The cholesterol-lowering drug fenofibrate has shown promise in early laboratory studies, but has no significant effect on the prognosis of COVID-19

A multicenter international randomized clinical trial led by scientists at the University of Pennsylvania School of Medicine showed no significant effect
of the cholesterol-lowering drug fenofibrate on the prognosis of COVID-19 after showing promise in early laboratory studies.
The findings were presented Monday at the American Heart Association's 2022 Scientific Meeting and published in
the journal Nature Metabolism.

"Although fenofibrate has a good effect on the SARS-CoV2 virus that causes COVID-19, our findings convincingly suggest that it is not an effective strategy
to reduce disease severity or prevent adverse outcomes for people with COVID-19.
" Julio Chirinos, professor of cardiovascular medicine at the University of Pennsylvania Perelman School of Medicine and co-director of clinical research in the T32 Cardiovascular Biology and Medical Training Program, said first author and principal investigator
of the trial.
"Although performing rigorous clinical trials takes time, complexity, and cost, they are critical to evaluating the efficacy of drugs in COVID-19 patients, as the effectiveness of drugs can differ significantly from
what in vitro studies may show.
Before the clinical implementation of drug therapy, it is necessary to conduct clinical trials, even for drugs that are already widely used for other indications
.
”

Fenofibrate is a widely used, low-cost generic drug for non-nofibrate that was previously approved by the U.
S.
Food and Drug Administration and many other regulatory agencies to reduce the amount of fatty substances in the blood, such as cholesterol and triglycerides, while increasing the "good" cholesterol (high-density lipoprotein cholesterol, or HDL).

The drug was originally studied for COVID-19 as part of an effort to test the potential benefits of
previously approved older drugs to the virus.
In laboratory studies, it has been found that the overproduction of certain fat molecules by cells is associated with
cellular damage caused by SARS-CoV2.
Fenofibrate affects the way cells process fat, thereby reducing viral replication
.
In other laboratory studies, fenofibrate also affects the cell receptors of the virus, reducing viral replication
.

The University of Pennsylvania School of Medicine is a sponsor of fenofibrate as a COVID-19 Metabolic Intervention Trial (FERMIN), which conducted the study and included 26 partner institutions
from North and South America, Europe, and Western Asia.

To test the drug's effectiveness in people, the research team recruited 701 participants, each of whom had first COVID-19 symptoms
in the past two weeks.
The research team randomly assigned 351 patients to 145 mg of fenofibrate (or equivalent preparation in other countries) and 350 patients to placebo
.
Patients were then ranked according to a new severity scoring system that measures disease severity, as well as factors
including death, use of invasive and noninvasive ventilators, length of stay, and length of stay in outpatients and symptom severity.

Compared with placebo, fenofibrate had no significant effect
on severity scores or death from any cause.
There was likewise no difference
in results within 30 days of initial randomization.
Importantly, the findings were consistent across countries and were not affected
by gender, age, ethnicity, body mass index, diabetes status, or when the patient started treatment.

The authors note that the drug has failed to achieve the same effect in humans as it does in laboratory cells, and there may be many potential explanations
.

"COVID-19 is complex, involving not only its toxic effects on cells, but also a complex set of systemic host responses," said
Jordana B.
Cohen, MD, assistant professor of renal electrolytes and hypertension at the University of Pennsylvania.
"Therefore, due to a wide range of potential phenomena throughout the organism, the effects of drugs observed in the Petri dish system on cells may not translate into beneficial effects
on COVID-19 patients.
" Our trial highlights the importance of not equating laboratory efficacy with clinical efficacy in the
context of COVID-19.
”

The research team calls for further research to assess whether other interventions designed to affect cellular metabolic pathways affect outcomes for COVID-19 patients
.

This study was supported
by the National Center for Advanced Translational Science (1-U01-TR-003734-01) and Abbott Laboratories.