Efficacy and safety of two neutralising monoclonal antibody therapies, sotrovimab and BRII-196 plus BRII-198, for adults hospitalised with COVID-19 (TICO): a randomised controlled trial

Abstract

Background We aimed to assess the efficacy and safety of two neutralising monoclonal antibody therapies (sotrovimab [Vir Biotechnology and GlaxoSmithKline] and BRII-196 plus BRII-198 [Brii Biosciences]) for adults admitted to hospital for COVID-19 (hereafter referred to as hospitalised) with COVID-19. Methods In this multinational, double-blind, randomised, placebo-controlled, clinical trial (Therapeutics for Inpatients with COVID-19 [TICO]), adults (aged ≥18 years) hospitalised with COVID-19 at 43 hospitals in the USA, Denmark, Switzerland, and Poland were recruited. Patients were eligible if they had laboratory-confirmed SARS-CoV-2 infection and COVID-19 symptoms for up to 12 days. Using a web-based application, participants were randomly assigned (2:1:2:1), stratified by trial site pharmacy, to sotrovimab 500 mg, matching placebo for sotrovimab, BRII-196 1000 mg plus BRII-198 1000 mg, or matching placebo for BRII-196 plus BRII-198, in addition to standard of care. Each study product was administered as a single dose given intravenously over 60 min. The concurrent placebo groups were pooled for analyses. The primary outcome was time to sustained clinical recovery, defined as discharge from the hospital to home and remaining at home for 14 consecutive days, up to day 90 after randomisation. Interim futility analyses were based on two seven-category ordinal outcome scales on day 5 that measured pulmonary status and extrapulmonary complications of COVID-19. The safety outcome was a composite of death, serious adverse events, incident organ failure, and serious coinfection up to day 90 after randomisation. Efficacy and safety outcomes were assessed in the modified intention-to-treat population, defined as all patients randomly assigned to treatment who started the study infusion. This study is registered with ClinicalTrials.gov , NCT04501978 . Findings Between Dec 16, 2020, and March 1, 2021, 546 patients were enrolled and randomly assigned to sotrovimab (n=184), BRII-196 plus BRII-198 (n=183), or placebo (n=179), of whom 536 received part or all of their assigned study drug (sotrovimab n=182, BRII-196 plus BRII-198 n=176, or placebo n=178; median age of 60 years [IQR 50–72], 228 [43%] patients were female and 308 [57%] were male). At this point, enrolment was halted on the basis of the interim futility analysis. At day 5, neither the sotrovimab group nor the BRII-196 plus BRII-198 group had significantly higher odds of more favourable outcomes than the placebo group on either the pulmonary scale (adjusted odds ratio sotrovimab 1·07 [95% CI 0·74–1·56]; BRII-196 plus BRII-198 0·98 [95% CI 0·67–1·43]) or the pulmonary-plus complications scale (sotrovimab 1·08 [0·74–1·58]; BRII-196 plus BRII-198 1·00 [0·68–1·46]). By day 90, sustained clinical recovery was seen in 151 (85%) patients in the placebo group compared with 160 (88%) in the sotrovimab group (adjusted rate ratio 1·12 [95% CI 0·91–...

COVID-19 vaccines in patients with cancer: immunogenicity, efficacy and safety

“…This decision is based on data from a positive study in which 1% of outpatients with symptomatic COVID-19 in the sotrovimab group versus 7% in the placebo group required hospitalization (relative risk reduction 85%, 97.24% CI 44–96%; P = 0.002) 206 despite the fact that no significant improvement in clinical outcomes was observed among adults treated while hospitalized with COVID-19 (ref. 207 ). Sotrovimab has in vitro activity against a broad range of VOCs including Omicron; therefore, this agent might be of clinical value in prophylaxis (pre-exposure and post-exposure) and as an early intervention in patients with cancer 116 , 203 , 208 , 209 .…”

Sotrovimab: First Approval

“…Interim futility analyses of two neutralizing monoclonal antibody therapies, namely sotrovimab and BRII-196 plus BRII-198, in a multinational, double-blind, randomized placebo-controlled phase III ACTIV-3 trial (NCT04501978) in hospitalized adults with COVID-19 have been reported [ 40 ]. There was no significant (based on 95% CI) difference between sotrovimab ( n = 182) and placebo ( n = 178) recipients with respect to a more favourable category on the pulmonary scale at day 5 (adjusted odds ratio 1.07; 95% CI 0.74–1.56), a more favourable category on the pulmonary-plus complication scale at day 5 (1.08; 0.74–1.58) and a more favorable sustained clinical recovery by day 90 (adjusted rate ratio 1.12; 0.91–1.37).…”

“…There was no significant (based on 95% CI) difference between sotrovimab ( n = 182) and placebo ( n = 178) recipients with respect to a more favourable category on the pulmonary scale at day 5 (adjusted odds ratio 1.07; 95% CI 0.74–1.56), a more favourable category on the pulmonary-plus complication scale at day 5 (1.08; 0.74–1.58) and a more favorable sustained clinical recovery by day 90 (adjusted rate ratio 1.12; 0.91–1.37). Enrolment in the sotrovimab arm was halted on the basis of the analysis [ 40 ].…”

Time to knock monoclonal antibodies off the platform for patients hospitalised with COVID-19

“…The ACTIV-3 Therapeutics for Inpatients with COVID-19 (TICO) platform was developed to assess multiple candidate mAbs in individuals hospitalised with moderate or severe COVID-19 within 12 days of symptom onset. In The Lancet Infectious Diseases , the ACTIV-3 TICO Study Group 6 report the results of two neutralising mAb treatments (sotrovimab and BRII-196 plus BRII-198) that were provided in addition to standard of care, typically including remdesivir and corticosteroids, in a double-blind, randomised fashion, predominantly before the availability of SARS-CoV-2 vaccines, and were compared with a pooled placebo group. Enrolment into the trial was stopped early after a prespecified interim futility analysis in 536 participants in the modified intention-to-treat population found no improvement in odds of favourable pulmonary outcome scores on day 5 after infusion with either sotrovimab or BRII-196 plus BRII-198 compared with placebo.…”

“…Based on intriguing results from the RECOVERY study on efficacy of casirivimab–imdevimab (REGN-COV2) in patients hospitalised with COVID-19, which showed benefit only in people who were retroactively determined to be seronegative for anti-spike IgG at randomisation, 7 similar serostatus-dependent effects could have been seen with sotrovimab or BRII-196 plus BRII-198, despite no overall benefit. In the study by the ACTIV-3/TICO Study Group, 6 513 of 536 patients in the mITT population had baseline anti-spike antibody levels measured, enabling a subgroup analysis stratified by serostatus. At the time of randomisation, 212 (41%) participants were positive for anti-spike neutralising antibodies.…”