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5th August 2022
Resistance mutations have been found to develop after a few days treatment with sotrovimab in patients infected with Omicron sub-variants and which significantly delays the time to viral clearance. This was the conclusion of a small study by researchers from the University of Amsterdam.
Sotrovimab is an human monoclonal antibody that targets a highly conserved epitope in the COVID-19 spike protein at a region that does not compete with binding of the angiotensin-converting enzyme 2. The monoclonal antibody has been approved by the EMA to treat confirmed COVID-19 in adults and adolescents who do not require supplemental oxygen therapy and who are at risk of progressing to severe COVID-19. However, there is a concern over the development of resistance mutations in monoclonal antibodies and this has already been observed with sotrovimab in patients infected with the delta variant. Sotrovimab is one of the few monoclonal antibodies that retains efficacy against the widely circulating Omicron BA.1 sub-lineage although whether resistance mutations can still develop in those infected with the omicron variant and its sub-variants is unclear.
In the present study, the Dutch team examined whether resistance mutations could develop during therapy with sotrovimab in patients infected with Omicron. A single 500mg dose of the drug was administered to a group of ambulatory, hospitalised, high-risk patients with COVID-19 and nasopharyngeal specimens were collected on days 0, 7 and 28 and subjected to whole-genome sequencing. For the primary outcome, the Dutch team set the emergence of spike protein resistance-associated mutations at positions E340 or P337 during treatment with sotrovimab as the primary outcome. The team used a Cox proportional hazard model to estimate the time to viral clearance with resistance mutations as a covariate.
Resistance mutations and outcomes
A total of 47 high-risk patients were studied but only 18 had more than one nasopharyngeal specimen taken and included in the final analysis. The remaining patients either declined or could not be contacted. For the final cohort, the mean age was 60.9 years (50% female) and 15 were immunocompromised due to either immunosuppressive conditions or treatments. All of the patients were given sotrovimab between 0 and 23 days after a positive PCR test for COVID-19.
Genomic analysis revealed that all patients were infected with the omicron variant, 17 with BA.1 and the remaining patient BA.2. Overall, 10 patients (56%) developed resistance mutations at spike position E340 or P337 within 3 to 31 days after treatment. Four patients developed resistance mutations to E340, all of whom were immunocompromised. Furthermore, mutations developed quickly with more than 50% having arisen between days 5 and 28. In comparison to those without mutations, the time to viral clearance was significantly longer (32 vs 19.6 days), giving a hazard ratio of 0.11 (95% CI 0.02 – 0.60) in patients displaying resistance mutations.
While accepting the study was based on a small number of patients and that they did to include clinical outcomes for resistant patients, the authors called for further studies to investigate the value of combination monoclonal antibody therapy combined with genomic sequencing for immunocompromised patients.
Birnie E et al. Development of Resistance-Associated Mutations After Sotrovimab Administration in High-risk Individuals Infected With the SARS-CoV-2 Omicron Variant JAMA 2022
2nd December 2021
Xevudy (sotrovimab) which is a monoclonal antibody, has been approved by the UK regulator, the MHRA, after data showing that it can reduce the risk of hospitalisation and death in people with mild to moderate COVID-19 infection and who are at an increased risk of developing severe disease.
According to a press release by the manufacturer, GSK who developed the drug in collaboration with Vir Biotechnology, Inc, Xevudy binds to an epitope on COVID-19 shared with SARS-CoV-1 (the virus responsible for SARS). This suggests that the particular epitope is highly conserved and may therefore be less susceptible to mutations and hence development resistance to the therapy.
The manufacturer has embarked on several clinical trials with Xevudy which have included COMET-ICE, which was a phase 3, multi-centre, double-blind, placebo-controlled trial investigated sotrovimab in adults with mild-to-moderate COVID-19 at high risk of progression to severe disease, who are not hospitalised and not requiring oxygen.
COMET-TAIL another phase 3 randomised, multi-centre, open label, non-inferiority trial for the early treatment of mild-to-moderate COVID-19 in high-risk non-hospitalised adult and paediatric patients (12 years of age and older).
Interim results from COMET-ICE have been published in which 583 non-hospitalised, symptomatic COVID-19 patients were randomised, 1:1, less than 5 days after the onset of symptoms and with at least one risk factor for disease progression. Treatment consisted of a single infusion of sotrovimab at a dose of 500 mg or placebo. The results showed that 3 patients (1%) in the sotrovimab group and 21 patients (7%) in the placebo group, had disease progression leading to hospitalisation or death, giving a relative risk reduction of 85% (95% CI 44% – 96%, p = 0.002).
The full results of the COMET-ICE, which included 1057 patients showed that all-cause hospitalisation lasting over 24 hours, or death was significantly reduced with sotrovimab (1%) vs placebo (6%), giving an adjusted relative risk reduction of 0.79 (95% CI, 50% – 91%, p <.001). In other words, Xevudy reduced the risk of hospitalisations for longer than 24 hours or death by 79%.
According to the SPC, Xevudy is indicated for ‘the treatment of symptomatic adults and adolescents (aged 12 years and over and weighing at least 40 kg) with acute covid-19 infection who do not require oxygen supplementation and who are at increased risk of progressing to severe covid infection.’ It should be given as a single 500 mg dose and the SPC adds that ‘It is recommended that Xevudy is administered within 5 days of onset of symptoms of COVID-19.’
In a statement by the MHRA, it is noted that currently, it is uncertain whether the drug is effective against the omicron variant.