ABSTRACT
BACKGROUND: Sotrovimab, a dual-action Fc-engineered human immunoglobulin G (IgG1) mAb, binds to a conserved epitope on the SARS-CoV- 2 receptor binding domain and was developed to treat mild to moderate COVID-19. A high concentration formulation is being evaluated to offer the potential for IM administration at lower volumes and at different injection sites. METHOD(S): COSMIC (NCT05280717) is a phase 1, open-label healthy volunteer study comprising three parts. Part A is an ongoing randomized, parallel group study investigating the relative bioavailability, safety, and tolerability of two concentrations of sotrovimab administered at different injection sites. A total of 215 subjects were randomized in a 2:2:1:1 ratio into 4 treatment arms: dorsogluteal injection (62.5 mg/mL), or 100 mg/mL administered as dorsogluteal, thigh, or deltoid injection(s). PK will be evaluated for 24 weeks post-dose. RESULT(S): Preliminary PK is available from 50 participants who received a 500 mg IM dose of sotrovimab of the higher concentration (100 mg/mL). Administration into thigh or deltoid resulted in higher geometric mean Cmax and AUCD1-15 and lower inter-subject variability compared to 100 mg/mL dorsogluteal. Following gluteal, thigh, or deltoid injections, the geometric mean (%CV) Cmax was 44.8 mug/mL (63.3), 70.9 mug/mL (35.5), and 65.1 mug/mL (27.1), respectively, and the geometric mean (%CV) AUCD1-15 was 534 day*mug/mL (67.5), 814 day*mug/mL (39.7), and 782 day*mug/mL (26.3), respectively. Median Tmax was earlier following thigh (4 days) and deltoid (5.5 days) injection than gluteal (7 days) injection. CONCLUSION(S): Administration of sotrovimab into thigh or deltoid muscles may improve exposure and reduce inter-subject variability compared to gluteal IM administration. These data may inform IM injection site selection for mAbs.
ABSTRACT
Background. There is a continued need for therapeutics for the treatment of COVID-19, including intramuscular (IM) agents, which will enable broader use across a variety of healthcare delivery settings. Methods. COMET-PEAK (NCT04779879) is a 3-part study evaluating the safety, tolerability, pharmacokinetics (Part A), and viral pharmacodynamics (PD) of sotrovimab as treatment in adults >= 18 years with early mild/moderate COVID-19. In Parts B and C, the safety, tolerability and viral PD of sotrovimab administered as a 500 mg intravenous (IV) infusion or as a 500 mg or 250 mg IM injection, respectively, was evaluated. The primary objective for Parts B and C was to compare the virologic response of sotrovimab IM to IV, with an endpoint of mean area under the curve (AUC) of SARS-CoV-2 viral load as measured by qRT-PCR from Day 1 to Day 8 (AUCD1-8) in nasopharyngeal swabs and predefined 90% confidence interval (CI) limits of 0.5-2.0 indicating equivalence. Results. A total of 167 and 157 participants were enrolled in Part B and C, respectively, from February-July 2021. The median age of participants was 47 and 42 years in Part B and C, respectively, and ~50% had >= 1 risk factor for progression to severe disease. The viral load at baseline and through Day 29 of follow-up for each arm is shown in Table 1 and Figure 1. The primary objective was met for both study parts: the ratio of the least square geometric mean viral load AUC(D1-8) of sotrovimab IM vs IV was 1.04 (90% CI, 0.98, 1.09) and 1.02 (90% CI, 0.94, 1.11), for Part B and C, respectively. Through Day 29 of follow-up, the most common adverse event was injection site reactions (ISRs) in the IM arms. A total of 10 (12%) participants in the 500 mg IM group and 4 (5%) participants in the 250 mg IM group experienced an ISR, all Grade 1. Serious adverse events were uncommon, and related to COVID-19 progression, including one death in the 250 mg IM arm (Table 2). ISRs aside, there were few treatment-related AEs (2/84 IV, 1/82 IM) in Part B, none serious. Conclusion. IM administration of sotrovimab 500 mg and 250 mg each demonstrated equivalence to 500 mg sotrovimab IV in viral load assessments. Overall, there were no treatment-related serious AEs and sotrovimab was well tolerated. An 500 mg IM formulation will allow for expanded treatment potential with sotrovimab.
