Intramuscular Versus Intravenous SARS-CoV-2 Neutralizing Antibody Sotrovimab for Treatment of COVID-19 (COMET-TAIL): A Randomized Non-inferiority Clinical Trial (preprint)

Background: Convenient administration of coronavirus disease 2019 (COVID-19) treatment in community settings is desirable. Sotrovimab is a pan-sarbecovirus dual-action monoclonal antibody formulated for intravenous (IV) or intramuscular (IM) administration for early treatment of mild/moderate COVID-19. Methods: This phase 3, randomized, multicenter, open-label study tested non-inferiority of IM to IV administration using a 3.5% absolute non-inferiority margin. From June to August 2021, patients aged [≥]12 years with COVID-19, not hospitalized or receiving supplemental oxygen, and at high risk for progression were randomized 1:1:1 to a single 500-mg IV sotrovimab infusion or 500-mg or 250-mg IM sotrovimab injection. The primary composite endpoint was progression to all-cause hospitalization for >24 hours for acute management of illness or all-cause death through day 29. Results: Sotrovimab 500 mg IM was non-inferior to 500 mg IV: 10/376 (2.7%) participants in the sotrovimab 500-mg IM group versus 5/378 (1.3%) in the sotrovimab 500-mg IV group met the primary endpoint (absolute adjusted risk difference: 1.06% [95% confidence interval [CI]: -1.15%, 3.26%]). The CI upper limit was lower than the prespecified non-inferiority margin of 3.5%. 250-mg IM group enrollment was discontinued early because a greater proportion of hospitalizations was seen in that group versus the 500-mg groups. Serious adverse events occurred in <1% to 2% of participants across groups. Four participants experienced serious disease related events and died (500 mg IM: 2/393 [<1%]; 250 mg IM: 2/195 [1%]). Conclusions: Sotrovimab 500-mg IM injection was well tolerated and non-inferior to IV administration. IM administration could expand outpatient treatment access for COVID-19.

Real-world effectiveness of sotrovimab for the treatment of SARS-CoV-2 infection during Omicron BA.2 subvariant predominance: a systematic literature review (preprint)

Purpose Emerging severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants have impacted the in vitro activity of sotrovimab 500 mg, with reduced fold change in EC50 for the Omicron BA.2 sublineage and onward. The correlation between this reduction and clinical efficacy outcomes is unknown. In the absence of clinical trials assessing the efficacy of sotrovimab against emerging variants, real-world evidence becomes a critical source of information. A systematic literature review (SLR) of published observational studies was undertaken to evaluate the effectiveness of sotrovimab on severe clinical outcomes during the Omicron BA.2 subvariant predominance period. Methods Searches of indexed electronic databases for peer-reviewed journals, preprint articles, and conference abstracts published between January 1, 2022 and November 3, 2022 were undertaken using a combination of search terms for COVID-19, sotrovimab, and observational study design. Study quality was assessed using the Newcastle Ottawa Scale (NOS). Results From the 343 unique titles and abstracts identified, five studies were eligible for inclusion in the SLR. Included studies displayed heterogeneity in study design and population. The OpenSAFELY study, which received a high NOS score and had a sufficient sample of patients treated with sotrovimab during BA.2 predominance, demonstrated clinical effectiveness during both BA.1 (adjusted hazard ratio (HR) 0.54, 95% confidence interval (CI) 0.33-0.88, p = 0.014) and BA.2 (adjusted HR 0.44, 95% CI 0.27-0.71, p = 0.001) periods vs molnupiravir. Furthermore, a US-based study that also received a high NOS score reported that sotrovimab was associated with a lower risk of 30-day all-cause hospitalization or mortality compared with no monoclonal antibody treatment during the BA.2 subvariant surge in March (adjusted relative risk (RR) 0.41, 95% CI 0.27-0.62) and April 2022 (adjusted RR 0.54, 95% CI 0.08-3.54). Although only a limited number of studies evaluated sotrovimab during both the BA.1 and BA.2 periods, these demonstrated that clinical outcomes in patients with COVID-19 treated with sotrovimab were consistently low across both periods. One large study directly compared data from the two periods and found no evidence of a difference in the clinical outcomes of sotrovimab-treated patients with sequencing-confirmed BA.1 and BA.2 (HR 1.17, 95% CI 0.74-1.86). Conclusion The observational data presented in this SLR provide evidence that the effectiveness of sotrovimab (IV 500 mg) is maintained against Omicron BA.2 in both ecological and sequencing-confirmed studies, either through the demonstration of low and comparable rates of severe clinical outcomes between the Omicron BA.1 and BA.2 periods, or by comparison against an active comparator or no treatment within the Omicron BA.2 period.

