Real-World Effectiveness of Sotrovimab for the Early Treatment of COVID-19: Evidence from the National COVID Cohort Collaborative (N3C)

Objectives: To describe and compare real-world outcomes for patients with mild-to-moderate COVID-19 at high risk for progression to severe COVID-19, treated with sotrovimab versus untreated. Method(s): Electronic health records from the National COVID Cohort Collaborative were used to identify US patients (aged >=12 years) diagnosed with COVID-19 (positive test or ICD-10: U07.1) in an ambulatory setting (26 May 2021-30 April 2022) who met Emergency Use Authorization high-risk criteria. Patients receiving the monoclonal antibody (mAb) sotrovimab within 10 days of diagnosis were assigned to the sotrovimab cohort with an index date on the day of infusion. Untreated patients (no evidence of early mAb treatment or prophylaxis mAb or oral antiviral treatment) were assigned to the untreated cohort with an imputed index date based on the time distribution between diagnosis and sotrovimab infusion for the sotrovimab cohort. The primary endpoint was hospitalization or death (both all-cause) within 29 days of index, reported as descriptive rates and adjusted (via inverse-probability-of-treatment weighting [IPTW]) odds ratios (OR) and 95% confidence intervals (CI). Result(s): Of nearly 2.9 million patients diagnosed with COVID-19 during the analysis time period, 4,992 met the criteria for the sotrovimab cohort and 541,325 were included in the untreated cohort. Patients in the sotrovimab cohort were older (60 versus 54 years), more likely to be male (40% versus 38%) and White (85% versus 75%), and met more EUA criteria (3 versus 2) versus the untreated cohort. The 29-day hospitalization or mortality rates were 3.5% (176/4,992) and 4.5% (24,163/541,325) in the sotrovimab and untreated cohorts respectively (unadjusted OR [95% CI]: 0.77 [0.67,0.90];p=0.001;IPTW-adjusted OR [95% CI]: 0.74 [0.61,0.91];p=0.004). Conclusion(s): Sotrovimab demonstrated clinical effectiveness in preventing severe outcomes (hospitalization, mortality) between 26 May 2021-30 April 2022, which included the Delta variant and early surge of Omicron BA.1/BA.2. Funding(s): GSK (Study 219020)Copyright © 2023

Real-world effectiveness of sotrovimab for the early treatment of COVID-19 in the US

The objective was to evaluate real-world effectiveness of sotrovimab, a monoclonal antibody (mAb) for the treatment of high-risk outpatients with COVID-19, in reducing the risk of mortality or hospitalization during the SARS-CoV-2 Delta and initial Omicron variant waves in the US. A retrospective analysis was conducted of de-identified, high-risk patients diagnosed with COVID-19 (index date) from 1 September 2021 to 28 February 2022 in the FAIR Health FH NPIC claims database. Patients were divided into 2 cohorts based on claimed procedural codes: treated with sotrovimab and not treated with any mAb (no mAb). Facility-reported mortality ("mortality"), all cause hospitalizations and intensive care unit (ICU) admissions <=30 days of index were identified. Multivariable logistic regression was conducted to estimate the risk of 30-day mortality or hospitalization, adjusting for demographic and clinical factors. Of the high-risk COVID-19 patients identified,13,140 were treated with sotrovimab and 1,283,284 received no mAb therapy. In the no mAb cohort, 0.59% died and 5.74% were hospitalized (of whom 30% in ICU). In the sotrovimab cohort, 0.08% died and 2.50% were hospitalized (of whom 15% in ICU). After adjusting for potential confounders, sotrovimab treatment was associated with 85% reduced odds of 30-day mortality (OR: 0.15, 95% CI: 0.08-0.31) and 61% reduced odds of 30-day hospitalization or mortality (OR: 0.39, 95% CI: 0.35-0.44) among high-risk COVID-19 patients. In this US real-world study of high-risk COVID-19 patients during the Delta and initial Omicron waves, treatment with sotrovimab was associated with reduced odds of mortality and hospitalization compared to no mAb treatment.

