publication . Article . 2021

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 (2a and 2b) trial

Benjamin Gaborit; Bernard Vanhove; Marie-Anne Vibet; Aurélie Le Thuaut; Karine Lacombe; Vincent Dubee; Florence Ader; Virginie Ferre; Eric Vicaut; Jéremie Orain; ...
Open Access English
  • Published: 01 Dec 2021
  • Publisher: HAL CCSD
  • Country: France
Abstract
Abstract Background Early inhibition of entry and replication of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a very promising therapeutic approach. Polyclonal neutralizing antibodies offers many advantages such as providing immediate immunity, consequently blunting an early pro-inflammatory pathogenic endogenous antibody response and lack of drug-drug interactions. By providing immediate immunity and inhibiting entry into cells, neutralizing antibody treatment is of interest for patient with COVID-19-induced moderate pneumonia. Convalescent plasma to treat infected patients is therefore a relevant therapeutic option currently under assessment (CORIMUNO-PLASM NCT04324047). However, the difficulties of collecting plasma on the long term are not adapted to a broad use across all populations. New polyclonal humanized anti-SARS-CoV2 antibodies (XAV-19) developed by Xenothera and administered intravenous. XAV-19 is a heterologous swine glyco-humanized polyclonal antibody (GH-pAb) raised against the spike protein of SARS-CoV-2, blocking infection of ACE-2-positive human cells with SARS-CoV-2. Methods Pharmacokinetic and pharmacodynamic studies have been performed in preclinical models including primates. A first human study with another fully representative GH-pAb from Xenothera is ongoing in recipients of a kidney graft. These studies indicated that 5 consecutive administrations of GH-pAbs can be safely performed in humans. The objectives of this 2-step phase 2 randomized double-blinded, placebo-controlled study are to define the safety and the optimal XAV-19 dose to administrate to patients with SARS-CoV-2 induced moderate pneumonia, and to assess the clinical benefits of a selected dose of XAV-19 in this population. Discussion This study will determine the clinical benefits of XAV-19 when administered to patients with SARS-CoV-2-induced moderate pneumonia. As a prerequisite, a first step of the study will define the safety and the dose of XAV-19 to be used. Such treatment might become a new therapeutic option to provide an effective treatment for COVID-19 patients (possibly in combination with anti-viral and immunotherapies). Further studies could later evaluate such passive immunotherapy as a potential post-exposure prophylaxis. Trial registration ClinicalTrials.gov NCT04453384, registered on 1 July 2020, and EUDRACT 2020-002574-27, registered 6 June 2020.
Persistent Identifiers
Sustainable Development Goals (SDG) [Beta]
Subjects
free text keywords: COVID-19, Anti-SARS-CoV-2 antibodies, Moderate pneumonia, Immunotherapy, Randomized controlled trial, Phase 2, [SDV]Life Sciences [q-bio], Pharmacology (medical), Medicine (miscellaneous), Study Protocol, lcsh:Medicine (General), lcsh:R5-920, Internal medicine, medicine.medical_specialty, medicine, Immunotherapy, medicine.medical_treatment, Therapeutic approach, Randomized controlled trial, law.invention, law, Severity of illness, Neutralizing antibody, biology.protein, biology, Pneumonia, medicine.disease, Placebo, business.industry, business, Population, education.field_of_study, education
Communities
Communities with gateway
OpenAIRE Connect image
Funded by
EC| BRIGHT
Project
BRIGHT
Treat severe cases of infection at COV with XAV-19
  • Funder: European Commission (EC)
  • Project Code: 962036
  • Funding stream: H2020 | SME-2b
Validated by funder
33 references, page 1 of 3

1. Zhu N, Zhang D, Wang W, Li X, Yang B, Song J, et al. A novel coronavirus from patients with pneumonia in China, 2019. N Engl J Med. 2020;382(8):727-33.

2. Wu Z, McGoogan JM. 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. JAMA. 2020;323(13):1239-42. [OpenAIRE]

3. Huang C, Wang Y, Li X, Ren L, Zhao J, Hu Y, et al. Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China. Lancet. 2020;395:497-506.

4. Hamming I, Timens W, Bulthuis MLC, Lely AT, Navis GJ, van Goor H. Tissue distribution of ACE2 protein, the functional receptor for SARS coronavirus. A first step in understanding SARS pathogenesis. J Pathol. 2004;203:631-7. [OpenAIRE]

5. Jeffers SA, Tusell SM, Gillim-Ross L, Hemmila EM, Achenbach JE, Babcock GJ, et al. CD209L (L-SIGN) is a receptor for severe acute respiratory syndrome coronavirus. Proc Natl Acad Sci U S A. 2004;101:15748-53. [OpenAIRE]

6. Xu Z, Shi L, Wang Y, Zhang J, Huang L, Zhang C, et al. Pathological findings of COVID-19 associated with acute respiratory distress syndrome. Lancet Respir Med. 2020;8:420-2.

