key: cord-0930681-oz2iyj8k
authors: Gupta, A.; Gonzalez-Rojas, Y.; Juarez, E.; Crespo Casal, M.; Moya, J.; Falci, D. R.; Sarkis, E.; Solis, J.; Zheng, H.; Scott, N.; Cathcart, A. L.; Hebner, C. M.; Sager, J.; Mogalian, E.; Tipple, C.; Peppercorn, A.; Alexander, E.; Pang, P. S.; Free, A.; Brinson, C.; Aldinger, M.; Shapiro, A. E.
title: Early Covid-19 Treatment With SARS-CoV-2 Neutralizing Antibody Sotrovimab
date: 2021-05-28
journal: nan
DOI: 10.1101/2021.05.27.21257096
sha: 8e2b78b2f6456b9d6923bd216b6f7e4e4ca16f25
doc_id: 930681
cord_uid: oz2iyj8k

Background: Coronavirus disease 2019 (Covid-19) disproportionately results in hospitalization and death in older patients and those with underlying comorbidities. Sotrovimab is a pan-sarbecovirus monoclonal antibody designed to treat such high-risk patients early in the course of disease, thereby preventing Covid-19 progression. Methods: In this ongoing, multicenter, double-blind, phase 3 trial, nonhospitalized patients with symptomatic Covid-19 and at least one risk factor for disease progression were randomized (1:1) to an intravenous infusion of sotrovimab 500 mg or placebo. The primary efficacy endpoint was the proportion of patients with Covid-19 progression, defined as hospitalization longer than 24 hours or death, through day 29. Results: In this preplanned interim analysis, which included an intent-to-treat population of 583 patients (sotrovimab, 291; placebo, 292), the primary efficacy endpoint was met. The risk of Covid-19 progression was significantly reduced by 85% (97.24% confidence interval, 44% to 96%; P = 0.002) with a total of three (1%) patients progressing to the primary endpoint in the sotrovimab group versus 21 (7%) patients in the placebo group. All five patients admitted to intensive care, including one who died by day 29, received placebo. Safety was assessed in 868 patients (sotrovimab, 430; placebo, 438). Adverse events were reported by 17% and 19% of patients receiving sotrovimab and placebo, respectively; serious adverse events were less common with sotrovimab (2%) versus placebo (6%). Conclusion: Sotrovimab reduced progression of Covid-19 in patients with mild/moderate disease, was well tolerated, and no safety signals were identified. Funded by Vir Biotechnology, Inc. and GlaxoSmithKline; ClinicalTrials.gov NCT04545060

The coronavirus disease 2019 (Covid-19) global pandemic is estimated to have killed over 3 million individuals worldwide. 1 In the United States alone, there were an estimated 960,000 to 2.4 million hospitalizations through Fall 2020 and, at the peak of the pandemic in January 2021, 79% of intensive care hospital beds were occupied by Covid-19 patients. [1] [2] [3] Older patients and those with certain comorbidities, such as obesity, diabetes mellitus, chronic pulmonary diseases, and chronic kidney disease, have been identified as those at highest risk of hospitalization or death. [4] [5] [6] [7] [8] Highly effective therapeutics directed against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the virus that causes Covid-19, are urgently needed for these high-risk individuals. Recent data suggest that one option is monoclonal antibody therapy, which can reduce the risk of hospitalization 9, 10 ; however, the emergence and proliferation of SARS-CoV-2 variants conferring resistance to some antibodies is deeply concerning. 11, 12 Furthermore, as additional variants of concern will likely continue to emerge, there is a high unmet medical need for therapeutics that, alone or in combination, can remain effective as the virus evolves. A monoclonal antibody that neutralizes SARS-CoV-2 by targeting an evolutionarily conserved epitope that lies outside the rapidly evolving receptor-binding motif is one possible solution-it would have an intrinsically higher barrier to resistance and, due to its nonoverlapping resistance profile, could be combined with receptor-binding motif-targeted antibodies when necessary to further heighten the barrier to resistance.

