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Novartis International AG / Novartis drug AfinitorR approved by FDA as first medication to treat patients with non-cancerous kidney tumors associated with TSC . Processed and transmitted by Thomson Reuters ONE. The issuer is solely responsible for the content of this announcement.
Basel, April 26, 2012 -Novartis announced today that the US Food and Drug Administration (FDA) approved AfinitorR (everolimus) tablets* for the treatment of adult patients with kidney tumors 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% of patients on everolimus experienced an angiomyolipoma response versus 0% 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% of trial 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=0.0011),.
"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 Center. "Today marks an important step for the TSC community, as Afinitor is now the only approved medicine to reduce the kidney tumor burden in these patients."
Up to 80% of patients with TSC, a genetic disorder that may cause non-cancerous tumors 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 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 tumors can be difficult to manage as they often form in both kidneys,. In addition, skin lesions occur in more than 90% 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 tumors called renal angiomyolipomas and brain tumors 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 pediatric 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 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 tumor cell growth and proliferation, blood vessel growth and altered cellular metabolism,. According to preclinical studies, by inhibiting mTOR activity in this signaling 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 behavioral issues.
In the study, 42% of patients on everolimus (33 of 79; 95% 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 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.
The most common adverse event (AE) in the everolimus arm (with an incidence of at least 30%) was stomatitis. The most common Grade 3-4 adverse reactions (incidence >= 2%) were stomatitis, amenorrhea and convulsion. The most common laboratory abnormalities (incidence >= 50%) were hypercholesterolemia, hypertriglyceridemia and anemia. The most common Grade 3-4 laboratory abnormality (incidence >= 3%) was hypophosphatemia. Adverse events observed in this study were for the most part consistent with the known safety profile of everolimus in the TSC setting.
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 tumors 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 CerticanR and ZortressR and is exclusively licensed to Abbott and sublicensed to Boston Scientific for use in drug-eluting stents.
Indications vary by country and not all indications are available in every country.
Important safety information about Afinitor/Votubia
The most common adverse drug reactions (incidence >=15%) are mouth ulcers, diarrhea, feeling weak or tired, skin problems (such as rash or acne), infections, nausea, swelling of extremities or other parts of the body, loss of appetite, headache, inflammation of lung tissue, abnormal taste, nose bleeds, inflammation of the lining of the digestive system, weight decreased and vomiting. The most common Grade 3-4 adverse drug reactions (incidence >=2%) are mouth ulcers, feeling tired, low white blood cells (a type of blood cell that fights infection), diarrhea, infections, inflammation of lung tissue, diabetes and amenorrhea. Cases of hepatitis B reactivation and blood clot in the lung and leg have been reported.
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*Known as VotubiaR (everolimus) tablets for certain patients with SEGA associated with TSC in the EU and Switzerland.
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