Report

Teaser, summary, work performed and final results

Periodic Reporting for period 2 - IB4SD-TRISTAN (Imaging Biomarkers (IBs) for Safer Drugs: Validation of Translational Imaging Methods in Drug Safety Assessment - Sofia ref.: 116106)

Teaser

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...

Summary

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. 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) drug-induced changes in fluxes through liver transporters causing drug-induced liver injury (DILI) and drug-drug interactions (DDIs), (2) drug-induced interstitial lung disease (DIILD), (3) harms arising from mal-distribution of large-molecule drugs.

Work performed

(WP2) drug-induced changes in fluxes through liver transporters causing drug-induced liver injury (DILI) and drug-drug interactions (DDIs)
• Regulatory consultation. The project received valuable advice from EMA and is preparing to engage with FDA.
• The project published a comprehensive review of imaging methods for assessing drug-induced liver toxicity which described the state of the art and unmet needs.
• Work to develop a valid and robust rat assay. The project established that the basic MR parameter (R1) used in the gadoxetate assay is highly repeatable and reproducible across preclinical research laboratories in phantoms. Reproducibility is currently being measured by MR between rats in different centres. Conference abstracts have been accepted and full papers are in preparation.
• Work to develop a valid and robust human assay. Methods have been established for all six major MR platforms and made available to the public on imi-tristan.eu. Work has started to establish that the basic pharmacologic parameter (k1) used in the gadoxetate assay is repeatable and reproducible across clinical MR platforms. Conference abstracts have been accepted and full papers are in preparation.
• Work specifically aimed at assessing BSEP function is underway and candidate tracers have been identified

(WP3) drug-induced interstitial lung disease (DIILD)

• Regulatory consultation. The project received valuable advice from EMA.
• Systematic Reviews on extentd and impact of DIILD have been published.
• Work to develop valid and robust rodent assays is underway. Two studies have been completed and submitted published. The key themes being explored are acute vs chronic DIILD, an inflammatory vs fibrotic vs mixed phenotypes.
• A collaboration with Peter Caravan (Boston) has been established to explore novel tracers for imaging biomarkers of DIILD. The first studies with these tracers are underway.
• Work to develop valid and robust clinical imaging assays using CT, proton MRI, and hyperpolarised xenon MRI is underway. Two multicentre studies of DIILD in man are live and recruiting patients. Conference abstracts have been presented, others have been accepted, and full papers are in preparation.
• ‘Emerging and novel imaging biomarkers in drug-induced interstitial lung disease’ Hot Topics session at the European Respiratory Society International Congress, Paris, Sept 2018, arranged by TRISTAN partners (https://bit.ly/2EqVxBO).

(WP4) harms arising from mal-distribution of large-molecule drugs.
• A review describing the current state-of-the art of 89Zr-chemistry has been published
• Novel 89Zr chelators have been developed and demonstrate improved stability in vitro and in vivo. A first manuscript describing these novel chelators has been submitted for publication and new studies are ongoing to develop site-specifically conjugated bimodal biologicals containing a chelator for Zr-89 labeling and a fluorophore. This fluorescent label allows in vivo fluorescence imaging and microscopic analysis to study the intracellular localization of the biological.
• A manuscript has been submitted that describes the GMP production of F-18 labeled IL-2 for in vivo imaging of activated T-cells. In addition, a new superior labeling method has been developed that allow faster and more efficient labeling of IL-2, and this method is better suitable for multi-center clinical studies. The in vivo evaluation of this tracer in animal models has been finalized and a manuscript is currently being prepared.
• TOF-SIMS and NanoSIMS analysis is being developed to assess the intratumoral and intracellular distribution of non-radioactive zirconium First results with TOF-SIMS demonstrate that this method is highly sensitive to detect non-radioactive zirconium in tumor tissue.
• Different approaches to imaging CD8 T-cells are currently being evaluated in preclinical tumor models. These approaches include an

Final results

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 those 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;
• 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, 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.

Website & more info

More info: https://www.imi-tristan.eu.