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. METHODS: This was a randomised, double-blind, placebo-controlled trial done in the USA, Romania, and Moldova in 2020-2021, before the emergence of omicron (B.1.1.529) and omicron-lineage variants. Uninfected and unvaccinated household contacts of infected individuals, judged by the investigator to be in good health, were randomly assigned (1:1) to receive 1200 mg CAS + IMD or placebo by subcutaneous injection according to a central randomisation scheme provided by an interactive web response system; randomisation was stratified per site by the test results of a local diagnostic assay for SARS-CoV-2 and age group at baseline. COVID-19 vaccines were prohibited before randomisation, but participants were allowed to receive COVID-19 vaccination during the follow-up period. Participants who developed COVID-19 symptoms during the follow-up period underwent RT-PCR testing. Prespecified endpoints included the proportion of previously uninfected and baseline-seronegative participants (seronegative-modified full analysis set) who had RT-PCR-confirmed COVID-19 in the follow-up period (post-hoc for the timepoints of months 2-5 and 6-8 only) and underwent seroconversion (ie, became seropositive, considered a proxy for any SARS-CoV-2 infections [symptomatic and asymptomatic]; prespecified up to day 57, post-hoc for all timepoints thereafter). We also assessed the incidence of treatment-emergent adverse events. This study is registered with ClinicalTrials.gov, NCT04452318. FINDINGS: From July 13, 2020, to Oct 4, 2021, 2317 participants who were RT-PCR-negative for SARS-CoV-2 were randomly assigned, of whom 1683 (841 assigned to CAS + IMD and 842 assigned to placebo) were seronegative at baseline. During the entirety of the 8-month study, CAS + IMD reduced the risk of COVID-19 by 81·2% (nominal p<0·0001) versus placebo (prespecified analysis). During the 7-month follow-up period, protection was greatest during months 2-5, with a 100% relative risk reduction in COVID-19 (nominal p<0·0001; post-hoc analysis). Efficacy waned during months 6-8 (post-hoc analysis). Seroconversion occurred in 38 (4·5%) of 841 participants in the CAS + IMD group and in 181 (21·5%) of 842 in the placebo group during the 8-month study (79·0% relative risk reduction vs placebo; nominal p<0·0001). Six participants in the placebo group were hospitalised due to COVID-19 versus none who received CAS + IMD. Serious treatment-emergent adverse events (including COVID-19) were reported in 24 (1·7%) of 1439 participants receiving CAS + IMD and in 23 (1·6%) of 1428 receiving placebo. Five deaths were reported, none of which were due to COVID-19 or related to the study drugs. INTERPRETATION: CAS + IMD is not authorised in any US region as of Jan 24, 2022, because data show that CAS + IMD is not active against omicron-lineage variants. In this study, done before the emergence of omicron-lineage variants, a single subcutaneous 1200 mg dose of CAS + IMD protected against COVID-19 for up to 5 months of community exposure to susceptible strains of SARS-CoV-2 in the pre-exposure prophylaxis setting, in addition to the post-exposure prophylaxis setting that was previously shown. FUNDING: Regeneron Pharmaceuticals, F Hoffmann-La Roche, US National Institute of Allergy and Infectious Diseases, US National Institutes of Health.

The IQ-CSRC prospective clinical Phase 1 study: "Can early QT assessment using exposure response analysis replace the thorough QT study?".

A collaboration between the Consortium for Innovation and Quality in Pharmaceutical Development and the Cardiac Safety Research Consortium has been formed to design a clinical study in healthy subjects demonstrating that the thorough QT (TQT) study can be replaced by robust ECG monitoring and exposure-response (ER) analysis of data generated from First-in-Man single ascending dose (SAD) studies. Six marketed drugs with well-characterized QTc effects were identified in discussions with FDA; five have caused QT prolongation above the threshold of regulatory concern. Twenty healthy subjects will be enrolled in a randomized, placebo-controlled study designed with the intent to have similar power to exclude small QTc effects as a SAD study. Two doses (low and high) of each drug will be given on separate, consecutive days to 9 subjects. Six subjects will receive placebo. Data will be analyzed using linear mixed-effects ER models. Criteria for QT-positive drugs will be the demonstration of an upper bound (UB) of the 2-sided 90% confidence interval (CI) of the projected QTc effect at the peak plasma level of the lower dose above the threshold of regulatory concern (currently 10 ms) and a positive slope of ER relationship. The criterion for QT-negative drug will be an UB of the CI of the projected QTc effect of the higher dose <10 ms. It is expected that a successful outcome in this study will provide evidence supporting replacement of the TQT study with ECG assessments in standard early clinical development studies for a new chemical entity.

Serum proprotein convertase subtilisin kexin type 9 is correlated directly with serum LDL cholesterol.

BACKGROUND: Proprotein convertase subtilisin kexin type 9 (PCSK9) is gaining attention as a key regulator of serum LDL-cholesterol (LDLC). This novel serine protease causes the degradation of hepatic LDL receptors by an unknown mechanism. In humans, gain-of-function mutations in the PCSK9 gene cause a form of familial hypercholesterolemia, whereas loss-of-function mutations result in significantly decreased LDLC and decreased cardiovascular risk. Relatively little is known about PCSK9 in human serum. METHODS: We used recombinant human PCSK9 protein and 2 different anti-PCSK9 monoclonal antibodies to build a sandwich ELISA. We measured PCSK9 and lipids in 55 human serum samples and correlated the results. We used the anti-PCSK9 antibodies to assay lipoprotein particle fractions separated by sequential flotation ultracentrifugation. RESULTS: Serum concentrations of PCSK9 ranged from 11 to 115 microg/L and were directly correlated with serum concentrations of LDLC (r = 0.45, P = 0.001) and total cholesterol (r = 0.50, P = 0.0003), but not with triglycerides (r = 0.15, P = 0.28) or HDL cholesterol concentrations (r = 0.13, P = 0.36). PCSK9 was not detectable in any lipoprotein particle fraction, including LDL. CONCLUSIONS: PCSK9 is present in human serum, likely not associated with specific lipoprotein particles. The circulating concentrations of human PCSK9 are directly correlated with LDL and total cholesterol concentrations.