7. Lin G-L, McGinley JP, Drysdale SB, Pollard AJ. Epidemiology and immune pathogenesis of viral sepsis. Front Immunol. 2018;9 [cited 2020 Jul 27]. Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6170629/.

8. Tian S, Hu W, Niu L, Liu H, Xu H, Xiao S-Y. Pulmonary pathology of earlyphase 2019 novel coronavirus (COVID-19) pneumonia in two patients with lung cancer. J Thorac Oncol. 2020;15:700-4.

9. Zhou F, Yu T, Du R, Fan G, Liu Y, Liu Z, et al. Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: a retrospective cohort study. Lancet. 2020;395:1054-62.

10. Qin C, Zhou L, Hu Z, Zhang S, Yang S, Tao Y, et al. Dysregulation of immune response in patients with COVID-19 in Wuhan, China. Clin Infect Dis. 2020;71(15):762-8.

11. Subbarao K, McAuliffe J, Vogel L, Fahle G, Fischer S, Tatti K, et al. Prior infection and passive transfer of neutralizing antibody prevent replication of severe acute respiratory syndrome coronavirus in the respiratory tract of mice. J Virol. 2004;78:3572-7.

12. Li W, Moore MJ, Vasilieva N, Sui J, Wong SK, Berne MA, et al. Angiotensinconverting enzyme 2 is a functional receptor for the SARS coronavirus. Nature. 2003;426(6965):450-4.

13. Yan R, Zhang Y, Li Y, Xia L, Guo Y, Zhou Q. Structural basis for the recognition of SARS-CoV-2 by full-length human ACE2. Science. 2020;367: 1444-8.

14. Vanhove B, Duvaux O, Rousse J, Royer P-J, Evanno G, Ciron C, et al. High neutralizing potency of swine glyco-humanized polyclonal antibodies against SARSCoV-2. bioRxiv. 2020;07.25.217158. https://doi.org/10.1101/2020.07.25.217158.

15. Salama A, Evanno G, Lim N, Rousse J, Le Berre L, Nicot A, et al. Anti-Gal and anti-Neu5Gc responses in nonimmunosuppressed patients after treatment with rabbit antithymocyte polyclonal IgGs. Transplantation. 2017;101:2501-7.

33 references, page 1 of 3
Abstract
Abstract Background Early inhibition of entry and replication of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a very promising therapeutic approach. Polyclonal neutralizing antibodies offers many advantages such as providing immediate immunity, consequently blunting an early pro-inflammatory pathogenic endogenous antibody response and lack of drug-drug interactions. By providing immediate immunity and inhibiting entry into cells, neutralizing antibody treatment is of interest for patient with COVID-19-induced moderate pneumonia. Convalescent plasma to treat infected patients is therefore a relevant therapeutic option currently under assessment (CORIMUNO-PLASM NCT04324047). However, the difficulties of collecting plasma on the long term are not adapted to a broad use across all populations. New polyclonal humanized anti-SARS-CoV2 antibodies (XAV-19) developed by Xenothera and administered intravenous. XAV-19 is a heterologous swine glyco-humanized polyclonal antibody (GH-pAb) raised against the spike protein of SARS-CoV-2, blocking infection of ACE-2-positive human cells with SARS-CoV-2. Methods Pharmacokinetic and pharmacodynamic studies have been performed in preclinical models including primates. A first human study with another fully representative GH-pAb from Xenothera is ongoing in recipients of a kidney graft. These studies indicated that 5 consecutive administrations of GH-pAbs can be safely performed in humans. The objectives of this 2-step phase 2 randomized double-blinded, placebo-controlled study are to define the safety and the optimal XAV-19 dose to administrate to patients with SARS-CoV-2 induced moderate pneumonia, and to assess the clinical benefits of a selected dose of XAV-19 in this population. Discussion This study will determine the clinical benefits of XAV-19 when administered to patients with SARS-CoV-2-induced moderate pneumonia. As a prerequisite, a first step of the study will define the safety and the dose of XAV-19 to be used. Such treatment might become a new therapeutic option to provide an effective treatment for COVID-19 patients (possibly in combination with anti-viral and immunotherapies). Further studies could later evaluate such passive immunotherapy as a potential post-exposure prophylaxis. Trial registration ClinicalTrials.gov NCT04453384, registered on 1 July 2020, and EUDRACT 2020-002574-27, registered 6 June 2020.
Persistent Identifiers
Sustainable Development Goals (SDG) [Beta]
Subjects
free text keywords: COVID-19, Anti-SARS-CoV-2 antibodies, Moderate pneumonia, Immunotherapy, Randomized controlled trial, Phase 2, [SDV]Life Sciences [q-bio], Pharmacology (medical), Medicine (miscellaneous), Study Protocol, lcsh:Medicine (General), lcsh:R5-920, Internal medicine, medicine.medical_specialty, medicine, Immunotherapy, medicine.medical_treatment, Therapeutic approach, Randomized controlled trial, law.invention, law, Severity of illness, Neutralizing antibody, biology.protein, biology, Pneumonia, medicine.disease, Placebo, business.industry, business, Population, education.field_of_study, education
Communities
Communities with gateway
OpenAIRE Connect image
Funded by
EC| BRIGHT
Project
BRIGHT
Treat severe cases of infection at COV with XAV-19
  • Funder: European Commission (EC)
  • Project Code: 962036
  • Funding stream: H2020 | SME-2b
Validated by funder
33 references, page 1 of 3

