One Week of Oral Camostat Versus Placebo in Nonhospitalized Adults With Mild-to-Moderate Coronavirus Disease 2019: A Randomized Controlled Phase 2 Trial

Clinical Infectious Diseases, Год журнала: 2023, Номер 77(7), С. 941 - 949

Опубликована: Июнь 5, 2023

Abstract Background Camostat inhibits severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in vitro. We studied the safety and efficacy of camostat ACTIV-2/A5401, a phase 2/3 platform trial therapeutics for COVID-19 nonhospitalized adults. Methods conducted study adults with mild-to-moderate randomized to oral 7 days or pooled placebo arm. Primary outcomes were time improvement symptoms through day 28, proportion participants SARS-CoV-2 RNA below lower limit quantification (LLoQ) from nasopharyngeal swabs 14, grade ≥3 treatment-emergent adverse events (TEAEs) 28. Results Of 216 (109 camostat, 107 placebo) who initiated intervention, 45% reported ≤5 at entry 26% met protocol definition higher risk progression COVID-19. Median age was 37 years. symptom 9 both arms (P = .99). There no significant differences <LLoQ on 3, 7, 14. Through 6 (5.6%) arm 5 (4.7%) hospitalized; 1 participant subsequently died. Grade TEAEs occurred 10.1% versus 6.5% .35). Conclusions In COVID-19, did not accelerate viral clearance improvement, reduce hospitalizations deaths. Clinical Trials Registration. ClinicalTrials.gov identifier: NCT 04518410.

Язык: Английский

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Clinical Trial Diversity, Equity, and Inclusion: Roadmap of the Cardiothoracic Surgical Trials Network

The Annals of Thoracic Surgery, Год журнала: 2024, Номер unknown

Опубликована: Март 1, 2024

Язык: Английский

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An ankyrin repeat chaperone targets toxic oligomers during amyloidogenesis

Protein Science, Год журнала: 2023, Номер 32(8)

Опубликована: Июль 11, 2023

Numerous age-linked diseases are rooted in protein misfolding; this has motivated the development of small molecules and therapeutic antibodies that target aggregation disease-linked proteins. Here we explore another approach: molecular chaperones with engineerable scaffolds such as ankyrin repeat domain (ARD). We tested ability cpSRP43, a small, robust, ATP- cofactor-independent plant chaperone built from an ARD, to antagonize aggregation. cpSRP43 delays multiple proteins including amyloid beta peptide (Aβ) associated Alzheimer's disease α-synuclein Parkinson's disease. Kinetic modeling biochemical analyses show targets early oligomers during Aβ aggregation, preventing their transition self-propagating nucleus on fibril surface. Accordingly, rescued neuronal cells toxicity extracellular Aβ42 aggregates. The substrate-binding composed primarily is necessary sufficient prevent protect against toxicity. This work provides example which ARD non-native mammalian harbors anti-amyloidal activity, may be exploited for bioengineering.

Язык: Английский

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Clinical development of antivirals against SARS-CoV-2 and its variants

Current Research in Microbial Sciences, Год журнала: 2023, Номер 6, С. 100208 - 100208

Опубликована: Дек. 3, 2023

The unceasing global spread of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) calls for the development novel therapeutics. Although many newly developed antivirals and repurposed have been applied to treatment disease 2019 (COVID-19), showing satisfactory clinical efficacy are few in number. In addition, loss sensitivity variants concern (VOCs) lack oral bioavailability also limited application some antivirals. These facts remind us develop more potent broad-spectrum with better pharmacokinetic/pharmacodynamic properties fight against infections from SARS-CoV-2, its variants, other human coronaviruses (HCoVs). this review, we summarize latest advancements by SARS-CoV-2 variants.

Язык: Английский

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The Designed Ankyrin Repeat Protein Antiviral Ensovibep for Nonhospitalized Patients With Coronavirus Disease 2019: Results From EMPATHY, a Randomized, Placebo-Controlled Phase 2 Study

Open Forum Infectious Diseases, Год журнала: 2024, Номер 11(6)

