Periodic Reporting for period 6 - IB4SD-TRISTAN (Imaging Biomarkers (IBs) for Safer Drugs: Validation of Translational Imaging Methods in Drug Safety Assessment - Sofia ref.: 116106)
Okres sprawozdawczy: 2022-01-01 do 2023-06-30
Before new drugs are marketed, regulatory authorities must be satisfied that the benefits from the new drug outweigh any harms that might occur. The characterization 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 processes, pathogenic processes, or responses to an exposure or intervention, including therapeutic interventions. 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 takes laboratory research findings in vitro and in vivo, and uses them to improve the design and interpretation of clinical studies. It takes clinical research findings, and uses them to improve human health. In addition, it takes clinical findings, and uses them to improve the design and interpretation of in vitro and in vivo laboratory studies.
TRISTAN aims to improve imaging methods and biomarkers for the prevention, mitigation and management of drug-induced harm to patients in three specific areas. These areas are (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 mal-distribution 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 processes, pathogenic processes, or responses to an exposure or intervention, including therapeutic interventions. 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 takes laboratory research findings in vitro and in vivo, and uses them to improve the design and interpretation of clinical studies. It takes clinical research findings, and uses them to improve human health. In addition, it takes clinical findings, and uses them to improve the design and interpretation of in vitro and in vivo laboratory studies.
TRISTAN aims to improve imaging methods and biomarkers for the prevention, mitigation and management of drug-induced harm to patients in three specific areas. These areas are (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 mal-distribution of large-molecule drugs.
(WP2) drug-induced changes in fluxes through liver transporters causing drug-induced liver injury (DILI) and drug-drug interactions (DDIs)
• The project has engaged with US FDA, which has approved a Biomarker Qualification Letter of Intent (LOI) submitted by the project. FDA has requested that TRISTAN submit a human liver biomarker qualification plan. This will be submitted to in 2023.
• Work to develop a valid and robust rat assay. All of the nonclinical work has been completed and data analysis has been completed, with scientific publications describing and validating the assay.
• Work to develop a valid and robust human assay. The clinical assay has been established in a study of rifampicin on liver transporter function in human volunteers: this will be submitted for publication in 2023. Further clinical studies will be completed in 2024.
• Exploratory work to develop and evaluate an imaging biomarker of BSEP function has been completed.
(WP3). The aim of this workpackage is to identify imaging biomarkers to facilitate the identification and follow-up of patients suffering from drug-induced interstitial lung disease (DIILD)). Clinical and preclinical (animal models) research is contributing to this aim. Since 2022 a number of important steps towards better imaging biomarkers for DIILD have been made;
Clinical:
· D3.4 and D3.5 (Manuscripts on 129 Xe MRI & CT in ILD patients and longitudinal examination of ILD patients with 129 Xe MRI & CT) are currently in progress and with key senior authors for feedback.
· Since approval of the Bleomycin study 6 patients have been enrolled
· A paper comparing xenon and oxygen-enhanced ventilation MRI was published in 2023
· D3.26: All patients for the retrospective study are included and image acquisition and segmentation is finished. We are still working on the radiomic feature extraction.
• Robust acute and chronic rat models of DIILD have been extensively characterized by longitudinal histology and gene expression profiling together with imaging by MRI, CT and PET to characterize the inflammatory vs fibrotic manifestations of DIILD. These studies have been completed and published.
•Work to develop an alternative animal model using another known DIILD inducing drug has so far been unsuccessful, not inducing pathological changes similar to those seen in patients.
• Work to develop valid and robust clinical imaging assays using CT, proton MRI, and hyperpolarised xenon MRI is underway and manuscripts validating the new methodologies in man have been submitted.
• Our initial planned multicentre trial in DIILD in oncology proved over-ambitious and was closed, and the resources redeployed towards more focused studies of DIILD in cancer patients, now recruiting.
(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 chelators are currently used to investigate the distribution of novel biologicals in animal models.
• A novel (GMP compliant) radiolabeling strategy has been developed to radiolabel IL-2 with F-18 for in vivo imaging of activated T-cells to investigate response to immunotherapy in cancer patients
• TOF-SIMS and NanoSIMS analysis is being developed to assess the intratumoral and intracellular distribution of non-radioactive zirconium to study intratumoral drug distrubtion
• Different approaches to imaging CD8 T-cells have been compared in preclinical tumor model
• GLP-1R ligands and IL-17/IL-18 antibodies have been successfully conjugated with DFO*, labeled with Zr-89, and evaluated in preclinical models.
