Summary

ISOTOPICS is a European research project which gathers 5 academic partners and 3 pharmaceutical companies in 5 European countries. The project aims at the development of new methods for the chemical labeling of drug candidates to streamline drug innovation and to decrease drug attrition (presently less than 10% of drugable compounds reach the market). ISOTOPICS will also train 15 PhD students to meet the need of industry by providing new researchers specialized in labeling chemistry with a dual academic/industrial culture. On top of the research carried out in the partner's lab, the training will include workshops with meetings, taught courses and lecture cycles as well as several inter-laboratory secondments.

Presentation

ISOTOPICS is an international research project granted by the European Commission for 4 years with a 4 million Euro budget. It gathers five academic partners: the French Alternative Energies and Atomic Energy Commission (CEA, Institute of Biology and Technology at Saclay as the project coordinator), the Centre of French National Scientific Research (CNRS, National Institute of Applied Sciences in Toulouse), the Department of Chemistry at the University of Oxford (UOXF), the Karolinska Institute PET Centre in Stockholm (KI) and the Cyclotron Research Centre of the University of Liège (ULG) with three major pharmaceutical companies: UCB-Pharma (Belgium), AstraZeneca (Sweden) and the Sanofi Group (Sanofi Aventis Deutschland GmbH  in Germany and Sanofi-Recherche in France). The research consortium ambition is to develop cutting-edge chemical methods applicable to the isotopic labeling of drug candidates to decrease drug attrition by tagging the tested compounds with easily detectable elements through structurally benign modifications. Fifteen PhD students specialized in isotopic labeling with a dual academic/industrial culture will be also trained.

Context

Drug discovery and development is a time-consuming (around 15 years), expensive (at least 1 billion Euro per new drug) and risky process since only one product on ten entering clinical trials will reach the market (even less when targeting the central nervous system). This dramatic attrition of drug candidates is mainly related to poor efficacy and unexpected adverse effects observed in Phase II clinical trials. This results in part from insufficiently addressed body distribution studies, accumulation and/or metabolization assessments which all are strongly limited by chemistry. As a matter of fact, studying the fate of drugs in vivo implies that a large number of molecules can be isotopically labeled with deuterium/tritium (isotopes of hydrogen), carbon-11/carbon-14 (radio-isotopes of carbon) and fluorine-18 (radio-isotope of fluorine, an element found in many drugs). Use of these isotopes permits the structurally benign labelling of chemicals and biochemicals (in contrast with the fluorescent labeling) and the detection of tiny amounts of product. Unfortunately, the number of isotopic labeling methods applicable to sensitive compounds (i.e. small molecule drugs, therapeutic proteins including antibodies and nucleic acids such as SiRNAs) remains limited.

Objectives

ISOTOPICS aims at the development of an innovative isotopic chemistry for the labeling of large series of drugs including chemicals and biologics with (radioactive but not only) isotopes of hydrogen, carbon and fluorine that can be detected and quantified in trace amounts in biological fluids and through whole-body imaging. A particular attention will be paid to the development of cutting-edge techniques for the late-stage labeling of high added-value molecules which is more economical and generates less chemical and radioactive wastes. This new chemistry is expected:

● To enable the easy and quick identification of new drug candidates that would not be selected from classical in vitro assays;

● To reject any drug-candidate which might display insufficient efficacy or unpredictable adverse effects before the compound is selected for clinical trials;

● To perform biodistribution studies and to provide pharmacokinetics/pharmacodynamics data in order to help with clinical trials (by determining active doses, formulation etc.);

● To develop concomitantly radiotracers which could be used for routine diagnostic (e.g. Positron Emission Tomography Imaging) in particular for personalized medicine applications.

All these methods will be designed to label a large number of high value-added (and thus sensitive) molecules such as small molecule drugs and large biologics.

Implementation

The ISOTOPICS research project will be implemented through extensive research in partners' labs to train 15 Early-Stage Researchers (ESRs) but also via inter-sector secondments (at least 2 secondments in both academic and industrial labs per ESR). The precise objectives will be set-up in real-time to address pressing industrial questions. This will lead the partners to carry out challenging researches in broader fields of chemistry with the constant opportunity of responding to major industrial issues. Research will be valorized by publication and patenting and exploited for the labeling of drugs under development. Theoretical training will include specialized taught courses, lectures by prominent scientists, "Open-your-Mind" sessions and soft-skills (inclusive of entrepreneurship, project management, quality and ethics, communication and presentation etc.).

Expected Impact

ISOTOPICS is anticipated to improve Drug Discovery and Development by decreasing drug attrition, streamlining the precocious in vivo evaluation of drug candidates to explore new therapeutic solutions, and training the next generation of (radio)labeling-specialized chemists with a strong background in medicinal chemistry. A reduction of drug development costs is expected to boost drug innovation, to strengthen the European position on the world drug market and to allow pharmaceutical companies to increase the number of therapeutic areas they are operating in. New radiotracers for real-time diagnostic medical imaging could be concomitantly developed from carbon-11/fluorine-18-labeled compounds which can be used for routine medical imaging for diagnostic and personalized medicine. The training of new scientists with a dual academic/industrial culture and a real entrepreneurial mindset might also help in the setting-up and growth of startups and SMEs specialized in isotopic labeling and preclinical studies to meet the increasing needs of the pharmaceutical industry. Open-access to most of data (in the limits of industrial property rights) will help in the dissemination of knowledge at the international level in order to participate in the global improvement of health and wellbeing.

Ethics

Although ISOTOPICS is expected to have indisputable positive scientific, industrial and societal impacts, the project employs a set of techniques that might worry the public and raise ethical questions such as the toxicity and radiotoxicity of products for the people and the environment, the use of human cells, possible animal experiments, clinical trials and drug safety issues. All these aspects are checked by the European Commission, the national safety agencies, an Ethics Committee internal to the project as well as an external Advisory Board.

● ISOTOPICS aims at the development of more efficient radiolabeling techniques which result in safer handling of radioactive products and decreased waste production. The choice of isotopes is dictated by several technical specifications (using easy detectable and structurally benign substitutes of hydrogen, carbon and fluorine, possible use for in vivo whole body imaging) but also by environmental concerns by using radioisotopes with a short half-life. All the experiments will be carried out in dedicated facilities in compliance with local radiation safety regulations and strictly controlled by onsite radiation safety services and external safety agencies.

● Thanks to their decay mode, use of carbon-11 and fluorine-18 has been validated by health agencies for the design and development of tracers routinely used in hospitals.

● Although ISOTOPICS will systematize in vivo preclinical experiments at an early-stage of drug discovery and development, it is expected to contribute in the reduction of animal testing (more molecules tested at the very beginning and finally less animals sacrificed by using in vivo quantitative whole-body imaging). Animal testing will comply with the '3R Principles' (Reduction, Refinement, Replacement) and will be only done when essential with the permanent concern of insuring animal welfare. All experiments will be controlled by an Ethics Committee and will be reported to the European Commission.

● ISOTOPICS does not include clinical trials though it is expected to promote Phase 0 assays (injection of tiny amounts of radioactive drugs to healthy and well-informed volunteers) in order to evaluate qualitatively and quantitatively the drug biodistribution in humans.

● One of the ISOTOPICS objectives is to decrease belated drug attrition however the difficult problem of possible biopersistence and resulting delayed adverse effects can be also tackled in order to strengthen drug safety.

● ISOTOPICS is also concerned about insuring the students with adequate working conditions (i.e. adapted and secured facilities) and will pay a particular attention to all ethical aspects regarding the recruitment procedures (especially in terms of non-discrimination and gender equality).