Treatment of SARS-CoV-2 infection with fenofibrate.

Key Messages

This comprehensive paper from Israeli researchers describes pre-clinical and prospective/retrospective research findings.

Preclinical experiments examined the metabolic response of lung epithelial cells to SARS-CoV-2 infection in primary cultures and COVID-19 patient samples. Fenofibrate reversed lipid accumulation and inhibited SARS-CoV-2 replication in infected cells.

A retrospective study of high-risk COVID-19 patients hospitalized for 3 or more days found that patients using fibrates (bezafibrate or ciprofibrate) were hospitalized for a significantly shorter duration.

An additional retrospective analysis of 2,123 Italian patients found significantly less COVID-19 history and severe illness in fenofibrate users.

A further validation study involved the retrospective analysis of 920,922 veterans with hypertension in the US Veteran’s Health Administration. Patients who were already taking fenofibrate and contracted COVID-19 were hospitalized for shorter periods, and had better outcomes across several indicators for disease severity.

This evidence led to the initiation of a clinical trial in an Israeli hospital. The study recruited 15 COVID-19 patients, all of whom experienced respiratory deterioration and severe pneumonia. Patients received 145 mg of fenofibrate daily (as Tricor) in addition to normal care, for 10 days or until discharge.

When compared to other patients admitted with severe COVID-19 who did not receive fenofibrate but were given similar care, the patients given fenofibrate showed a rapid decline in CRP, an indicator of inflammation, and were discharged on average 3 days earlier.

Among patients treated with fenofibrate, there were reduced rates of mechanical ventilation, reduced need for supplemental oxygen by day 7 and no mortality.

Research Square

Publication Date: August 12, 2021
Peer Reviewed: No
Publication Type: Original | Clinical Prospective, Clinical Retrospective, Preclinical
DOI: https://www.doi.org/10.21203/rs.3.rs-770724/v1

Metabolic Regulation of SARS-CoV-2 Infection

Yaakov Nahmias, Avner Ehrlich, Konstantinos Ioannidis, Makram Nasar, Ismaeel Abu Alkian, Matan Hofree, Sigal Shafran Tikva, Nir Rainy, Inbal Houri, Arrigo Cicero, Chiara Pavanello, Cesare Sirtori, Jordana Cohen, Julio Chirinos, Lisa Deutsch, Amichai Gottlieb, Oren Shibolet, Shlomo Maayan

Abstract

Viruses are efficient metabolic engineers that actively rewire host metabolic pathways to support their lifecycle, presenting attractive metabolic targets for intervention. Here we chart the metabolic response of lung epithelial cells to SARS-CoV-2 infection in primary cultures and COVID-19 patient samples. Bulk and single-cell analyses show that viral replication induces endoplasmic stress and lipid accumulation. Protein expression screen suggests a role for viral proteins in mediating this metabolic response even in the absence of replication. Metabolism-focused drug screen showed that fenofibrate reversed lipid accumulation and blocked SARS-CoV-2 replication. Analysis of 3,233 Israeli patients hospitalized due to COVID-19 supported in vitro findings. Patients taking fibrates showed significantly lower markers of immunoinflammation and faster recovery. Additional corroboration was received by comparative epidemiological analysis from cohorts in Europe and the United States. A subsequent prospective interventional open-label study was carried out in 15 patients hospitalized with severe COVID-19. The patients were treated with 145 mg/day of nanocrystallized fenofibrate (TriCor®) in addition to standard-of-care. Patients receiving fenofibrate demonstrated a rapid reduction in inflammation and a significantly faster recovery compared to control patients admitted during the same period and treated with the standard-of-care. Taken together, our data show that elevated lipid metabolism underlies critical aspects of COVID-19 pathogenesis, suggesting that pharmacological modulation of lipid metabolism should be strongly considered for the treatment of coronavirus infection.