Periodic Reporting for period 1 - sbli-ant3310 (A novel combination treatment effective against all multidrug-resistant pathogens deemed as a critical priority by the WHO)
Periodo di rendicontazione: 2023-02-01 al 2024-02-29
Antibiotic resistance is a major public health problem that poses several risks for our societies:
- A high epidemiological risk, associated with unsustainable mortality forecasts (10 million by 2050).
- A risk for medical practice as it is not just a question of controlling infections, but of guaranteeing the safety of infection-prone practices such as chemotherapy, surgery, and transplants.
- And finally, a risk for the global economy, with costs to healthcare systems in the region of 100,000 billion dollars a year.
A recent study (1) estimated that in 2019, 1.27 million deaths worldwide were the result of antibiotic resistance and 4.95 million were associated with it. The WHO released in 2022 a report(2) evaluating the pipelines of antibacterial candidates in different stages of development and pointed out the insufficiency of such antibacterial agents to tackle the challenge of increasing emergence and spread of antimicrobial resistance. In addition, the market access remains challenging and different organizations, such as the European Union, are currently working on new incentives to improve the accessibility and availability of antimicrobial medicinal products.
In this context, ANTABIO's mission is to develop innovative solutions to treat severe infections caused by antibiotic-resistant gram-negative bacteria, recognized as first priority by the WHO. MEM-ANT3310 is the combination of a well-known antibiotic, the meropenem (MEM), and Antabio’s innovative and proprietary serine-beta-lactamase inhibitor ANT3310. ANT3310 represents a significant breakthrough as it completely inhibits a broad range of beta-lactamases, including the Klebsiella pneumoniae carbapenemases (KPC) and oxacillin-hydrolysing (OXA) type enzymes found in Carbapenem-Resistant Enterobacterales (CRE) and Carbapenem-Resistant Acinetobacter baumannii (CRAB), and restores meropenem activity against these deadly pathogens. This is critical for the treatment of polymicrobial infections such as those causing hospital-acquired pneumonia (HAP) and ventilator-associated pneumonia (VAP) and complicated Urinary Tract Infection (cUTI).
Antabio SAS has entered into a grant agreement with the European Innovation Council and European SMEs Executive Agency (EISMEA) in February 2023 in relation to the project “A novel combination treatment effective against all multidrug-resistant pathogens deemed as a critical priority by the WHO” (sbli-ant3310). The objective of the project is to bring Antabio’s lead program MEM-ANT3310 to a clinical Proof-of-Concept (Phase 2 clinical study), in order to attract the interest of a pharmaceutical company which will bring it to the market. MEM-ANT3310 has the potential to become a key player in the small numbers of treatment available to hospitalized patients infected by Carbapenem-resistant pathogens.
In May 2023, Antabio announced the first subjects dosed in Phase 1 First-in-Human clinical trial of MEM-ANT3310. The Phase 1 clinical trial is designed to assess the safety, tolerability, and pharmacokinetic (PK) profile of single and multiple ascending doses (SAD/MAD) of intravenous ANT3310 administered alone, followed by an assessment of the combination (DDI) of ANT3310 with MEM in healthy volunteers. The in-life portion of SAD, MAD and DDI have been completed with promising results and the final report is expected in Q2 2024. This was a critical step for the program to pursue the R&D activities supported by the EIC.
(1) Global burden of bacterial antimicrobial resistance in 2019: a systematic analysis. Murray et al. The Lancet (2022)
(2) https://www.who.int/publications/i/item/9789240047655
- A high epidemiological risk, associated with unsustainable mortality forecasts (10 million by 2050).
- A risk for medical practice as it is not just a question of controlling infections, but of guaranteeing the safety of infection-prone practices such as chemotherapy, surgery, and transplants.
- And finally, a risk for the global economy, with costs to healthcare systems in the region of 100,000 billion dollars a year.
A recent study (1) estimated that in 2019, 1.27 million deaths worldwide were the result of antibiotic resistance and 4.95 million were associated with it. The WHO released in 2022 a report(2) evaluating the pipelines of antibacterial candidates in different stages of development and pointed out the insufficiency of such antibacterial agents to tackle the challenge of increasing emergence and spread of antimicrobial resistance. In addition, the market access remains challenging and different organizations, such as the European Union, are currently working on new incentives to improve the accessibility and availability of antimicrobial medicinal products.
In this context, ANTABIO's mission is to develop innovative solutions to treat severe infections caused by antibiotic-resistant gram-negative bacteria, recognized as first priority by the WHO. MEM-ANT3310 is the combination of a well-known antibiotic, the meropenem (MEM), and Antabio’s innovative and proprietary serine-beta-lactamase inhibitor ANT3310. ANT3310 represents a significant breakthrough as it completely inhibits a broad range of beta-lactamases, including the Klebsiella pneumoniae carbapenemases (KPC) and oxacillin-hydrolysing (OXA) type enzymes found in Carbapenem-Resistant Enterobacterales (CRE) and Carbapenem-Resistant Acinetobacter baumannii (CRAB), and restores meropenem activity against these deadly pathogens. This is critical for the treatment of polymicrobial infections such as those causing hospital-acquired pneumonia (HAP) and ventilator-associated pneumonia (VAP) and complicated Urinary Tract Infection (cUTI).
Antabio SAS has entered into a grant agreement with the European Innovation Council and European SMEs Executive Agency (EISMEA) in February 2023 in relation to the project “A novel combination treatment effective against all multidrug-resistant pathogens deemed as a critical priority by the WHO” (sbli-ant3310). The objective of the project is to bring Antabio’s lead program MEM-ANT3310 to a clinical Proof-of-Concept (Phase 2 clinical study), in order to attract the interest of a pharmaceutical company which will bring it to the market. MEM-ANT3310 has the potential to become a key player in the small numbers of treatment available to hospitalized patients infected by Carbapenem-resistant pathogens.