Real-world Effectiveness of Sotrovimab for the Early Treatment of COVID-19 in the US

Background. Sotrovimab, a monoclonal antibody (mAb), received Emergency Use Authorization (EUA) for the treatment of high-risk outpatients with symptomatic COVID-19. The study objective was to evaluate real-world effectiveness of sotrovimab (500 mg intravenous) in reducing the risk of mortality or hospitalization during the SARS-CoV-2 Delta and initial Omicron variant waves in the US. Methods. A retrospective analysis was conducted of de-identified patients (pts) diagnosed with COVID-19 (ICD-10: U07.1) from 9/1/2021 to 2/28/2022 in the FAIR Health FH NPIC claims database. Pts were divided into 2 cohorts based on HCPCS codes: treated with sotrovimab and not treated with any mAb (no mAb). Pts meeting EUA high-risk criteria were identified via pre-specified ICD-10-CM diagnoses in records <= 24 months prior to their first COVID-19 diagnosis (index date). Facility-reported mortality (referred to as 'mortality'), all cause hospitalizations and intensive care unit (ICU) admissions within 30 days of index were identified. Chi-square test, ANOVA, or t-tests were performed to statistically compare cohorts at a 0.05 level of significance (2-sided). P-values were not adjusted for multiplicity. Multivariable logistic regression was conducted to estimate the risk of mortality or hospitalization within 30 days, adjusting for demographic and clinical factors. Results. Of the high-risk COVID-19 pts identified, 13,140 were treated with sotrovimab and 1,283,284 received no mAb therapy. Compared to the no mAb cohort, the sotrovimab cohort was older, had more baseline conditions, and were more likely to be female (all p < 0.0001). In the no mAb cohort, 0.59% died and 5.74% were hospitalized (of whom 30% in ICU). In the sotrovimab cohort, 0.08% died and 2.50% were hospitalized (of whom 15% in ICU). After adjusting for potential confounders, treatment with sotrovimab was associated with 83% reduced odds of 30-day mortality (OR: 0.17, 95% CI: 0.09-0.31) and 61% reduced odds of 30-day hospitalization or mortality (OR: 0.39, 95% CI: 0.35-0.43) among high-risk COVID-19 pts. Conclusion. In this US real-world observational study of high-risk COVID-19 pts during the Delta and initial Omicron waves, treatment with sotrovimab was associated with reduced odds of mortality and hospitalization compared to no mAb treatment.

Exhale to online-transitioning a group exercise programme to a telehealth model in a palliative care setting

Aim: Due to the Covid-19 pandemic, specialist palliative care services have had to adapt the delivery of service for patient safety, particularly outpatient group interventions.The physiotherapy department had successfully run an exercise and education programme for patients with advanced lung disease who are severely deconditioned, breathless and unsuitable for inclusion in standard rehabilitation programmes. The aim of this project was to adapt the programme from its original format and transition it to an evidence-based telehealth(TH) programme. Design: We reviewed evidence-based literature examining successful TH service delivery and liaised with an established TH pulmonary rehabilitation service. Results: Through our research, we identified the following areas of concern;Technology-Considerations for selecting a videoconferencing platform included user-friendliness and quality of audio-visual functions. Instruction leaflets to assist patients navigate the platform were developed. Security measures such as the ability to provide password protected meetings and data encryption were considered. Safety-A home visit was completed, including a review of exercise precautions. It was recommended that a second person be present during classes. A risk assessment was completed for those without a second person. Classes were facilitated by two physiotherapists;one leading the class while the other monitored patients for adverse events. This programme has been successfully running for 3 months with no adverse events. Conclusion/Lessons learned: This project has given us insight into the benefits of having an online platform. Initial concerns regarding patients' ability to master technology were eased and only minimal troubleshooting was required. Future research should investigate whether it is sustainable over a longer period without affecting quality of care. Existing research was limited and this project has provided a platform for which guidelines may be developed.

The efficacy of remote virtual care in comparison to traditional clinical visits for elective orthopaedic patients: A meta-analysis of prospective randomised controlled trials.

INTRODUCTION: The Orthopaedic Trauma Association has recommended limitation of in-person encounters to absolute necessity. One method of ensuring standard patient care within these guidelines is through the implementation of telemedicine. AIMS: To evaluate the efficacy of telemedicine for elective orthopaedic patients in the recovery and/or rehabilitation period. METHODS: A systematic review and meta-analysis of articles in Medline/PubMed and The Cochrane Library databases was performed according to the PRISMA guidelines for prospective randomised controlled trials to compare clinical and symptomatic measures for elective patients managed routinely with remote care compared to those managed with standard in-clinic management. To be included for meta-analysis, parameters must be evaluated in ≥3 studies. RESULTS: Eleven studies were included in the meta-analyses. Both telemedicine and control cohorts were comparable for patient satisfaction (RR, 0.98; 95% CI, 0.90-1.07; I2 = 0%; p = 0.52) and patient retention analysis (RR, 1.25; 95% CI, 0.51-3.06; p = 0.54; I2 = 0%). Similarly, there was no statistical difference appreciated between cohorts for overall Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) score (p = 0.30), Timed Up and Go Test (p = 0.40), and Stair Test (p = 0.18). Significant difference did exist for visual analogue scale (VAS) scores (p = 0.02) in favour of in-clinic management. CONCLUSION: Telemedicine will serve an integral aspect of healthcare delivery throughout the current COVID-19 pandemic and beyond in an effort to deliver safe, efficient and time-sensitive care to the orthopaedic patient population. The results of our meta-analyses indicate that virtual consultations are as effective as traditional in-person consultations for the care of elective orthopaedic patients in the recovery and rehabilitation period. However, further studies are needed to evaluate for initial consultations and certain sub-specialties of orthopaedics.

