Novartis Drug Votubia Recommended By CHMP for Approval in the EU for Children and Adults With SEGA

Novartis Drug Votubia Recommended By CHMP for Approval in the EU for Children and Adults With SEGA Associated With Tuberous Sclerosis* If approved, Votubia (everolimus) will be first medication in EU for subependymal giant cell astrocytoma (SEGA) associated with tuberous sclerosis complex (TSC)

* CHMP opinion based on Phase II study of 28 patients showing 33% experienced a SEGA tumor reduction of 50% or greater at six months relative to baseline[1]

* Brain surgery is only treatment option in EU for growing SEGAs, benign brain tumors that primarily affect children and adolescents[1],[2],[3],[4]

* Worldwide regulatory submissions for everolimus to treat this patient population are under way; first approval received in the US in 2010 as Afinitor®

Basel, June 24, 2011 - 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 patients aged 3 years and older with subependymal giant cell astrocytoma (SEGA) associated with tuberous sclerosis complex (TSC), who require therapeutic intervention but are not amenable to surgery. If approved, Votubia will be the first medication available for these patients in the European Union (EU).

Tuberous sclerosis complex, also known as tuberous sclerosis (TS), may cause benign tumors to form in vital organs and can affect many different parts of the body, most commonly the brain[5],[6]. Signs of TSC vary depending on which system and which organs are involved[5]. SEGAs, or benign brain tumors, occur in up to 20% of patients with TSC[1]. Tuberous sclerosis complex is also associated with a variety of resulting disorders including seizures, swelling in the brain (hydrocephalus), developmental delays and skin lesions[1],[2],[5]. Currently, brain surgery is the only treatment option for patients in the EU with growing SEGAs associated with TSC[1].

The CHMP positive opinion is for a conditional approval based on a prospective, open-label, single-arm, Phase II study of 28 patients. Results showed that 78% of patients (21 of 27) experienced a reduction of 30% or greater in the size of their largest SEGA and 33% (9 of 27) experienced a reduction of 50% or greater at six months relative to baseline[1].

"The positive CHMP opinion for Votubia is encouraging as it may lead to the approval of the first medication in the European Union for patients with this challenging disease," said Hervé Hoppenot, President of Novartis Oncology. "Our focus on tuberous sclerosis complex research reflects the commitment Novartis has made to develop innovative therapies to help address unmet medical needs."

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.

Regulatory approvals have already been granted for SEGA associated with TSC in the United States, Switzerland, Brazil, Colombia, Guatemala, the Philippines and South Korea. Additional submissions to global regulatory agencies are under way worldwide.

Everolimus targets mTOR, a protein that acts as an important regulator of tumor cell division, blood vessel growth and cell metabolism[8]. Tuberous sclerosis complex is caused by defects in the TSC1 and/or TSC2 genes[5]. 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[1]. By inhibiting mTOR activity in this protein pathway, everolimus may reduce cell proliferation, blood vessel growth and glucose uptake related to SEGA associated with TSC[1].

Tuberous sclerosis complex is a genetic disorder affecting approximately one to two million people worldwide[5]. In Europe, the prevalence in the general population is estimated to be nearly nine cases per 100,000[7].

About the Phase II Study

This prospective, open-label, single-arm study was conducted in 28 patients aged three years and above (median age=11, range 3-34) with evidence of serial SEGA growth[1].

In the study, 78% of patients (21 of 27) experienced a reduction of 30% or greater in the size of their largest SEGA and 33% (9 of 27) experienced a reduction of 50% or greater at six months relative to baseline. This evidence is based on an analysis of change in SEGA volume. No patient developed a new SEGA, had worsening hydrocephalus or required surgery or other therapy for SEGA while receiving everolimus[1].

The most common adverse reactions reported (incidence >=10%) in the prospective, open-label, single-arm trial were infections, increased aspartate transaminase (AST), mouth sores, increased cholesterol, decreased white blood cell count, increased alanine transaminase (ALT), increased triglycerides, decreased hemoglobin, fever, decreased glucose, acneiform dermatitis, increased glucose, diarrhea, decreased platelet counts, acne, cough and increased creatinine. The only grade 3 adverse reactions were infections (single cases of sinusitis, pneumonia, tooth infection and viral bronchitis), and single cases of mouth sores, elevated AST concentrations and decreased neutrophil count. No grade 4 adverse reactions were reported. 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 Phase II study submitted to the EMA are based on the cut-off date of December 9, 2009.

About everolimus

Votubia® (everolimus) tablets is approved in Switzerland for the treatment of patients 3 years of age and older, with SEGA associated with 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 TS 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. Novartis has submitted a marketing application for everolimus to the European Medicines Agency (EMA) for this use, and additional regulatory submissions are under way worldwide.

Afinitor is approved in the 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 additional indications 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.

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