Letermovir is a novel antiviral in clinical development for prophylaxis against human cytomegalovirus in immunocompromised transplant recipients. This two-part, single-center, randomized, double-blind, placebo-controlled trial evaluated the safety and pharmacokinetics of a hydroxypropyl β-cyclodextrin (HPβCD)-based intravenous formulation of letermovir in healthy women. Subjects received single, escalating doses (120, 240, 480, 720, and 960 mg; 6 letermovir, 2 placebo per cohort) or multiple, oncedaily doses (240 mg; 8 letermovir, 4 placebo) of HPβCD-formulated letermovir and the associated pharmacokinetic profiles and adverse events were investigated. Single-dose and multiple-dose regimens were generally well tolerated. Single-dose escalation resulted in a slightly more-than-dose-proportional increase in the area under the letermovir plasma concentrationtime curve (AUC), whereas increase in the maximal observed letermovir plasma concentration (C max ) was dose proportional. Human cytomegalovirus (HCMV) disease is commonly reported in immunocompromised individuals, notably in transplant recipients. In the absence of appropriate prophylactic treatment during allogeneic hematopoietic stem-cell transplant (HSCT), 80% of patients with HCMV-positive disease develop symptoms of HCMV disease.1 The most serious clinical manifestation of this infection is HCMV pneumonia, with an associated mortality rate >50%.1 In addition to pneumonia, other clinical manifestations of HCMV disease include gastrointestinal complications that render the ingestion and absorption of oral drugs difficult, further complicating treatment. clovir, which act as DNA polymerase inhibitors and are associated with significant toxicity and the potential of drug resistance development.2 Therefore, there is a need to develop new antivirals with a novel mode of action to nucleosides and a lower toxicity, while maintaining activity against resistant strains. This need was compounded by recent findings regarding two candidate anti-HCMV agents, maribavir and brincidofovir (CMX001), that failed to demonstrate efficacy in clinical phase III trials. 3,4 Letermovir (AIC246) is a novel drug being initially developed for prophylactic treatment against HCMV in HSCT recipients. It belongs to a class of anti-HCMV agents (terminase inhibitors) that inhibit the formation and release of infectious virus particles by targeting viral DNA processing. [5][6][7][8][9]
Avelumab is an IgG1 anti–programmed death ligand 1 (anti–PD-L1) monoclonal antibody that has been approved as a monotherapy for metastatic Merkel cell carcinoma and advanced urothelial carcinoma, and in combination with axitinib for advanced renal cell carcinoma. Avelumab is cleared faster and has a shorter half-life than other anti–PD-L1 antibodies, such as atezolizumab and durvalumab, but the mechanisms underlying these differences are unknown. IgG antibodies can be cleared through receptor-mediated endocytosis after binding of the antibody Fab region to target proteins, or via Fcγ receptor (FcγR)-mediated endocytosis. Unlike other approved anti–PD-L1 antibodies, avelumab has a native Fc region that retains FcγR binding capability. We hypothesized that the rapid clearance of avelumab might be due to the synergistic effect of both FcγR-mediated and PD-L1 target–mediated internalization. To investigate this, we performed in vitro and in vivo studies that compared engineered variants of avelumab and atezolizumab to determine mechanisms of cellular internalization. We found that both FcγR and PD-L1 binding contribute to avelumab internalization. While FcγR binding was the dominant mechanism of avelumab internalization in vitro , with CD64 acting as the most important FcγR, studies in mice and cynomolgus monkeys showed that both FcγR and PD-L1 contribute to avelumab elimination, with PD-L1 binding playing a greater role. These studies suggest that the rapid internalization of avelumab might be due to simultaneous binding of both PD-L1 and FcγR in trans. Our findings also provide a basis to alter the clearance and half-life of monoclonal antibodies in therapeutic development.
Renal impairment increased exposure to letermovir, although age was a confounding factor.
Introduction: Several programmed death-ligand 1 (PD-L1) immunohistochemistry (IHC) assays have been developed independently within clinical programs for therapeutic anti-programmed cell death protein 1 (anti-PD-1) or PD-L1 antibodies, necessitating assessment of assay comparability. We characterized the Dako PD-L1 IHC 73-10 assay used in clinical trials of avelumab (anti-PD-L1) or bintrafusp alfa (M7824; bifunctional immunotherapy) and compared it with the Dako PD-L1 IHC 22C3 pharmDx assay, an approved companion diagnostic for pembrolizumab monotherapy in patients with advanced NSCLC. Methods: Formalin-fixed, paraffin-embedded NSCLC tumor samples from a commercial source and from the JAVELIN Solid Tumor phase 1 trial of avelumab (NCT01772004) were stained using the 73-10 and 22C3 IHC assays with a standard protocol. Results: Both assays displayed expected PD-L1 staining patterns. In 148 commercial NSCLC samples, the 73-10 assay stained greater than or equal to 1%, greater than or equal to 50%, and greater than or equal to 80% of tumor cells as PD-L1þ in 64.2%, 36.5%, and 23.6% of the samples, respectively, whereas the 22C3 assay stained 20.3% of the samples as greater than or equal to 50% PD-L1þ. In 83 NSCLC clinical trial samples, the 73-10 assay stained 79.5% and 31.3% of the samples as greater than or equal to 1% and greater than or equal to 80% PD-L1þ, respectively, whereas the 22C3 assay stained 59.0% and 21.7% as greater than or equal to 1% and greater than or equal to 50% PD-L1þ, respectively. Efficacy of avelumab was similar in the subgroups classified with the 73-10 and 22C3 assays using greater than or equal to 80% and greater than or equal to 50% PD-L1þ cutoffs, with objective response rates of 26.9% and 33.3%, respectively.
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