SARS-CoV-2 infection induces EMT-like molecular changes, including ZEB1-mediated repression of the viral receptor ACE2, in lung cancer models

Background: SARS-CoV-2 infection is the cause of the respiratory illness COVID-19, which presents most frequently with respiratory symptoms. SARS-CoV-2 cell entry requires interactions with ACE2 and TMPRSS2 on the surface of the host cell. Cancer patients and, specifically, those with thoracic malignancies seem to experience poorer clinical outcomes. Methods: We utilized bulk and single-cell transcriptional data from a combination of normal and malignant tissues and cells from aerodigestive and respiratory tracts to explore mechanisms governing the expression of ACE2 and TMPRSS2. Additionally, we determined the effect of EMT induction, ZEB1 modulation, and SARS-CoV-2 infection on ACE2 expression. Results: Our bulk data suggests that aerodigestive and lung cancer models express a broad range of ACE2 and TMRPSS2, particularly in epithelial cells, and would serve as good models for studying SARS-CoV-2 infection. We assessed the relationship between ACE2 and epithelial differentiation in numerous datasets, and found consistent positive correlations with transcriptional and microRNA signifiers of epithelial differentiation. The miR-200 family – zinc finger E-box-binding homeobox 1 (ZEB1) pathway, which is an established regulator of EMT, also directly regulates ACE2 expression, likely via putative ZEB1 repressor sites located in the ACE2 promoter. Furthermore, SARS-CoV-2 infection reduces ACE2 expression and shifts cells to a more mesenchymal phenotype with loss of EPCAM and upregulation of ZEB1 and other EMT-associated genes. Conclusions: ACE2-positive cells are almost exclusively epithelial and unexpectedly rare, considering the devastating impact of this infection. Following viral entry, SARS-CoV-2 infection induces molecular changes within the cells that are reminiscent of EMT, including increased ZEB1. ZEB1, in turn, appears to directly repress the expression of ACE2. This SARS-CoV-2-induced ACE2 deficiency, compounded by the downregulation of genes, including claudins, which play a critical role in restricting epithelial and endothelial permeability, exposes respiratory cells to increased risk of edema and acute respiratory distress syndrome (ARDS). Legal entity responsible for the study: The authors. Funding: NIH/NCI R01-CA207295 (L.A.B.), NIH/NCI U01-CA213273 (L.A.B., J.V.H.), CCSG P30-CA01667 (L.A.B.), University of Texas SPORE in Lung Cancer P5-CA070907 (L.A.B., D.L.G., J.V.H., C.M.G.), the Department of Defense (LC170171;L.A.B.), Khalifa Bin Zayed Al Nahyan Foundation (C.M.G.), RP170067 (EMP), through generous philanthropic contributions to The University of Texas MD Anderson Lung Cancer Moon Shot Program and Andrew Sabin Family Fellowship, and The Rexanna Foundation for Fighting Lung Cancer. Disclosure: C. Gay: Research grant/Funding (self): Astra Zeneca. J.V. Heymach: Advisory/Consultancy: AstraZeneca;Advisory/Consultancy: Boehringer Ingelheim;Advisory/Consultancy: Exelixis;Advisory/Consultancy: Genentech;Advisory/Consultancy: GlaxoSmithKline;Advisory/Consultancy: Guardant Health;Advisory/Consultancy: Hengrui;Advisory/Consultancy: Spectrum. L.A. Byers: Advisory/Consultancy, Research grant/Funding (self): AstraZeneca;Advisory/Consultancy, Research grant/Funding (self): AbbVie;Advisory/Consultancy, Research grant/Funding (self): GenMab;Advisory/Consultancy: BergenBio;Advisory/Consultancy: Pharma Mar SA;Advisory/Consultancy, Research grant/Funding (self): Sierra Oncology;Advisory/Consultancy: Merck;Advisory/Consultancy: Bristol Myers Squibb;Advisory/Consultancy: Genentech;Advisory/Consultancy: Pfizer;Research grant/Funding (self): Tolero Pharmaceuticals. All other authors have declared no conflicts of interest.

