Drugs of today
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Pertuzumab is a humanized monoclonal antibody directed at the dimerization domain of the receptor tyrosine-protein kinase erbB-2 (HER2) receptor. It possesses a unique and complimentary mechanism of action compared to trastuzumab, which has historically been the cornerstone of therapy for HER2-amplified breast cancer. Clinical trials demonstrate improved outcomes, with minimal increases in toxicity with the addition of pertuzumab to trastuzumab in patients with HER2-positive metastatic breast cancer, indicating the advantage of dual HER2 receptor blockade. Pertuzumab is approved as first-line therapy in combination with trastuzumab and docetaxel for HER2-positive metastatic breast cancer, with future opportunities to investigate its efficacy in other stages of breast cancer, as well as in the treatment of other malignancies.
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Axitinib is a small-molecule protein-tyrosine kinase receptor inhibitor specifically targeting this family of receptors, in addition to platelet-derived growth factor receptor and proto-oncogene c-Kit. Improved knowledge of kidney cancer development, and specifically mutations in the VHL gene, has supported the targeting of angiogenesis pathways. Axitinib is the most recently approved agent for use in metastatic renal cell carcinoma. This review will focus on the preclinical pharmacology, pharmacokinetics and clinical activity of this agent, and describe its place in the current treatment of renal cell carcinoma.
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Chronic myeloid leukemia (CML) is an uncommon malignancy, the treatment and prognosis of which have dramatically shifted over the last decade. Characterized by a translocation between chromosomes 9 and 22, known as the Philadelphia chromosome, small-molecule tyrosine kinase inhibitors (TKIs) targeted against the oncogenic BCR-ABL fusion protein have changed this once fatal disease into the model of targeted therapy. This article will review the pharmacological and clinical data supporting the use of imatinib and the second-generation TKIs dasatinib and nilotinib, and the novel TKIs bosutinib and ponatinib.
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The autoimmune disease rheumatoid arthritis (RA) causes severe disability through chronic and destructive inflammation of the synovial joints. Currently available therapeutic options, including disease-modifying antirheumatic drugs (DMARDs) and biologic agents, often fail to adequately prevent disease progression. ⋯ Tofacitinib has been evaluated in phase II, phase III and long-term extension studies, as both monotherapy and in combination with methotrexate and other DMARDs, and demonstrates statistically significant and clinically meaningful improvements in the signs and symptoms of RA, patient health, physical functioning and quality of life, while having a manageable safety profile. It is currently under evaluation for approval for the treatment of adults with RA by several regulatory agencies around the world.
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Vismodegib is a novel, small-molecule inhibitor of smoothened, a key component of the hedgehog signaling pathway. Increased hedgehog pathway signaling is critical in the development of hereditary and spontaneous basal cell carcinomas of the skin, and has been implicated in the development of a number of other tumors. ⋯ Clinically, phase I and II studies showed dramatic anticancer activity in patients with advanced basal cell carcinomas. In January 2012, vismodegib was approved by the FDA for the treatment of unresectable or metastatic basal cell carcinomas of the skin.