XEVUDY Concentrate for solution for infusion Ref.[28113] Active ingredients: Sotrovimab

Pharmacotherapeutic group: immune sera and immunoglobulins: immunoglobulins, specific immunoglobulins
ATC code: not yet assigned

Mechanism of action

Sotrovimab is a human IgG1 mAb that binds to a highly conserved epitope on the spike protein receptor binding domain of SARS-CoV-2.

Antiviral activity

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.

Antiviral resistance

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.

Clinical efficacy

Study 214367 (COMET-ICE) was a Phase II/III randomised, double-blind, placebo-controlled study which evaluated sotrovimab as treatment for COVID-19 in non-hospitalised adult patients who did not require any form of oxygen supplementation at study entry. The study included patients with symptoms for ≤5 days and laboratory confirmed SARS-CoV-2 infection. Eligible patients had at least 1 of the following: diabetes, obesity (BMI>30), chronic kidney disease, congestive heart failure, chronic obstructive pulmonary disease, or moderate to severe asthma, or were aged 55 years and older.

Patients were randomised to a single 500 mg infusion of sotrovimab (N=528) or placebo (N=529) over 1 hour (Intent to Treat [ITT] population at Day 29). In the ITT population, 46% were male and the median age was 53 years (range: 17-96), with 20% aged 65 years or older and 11% over 70 years. Treatment was given within 3 days of COVID-19 symptom onset in 59% and 41% were treated within 4-5 days. The four most common pre-defined risk factors or comorbidities were obesity (63%), 55 years of age or older (47%), diabetes requiring medicine (22%) and moderate to severe asthma (17%).

The adjusted relative risk reduction in hospitalisation or death by Day 29 in the ITT population was 79% (95% CI: 50%, 91%). The difference was driven by rates of hospitalisation, with no deaths in the sotrovimab arm and two deaths in the placebo arm up to Day 29. No patients in the sotrovimab arm, versus 14 in the placebo arm, required high flow oxygen or mechanical ventilation up to Day 29.

Table 2. Results of primary and secondary endpoints in the ITT population (COMET-ICE):

^a No participants required intensive care unit (ICU) stay in the sotrovimab arm versus 9 participants in the placebo arm.
^b Progression to develop severe and/or critical respiratory COVID-19 defined as the requirement for supplemental oxygen (low flow nasal cannulae/face mask, high flow oxygen, non-invasive ventilation, mechanical ventilation or extracorporeal membrane oxygenation [ECMO]).

Paediatric population

The European Medicines Agency has deferred the obligation to submit the results of studies with Xevudy in one or more subsets of the paediatric population in the treatment of COVID-19 (see section 4.2 for information on paediatric use).