Publications by authors named "Bret Musser"
Article Synopsis
- The study investigates how antiviral monoclonal antibodies (mAbs), particularly casirivimab and imdevimab (CAS+IMD), affect immune responses when individuals are vaccinated against SARS-CoV-2 after receiving mAb treatment.
- It was found that the presence of CAS+IMD during vaccination reduced the effectiveness of the vaccine in generating neutralizing antibodies, though other immune responses remained intact.
- This reduction in antibody production is linked to "epitope masking," but can be reversed with booster shots, and influences the immune response differently in those who had not yet begun their natural immunity when treated with mAbs.
Article Synopsis
- Fibrodysplasia ossificans progressiva (FOP) is a rare condition where bones form in soft tissue, referred to as heterotopic ossification (HO), and this study examined imaging methods to identify and measure new HO lesions.
- The research analyzed data from a phase 2 clinical trial comparing the effectiveness of garetosmab (a therapy) with a placebo in adults with FOP, utilizing both PET/CT and CT scans to detect lesions over 28 weeks.
- Results showed that both PET/CT and CT-only methods detected a similar number and volume of new lesions, indicating that CT-only imaging is an effective alternative for monitoring HO changes in FOP patients.
Article Synopsis
- Passive administration of the monoclonal antibody cocktail CAS + IMD showed positive clinical outcomes in hospitalized COVID-19 patients, particularly those who were seronegative at the start of treatment.
- The study involved 46 patients and used advanced immunoprofiling techniques to assess how the antibody treatment influenced immune responses over time, from October 2020 to April 2021.
- Results indicated that CAS + IMD not only reduced acute inflammation but also enhanced recovery without harming the host's T cell immune response, suggesting a beneficial anti-inflammatory effect that needs further exploration.
Heart failure is a leading cause of morbidity and mortality. Elevated intracardiac pressures and myocyte stretch in heart failure trigger the release of counter-regulatory natriuretic peptides, which act through their receptor (NPR1) to affect vasodilation, diuresis and natriuresis, lowering venous pressures and relieving venous congestion. Recombinant natriuretic peptide infusions were developed to treat heart failure but have been limited by a short duration of effect.
View Article and Find Full Text PDFBackground: Deeper insight is needed on how monoclonal antibodies (mAbs) affect vaccine-mediated immune responses when targeting the same protein. We describe the first prospective randomised trial designed to understand mAb-mediated alterations in vaccine-induced immune responses to SARS-CoV-2 spike protein epitopes.
Methods: This randomised, open-label, parallel-group study assessed the potential interaction of a mAb combination, casirivimab and imdevimab, with a vaccine, Moderna's mRNA-1273, in healthy SARS-CoV-2 immunologically naive, seronegative adults at six centres in the USA.
Background: Virologic determinants of seroconversion to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection were defined in a post hoc analysis of prospectively studied vaccine- and infection-naïve individuals at high risk for coronavirus disease 2019 (COVID-19).
Methods: This phase 3 COVID-19 prevention trial (NCT04452318) with casirivimab and imdevimab was conducted in July 2020-February 2021, before widespread vaccine availability. Placebo-treated participants who were uninfected (SARS-CoV-2 quantitative reverse transcription polymerase chain reaction [RT-qPCR] negative) and seronegative were assessed weekly for 28 days (efficacy assessment period [EAP]) for COVID-19 symptoms and SARS-CoV-2 infection by RT-qPCR of nasopharyngeal swab samples and for serostatus by antinucleocapsid immunoglobulin (Ig) G.
Deficiency in the adipose-derived hormone leptin or leptin receptor signaling causes class 3 obesity in individuals with genetic loss-of-function mutations in leptin or its receptor LEPR and metabolic and liver disease in individuals with hypoleptinemia secondary to lipoatrophy such as in individuals with generalized lipodystrophy. Therapies that restore leptin-LEPR signaling may resolve these metabolic sequelae. We developed a fully human monoclonal antibody (mAb), REGN4461 (mibavademab), that activates the human LEPR in the absence or presence of leptin.
View Article and Find Full Text PDFArticle Synopsis
- - Fibrodysplasia ossificans progressiva (FOP) is a rare condition that causes painful heterotopic ossification in connective tissues, leading to disability.
- - In the LUMINA-1 phase 2 trial, adults with FOP were given either garetosmab (an activin A-blocking antibody) or a placebo over two 28-week periods, focusing on safety and effects on HO lesions.
