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

Pharmacotherapeutic group: Immune sera and immunoglobulins, antiviral monoclonal antibodies
ATC code: J06BD05

Mechanism of action

Sotrovimab is a human IgG1 mAb that binds to a 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.

Table 2. Sotrovimab neutralisation data for SARS-CoV-2 variants:

^a Based on EC₅₀ fold change compared to wild-type. No change: ≤5-fold change in EC₅₀ compared to wild-type.
^b Variant has not been named by the WHO.
^c The BA.2.86, BN.1 and JN.1 variants contain the K356T substitution.

Antiviral resistance

Cell culture studies

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 virus-like particle (VLP) assay.

Table 3 shows the activity data for sotrovimab against epitope sequence polymorphisms evaluated in pseudotyped VLP assessments in cell culture using the Wuhan-Hu-1 and Omicron BA.1, BA.2 and BA.5 spike proteins.

Table 3. Sotrovimab pseudotyped VLP assessments in cell culture against epitope substitutions:

^a Based on EC₅₀ fold change relative to each spike viral variant. No change: ≤5-fold change; –: depicts not tested.
^b Wuhan-Hu-1 strain
^c Omicron lineages

Clinical studies

SARS-CoV-2 viruses with baseline and treatment-emergent substitutions at amino acid positions associated with reduced susceptibility to sotrovimab in vitro were observed in patients enrolled in clinical studies who received a 500 mg intravenous infusion of sotrovimab (Table 4). In the COMET-ICE and COMET-TAIL studies, among patients who were treated with a 500 mg intravenous infusion of sotrovimab and had a substitution detected at amino acid positions 337 and/or 340 at any visit baseline or post-baseline, 1 of 32 and none of 33 patients, respectively, met the primary endpoint for progression to hospitalisation for >24 hours for acute management of any illness or death from any cause through Day 29. This single patient had E340K detected post-baseline and was infected with the Epsilon variant of SARS-CoV-2.

Table 4. Baseline and treatment-emergent substitutions detected in sotrovimab-treated patients at amino acid positions associated with reduced susceptibility to sotrovimab:

^a n = number of sotrovimab-treated patients with a baseline substitution detected at spike amino acid positions 337 or 340. Spike position 356 was also included for the LUNAR study which enrolled patients with Omicron BA.2, BA.4 or BA.5 lineage SARS-CoV-2 variants; N = total number of sotrovimab-treated patients with baseline sequence results.
^b n = number of sotrovimab-treated patients with treatment-emergent substitutions detected at spike amino acid positions 337 or 340. Spike position 356 was also included for the LUNAR study which enrolled patients with Omicron BA.2, BA.4 or BA.5 lineage variants; N = total number of sotrovimab-treated patients with paired baseline and post-baseline sequence results.
^c A multicentre, single arm, prospective, genomic surveillance study that followed non-hospitalised immunocompromised patients who received 500 mg intravenous infusion of sotrovimab.

Immunogenicity

Treatment-emergent anti-drug antibodies (ADAs) to a single 500 mg intravenous infusion of sotrovimab were detected in 9% (101/1101) of participants, in controlled clinical studies with follow up durations of 18-36 weeks. No participants with confirmed treatment-emergent ADAs had neutralising antibodies against sotrovimab, and there was no evidence of an association of ADA with any impact on the safety, efficacy, or pharmacokinetics after a single intravenous infusion.

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, non-vaccinated 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 and was conducted when the wild-type Wuhan-Hu-1 virus was predominant, with the highest frequency of variants being Alpha and Epsilon. 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. In the Intent to Treat (ITT) population at Day 29, 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 5. 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).