A Phase 2b, Randomized, Double-blind, Placebo-Controlled Multicenter Study Evaluating Antiviral Effects, Pharmacokinetics, Safety, and Tolerability of Presatovir in Hematopoietic Cell Transplant Recipients with Respiratory Syncytial Virus Infection of the Lower Respiratory Tract

Marty, Francisco M.; Chemaly, Roy F.; Mullane, Kathleen M.; Lee, Dong Gun; Hirsch, Hans H.; Small, Catherine B.; Bergeron, Anne; Shoham, Shmuel; Ljungman, Per; Waghmare, Alpana; Blanchard, Élodie; Kim, Yae Jean; McKevitt, Matthew; Porter, Danielle; Jordan, Robert; Guo, Ying; German, Polina; Boeckh, Michael; Watkins, Timothy R.; Chien, Jason W.; Dadwal, Sanjeet

doi:10.1093/cid/ciz1167

Cited by 54 publications

(40 citation statements)

References 24 publications

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“…Presatovir, a respiratory syncytial virus (RSV) fusion inhibitor, showed an EC 50 of 2.53 μM and SI of >37.9. The EC 50 of presatovir against SARS-CoV-2 is 7,000-fold less potent than against RSV 19 , establishing that clinical exposures are below the EC 50 determined for SARS-CoV-2 20 , precluding the potential for COVID-19 therapy. Cobicistat, a selective mechanism-based inhibitor of CYP3A enzymes, weakly inhibited SARS-CoV-2-Nluc (EC 50 2.7 μM) with a modest SI of 17.3.…”

Section: Resultsmentioning

confidence: 95%

A nanoluciferase SARS-CoV-2 for rapid neutralization testing and screening of anti-infective drugs for COVID-19

Xie

Muruato

Zhang

et al. 2020

Preprint

106

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1A high-throughput platform would greatly facilitate COVID-19 serological testing and 2 antiviral screening. Here we report a nanoluciferase SARS-CoV-2 (SARS-CoV-2-Nluc) that is 3 genetically stable and replicates similarly to the wild-type virus in cell culture. We demonstrate 4 block an authentic viral infection. However, the low throughput and long assay turnaround time 4 2 make PRNT impossible for large scale diagnosis, representing a critical gap for COVID-19 4 3 response and countermeasure development. 4The goals of this study were to (i) develop a rapid neutralization assay that maintains the 4 5 gold standard of PRNT for serological COVID-19 diagnosis, (ii) establish a high-throughput 4 6 assay for reliable antiviral screening, and (ii) screen exploratory and FDA-approved anti-4 7 infective drugs for potential COVID-19 repurposing. We established a nanoluciferase SARS-4 8CoV-2 (SARS-CoV-2-Nluc) as a platform for rapid serodiagnosis and high-throughput drug 4 9

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Section: Resultsmentioning

confidence: 95%

A nanoluciferase SARS-CoV-2 for rapid neutralization testing and screening of anti-infective drugs for COVID-19

Xie

Muruato

Zhang

et al. 2020

Preprint

106

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“…Presatovir was subsequently advanced to phase IIb trials in hospitalized patients suffering from RSV infection and in lung and hematopoietic stem cell transplant recipients [97][98][99]. Treatment was overall well-tolerated with minimal adverse effect, but presatovir disappointed overall in these much larger patient groups with confirmed RSV infections, despite its encouraging original performance in the human challenge model.…”

Section: Clinical Efficacy Of Small Molecule F Protein Inhibitorsmentioning

confidence: 99%

“…The compound failed to significantly reduce virus load in any of the patient groups tested. Moreover, presatovir had no impact on the duration of hospitalization in the adult patient cohort [97], did not alleviate disease symptoms or improve lung function in the lung transplant recipients [98], and did not lower the rate of respiratory failure or reduce overall mortality in the stem cell transplant recipients [99].…”