- - Although the primary efficacy endpoint was not met in the first period, garetosmab significantly reduced the development of new HO lesions in the second period compared to placebo, with ongoing investigations into its effectiveness.
Severe, protracted symptoms are associated with poor outcomes in severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. In a placebo-controlled study of casirivimab and imdevimab (CAS + IMD) in persons at high risk of severe coronavirus disease 2019 (COVID-19; n = 3816), evolution of individual symptoms was assessed for resolution patterns across risk factors, and baseline SARS-CoV-2-specific antibody responses against S1 and N domains. CAS + IMD versus placebo provided statistically significant resolution for 17/23 symptoms, with greater response linked to absence of endogenous anti-SARS-CoV-2 immunoglobulin (Ig)G, IgA, or specific neutralizing antibodies at baseline, or high baseline viral load.
View Article and Find Full Text PDFBackground: Atopic march refers to the sequential development of allergic diseases from infancy through adolescence, typically beginning with atopic dermatitis (AD), followed by food allergy and then airway diseases, later evolving to broader or worsened spectrum of allergic diatheses. No intervention has shown to alter its course.
Objective: We sought to determine the rate of acquisition of new or worsened allergic events for dupilumab versus placebo in patients with AD.
Importance: The monoclonal antibody combination of casirivimab and imdevimab reduced viral load, hospitalization, or death when administered as a 1200-mg or greater intravenous (IV) dose in a phase 3 COVID-19 outpatient study. Subcutaneous (SC) and/or lower IV doses should increase accessibility and/or drug supplies for patients.
Objective: To assess the virologic efficacy of casirivimab and imdevimab across different IV and SC doses compared with placebo.
Background: There is an unmet need for COVID-19 prevention in patient populations who have not mounted or are not expected to mount an adequate immune response to complete COVID-19 vaccination. We previously reported that a single subcutaneous 1200 mg dose of the monoclonal antibody combination casirivimab and imdevimab (CAS + IMD) prevented symptomatic SARS-CoV-2 infections by 81·4% in generally healthy household contacts of SARS-CoV-2-infected individuals over a 1-month efficacy assessment period. Here we present additional results, including the 7-month follow-up period (months 2-8), providing additional insights about the potential for efficacy in pre-exposure prophylaxis settings.
View Article and Find Full Text PDFObjectives: A phase 1, double-blind, placebo-controlled trial was conducted to evaluate the safety, tolerability, and exploratory efficacy of repeat monthly doses of subcutaneous (SC) casirivimab and imdevimab (CAS+IMD) in uninfected adult volunteers.
Methods: Participants were randomized (3:1) to SC CAS+IMD 1200 mg or placebo every 4 weeks for up to six doses. Primary and secondary end points evaluated safety, pharmacokinetics, and immunogenicity.
Background: Open-label platform trials and a prospective meta-analysis suggest efficacy of anti-interleukin (IL)-6R therapies in hospitalized patients with coronavirus disease 2019 (COVID-19) receiving corticosteroids. This study evaluated the efficacy and safety of sarilumab, an anti-IL-6R monoclonal antibody, in the treatment of hospitalized patients with COVID-19.
Methods: In this adaptive, phase 2/3, randomized, double-blind, placebo-controlled trial, adults hospitalized with COVID-19 received intravenous sarilumab 400 mg or placebo.
Article Synopsis
- The study aimed to assess the effectiveness of a combination treatment of casirivimab and imdevimab in preventing the development of symptomatic COVID-19 from early asymptomatic SARS-CoV-2 infections.
- Conducted as a phase 3 trial with 314 participants who were close contacts of infected individuals, this randomized, double-blind study compared the treatment group to a placebo group.
- Results showed that the treatment significantly reduced the progression to symptomatic disease, with 29% of treated participants developing symptoms compared to 42% in the placebo group, indicating a promising avenue for treating asymptomatic infections.
Article Synopsis
- In the REGEN-COV adaptive trial, a combination of monoclonal antibodies significantly reduced both viral load and hospital visits in COVID-19 patients compared to a placebo.
- In the phase 3 trial, outpatients with COVID-19 received either REGEN-COV or placebo, leading to a substantial decrease in hospitalization or death rates (1.3% in the 2400-mg group vs. 4.6% in placebo).
- The treatment also expedited symptom resolution by an average of 4 days and effectively reduced viral load more rapidly than the placebo across various patient subgroups.
