Drugs of today
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Review
Tagraxofusp, a novel CD123-directed cytotoxin to treat blastic plasmacytoid dendritic cell neoplasm.
Tagraxofusp is a toxin-cytokine fusion protein consisting of engineered diphtheria toxin (DT) and interleukin-3 (IL-3). The IL-3 domain binds to the cluster of differentiation 123 (CD123) and translocates DT into the cytosol, which leads to cell death. Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a rare and aggressive hematologic malignancy with a strong expression of CD123. ⋯ On December 21, 2018, the United States Food and Drug Administration (FDA) approved tagraxofusp for the treatment of adults and children with newly diagnosed or relapsed/refractory BPDCN, becoming the first FDA-approved drug for this disease. In this review, we examine the preclinical studies and phase I/II clinical studies that led to FDA approval of tagraxofusp, focusing on its molecular pharmacology, pharmacokinetics, efficacy and safety profile. We also discuss future directions regarding BPDCN management.
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Plasma protein transthyretin (TTR) can undergo conformational change resulting in the formation of amyloid fibrils that can then cause amyloidosis. This can occur spontaneously in individuals over the age of 70-80 resulting in wild-type transthyretin amyloidosis (ATTR) (with cardiomyopathy). This then progresses to fatal cardiac failure. ⋯ Until recently, there has been no specific treatment for these conditions. However, a detailed search for compounds that stabilize TTR resulted in the discovery of tafamidis. This compound stabilizes TTR and has been found to significantly reduce the progression of both wild-type ATTR amyloidosis and hereditary ATTR amyloidosis.