key: cord-0714383-r4jq46ka authors: Gaborit, B.; Dailly, E.; Vanhove, B.; Josien, R.; Lacombe, K.; Dubee, V.; Ferre, V.; Brouard, S.; Ader, F.; Vibet, M.-A.; Le Thuaut, A.; Danger, R.; Omnes, A. O.; Berly, L.; Chiffoleau, A.; Jobert, A.; Duvaux, O.; Raffi, F. title: Pharmacokinetics and safety of XAV-19, a swine glyco-humanized polyclonal anti-SARS-CoV-2 antibody, for COVID-19-related moderate pneumonia: a randomized, double-blind, placebo-controlled, phase IIa study date: 2021-04-20 journal: nan DOI: 10.1101/2021.04.15.21255549 sha: 3f8ea5f3ccd3d5d0462c77ac9a1aff25d6330011 doc_id: 714383 cord_uid: r4jq46ka Background: We assessed the pharmacokinetics and safety of XAV-19, a swine glyco-humanized polyclonal antibody against SARS-CoV-2, in COVID-19-related moderate pneumonia. In vitro, 100% neutralization activity is seen with XAV-19 concentrations above 5 microg/mL. Methods: In this phase 2a trial, adults with COVID-19-related moderate pneumonia of [≤]10 days duration were randomized to infusion of XAV-19 0.5 mg/kg at day 1 and day 5 (group 1), 2 mg/kg at day 1 and day 5 (group 2), 2 mg/kg at day 1 (group 3) or placebo. Results: Eighteen patients (n=7 for group 1, n=1 for group 2, n=5 for group 3, and n=5 for placebo) were enrolled. Baseline characteristics were similar across groups, XAV-19 serum concentrations (microg/mL, median, range) at Cmax and at day 8 were 9.1 (5.2-18.1) and 6.4 (2.8-11.9), 71.5 and 47.2, and 50.4 (29.1-55.0) and 20.3 (12.0-22.7) for groups 1, 2 and 3, respectively (p=0.012). Terminal half-life (median, range) was estimated at 11.4 (5.5-13.9) days for 2 mg/kg of XAV-19 at day 1. Serum XAV-19 concentrations were above the target concentration of 10 microg/mL (tow fold the in vitro 100% inhibitory concentration [IC100]) from the end of perfusion to more than 8 days for XAV-19 2 mg/kg at day 1. No hypersensitivity or infusion-related reactions were reported during treatment, there was no discontinuation for adverse events and no serious adverse events related to study drug. Conclusions: Single intravenous dose of 2 mg/kg of XAV-19 demonstrated high serum concentrations, predictive of potent durable neutralizing activity with good tolerability. Since the first identification of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) from patients with bilateral pneumonia, in Wuhan, China, during December 2019, the ongoing pandemic of coronavirus disease 2019 has affected more than 127 Million people and caused death in 2.8 Million [1, 2] . Among patients hospitalised for COVID-19, 15-20% develop a severe respiratory failure requiring admission to intensive care unit [3] . Corticosteroids and anticoagulant therapy have improved prognosis of patients requiring respiratory support for severe or critical pneumonia [4, 5] . Multitargeted interventions in severe COVID-19, combining potent antiviral(s), steroids, anticoagulants and in most severe cases adjunctive immune-based therapy such as tocilizumab, could constitute an optimized cocktail to halt further progress to respiratory failure, acute respiratory distress syndrome (ARDS), multi-organ dysfunction, and death [6] [7] [8] . In an ongoing trial, we are investigating XAV-19, a swine glyco-humanized polyclonal SARS-CoV-2neutralizing antibody [9] , in hospitalized patients with COVID-19 pneumonia requiring low flow oxygen supplementation [10] . The main hypothesis is that reducing viral burden and improving specific immunity by passive antibodies administration at hospital entry of patients hospitalized for COVID-19related moderate pneumonia within 10 days of first symptom onset could lead to clinical benefit. Animal-derived heterologous polyclonal antibodies, used as a passive heterologous immunotherapy, could represent a highly efficient alternative to the use of monoclonal antibodies in COVID-19 by targeting multiple antigen epitopes. The dose rationale for the administration of XAV-19 was based on assessment of in vitro inhibitory potency of XAV-19 on SARS-CoV-2 virus and the target serum concentration was established at 10 µg/mL [9, 11] . Here, we report results of the first part of this ongoing clinical trial involving patients hospitalized for COVID-19-related moderate pneumonia requiring oxygen supplementation. In this phase IIa of the trial, objectives of this first-in-human administration of XAV-19 were to assess its pharmacokinetics and safety. All rights reserved. No reuse allowed without permission. (which was not certified by peer review) 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 April 20, 2021. ; https://doi.org/10.1101/2021.04. 