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The copyright holder for this preprint this version posted May 28, 2021. ; https://doi.org/10.1101/2021.05.27.21257096 doi: medRxiv preprint 6 Sotrovimab, formerly known as VIR-7831, is an engineered human monoclonal antibody that neutralizes SARS-CoV-2 and multiple other sarbecoviruses, including SARS-CoV, the virus responsible for the SARS outbreak two decades ago. 13 In fact, the parental form of sotrovimab, S309, was isolated from a SARS survivor. 13 We hypothesized that a monoclonal antibody that neutralizes all sarbecoviruses would target a highly conserved epitope that would be functionally retained as SARS-CoV-2 evolves (Fig. 1 11, 14, 15 In contrast, many of the other monoclonal antibodies being developed for Covid-19 bind to the receptor-binding motif that engages the angiotensin-converting enzyme 2 (ACE2) receptor and is one of the most mutable and immunogenic regions of the virus; in some cases, these antibodies do not retain activity against the variants. [16] [17] [18] [19] Sotrovimab contains a two-amino acid Fc modification (termed LS) to increase half-life and potentially improve bioavailability in the respiratory mucosa through enhanced engagement with the neonatal Fc receptor. [20] [21] [22] This modification potentially allows therapeutic concentrations for longer durations. [20] [21] [22] Sotrovimab has demonstrated potent effector functions in vitro, which have the potential to result in immune-mediated viral clearance. 13, 14 . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) Here, we report the results from a preplanned interim analysis of the COvid-19 Monoclonal antibody Efficacy Trial-Intent to Care Early (COMET-ICE) study evaluating the efficacy and safety of treatment with sotrovimab in high-risk, ambulatory patients with mild/moderate Covid-19. The trial is currently closed for enrollment; data collection is ongoing. Additional efficacy, safety, and laboratory data, as well as initial immunogenicity data, will be reported subsequently.

This phase 3, randomized, double-blind, multicenter, placebo-controlled study is evaluating a single intravenous infusion of sotrovimab 500 mg for the prevention of progression of CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review)

The copyright holder for this preprint this version posted May 28, 2021. ; https://doi.org/10.1101/2021.05.27.21257096 doi: medRxiv preprint 8 and the Sponsors and trial investigators participated in data collection, analysis, and interpretation.

Adult patients 18 years of age or older with a positive reverse-transcriptase-polymerase-chainreaction or antigen SARS-CoV-2 test result and onset of symptoms within the prior 5 days were screened for eligibility; screening was performed within 24 hours before study drug administration. Patients were required to be at high risk for Covid-19 progression, defined as older adults (age ≥ 55 years) or adults with at least one of the following risk factors: diabetes requiring medication, obesity (body-mass index >30 kg/m 2 ), chronic kidney disease (estimated glomerular filtration rate <60 mL/min/1.73 m 2 ), 23 congestive heart failure (New York Heart Association class II or higher), chronic obstructive pulmonary disease, and moderate to severe asthma. 24 Patients with already severe Covid-19, defined by shortness of breath at rest, respiratory distress, or requiring supplemental oxygen, were excluded. Full inclusion and exclusion criteria are described in the Supplementary Appendix.

Eligible patients were randomized 1:1 using an interactive web response system to receive either a single 500-mg, 1-hour infusion of sotrovimab or equal volume saline placebo on day 1 (Fig. 2) .

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The primary endpoint was the proportion of patients with hospitalization for more than 24 hours or death, due to any cause, through day 29. Secondary efficacy endpoints included the proportion of patients with an emergency room visit, hospitalization, or death; mortality; patient-reported outcomes; changes in viral load; and the proportion of patients who progressed to require supplemental oxygen.

Safety endpoints included adverse events, serious adverse events, and adverse events of special interest, defined as infusion-related reactions (including hypersensitivity reactions), immunogenicity testing for anti-drug antibodies, and evaluation of antibody-dependent enhancement. All hospitalizations, including those due to Covid-19, were counted as serious adverse events.

