The US Food and Drug Administration (FDA) has approved Novartis' drug Afinitor (everolimus) tablets for the treatment of adult patients with kidney tumours known as renal angiomyolipomas and tuberous sclerosis complex (TSC), who do not require immediate surgery. This marks the first approval of a medical treatment in this patient population.

The accelerated approval was based on the phase III EXIST-2 (EXamining everolimus In a Study of TSC) trial, which found that 42 per cent of patients on everolimus experienced an angiomyolipoma response versus 0 per cent of patients in the placebo arm (p<0.0001). The time to angiomyolipoma progression was also statistically significantly longer in patients on everolimus (p<0.0001). Among the 97 per cent of trial patients with skin lesions, one of the key concerns for the majority of patients with TSC, a 26 per cent response rate was seen with everolimus versus 0 per cent with placebo (p=0.0011).

“Renal angiomyolipomas are one of the greatest causes of morbidity and mortality in adult TSC patients and can be one of the most challenging aspects of the disease to treat,” said John Bissler, MD, Clark D West Endowed Chair of Nephrology at Cincinnati Children's Hospital Medical Centre. “Today marks an important step for the TSC community, as Afinitor is now the only approved medicine to reduce the kidney tumour burden in these patients.”

Up to 80 per cent of patients with TSC, a genetic disorder that may cause non-cancerous tumours to form in vital organs, will develop renal angiomyolipomas. Typical onset occurs between the ages of 15 and 30 and prevalence increases with age. Over time, these tumours 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 often form in both kidneys. In addition, skin lesions occur in more than 90 per cent of patients with TSC. They may develop in infancy, can become more prevalent with age and cause disfigurement.

“With this FDA approval, Afinitor becomes the first medical option to treat two of the most debilitating manifestations of this challenging, lifelong disease - kidney tumours called renal angiomyolipomas and brain tumours known as SEGAs,” said Hervé Hoppenot, president, Novartis Oncology. “This approval further strengthens our commitment to address unmet needs in TSC as we continue to research everolimus and mTOR inhibition across other manifestations of the disease.”

Based on an effect on a clinical endpoint other than survival or irreversible morbidity, this indication was approved under the FDA's accelerated approval program, which provides patients access to a treatment for a serious or life-threatening illness and that provides meaningful therapeutic benefit to patients over existing treatments. Novartis previously received approval for everolimus for the treatment of adult and paediatric patients, aged three or older, with subependymal giant cell astrocytoma (SEGA) associated with TSC who require therapeutic intervention but are not candidates for curative surgical resection in the US, and in more than 40 additional countries. Filings for renal angiomyolipoma are under way in multiple countries outside of the US.

Afinitor 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, 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.

Affecting approximately one to two million people worldwide, TSC can affect many different parts of the body, including the kidneys and brain, as well as the heart, lungs and skin. Tuberous sclerosis complex is associated with a variety of resulting disorders, including skin lesions, seizures, swelling in the brain (hydrocephalus), kidney failure, developmental delays and behavioural issues.

EXIST-2 is the first double-blind, randomized, placebo-controlled, international, multi-centre 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 starting dose of 10 mg. By the cut-off of October 14, 2011, the median treatment duration in the double-blind period was 48 weeks in the everolimus arm and 45 weeks in the placebo arm.

In the study, 42 per cent of patients on everolimus (33 of 79; 95% CI 30.8-53.4) experienced an angiomyolipoma response versus 0 per cent on placebo (0 of 39; 95% CI 0.0-9.0)(p<0.0001), defined as a 50 per cent 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 superiority to placebo for both supportive efficacy outcomes measured: time to angiomyolipoma progression and skin lesion response rate. There were three patients in the Afinitor 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 (p<0.0001; HR 0.08, 95% CI 0.02-0.37). 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 now approved as Afinitor (everolimus) tablets in the United States (US) for the treatment of adult patients with renal angiomyolipomas and tuberous sclerosis complex (TSC), who do not require 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. Everolimus is also approved in the European Union (EU) as Votubia (everolimus) tablets and in the US as Afinitorto treat adult and paediatric patients, aged three years or older, with SEGA associated with TSC who require therapeutic intervention but are not candidates or amenable for surgery. The effectiveness of everolimus is based on an analysis of change in SEGA volume in patients three years of age and older. Further clinical benefit has not been demonstrated.

Everolimus is approved as Afinitor in more than 80 countries including the US and throughout the EU in the adult oncology settings of advanced renal cell carcinoma following progression on or after vascular endothelial growth factor (VEGF)-targeted therapy in the EU and after failure of treatment with sunitinib or sorafenib in the US. Afinitor is approved for the treatment of locally advanced, metastatic or unresectable progressive neuroendocrine tumours of pancreatic origin in adults in the US and EU.

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

Afinitor/Votubia can cause serious side effects including lung or breathing problems, infections, and renal failure which can lead to death. Mouth ulcers and mouth sores are common side effects. Afinitor/Votubia can affect blood cell counts, kidney and liver function, and blood sugar and cholesterol levels. Afinitor/Votubia may cause fetal harm in pregnant women. Women taking Afinitor/Votubia should not breast feed.