SANOFI-AVENTIS DEUTSCHLAND GMBH

This Action will contribute to the sustainable development of European chemical industries in the coming decades by delivering an ambitious doctoral training programme that draws on expertise from industry and academia across 4 European countries. The research agenda and experiential training will grow the skills base beyond approaches that have relied upon a limited set of molecular scaffolds and a relatively small sub-set of reactions to exploit new reaction paradigms and platforms (e.g. high throughput experimentation, photoredox & electrochemistry) that meet the needs of modern drug discovery science.

Biological drugs such as peptides, proteins, oligonucleotides and analogs provide the patients with more efficacious and less toxic treatments and have lower attrition rates than chemical drugs since 1 on 9 new biological entities entering clinical trials reaches the market (1 on 16 for chemical drugs). Consequently, 15 on 24 top blockbuster drugs were biotherapeutics in 2020 (world-market share of about 40% of $175 billion of revenue per year). In order to reduce the immunogenicity of biodrugs, to overcome their fragility and to increase their capacity to reach quickly and massively their target, reduced-size biologics are extensively developed. However, radiolabeling of large molecules by grafting bifunctional chelating agents which do not alter significantly their biological activity is thus no longer possible with smaller biodrugs. It is therefore of paramount importance to devise new radiolabeling approaches carried out on tiny quantities in aqueous media and very soft conditions. It is also crucial to train a new generation of radiochemists in order to implement these methods and to meet the needs of the European industry. ISOBIOTICS ambitions: 1) to develop new chemically-benign strategies for the last-stage radiolabeling of large peptides, small/medium-size proteins, oligonucleotides and analogs with deuterium, tritium and carbon-14 (preclinical and phase 0 clinical evaluation), and fluorine-18 (phase I-III clinical trials); 2) to educate a new generation of young talented PhD students specialized in the radiolabeling of biologics through a combination of interdisciplinary lab research, transdisciplinary and intersectorial secondments, technical taught courses, scientific lectures and complementary skills workshops; 3) to ensure the appropriate dissemination, exploitation and communication of all ISOBIOTICS outputs in order to maximize the project’s impact and radiance; 4) to secure the students employment and the sustainability of training structures.

Excessive attrition rates during clinical trials dramatically impact on Drug Discovery and Development (DDD). Absorption, Distribution, Metabolism and Excretion studies carried out on larger series of drug candidates at an earlier stage of the DDD timeline and evaluation of drug efficacy through better assessment of pharmacokinetic/pharmacodynamic relationships, target engagement and receptor occupancy are critically important approaches for de-risking drug innovation since they facilitate early identification of the candidates that display the best in vivo profile. When successfully implemented, this strategy can accelerate the discovery of new therapeutic solutions to existing and emerging diseases, and enhance European pharmaceutical innovation. For implementation, large sets of isotopically-labeled molecules are required and consequently, a huge revival of labeling techniques is urgently needed. Another crucial issue is the scarcity of expert radiochemists in Europe and the lack of first class training programs in this inter-disciplinary field merging chemistry, radiochemistry and medicinal chemistry. The aims of ISOTOPICS are: i) to train the next generation of European chemists with expertise in isotopic labeling and advanced medicinal chemistry through a first-class taught and 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; iii) to work closely with the European pharmaceutical industry to apply the new labeling methods to drugs currently in development in order to provide solutions to the most pressing problems in drug innovation. This highly interdisciplinary project is expected to have a profound beneficial impact on drug innovation in Europe by providing novel efficient techniques and new experts in the fields of labeling and medicinal chemistries.

Reducing lead times of new medicinal drugs to the market by reducing process development and clinical testing timeframes is a critical driver in increasing European (bio)pharmaceutical industry competitiveness. Despite new therapeutic principles (e.g. the use of pluripotent stem cells, regenerative medicine and treatments based on personalised medicine or biosimilars) or regulatory initiatives to enable more efficient production, such as Quality by design (QbD) with associated Process Analytical Technology (PAT) tools , the slow progress in the development of new bioactive compounds still limits the availability of cheap and effective medicines. In addition, the competitiveness of European (bio)pharma industry is impacted by the unavailability of suitably trained personnel. Fundamental changes in the education of scientists have to be realised to address the need for changes in the traditional ‘big pharma’ business model and the focus on ‘translational medicine – more early stage clinical trials with patients, more external innovation and more collaboration’ . These changes in education should be based on combining cutting-edge science from the early stage of product development through to manufacturing with innovation and entrepreneurship as an integral part of the training. The Rapid Bioprocess Development ITN, employing 15 ESRs, brings together industrialist and academic experts with its main aim to address this critical need by developing an effective training framework in rapid development of novel bioactive molecules from the very early stages of potency and efficacy testing to the biomanufacturing process characterisation and effective monitoring. The main focus of the research is on oncology related proteins and recombinant proteins to be used in diabetes treatment, although the resulting monitoring and modelling methods will be applicable to other bioactive molecule process development as demonstrated by validation on a range of relevant bioactives.