15.21255549 doi: medRxiv preprint This is an ongoing multicenter, randomized, double-blind, placebo-controlled, phase IIa-III clinical trial involving hospitalized patients with COVID-19-related moderate pneumonia requiring low-flow oxygen supplementation [10] . The first part was conducted as a phase IIa, first-in-human dose-ranging study at four sites in France, to assess the pharmacokinetics and safety of XAV-19, to select the optimal dose for the second part of the trial, designed as a phase III for which recruitment is ongoing. This study was conducted in accordance with good clinical practice procedures, all applicable regulatory requirements, and the guiding principles of the Declaration of Helsinki. The study protocol was reviewed and approved by the Ethics Committee OUEST VI (20.06.15.31306). All patients provided written informed consent before the entry in the study. The study is registered with ClinicalTrial.gov, NCT04453384. We prospectively identified hospitalized adults aged between 18 and 85 years, with SARS-CoV-2 infection confirmed by a positive RT-PCR and onset of first symptoms less than 10 days prior to enrolment. Inclusion criteria included COVID-19-related moderate pneumonia defined by SpO2 ≥ 92% on oxygen supplementation ≤ 6L/min by low-flow nasal cannula or mask (score of 4 on the World Health Organization 7-point Clinical Progression Scale (WHO-CPS)) and evidence of pulmonary involvement on lung examination (rales/crackles) and/or chest-imaging (Chest X-ray or computed tomography). Exclusion criteria were evidence of multiorgan failure, receipt of immunoglobulins or any blood products in the past 30 days, psychiatric or cognitive illness or recreational drug/alcohol use that would affect subject safety or compliance, end-stage renal disease (eGFR < 15 mL/min/1,73 m 2 ), child-Pugh C-stage liver cirrhosis, decompensated cardiac insufficiency, known allergy, hypersensitivity or intolerance to the study drug or to any of its components, life expectancy estimated to be less than 6 months patient under guardianship or trusteeship, pregnancy or lack of effective contraception in women of childbearing potential. Eligible participants were assigned to two consecutive groups of approximately eight patients per cohort of ascending dose, in a 1:1 randomization scheme per dose for the first two patients and a five active and one placebo randomization scheme per dose for the six following participants of each cohort. The two doses of XAV-19 were 0.5 mg/kg and 2 mg/kg administered over one hour intravenous infusion at All rights reserved. No reuse allowed without permission. (which was not certified by peer review) 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 April 20, 2021. ; https://doi.org/10.1101/2021.04.15.21255549 doi: medRxiv preprint days 1 and 5. After inclusion of the first two participants in each cohort, the safety and tolerability of the treatment was assessed up to 8 days post-infusion by an independent data monitoring committee before continuation of enrolment. Following blinded analysis of the first cohort (0.5mg/kg at D1 and D5) and of the first two patients (one active and one placebo) of the second cohort (2mg/kg at D1 and D5), the remaining patients of the second cohort received a single infusion of 2 mg/kg of XAV-19 at day 1. All patients also received therapy for COVID-19 according to standard of care (SOC) in the participating centres. This SOC included use of dexamethasone and other treatments per local practice and national guidelines at time of the study, which may include, not exclusively, antibiotics, antiviral treatment, immune therapies not based on antibodies administration and anticoagulants. Simple randomization was done using web-based simple (unstratified) allocation by trained clinical research staff. Study investigators, all research and analysis teams, and patients were masked to treatment allocation. The study medications were prepared and dispensed by the hospital pharmacy and presented as ready-to-use aqueous solutions in prelabelled infusion kits according to regulatory requirements. The study medication was then administered to the patients by the medical ward' nurses, upon receipt. Medical history and demographic data were collected at screening. Before dosing, patients underwent evaluation of vital signs, physical examination, assessments for pneumonia, blood haematology and chemistry as well as nasopharyngeal swab for SARS-CoV-2 RT-PCR. Patients also had a 12-lead electrocardiogram, and if clinically required chest x-rays and/or CT scan. During and for the 2 hours after study treatment infusion, vital signs (temperature, respiratory rate, heart rate, systolic and diastolic blood pressures, and oxygen saturation) were monitored every 30 minutes, and particular attention was paid to occurrence of hypersensitivity or infusion-related reactions. Patients were followed for 2 months after the first infusion, with clinical