key: cord-0761361-4da6gdyj
authors: Elneil, Sohier; Lalezari, Jacob P.; Pourhassan, Nader Z.
title: Case study of a critically ill person with COVID-19 on ECMO successfully treated with leronlimab
date: 2021-03-23
journal: J Transl Autoimmun
DOI: 10.1016/j.jtauto.2021.100097
sha: 74fc3e48ba3bd7389cbbcce0416e8ff09a61f619
doc_id: 761361
cord_uid: 4da6gdyj

The number of confirmed cases of infection with SARS-CoV-2, the virus causing Coronavirus disease 2019 (COVID-19), continues to increase and is associated with substantial morbidity and mortality in virtually every country in the world. Although in the long-term mass vaccinations remains the most promising approach to control the pandemic, evidence suggests that new variants of the virus have emerged that may be able to evade the immune responses triggered by current vaccines. Therefore despite the recent approval of a number of SARS-CoV-2 vaccines there remains considerable urgency for effective treatments for COVID-19. Severe-to-critical COVID-19 has been shown to be associated with a dysregulated host immune response to SARS-CoV-2 with elevated levels of C-C chemokine receptor type 5 (CCR5) ligands including chemokine C-C ligands 3, 4, 5, as well as interleukins 6 and 10. Leronlimab, a CCR5-specific humanised IgG4 monoclonal antibody originally developed for the treatment of HIV has been studied for the treatment of COVID-19. In the TEMPEST trial which compared leronlimab to placebo in subjects with mild-to-moderate COVID-19, a post hoc analysis showed that leronlimab led to improvements from baseline in National Early Warning Score 2 (NEWS2) at Day 14 in the sub-set of people with more severe disease. Data has also been released on a further ongoing, randomized, placebo-controlled phase 3 registrational trial of leronlimab in 394 people with severe-to-critical COVID-19. The results show that Day 28 mortality was reduced (P=0.0319) in the subset of participants receiving leronlimab plus other pre-specified commonly used COVID-19 treatments including dexamethasone administered as part of their standard of care (SOC) compared to participants receiving placebo plus other pre-specified commonly used COVID-19 treatments including dexamethasone as part of their SOC. Several cases have recently been reported demonstrated that treatment with leronlimab restores immune function and achieves clinical improvement in people with critical COVID-19. Here we report on a further case of a critically ill person who was treated with leronlimab. This person had been on extracorporeal membrane oxygenation (ECMO) for an extended period of time before receiving 4 doses of leronlimab. The male subject received his first dose of leronlimab on Day 79 of hospitalization he was weaned off ECMO by Day 84 and discharged from the ECMO intensive care unit on Day 91. He continues to improve and is currently in rehabilitation.