Section: Clinical Efficacy Of Small Molecule F Protein Inhibitorsmentioning

confidence: 99%

Structural Insight into Paramyxovirus and Pneumovirus Entry Inhibition

Aggarwal

Plemper

2020

Viruses

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Paramyxoviruses and pneumoviruses infect cells through fusion (F) protein-mediated merger of the viral envelope with target membranes. Members of these families include a range of major human and animal pathogens, such as respiratory syncytial virus (RSV), measles virus (MeV), human parainfluenza viruses (HPIVs), and highly pathogenic Nipah virus (NiV). High-resolution F protein structures in both the metastable pre-and the postfusion conformation have been solved for several members of the families and a number of F-targeting entry inhibitors have progressed to advanced development or clinical testing. However, small-molecule RSV entry inhibitors have overall disappointed in clinical trials and viral resistance developed rapidly in experimental settings and patients, raising the question of whether the available structural information may provide a path to counteract viral escape through proactive inhibitor engineering. This article will summarize current mechanistic insight into F-mediated membrane fusion and examine the contribution of structural information to the development of small-molecule F inhibitors. Implications are outlined for future drug target selection and rational drug engineering strategies.Viruses 2020, 12, 342 2 of 16 from its natural bat host to domestic animals, resulting in case/fatality rates reaching from 40% to over 90% [9]. Continued spillover into the human population must be expected, and human-to-human transmission through respiratory secretions, urine, and saliva has been documented [10].Of the pneumoviruses, RSV infects almost all children before two years of age and is responsible for over 100,000 hospitalizations yearly in the United States alone. The monoclonal antibody palivizumab has been approved for immunoprophylaxis against RSV infection [11], however, use is restricted to high-risk patients due to the high-cost and need for prophylactic administration.Given the health, medical and economic burden associated with paramyxo-and pneumovirus infections, a major and currently unmet clinical need exists to expedite the development of novel safe and effective therapeutics for improved disease management and outbreak control. Current direct-acting therapeutics predominantly focus on preventing viral entry through neutralizing antibodies (nAbs) and on small-molecules targeting the envelope glycoproteins or inhibiting the viral RNA-dependent RNA polymerase (RdRP) complex. Reflecting major efforts to identify a cost-effective alternative to high-price passive immunization with anti-RSV nAbs, a number of compounds have entered advanced preclinical development and clinical testing in recent years (Table 1). Breakthroughs in the structural and functional characterization of the viral entry machinery and polymerase complexes in the past decade [12][13][14][15][16][17][18][19][20][21] have furthermore created a novel opportunity for structure-informed mechanistic characterization and ligand optimization.

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“…Presatovir, a small molecule fusion inhibitor, was recently evaluated in phase 2b randomized trials in both HSCT and lung transplant patients. 106,107 Unfortunately, presatovir administration was not associated with improvement in viral load or clinical outcomes in either trial. A novel oral viral replication inhibitor ALS-008176 has shown promise in a small RSV challenge study in healthy adults, but further trials are required before it can be recommended for routine use.…”

Section: Treatmentmentioning

confidence: 90%

Other Respiratory Viruses as a Cause of Community-Acquired Pneumonia

Walter

2020

Semin Respir Crit Care Med

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AbstractCommunity-acquired pneumonia (CAP) is a major cause of morbidity and mortality worldwide. There is growing appreciation of the burden of noninfluenza viral pathogens in CAP. Due to multiple factors including pneumococcal vaccination programs, declining rates of cigarette smoking, an aging population, and increasingly sensitive diagnostic tests, respiratory viruses are now the most common pathogens detected in CAP, outpacing Streptococcus pneumoniae. Noninfluenza respiratory pathogens are widely accepted as causal pathogens in CAP including in immunocompetent patients. This review provides an overview of five noninfluenza respiratory viral pathogens commonly implicated in CAP pathogenesis: rhinovirus, human metapneumovirus, respiratory syncytial virus, human parainfluenza virus, and human adenoviruses. Nucleic acid amplification testing platforms and their impact on antimicrobial stewardship efforts are also considered.

show abstract

A Phase 2b, Randomized, Double-blind, Placebo-Controlled Multicenter Study Evaluating Antiviral Effects, Pharmacokinetics, Safety, and Tolerability of Presatovir in Hematopoietic Cell Transplant Recipients with Respiratory Syncytial Virus Infection of the Lower Respiratory Tract

Cited by 54 publications

References 24 publications

A nanoluciferase SARS-CoV-2 for rapid neutralization testing and screening of anti-infective drugs for COVID-19

A nanoluciferase SARS-CoV-2 for rapid neutralization testing and screening of anti-infective drugs for COVID-19

Structural Insight into Paramyxovirus and Pneumovirus Entry Inhibition

Other Respiratory Viruses as a Cause of Community-Acquired Pneumonia

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