In May 2023, Antabio announced the first subjects dosed in Phase 1 First-in-Human clinical trial of MEM-ANT3310. The Phase 1 clinical trial is designed to assess the safety, tolerability, and pharmacokinetic (PK) profile of single and multiple ascending doses (SAD/MAD) of intravenous ANT3310 administered alone, followed by an assessment of the combination (DDI) of ANT3310 with MEM in healthy volunteers. The in-life portion of SAD, MAD and DDI have been completed with promising results and the final report is expected in Q2 2024. This was a critical step for the program to pursue the R&D activities supported by the EIC.
(1) Global burden of bacterial antimicrobial resistance in 2019: a systematic analysis. Murray et al. The Lancet (2022)
(2) https://www.who.int/publications/i/item/9789240047655
During the first period of the project (between February, 1st 2023 and February, 29th 2024), different activities were performed in order to prepare the Phase I lung pharmacokinetic (PK) clinical study anticipated in 2025.
First, a stable standard of ANT3310 has been successfully produced which will be used as an internal control of ANT3310 in the development of bioanalytical methods and analysis of clinical samples. These bioanalytical methods developments have been initiated at the end of February 2024. These bioanalytical methods will allow the analysis of bronchoalveolar lavage fluid (BALF) samples from clinical study subjects.
In parallel, several process optimizations were performed in order to improve the stability of the formulated drug product and facilitating the drug substance’s batch production. These processes mainly concerned the development of a lyophilization drug product, or the synthesis of the main drug substance intermediate and are under finalisation at the time of report.
Then, in order to cover the Phase I lung pharmacokinetic (PK) clinical study, the production of a clinical batch has been initiated. This batch of Clinical Units is manufactured according to Good Manufacturing Practices (GMP) to comply with the requirements.
Meanwhile, efficacy studies were performed in a murine model of complicated urinary tract infection (cUTI), an existing infection models to confirm the in vivo efficacy of MEM-ANT3310. The studies implicated the intra-renal injection of 4 bacterial isolates in different mice then administrated MEM alone or in combination with the ANT3310 and analysed the bacterial burdens in kidney tissue. The results showed that ANT3310 sufficiently inhibit the beta-lactamase enzymes produced by the MEM-resistant organisms, restoring MEM activity and providing reductions in bacterial burden.
Finally, susceptibility testing was performed on recent clinical isolates from hospitalized patients with NP or cUTI to MEM-ANT3310 and on recent clinical isolates of Acinetobacter species to confirm their susceptibility to MEM-ANT3310.
First, a stable standard of ANT3310 has been successfully produced which will be used as an internal control of ANT3310 in the development of bioanalytical methods and analysis of clinical samples. These bioanalytical methods developments have been initiated at the end of February 2024. These bioanalytical methods will allow the analysis of bronchoalveolar lavage fluid (BALF) samples from clinical study subjects.
In parallel, several process optimizations were performed in order to improve the stability of the formulated drug product and facilitating the drug substance’s batch production. These processes mainly concerned the development of a lyophilization drug product, or the synthesis of the main drug substance intermediate and are under finalisation at the time of report.
Then, in order to cover the Phase I lung pharmacokinetic (PK) clinical study, the production of a clinical batch has been initiated. This batch of Clinical Units is manufactured according to Good Manufacturing Practices (GMP) to comply with the requirements.
Meanwhile, efficacy studies were performed in a murine model of complicated urinary tract infection (cUTI), an existing infection models to confirm the in vivo efficacy of MEM-ANT3310. The studies implicated the intra-renal injection of 4 bacterial isolates in different mice then administrated MEM alone or in combination with the ANT3310 and analysed the bacterial burdens in kidney tissue. The results showed that ANT3310 sufficiently inhibit the beta-lactamase enzymes produced by the MEM-resistant organisms, restoring MEM activity and providing reductions in bacterial burden.
Finally, susceptibility testing was performed on recent clinical isolates from hospitalized patients with NP or cUTI to MEM-ANT3310 and on recent clinical isolates of Acinetobacter species to confirm their susceptibility to MEM-ANT3310.
Based on the broad spectrum of ANT3310’s activity in key pathogens, the project MEM-ANT3310 has major potential impacts:
- Increase of survival rates from CRAB infections improving significantly the pipeline of potential treatments.
- Reduction of the risk of severe and costly outcomes associated with cancer treatment or routine surgical procedures that are at high risk of infection (knee replacement, C-section, etc)
- Reduction of hospitalisation costs associated with medical care as well as the indirect costs that result from work absenteeism, decreased labour efficiency, disruptions in international trade, and decreased livestock production.
By providing effective treatment, this project can achieve positive clinical outcomes in 7-10 days which in the case of CRAB infections means both the saving of lives and shortening the duration of hospitalisation by approx. 50%.
- Increase of survival rates from CRAB infections improving significantly the pipeline of potential treatments.
- Reduction of the risk of severe and costly outcomes associated with cancer treatment or routine surgical procedures that are at high risk of infection (knee replacement, C-section, etc)
- Reduction of hospitalisation costs associated with medical care as well as the indirect costs that result from work absenteeism, decreased labour efficiency, disruptions in international trade, and decreased livestock production.
By providing effective treatment, this project can achieve positive clinical outcomes in 7-10 days which in the case of CRAB infections means both the saving of lives and shortening the duration of hospitalisation by approx. 50%.