ABSTRACT
Background. Sotrovimab (VIR-7831) is an engineered human monoclonal antibody targeting a conserved region of the SARS-CoV-2 spike protein;it has been shown to have a favorable safety profile and be effective for early treatment of highrisk COVID-19 patients. The COMET-TAIL phase 3 study evaluated sotrovimab administered intravenously (IV) or intramuscularly (IM) for the treatment of participants with mild to moderate COVID-19 who are at high risk of disease progression. Methods. Between June to August 2021, 973 participants were randomized and received sotrovimab by 500 mg IV infusion or by 500 or 250 mg IM injection. Deep sequencing of the spike gene was performed on nasopharyngeal samples. Baseline (BL;Day 1 or Day 3), post-BL (Day 5 or later), treatment-emergent (TE) substitutions at sotrovimab epitope positions, and presence of variants of concern/interest (VOC/ VOI), were evaluated at a >=5% allelic frequency. Phenotypic analyses were conducted using a pseudotyped virus assay. Results. Sequences were available from 764 participants (500 mg IV: 314/393;500 mg IM: 302/387;250 mg IM: 148/193). Consistent with VOC circulation during enrollment, the Delta variant was detected in 88.2% (674/764) of participants. Alpha and Mu variants were also seen at >2% prevalence. Of the 764 participants, 26 met the primary endpoint for clinical progression to hospitalization >24 hours or death due to any cause through day 29 and were infected with Delta (500 mg IV: 4;500 mg IM: 9;250 mg IM: 11), Alpha (500 mg IM: 1), or Mu (500 mg IV: 1) variants. Substitutions at sotrovimab epitope positions were similar across arms and were detected in 82/764 (10.7%) participants at any visit (500 mg IV: 42/314;500 mg IM: 27/302;250 mg IM: 13/148). Of these, 2 participants experienced clinical progression: 1 participant infected with the Mu variant (500 mg IV) carried the characteristic R346K substitution at BL;1 participant infected with the Delta variant (500 mg IM) had P337L and E340K substitutions detected at Day 3 and P337L was enriched at Day 8. The predominant TE epitope substitutions included P337L and E340A/K/V, which confer reduced susceptibility to sotrovimab in vitro. Conclusion. Overall, TE epitope substitutions were not associated with clinical progression.
ABSTRACT
Background. Sotrovimab is a human monoclonal antibody targeting a conserved region of the SARS-CoV-2 spike (S) protein. COMET-PEAK was a 3-part, phase 2 study that evaluated intravenous (500 mg) and intramuscular (500 mg and 250 mg) administration of sotrovimab in outpatients (n=353) with mild-to-moderate COVID-19. We assessed amino acid substitutions in the SARS-CoV-2 S protein and circulating variants of concern/interest (VOC/VOI) in COMET-PEAK participants (enrolled Feb-July 2021). Methods. Mid-turbinate (Part A) or nasopharyngeal (Part B/C) samples were obtained from all participants at Baseline and Post-Baseline visits. Next generation sequencing of the SARS-CoV-2 S gene was conducted using Illumina MiSeq with a >=5% allelic frequency cut-off for samples with a viral load above 3.0 log10 copies/mL. Baseline, post-baseline and treatment-emergent (TE) substitutions were assessed, and prevalence of VOC/VOI was evaluated. Phenotypic analyses of epitope substitutions were conducted using a pseudotyped virus assay. Results. In total, 282/353 participants had sequencing results for >=1 visit (253 baseline, 248 post-baseline), and 219 had paired baseline and post-baseline sequences;among these, 149 (68%) had TE substitutions in the S protein (26 [12%] in the epitope). E340K was the predominant TE substitution in the epitope (15 [7%]). Across all arms 92/245 (38%) experienced virologic rebound, 8 of whom (Part A: 2;Part B: 2;Part C: 4) had TE substitutions in the epitope;none had evidence of clinical progression to severe disease. Prevalence of VOC/VOI or single amino acid substitutions of concern was 94% (266/282);the most frequent were Alpha (Part A: 8/16 [50%];Part B: 75/128 [59%]) and Delta (Part C: 99/122 [81%]). Of 7 participants with evidence of clinical progression, none had S protein substitutions in the epitope and all hadVOC/VOI (3Alpha, 3 Delta, 1 Gamma). Sotrovimab effectively neutralized most epitope substitutions tested in vitro;P337L and E340A/K/V conferred significantly reduced susceptibility. Conclusion. There was no evidence that sotrovimab epitope substitutions were associated with clinical progression or virologic rebound. These data are consistent with those from the COMET-ICE study.