1. Zhu N, Zhang D, Wang W, Li X, Yang B, Song J, et al. A novel coronavirus from patients with pneumonia in China, 2019. N Engl J Med. 2020;382(8):727-33.

2. Wu Z, McGoogan JM. 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. JAMA. 2020;323(13):1239-42. [OpenAIRE]

3. Huang C, Wang Y, Li X, Ren L, Zhao J, Hu Y, et al. Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China. Lancet. 2020;395:497-506.

4. Hamming I, Timens W, Bulthuis MLC, Lely AT, Navis GJ, van Goor H. Tissue distribution of ACE2 protein, the functional receptor for SARS coronavirus. A first step in understanding SARS pathogenesis. J Pathol. 2004;203:631-7. [OpenAIRE]

5. Jeffers SA, Tusell SM, Gillim-Ross L, Hemmila EM, Achenbach JE, Babcock GJ, et al. CD209L (L-SIGN) is a receptor for severe acute respiratory syndrome coronavirus. Proc Natl Acad Sci U S A. 2004;101:15748-53. [OpenAIRE]

6. Xu Z, Shi L, Wang Y, Zhang J, Huang L, Zhang C, et al. Pathological findings of COVID-19 associated with acute respiratory distress syndrome. Lancet Respir Med. 2020;8:420-2.

7. Lin G-L, McGinley JP, Drysdale SB, Pollard AJ. Epidemiology and immune pathogenesis of viral sepsis. Front Immunol. 2018;9 [cited 2020 Jul 27]. Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6170629/.

8. Tian S, Hu W, Niu L, Liu H, Xu H, Xiao S-Y. Pulmonary pathology of earlyphase 2019 novel coronavirus (COVID-19) pneumonia in two patients with lung cancer. J Thorac Oncol. 2020;15:700-4.

9. Zhou F, Yu T, Du R, Fan G, Liu Y, Liu Z, et al. Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: a retrospective cohort study. Lancet. 2020;395:1054-62.

10. Qin C, Zhou L, Hu Z, Zhang S, Yang S, Tao Y, et al. Dysregulation of immune response in patients with COVID-19 in Wuhan, China. Clin Infect Dis. 2020;71(15):762-8.

11. Subbarao K, McAuliffe J, Vogel L, Fahle G, Fischer S, Tatti K, et al. Prior infection and passive transfer of neutralizing antibody prevent replication of severe acute respiratory syndrome coronavirus in the respiratory tract of mice. J Virol. 2004;78:3572-7.

12. Li W, Moore MJ, Vasilieva N, Sui J, Wong SK, Berne MA, et al. Angiotensinconverting enzyme 2 is a functional receptor for the SARS coronavirus. Nature. 2003;426(6965):450-4.

13. Yan R, Zhang Y, Li Y, Xia L, Guo Y, Zhou Q. Structural basis for the recognition of SARS-CoV-2 by full-length human ACE2. Science. 2020;367: 1444-8.

14. Vanhove B, Duvaux O, Rousse J, Royer P-J, Evanno G, Ciron C, et al. High neutralizing potency of swine glyco-humanized polyclonal antibodies against SARSCoV-2. bioRxiv. 2020;07.25.217158. https://doi.org/10.1101/2020.07.25.217158.

15. Salama A, Evanno G, Lim N, Rousse J, Le Berre L, Nicot A, et al. Anti-Gal and anti-Neu5Gc responses in nonimmunosuppressed patients after treatment with rabbit antithymocyte polyclonal IgGs. Transplantation. 2017;101:2501-7.

33 references, page 1 of 3
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