Sotrovimab is a human IgG1 mAb that binds to a highly conserved epitope on the spike protein receptor binding domain of SARS-CoV-2.
Sotrovimab neutralised wild-type SARS-CoV-2 virus in vitro with a half maximal effective concentration (EC50) of 100.1 ng/mL.
Pseudotyped virus-like particle (VLP) assessments indicated less than 3-fold changes in sotrovimab EC50 values compared to wild-type against the following variant spike proteins: Alpha (B.1.1.7; 2.30-fold change in EC50 value); Beta (B.1.351; 0.60-fold change in EC50 value); Gamma (P.1; 0.35-fold change in EC50 value); Epsilon (B.1.427/B.1.429; 0.70-fold change in EC50 value); Iota (B.1.526; 0.6-fold change in EC50 value), Kappa (B.1.617.1; 0.7-fold change in EC50 value), Delta (B.1.617.2; 1-fold change in EC50 value), Lambda (C.37; 1.5-fold change in EC50 value), Delta Plus (AY.1; 1.1-fold change in EC50 value, AY.2; 1.3-fold change in EC50 value), Mu (B.1.621; 1.3-fold change in EC50 value) and Omicron (B.1.1.529; 2.7-fold change in EC50 value).
Microneutralisation data from authentic SARS-CoV-2 variant virus indicated the following changes in sotrovimab EC50 values compared to wild-type: Alpha, 3-fold change in EC50 value; Beta, 1.2-fold change in EC50 value; Gamma, 1.6-fold change in EC50 value; Kappa, 0.9-fold change in EC50 value and Delta, 0.4-fold change in EC50 value.
No viral breakthrough was observed when virus was passaged for 10 passages (34 days) in the presence of fixed concentration of antibody at the lowest concentration tested (~10x EC50). Forcing the emergence of resistance variants through an increasing concentration selection method identified E340A as a sotrovimab mAb resistance mutant (MARM). An E340A substitution emerged in cell culture selection of resistant virus and had a >100-fold reduction in activity in a pseudotyped VLP assay.
A pseudotyped VLP assessment in cell culture showed that the epitope sequence polymorphisms K356T, P337H/L/R/T and E340A/K/G conferred reduced susceptibility to sotrovimab based on observed fold-increase in EC50 value (shown in parentheses): E340K (>297), P337R (>276), P337L (180), E340A (>100), E340G (27), P337H (7.50), K356T (5.90) and P337T (5.438). The presence of the highly prevalent D614G variant, either alone or in combination, did not alter the neutralisation activity of sotrovimab.
In the COMET-ICE clinical trial post-baseline epitope variants were detected in 20 patients in the sotrovimab arm (A344V [6.2%]; R346G [5.2%]; K356R [7.5%]; E340A [99.0%]; E340V [73.1%]; P337L/E340K [49.4%/54.8%]; 2 patients with S359G [12.2% and 8.3%]; 5 patients with E340K [8.0%-99.9%]; 7 patients with C361T [5.0%-15.7%]). Of the variants detected at baseline and postbaseline in either treatment arm, 14 (L335F, L335S, P337L, G339C, E340A, E340K, A344V, R346I, R346G, K356N, K356R, R357I, I358V and S359G) have been assessed phenotypically using a pseudotyped VLP system. Sotrovimab retains activity against L335F (0.8-fold change in EC50 value), L335S (0.9-fold change in EC50 value), G339C (1.2-fold change in EC50 value), A344V (1.1-fold change in EC50 value), R346I (1.7-fold change in EC50 value), R346G (0.9-fold change in EC50 value), K356N (1.1-fold change in EC50 value), K356R (0.8-fold change in EC50 value), R357I (1-fold change in EC50 value), I358V (0.7-fold change in EC50 value), and S359G (0.8-fold change in EC50 value). P337L, E340A and E340K confer reduced susceptibility to sotrovimab (>180-fold, >100-fold and >297-fold change in EC50 value, respectively), but their effect on the clinical response to treatment is not known.
The geometric mean Cmax following a 1 hour IV infusion was 117.6 µg/mL (N=290, CV% 46.5), and the geometric mean Day 29 concentration was 24.5 µg/mL (N=372, CV% 42.4).
Based on non-compartmental analysis, the mean steady-state volume of distribution was 8.1 L.
Sotrovimab is degraded by proteolytic enzymes which are widely distributed in the body.
Based on non-compartmental analysis, the mean systemic clearance (CL) was 125 mL/day, with a median terminal half-life of approximately 49 days.
Based on population pharmacokinetic analyses, there was no difference in sotrovimab pharmacokinetics in elderly patients.
Sotrovimab is too large to be excreted renally, thus renal impairment is not expected to have any effect on elimination. Furthermore, based on population pharmacokinetic analyses there was no difference in sotrovimab pharmacokinetics in patients with mild or moderate renal impairment.
Sotrovimab is degraded by widely distributed proteolytic enzymes, not restricted to hepatic tissue, therefore changes in hepatic function are not expected to have any effect on elimination. Furthermore, based on population pharmacokinetic analyses there was no difference in sotrovimab pharmacokinetics in patients with mild to moderate elevations in alanine aminotransferase (1.25 to <5 x ULN).
The pharmacokinetics of sotrovimab have not been evaluated in patients aged less than 18 years. The recommended dose for adolescents aged from 12 years and from 40 kg body weight is predicted to result in serum concentrations of sotrovimab similar to those in adults based on an allometric scaling approach, which accounted for effect of body weight changes associated with age on clearance and volume of distribution.
Genotoxicity and carcinogenicity studies have not been conducted with sotrovimab.
Nonclinical reproductive and developmental toxicity studies have not been conducted with sotrovimab.
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