Effect of Bamlanivimab as Monotherapy or in Combination with Etesevimab or Sotrovimab on Persistently High Viral Load in Patients with Mild-to-Moderate COVID-19: A Randomized, Phase 2 BLAZE-4 Trial

Infectious Diseases and Therapy, Journal Year: 2024, Volume and Issue: 13(2), P. 401 - 411

Published: Jan. 30, 2024

Treatment with monoclonal antibodies provides rapid, passive immunity and may stop COVID-19 disease progression. The study evaluated the effect of bamlanivimab (BAM) or BAM + etesevimab (ETE)/sotrovimab compared to placebo on SARS-CoV-2 viral load in patients COVID-19. phase 2, randomized, single-dose included aged between ≥ 18 < 65 years, not hospitalized at time randomization, had 1 mild moderate symptoms. Study arms 1–6 (placebo, 175 mg ETE 350 mg, 700 1400 2800 alone, respectively), unintentional dosing; 7 8 (BAM sotrovimab 500 placebo, respectively). primary endpoint was proportion log > 5.27 day (persistently high [PHVL]) who received (ETE sotrovimab). A total 725 patients, mean age 39.6 years (range 18–75 years), 50.2% male were randomized infused drug 1–6; a 202 38 18–63 53.5% female 8. significantly lower 2–6 arm experienced PHVL placebo. On 7, 3, 6 consistently greater reduction than Significant improvement observed clearance symptom by 29 some No new safety concerns combinations. demonstrated that mild-to-moderate treated sotrovimab) 7. ClinicalTrials.gov identifier, NCT04634409.

Language: Английский

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Protective effect and molecular mechanisms of human non-neutralizing cross-reactive spike antibodies elicited by SARS-CoV-2 mRNA vaccination

Cell Reports, Journal Year: 2024, Volume and Issue: 43(11), P. 114922 - 114922

Published: Nov. 1, 2024

Neutralizing antibodies correlate with protection against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Recent studies, however, show that binding antibody titers, in the absence of robust neutralizing activity, also disease progression. Non-neutralizing cannot directly protect infection but may recruit effector cells and thus contribute to clearance infected cells. Additionally, they often bind conserved epitopes across multiple variants. Here, we characterize 42 human monoclonal (mAbs) from 2019 (COVID-19)-vaccinated individuals. Most these exhibit no activity vitro, several non-neutralizing provide lethal challenge SARS-CoV-2 different animal models. A subset those mAbs shows a clear dependence on Fc-mediated functions. We have determined structures three antibodies, two targeting receptor-binding domain one binds subdomain 1 region. Our data confirm real-world observation humans can be protective.

Language: Английский

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Safety and tolerability of intramuscular sotrovimab administered at different injection sites: results from the Phase 1 COSMIC study

mAbs, Journal Year: 2025, Volume and Issue: 17(1)

Published: Jan. 29, 2025

ClinicalTrials.gov identifier, NCT05280717.

Language: Английский

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Safety and Efficacy of Combined Tixagevimab and Cilgavimab Administered Intramuscularly or Intravenously in Nonhospitalized Patients With COVID-19

JAMA Network Open, Journal Year: 2023, Volume and Issue: 6(4), P. e2310039 - e2310039

Published: April 26, 2023

Development of effective, scalable therapeutics for SARS-CoV-2 is a priority.

Language: Английский

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Population pharmacokinetics and exposure‐response analysis of a single dose of sotrovimab in the early treatment of patients with mild to moderate COVID‐19

CPT Pharmacometrics & Systems Pharmacology, Journal Year: 2023, Volume and Issue: 12(6), P. 853 - 864

Published: March 16, 2023

Sotrovimab is a recombinant human monoclonal antibody that has been shown to prevent progression hospitalization or death in non-hospitalized high-risk patients with mild moderate coronavirus disease 2019 following either intravenous (i.v.) intramuscular (i.m.) administration. Population pharmacokinetic (PopPK) and exposure-response (ER) analyses were performed characterize single dose sotrovimab pharmacokinetics (PK) the relationship between exposure response (probability of progression), as well covariates may contribute between-participant variability PK efficacy i.v. i.m. was described by two-compartment model linear elimination; absorption characterized sigmoid model. PopPK covariate analysis led addition effect body weight on systemic clearance peripheral volume distribution, sex bioavailability first-order rate (KA), mass index KA. However, magnitude not pronounced therefore expected be clinically relevant based available data date. For ER analysis, measures predicted using final An developed measure concentration at 168 h probability within dataset for COMET-TAIL. The number risk factors (≤1 vs. >1) incorporated an additive shift model-estimated placebo but had no impact overall drug response. Limitations generalization these results describe exposure-progression across severe acute respiratory syndrome-coronavirus 2 variants.

