key: cord-0893366-5ajydyaf authors: Stein, D.; Oviedo-Orta, E.; Kampman, W. A.; McGinniss, J.; Betts, G.; McDermott, M.; Holly, B.; Lancaster, J. M.; Braunstein, N.; Yancopoulos, G. D.; Weinreich, D. M. title: Compassionate Use of REGEN-COV(R) in Patients with COVID-19 and Immunodeficiency-Associated Antibody Disorders date: 2021-11-09 journal: nan DOI: 10.1101/2021.11.05.21265911 sha: fea64872be09657e4354caf3e19682f9c3ca48f5 doc_id: 893366 cord_uid: 5ajydyaf Background: Patients with immunodeficiency-associated antibody disorders are at a higher risk of prolonged/persistent coronavirus disease 2019 (COVID-19) infection, having no viable treatment options. Methods: This is a retrospective analysis of patients with primary and/or secondary immunodeficiency-associated antibody disorders who received casirivimab and imdevimab (REGEN-COV(R)) under emergency compassionate use. The objectives were to describe safety and response to REGEN-COV, with a focus on the subset of patients who had disease duration [≥]21 days prior to treatment. Quantitative (change in oxygenation status and/or viral load) and/or qualitative (physician-reported clinical status) patient outcomes data are reported. Results: Data is available from 64 patients who received REGEN-COV. Improvement in [≥]1 outcome measure was observed in 90.6% of the overall patient group. Thirty-seven of these had COVID-19 duration [≥]21 days prior to treatment, with a mean time from RT-PCR diagnosis to REGEN-COV administration of 60.5 days. Of the 29 patients with disease duration [≥]21 days prior to treatment who had available outcome data, 96.6% showed improvement in [≥]1 outcome measure evaluated following use of REGEN-COV. In the 14 patients who had post-treatment RT-PCR results available, 11 (78.6%) reported a negative RT-PCR following treatment with REGEN-COV, with 5 patients (45.5%) reporting a negative RT-PCR within 5 days of treatment and 8 (72.7%) reporting a negative RT-PCR within 21 days of treatment. Conclusions: In this retrospective analysis of immunodeficient patients who were granted REGEN-COV under the compassionate use program, REGEN-COV treatment was associated with rapid viral clearance and clinical improvement in the evaluable patients with long-standing COVID-19. ≥ 21 days prior to treatment who had available outcome data, 96.6% showed improvement in 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 November 9, 2021. ; https://doi.org/10.1101/2021.11.05.21265911 doi: medRxiv preprint Page 4 treatment was associated with rapid viral clearance and clinical improvement in the evaluable patients with long-standing COVID-19. . 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 November 9, 2021. ; https://doi.org/10.1101/2021.11.05.21265911 doi: medRxiv preprint Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causal agent of coronavirus disease 2019 (COVID- 19) , first emerged in 2019, and has led to a global pandemic. Patients infected with SARS-CoV-2 are at risk of developing a range of respiratory conditions, from mild to severe symptoms, and sometimes fatal illness [1] . Patients with either primary or secondary immunodeficiency-associated antibody disorders that have an inherited or acquired inability to produce antibodies against infective agents have a high risk of suffering from prolonged or persistent SARS-CoV-2 infection, increasing their morbidity and mortality risk [2] [3] [4] . These patients are also likely to show lack of, or significantly less effective, protective immune responses to vaccines [5] , and may have to rely on alternate prevention and treatment regimes. The treatment of immunocompromised patients with COVID-19 using convalescent plasma is controversial due to lack of specificity and variable content of potent neutralizing antibodies [6] [7] [8] . In February 2021, the United States Food and Drug Administration issued a revision of the Emergency Use Authorization for COVID-19 convalescent plasma, for the treatment of hospitalized patients with COVID-19 who have impaired humoral immunity and cannot produce an adequate antibody response [9]. However, results from 3 small randomized controlled trials in patients with moderate-to-severe COVID-19 showed no significant differences in improved clinical outcomes between the convalescent plasma-treated and placebo groups [10-12]. Casirivimab and imdevimab (REGEN-COV ® ) is a combination of 2 human, immunoglobulin G1 monoclonal antibodies (mAbs) that bind the receptor-binding . 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 November 9, 2021. ; https://doi.org/10.1101/2021.11.05.21265911 doi: medRxiv preprint Page 6 domain of the SARS-CoV-2 spike protein and block interaction with angiotensinconverting enzyme 2 [13] . REGEN-COV targets separate non-overlapping epitopes thereby neutralizing SARS-CoV-2, with a reduced likelihood of viral escape due to genetic mutations [14] . Furthermore, this combination of mAbs has been shown to retain neutralization potency against multiple SARS-CoV-2 variants [14] . The blood levels of SARS-CoV-2 neutralizing activity that are achieved with REGEN-COV are approximately 10,000-to 100,000-fold higher than that achievable with high-titer convalescent plasma. Correspondingly, REGEN-COV has demonstrated convincing activity across multiple phase 2 and 3 studies and across the continuum of the disease, including pre-and post-exposure prophylaxis [15] , as well as in the treatment of both outpatients and hospitalized patients [16] [17] [18] [19] . Across these studies, the greatest benefit was observed in patients who had not yet developed their own innate immune response at baseline (ie, who did not make their own anti-SARS-CoV-2 antibodies and are thus termed "seronegative"); such high-risk seronegative patients may share characteristics with individuals with an immunodeficiency who cannot mount an antibody response. . 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 November 9, 2021. ; https://doi.org/10.1101/2021.11.05.21265911 doi: medRxiv preprint Page 7 This is a retrospective, descriptive data analysis using de-identified patient data from The objective of this retrospective analysis was to describe safety and response to REGEN-COV in patients with primary and/or secondary immunodeficiencyassociated antibody disorders that were evaluated and approved for drug use under . 