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Background Sotrovimab is a human monoclonal antibody targeting a conserved region of the SARS-CoV-2 spike (S) protein. COMET-PEAK was a 3-part, phase 2 study that evaluated intravenous (500 mg) and intramuscular (500 mg and 250 mg) administration of sotrovimab in outpatients (n=353) with mild-to-moderate COVID-19. We assessed amino acid substitutions in the SARS-CoV-2 S protein and circulating variants of concern/interest (VOC/VOI) in COMET-PEAK participants (enrolled Feb–July 2021). Methods Mid-turbinate (Part A) or nasopharyngeal (Part B/C) samples were obtained from all participants at Baseline and Post-Baseline visits. Next generation sequencing of the SARS-CoV-2 S gene was conducted using Illumina MiSeq with a ≥5% allelic frequency cut-off for samples with a viral load above 3.0 log10 copies/mL. Baseline, post-baseline and treatment-emergent (TE) substitutions were assessed, and prevalence of VOC/VOI was evaluated. Phenotypic analyses of epitope substitutions were conducted using a pseudotyped virus assay. Results In total, 282/353 participants had sequencing results for ≥1 visit (253 baseline, 248 post-baseline), and 219 had paired baseline and post-baseline sequences; among these, 149 (68%) had TE substitutions in the S protein (26 [12%] in the epitope). E340K was the predominant TE substitution in the epitope (15 [7%]). Across all arms 92/245 (38%) experienced virologic rebound, 8 of whom (Part A: 2; Part B: 2; Part C: 4) had TE substitutions in the epitope; none had evidence of clinical progression to severe disease. Prevalence of VOC/VOI or single amino acid substitutions of concern was 94% (266/282); the most frequent were Alpha (Part A: 8/16 [50%]; Part B: 75/128 [59%]) and Delta (Part C: 99/122 [81%]). Of 7 participants with evidence of clinical progression, none had S protein substitutions in the epitope and all had VOC/VOI (3 Alpha, 3 Delta, 1 Gamma). Sotrovimab effectively neutralized most epitope substitutions tested in vitro; P337L and E340A/K/V conferred significantly reduced susceptibility. Conclusion There was no evidence that sotrovimab epitope substitutions were associated with clinical progression or virologic rebound. These data are consistent with those from the COMET-ICE study. Funding Vir Biotechnology/GSK (NCT04779879). Disclosures Phillip J Yates, PhD, GlaxoSmithKline: Employee Jennifer Moore, MD, GlaxoSmithKline: Employee Jennifer Han, MD, GlaxoSmithKline: Employee Andrew Skingsley, MD, GlaxoSmithKline: Employee|GlaxoSmithKline: Stocks/Bonds Gretja Schnell, PhD, Vir Biotechnology: Employee|Vir Biotechnology: Stocks/Bonds Andrea L. Cathcart, PhD, Vir Biotechnology: Employee|Vir Biotechnology: Stocks/Bonds Melissa Aldinger, PharmD, Vir Biotechnology: Employee|Vir Biotechnology: Stocks/Bonds Amanda Peppercorn, MD, GlaxoSmithKline: Employee|GlaxoSmithKline: Stocks/Bonds Jill Walker, PhD, GlaxoSmithKline: Employee.

Background There is a continued need for therapeutics for the treatment of COVID-19, including intramuscular (IM) agents, which will enable broader use across a variety of healthcare delivery settings. Methods COMET-PEAK (NCT04779879) is a 3-part study evaluating the safety, tolerability, pharmacokinetics (Part A), and viral pharmacodynamics (PD) of sotrovimab as treatment in adults ≥ 18 years with early mild/moderate COVID-19. In Parts B and C, the safety, tolerability and viral PD of sotrovimab administered as a 500 mg intravenous (IV) infusion or as a 500 mg or 250 mg IM injection, respectively, was evaluated. The primary objective for Parts