Novartis today announced the availability of everolimus to treat adult patients with kidney tumours (renal angiomyolipoma) associated with Tuberous Sclerosis Complex (TSC) who are at risk of complications (based on factors such as tumour size, 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.

This announcement follows the recommendation of Votubia in this indication by the European Medicines Agency and marks the first approval of a medical treatment in this patient population.

The once daily pill reduced the size of potentially life threatening kidney tumours by at least half in 42% of patients at approximately 12 weeks and this response was maintained by 55% of patients at 6 months.

Furthermore at six months, 4 out of 5 (80%) patients were recorded as having clinically beneficial tumour reductions of at least 30%.

Everolimus therefore provides an alternative for patients who previously faced embolisation or surgery as the only treatment option for kidney tumours.

Tuberous Sclerosis Complex (TSC) is a genetic disorder caused by defects in the TSC1 and/or TSC2 genes. When these genes are defective, mTOR (mammalian target of rapamycin) a protein that acts as an important regulator of cell division, blood vessel growth and cell metabolism is overactivated.

When this mTOR pathway is overactivated, it can cause uncontrolled cell growth in vital organs and affect many different parts of the body, including the brain and kidney as well as the heart, lungs and skin. Everolimus works by inhibiting mTOR activity in this signalling pathway to reduce cell growth and the size of tumours.

TSC is estimated to affect approximately 6600 people in the UK.

Kidney tumours affect up to 80% of patients with Tuberous Sclerosis Complex and growing tumours may lead to complications such as life threatening bleeding or kidney failure.

Recommended treatment options for kidney tumours associated with Tuberous Sclerosis 

Complex have previously been limited to surgical interventions, most commonly embolisation or the full or partial removal of the affected kidney.

“Kidney tumours affect the vast majority of patients with Tuberous Sclerosis Complexand over time can cause debilitating symptoms, a decline in renal function and possibly progress to kidney transplant or dialysis,” said Dr. Chris Kingswood, Consultant Renal Physician, Royal Sussex County Hospital, Brighton.

”Everolimus has the potential to redefine the way people with Tuberous Sclerosis Complexkidney tumours are treated”.  

The approval of everolimus was based on the Phase III EXIST-2 (EXamining everolimus In a Study of TSC) trial, a randomised, double-blind, placebo-controlled, multi-centre study of 118 patients.

The EXIST-2 study is the largest ever study of Tuberous Sclerosis patients to date; four UK centres took part (London, Brighton, Cardiff and Belfast) enrolling a total of nine patients.

The trial found 42% of patients treated with everolimus achieved angiomyolipoma response versus 0% of patients in the placebo arm (p< 0.0001); response was defined as ≥ 50% reduction in tumour volume, plus absence of new angiomyolipoma ≥ 1cm in longest diameter, plus no increase in renal volume >20% and absence of grade ≥ 2 angiomyolipoma related bleeding.

At 6 months, 80% of patients in the everolimus groups had ≥30% reduction and 55% of patients had ≥50% reduction in tumour volume.

The most important outcome of this study was that Votubia prevented AML growth in 98% of people on everolimus at 6 months. In contrast 17% of patients receiving placebo had AMLs which continued to grow. It is the increasing size of the AML that correlates with the risk of bleeding.

Everolimus also demonstrated improvement when compared to placebo for both key secondary endpoints measured: time to tumour progression and skin lesion response rate:

• Median time to tumour progression was 11.4 months in the placebo arm and was not reached in the everolimus arm (p<0.0001).¹
• 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’s Global Assessment in 26% of patients on everolimus, compared with 0% of patients on placebo (p=0.0002).¹  Please note that Votubia is not licensed to treat skin lesions.

 The most common adverse reactions reported in the everolimus arm (with an incidence of at least 20%) included stomatitis, nasopharyngitis, headache, cough and hypercholesterolaemia. Of note, four grade 4 adverse events were reported for the everolimus group; 2 were laboratory abnormalities (neutropaenia and increased blood uric acid, respectively) reported by the central laboratory, 1 was convulsion and 1 was hypertensive crisis.

Amenorrhoea occurred in 15.4% and 3.8% of female patients in the everolimus and placebo groups, respectively.  Serious adverse events were reported in a similar proportion of patients in both the everolimus (19.0%) and the placebo (17.9%) groups.  There was one death that occurred on study in the everolimus group.  This was due to status epilepticus and was considered unrelated to treatment.

Availability for UK patients follows approval by the European Medicines Agency on 31^st October 2012. Additional regulatory submissions for everolimus in Tuberous Sclerosis Complex are under way worldwide.

“For the first time, patients with kidney tumours associated with Tuberous Sclerosis Complex have an approved effective non-surgical option,” said Ibrahim Elhoussieny UK Oncology Medical Director, Novartis UK & Ireland. “This approval suggests the potential of Votubia to treat a wide range of manifestations associated with Tuberous Sclerosis Complex, a debilitating, lifelong disease where there remains a critical need for effective treatment options,” he added. 

Source: Novartis