent/21.5 per cent vs 4.2 per cent), and diarrhea (17.1 per cent/21.5 per cent vs 5.0 per cent). Serious AEs reported were 13.7 per cent/13.8 per cent vs 2.5 per cent.

"There has been a long-standing need to find a treatment option for TSC patients that provides control of treatment-resistant seizures and we are encouraged that data from the EXIST-3 study show everolimus may have this potential," said Alessandro Riva, MD, global head, Novartis Oncology Development and Medical Affairs. "Over the past decade, Novartis has remained committed to the TSC community, improving care for patients and conducting research we hope will bring us closer to addressing some of the most debilitating TSC manifestations."

Tuberous sclerosis complex is a rare genetic disorder affecting up to one million people worldwide and everolimus is the only approved non-surgical option indicated for treating non-cancerous brain and kidney tumors in certain patients with TSC. EXIST-3 study results show that everolimus is the first adjunctive therapy to achieve clinically significant seizure control in TSC patients and will be the basis for discussion with health authorities worldwide.

Everolimus works by inhibiting the mammalian target of rapamycin (mTOR), a protein that regulates multiple cellular functions. TSC is caused by mutations in the TSC1 or TSC2 genes, resulting in hyperactive signaling of the mTOR pathway which can lead to increased cellular growth and proliferation, neuronal hyper-excitability, abnormalities in cortical architecture and network function and impaired synaptic plasticity. Pre-clinical research suggests that hyperactive mTOR activity may influence several mechanisms of epileptogenesis, the gradual process by which the brain develops epilepsy.

EXIST-3 is a phase III, three-arm, randomized, double-blind, placebo-controlled study of the efficacy and safety of high and low exposure ranges of everolimus as adjunctive therapy in patients with TSC who have treatment-resistant seizures, defined as seizures persisting despite the use of two AEDs. The study enrolled male and female participants (ages 2.2-56.3) with clinically defined TSC, who were on stable doses of one to three AEDs for at least four weeks prior to a two month, pre-randomization, evaluation period.

The primary objective was to assess the effectiveness of adjunctive everolimus as compared to placebo in reducing seizures in patients with TSC who are taking one to three AEDs. Secondary objectives include the percentage of patients free from seizure during the maintenance period and change in seizure frequency.

The most frequent >=10 per cent all grade adverse events (AEs) reported with everolimus LE/HE vs placebo included stomatitis (28.2 per cent/30.8 per cent vs 3.4 per cent), mouth ulceration (23.9 per cent/21.5 per cent vs 4.2 per cent), diarrhea (17.1 per cent/21.5 per cent vs 5.0 per cent), nasopharyngitis (13.7 per cent/16.2 per cent vs 16.0 per cent), upper respiratory tract infection (12.8 per cent/15.4 per cent vs 12.6 per cent), aphthous ulcer (4.3 per cent/14.6 per cent vs 1.7 per cent) pyrexia (fever) (19.7 per cent/13.8 per cent vs 5.0 per cent), vomiting (12.0 per cent/10.0 per cent vs 9.2 per cent), cough (11.1 per cent/10.0 per cent vs 3.4 per cent) and rash (6.0 per cent/10.0 per cent vs 2.5 per cent).

Tuberous sclerosis complex (TSC) may cause non-cancerous tumors to form in vital organs including the brain, kidney, heart, lungs and skin, as well as resulting disorders such as epilepsy, autism, cognitive impairment, behavioral problems and psychiatric disorders. Many people with TSC show evidence of the disease in the first year of life. However, because manifestations vary from person to person and can take years to develop, many children are not diagnosed until later in life, often with the onset of seizures, skin lesions or other significant symptoms, such as developmental delays. Because TSC is a lifelong condition, the latest professional diagnostic guidelines issued in 2012 advise that individuals be monitored by a doctor experienced with the disorder to ensure tumor growth or new symptoms are identified early.

In the European Union (EU), everolimus is approved as Votubia for the treatment of adult patients with renal angiomyolipoma associated with tuberous sclerosis complex (TSC) who are at risk of complications (based on factors such as tumor size or presence of aneurysm, or presence of multiple or bilateral tumors) but who do not require immediate surgery. The evidence is based on analysis in sum of angiomyolipoma volume. Votubia is also indicated in the EU for the treatment of patients with subependymal giant cell astrocytoma (SEGA) associated with TSC who require therapeutic intervention but are not amenable to surgery. The evidence is based on analysis of change in SEGA volume. Further clinical benefit, such as improvement in disease-related symptoms, has not been demonstrated.

In the United States (US), everolimus is approved as Afinitor for the treatment of adult patients with renal angiomyolipoma and TSC, not requiring immediate surgery. Afinitor tablets and Afinitor Disperz are also indicated in the US in pediatric and adult patients with TSC for the treatment of SEGA that requires therapeutic intervention but cannot be curatively resected.

Additionally, Afinitor is approved in 99 countries, including the US and throughout the EU, for locally advanced, metastatic or unresectable progressive neuroendocrine tumours (NET) of pancreatic origin and in the US for the treatment of adult patients with progressive, well-differentiated, nonfunctional NET of gastrointestinal (GI) or lung origin that are unresectable, locally advanced or metastatic. It is also approved in >120 countries including the US and EU for advanced renal cell carcinoma following progression on or after vascular endothelial growth factor (VEGF)-targeted therapy (in the US, specifically following sunitinib and sorafenib). Afinitor is also approved in 102 countries including the US and EU for advanced HR+/HER2- breast cancer in combination with exemestane, after prior endocrine therapy.

Everolimus is also available from Novartis under the brand names Afinitor, Certican and Zortress for use in oncology and transplant patient populations and is exclusively licensed to Abbott and sublicensed to Boston Scientific for use in drug-eluting stents.

Indications vary by country and not all indications are available in every country.