A Randomized Placebo-Controlled Trial of Leronlimab in Mild-To-Moderate COVID-19

• Published in: Clinical therapeutics Vol. 46; no. 11; pp. 891 - 899
• Main Authors: Seethamraju, Harish, Yang, Otto O., Loftus, Richard, Ogbuagu, Onyema, Sammartino, Daniel, Mansour, Ali, Sacha, Jonah B., Ojha, Sohita, Hansen, Scott G., Arman, Arvin Cyrus, Lalezari, Jacob P.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.11.2024; Elsevier Limited
• Subjects: Adult; Aged; Antibodies; Antibodies, Monoclonal, Humanized - therapeutic use; CC chemokine receptors; Chemokines; Clinical outcomes; Clinical trials; Cough; COVID-19; COVID-19 Drug Treatment; Cytokines; Double-Blind Method; Dyspnea; Female; Humans; Immune response; Immune system; Immunity (Disease); Immunoglobulin G; Immunology; Immunomodulators; Infections; Internal Medicine; Kinases; Leronlimab; Ligands; Lymphocytes; Male; Medical treatment; Middle Aged; Monoclonal antibodies; Mortality; Myalgia; NEWS2; Pathophysiology; Placebo effect; Placebos; Randomized placebo-controlled trial; Replication; Respiration; Respiratory diseases; Respiratory distress syndrome; Respiratory failure; SARS-CoV-2; Severe acute respiratory syndrome coronavirus 2; Severity of Illness Index; Steroids; Treatment Outcome; Viral infections; PP; CRO; SAS; RANTES; RAS; CXCL13; IWRS; mITT; CXCL16; COVID-19; ANCOVA; NF-κB; SARS-CoV-2; NEWS2; MIP-1β; PI3K; CCL5; RT-PCR; CCL4; MIP-1α; CCL3; TGF-β; Randomized placebo-controlled trial; SMAD; CCR5; IFN-ƴ; BMI; CCL21; HIF; IL-1; JAK-STAT; MedDRA; Leronlimab; IgG4; AKT; IL-12; pVAT; Ang II; IL-6; ACE2; MEK; JAK; ERK; interleukin 12; extracellular signal-regulated kinase; Nuclear factor kappa-light-chain-enhancer of activated B cells; statistical analysis system; macrophage inflammatory proteins 1-alpha; interleukin 6; interleukin 1; Regulated on Activation, Normal T Expressed and Secreted; Janus kinase; interferon gamma; body mass index; chemokine C–C motif ligand 4; chemokine C–C motif ligand 5; chemokine C–C motif ligand 3; Immunoglobulin G4; Mitogen-activated ERK kinase; chemokine C-X-C motif ligand 13; corona virus disease caused by the SARS-CoV-2 virus; reverse transcriptase-polymerase chain reaction; interactive web-based response system; angiotensin II; analysis of covariance; phosphoinositide 3-kinase; Contract Research Organization; transforming growth factor beta; chemokine C–C motif ligand 21; Medical Dictionary for Regulatory Activities; chemokine C-X-C motif ligand 16; severe acute respiratory syndrome coronavirus 2; angiotensinogen converting enzyme 2; Janus kinase/signal transducers and activators of transcription; national early warning score 2; macrophage inflammatory proteins 1-beta; protein kinase B; perivascular adipose tissue; C-C chemokine receptor 5; suppressor of mothers against decapentaplegic; hypoxia-inducible factor; per-protocol; modified intention-to-treat; from “rat sarcoma virus”
• ISSN: 0149-2918; 1879-114X; 1879-114X
• DOI: 10.1016/j.clinthera.2024.08.019

•Leronlimab is an investigational CCR5-specific humanized IgG4 monoclonal antibody.•In COVID-19 leronlimab appears to have improved NEWS2 scores compared to placebo.•In COVID-19 leronlimab may be associated with fewer AEs compared to placebo. Early in the course of the SARS-CoV-2 pandemic it was hypothesised that host genetics played a role in the pathophysiology of COVID-19 including a suggestion that the CCR5-Δ32 mutation may be protective in SARS-CoV-2 infection. Leronlimab is an investigational CCR5-specific humanized IgG4 monoclonal antibody currently in development for HIV-1 infection. We aimed to explore the impact of leronlimab on the severity of disease symptoms among participants with mild-to-moderate COVID-19. The TEMPEST trial was a randomized, double-blind, placebo-controlled study in participants with mild-to-moderate COVID-19. Participants were randomly assigned in a 2:1 ratio to receive subcutaneous leronlimab (700 mg) or placebo on days 0 and 7. The primary efficacy endpoint was assessed by change in total symptom score based on fever, myalgia, dyspnea, and cough, at end of treatment (day 14). Overall, 84 participants were randomized and treated with leronlimab (n = 56) or placebo (n = 28). No difference was observed in change in total symptom score (P = 0.8184) or other pre-specified secondary endpoints between treatments. However, in a post hoc analysis, 50.0% of participants treated with leronlimab demonstrated improvements from baseline in National Early Warning Score 2 (NEWS2) at day 14, compared with 20·8% of participants in the placebo group (post hoc; p = 0.0223). Among participants in this trial with mild-to-moderate COVID-19 adverse events rates were numerically but not statistically significantly lower in leronlimab participants (33.9%) compared with placebo participants (50.0%). At the time the TEMPEST trial was designed although CCR5 was known to be implicated in COVID-19 disease severity the exact pathophysiology of SARS-CoV-2 infection was poorly understood. Today it is well accepted that SARS-CoV-2 infection in asymptomatic-to-mild cases is primarily characterized by viral replication, with a heightened immune response, accompanied by diminished viral replication in moderate-to-severe disease and a peak in inflammatory responses with excessive production of pro-inflammatory cytokines in critical disease. It is therefore perhaps not surprising that no differences between treatments were observed in the primary endpoint or in pre-specified secondary endpoints among participants with mild-to-moderate COVID-19. However, the results of the exploratory post hoc analysis showing that participants in the leronlimab group had greater improvement in NEWS2 assessment compared to placebo provided a suggestion that leronlimab may be associated with a lower likelihood of people with mild-to-moderate COVID-19 progressing to more severe disease and needs to be confirmed in other appropriately designed clinical trials. ClinicalTrials.gov number, NCT04343651 https://classic.clinicaltrials.gov/ct2/show/NCT04343651