Periodic Reporting for period 2 - FAIR (FLAGELLIN AEROSOL THERAPY AS AN IMMUNOMODULATORY ADJUNCT TO THE ANTIBIOTIC TREATMENT OF DRUG-RESISTANT BACTERIAL PNEUMONIA)
Berichtszeitraum: 2021-07-01 bis 2022-12-31
Bacterial pneumonia is a leading cause of morbidity and mortality worldwide. Antibiotics constitute the standard of care but are faced with the emergence of antimicrobial resistance (AMR) and the curative failure. The FAIR consortium aims at assessing an adjunct to antibiotic therapy as an emerging concept of overcome AMR in pneumonia. The project leverages (i) a unique immunomodulatory flagellin that enhances airway epithelial innate immune defences and increases the therapeutic outcome relative to antibiotic alone, and (ii) airway-specific aerosol delivery by nebulization.
FAIR’s objectives are to:
• develop nebulization modalities for optimal airway targeting and rapid action at the infection site
• demonstrate that nebulized flagellin strengthens the response to antibiotics in relevant preclinical models of antibiotic-resistant pneumonia
• identify host immune factors required for the gain of protection with systems biology
• implement pharmacokinetics/pharmacodynamics model-based design and simulation for clinical validation
• assess nebulized flagellin’s safety in a Phase I clinical trial.
• analyse the acceptability and economic relevance of the therapy
• identify stratification markers that predict the course of pneumonia and treatment in antibiotic-treated cohorts.
Expected outcomes include the enrichment of the pipeline of novel treatments against pneumonia, reinforcement of EU capacity to control AMR and infections, the Phase I safety report on nebulized flagellin, recommendations for future trials, and acceptability by the stakeholders and cost-effectiveness for public health. FAIR will develop new avenues of research on mechanisms of action of the adjunct flagellin, and will define (for future trials) the subpopulation of patients that might benefit most from this treatment. Our industrial partnerships and exploitation plan will enable straightforward development of drug and nebuliser device, and bring innovation to the patients.
FAIR’s objectives are to:
• develop nebulization modalities for optimal airway targeting and rapid action at the infection site
• demonstrate that nebulized flagellin strengthens the response to antibiotics in relevant preclinical models of antibiotic-resistant pneumonia
• identify host immune factors required for the gain of protection with systems biology
• implement pharmacokinetics/pharmacodynamics model-based design and simulation for clinical validation
• assess nebulized flagellin’s safety in a Phase I clinical trial.
• analyse the acceptability and economic relevance of the therapy
• identify stratification markers that predict the course of pneumonia and treatment in antibiotic-treated cohorts.
Expected outcomes include the enrichment of the pipeline of novel treatments against pneumonia, reinforcement of EU capacity to control AMR and infections, the Phase I safety report on nebulized flagellin, recommendations for future trials, and acceptability by the stakeholders and cost-effectiveness for public health. FAIR will develop new avenues of research on mechanisms of action of the adjunct flagellin, and will define (for future trials) the subpopulation of patients that might benefit most from this treatment. Our industrial partnerships and exploitation plan will enable straightforward development of drug and nebuliser device, and bring innovation to the patients.
Bacterial pneumonia is a leading cause of morbidity and mortality worldwide. Antibiotics constitute the standard of care but are faced with the emergence of antimicrobial resistance (AMR) and the failure to cure. The FAIR consortium aims at assessing an adjunct to antibiotic therapy as an emerging concept to overcome AMR in pneumonia. The project leverages (i) a unique immunomodulatory compound called FLAMOD that enhances airway epithelial innate immune defences and increases the therapeutic outcome relative to antibiotics alone, and (ii) airway-specific aerosol delivery by nebulisation.
During this FAIR reporting period (M19-36), the following objectives were achieved:
• FAIR achieved an efficient coordination and management of the project, a successful organisation of regular meetings of the governing bodies, a practical and secured plan for data management, and a well-targeted communication and dissemination (https://fair-flagellin.eu).
• The FLAMOD Drug Product production and release for the phase 1 clinical trial have been completed and the first year of the stability program studies have been achieved. The certified vendor for the completion of the regulatory toxicology studies was selected and the studies are scheduled to commence Q1 of 2023.
• The pharmacokinetics and pharmacodynamics of inhaled FLAMOD have been defined using preclinical models. These preclinical models have also served to further define the potency of inhaled FLAMOD as an adjunct therapeutic on top of standard-of-care antibiotics in the treatment of respiration tract infections caused by antibiotic-resistant bacteria. Collectively, these data have been used to inform the mathematical modelling and simulation platform for the optimal FLAMOD dose and trial design to be implemented in the phase 1 clinical trial.