assessment, including respiratory status Drug concentration was assessed at Charles River Laboratories, Evreux, France, with a validated swine IgG-specific sandwich ELISA, presenting a lower limit of quantification of approximately 50 ng/mL in All rights reserved. No reuse allowed without permission. (which was not certified by peer review) 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 April 20, 2021. ; https://doi.org/10.1101/2021.04.15.21255549 doi: medRxiv preprint human serum. The use of concomitant medications was recorded throughout the study. Patients were also regularly assessed for adverse events and possible relation to the investigational medicinal product. The two primary outcomes were the pharmacokinetic measurement of the serum concentration of XAV-19 at day 8 and tolerability over 29 days, comparing the XAV-19 treated participants and placebo group. according to manufacturer's instructions. Viral nucleic acids were detected using a multiplex SARS-CoV-2 RT-qPCR, using RdRp-IP2 and RDRP IP4 adapted from Charité Protocol and National Reference Centre for Respiratory Viruses Institute Pasteur [12, 13] When a sample was positive, quantification of the number of RNA copies was done by RT-qPCR using a specific in vitro transcribed RNA, according to a scale ranging from 2.2 to 10 log10 c/mL. All rights reserved. No reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The safety population included all subjects randomized into the study who received at least one dose of study drug. The intent-to-treat exposed (ITT-E) population was defined as all subjects who met study criteria and were randomized into the study with documented evidence of having received at least one dose of randomized treatment and at least one post-baseline measurement of serum XAV-19 titers. The per-protocol population was defined as all subjects included in the ITT-E population excluding those who had at least one major protocol deviation. Placebo patients were pooled for the purpose of analysis. The PK concentration population included all subjects who completed the study drug schedule. Categorical variables were summarized by percent and comparisons were assessed using an exact Fisher test. Continuous variables were summarized by means and standard error, and medians and interquartile range, comparisons between groups were done using a Kruskal-Wallis test. The primary endpoint was evaluated for ITT-E population by a Kruskal-Wallis test between placebo patients and treated patients. The number of adverse events was compared between groups of patients using an exact Fisher test. Comparisons of pharmacokinetic parameters were conducted using Kruskal-Wallis test. The relationship between AUC0-and cumulative administered dose of XAV 19 was explored by a linear regression model. Groups of treatment were described according to variables in of the secondary endpoints. A p-value < 0.05 was defined as significant. Between Aug 30 th , 2020 and Dec 7 th , 2020, 18 patients with COVID-19-related moderate pneumonia were randomized, one withdrew consent before day 5 second infusion (cohort 1) and 17 completed all study visits (Supplemental Figure 1) . Hence the safety population is constituted of 18 patients, whereas the ITT-E population was constituted of 17 patients. Demographics and baseline characteristics of the 17 patients were similar across groups ( Table 1) . Of the 17 analyzed patients, 12 were treated with XAV-19 (0.5 mg/kg at days 1 and 5 n=6, 2 mg/kg at days 1 and 5 n=1, 2 mg/kg at day 1 n=5) and five with placebo, 11 (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. Pharmacokinetic parameters of XAV-19 are presented in Table 2 . XAV-19 serum concentrations (median [range]) at day 8 were 6.4 µg/mL [2.8-11.9] in patients who received 0.5 mg/kg of XAV-19 at days 1 and 5, 20.3 µg/mL (12.0-22.7) for those who received 2 mg/kg at day 1, 47.2 for for the one who received 2 mg/kg at days 1 and 5 (p=0.012 between groups) ( Table 2) . Serum concentrations were above 29 µg/mL in all patients at day 1 post-infusion of 2 mg/kg of XAV-19 ( Table 2) . Based on a target neutralization threshold of 10 µg/mL of XAV-19, all patients treated with 2 mg/kg (1 or 2 infusions) had serum concentrations above the target at day 8. A proportional relationship between cumulative administered dose and AUC0-was found suggesting a linear pharmacokinetic for XAV-19 between these doses (Figure 1 ). According to this linearity, no significant difference between t1/2 values was observed between the groups of patients. The half-life [median; range; n =12] for all XAV-19 doses was 13·0 (0.7-19.4) days, which allowed to maintain serum concentration of XAV-19 above the previously defined target serum level of 10 µg/mL (two fold the 100% neutralization