Background: REGEN-COV (previously known as REGN-COV2), a combination of the monoclonal antibodies casirivimab and imdevimab, has been shown to markedly reduce the risk of hospitalization or death among high-risk persons with coronavirus disease 2019 (Covid-19). Whether subcutaneous REGEN-COV prevents severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and subsequent Covid-19 in persons at high risk for infection because of household exposure to a person with SARS-CoV-2 infection is unknown.
Methods: We randomly assigned, in a 1:1 ratio, participants (≥12 years of age) who were enrolled within 96 hours after a household contact received a diagnosis of SARS-CoV-2 infection to receive a total dose of 1200 mg of REGEN-COV or matching placebo administered by means of subcutaneous injection.
Background: Casirivimab and imdevimab (REGEN-COV™) markedly reduces risk of hospitalization or death in high-risk individuals with Covid-19. Here we explore the possibility that subcutaneous REGEN-COV prevents SARS-CoV-2 infection and subsequent Covid-19 in individuals at high risk of contracting SARS-CoV-2 by close exposure in a household with a documented SARS-CoV-2-infected individual.
Methods: Individuals ≥12 years were enrolled within 96 hours of a household contact being diagnosed with SARS-CoV-2 and randomized 1:1 to receive 1200 mg REGEN-COV or placebo via subcutaneous injection.
Importance: Easy-to-administer antiviral treatments may be used to prevent progression from asymptomatic infection to COVID-19 and to reduce viral carriage.
Objective: Evaluate the efficacy and safety of subcutaneous casirivimab and imdevimab antibody combination (REGEN-COV) to prevent progression from early asymptomatic SARS-CoV-2 infection to COVID-19.
Design: Randomized, double-blind, placebo-controlled, phase 3 study that enrolled asymptomatic close contacts living with a SARS-CoV-2-infected household member (index case).
Background: REGN3048 and REGN3051 are human monoclonal antibodies (mAb) targeting the spike glycoprotein on the Middle East respiratory syndrome coronavirus (MERS-CoV), which binds to the receptor dipeptidyl peptidase-4 (DPP4) and is necessary for infection of susceptible cells.
Methods: Preclinical study: REGN3048, REGN3051 and isotype immunoglobulin G (IgG) were administered to humanized DPP4 (huDPP4) mice 1 day prior to and 1 day after infection with MERS-CoV (Jordan strain). Virus titers and lung pathology were assessed.
Background: Recent data suggest that complications and death from coronavirus disease 2019 (Covid-19) may be related to high viral loads.
Methods: In this ongoing, double-blind, phase 1-3 trial involving nonhospitalized patients with Covid-19, we investigated two fully human, neutralizing monoclonal antibodies against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike protein, used in a combined cocktail (REGN-COV2) to reduce the risk of the emergence of treatment-resistant mutant virus. Patients were randomly assigned (1:1:1) to receive placebo, 2.
An urgent global quest for effective therapies to prevent and treat coronavirus disease 2019 (COVID-19) is ongoing. We previously described REGN-COV2, a cocktail of two potent neutralizing antibodies (REGN10987 and REGN10933) that targets nonoverlapping epitopes on the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike protein. In this report, we evaluate the in vivo efficacy of this antibody cocktail in both rhesus macaques, which may model mild disease, and golden hamsters, which may model more severe disease.
View Article and Find Full Text PDFThis double-blind, randomized crossover study assessed the effect of acetaminophen (1000 mg every 8 hours) versus indomethacin (50 mg every 8 hours) versus placebo on cyclooxygenase enzymes (COX-1 and COX-2). Urinary excretion of 2,3-dinor-6-keto-PGF1α, (prostacyclin metabolite, PGI-M; COX-2 inhibition) and 11-dehydro thromboxane B2 (thromboxane metabolite, Tx-M; COX-1 inhibition) were measured after 1 dose and 5 days of dosing. Peak inhibition of urinary metabolite excretion across 8 hours following dosing was the primary end point.
View Article and Find Full Text PDFBackground: This study investigated a framework that leverages the relationship between biomarkers and a target clinical endpoint to optimize an early development plan.
Methods: Different biomarker designs were assessed for proof of concept (PoC) and dose finding (DF) to improve phase 2b (Ph2b) design as well as phase 3 (Ph3) dose choice. A case study using a Bayesian trivariate normal distribution model for 2 biomarkers and a clinically relevant endpoint was utilized with simulation to assess performance characteristics.