A preplanned interim analysis for safety, futility, and profound efficacy was triggered when approximately 41% of the required number of study patients reached day 29. Sample size calculations were based on a group sequential design with two interim analyses to assess both futility due to lack of efficacy or profound efficacy. A Lan-DeMets alpha spending function to control type I error was used, employing a Pocock analog rule for futility and a Hwang-Shih-DeCani (with parameter γ = 1) analog for efficacy. 25 The overall sample size of 1360 would have . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

The copyright holder for this preprint this version posted May 28, 2021. ; https://doi.org/10.1101/2021.05.27.21257096 doi: medRxiv preprint provided approximately 90% power to detect a 37.5% relative efficacy in reducing progression of Covid-19 through day 29 at the overall two-sided 5% significance level, with an assumed progression rate of 16% in the placebo group.

The interim analysis intent-to-treat (ITT) population included all randomized patients through the prespecified interim analysis cutoff date of January 19, 2021, irrespective of whether they received study drug. The interim analysis safety analysis population included all patients who received study medication and were randomized through February 17, 2021; patients were grouped according to the actual treatment received. The primary endpoint was analyzed in the ITT population using a Poisson regression model with robust sandwich estimators adjusting for treatment, duration of symptoms, age, and gender. Missing progression status was imputed under a missing at random assumption, using multiple imputation. Based on this analysis model, the statistical significance testing, the relative risk of progression, and its appropriate confidence interval (CI) are provided using the adjusted significance level for this interim analysis.

As a result of profound efficacy, an independent data monitoring committee recommended that enrollment in the study be stopped on March 10, 2021, at which time 1057 patients had been randomized. Analyses of all secondary and exploratory endpoints will be conducted when all patients have completed day 29.

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Of 795 patients screened, 583 were randomized through January 19, 2021 to sotrovimab (291 patients) or placebo (292 patients); these patients comprise the interim analysis ITT population Treatment groups in the ITT population were well balanced for baseline demographic and disease characteristics (Table 1) . Overall, 22% of patients were greater than 65 years of age, 7%

were Black or African American, 63% were Hispanic or Latino, and 42% had two or more . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

The copyright holder for this preprint this version posted May 28, 2021. ; https://doi.org/10.1101/2021.05.27.21257096 doi: medRxiv preprint conditions considered to be risk factors for Covid-19 progression. The most common risk factors were obesity, age 55 years or older, and diabetes requiring medication. The most common presenting symptoms (>60% of all patients) were cough, muscle aches/myalgia, headache, and fatigue (Table S1 in the Supplementary Appendix). Baseline demographic and disease characteristics in the safety analysis population were similar across treatment groups and are reported in Table S2 in the Supplementary Appendix.

Treatment with sotrovimab resulted in an 85% reduction in the need for hospitalization over 24 hours or death, due to any cause, compared with placebo (relative risk, 0.15 [97.24% CI, 0.04 to 0.56]). Three (1%) patients progressed to the primary endpoint in the sotrovimab group versus 21 (7%) patients in the placebo group (P = 0.002) ( Table 2 ). The primary reasons for the 24 hospitalizations of more than 24 hours were consistent with progressive Covid-19 (Table S3 in the Supplementary Appendix), with one likely exception: a patient in the sotrovimab group, with a notable past medical history of small intestinal obstruction, presented 22 days after infusion with a small intestinal obstruction. Regarding the severity of these hospitalizations, all five patients who required admission to intensive care were in the placebo group; two of these five patients required invasive mechanical ventilation and a third declined intubation and subsequently died by day 29. Emergency room visits or hospitalizations for less than 24 hours were observed in fewer patients in the sotrovimab group compared with the placebo group (Table 2) .

. CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. Infusion-related reactions were observed in a similar proportion of patients receiving sotrovimab (1%) compared with placebo (1%). One patient receiving sotrovimab had an infusion-related reaction that was considered related to study treatment: moderate (grade 2) dyspnea.

Serious adverse events occurred in 2% of patients receiving sotrovimab and 6% of patients receiving placebo. Most of these events were hospitalizations due to Covid-19-related causes.

No serious adverse events were considered related to sotrovimab. One patient in the placebo group died after day 29; this patient died due to Covid-19 pneumonia on day 37.

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No trends were observed in hematologic, liver, or chemistry laboratory data. Overall, laboratory results were similar in the sotrovimab and placebo groups.

