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Reporting period: 2016-01-01 to 2017-12-31

Presently, less than one drugable compound on ten entering clinical trials effectively reaches the market. This drug attrition is mainly due to insufficient preclinical studies of drugable compounds. Drug Design and Development might be derisked by the use of isotopic (radio)labeling which enables to tag and trace drugs candidates in vivo at the early stage of drug research. However, this task is often difficult and time-consuming due to the scarcity of efficacious late-stage labeling methods and the lack of specialized chemists, familiar with isotopic chemistry but also medicinal chemistry applied in both academic and industrial sector.
The ISOTOPICS Innovative Training Network, gathering 5 academics and 3 industrial beneficiaries, has therefore defined 3 main objectives:
i) To train 15 Early Stage Researchers (ESRs) as the next generation of European chemists with expertise in isotopic labeling and advanced medicinal chemistry through a first-class research training program combined with a highly interactive secondments plan;
ii) To develop innovative and general isotopic labeling chemistry and radiochemistry to streamline the synthesis of labeled small-molecule drugs and biologics for therapy but also for diagnosis. The project is limited to hydrogen isotopes (2H, 3H), carbon radio-isotopes (11C, 14C) and fluorine radio-isotope (18F) which are well-admitted for such preclinical/clinical studies by the Drug Regulation Agencies.
iii) To work closely with the European pharmaceutical industry to apply the new labeling methods to drugs currently in development.
The collaborative training and research program of ISOTOPICS is outlined in six work packages (WP). During the 2-first years of the project, the implementation of each WP was achieved as follows:
The hiring of a full-time project manager in February 2016 was the first step in the project management. The recruitment of the 15 ESRs was completed in February 2017. The organisation of 4 ISOTOPICS meetings, attended by all Principal Investigators (PIs), ESRs and the Advisory Board Members, was done during the 1st reporting period. These meetings gave the opportunity to the ESRs to expose their personal background and PhD project and to all the PIs to discuss about the implementation of the ISOTOPICS project. This was also the opportunity attend plenary lectures given by prominent external scientists.
The end of the first year of PhD implementation (roughly September 2016-September 2017) was marked by first tangible scientific results with (to mention only a few) remarkable advances in the fields of late-stage deuterium and tritium labeling of model molecules through straightforward hydrogen exchange processes, the development of the first carboxyl exchange strategy and the chemically benign labeling of tryptophan residues in biomolecules.
First applications to the labeling of marketed drugs and interesting biologics have been recently achieved. The obtained results are characterized by: 1) the late-stage labeling of native drugs instead of precursors; 2) labeling of biotherapeutics (proteins and glycosylated derivatives, SiRNAs etc.) thanks to the growing importance of biologics in the therapeutic arsenal.
Since the beginning of ISOTOPICS, 3 trainings have been organised for our ESRs. During the 1st session (November 2016; Saclay, France) the ESRs acquired basic knowledge in radiological safety (later completed by an e-learning session) and have attended a series of courses about 2H/3H, 11C/14C, 18F-labeling and nanoparticles. They also participated in a workshop about PhD induction and communication. In the 2nd session (April 2017; Frankfurt, Germany), they were given general courses about medicinal chemistry, drug development and ethics applied to the pharmaceutical industry. The last training session (November 2017; Liège, Belgium) included courses and lectures about Good Manufacturing Practices, use of isotopes for the quantitative analysis of biomolecules but also management and entrepreneurship workshops. The ESRs have also visited laboratories in beneficiary premises and enjoyed nice social events with the organizing teams. Several ESRs have started their secondments as scheduled in Partners’ institutions in order to get an experience in a distinct sector. In some cases, the secondments plan was reconsidered to be adapted to the new scientific needs which have evolved.
The ISOTOPICS website was activated in early January 2016 and regularly updated to inform about the goals, the ESRs profiles and the events of the project. The first ISOTOPICS Newsletter, edited by the ESRs in February 2017, is available on the website. The CEA (coordinator organisation) gave emphasis to the ISOTOPICS project in a web article on the CEA web portal in February 2017. In October 2017, the management team published an article entitled “Enhancing Pharmaceutical Innovation” in the open-access IMPACT journal to advertise scientists, national institutions and policy makers about the objectives and the expected impact of ISOTOPICS. Moreover, during the 1st reporting period of the project, the ISOTOPICS ESRs attended over 10 scientific national and international symposia and workshops to present their research results in posters or oral communications. Finally, one article has been published and another accepted in a peer-reviewed scientific jour
ISOTOPICS has initiated and/or reinforced partnerships between European academic and non-academic researchers in the isotopic labeling chemistry environment. It will foster the development and enhance productivity of the European research in this scientific field. As described in the ISOTOPICS scientific work packages (WP2 and WP3), a particular effort is made to design late-stage straightforward and efficacious isotopic labeling methods with a particular interest in labeling fragile biomolecules. The 15 ISOTOPICS ESRs beneficiated from a first-class training program and gained valuable experience on research and innovation in isotopic chemistry. It will therefore have great impact on their future careers. The ISOTOPICS project is expected, in fine, to boost innovation and development of the European academic research and pharmaceutical Industry.
ISOTOPICS consortium in November 2017