Tuberous sclerosis is a genetic disorder that may cause benign tumors to form in vital organs and can affect many different parts of the body, most commonly the brain,. Signs of TS vary depending on which system and which organs are involved. SEGAs, or benign brain tumors, occur in up to 20% of patients with TS and may lead to a variety of resulting disorders including seizures, swelling in the brain, developmental delays and skin lesions,. Prior to this approval, surgery was the only treatment option for Swiss patients with growing SEGAs associated with TS.
The approval is based on a prospective, open-label, single-arm Phase II study of 28 patients. Results showed 75% of patients (21 of 28) experienced a reduction of 30% or greater in the size of their largest SEGA and 32% (9 of 28) experienced a reduction of 50% or greater at six months relative to baseline. Of 16 patients with seizures at the start of the study, nine experienced decreases in seizure frequency, six reported no change and one experienced an increase at 6 months relative to baseline. Facial angiofibromas (red elevated skin lesions) improved in 87% of patients (13 of 15 evaluated patients) from baseline to six months.
"This approval of Votubia is significant for children and adults who have SEGA associated with tuberous sclerosis and, until now, have had limited treatment options," said Hervé Hoppenot, President, Novartis Oncology. "This milestone represents our first approval in Europe for Votubia and underscores our commitment to help patients worldwide improve their management of this difficult-to-treat disease."
Everolimus targets mTOR, a protein that acts as an important regulator of tumor cell division, blood vessel growth and cell metabolism. Tuberous sclerosis is caused by defects in the TSC1 and TSC2 genes. When these genes are defective, mTOR activity is increased, which can cause uncontrolled tumor cell growth and proliferation, blood vessel growth and altered cellular metabolism, leading to the formation of benign tumors throughout the body, including the brain. By inhibiting mTOR activity in this protein pathway, everolimus may reduce cell proliferation, blood vessel growth and glucose uptake related to SEGA associated with TS.
Regulatory approvals have also been granted in this disease setting in the United States, Brazil, Guatemala and the Philippines. Submissions to the European Medicines Agency (EMA) and other global regulatory agencies are under review.
Tuberous sclerosis affects approximately one to two million people worldwide. In Europe, the prevalence in the general population is estimated to be nearly nine cases per 100,000. SEGAs occur in up to 20% of patients with TS.
About the Phase II study
In a prospective, open-label, single-arm study, 28 patients aged three years and above (median age=11, range 3-34) with evidence of SEGA growth initially received everolimus orally at a dose of 3 mg/m daily or every other day. In total, 16 of the 28 patients were treated with Votubia for at least 21 months.
In the study, 75% of patients (21 of 28) experienced a reduction of 30% or greater in the size of their largest SEGA and 32% (9 of 28) experienced a reduction of 50% or greater at six months relative to baseline.
Of 16 patients with seizures at the start of the study for whom 24-hour video electroencephalograms (EEG) were available, nine experienced decreases in seizure frequency, six reported no change and one experienced an increase at six months relative to baseline. Facial angiofibromas improved in 87% of patients (13 of 15 evaluated patients) from baseline to six months. None of the patients developed new symptoms of intracranial pressure or an increase in hydrocephalus (swelling in the brain). No patient underwent surgery.
The most common adverse events reported (incidence >=30%) in the prospective, open-label, single-arm trial were mouth sores, upper respiratory tract infections, sinusitis, middle ear infections and fever. However, the reliability of the frequency of adverse reactions and laboratory abnormalities reported in this trial is limited because of the small number of patients.
All data from the study submitted to Swissmedic are based on the cut-off date of December 9, 2009.
Votubia® (everolimus) tablets is approved in Switzerland for the treatment of patients 3 years of age and older, with SEGA associated with tuberous sclerosis (TS), for whom surgery is not a suitable option. Should everolimus be approved in the EU, the trade name will be Votubia. In the US, Afinitor® (everolimus) tablets is approved to treat patients with SEGA associated with tuberous sclerosis who require therapeutic intervention but are not candidates for curative surgical resection. The effectiveness of everolimus is based on an analysis of change in SEGA volume. Clinical benefit such as improvement in disease-related symptoms or increase in overall survival has not been shown.
Afinitor is approved in the US for the treatment of progressive neuroendocrine tumors of pancreatic origin in patients with unresectable, locally advanced or metastatic disease. The FDA determined that the safety and effectiveness of Afinitor in the treatment of patients with carcinoid tumors have not been established.
Afinitor is approved in the European Union (EU) for the treatment of patients with advanced renal cell carcinoma (RCC) whose disease has progressed on or after treatment with vascular endothelial growth factor (VEGF)-targeted therapy and also in the US for the treatment of patients with advanced RCC after failure of treatment with sunitinib or sorafenib.
In the EU, everolimus is available in different dosage strengths for the non-oncology patient population under the trade name Certican® for the prevention of organ rejection in heart and kidney transplant recipients. In the US, everolimus is available in different dosage strengths under the trade name Zortress® for the prophylaxis of organ rejection in adult patients at low-moderate immunologic risk receiving a kidney transplant.
Everolimus is exclusively licensed to Abbott and sublicensed to Boston Scientific for use in drug-eluting stents.
Not all indications are available in every country. Because of the uncertainty of clinical trials, there is no guarantee that everolimus will become commercially available for SEGAs anywhere else in the world.
Important Safety Information about Votubia/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. Votubia can affect blood cell counts, kidney and liver function, blood sugar and cholesterol levels. Votubia may cause fetal harm in pregnant women. Women taking Votubia should not breast feed.
The most common adverse drug reactions (incidence >=15%) are mouth ulcers, rash, diarrhea, fatigue, acneiform dermatitis, infections, weakness, nausea, peripheral swelling, decreased appetite, headache, pneumonitis, abnormal taste, nose bleeds, mucosal inflammation, weight decreased and vomiting. The most common grade 3-4 adverse drug reactions (incidence >=2%) are mouth ulcers, fatigue, decreased white blood cell count, diarrhea, infections, pneumonitis and diabetes mellitus. Cases of hepatitis B reactivation and pulmonary embolism have been reported.