Periodic Reporting for period 2 - EPIC-CROWN-2 (Equine Polyclonal antibodies Immunotherapy against COVID-19/SARS-CoV2–VOC)
Période du rapport: 2022-06-01 au 2023-11-30
The highly contagious SARS-CoV-2 virus has generated an unprecedented pandemic with global dramatic health and socioeconomic consequences that need an urgent mitigation. Despite the progression of the global use of efficient vaccines, an
increased transmissibility of variants of concern (VOC) is predominantly observed. The reduced sensitivity of VOCs to
neutralizing response could become a serious obstacle for efficient vaccination. The absence of approved specific antiviral
therapies for vaccinated-non-responders along with the rare anti-inflammatory therapies, passive immunotherapies with
polyclonal immunoglobulins could be considered a part of the solution. The main objective of EPIC-CROWN-2 project is to
rapidly assess, in clinical trials (phase IIa/IIb), an EMA-authorized antiviral immunotherapy based on potent and broad equine
neutralizing anti-SARS-CoV-2 polyclonal F(ab’)2 antibodies in COVID-19 patients, including those infected by VOC. In order to
save lives and reduce the use and costs of critical care, this therapeutic solution specifically targets hospitalized COVID-19
patients. To optimize the indications for the treatment, potency and breath of F(ab’)2 against variants will be assessed by in
vitro and in vivo studies. Prospective studies will respectively be done on immune assessment in treated patients and on
mitigation of exacerbated immune responses in vivo. Fab’entech coordinates the EPIC-CROWN-2 consortium formed by an
outstanding group of experts of different domains of the project that include clinical trials (HISS, Greece), virology (IMAS12,
Spain) and immunopathology models (BNITM, Germany) and immunopathology mitigation (IRD, France). Most of them
having already been working together in European projects. Importantly, EPIC-CROWN-2 isin contact with the large European
trial network EU-RESPONSE and specifically in the new multinational European Adaptive Platform Trial “SolidAct”. This
ambitious project should have an important societal and economic impact, by providing a therapeutic solution in fast time to
a high medical need.
increased transmissibility of variants of concern (VOC) is predominantly observed. The reduced sensitivity of VOCs to
neutralizing response could become a serious obstacle for efficient vaccination. The absence of approved specific antiviral
therapies for vaccinated-non-responders along with the rare anti-inflammatory therapies, passive immunotherapies with
polyclonal immunoglobulins could be considered a part of the solution. The main objective of EPIC-CROWN-2 project is to
rapidly assess, in clinical trials (phase IIa/IIb), an EMA-authorized antiviral immunotherapy based on potent and broad equine
neutralizing anti-SARS-CoV-2 polyclonal F(ab’)2 antibodies in COVID-19 patients, including those infected by VOC. In order to
save lives and reduce the use and costs of critical care, this therapeutic solution specifically targets hospitalized COVID-19
patients. To optimize the indications for the treatment, potency and breath of F(ab’)2 against variants will be assessed by in
vitro and in vivo studies. Prospective studies will respectively be done on immune assessment in treated patients and on
mitigation of exacerbated immune responses in vivo. Fab’entech coordinates the EPIC-CROWN-2 consortium formed by an
outstanding group of experts of different domains of the project that include clinical trials (HISS, Greece), virology (IMAS12,
Spain) and immunopathology models (BNITM, Germany) and immunopathology mitigation (IRD, France). Most of them
having already been working together in European projects. Importantly, EPIC-CROWN-2 isin contact with the large European
trial network EU-RESPONSE and specifically in the new multinational European Adaptive Platform Trial “SolidAct”. This
ambitious project should have an important societal and economic impact, by providing a therapeutic solution in fast time to
a high medical need.
To assess the beneficial impacts of the therapy developed in clinic, the anti-SARS-CoV-2 polyclonal F(ab’)2 antibodies, HISS
and Fab’entech partners worked together to submit all the regulatory documentation for the Clinical Trial Application (CTA)
to Health Authorities and Ethics Committee allowing the phase 2a to be launched in March 2022. The clinical trial is still
ongoing on 30 hospitalized COVID-19 patients. A phase IIb trial on 270 patients is under preparation for submission to Greek
ethical committee in September 2022, followed by 3 others European countries.
The analyses of the impact of SARS-CoV-2 VOC within clinical batches of polyclonal F(ab’)2 (FBR-002) antibodies were realized
by BNITM and IMASS. A vector collection of variants was built to measure the neutralizing potency of the product against
VOC. A high neutralizing potency has been achieved, including Omicron, with 2-3 orders of magnitude of what is normally
achieved in response to SARS-CoV-2 infection and/or vaccination; comforting us in the efficacy of the product developed.
These results are under review for publication in Journal of Infectious Disease.
A model of humanized mice is also in preparation to evaluate product efficacy in vivo, against D614G and Delta SARS-CoV-2
strains. To improve the indication of the treatment and perform the immune assessment, the in vivo studies have been set
up and the characterization of the humanized mouse model permissive for SARS-CoV-2 infection was performed. The staining
of histology sections, in which we were able to detect SARS-CoV-2 positive cells in the lungs of infected mice was established.
Specific stanning against Caspase 3 showed intense apoptotic areas in the lungs of severe infected mice.
The immune profile of COVID-19 patients, with or without treatment, will be performed during the phase 2b; however, all
the sensitive methods have already been developed by IRD and BNITM to measure biomarkers in clinical samples collected
during the assay.
and Fab’entech partners worked together to submit all the regulatory documentation for the Clinical Trial Application (CTA)
to Health Authorities and Ethics Committee allowing the phase 2a to be launched in March 2022. The clinical trial is still
ongoing on 30 hospitalized COVID-19 patients. A phase IIb trial on 270 patients is under preparation for submission to Greek
ethical committee in September 2022, followed by 3 others European countries.