Elevated AXL expression following SARS-CoV-2 infection in non-small cell lung cancer

Background: Patients with thoracic cancers affected by the coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), appear to have poor clinical outcomes. AXL, a TAM (Tyro3, AXL, Mer) family receptor tyrosine kinase, is a known mediator of epithelial to mesenchymal transition (EMT) and therapeutic resistance in non-small cell lung cancer (NSCLC) and other cancers. Additionally, AXL plays a role in efficient Ebola and Zika viral entry and infection and AXL inhibition has demonstrated antiviral activities. Recently, bemcentinib, a highly selective and potent AXL inhibitor with antiviral activity, has been fast-tracked as the first potential treatment for assessment in the United Kingdom’s ACcelerating COVID-19 Research & Development (ACCORD) multicenter, randomized phase II trial. Methods: We analyzed mRNA expression of AXL and other TAM family members as well as angiotensin-converting enzyme 2 (ACE2), the SARS-CoV-2 receptor, in treatment-naïve (n=1016) and previously treated (n=239) NSCLC tumors and in a panel of NSCLC cell lines (n=70). We also analyzed AXL mRNA levels in NSCLC cell lines (n=3) infected with SARS-CoV-2. Results: In treatment-naïve and previously-treated NSCLC tumors, AXL mRNA expression was higher in mesenchymal tumors, as expected, and inversely correlated with ACE2. Similarly, in NSCLC cell lines, high ACE2 expression was associated with low AXL mRNA and protein expression. Notably, expression of ACE2 was downregulated while that of AXL and ZEB1, an EMT transcription factor, were upregulated in NSCLC cells infected with SARS-CoV-2 as compared to mock infected cells, suggesting a shift to a more mesenchymal phenotype. Treatment with bemcentinib for 24h downregulated ZEB1 expression in mesenchymal cell lines, reversing EMT. Conclusions: These data, in the context of ACE2’s role in preventing acute respiratory distress syndrome, suggest a shift from ACE2-expressing epithelial cells to a more mesenchymal phenotype characterized by low ACE2 and high AXL expression, upon infection of NSCLC cells with SARS-CoV-2. In addition to bemcentinib’s antiviral activity, it can also reverse EMT, further supporting AXL and EMT as novel therapeutic targets for COVID-19 treatment. Legal entity responsible for the study: Lauren A. Byers. Funding: NIH/NCI CCSG P30-CA016672 (Bioinformatics Shared Resource), NIH/NCI T32 CA009666, ASCO Young Investigator Award (C.M.G.);University of Texas SPORE in Lung Cancer P5-CA070907 (L.A.B. C.M.G.), NIH/NCI R01-CA207295, NIH/NCI U01-CA213273, the Department of Defense (LC170171) (L.A.B.), The LUNGevity foundation (D.G., L.A.B.), through generous philanthropic contributions to The University of Texas MD Anderson Lung Cancer Moon Shot Program (J.V.H., J.W., L.A.B.);an Andrew Sabin Family Fellowship (L.A.B.), and The Rexanna Foundation for Fighting Lung Cancer (J.V.H., L.A.B.). Disclosure: C. Gay: Research grant/Funding (self): AstraZeneca. D. Gibbons: Advisory/Consultancy, Research grant/Funding (self): AstraZeneca;Advisory/Consultancy: GlaxoSmithKline;Advisory/Consultancy: Sanofi;Advisory/Consultancy, Research grant/Funding (self): Janssen;Research grant/Funding (self): Takeda;Research grant/Funding (self): Ribon Therapeutics;Research grant/Funding (self): Astellas. J.V. Heymach: Advisory/Consultancy, Research grant/Funding (self): AstraZeneca;Advisory/Consultancy: Boehringer Ingelheim;Advisory/Consultancy: Exelixis;Advisory/Consultancy: Genentech;Advisory/Consultancy, Research grant/Funding (self): GlaxoSmithKline;Advisory/Consultancy: Guardant Health;Advisory/Consultancy: Hengrui;Advisory/Consultancy: Lilly;Advisory/Consultancy: Novartis;Advisory/Consultancy, Research grant/Funding (self), Licensing/Royalties: Spectrum;Advisory/Consultancy: EMD Serono;Advisory/Consultancy: Synta;Research grant/Funding (self): Bayer. L.A. Byers: Advisory/Consultancy, Research grant/Funding (self): AstraZeneca;AbbVie;GenMab;Sierra Oncology;Advisory/Consultancy: BergenBio;Pharma Mar SA;Merck;Bristol Myers Squibb;G nentech;Pfizer;Research grant/Funding (self): Tolero Pharmaceuticals. All other authors have declared no conflicts of interest.