Language: Английский

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Advancing research and development of anti-infectives for children with a focus on antiretroviral therapy: A clinical development perspective

International Journal of Antimicrobial Agents, Journal Year: 2024, Volume and Issue: 64(4), P. 107306 - 107306

Published: Aug. 13, 2024

The HIV treatment landscape for adults has progressed dramatically in recent decades; however, paediatric populations continue to experience delayed and limited access effective safe antiretroviral therapy options. Despite current incentive programmes, formulation research development approved drug dosing children have been limited, particularly neonates (aged <4 wk). Regulatory approval of formulations may lag behind adult approvals by years. Formulation trial design adjustments complicate development, all which are vital accommodate physiological differences, organ maturation, rapid weight gain, most significant the youngest children. To facilitate more anti-infective populations, regulatory agencies provide guidelines that include extrapolating efficacy safety data from relevant populations; using pharmacokinetic (PK) bridging modelling reduce sample sizes limit number PK studies needed before analyses; enrolling age- or weight-based cohorts parallel rather than sequentially clinical trials. Ensuring drugs poses an additional challenge, as uncertainty demand leads manufacturing supply complexity with potentially higher costs can be a barrier uptake. Here we summarise challenges living HIV, not unique antiretrovirals. We aim propose strategies how model-based approaches global partnerships overcome some these barriers accelerate particular reference lessons learnt could extended other anti-infectives.

Language: Английский

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Safety, Virology, Pharmacokinetics, and Clinical Experience of High-Dose Intravenous Sotrovimab for the Treatment of Mild to Moderate COVID-19: An Open-Label Clinical Trial

Open Forum Infectious Diseases, Journal Year: 2023, Volume and Issue: 10(7)

Published: July 1, 2023

Abstract Background Five hundred milligrams of intravenous (IV) sotrovimab has been shown to be well tolerated and efficacious against pre-Omicron strains in treating patients with mild moderate coronavirus disease 2019 (COVID-19) at high risk for progression. Methods This was an open-label, single-arm substudy phase 3 COMET-TAIL (NCT04913675) assessing the safety tolerability a 2000 mg IV dose sotrovimab. Symptomatic (aged ≥18 years) COVID-19 progression were enrolled from June 30 through July 11, 2022, when Omicron BA.5, BA.2.12.1, BA.4 predominant circulating variants United States. The primary end point occurrence adverse events (AEs), serious AEs (SAEs), special interest, disease-related (DREs) day 8. Safety, pharmacokinetics, viral load, hospitalization &gt;24 hours acute management illness or death 29 assessed. Results All participants (n = 81) Hispanic, 58% female, 51% aged ≥55 years. Through 8, no AEs, including infusion-related reactions hypersensitivity, reported; 2 reported DREs (mild cough, n 2). One SAE (acute myocardial infarction), which considered unrelated by investigator, occurred on 27 only reported. Maximum serum concentration (geometric mean) 745.9 µg/mL. Viral load decreased baseline 29; (3%) had persistently (≥4.1 log10 copies/mL) Conclusions Two thousand tolerated, signals observed. Trial registration ClinicalTrials.gov Identifier: NCT04913675.

Language: Английский

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Pharmacokinetics, Safety, and Tolerability of Anti-SARS-CoV-2 Monoclonal Antibody, Sotrovimab, Delivered Intravenously or Intramuscularly in Japanese and Caucasian Healthy Volunteers

Clinical Pharmacokinetics, Journal Year: 2023, Volume and Issue: 63(1), P. 57 - 68

Published: Nov. 13, 2023

Sotrovimab 500 mg administered by a single intravenous (IV) infusion has been granted special approval for emergency use in Japan treatment of SARS-CoV-2 infection adults and children aged ≥ 12 years weighing 40 kg. This Phase 1, single-dose study investigated the pharmacokinetics, safety, tolerability IV or intramuscular (IM) sotrovimab doses versus placebo healthy Japanese Caucasian volunteers. was two-part, randomized, placebo-controlled, single-blind study. In Part participants received matching on Day 1. 2, IM dose as two 4 mL injections. There no effect ethnicity peak total serum exposure through Week 18; after adjusting body weight, point estimate 90 % confidence interval ratio between fell within conventional bioavailability bounds (80–125%). Geometric mean Cmax AUClast following administration were higher compared with participants, even adjustment weight. Overall, well tolerated both participants. After exposures similar administration. Higher not associated any safety signals. ClinicalTrials.Gov: NCT04988152.

Language: Английский

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Adverse drug reactions associated with COVID-19 management

Naunyn-Schmiedeberg s Archives of Pharmacology, Journal Year: 2024, Volume and Issue: 397(10), P. 7353 - 7376

Published: May 14, 2024

Language: Английский

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Resistance analysis in the phase III COMET-TAIL study: treatment of COVID-19 with intramuscular or intravenous sotrovimab

Future Virology, Journal Year: 2024, Volume and Issue: 19(5), P. 185 - 198

Published: March 23, 2024

Aim: Sotrovimab, an engineered human monoclonal antibody, targets a conserved region of the SARS-CoV-2 spike protein. The phase III COMET-TAIL study evaluated noninferiority intravenous versus intramuscular sotrovimab for early treatment high-risk COVID-19 in 973 participants. Materials & methods: We investigated prevalence variants concern/interest (VOC/VOI) and characterized baseline, postbaseline treatment-emergent epitope amino acid substitutions. Results: Delta variant was predominant; Alpha, or Mu were detected participants meeting primary clinical endpoint progression. Of 82 with substitutions, two baseline substitutions met Conclusion: Overall, there no evidence that specific VOC/VOI, impacted

Language: Английский

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