Safety, Virology, Pharmacokinetics, and Clinical Experience of High-dose Intravenous Sotrovimab for the Treatment of Mild to Moderate COVID-19: An Open-label Clinical Trial (preprint)

Background: 500 mg intravenous (IV) sotrovimab has been shown to be well tolerated and efficacious against pre-Omicron strains in treating patients with mild to moderate coronavirus disease 2019 (COVID-19) at high risk for disease progression. Methods: This was an open-label, single-arm substudy of phase 3 COMET-TAIL (NCT04913675) assessing the safety and tolerability of a 2000 mg IV dose of sotrovimab. Symptomatic patients (aged [≥]18 years) with COVID-19 at high risk for progression were enrolled from June 30 through July 11, 2022, when Omicron BA.5, BA.2.12.1, and BA.4 were the predominant circulating variants in the United States. The primary endpoint was occurrence of adverse events (AEs), serious AEs (SAEs), AEs of special interest, and COVID-19 disease-related events (DREs) through Day 8. Safety, pharmacokinetics, viral load, and hospitalization >24 hours for acute management of illness or death through Day 29 were assessed. Results: All participants (n=81) were Hispanic, 58% were female, and 51% were aged [≥]55 years. Through Day 8, no AEs, including infusion-related reactions or hypersensitivity, were reported; 2 participants reported DREs (mild cough, n=2). One SAE (acute myocardial infarction), which was considered unrelated to sotrovimab or COVID-19 by the investigator, occurred on Day 27 and was the only hospitalization reported. Maximum serum concentration (geometric mean) was 745.9 g/mL. Viral load decreased from baseline through Day 29; only 2 participants (3%) had persistently high viral load ([≥]4.1 log10 copies/mL) at Day 8. Conclusions: 2000 mg IV sotrovimab was well tolerated, with no new unanticipated safety signals observed.

Population Pharmacokinetics and Exposure-Response Analysis of Sotrovimab in the Early Treatment of COVID-19 (preprint)

Sotrovimab is a recombinant human monoclonal antibody that has been shown to prevent progression to hospitalization or death from severe disease in non-hospitalized high-risk patients with mild-to-moderate COVID-19 following either intravenous (IV) or intramuscular (IM) administration. Population pharmacokinetic (popPK) and exposure-response (ER) analyses were performed to characterize sotrovimab PK and the relationship between exposure and response (probability of progression), as well as covariates that may contribute to between-participant variability in sotrovimab PK and efficacy following IV or IM administration. Sotrovimab PK was described by a two-compartment model with linear elimination; IM absorption was characterized by a sigmoid absorption model. PopPK covariate analysis led to the addition of the effect of body weight on systemic clearance and peripheral volume of distribution, sex on IM bioavailability and first-order absorption rate (KA), and body mass index on KA. However, the magnitude of covariate effect was not pronounced and was therefore not expected to be clinically relevant based on available data to date. For ER analysis, sotrovimab exposure measures were predicted using the final popPK model. An ER model was developed using the exposure measure of sotrovimab concentration at 168 hours that described the relationship between exposure and probability of progression within the ER dataset for COMET-TAIL. The number of risk factors ([≤]1 vs >1) was incorporated as an additive shift on the model-estimated placebo response but had no impact on overall drug response. Limitations in the ER model may prevent generalization of these results to describe the sotrovimab exposure-progression relationship across SARS-COV-2 variants.