Home » Drug Information » FDA Approved Drugs » 2012
Medical Areas: Nephrology | Oncology | Family Medicine | Infections and Infectious Diseases
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The following drug information is obtained from various newswires, published
medical journal articles, and medical conference presentations.
Approval Status: Approved April 2012
Treatment Area: renal angiomyolipoma associated with tuberous sclerosis complex
Afinitor (everolimus) is an inhibitor of mTOR (mammalian target of rapamycin), a serine-threonine kinase, downstream of the PI3K/AKT pathway. The mTOR pathway is dysregulated in several human cancers. Everolimus binds to an intracellular protein, FKBP-12, resulting in an inhibitory complex formation and inhibition of mTOR kinase activity. Inhibition of mTOR by everolimus has been shown to reduce cell proliferation, angiogenesis, and glucose uptake in in vitro and/or in vivo studies.
Afinitor is specifically indicated for the treatment of renal angiomyolipoma associated with tuberous sclerosis complex in adults who do not require immediate surgery.
Afinitor is supplied as a tablet designed for oral administration. The recommended initial dose of the drug is 10 mg per day administered whole with or without food. Based on clinical conditions, Afinitor dosage may be increased in 5 mg increments not to exceed 20 mg per day.
The FDA approval of Afinitor was based on the results of a double-blind, placebo-controlled phase III trial dubbed EXIST-2. The study enrolled 113 adults with renal angiomyolipoma as a feature of tuberous sclerosis complex (TSC) and 5 adults with sporadic lymphangioleiomyomatosis. Subjects were randomized 2:1 to be treated with Afinitor 10 mg per day or matching placebo until disease progression or unacceptable toxicity. CT and MRI scans assessed disease levels at baseline, 12, 24, and 48 weeks and annually thereafter. Clinical and photographic review of skin lesions were reviewed at baseline and every 12 weeks until treatment discontinuation. The primary efficacy endpoint of angiomyolipoma response rate was evaluated by independent central radiology review and was reached. 42% of the subjects treated with Afinitor 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 the Afinitor arm (p<0.0001). Of the 97% of subjects with skin lesions, a 26% response rate was seen in subjects treated with Afinitor versus 0% with placebo (p=0.0011).
Adverse reactions associated with Afinitor may include, but are not limited to, the following:
Mechanism of Action
Afinitor is an inhibitor of mTOR (mammalian target of rapamycin), a serine-threonine kinase, downstream of the PI3K/AKT pathway. The mTOR pathway is dysregulated in several human cancers. Everolimus binds to an intracellular protein, FKBP-12, resulting in an inhibitory complex formation and inhibition of mTOR kinase activity. Everolimus reduced the activity of S6 ribosomal protein kinase (S6K1) and eukaryotic elongation factor 4E-binding protein (4E-BP), downstream effectors of mTOR, involved in protein synthesis. In addition, everolimus inhibited the expression of hypoxia-inducible factor (e.g., HIF-1) and reduced the expression of vascular endothelial growth factor (VEGF). Inhibition of mTOR by everolimus has been shown to reduce cell proliferation, angiogenesis, and glucose uptake in in vitro and/or in vivo studies.
For additional information regarding the use of Afinitor or renal angiomyolipomas associated with tuberous sclerosis complex, please visit the Afinitor web page.