In this preplanned interim analysis of the COMET-ICE study, a single 500-mg dose of sotrovimab profoundly reduced the risk of hospitalization (>24 hours) or death in high-risk adults with symptomatic Covid-19 by 85% compared with placebo (P = 0.002). For every 17 high-risk patients with symptomatic Covid-19, sotrovimab prevented one hospitalization.

Importantly, among those who were hospitalized, no patient who received sotrovimab required admission to intensive care compared with five patients who received placebo, suggesting that sotrovimab may also prevent more severe complications of Covid-19 in addition to preventing the need for hospitalization itself. Furthermore, as a result of investigator site selection, over 60% of the study population consisted of patients self-identifying as Hispanic or Latino; thus, this trial is one of the first to demonstrate efficacy in a population that has been largely underrepresented in Covid-19 clinical trials, despite the disproportionately negative impact the pandemic has had in this ethnic group. Overall, sotrovimab was well tolerated, and no safety signals were identified in this study. There was also no evidence of antibody-dependent enhancement with sotrovimab, which would have manifested as worsening of disease compared with placebo. 26 . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

The copyright holder for this preprint this version posted May 28, 2021. Importantly, treatments for Covid-19 will need to retain activity even in the face of a rapidly evolving virus. To that end, sotrovimab was selected to have an intrinsically high barrier to resistance as a result of targeting a pan-sarbecovirus epitope. 14 In one analysis, among more than 584,000 sequences in the Global Influenza Surveillance and Response System database (Global Initiative on Sharing All Influenza Data), amino acid positions comprising the sotrovimab epitope were at least 99.96% conserved in naturally occurring viruses. 14 Moreover, when necessary to further enhance breadth and barrier to resistance, sotrovimab can likely be combined with currently authorized receptor-binding motif-targeted antibodies due to its nonoverlapping resistance profile.

This interim report has three major limitations. First, with only three hospitalizations in the sotrovimab group, it is not possible to determine which patient or disease characteristics might be associated with sotrovimab treatment failure. Second, the safety dataset was moderate in size . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

The copyright holder for this preprint this version posted May 28, 2021. ; https://doi.org/10.1101/2021.05.27.21257096 doi: medRxiv preprint 16 (430 patients) and thus a rare (much less than 1%) adverse event may not have been observed, though one would not be expected as sotrovimab was derived from an antibody isolated from a recovered SARS-CoV patient, has minimal engineering, and targets a viral epitope (not a host epitope). Third, secondary and exploratory endpoint analyses are excluded from this interim report since the study is ongoing; such analyses are needed to further determine the potential additional benefits of sotrovimab.

This study has two key scientific and medical ramifications, beyond demonstrating the therapeutic value of sotrovimab. First, the results indicate that a non-receptor-binding motif binding antibody, which does not directly block the ACE2 receptor interaction, can be clinically therapeutic, and suggests a role for other receptors. 27 Second, as sotrovimab has potent effector function, the absence of safety signals and profound efficacy strongly suggest that effector function is neither detrimental nor associated with antibody-dependent enhancement. 26 In fact, preclinical models of Covid-19 suggest that its potent effector function may be beneficial. 13, 14 In conclusion, results from this interim analysis of the COMET-ICE trial strongly support that sotrovimab can be an important therapeutic for the outpatient treatment of Covid-19. Notably, a 500-mg dose may also enable intramuscular administration, increasing the convenience of and access to antibody therapeutics for patients with Covid-19. Studies are currently underway to evaluate this route of administration. Importantly, as a component of a comprehensive pandemic . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

The copyright holder for this preprint this version posted May 28, 2021. ; https://doi.org/10.1101/2021.05.27.21257096 doi: medRxiv preprint 17 preparedness strategy, a pan-sarbecovirus antibody has the potential to be an off-the-shelf, readyto-deploy therapeutic for future coronavirus pandemics.

Medical writing support was provided by Caryn Gordon, PharmD, and Courtney St. Amour, PhD, of Cello Health Communications/SciFluent, and was funded by Vir Biotechnology, Inc.

We thank Krystyna Grycz, Jordan Clark, and Minnie Kuo, of Vir Biotechnology, Inc., for clinical operations support.

This study was sponsored by Vir Biotechnology, Inc., in collaboration with GlaxoSmithKline.