Опубликована: Май 3, 2024

Abstract Background The coronavirus disease 2019 (COVID-19) pandemic was characterized by rapid evolution of severe acute respiratory syndrome 2 (SARS-CoV-2) variants, affecting viral transmissibility, virulence, and response to vaccines/therapeutics. EMPATHY (NCT04828161), a phase study, investigated the safety/efficacy ensovibep, multispecific designed ankyrin repeat protein (DARPin) with multivariant in vitro activity, ambulatory patients mild moderate COVID-19. Methods Nonhospitalized, symptomatic (N = 407) COVID-19 were randomized receive single-dose intravenous ensovibep (75, 225, or 600 mg) placebo followed until day 91. primary endpoint time-weighted change from baseline log10 SARS-CoV-2 load through 8. Secondary endpoints included proportion COVID-19–related hospitalizations, emergency room (ER) visits, and/or all-cause mortality 29; time sustained clinical recovery safety Results Ensovibep showed superiority versus reducing load; treatment differences −0.42 (P .002), −0.33 .014), −0.59 < .001) for 75, mg, respectively. Ensovibep-treated had fewer ER (relative risk reduction: 78% [95% confidence interval, 16%–95%]) shorter median than placebo. Treatment-emergent adverse events occurred 44.3% 54.0% arms; grade 3 consistent morbidity. Two deaths reported none ensovibep. Conclusions All doses antiviral efficacy benefits an acceptable profile nonhospitalized

Язык: Английский

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Adverse drug reactions associated with COVID-19 management

Naunyn-Schmiedeberg s Archives of Pharmacology, Год журнала: 2024, Номер 397(10), С. 7353 - 7376

Опубликована: Май 14, 2024

Язык: Английский

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Design of targeted antiviral polypeptides specific to SARS-CoV-2. Challenges and prospects

Russian Chemical Reviews, Год журнала: 2024, Номер 93(6), С. RCR5128 - RCR5128

Опубликована: Июнь 1, 2024

The COVID-19 epidemic demanded the rapid development of high-affinity molecules different types aimed at a single target, S-protein SARS-CoV-2. simultaneous and testing such provide unique opportunity to compare features biotechnological platforms for creating therapeutic proteins. This review considers classical antibodies, variable lymphocyte receptors, single-domain artificial scaffolds (DARPins, affibodies, VH), that are compared in terms affinity, neutralizing activity, size compatibility with delivery methods. It can be concluded all used have produced proteins specifically bind coronavirus S-protein. highest affinity targeting virus protein was achieved by developing nanobodies combining several binding modules into multivalent constructs high avidity. Based on results <i>in vivo</i> experiments, it surface antigens SARS-CoV-2 is necessary but not sufficient condition suppression due peculiarities biology this virus. experience gained agents against will useful design effective targeted drugs treatment known new viral infections.<br>The bibliography includes 126 references.

Язык: Английский

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Lessons Learned from National Heart, Lung, and Blood Institute Covid-19 Clinical Trials

NEJM Evidence, Год журнала: 2024, Номер 3(11)

Опубликована: Окт. 22, 2024

In response to the Covid-19 pandemic, National Heart, Lung, and Blood Institute launched five multisite clinical trials testing candidate host tissue–directed medical interventions hasten recovery, improve function, reduce morbidity mortality. Speed, flexibility, collaboration were essential. This article from Steering Executive committees describes Collaborating Network of Networks for Evaluating Therapeutic Strategies (CONNECTS) research program that enrolled 6690 participants evaluated 18 intervention strategies using 10 molecular agents across care continuum (outpatient, inpatient, post discharge), reports lessons learned this initiative. Successes include rapid trial execution through adaptive platform designs. Challenges impeded efficiency included time required execute subcontracts, constraints on workforce, limited infrastructure in nonacademic settings.

Язык: Английский

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Efficacy and Safety of Ensovibep for Adults Hospitalized With COVID-19

Annals of Internal Medicine, Год журнала: 2023, Номер 176(2)