activity in vitro) during 15 days after a single 2 mg/kg administration for most patients (Figure 2 ) [9] . After a single infusion of the 2 mg/kg dose, the volume of distribution (L) and the clearance (L/h) (median; range; n=5) were respectively 4.9 (4.0-8.7) and 0.015 (0.010-0.021). A summary of the adverse events is presented in Table 3 . XAV-19 was well tolerated, with no differences in adverse events nature and rate between placebo and XAV-19 group and no serious adverse events related to the study drug. Only two patients experienced drug-related grade 1 adverse event (one had lymphadenopathy in the placebo group, one had localized transient ecchymotic rash at day 15 in the 0·5 mg/kg group). Severe adverse events occurred in three patients in the placebo group with two grade 3 events (worsening asthenia and increased dyspnoea) and one grade 4 event (respiratory distress), and in five patients in the XAV-19 group with two grade 4 events (worsening respiratory distress) and three grade 3 events (respiratory failure and two hepatobiliary disorders) (Supplemental Tables 1 and 2) . No hypersensitivity or infusion-related reactions were reported during treatment, and there were no All rights reserved. No reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (Figure 4) . This study was a randomized, double-blind, placebo-controlled, multicentre, phase IIa trial evaluating the optimal dose and the safety of XAV-19, a swine-derived glyco-humanized polyclonal SARS-CoV-2-neutralizing antibody, in patients admitted to hospital with COVID-19-related moderate pneumonia. The results of this first-in-human trial have shown that a single infusion of XAV-19 at 2 mg/kg maintained serum concentration of XAV19 well above the predicted neutralization target concentration of 10µg/mL during at least 8 days post-infusion [9] . The median elimination half-life for XAV-19 2 mg/kg was estimated at 11.4 days, which provides rationale for a single infusion to maintain in vivo neutralizing activity for at least 8 days. Our data also suggest that XAV-19 might enhance viral clearance, even in patients admitted to hospital after on average one week of onset of SARS-CoV-2 symptoms, although our analysis was exploratory and performed on a limited number of patients. Studies have shown that symptom onset is not a sufficient predictor of level of viral load in respiratory secretions, as high viral loads might persist for 2 weeks, nor of individual innate immune response or ability of this immune response to control ongoing viral replication [14] [15] [16] . Then, although maximal benefit of any antiviral therapy, either specific antiviral or neutralizing antibodies, is expected when treatment is started earlier in the illness, benefit could also persist in patients treated with longer duration of symptoms, as demonstrated with remdesevir [6] . All rights reserved. No reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. XAV-19 was well tolerated and no major safety issues or dose-related trends were identified. The clinical outcome of COVID-19 was not different in both groups, but numbers were too small in this phase IIa study to see any trend. Rate of worsening of respiratory failure, based on WHO scale, was within expected range based on characteristics of enrolled population, and the death observed at day 59 was unrelated to study drug or COVID-19 [20, 21] . No immediate hypersensitivity reactions or infusionrelated reactions were reported in our study contrasting to reports and warning with cocktail of antispike monoclonal antibodies [19] . An important limitation of this phase IIa portion of our trial is the small sample size, that did not allow to determine if XAV-19 was associated with improved outcomes. This question will be rigorously tested in the analysis of the phase III part of this ongoing trial. Even if the number of patients who received XAV-19 was low, there were no safety concerns. Second, higher doses of XAV-19 were not explored. However, the 2 mg/kg dose achieved sustained active concentrations. All rights reserved. No reuse allowed without permission. (which was not certified by peer review) 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 April 20, 2021. ; In conclusion, XAV-19 was well tolerated in patients admitted to hospital for COVID-related moderate pneumonia requiring low-flow oxygen supplementation. The pharmacokinetic results of a single infusion of 2 mg/kg suggest that this dose has the potential to successfully block viral diffusion in humans and supports the selection of this regimen for the ongoing multicentre randomized (1:1), doubleblind, placebo-controlled phase III trial (ClinicalTrial.gov, NCT04453384) involving 400 patients. BG reports receipt non-financial support from Gilead Sciences and