The analyses of the impact of SARS-CoV-2 VOC within clinical batches of polyclonal F(ab’)2 (FBR-002) antibodies were realized
by BNITM and IMASS. A vector collection of variants was built to measure the neutralizing potency of the product against
VOC. A high neutralizing potency has been achieved, including Omicron, with 2-3 orders of magnitude of what is normally
achieved in response to SARS-CoV-2 infection and/or vaccination; comforting us in the efficacy of the product developed.
These results are under review for publication in Journal of Infectious Disease.
A model of humanized mice is also in preparation to evaluate product efficacy in vivo, against D614G and Delta SARS-CoV-2
strains. To improve the indication of the treatment and perform the immune assessment, the in vivo studies have been set
up and the characterization of the humanized mouse model permissive for SARS-CoV-2 infection was performed. The staining
of histology sections, in which we were able to detect SARS-CoV-2 positive cells in the lungs of infected mice was established.
Specific stanning against Caspase 3 showed intense apoptotic areas in the lungs of severe infected mice.
The immune profile of COVID-19 patients, with or without treatment, will be performed during the phase 2b; however, all
the sensitive methods have already been developed by IRD and BNITM to measure biomarkers in clinical samples collected
during the assay.
All the regulatory documentation for the Clinical Trial Application (CTA) for the Phase 2a CTA were prepared and submitted
to Health Authorities and Ethics Committee. The decision was made to split the phase 2a/b clinical trial in 2 distinct trials: eg
a Phase 2a first and then later a Phase 2b. The Phase 2a was launched in March 2022 and is still ongoing.
The neutralization coverage for the different variants was measured and reached >200000 IU/mL for most of VoC tested. As
expected, Omicron showed the highest reduction in neutralization (5- and 4.3-fold for BA.1 and BA.2 as compared with the
ancestral D614G sequence) however titers were >105 IU/mL. This neutralizing titer against Omicron is in fact two orders of
magnitude higher that those obtained after booster vaccination in either naïve or COVID-19 convalescent individuals. This
potency is significant considering the limited availability of monoclonal antibodies that are active against both Omicron
subvariants. This approach will have a high medical and societal impact enabling specific patient management with a curative
treatment.
About the preclinical studies, the in vivo model was set up and all the data indicate that SARS-CoV-2-infected mice developed
pneumonia and acute respiratory distress syndrome (ARDS)-Like, similar to what seen in humans. The levels of Surfactant
protein D (SP-D) in the serum of infected and non-infected mice have been shown to be a candidate biomarker for severe
disease in Influenza and Covid19 patients Our data showed that the levels of SP-D in serum correlated with disease severity
in our mouse model.
Regarding the industrial production, lessons have been learnt from the first batch purified before the project (from 80L) and
the feasibility to scale up to a large volume has been validated by FAB team in collaboration with its subcontractor. A large
320 L clinical batch was purified end of March 2022.
These achievements reinforce the idea that the project could allow to bring a cost-effective therapeutic solution to respond
to the unmet need.
Also, in order to contribute making the EU the first carbon neutral continent by 2050, additional efforts will be made by EPICCROWN-2 to deliver our solution more sustainably and to positively impact on the environment. In April 2021, in connection
with this authorization dossier, FAB received a prefectural order confirming the possibility of producing in accordance with
the current environmental regulations. FAB's production activities do not pollute the environment; in particular, these
activities do not emit greenhouse gases (GES in French).
to Health Authorities and Ethics Committee. The decision was made to split the phase 2a/b clinical trial in 2 distinct trials: eg
a Phase 2a first and then later a Phase 2b. The Phase 2a was launched in March 2022 and is still ongoing.
The neutralization coverage for the different variants was measured and reached >200000 IU/mL for most of VoC tested. As
expected, Omicron showed the highest reduction in neutralization (5- and 4.3-fold for BA.1 and BA.2 as compared with the
ancestral D614G sequence) however titers were >105 IU/mL. This neutralizing titer against Omicron is in fact two orders of
magnitude higher that those obtained after booster vaccination in either naïve or COVID-19 convalescent individuals. This
potency is significant considering the limited availability of monoclonal antibodies that are active against both Omicron
subvariants. This approach will have a high medical and societal impact enabling specific patient management with a curative
treatment.
About the preclinical studies, the in vivo model was set up and all the data indicate that SARS-CoV-2-infected mice developed
pneumonia and acute respiratory distress syndrome (ARDS)-Like, similar to what seen in humans. The levels of Surfactant
protein D (SP-D) in the serum of infected and non-infected mice have been shown to be a candidate biomarker for severe
disease in Influenza and Covid19 patients Our data showed that the levels of SP-D in serum correlated with disease severity
in our mouse model.
Regarding the industrial production, lessons have been learnt from the first batch purified before the project (from 80L) and
the feasibility to scale up to a large volume has been validated by FAB team in collaboration with its subcontractor. A large
320 L clinical batch was purified end of March 2022.
These achievements reinforce the idea that the project could allow to bring a cost-effective therapeutic solution to respond
to the unmet need.
Also, in order to contribute making the EU the first carbon neutral continent by 2050, additional efforts will be made by EPICCROWN-2 to deliver our solution more sustainably and to positively impact on the environment. In April 2021, in connection
with this authorization dossier, FAB received a prefectural order confirming the possibility of producing in accordance with
the current environmental regulations. FAB's production activities do not pollute the environment; in particular, these
activities do not emit greenhouse gases (GES in French).