Agonist antibody to guanylate cyclase receptor NPR1 regulates vascular tone.

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.

Effect of timing of casirivimab and imdevimab administration relative to mRNA-1273 COVID-19 vaccination on vaccine-induced SARS-CoV-2 neutralising antibody responses: a prospective, open-label, phase 2, randomised controlled trial.

Background: 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.

Differential modulation of allergic rhinitis nasal transcriptome by dupilumab and allergy immunotherapy.

Background: Nasal epithelial cells are important regulators of barrier function and immune signaling; however, in allergic rhinitis (AR) these functions can be disrupted by inflammatory mediators. We aimed to better discern AR disease mechanisms using transcriptome data from nasal brushing samples from individuals with and without AR.

Methods: Data were drawn from a feasibility study of individuals with and without AR to Timothy grass and from a clinical trial evaluating 16 weeks of treatment with the following: dupilumab, a monoclonal antibody that binds interleukin (IL)-4Rα and inhibits type 2 inflammation by blocking signaling of both IL-4/IL-13; subcutaneous immunotherapy with Timothy grass (SCIT), which inhibits allergic responses through pleiotropic effects; SCIT + dupilumab; or placebo.

Nasopharyngeal Viral Load Is the Major Driver of Incident Antibody Immune Response to SARS-CoV-2 Infection.

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.

Preclinical, randomized phase 1, and compassionate use evaluation of REGN4461, a leptin receptor agonist antibody for leptin deficiency.

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.

A Prospective Study of Key Correlates for Household Transmission of Severe Acute Respiratory Syndrome Coronavirus 2.

Background: Randomized controlled trials evaluated monoclonal antibodies for the treatment (Study 2067) and prevention (Study 2069) of coronavirus disease 2019 (COVID-19). Household contacts of the infected index case in Study 2067 were enrolled in Study 2069 and prospectively followed; these cohorts provided a unique opportunity to evaluate correlates of transmission, specifically viral load.

Methods: This post hoc analysis was designed to identify and evaluate correlates of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) transmission, adjusting for potential confounding factors related to source SARS-CoV-2 viral load and risk of SARS-CoV-2 acquisition in this population.

Examining protective effects of SARS-CoV-2 neutralizing antibodies after vaccination or monoclonal antibody administration.

While new vaccines for SARS-CoV-2 are authorized based on neutralizing antibody (nAb) titer against emerging variants of concern, an analogous pathway does not exist for preventative monoclonal antibodies. In this work, nAb titers were assessed as correlates of protection against COVID-19 in the casirivimab + imdevimab monoclonal antibody (mAb) prevention trial (ClinicalTrials.gov #NCT4452318) and in the mRNA-1273 vaccine trial (ClinicalTrials.

Effectiveness of Casirivimab and Imdevimab Antibody Combination in Immunocompromised Hospitalized Patients With Coronavirus Disease 2019: A Post Hoc Analysis in a Phase 1/2/3 Double-Blind Trial.

Background: Individuals who are immunocompromised (IC) are at high risk for severe coronavirus disease 2019 (COVID-19).

Methods: Post hoc analyses of a double-blind trial conducted prior to Omicron (June 2020-April 2021), in hospitalized patients with COVID-19 assessed viral load, clinical outcomes, and safety of casirivimab plus imdevimab (CAS + IMD) versus placebo in IC versus overall study patients.

Results: Ninety-nine of 1940 (5.

Casirivimab and Imdevimab Treatment Reduces Viral Load and Improves Clinical Outcomes in Seropositive Hospitalized COVID-19 Patients with Nonneutralizing or Borderline Neutralizing Antibodies.

We conducted a analysis in seropositive patients who were negative or borderline for functional neutralizing antibodies (NAbs) against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) at baseline from a phase 1, 2, and 3 trial of casirivimab and imdevimab (CAS+IMD) treatment in hospitalized coronavirus disease 2019 (COVID-19) patients on low-flow or no supplemental oxygen prior to the emergence of Omicron-lineage variants. Patients were randomized to a single dose of 2.4 g CAS+IMD, 8.

Virologic Efficacy of Casirivimab and Imdevimab COVID-19 Antibody Combination in Outpatients With SARS-CoV-2 Infection: A Phase 2 Dose-Ranging Randomized Clinical Trial.

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.

REGN1908/1909 prevented cat allergen-induced early asthmatic responses in an environmental exposure unit.

Background: The dominant allergen in cat dander, Felis domesticus allergen 1 (Fel d 1), is a persistent trigger for allergic rhinitis and asthma symptoms.

Objective: We evaluated the efficacy of Fel d 1 monoclonal antibodies (REGN1908/1909) in preventing cat allergen-induced early asthmatic responses (EARs) in cat-allergic patients with mild asthma.

Methods: Patients were randomized to single-dose REGN1908/1909 600 mg (n = 29) or placebo (n = 27).

Casirivimab and Imdevimab for the Treatment of Hospitalized Patients With COVID-19.

Background: The open-label RECOVERY study reported improved survival in hospitalized, SARS-CoV-2 seronegative patients treated with casirivimab and imdevimab (CAS + IMD).

Methods: In this phase 1/2/3, double-blind, placebo-controlled trial conducted prior to widespread circulation of Delta and Omicron, hospitalized COVID-19 patients were randomized (1:1:1) to 2.4 g or 8.

Efficacy and safety of a single dose of casirivimab and imdevimab for the prevention of COVID-19 over an 8-month period: a randomised, double-blind, placebo-controlled trial.

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.

Repeat subcutaneous administration of casirivimab and imdevimab in adults is well-tolerated and prevents the occurrence of COVID-19.

Objectives: 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.

Efficacy and Safety of Sarilumab in Hospitalized Patients With Coronavirus Disease 2019: A Randomized Clinical Trial.

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.

Subcutaneous REGEN-COV Antibody Combination to Prevent Covid-19.

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.

The monoclonal antibody combination REGEN-COV protects against SARS-CoV-2 mutational escape in preclinical and human studies.

Monoclonal antibodies against SARS-CoV-2 are a clinically validated therapeutic option against COVID-19. Because rapidly emerging virus mutants are becoming the next major concern in the fight against the global pandemic, it is imperative that these therapeutic treatments provide coverage against circulating variants and do not contribute to development of treatment-induced emergent resistance. To this end, we investigated the sequence diversity of the spike protein and monitored emergence of virus variants in SARS-COV-2 isolates found in COVID-19 patients treated with the two-antibody combination REGEN-COV, as well as in preclinical in vitro studies using single, dual, or triple antibody combinations, and in hamster in vivo studies using REGEN-COV or single monoclonal antibody treatments.

Subcutaneous REGEN-COV Antibody Combination for Covid-19 Prevention.

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.