ABSTRACT
Background: Sotrovimab is a pan-sarbecovirus monoclonal antibody clinically evaluated for prevention of progression of COVID-19 in high-risk patients early in the course of infection. We investigated the rate of prevention of hospitalization or death by baseline anti-SARS-CoV-2 serostatus. Methods: COMET-ICE (NCT04545060) was a multicenter, double-blind, Phase III trial in nonhospitalized adults with symptomatic COVID-19 and ≥1 risk factor for disease progression. Participants were randomized 1:1 to an IV infusion of sotrovimab 500 mg or placebo. The primary efficacy endpoint was all-cause hospitalization >24 hours or death due to any cause within 29 days. Anti-nucleocapsid SARS-CoV-2 antibody was measured by the Abbott SARS-CoV-2 IgG assay run on the Architect i2000SR immunoassay analyzer. Results: In the final dataset (N=1057), the adjusted relative risk (RR) reduction in all-cause hospitalization or death due to any cause in the sotrovimab group compared to the placebo group was 79% (p<0.001) at Day 29. 70% and 19% of participants were seronegative and seropositive for anti-nucleocapsid protein at baseline, respectively. 11% of participants had unknown antibody status and were excluded. In the seronegative subgroup, 4/365 (1%) participants in the sotrovimab group met the primary endpoint compared to 26/375 (7%) in the placebo group (84% reduction in risk [RR: 0.16;95% CI: 0.06, 0.45]). Of the 4 seronegative participants who received sotrovimab and met the primary endpoint, 1 participant was hospitalized for small intestinal obstruction that was likely unrelated to COVID-19. Two of the 26 seronegative participants in the placebo arm who met the primary endpoint died compared to no deaths in the sotrovimab group. In the seropositive subgroup, conclusions are limited by small numbers. Numerically fewer participants in the sotrovimab group (2/105, 2%) were hospitalized compared to the placebo group (4/97, 4%). Importantly, both hospitalized seropositive participants in the sotrovimab group had an alternative reason for their hospitalization that was likely unrelated to COVID-19 (diabetic foot ulcer, non-small cell lung cancer). Progression rates in the sotrovimab arm were low and similar regardless of serostatus (1% seronegative, 2% seropositive). Safety profile by serostatus was consistent with that reported in the overall population. Conclusion: Sotrovimab appeared to consistently reduce the likelihood of a COVID-19-related hospitalization or death regardless of baseline serostatus.
ABSTRACT
Background. COVID-19 disproportionately results in hospitalization and death in older patients and those with underlying comorbidities. Sotrovimab is a pan-sarbecovirus monoclonal antibody that binds a highly conserved epitope of the SARSCoV-2 receptor binding domain and has an Fc modification that increases half-life. Sotrovimab retains activity against UK, S. Africa, Brazil, India, New York and California variants in vitro. Objectives. To evaluate the efficacy and safety of treatment with sotrovimab in high-risk, non-hospitalized patients with mild/moderate COVID-19, as part of the COMET-ICE clinical trial. Methods. Multicenter, double-blind, phase 3 trial in non-hospitalized patients with symptomatic COVID-19 and ≥1 risk factor for disease progression were randomized 1:1 to an IV infusion of sotrovimab 500 mg or placebo. The primary efficacy endpoint was the proportion of patients with COVID-19 progression, defined as hospitalization > 24 hours or death, due to any cause, ≤29 days of randomization. Results. The study met the pre-defined primary efficacy endpoint in a preplanned interim analysis: the risk of COVID-19 progression was significantly reduced by 85% (97.24% CI, 44% to 96%;P = 0.002) in 583 patients. In the final intention-to-treat analysis (N = 1057), the adjusted relative risk reduction was 79% (95% CI, 50% to 91%;p< 0.001) through Day 29 in recipients of sotrovimab (n=528) vs. placebo (n=529). Treatment with sotrovimab (ITT) resulted in a numerical reduction in the need for ER visits for illness management, hospitalization for acute illness management (any duration) or death (any cause) compared to placebo. No participants on sotrovimab required ICU admission, compared to 9 participants on placebo, of whom 4 participants required mechanical ventilation. No participants who received sotrovimab died, compared to 4 participants on placebo. The incidence of adverse events was similar between treatment arms and SAEs were numerically more common in the placebo arm. Conclusion. Treatment with sotrovimab 500 mg IV resulted in a clinically and statistically significant reduction in progression of COVID-19 to hospitalization or death in patients with mild/moderate disease and was well-tolerated.