Drugs of today
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In May of 2019, the adeno-associated virus (AAV)-based gene therapy onasemnogene abeparvovec-xioi (Zolgensma) became the second Food and Drug Administration (FDA)-approved gene therapy with designated use for infants diagnosed with spinal muscular atrophy (SMA). The decision came nearly 10 years after results of the first preclinical models were initially reported. While the journey was an arduous one, the approval was an indication of the remarkable success of the first in-human clinical trials. ⋯ Children with SMA type 1 cannot lift their heads without assistance and do not live past their second birthday. With Zolgensma, the first treated children with SMA type 1 have reached 5 years of age and some of them achieved the ability to sit unassisted or even walk. In this article, we review the work that led to FDA approval with emphasis on the development of preclinical and clinical studies.
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Emapalumab-Igsz (Gamifant) is a human monoclonal antibody directed against interferon-γ (IFN-γ), and the first Food and Drug Administration (FDA)-approved therapy for primary hemophagocytic lymphohistiocytosis (HLH). HLH is a disorder characterized by hypercytokinemia in the setting of unbridled immune activation, and emapalumab represents the first therapeutic developed to address the underlying pathophysiology of HLH. ⋯ Additional studies of emapalumab are currently ongoing in adults and other pediatric populations. Here, we will review the pharmacology, safety and efficacy of emapalumab for the treatment of HLH.
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The antibody-drug conjugate enfortumab vedotin is a fully humanized monoclonal antibody targeting Nectin-4 linked to a microtubule-disrupting agent, monomethyl auristatin E, via a protease-cleavable maleimidocaproyl valine-citrulline linker. In this article, we provide a comprehensive review of the preclinical and clinical activity of enfortumab vedotin, which has been recently approved in the U. S. for the treatment of adult patients with locally advanced or metastatic urothelial carcinoma who have previously received a programmed cell death protein 1 (PD-1)/programmed cell death 1 ligand 1 (PD-L1) inhibitor as well as platinum-containing chemotherapy in the neoadjuvant/adjuvant, locally advanced or metastatic setting. Enfortumab vedotin is the first antibody-drug conjugate approved for patients with urothelial carcinoma.
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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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BRAF V600E mutations are associated with 8-10% of metastatic colorectal cancers (mCRC) and carry a poor prognosis with limited therapeutic options. In contrast to metastatic melanoma, BRAF inhibition alone or in combination with mitogen-activated protein kinase kinase (MEK) inhibitors has shown little utility in the treatment of BRAF V600E-mutant mCRC. This is secondary to upstream activation of the epidermal growth factor receptor (EGFR) pathway and other escape mechanisms. ⋯ The trial met all its endpoints and is now included in NCCN (National Comprehensive Cancer Network) guidelines. Herein we provide updates in treatment options for patients with BRAF V600E-mutant mCRC, focusing on the practice-changing BEACON-triplet regimen, the first chemotherapy-free combination regimen for mCRC. This combination is being explored frontline in the ANCHOR clinical trial.