Sotrovimab for COVID-19 pneumonia lowers risk of death in specific subgroup

In the treatment of hospitalized patients with COVID-19 pneumonia, the use of the neutralizing monoclonal antibody sotrovimab in addition to usual care reduces mortality but only in the subgroup of those with a high baseline serum SARS-CoV-2 antigen concentration, according to the open-label RECOVERY trial.

The primary outcome of 28-day mortality among patients who had a high antigen level at baseline was significantly lower for those who received sotrovimab than for those who received usual care alone (23 percent vs 29 percent; rate ratio [RR], 0.75, 95 percent confidence interval [CI], 0.56–0.99; p=0.046). This benefit was not seen in the overall population (21 percent vs 22 percent; RR, 0.95, 0.77–1.16; p=0.60). [Lancet Infect Dis 2025;doi:10.1016/S1473-3099(25)00361-5]

Time to discharge from hospital within 28 days did not significantly differ between the sotrovimab and usual care arm both in the high-antigen-level subgroup (median, 13 vs 16 days; RR, 1.12, 95 percent CI, 0.93–1.34) and the overall population (median, 11 vs 11 days; RR, 0.96, 95 percent CI, 0.85–1.08).

Furthermore, compared with usual care, sotrovimab did not reduce the risk of the composite secondary outcome of invasive ventilation or death both in the high-antigen-level subgroup (24 percent vs 29 percent; RR, 0.82, 95 percent CI, 0.64–1.03) and the overall population (23 percent vs 23 percent; RR, 0.98, 95 percent CI, 0.84–1.16).

Safety outcomes

Infusion reactions with sotrovimab occurred in 12 patients (2 percent). Of these, nine did not require any intervention, two required antihistamines or steroids only, and one required adrenaline. Two cases of infusion reactions, including one episode of anaphylaxis, were documented as serious adverse reactions, both of which resolved.

Cause-specific mortality, new cardiac arrhythmia, thrombosis, bleeding, non-coronavirus infections, hypoglycaemia or hyperglycaemia, seizures, acute kidney injury, or liver injury did not differ between sotrovimab and usual care.

Viral resistance

“Neutralizing monoclonal antibodies emerged as powerful therapeutic tools during the pandemic, which has highlighted their potential uses but also their limitations, particularly the loss of activity against emergent viral variants,” the investigators noted.

High-level sotrovimab resistance was detected in Omicron lineages that became globally dominant in early 2024, including BA.2.86 and JN.1. And the drug is probably no longer useful against currently circulating variants that have retained sotrovimab resistance mutations, the investigators said. [Viruses 2024;16:217] 

In RECOVERY, viral load and sequencing data showed that more than 99 percent of the patients were infected with Omicron variants BA.1, BA.2, BA.5, or XBB. Among patients recruited in 2022 (96 percent), 14 had mutations conferring sotrovimab resistance at baseline. A new sotrovimab resistance mutation was detected in three patients at follow-up.

In the remaining 4 percent of patients recruited later, 14 patients were infected with BA.2.86 variants, which contained the lineage-defining K356T spike mutation associated with high-level sotrovimab resistance.

While there is a need for newer monoclonal antibody therapies with reliable and durable neutralizing activity against current and future SARS-CoV-2 variants, the findings from RECOVERY indicate that targeted neutralizing antibody therapy could potentially still benefit some patients admitted to hospital who are at high risk of death in an era of widespread vaccination and Omicron infection, according to the investigators.

RECOVERY population

A total of 1,723 patients (mean age 70.7 years, 60 percent male) hospitalized with COVID-19 pneumonia across several hospitals in the UK were included in RECOVERY. These patients were randomly assigned to receive usual care plus a single 1 g infusion of sotrovimab (n=828) or usual care alone (n=895).

The median time since symptom onset was 6 days, and most patients (85 percent) were receiving oxygen or ventilatory support, with 36 percent receiving remdesivir. Of the patients, 720 (42 percent) had a high antigen level at baseline, 717 (42 percent) had a low antigen level, and 286 (17 percent) had an unknown antigen status. Most patients (81 percent) were vaccinated, 82 percent of 1,438 patients with known serostatus had anti-spike antibodies at baseline, and 99 percent of 1,026 patients with sequenced samples were infected with omicron variants. Around a quarter of the population (24 percent) were severely immunocompromised.