Novartis has announced that the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) adopted a positive opinion for 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. Votubia would be the first medication available in the European Union (EU) for these patients.

"Today's positive CHMP opinion for Votubia is important for patients in the EU with TSC, as renal angiomyolipoma is among the most difficult-to-treat manifestations of this debilitating disease," said Hervé Hoppenot, President, Novartis Oncology. "There remain many unmet medical needs in TSC, and Novartis is committed to understanding and improving the lives of people affected by this rare disease through clinical research, education and collaboration with the global TSC community."

In the EU, the European Commission generally follows the recommendations of the CHMP and delivers its final decision within three months of the CHMP recommendation. The decision will be applicable to all 27 EU member states plus Iceland and Norway. In Europe, everolimus has orphan drug designation for TSC. Orphan drugs are those that treat a condition which affects no more than five in 10,000 people in the EU.

The CHMP positive opinion is based on data from the phase III EXIST-2 (EXamining everolimus In a Study of TSC) trial, which found that 42% of patients on everolimus experienced an angiomyolipoma response versus 0% of patients in the placebo arm (p<0.0001). The evidence is based on analysis of change in sum of 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). Among the 97% of patients with skin lesions, one of the key concerns for the majority of patients with TSC, a 26% response rate was seen with everolimus versus 0% with placebo (p=0.0002).

Everolimus works by inhibiting mTOR, a protein implicated in many tumor-causing pathways. TSC is caused by defects in the TSC1 and/or TSC2 genes. When these genes are defective, mTOR activity is increased, which 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.

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

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 tumor 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 superiority to placebo for both supportive efficacy outcomes 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 statistically significantly longer in patients on everolimus (hazard ratio [HR] 0.08, 95% CI 0.02-0.37; p<0.0001). Skin lesion response rate was significantly 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.

Everolimus is approved as Afinitor (everolimus) tablets in the United States (US) for the treatment of adult patients with renal angiomyolipomas and tuberous sclerosis complex (TSC), not requiring immediate surgery. The effectiveness of Afinitor 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. Should everolimus be approved in the European Union (EU) for this patient population, the trade name will be Votubia.