• The GMP production of 89Zr-pembrolizumab has been established and imaging studies with 89Zr-pembrolizumab have been performed in humanized mice, non-human primates and cancer patients.
• The project has engaged with US FDA, which has approved a Biomarker Qualification Letter of Intent (LOI) submitted by the project. FDA has requested that TRISTAN submit a human liver biomarker qualification plan. This will be submitted to in 2023.
• Work to develop a valid and robust rat assay. All of the nonclinical work has been completed and data analysis has been completed, with scientific publications describing and validating the assay.
• Work to develop a valid and robust human assay. The clinical assay has been established in a study of rifampicin on liver transporter function in human volunteers: this will be submitted for publication in 2023. Further clinical studies will be completed in 2024.
• Exploratory work to develop and evaluate an imaging biomarker of BSEP function has been completed.
(WP3). The aim of this workpackage is to identify imaging biomarkers to facilitate the identification and follow-up of patients suffering from drug-induced interstitial lung disease (DIILD)). Clinical and preclinical (animal models) research is contributing to this aim. Since 2022 a number of important steps towards better imaging biomarkers for DIILD have been made;
Clinical:
· D3.4 and D3.5 (Manuscripts on 129 Xe MRI & CT in ILD patients and longitudinal examination of ILD patients with 129 Xe MRI & CT) are currently in progress and with key senior authors for feedback.
· Since approval of the Bleomycin study 6 patients have been enrolled
· A paper comparing xenon and oxygen-enhanced ventilation MRI was published in 2023
· D3.26: All patients for the retrospective study are included and image acquisition and segmentation is finished. We are still working on the radiomic feature extraction.
• Robust acute and chronic rat models of DIILD have been extensively characterized by longitudinal histology and gene expression profiling together with imaging by MRI, CT and PET to characterize the inflammatory vs fibrotic manifestations of DIILD. These studies have been completed and published.
•Work to develop an alternative animal model using another known DIILD inducing drug has so far been unsuccessful, not inducing pathological changes similar to those seen in patients.
• Work to develop valid and robust clinical imaging assays using CT, proton MRI, and hyperpolarised xenon MRI is underway and manuscripts validating the new methodologies in man have been submitted.
• Our initial planned multicentre trial in DIILD in oncology proved over-ambitious and was closed, and the resources redeployed towards more focused studies of DIILD in cancer patients, now recruiting.
(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 chelators are currently used to investigate the distribution of novel biologicals in animal models.
• A novel (GMP compliant) radiolabeling strategy has been developed to radiolabel IL-2 with F-18 for in vivo imaging of activated T-cells to investigate response to immunotherapy in cancer patients
• TOF-SIMS and NanoSIMS analysis is being developed to assess the intratumoral and intracellular distribution of non-radioactive zirconium to study intratumoral drug distrubtion
• Different approaches to imaging CD8 T-cells have been compared in preclinical tumor model
• GLP-1R ligands and IL-17/IL-18 antibodies have been successfully conjugated with DFO*, labeled with Zr-89, and evaluated in preclinical models.
• The GMP production of 89Zr-pembrolizumab has been established and imaging studies with 89Zr-pembrolizumab have been performed in humanized mice, non-human primates and cancer patients.
TRISTAN expects that its imaging methods and biomarkers have impact in 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, TRISTAN considers that 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 considers that imaging in clinical trials of IMPs may help:
• prevent IMPs which carry unacceptable risks being progressed further in man;
• determine doses and schedules incurring no safety concern;
• determine whether worrying drug-induced signs and symptoms 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 and to manage patients with signs and symptoms of drug-induced harm.
• Provide imaging biomarkers of disease, and drug-induced safety-liability biomarkers.
In the imaging of patients who are prescribed drugs which have been approved by regulatory authorities, TRISTAN considers that imaging 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, TRISTAN expects that fewer patients will be suffer drug-induced harm to the liver, drug-induced harm 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, TRISTAN considers that 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 considers that imaging in clinical trials of IMPs may help:
• prevent IMPs which carry unacceptable risks being progressed further in man;
• determine doses and schedules incurring no safety concern;
• determine whether worrying drug-induced signs and symptoms 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 and to manage patients with signs and symptoms of drug-induced harm.
• Provide imaging biomarkers of disease, and drug-induced safety-liability biomarkers.
In the imaging of patients who are prescribed drugs which have been approved by regulatory authorities, TRISTAN considers that imaging 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, TRISTAN expects that fewer patients will be suffer drug-induced harm to the liver, drug-induced harm 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.