MSD, outside of the submitted work. BV is an employee and chief scientific officer/operating officer of Xenothera, and own shares and holds share options in Xenothera. KL reports receipt of personal fees from and non-financial support from Abbvie, Chiesi, Healthcare, Janssen, MSD and ViiV outside of the submitted work. VD reports receipt non-financial support from Gilead Sciences, MSD and Sanofi-Pasteur, outside of the submitted work. OD is a cofounder of Xenothera, is the CEO of Xenothera and own shares and holds share options in Xenothera. FR reports receipt of personal fees from Abbvie, Gilead Sciences, Janssen, MSD and ViiV Healthcare, outside of the submitted work. All other authors report no conflict of interest. All rights reserved. No reuse allowed without permission. (which was not certified by peer review) 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 April 20, 2021. ; The data analysed and presented in this study are available from the corresponding author on reasonable request, providing the request meets local ethical and research governance criteria after publication. Data collected during the study may be processed electronically, in accordance with the requirements of the CNIL (compliance with reference methodology MR001). The study protocol is provided in the appendix. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. All rights reserved. No reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. All rights reserved. No reuse allowed without permission. (which was not certified by peer review) 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 April 20, 2021. ; Figure 3 . Clinical Status According to 7-Category WHO Ordinal Scale between screening (day 0) and last-follow-up (day 60) in placebo (n = 5) and XAV-19 (n = 12) groups. Figure 4 . Nasopharyngeal viral load over time in placebo (n = 5) and XAV-19 2mg/kg (n = 4) groups. D = day, LOD= limit of detection (2.2 log10 copies/mL), 0 = no signal detected All rights reserved. No reuse allowed without permission. (which was not certified by peer review) 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 April 20, 2021. A Novel Coronavirus from Patients with Pneumonia in China Characteristics of and Important Lessons From the Coronavirus Disease 2019 (COVID-19) Outbreak in China: Summary of a Report of 72 314 Cases From the Chinese Center for Disease Control and Prevention Effect of Intermediate-Dose vs Standard-Dose Prophylactic Anticoagulation on Thrombotic Events, Extracorporeal Membrane Oxygenation Treatment, or Mortality Among Patients With COVID-19 Admitted to the Intensive Care Unit: The INSPIRATION Randomized Clinical Trial Dexamethasone in Hospitalized Patients with Covid-19 Remdesivir for the Treatment of Covid-19 -Final Report Virological assessment of hospitalized patients with COVID-2019 Plea for multitargeted interventions for severe COVID-19 High neutralizing potency of swine glyco-humanized polyclonal antibodies against SARS-CoV-2 Evaluation of the safety and efficacy of XAV-19 in patients with COVID-19-induced moderate pneumonia: study protocol for a randomized, double-blinded, placebo-controlled phase 2 (IIa and 2b) trial XAV-19, a novel swine glyco-humanized polyclonal antibody against SARS-CoV-2 spike, efficiently neutralizes B.1.1.7 British and B.1.351 South-African variants Detection of 2019 novel coronavirus (2019-nCoV) by real-time RT-PCR Clinical and virological data of the first cases of COVID-19 in Europe: a case series Identification and validation of clinical phenotypes with prognostic implications in patients admitted to hospital with COVID-19: a multicentre cohort study. The Lancet Infectious Diseases Longitudinal profiling of respiratory and systemic immune responses reveals myeloid cell-driven lung inflammation in severe COVID-19 Global absence and targeting of protective immune states in severe COVID-19 REGN-COV2, a Neutralizing Antibody Cocktail, in Outpatients with Covid-19 SARS-CoV-2 Neutralizing Antibody LY-CoV555 in Outpatients with Covid-19 Effect of Bamlanivimab as Monotherapy or in Combination With Etesevimab on Viral Load in Patients With Mild to Moderate COVID-19: A Randomized Clinical Trial Clinical predictors of mortality due to COVID-19 based on an analysis of data of 150 patients from Wuhan, China Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: a retrospective cohort study No reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity Adverse events by system organ class and grade occurring in either treatment group to day 29 (safety population) We thank clinical and research teams, as well as pharmacists and virologists at all the participating clinical centres, who contributed to the management of the study patients for their commitment to providing optimal patient care.