Periodic Reporting for period 7 - IB4SD-TRISTAN (Imaging Biomarkers (IBs) for Safer Drugs: Validation of Translational Imaging Methods in Drug Safety Assessment - Sofia ref.: 116106)
Reporting period: 2023-07-01 to 2024-12-31
Before new drugs are marketed, regulatory authorities must be satisfied that the benefits from the new drug outweigh any harms that might occur. The characterisation and amelioration of potential harms is called Drug Safety Assessment.
Biomarkers are important in Drug Safety Assessment. A Biomarker is a defined characteristic that is measured as an indicator of normal biological or pathogenic processes, or as responses to an exposure or intervention, including therapeutics. Molecular, histologic, radiographic (imaging), or physiologic characteristics are all types of Biomarkers.
Translational research is focused on the so-called "translational gaps" in medical research. It uses in vitro and in vivo laboratory research findings to improve the design and interpretation of clinical studies. It uses clinical research findings to improve human health. In addition, translational research uses clinical findings to improve the design and interpretation of in vitro and in vivo laboratory studies.
IB4SD-TRISTAN ("TRISTAN") was a project devised in response to the 7th call for research proposals under IMI 2, on the validation of translational imaging methods in drug safety assessment. TRISTAN succeeded in improving imaging methods and biomarkers for the prevention, mitigation and management of drug-induced harm to patients in its three specific areas. These areas were (1) (WP2) drug-induced changes in fluxes through liver transporters causing drug-induced liver injury (DILI) and drug-drug interactions (DDIs), (2) (WP3) drug-induced interstitial lung disease (DIILD), (3) (WP4) harms arising from maldistribution of large-molecule drugs.
Biomarkers are important in Drug Safety Assessment. A Biomarker is a defined characteristic that is measured as an indicator of normal biological or pathogenic processes, or as responses to an exposure or intervention, including therapeutics. Molecular, histologic, radiographic (imaging), or physiologic characteristics are all types of Biomarkers.
Translational research is focused on the so-called "translational gaps" in medical research. It uses in vitro and in vivo laboratory research findings to improve the design and interpretation of clinical studies. It uses clinical research findings to improve human health. In addition, translational research uses clinical findings to improve the design and interpretation of in vitro and in vivo laboratory studies.
IB4SD-TRISTAN ("TRISTAN") was a project devised in response to the 7th call for research proposals under IMI 2, on the validation of translational imaging methods in drug safety assessment. TRISTAN succeeded in improving imaging methods and biomarkers for the prevention, mitigation and management of drug-induced harm to patients in its three specific areas. These areas were (1) (WP2) drug-induced changes in fluxes through liver transporters causing drug-induced liver injury (DILI) and drug-drug interactions (DDIs), (2) (WP3) drug-induced interstitial lung disease (DIILD), (3) (WP4) harms arising from maldistribution of large-molecule drugs.
(WP2) Drug-induced changes in fluxes through liver transporters causing drug-induced liver injury (DILI) and drug-drug interactions (DDIs)
• Regulatory engagement: the biomarkers have been entered into the US FDA Biomarker Qualification Program [DDT Number: 000096].
• For the rat assay, MRI acquisition and analysis have been validated in multiple laboratories and fully described in publications.
• For the clinical assay, MRI acquisition and analysis have been validated in multiple sites and scanners in three clinical studies on liver transporter function in human volunteers and patients.
• Exploratory work to develop and evaluate an imaging biomarker of BSEP function has been published.
(WP3) Identification of imaging biomarkers to facilitate the detection and follow-up of patients suffering from drug-induced interstitial lung disease (DIILD) through clinical and preclinical (animal models) research.
· Robust acute and chronic rat models of DIILD have been extensively characterized using longitudinal histology, gene expression profiling and imaging by MRI, CT and PET to distinguish inflammatory vs fibrotic manifestations of DIILD. These have been fully described in publications.
· Clinical studies of 129 Xe MRI and CT biomarkers in ILD patients and in bleomycin-induced DIILD have been completed.
· A study of FDG PET biomarkers in human DIILD has been completed.
(WP4). Harms arising from mal-distribution of large-molecule drugs.
• Novel 89Zr chelators have been developed and demonstrate improved stability in vitro and in vivo. The have been used to investigate the distribution of novel biologicals in animal models.
• A novel (GMP compliant) radiolabelling strategy has been developed to radiolabel IL-2 with 18F for in vivo imaging of activated T-cells to investigate response to immunotherapy in cancer patients.
• TOF-SIMS and NanoSIMS analysis assessed the intratumoral and intracellular distribution of non-radioactive zirconium and intratumoral drug distribution.
• Different approaches to imaging CD8 T-cells were compared in preclinical tumour model.
• GLP-1R ligands and IL-17/IL-18 antibodies were successfully conjugated with DFO*, labelled with 89Zr, and evaluated in preclinical models.
• The GMP production of 89Zr-pembrolizumab was established, and imaging studies performed in humanized mice, non-human primates and cancer patients.
• Regulatory engagement: the biomarkers have been entered into the US FDA Biomarker Qualification Program [DDT Number: 000096].
• For the rat assay, MRI acquisition and analysis have been validated in multiple laboratories and fully described in publications.
