Are Monoclonal Antibodies Beneficial for Hospitalised COVID-19 Patients?

The peer-review journal The Lancet Respiratory Medicine recently published an Editorial written by Thomas L Holland and colleagues reviewing the results of the U.S. NIH’s ACTIV-3 trial comparing the monoclonal antibody combination intravenous tixagevimab−cilgavimab (Evusheld) with patients hospitalized with COVID-19.

Monoclonal antibodies (mAbs) that neutralize SARS-CoV-2 have consistently reduced hospitalization or death in outpatients with mild to moderate COVID-19. Conversely, the results of randomized trials in patients who are hospitalized are mixed.

The U.S. FDA initially authorized mAbs to treat or prevent COVID-19 in 2021. As of July 3, 2022, about 771,553 Evusheld doses have been distributed in the USA.

This Editorial was edited and excerpts are inserted below.

On July 8, 2022, The Lancet Respiratory Medicine reported ACTIV-3 found Evusheld treatment was associated with decreased mortality in some hospitalized patients.

The RECOVERY trial compared Evusheld with standard care in 9,785 patients hospitalized with COVID-19. Although treatment was not associated with a 28-day mortality benefit in the overall cohort (RR 0·94 [95% CI 0·86–1·03]), mortality was lower in patients who were seronegative at the time of enrolment (RR 0·80 [0·70–0·91]).

In the patients who were hospitalized, Evusheld treatment was most beneficial in the seronegative patient subgroup.

Conversely, three monoclonal antibodies (bamlanivimab, sotrovimab, BRII-196/BRII-198) previously evaluated in the ACTIV-3 platform failed the early futility analysis, which assessed pulmonary function at day 5 by means of a seven-category ordinal scale.

However, tixagevimab–cilgavimab passed the early futility analysis and was permitted to continue enrolment.

The question now facing clinicians is whether the results of this trial should lead to the recommendation of intravenous tixagevimab–cilgavimab therapy for patients who are hospitalized.

This is challenging to answer for several reasons relating to the dynamic nature of both the virus and the host.

To first consider the virus, the in vitro activity of tixagevimab–cilgavimab, like other monoclonal antibodies, varies with emerging SARS-CoV-2 variants. It is unclear whether changes in in-vitro potency are clinically meaningful and how those changes affect efficacy.

Ideally, each monoclonal antibody would be studied clinically against each SARS-CoV-2 variant.

However, this is not feasible, making applying these results to present and future variants difficult.

Note: The U.S. NIH OpenData portal publishes a comparison of COVID-19 treatments against various coronavirus variants.

Furthermore, even if the relative efficacy shown in these trials is consistent across variants, the absolute benefit of therapy will change as mortality associated with SARS-CoV-2 changes.

It is not appropriate to extrapolate the magnitude of a mortality benefit in a predominantly delta variant landscape to the current disease course of an omicron-subvariant-infected patient, especially when the former variant was associated with significantly worse outcomes.

Considering the host, 73% of patients in this study were unvaccinated, and the mortality benefit observed with monoclonal antibodies in hospitalized patients appears limited to seronegative patients.

Indeed, in ACTIV-3, 28-day mortality was identical (13%) in the tixagevimab–cilgavimab and placebo groups in the subset of patients who were vaccinated.

With up to five vaccine doses now recommended by the U.S. FDA, and the decreased risk of death in those vaccinated, the efficacy of tixagevimab–cilgavimab in these patients is unclear.

Furthermore, nearly all unvaccinated patients have now been previously infected with SARS-CoV-2.

The presence of infection-derived immunity further limits the seronegative population in which monoclonal antibodies have shown benefits.

These factors collectively underscore the challenges of developing and evaluating monoclonal antibody therapies in the face of a rapidly mutating virus and evolving host population.

Should we use intravenous tixagevimab–cilgavimab in patients who are hospitalized?

It might be reasonable to consider therapy in patients either known to be seronegative or severely immunocompromised and unlikely to respond robustly to vaccination.

Although it might be enticing to expand tixagevimab–cilgavimab use beyond these populations, it is not supported by the evidence, and future studies are needed to ascertain the role of monoclonal antibodies in a population that is no longer immune-naive.

Importantly, these same limitations and questions hold true for other antiviral agents used in both the inpatient and outpatient settings for COVID-19.

The authors and study teams of ACTIV-3 and all previous trials should be applauded for their impressive work in establishing the benefit of various therapies during a rapidly evolving pandemic landscape.

However, new trials adequately powered to current event rates within the emerging variant and immunity landscape are needed to establish whether there is a benefit to any antiviral or immunomodulatory therapy for patients with COVID-19.

Note: The U.S. FDA revised the Evusheld Fact Sheet for Healthcare Providers on June 29, 2022, to recommend repeat dosing every six months with a dose of 300 mg of tixagevimab and 300 mg cilgavimab if patients need ongoing protection.

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