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The copyright holder for this preprint this version posted May 28, 2021. ; https://doi.org/10.1101/2021.05.27.21257096 doi: medRxiv preprint . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

The copyright holder for this preprint this version posted May 28, 2021. . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

The copyright holder for this preprint this version posted May 28, 2021. . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) (11) ITT denotes intent-to-treat, SD standard deviation, eGFR estimated glomerular filtration rate, MDRD Modification of Diet in Renal Disease, NYHA New York Heart Association.

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The copyright holder for this preprint this version posted May 28, 2021. ; https://doi.org/10.1101/2021.05.27.21257096 doi: medRxiv preprint 24 *Race data were not available for one patient in the sotrovimab group and one patient in the placebo group. †Body-mass index is the weight in kilograms divided by the square of the height in meters. ‡One patient in the sotrovimab group had a symptom duration of 6 days.

. CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review)

The copyright holder for this preprint this version posted May 28, 2021. ; https://doi.org/10.1101/2021.05.27.21257096 doi: medRxiv preprint 28 Related to study treatment* 0 0 *Relatedness was determined by individual study investigators while blinded to study treatment. †A patient was permanently discontinued from the completion of drug infusion if they experienced life-threatening infusion-related reactions, including severe allergic or hypersensitivity reactions during the intravenous infusion. ‡For both patients, the adverse event was infusion extravasation; both infusions were completed. §Infusion-related reactions were defined as adverse events with preferred terms of pyrexia, chills, dizziness, dyspnea, pruritus, rash, and infusion-related reaction within 24 hours of study drug administration. ¶In addition to the patient in the placebo group who died by day 29, another patient in the placebo group died due to Covid-19 pneumonia on day 37; this patient was admitted to the hospital prior to day 29 and was thus considered to have met the primary endpoint definition of Covid-19 progression.

. CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The SARS-CoV-2 receptor-binding domain is shown, with the ACE2 receptor-binding motif in green and the sotrovimab epitope in orange.

ACE2 denotes angiotensin-converting enzyme 2.

Estimation of US SARS-CoV-2 infections, symptomatic infections, hospitalizations, and deaths using seroprevalence surveys

Estimated incidence of COVID-19 illness and hospitalization -United States

Factors associated with hospital admission and critical illness among 5279 people with coronavirus disease 2019 in New York City: prospective cohort study

Development and validation of a clinical risk score to predict the occurrence of critical illness in hospitalized patients with COVID-19

Phenotypic characteristics and prognosis of inpatients with COVID-19 and diabetes: the CORONADO study

Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China

Severe outcomes among patients with coronavirus disease 2019 (COVID-19) -United States

SARS-CoV-2 neutralizing antibody LY-CoV555 in outpatients with Covid-19

REGN-COV2, a neutralizing antibody cocktail, in outpatients with Covid-19

Antibody resistance of SARS-CoV-2 variants B.1.351 and B.1.1.7. Nature

Resistance of SARS-CoV-2 variants to neutralization by monoclonal and serum-derived polyclonal antibodies

Cross-neutralization of SARS-CoV-2 by a human monoclonal SARS-CoV antibody

The dual function monoclonal antibodies VIR-7831 and VIR-7832 demonstrate potent in vitro and in vivo activity against SARS-CoV-2. bioRxiv 2021

SARS-CoV-2 immune evasion by variant

Epub ahead of print

Neutralising antibody escape of SARS-CoV-2 spike protein: risk assessment for antibody-based Covid-19 therapeutics and vaccines

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The copyright holder for this preprint this version posted May 28, 2021. ITT denotes intent-to-treat, CI confidence interval.*Inferential testing of secondary endpoints has not been performed at this interim analysis. †One patient was hospitalized for less than 24 hours for diabetes management. ‡Severe or critical progression as manifested by supplemental oxygen use.. CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

The copyright holder for this preprint this version posted May 28, 2021. . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

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The copyright holder for this preprint this version posted May 28, 2021. ; https://doi.org/10.1101/2021.05.27.21257096 doi: medRxiv preprint . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review)The copyright holder for this preprint this version posted May 28, 2021. ; https://doi.org/10.1101/2021.05.27.21257096 doi: medRxiv preprint