SARS-CoV-2 infects metabolically-primed epithelial cells in lung cancer models

Background: The novel coronavirus SARS-CoV-2 is the cause of the respiratory illness COVID-19—a global pandemic affecting over 4 million individuals worldwide. Viruses efficiently replicate by hijacking host cell machinery to obtain macromolecules and energy by similar mechanisms as cancer cells. Since viral infection is known to alter cellular nutrient requirements, this study explores the metabolites and metabolic pathways associated with SARS-CoV-2 infection. Methods: Bulk and single-cell seequencing data from cell lines and tumor samples were retrieved from publically available datasets. Transcriptional data were retrieved from publically available datasets of gefitinib- and erlotinib-resistant EGFR-mutant cell lines and Calu3 and A549 cells mock treated or infected with SARS-CoV-2. Single-cell RNAseq datasets of EGFR-mutant PC-9 mock and osimertinib treated were downloaded from GEO. 225 metabolites were profiled in CCLE cell lines using LC-MS. Results: To identify metabolic features of cells able to be infected by SARS-CoV-2 via the ACE2 receptor, metabolites associated with ACE2 expression were investigated. ACE2 expression positively correlates with glutamine in upper aerodigestive tract cell lines. Consistent with this, ACE2 expression was examined against a list of 253 metabolism-associated genes and GLUL, which encodes an enzyme (glutamine synthetase) responsible for conversion of glutamate to glutamine, was significantly positively correlated in NSCLC, HNSCC, and SCLC cell lines and confirmed in human tumor datasets. Additionally, GLS, which encodes the enzyme (glutaminase) that catalyzes the opposing reaction, is negatively correlated with ACE2 expression. Further, we analyzed RNA sequencing data from NSCLC cell lines infected with SARS-CoV-2 for 24 hours and revealed that upon infection there is a down regulation of GLUL signifying a metabolic-shift away from glutamine as the cells undergo EMT. Conclusions: We show that SARS-CoV-2 targeting of ACE-2 expressing, metabolically-primed epithelial cells is advantageous to exploit the abundance of glutamine to synthesize nucleotides for rapid replication and viral spread. Legal entity responsible for the study: Lauren A. Byers. Funding: NIH/NCI R01-CA207295 (L.A.B.), NIH/NCI U01-CA213273 (L.A.B., J.V.H.), CCSG P30-CA01667 (L.A.B.), University of Texas SPORE in Lung Cancer P5-CA070907 (L.A.B., D.L.G., J.V.H., C.M.G.), the Department of Defense (LC170171;L.A.B.), Khalifa Bin Zayed Al Nahyan Foundation(C.M.G.), The University of Texas MD Anderson Cancer Center-Oropharynx Cancer Program generously supported by Mr. and Mrs. Charles W. Stiefel (F.M.J.), through generous philanthropic contributions to The University of Texas MD Anderson Lung Cancer Moon Shot Program and Andrew Sabin Family Fellowship, and The Rexanna Foundation for Fighting Lung Cancer. Disclosure: C. Gay: Research grant/Funding (self): AstraZeneca. S. Heeke: Honoraria (self): Qiagen;Boehringer Ingelheim;Travel/Accommodation/Expenses: Roche. D. Gibbons: Advisory/Consultancy, Research grant/Funding (self): AstraZeneca;Janssen;Advisory/Consultancy: GlaxoSmithKline;Sanofi;Research grant/Funding (self): Takeda;Ribon Therapeutics;Astellas. J.V. Heymach: Advisory/Consultancy, Research grant/Funding (self): AstraZeneca;Advisory/Consultancy: Boehringer Ingelheim;EMD Serono;Novartis;Lilly;Hengrui;Guardant Health;GSK;Genentech;Exelixis;Synta;Advisory/Consultancy, Research grant/Funding (self), Licensing/Royalties: Spectrum;Research grant/Funding (self): Bayer;GlaxoSmithKline. L.A. Byers: Advisory/Consultancy: Pfizer;Genentech;: Bristol Myers Squibb;Merck;Pharma Mar SA;BergenBio;Advisory/Consultancy, Research grant/Funding (self): Sierra Oncology;GenMab;AstraZeneca;AbbVie;Research grant/Funding (self): Tolero Pharmaceuticals. All other authors have declared no conflicts of interest.