Опубликована: Фев. 1, 2023

LettersFebruary 2023Efficacy and Safety of Ensovibep for Adults Hospitalized With COVID-19FREETeluguakula Narasaraju, PhD, Amita Krishnappa, MD, Marko Radic, Vincent T.K. Chow, PhDTeluguakula PhDAdichunchanagiri Institute Medical Sciences, Karnataka, India, MDAdichunchanagiri PhDUniversity Tennessee Health Science Center, Memphis, Tennessee, PhDNational University Singapore, Kent Ridge, SingaporeAuthor, Article, Disclosure Informationhttps://doi.org/10.7326/L22-0455 SectionsAboutVisual AbstractPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissions ShareFacebookTwitterLinkedInRedditEmail TO THE EDITOR: The ACTIV-3/TICO (Accelerating COVID-19 Therapeutic Interventions Vaccines/Therapeutics Inpatients with COVID-19) Study Group (1) analyzed the efficacy safety ensovibep. This designed ankyrin repeat protein inhibits interaction SARS-CoV-2 spike its host receptor, angiotensin-converting enzyme 2. randomized controlled trial was a follow-up earlier studies that showed antiviral activity ensovibep in hamster model as well reduced hospitalizations improved clinical outcomes outpatients mild moderate COVID-19. In contrast those findings, administration severely ill patients hospitalized did not exhibit any protection. prematurely discontinued because it failed early futility assessment could establish power primary outcome study design has several shortcomings.First, this proof concept ensovibep.Second, randomly assigning blinding participants provide an unbiased approach; however, 7 ordinal pulmonary or pulmonary-plus scales used are unlikely direct correlation signatures specific ensovibep-mediated effects, including lung viral loads virus-inflicted alveolar–epithelial cytopathic injury.Third, combining remdesivir treatment regimen is beneficial effects.Finally, lack realistic data on replication kinetics at onset raises questions about rationale trial. Several trials evaluated combinations monoclonal antibodies (for example, tixagevimab–cilgavimab sotrovimab BRII-196 plus BRII-198) basis similarly yielded inconsistent findings fell short proving their these (2, 3).When drugs targeting virus entry lungs evaluated, inclusion additional criteria support essential. Viral titers nasopharyngeal oropharyngeal samples unfortunately do correlate deeper lungs, use invasive methods collect may be possible Instead, measuring plasma RNA better indicator determine effects (4). addition, markers alveolar epithelial injury such podoplanin (a marker type I epithelium) surfactant C II (5) sputum represent alveolitis lungs. As such, evaluating pathophysiology must substantiated by more prudent relevant drug target–specific signatures.References1. Group. Efficacy adults A Ann Intern Med. 2022;175:1266-74. [PMID: 35939810] doi:10.7326/M22-1503 LinkGoogle Scholar2. ACTIV-3-Therapeutics (TICO) Tixagevimab–cilgavimab hospitalised COVID-19: randomised, double-blind, phase 3 Lancet Respir 2022;10:972-84. 35817072] doi:10.1016/S2213-2600(22)00215-6 CrossrefMedlineGoogle Scholar3. ACTIV-3/Therapeutics two neutralising antibody therapies, BRII-198, (TICO): randomised Infect Dis. 2022;22:622-35. 34953520] doi:10.1016/S1473-3099(21)00751-9 Scholar4. Jacobs JL, Bain W, Naqvi A, et al. Severe acute respiratory syndrome coronavirus 2 viremia associated disease 2019 severity predicts outcomes. Clin 2022;74:1525-33. 34374761] doi:10.1093/cid/ciab686 Scholar5. Ashar HK, Pulavendran S, Rudd JM, Administration CXC chemokine receptor (CXCR2) antagonist, SCH527123, together oseltamivir suppresses NETosis protects mice from lethal influenza piglets swine-influenza infection. Am J Pathol. 2021;191:669-85. 33453177] doi:10.1016/j.ajpath.2020.12.013 Scholar Comments0 CommentsSign Submit Comment Author, InformationAffiliations: Adichunchanagiri IndiaUniversity TennesseeNational SingaporeDisclosures: Authors have reported no disclosures interest. Forms can viewed www.acponline.org/authors/icmje/ConflictOfInterestForms.do?msNum=L22-0455. PreviousarticleNextarticle Advertisement FiguresReferencesRelatedDetailsSee AlsoEfficacy COVID-19Efficacy Eleftherios Mylonakis , Christina Barkauskas Garyfallia Poulakou Barnaby E. Young Metrics Current IssueFebruary 2023Volume 176, Issue 2KeywordsCOVID-19Clinical trialsCritical careData monitoring boardsHealth statisticsHospital medicineHospitalizationsInfectious diseasesSafetyVeteran care ePublished: 21 February 2023 Published: Copyright & PermissionsCopyright © American College Physicians. All Rights Reserved.PDF downloadLoading ...

Язык: Английский

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Transport of Designed Ankyrin Repeat Proteins through reconstituted human bronchial epithelia and protection against SARS-CoV-2

Scientific Reports, Год журнала: 2023, Номер 13(1)

Опубликована: Апрель 4, 2023

Abstract Clinical studies have proven antiviral effectiveness of treatment with a Designed Ankyrin Repeat Protein (DARPin) specific against the spike protein severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2). More information on transport mechanisms and efficiency to site action is desirable. Transepithelial migration through air–liquid interface (ALI) cultures reconstituted human bronchial epithelia (HBE) was assessed by Enzyme-Linked Immunosorbent Assays Confocal Laser Scanning Microscopy for different DARPin designs in comparison monoclonal antibody. Antiviral efficacy authentic SARS-CoV-2, applied apically HBE, investigated based viral titers genome equivalents, after administration therapeutic candidates basal side. translocation all antibody efficient dose dependent. Small DARPins migrated more efficiently than larger molecules, indicating involved. Microscopic analyses support this, demonstrating passive paracellular smaller transcellular molecules. All side HBE conferred effective protection SARS-CoV-2 infection. In summary, we shown that translocate across intact airway confer infection replication.

Язык: Английский

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