The European Commission (EC) has approved Novartis' Votubia (everolimus) tablets 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 tumour size or presence of aneurysm, or presence of multiple or bilateral tumours) but who do not require immediate surgery. This marks the first approval of a medical treatment in this patient population in Europe.

"Renal angiomyolipomas affect the vast majority of patients with TSC and over time can cause debilitating symptoms, a decline in renal function, and possibly even the need for kidney transplant or dialysis," said Dr Chris Kingswood, Royal Sussex County Hospital, Brighton, United Kingdom. "This approval represents a major advance in the treatment of the disease in Europe, giving clinicians a non-surgical option to manage TSC kidney tumours."

This approval is based on data from the phase III EXIST-2 (EXamining everolimus In a Study of TSC) trial, which found that 42% of patients taking everolimus experienced an angiomyolipoma response versus 0% of patients in the placebo arm (p<0.0001). The evidence is based on analysis of the change in the sum of the angiomyolipoma volume. Median time to angiomyolipoma progression was 11.4 months in the placebo arm and was not reached in the everolimus arm (p<0.0001).

"For the first time, European patients living with renal angiomyolipoma associated with TSC now have an effective non-surgical option," said Hervé Hoppenot, president, Novartis Oncology. "This approval reinforces the potential of Votubia to treat a wide range of manifestations associated with TSC, a debilitating, lifelong disease where there remains critical unmet need."

Up to 80% of patients with TSC, a genetic disorder that may cause non-cancerous tumours to form in vital organs, develop renal angiomyolipomas. Typical onset occurs between the ages of 15 and 30 and prevalence increases with age. Over time, these kidney tumours may grow large enough to cause severe internal bleeding, require emergency surgical interventions, such as embolization and nephrectomy, and lead to kidney failure or cardiovascular diseases. The tumours can be difficult to manage as they may be numerous and often form in both kidneys. In the EU, approximately 7,000 TSC patients have large growing renal tumours (>3 cm) at risk of bleeding.

Everolimus works by inhibiting mTOR, a protein implicated in many tumour-causing pathways. TSC is caused by defects in the TSC1 and/or TSC2 genes. When these genes are defective, mTOR activity is increased and can cause uncontrolled tumour cell growth and proliferation, blood vessel growth and altered cellular metabolism. According to preclinical studies, by inhibiting mTOR activity in this signalling pathway, everolimus reduces cell proliferation and blood vessel growth.

This EC approval follows a positive opinion from the Committee for Medicinal Products for Human Use (CHMP) adopted for Votubia in September 2012 for the treatment of renal angiomyolipoma associated with TSC and applies to all 27 EU member states, plus Iceland and Norway.

EXIST-2 is the first double-blind, randomized, placebo-controlled, international, multicenter phase III study for the treatment of patients with renal angiomyolipoma associated with TSC. Trial patients (median age=31, range 18-61) were randomized 2:1 to receive either everolimus (n=79) or placebo (n=39) at a daily dose of 10 mg. The median duration of blinded study treatment was 48 weeks in the everolimus arm and 45 weeks in the placebo arm.

In the study, 42% of patients on everolimus (33 of 79; 95% confidence interval [CI] 30.8-53.4) experienced an angiomyolipoma response versus 0% on placebo (0 of 39; 95% CI 0.0-9.0; p<0.0001), defined as a 50% or greater reduction in the sum of angiomyolipoma volume relative to baseline, the absence of new tumour growth at least 1 cm in longest diameter, absence of kidney volume increase of 20% or greater and no renal angiomyolipoma-related bleeding of Grade 2 or higher.

Everolimus demonstrated improvement when compared to placebo for both key secondary endpoints measured: time to angiomyolipoma progression and skin lesion response rate. There were three patients in the everolimus arm and eight patients in the placebo arm with documented angiomyolipoma progression by central radiologic review. The time to angiomyolipoma progression was longer in patients on everolimus (hazard ratio [HR] 0.08, 95% CI 0.02-0.37; p<0.0001). Skin lesion response rate was higher in the everolimus arm. A partial clinical response in skin lesions (corresponding to a 50% or greater improvement) was observed by Physician Global Assessment in 26% of patients on everolimus, compared with 0% of patients on placebo (p=0.0011). No complete responses were observed.

The most common adverse reactions reported in the everolimus arm during the double-blind period (with an incidence at least 15%) included stomatitis, hypercholesterolemia, aphthous stomatitis, mouth ulceration and acne. The most common Grade 3 adverse reactions in the everolimus arm (with an incidence of at least 2%) were amenorrhea, aphthous stomatitis and mouth ulceration. The most common laboratory abnormalities (incidence >= 50%) were hypercholesterolemia, hypertriglyceridemia and anaemia. The most common Grade 3-4 laboratory abnormality (incidence >= 3%) was hypophosphatemia.

Everolimus is now approved in the European Union (EU) as Votubia (everolimus) tablets 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 tumour size or presence of aneurysm, or presence of multiple or bilateral tumours) but who do not require immediate surgery. The evidence is based on analysis of change in sum of angiomyolipoma volume. Everolimus is also approved in the United States (US) as Afinitor (everolimus) tablets for the treatment of adult patients with renal angiomyolipomas and TSC, who do not require immediate surgery. The effectiveness of Votubia in treatment of renal angiomyolipoma is based on an analysis of durable objective responses in patients treated for a median of 8.3 months. Further follow-up of patients is required to determine long-term outcomes.

Everolimus is also approved in the EU as Votubia for the treatment of patients aged 3 years and older 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 US, everolimus is approved as Afinitor and Afinitor Disperz in paediatric and adult patients with TSC for the treatment of SEGA that requires therapeutic intervention but cannot be curatively resected. The effectiveness is based on demonstration of durable objective response, as evidenced by reduction in SEGA tumour volume. Improvement in disease-related symptoms and overall survival in patients with SEGA and TSC have not been demonstrated.

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