B and C was to compare the virologic response of sotrovimab IM to IV, with an endpoint of mean area under the curve (AUC) of SARS-CoV-2 viral load as measured by qRT-PCR from Day 1 to Day 8 (AUCD1-8) in nasopharyngeal swabs and predefined 90% confidence interval (CI) limits of 0.5-2.0 indicating equivalence. Results A total of 167 and 157 participants were enrolled in Part B and C, respectively, from February-July 2021. The median age of participants was 47 and 42 years in Part B and C, respectively, and ∼50% had ≥ 1 risk factor for progression to severe disease. The viral load at baseline and through Day 29 of follow-up for each arm is shown in Table 1 and Figure 1. The primary objective was met for both study parts: the ratio of the least square geometric mean viral load AUC(D1-8) of sotrovimab IM vs IV was 1.04 (90% CI, 0.98, 1.09) and 1.02 (90% CI, 0.94, 1.11), for Part B and C, respectively. Through Day 29 of follow-up, the most common adverse event was injection site reactions (ISRs) in the IM arms. A total of 10 (12%) participants in the 500 mg IM group and 4 (5%) participants in the 250 mg IM group experienced an ISR, all Grade 1. Serious adverse events were uncommon, and related to COVID-19 progression, including one death in the 250 mg IM arm (Table 2). ISRs aside, there were few treatment-related AEs (2/84 IV, 1/82 IM) in Part B, none serious. Conclusion IM administration of sotrovimab 500 mg and 250 mg each demonstrated equivalence to 500 mg sotrovimab IV in viral load assessments. Overall, there were no treatment-related serious AEs and sotrovimab was well tolerated. An 500 mg IM formulation will allow for expanded treatment potential with sotrovimab. Funding Vir/GSK (NCT04779879). Disclosures Anil K. Gupta, MD, Vir Biotechnology: Advisor/Consultant|Vir Biotechnology: Grant/Research Support|Vir Biotechnology: Speaker Moti Ramgopal, MD, FACP, FIDSA, AbbVie: Grant/Research Support|Gilead Sciences Inc.: Advisor/Consultant|Gilead Sciences Inc.: Grant/Research Support|Gilead Sciences Inc.: Honoraria|Gilead Sciences Inc.: Stocks/Bonds|GlaxoSmithKline: Advisor/Consultant|GlaxoSmithKline: Grant/Research Support|GlaxoSmithKline: Honoraria|GlaxoSmithKline: Stocks/Bonds|Janssen Research & Development LLC: Advisor/Consultant|Janssen Research & Development LLC: Grant/Research Support|Janssen Research & Development LLC: Honoraria|Janssen Research & Development LLC: Stocks/Bonds|Merck: Advisor/Consultant|Merck: Grant/Research Support|Merck: Honoraria|Merck: Stocks/Bonds|Shionogi: Grant/Research Support|ViiV: Advisor/Consultant|ViiV: Grant/Research Support Jennifer Han, MD, GlaxoSmithKline: Employee Jennifer Moore, MD, GlaxoSmithKline: Employee Rudrani Banerjee, PhD, GSK: Employee|GSK: Stocks/Bonds Phillip Yates, PhD, GSK: Employee during conduct of this research|GSK: Stocks/Bonds Jill Walker, PhD, GlaxoSmithKline: Employee Gretja Schnell, PhD, Vir Biotechnology: Employee|Vir Biotechnology: Stocks/Bonds Mary Beth Connolly, PharmD, GSK: Employee|GSK: Stocks/Bonds Andrea L. Cathcart, PhD, Vir Biotechnology: Employee|Vir Biotechnology: Stocks/Bonds Varsha Imber, MSc, GSK: Employee|GSK: Stocks/Bonds Rabia Anselm, n/a, GSK: Employee|GSK: Stocks/Bonds Lindsay Winograd, MSc, GSK: Employee|GSK: Stocks/Bonds Nancy Haeusser, n/a, GSK: Employee|GSK: Stocks/Bonds Scott Segal, MD, GSK: Employee|GSK: Stocks/Bonds Andrew Skingsley, MD, GlaxoSmithKline: Employee|GlaxoSmithKline: Stocks/Bonds Melissa Aldinger, PharmD, Vir Biotechnology: Employee|Vir Biotechnology: Stocks/Bonds Amanda Peppercorn, MD, GlaxoSmithKline: Employee|GlaxoSmithKline: Stocks/Bonds.