• Mathematical modelling and simulation approaches leveraging published knowledge and experimental data obtained in the in vitro and preclinical FAIR investigations were applied to gain knowledge about the pharmacokinetics of FLAMOD, i.e. the processes of absorption, distribution, metabolism and elimination in the body, and the pharmacodynamics, i.e. the influence of FLAMOD on the innate immune system. Based on these models, an optimal dose of FLAMOD targeted to the lung, as well as the potential systemic exposure to FLAMOD in humans was derived.
• A protocol writing group and clinical trial committee have been established for the phase 1 clinical trial. Preparatory work on the approval package has commenced, including the selection of the subcontracting entities responsible for the writing of the Investigator’s Brochure and the preparation of the pharmaceutical-grade buffer.
• The mid-term recruitment report for the prospective BIO-PNEU study was submitted and important progress has been made in biomarker discovery and clinical-outcome-based stratification for patients with severe pneumonia, to identify patients who might in future benefit from adjunct FLAMOD therapy.
• To examine if the use of FLAMOD would be acceptable to patients and clinicians and whether it could be adapted to meet their needs, surveys and interviews in several different languages have been conducted and extended to a larger audience.
• FAIR has performed a systematic evidence-based review on how current treatments or pneumonia work. This review will inform the economic decision model that will be used to estimate the healthcare economics and benefits of treatments with nebulised FLAMOD.
• The ethics requirements were continuously reported and monitored by the FAIR’s Independent Ethics Advisor.
During this FAIR reporting period (M19-36), the following objectives were achieved:
• FAIR achieved an efficient coordination and management of the project, a successful organisation of regular meetings of the governing bodies, a practical and secured plan for data management, and a well-targeted communication and dissemination (https://fair-flagellin.eu).
• The FLAMOD Drug Product production and release for the phase 1 clinical trial have been completed and the first year of the stability program studies have been achieved. The certified vendor for the completion of the regulatory toxicology studies was selected and the studies are scheduled to commence Q1 of 2023.
• The pharmacokinetics and pharmacodynamics of inhaled FLAMOD have been defined using preclinical models. These preclinical models have also served to further define the potency of inhaled FLAMOD as an adjunct therapeutic on top of standard-of-care antibiotics in the treatment of respiration tract infections caused by antibiotic-resistant bacteria. Collectively, these data have been used to inform the mathematical modelling and simulation platform for the optimal FLAMOD dose and trial design to be implemented in the phase 1 clinical trial.
• Mathematical modelling and simulation approaches leveraging published knowledge and experimental data obtained in the in vitro and preclinical FAIR investigations were applied to gain knowledge about the pharmacokinetics of FLAMOD, i.e. the processes of absorption, distribution, metabolism and elimination in the body, and the pharmacodynamics, i.e. the influence of FLAMOD on the innate immune system. Based on these models, an optimal dose of FLAMOD targeted to the lung, as well as the potential systemic exposure to FLAMOD in humans was derived.
• A protocol writing group and clinical trial committee have been established for the phase 1 clinical trial. Preparatory work on the approval package has commenced, including the selection of the subcontracting entities responsible for the writing of the Investigator’s Brochure and the preparation of the pharmaceutical-grade buffer.
• The mid-term recruitment report for the prospective BIO-PNEU study was submitted and important progress has been made in biomarker discovery and clinical-outcome-based stratification for patients with severe pneumonia, to identify patients who might in future benefit from adjunct FLAMOD therapy.
• To examine if the use of FLAMOD would be acceptable to patients and clinicians and whether it could be adapted to meet their needs, surveys and interviews in several different languages have been conducted and extended to a larger audience.
• FAIR has performed a systematic evidence-based review on how current treatments or pneumonia work. This review will inform the economic decision model that will be used to estimate the healthcare economics and benefits of treatments with nebulised FLAMOD.
• The ethics requirements were continuously reported and monitored by the FAIR’s Independent Ethics Advisor.
Briefly, FAIR expects to impact on:
• patients and clinicians: meeting a medical need by improving clinical care, social functioning, and quality of life
• society in general: longer-term reductions in the cost and global burden of pneumonia
• research: new avenues for antibiotics in the context of immunity and PK/PD modelling of nebulized biologics
• industry: the exploitation of nebulizers, drug formulations, cell-based assays, and prognostic tools.
The accomplishments achieved during the second reporting period of the FAIR project are promising in their contribution to the expected impacts.
• patients and clinicians: meeting a medical need by improving clinical care, social functioning, and quality of life
• society in general: longer-term reductions in the cost and global burden of pneumonia
• research: new avenues for antibiotics in the context of immunity and PK/PD modelling of nebulized biologics
• industry: the exploitation of nebulizers, drug formulations, cell-based assays, and prognostic tools.
The accomplishments achieved during the second reporting period of the FAIR project are promising in their contribution to the expected impacts.