Recognizing Early Signs in the Translational Phase is Essential for Drug Development in Cardiovascular Medicine

We have just returned from a very inspiring Winter Meeting on Translational Heart Failure Research, organized by the Heart Failure Association of the European Society of Cardiology (ESC) in collaboration with the ESC Working Group of Myocardial Function. In keeping with the traditions of this meeting there was a strong focus of enabling young researchers to confer with a faculty of seasoned colleagues about translational aspects of heart failure therapy development. The first session of the 2023 meeting was dedicated to ‘How to avoid translational failures’ and included a lecture on why and how to ‘see early signs in the translational phase to avoid subsequent problems in the clinical stage’. This is an extremely important subject not only to avoid loss of time and the misallocation of funds and resources, but foremost to avoid patients entering clinical phases that are destined to fail or, conversely, to reduce the risk that promising new therapies will be overlooked. In assessing these early signs it is important to take a wide view of the situation—information acquired in the preclinical phase for a new chemical entity or a novel method may provide valuable, even essential, information during the development of different chemical entities or a related method. This principle extends to ‘negative’ findings such as warning signs linked to the chosen molecular target itself, or to prodrug construction. Ignoring early signals is often costly and can become dangerous when candidate therapies move into clinical evaluation. One can readily recognize the consequences in all three examples. On one hand, time and resources lost and patients enrolled in fruitless trials, on the other, patients waiting too long for a successful treatment to be introduced in clinical use. All these outcomes are clear evidence of limitations in the methodology of drug development. A separate but connected consideration is that, from an industrial perspective, failures in drug development may contribute to funds being diverted to other areas seen as more lucrative, with consequences for future research in what may be seen as ‘niche’ areas such as e.g. acute heart failure. The central lesson we take from these examples is the necessity of continuous and open scientific discussions among independent researchers, trialists, representatives of the pharma-industry and regulatory authorities. Moreover, while the significance of the step-by-step approach for cardiovascular drug development cannot be underestimated, every effort should be made to avoid siloed activity and thinking by all of these participants. In the current complicated business environment, we are grateful to companies that still support innovative research and expensive clinical developments. We also know that to attract and retain the support of investors it is crucial for such companies to create expectations. Acute, chronic, and advanced heart failure are, however, not simple therapeutic development arenas,14 and it would be both morally and commercially wrong to encourage overoptimistic expectations.15 Close and rigorous scrutiny of early signs in the translational phase is crucial to avoid mistakes and to optimize the development of new therapeutics. Zoltán Papp and Attila Borbély have nothing to declare. Piero Pollesello is full time employee at Orion Pharma.