• For the clinical assay, MRI acquisition and analysis have been validated in multiple sites and scanners in three clinical studies on liver transporter function in human volunteers and patients.
• Exploratory work to develop and evaluate an imaging biomarker of BSEP function has been published.
(WP3) Identification of imaging biomarkers to facilitate the detection and follow-up of patients suffering from drug-induced interstitial lung disease (DIILD) through clinical and preclinical (animal models) research.
· Robust acute and chronic rat models of DIILD have been extensively characterized using longitudinal histology, gene expression profiling and imaging by MRI, CT and PET to distinguish inflammatory vs fibrotic manifestations of DIILD. These have been fully described in publications.
· Clinical studies of 129 Xe MRI and CT biomarkers in ILD patients and in bleomycin-induced DIILD have been completed.
· A study of FDG PET biomarkers in human DIILD has been completed.
(WP4). Harms arising from mal-distribution of large-molecule drugs.
• Novel 89Zr chelators have been developed and demonstrate improved stability in vitro and in vivo. The have been used to investigate the distribution of novel biologicals in animal models.
• A novel (GMP compliant) radiolabelling strategy has been developed to radiolabel IL-2 with 18F for in vivo imaging of activated T-cells to investigate response to immunotherapy in cancer patients.
• TOF-SIMS and NanoSIMS analysis assessed the intratumoral and intracellular distribution of non-radioactive zirconium and intratumoral drug distribution.
• Different approaches to imaging CD8 T-cells were compared in preclinical tumour model.
• GLP-1R ligands and IL-17/IL-18 antibodies were successfully conjugated with DFO*, labelled with 89Zr, and evaluated in preclinical models.
• The GMP production of 89Zr-pembrolizumab was established, and imaging studies performed in humanized mice, non-human primates and cancer patients.
TRISTAN’s imaging methods and biomarkers are designed to impact the prevention, mitigation and management of drug-induced harm in several different ways, as follows.
In the imaging of animals exposed to investigational substances prior to first investigational use in humans, imaging of animals during and after exposure to investigational substances may help:
• Prevent harmful investigational substances ever being progressed into man.
• Provide translational imaging biomarkers that can better predict potential safety liabilities of medicines earlier in the drug discovery and development process.
• Reduce attrition at late stage clinical trials.
Through imaging of healthy volunteers and patient volunteers exposed to Investigational Medicinal Product (IMPs) in clinical trials, TRISTAN’s imaging biomarkers in clinical trials of IMPs may help:
• prevent IMPs with unacceptable risks from progressing further in man;
• determine posologies without safety concern;
• determine whether drug-induced signs and symptoms seen are benign and/or reversible, or whether they predict serious and/or irreversible harm;
• provide an evidence base for subsequent use of these imaging biomarkers in drug labelling to exclude subsets of patients at enhanced risk of harm;
• provide an evidence base for subsequent use of these imaging biomarkers in drug labelling to manage patients with signs and symptoms of drug-induced harm;
• provide imaging biomarkers of disease;
• provide drug-induced safety-liability biomarkers.
In the imaging of patients who are prescribed drugs which have been approved by regulatory authorities, TRISTAN’s imaging biomarkers in patients may help:
• exclude subsets of patients at enhanced risk of harm;
• manage patients with signs and symptoms of drug-induced harm.
In consequence:
• fewer patients will be suffer drug-induced harm to the liver, or to the lung, or harms arising from mal-distribution of large-molecule drugs;
• the costs of unsuccessful drug development will drop, reducing the overall costs of drug development;
• small businesses will benefit by providing validated imaging assays.
In the imaging of animals exposed to investigational substances prior to first investigational use in humans, imaging of animals during and after exposure to investigational substances may help:
• Prevent harmful investigational substances ever being progressed into man.
• Provide translational imaging biomarkers that can better predict potential safety liabilities of medicines earlier in the drug discovery and development process.
• Reduce attrition at late stage clinical trials.
Through imaging of healthy volunteers and patient volunteers exposed to Investigational Medicinal Product (IMPs) in clinical trials, TRISTAN’s imaging biomarkers in clinical trials of IMPs may help:
• prevent IMPs with unacceptable risks from progressing further in man;
• determine posologies without safety concern;
• determine whether drug-induced signs and symptoms seen are benign and/or reversible, or whether they predict serious and/or irreversible harm;
• provide an evidence base for subsequent use of these imaging biomarkers in drug labelling to exclude subsets of patients at enhanced risk of harm;
• provide an evidence base for subsequent use of these imaging biomarkers in drug labelling to manage patients with signs and symptoms of drug-induced harm;
• provide imaging biomarkers of disease;
• provide drug-induced safety-liability biomarkers.
In the imaging of patients who are prescribed drugs which have been approved by regulatory authorities, TRISTAN’s imaging biomarkers in patients may help:
• exclude subsets of patients at enhanced risk of harm;
• manage patients with signs and symptoms of drug-induced harm.
In consequence:
• fewer patients will be suffer drug-induced harm to the liver, or to the lung, or harms arising from mal-distribution of large-molecule drugs;
• the costs of unsuccessful drug development will drop, reducing the overall costs of drug development;
• small businesses will benefit by providing validated imaging assays.