SARS-CoV-2 with elevated levels of C-C chemokine receptor type 5 (CCR5) ligands including chemokine C-C ligands 3, 4, 5, as well as interleukins 6 and 10. Leronlimab, a CCR5-specific humanised IgG4 monoclonal antibody originally developed for the treatment of HIV has been studied for the treatment of COVID-19. In the TEMPEST trial which compared leronlimab to placebo in subjects with mild-to-moderate COVID-19, a post hoc analysis showed that leronlimab led to improvements from baseline in National Early Warning Score 2 (NEWS2) at Day 14 in the sub-set of people with more severe disease. Data has also been released on a further ongoing, randomized, placebo-controlled phase 3 registrational trial of leronlimab in 394 people with severe-to-critical COVID-19. The results show that Day 28 mortality was reduced (P=0.0319) in the subset of participants receiving leronlimab plus other pre-specified commonly used COVID-19 treatments including dexamethasone administered as part of their standard of care (SOC) compared to participants receiving placebo plus other pre-specified commonly used COVID-19 treatments including dexamethasone as part of their SOC. Several Data suggest that a key factor in the pathogenesis of severe COVID-19 are pro-inflammatory cytokines and chemokines from activated macrophages, initially in the lungs but then systemically. [4, 5] Patients with severe-to-critical COVID-19 have been shown to have elevated levels of C-C chemokine receptor type 5 (CCR5) ligands including C-C ligand (CCL) 3 (or MIP-1α), CCL4 (or MIP-1 β), CCL5 (or RANTES), as well as interleukin (IL) 6 and IL-10. [6] [7] [8] [9] [10] Recently a genome-wide association study (GWAS) among people with severe COVID-19 has shown a strong association with genetic variants in the region on the short arm of chromosome 3 to which CCR5 maps. [11] There has also been an intriguing observation that people with the CCR5-Δ32 gene variant, which results in a non-functional CCR5 receptor, are less likely to suffer severe COVID-19. [12] J o u r n a l P r e -p r o o f Considering the apparent role of the chemokine receptor-ligand system in the morbidity and mortality associated with COVID-19 pharmaceutical approaches that target this system have been proposed as a promising approach to treatment. [13] Indeed recent reports from clinical trials with IL-6 receptor antagonists, tocilizumab and sarilumab have suggested these agents may provide some benefit in subjects with critical COVID-19. [14, 15] However, it should be cautioned that other reports have failed to show a benefit from the IL-6 receptor antagonist tocilizumab, and even suggested that addition of tocilizumab to standard of care (SOC) may have been associated with increase mortality. [16] Another drug in development for COVID-19 is leronlimab, a C-C chemokine receptor type 5 (CCR5)-specific humanised IgG4 monoclonal antibody originally developed for the treatment of HIV for which it has been shown to be effective and well tolerated. [17] [18] [19] The recently completed TEMPEST trial (NCT04343651) compared leronlimab to placebo in subjects with mild-to-moderate COVID-19. [20] Although the trial did not meet its primary efficacy endpoint, in a post hoc analysis in the subset of subjects with more severe disease a higher proportion of leronlimab-treated subjects (50%; 24/48) versus placebo-treated subjects (21%; 5/24) showed improvement in National Early Warning Score 2 (NEWS2) -a risk score for rapid clinical deterioration requiring critical care intervention (post hoc p=0.0223). Data has also been released on the CD12_COVID-19 trial (NCT04347239), which is an ongoing, randomized, No adverse safety issues were identified with the administration of leronlimab in this subject.

Oxygen therapy and intravenous antibiotics for ventilator-associated pneumonia were administered post weaning off ECMO. At last follow up the subject's condition continues to improve and he is undergoing rehabilitation.

Recent data suggest that severely dysregulated host immune responses to SAR-CoV-2, referred to as 'cytokine storm', may predominately mediate the morbidity and mortality of severe-tocritical COVID-19. [13, 22, 23] Cytokine storm primarily leads to lung inflammation causing acute respiratory distress syndrome (ARDS), but cytokine storm can also result in severe extrapulmonary manifestations, including thrombotic complications, myocardial dysfunction, and liver and kidney injury. [24] CCR5-expressing proinflammatory immune cells such as activated T-cells and macrophages are thought to play a key role in the cytokine storm response to COVID-19, suggesting that drug interventions that target the CCR5 system may represent a promising approach to treating COVID-19. [13] Leronlimab is a C-C chemokine receptor type 5 (CCR5)-specific humanised IgG4 monoclonal antibody. In a Phase 2, placebo-controlled, randomized clinical trial in subjects with mild-tomoderate COVID-19 leronlimab was shown to provide clinical benefit, primarily in subjects with more severe disease. A number of recent case series have demonstrated that treatment with leronlimab restores immune function and achieves clinical improvement in people with critical COVID-19. Taken together therapeutic interventions that target the chemokine receptor-ligand system may be an effective approach to treating COVID-19 because chemotaxis and trafficking J o u r n a l P r e -p r o o f of CCR5 expressing proinflammatory immune cells are thought to play an important role in this process. Importantly the long-term safety of leronlimab is already well established in the treatment of HIV. [17] [18] [19] This case is of particular interest because to the best of our knowledge this subject received ECMO for the longest period of any person in the United Kingdom with COVID-19 (66 days). He received his first dose of leronlimab on Days 79 after diagnosis and was successfully weaned off ECMO between Days 82 to 84 and discharged from the ECMO intensive care unit on Day 91.