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 November 9, 2021. ; https://doi.org/10.1101/2021.11.05.21265911 doi: medRxiv preprint Page 8 compassionate use. Response to REGEN-COV is described using quantitative patient outcome data (change in oxygenation status and/or viral load) and/or qualitative patient outcome data (physician-reported clinical status). Serious adverse events and death were also evaluated. Oxygenation status is described as oxygen requirement and correlated oxygen saturations. Viral load is described by either SARS-CoV-2 RT-PCR status (negative or positive) and/or cycle threshold (Ct) values in RT-PCR, prior to and after compassionate use of REGEN-COV. Descriptive safety data are also presented. The treating physician was responsible for compliance in accordance with the . 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 November 9, 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. Table 1) . Of note, these 14 patients had a mean time since RT-PCR diagnosis prior to treatment of 62.8 days (median 53.5; range 25-215; Figure 2 ). In the overall patient group, 62.4% were male, the mean age was 47.4 years Table 1 ). . 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 November 9, 2021. In the overall patient group, 10/85 patients (11.8%) experienced serious adverse events (SAEs; as defined by physician-completion of an SAE form), of which only 1 event was an infusion-related reaction judged as possibly related to REGEN-COV. Two patients who experienced SAEs had a COVID-19 duration ≥ 21 days prior to treatment. There were 2 deaths reported, neither of which were attributed by the . 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 November 9, 2021. ; https://doi.org/10.1101/2021.11.05.21265911 doi: medRxiv preprint Page 12 investigator to treatment with REGEN-COV: 1 from hypoxia; and 1 from respiratory failure secondary to chronic COVID-19 and diffuse alveolar hemorrhage complicated by pulmonary aspergillosis. The events reported were consistent with COVID-19 and its associated complications and due to patients' concurrent medical conditions. . 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 November 9, 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. The copyright holder for this preprint this version posted November 9, 2021. ; https://doi.org/10.1101/2021.11.05.21265911 doi: medRxiv preprint Page 14 As far as we are aware, this is the first report describing outcomes following REGEN-COV treatment for COVID-19 in a series of patients with primary and/or secondary immunodeficiency-associated antibody disorders. In this retrospective analysis, 96.6% of patients with COVID-19 duration This case series provides data which are consistent with the totality of the data from phase 2 and 3 studies of REGEN-COV [15] [16] [17] [18] [19] , in which the greatest benefit with REGEN-COV was seen in high-risk patients who had not yet mounted their own antibody response, and thus may share some characteristics consistent with immunodeficient patients. In those studies, REGEN-COV treatment in those who had not yet mounted their own immune response was associated with robust and rapid reduction in viral load as well as improvement in clinical outcome measures. The data from this case series describe high recovery rates comparable to those in the phase 2 and 3 studies who had not yet mounted an immune response. In some territories, REGEN-COV is approved for the treatment and prevention of The authors would like to thank the patients, their families, and the physicians involved in this work, as well as Caryn Trbovic, PhD, from Regeneron Pharmaceuticals for medical writing support; and Prime, Knutsford, UK, for formatting and copy-editing suggestions and for assistance with development of the manuscript. . 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 November 9, 2021. ; https://doi.org/10.1101/2021.11.05.21265911 doi: medRxiv preprint Patients may report more than 1 condition. . 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 November 9, 2021. ; https://doi.org/10.1101/2021.11.05.21265911 doi: medRxiv preprint Page 23 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 November 9, 2021. 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 November 9, 2021. 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 November 9, 2021. ; https://doi.org/10.1101/2021.11.05.21265911 doi: medRxiv preprint Clinical characteristics of 138 hospitalized patients with 2019 novel coronavirus-infected pneumonia in Wuhan, China COVID-19 in persons with haematological cancers Convalescent plasma therapy for B-celldepleted patients with protracted COVID-19 COVID-19: consider cytokine storm syndromes and immunosuppression A review of vaccinations in adult patients with secondary immunodeficiency A review of COVID-19 convalescent plasma use in COVID-19 with focus on proof of efficacy Association of Convalescent Plasma Page 19 Antibody cocktail to SARS-CoV-2 spike protein prevents rapid mutational escape seen with individual antibodies Subcutaneous REGEN-COV Antibody Combination to Prevent Covid-19 Casirivimab and imdevimab in patients admitted to hospital with COVID-19 (RECOVERY): a randomised, controlled, open-label REGN-COV2, a neutralizing antibody cocktail, in outpatients with Covid-19 REGEN-COV antibody combination and outcomes in outpatients with Covid-19 The effectiveness of Review and Meta-analysis. JAMA 2021; 325(12): 1185-95.. 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 November 9, 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. The copyright holder for this preprint this version posted November 9, 2021. ; https://doi.org/10.1101/2021.11.05.21265911 doi: medRxiv preprint convalescent plasma and hyperimmune immunoglobulin for the treatment 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. . 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 November 9, 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)The copyright holder for this preprint this version posted November 9, 2021. ; https://doi.org/10.1101/2021.11.05.21265911 doi: medRxiv preprint