Background Sotrovimab (VIR-7831) is an engineered human monoclonal antibody targeting a conserved region of the SARS-CoV-2 spike protein; it has been shown to have a favorable safety profile and be effective for early treatment of high-risk COVID-19 patients. The COMET-TAIL phase 3 study evaluated sotrovimab administered intravenously (IV) or intramuscularly (IM) for the treatment of participants with mild to moderate COVID-19 who are at high risk of disease progression. Methods Between June to August 2021, 973 participants were randomized and received sotrovimab by 500 mg IV infusion or by 500 or 250 mg IM injection. Deep sequencing of the spike gene was performed on nasopharyngeal samples. Baseline (BL; Day 1 or Day 3), post-BL (Day 5 or later), treatment-emergent (TE) substitutions at sotrovimab epitope positions, and presence of variants of concern/interest (VOC/VOI), were evaluated at a ≥5% allelic frequency. Phenotypic analyses were conducted using a pseudotyped virus assay. Results Sequences were available from 764 participants (500 mg IV: 314/393; 500 mg IM: 302/387; 250 mg IM: 148/193). Consistent with VOC circulation during enrollment, the Delta variant was detected in 88.2% (674/764) of participants. Alpha and Mu variants were also seen at >2% prevalence. Of the 764 participants, 26 met the primary endpoint for clinical progression to hospitalization >24 hours or death due to any cause through day 29 and were infected with Delta (500 mg IV: 4; 500 mg IM: 9; 250 mg IM: 11), Alpha (500 mg IM: 1), or Mu (500 mg IV: 1) variants. Substitutions at sotrovimab epitope positions were similar across arms and were detected in 82/764 (10.7%) participants at any visit (500 mg IV: 42/314; 500 mg IM: 27/302; 250 mg IM: 13/148). Of these, 2 participants experienced clinical progression: 1 participant infected with the Mu variant (500 mg IV) carried the characteristic R346K substitution at BL; 1 participant infected with the Delta variant (500 mg IM) had P337L and E340K substitutions detected at Day 3 and P337L was enriched at Day 8. The predominant TE epitope substitutions included P337L and E340A/K/V, which confer reduced susceptibility to sotrovimab in vitro. Conclusion Overall, TE epitope substitutions were not associated with clinical progression. Funding Vir & GSK (NCT04913675) Disclosures Maria L. Agostini, PhD, Vir Biotechnology, Inc: Employee|Vir Biotechnology, Inc: Stocks/Bonds Gretja Schnell, PhD, Vir Biotechnology: Employee|Vir Biotechnology: Stocks/Bonds Julia di Iulio, PharmD, PhD, MBA, Vir Biotechnology: Employee|Vir Biotechnology: Stocks/Bonds Anita Kohli, MD, GlaxoSmithKline: Third party funding to Vir|Vir Biotechnology Inc: Support as a trial site paid to my institution and non-financial support for medical writing support Adrienne E. Shapiro, MD, PhD, Vir Biotechnology: Support as a trial site paid to my institution and non-financial support for medical writing GlaxoSmithKline third party funding to Vir support Elias H. Sarkis, MD, Abbvie: Grant/Research Support|Abbvie: Speakers Bureau|Eisai: Grant/Research Support|GlaxoSmithKline: Third party funding to Vir|Ironshore: Grant/Research Support|Janssen: Speakers Bureau|Lilly: Grant/Research Support|Otsuka: Grant/Research Support|Teva: Speakers Bureau|Vir Biotechnology Inc: Support as a trial site paid to my institution and non-financial support for medical writing support Dave Inman, MSc, GlaxoSmithKline: Employee|GlaxoSmithKline: Stocks/Bonds Amanda Peppercorn, MD, GlaxoSmithKline: Employee|GlaxoSmithKline: Stocks/Bonds Andrew Skingsley, MD, GlaxoSmithKline: Employee|GlaxoSmithKline: Stocks/Bonds Leah A. Gaffney, PhD, Vir Biotechnology: Employee|Vir Biotechnology: Stocks/Bonds Melissa Aldinger, PharmD, Vir Biotechnology: Employee|Vir Biotechnology: Stocks/Bonds Christy M. Hebner, PhD, Vir Biotechnology: Employee|Vir Biotechnology: Stocks/Bonds Andrea L. Cathcart, PhD, Vir Biotechnology: Employee|Vir Biotechnology: Stocks/Bonds.

Objectives: To evaluate the effect of pH-altering agents on S/GSK1349572 exposure in healthy subjects. Methods: S/GSK1349572 is an unboosted, once-daily, next-generation HIV integrase inhibitor. In the first study, 16 subjects received four single-dose treatments: (i) S/GSK1349572 50 mg; (ii) S/GSK1349572 50 mg with a multivitamin (MVI; One A Day Maximum); (iii) S/GSK1349572 50 mg with a liquid antacid (Maalox Advanced Maximum Strength); and (iv) S/GSK1349572 50 mg 2 h before an antacid. In the second study, 12 subjects received a single dose of S/GSK1349572 alone and on day 5 of omeprazole. Results: All treatments were well tolerated. MVI co-administration modestly decreased S/GSK1349572 AUC by 33%. Concurrent antacid co-administration reduced S/GSK1349572 AUC by 74% and staggered antacid dosing significantly diminished this interaction, with a reduction in S/GSK1349572 AUC of 26%. Omeprazole did not significantly affect S/GSK1349572 exposure. Conclusions: S/GSK1349572 can be taken with proton pump inhibitors and MVIs without dose adjustment but should be administered 2 h before or 6 h after antacids.

Aspergillus spp. are ubiquitous environmental fungi that are increasingly recognized as a cause of severe illness and mortality in immunocompromised patients. More than 60 outbreaks of healthcare-associated invasive aspergillosis have been described in the English literature. Information gained from outbreak investigations, especially control measures, form the basis for current guidelines to prevent healthcare-associated aspergillosis. Guidelines from the Centers for Disease Control and Prevention (CDC) and Healthcare Infection Control Practices Advisory Committee (HICPAC) provide evidence-based recommendations for preventing healthcare-associated aspergillosis and should be adopted by healthcare facilities.