Periodic Reporting for period 3 - FAIR (FLAGELLIN AEROSOL THERAPY AS AN IMMUNOMODULATORY ADJUNCT TO THE ANTIBIOTIC TREATMENT OF DRUG-RESISTANT BACTERIAL PNEUMONIA)
Período documentado: 2023-01-01 hasta 2024-06-30
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 subsequent curative failure. 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 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 data analysis, 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 data analysis, 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.
The main achievements of the FAIR project to date are summarized below:
• 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) including the organization of a webinar and preparatory work for a course on nebulized drugs for the next reporting period, have been produced.
• The production and release of flagellin/FLAMOD Drug Product for the phase 1 clinical trial have been completed and the stability program studies are ongoing. The regulatory toxicology studies as well as the Investigational Medicinal Product Dossier (IMPD) have been completed and provided to the phase 1 clinical trial Sponsor for the regulatory submission of the Clinical Trial Application (CTA) package.
• Mathematical modelling and simulation approaches have been applied to integrate published knowledge and experimental data from in vitro and preclinical FAIR investigations. These models have provided valuable insights into the pharmacokinetics of FLAMOD, in the body, and its pharmacodynamics, including its effects on the innate immune system. Preclinical investigations have further defined the potency of inhaled FLAMOD as an adjunct therapy to standard-of-care antibiotics in treating respiratory tract infections. This data-driven approach has been critical in determining the optimal lung-targeted dose and potential systemic exposure in humans, informing the dosing and design of the Phase 1 clinical trial.
• Significant progress has been made in preparing the Phase 1 clinical trial approval package. By the end of this reporting period, the package was nearing completion, with plans to submit it to regulatory authorities in Q3 of 2024. The clinical trial is expected to commence in Q4 of 2024, marking a pivotal step towards evaluating the safety and biological activity of FLAMOD in healthy individuals.
• Advances in biomarker discovery have led to the identification and validation of several markers from two patient cohorts, which have been corroborated in independent cohorts. These biomarkers are crucial in stratifying patients with severe pneumonia, enabling the identification of those who are most likely to benefit from flagellin/FLAMOD aerosol therapy.
• To assess the future acceptability of FLAMOD among patients and clinicians, comprehensive surveys and interviews were conducted and finalized. The findings indicate that the proposed/future procedure to administrate the nebulized FLAMOD, used as an adjunct to antibiotic treatment, is well-accepted by both clinicians and patients.
• A systematic, evidence-based review has been conducted to evaluate the effectiveness of current pneumonia treatments. This review will inform the development of an economic decision model, which will be used to estimate the healthcare economics and potential benefits of treatments involving nebulized FLAMOD.
• Throughout the project, ethics requirements have been continuously monitored and reported by FAIR’s Independent Ethics Advisor.
• 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) including the organization of a webinar and preparatory work for a course on nebulized drugs for the next reporting period, have been produced.
• The production and release of flagellin/FLAMOD Drug Product for the phase 1 clinical trial have been completed and the stability program studies are ongoing. The regulatory toxicology studies as well as the Investigational Medicinal Product Dossier (IMPD) have been completed and provided to the phase 1 clinical trial Sponsor for the regulatory submission of the Clinical Trial Application (CTA) package.
• Mathematical modelling and simulation approaches have been applied to integrate published knowledge and experimental data from in vitro and preclinical FAIR investigations. These models have provided valuable insights into the pharmacokinetics of FLAMOD, in the body, and its pharmacodynamics, including its effects on the innate immune system. Preclinical investigations have further defined the potency of inhaled FLAMOD as an adjunct therapy to standard-of-care antibiotics in treating respiratory tract infections. This data-driven approach has been critical in determining the optimal lung-targeted dose and potential systemic exposure in humans, informing the dosing and design of the Phase 1 clinical trial.
• Significant progress has been made in preparing the Phase 1 clinical trial approval package. By the end of this reporting period, the package was nearing completion, with plans to submit it to regulatory authorities in Q3 of 2024. The clinical trial is expected to commence in Q4 of 2024, marking a pivotal step towards evaluating the safety and biological activity of FLAMOD in healthy individuals.
• Advances in biomarker discovery have led to the identification and validation of several markers from two patient cohorts, which have been corroborated in independent cohorts. These biomarkers are crucial in stratifying patients with severe pneumonia, enabling the identification of those who are most likely to benefit from flagellin/FLAMOD aerosol therapy.
• To assess the future acceptability of FLAMOD among patients and clinicians, comprehensive surveys and interviews were conducted and finalized. The findings indicate that the proposed/future procedure to administrate the nebulized FLAMOD, used as an adjunct to antibiotic treatment, is well-accepted by both clinicians and patients.
• A systematic, evidence-based review has been conducted to evaluate the effectiveness of current pneumonia treatments. This review will inform the development of an economic decision model, which will be used to estimate the healthcare economics and potential benefits of treatments involving nebulized FLAMOD.
• Throughout the project, ethics requirements have been continuously monitored and reported by 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 third reporting period of the FAIR project demonstrate significant progress toward these 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 third reporting period of the FAIR project demonstrate significant progress toward these expected impacts.