Considering the length of time this subject was on ECMO and the speed of the subject's response to leronlimab we believe that this case adds critical insight to the growing body of evidence for leronlimab in treatment of critical COVID-19.

J o u r n a l P r e -p r o o f

Characteristics of and Important Lessons From the Coronavirus Disease 2019 (COVID-19) Outbreak in China: Summary of a Report of 72 314 Cases From the Chinese Center for Disease Control and Prevention

Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: a retrospective cohort study

Fast-spreading COVID variant can elude immune responses

Pathological inflammation in patients with COVID-19: a key role for monocytes and macrophages

Cytokine release syndrome in severe COVID-19

Disruption of CCR5 signaling to treat COVID-19-associated cytokine storm: case series of four critically ill patients treated with leronlimab

COVID-19 severity correlates with airway epithelium-immune cell interactions identified by single-cell analysis

Immune-Based Prediction of COVID-19 Severity and Chronicity Decoded Using Machine Learning

Disruption of the CCL5/RANTES-CCR5 Pathway Restores Immune Homeostasis and Reduces Plasma Viral Load in Critical COVID-19, medRxiv

Clinical Characteristics and Outcomes of COVID-19 Patients Receiving Compassionate Use Leronlimab

Genomewide Association Study of Severe Covid-19 with Respiratory Failure

The CCR5-delta32 variant might explain part of the association between COVID-19 and the chemokine-receptor gene cluster

Chemokine receptor gene polymorphisms and COVID-19: Could knowledge gained from HIV/AIDS be important?

Interleukin-6 Receptor Antagonists in Critically Ill Patients with Covid-19 -Preliminary report

Tocilizumab in patients with severe COVID-19: a retrospective cohort study

Effect of tocilizumab on clinical outcomes at 15 days in patients with severe or critical coronavirus disease 2019: randomised controlled trial

PRO 140, a monoclonal antibody targeting CCR5, as a long-acting, single-agent maintenance therapy for HIV-1 infection

Phase 2a study of the CCR5 monoclonal antibody PRO 140 administered intravenously to HIV-infected adults

The return of PRO 140, a CCR5-directed mAb

A Phase 2 Study of Leronlimab for Mild to Moderate Coronavirus Disease

CytoDyn to File Accelerated Rolling Review with MHRA and Interim Order (IO) with Health Canada for COVID-19

Dysregulation of Immune Response in Patients With Coronavirus

COVID-19: consider cytokine storm syndromes and immunosuppression

Extrapulmonary manifestations of COVID-19

As per the CReiT 

All authors attest that they meet the current International Committee of Medical Journal Editors (ICMJE) criteria for Authorship.

The authors declare that the work described has not involved experimentation on humans or animals.

The authors declare that informed consent was obtained. Treatment was conducted in accordance with the FDA requirements.

This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

J o u r n a l P r e -p r o o f Highlights • Leronlimab is a C-C chemokine receptor type 5 (CCR5)-specific humanized IgG4 monoclonal antibody. The CCR5 receptor is involved in recruiting inflammatory cells including T cells and macrophages • Infection with SARS-CoV-2 leads to a dysregulated host immune response which is hypothesised to mediate the morbidity and mortality of COVID-19 • Leronlimab may disrupt CCR5-related recruitment of inflammatory cells thereby restoring immune function and improving survival • Several cases of critically ill patients received leronlimab through compassionate use have been reported to be associated with recovery from COVID-19.

☐ The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.☒The authors declare the following financial interests/personal relationships which may be considered as potential competing interests:Sohier Elneil -nothing to declare Jacob Lalezari -is a paid consultant to CytoDyn Nader Pourhassan -is an employee of CytoDyn J o u r n a l P r e -p r o o f