Early Promise for PCSK9 Inhibition in Severe COVID-19

PCSK9 inhibitors may have a role in dampening vascular inflammation to improve outcomes in severe COVID-19, a pilot study suggested.

Among people with severe COVID-19 with respiratory failure and heightened inflammation, the advantage of getting PCSK9 inhibition therapy was a significantly reduced incidence of death or need for intubation at 30 days (23.3% vs 53.3% with placebo), according to Eliano Navarese, MD, PhD, of Nicolaus Copernicus University in Bydgoszcz, Poland, and colleagues on the IMPACT-SIRIO 5 team.

The clinical benefit was supported by large changes in circulating interleukin (IL)-6 levels after treatment (-56% vs -21%), they stated in the Journal of the American College of Cardiology.

Notably, patients with baseline IL-6 above the median -- 51.29 pg/mL -- had a lower mortality rate with PCSK9 inhibition compared with placebo (12.5% vs 50%). "Although our study was not powered to address mortality alone, its reduction with PCSK9 inhibitor in patients presenting higher baseline IL-6 levels suggests that inflammatory intensity may drive therapeutic benefits," the authors wrote.

The PCSK9 monoclonal antibody drug class was originally developed as an adjunctive therapies to lower LDL cholesterol. The agent tested in the present study, evolocumab (Repatha), was first FDA approved in 2015 and has since also won an indication for cardiovascular prevention.

Now there is growing interest in PCSK9 inhibitors as potential anti-inflammatory agents targeting the IL-6-mediated inflammatory pathway implicated in severe COVID-19.

"Although we found a moderate association between baseline levels of LDL-C [LDL cholesterol] and IL-6 in the present study, it is possible that the greatest benefit of PCSK9 inhibition in severe COVID-19 resides in mechanisms distinct from increased LDL receptor expression, including direct inhibition of PCSK9-triggered inflammation," according to Navarese's group.

"Such interpretation would explain why the positive findings of the present study have not been consistently observed in trials involving other lipid-lowering agents such as statins," they surmised.

The authors cautioned that their study was not designed to show any superior efficacy or safety of PCSK9 inhibition in patients with COVID-19.

Whether the observed clinical results of PCSK9 inhibition are due to LDL lowering or LDL-independent effects is also beyond the scope of this hypothesis-generating trial, according to an editorial comment by Sascha Goonewardena, MD, of the University of Michigan in Ann Arbor, and Robert Rosenson, MD, of Mount Sinai Icahn School of Medicine in New York City.

"Regardless of the specific mechanisms, the effects of PCSK9i [PCSK9 inhibition] on inflammation and clinical outcomes in COVID-19 are provocative and warrant further investigation, and ongoing studies of lipid-modulating therapies in COVID-19 will further illuminate the connection between lipoprotein metabolism and inflammation," they wrote.

IMPACT-SIRIO 5 was conducted from June 2021 to May 2022 with 60 patients hospitalized for severe COVID-19 at four sites in northern Poland. Eligibility criteria included ground-glass opacity pneumonia and arterial partial oxygen pressure to fraction of inspired oxygen ratio ≤300 mm Hg and serum levels of IL-6 above the upper reference limit.

The double-blind trial had patients randomized to a single 140-mg subcutaneous injection of evolocumab or placebo during their hospitalization (on average 8-9 days from symptom onset). Usual COVID-19 therapies were applied as usual to both groups. No selective IL-6 inhibitors were administered.

The randomized cohort was on average age 66, with just under 40% women, and a mean BMI nearing 30.

Compared with placebo, evolocumab was associated with shorter hospital stays (16 vs 22 days) and fewer days required of oxygen therapy (13 vs 20 days).

There were no safety signals reported in terms of thrombotic, serious adverse arrhythmic, or myocarditis events.

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