This issue of DDW, as always, carries a series of articles all of which reflect, in one way or another, the matters which are currently exercising the minds of those involved in drug discovery. For a considerable time now the most common theme by far has been the increasing price of drugs due largely to increased development costs which, in turn, are due in large part to the costs incurred by compounds which fail in the development process, especially in the later stages.
The author of one of our articles quotes a number of striking relevant statistics. She quotes, for example, from one study which found that from 2013-15 24% of candidates in Phase II and Phase III trials failed on safety grounds and 54% lacked adequate efficacy. She goes on to point out that rigorous validation of targets in the pre-clinical stages of development should reduce these failures but in what he describes as the ‘Age of Big Data’ this is far easier said than done. The number of potential new targets for useful drugs is constantly increasing but there is insufficient information about most of them to decide readily which are the likely ‘winners’. One solution to this problem, she suggests, may lie in the use of RNA interference (RNAi) in tandem with CRISPR/Cas9 genome editing technologies. This combination gives the ability to quickly and precisely genetically engineer mouse models of clinical disorders. These animals can then be used in in vivo preclinical studies to validate potential new targets.
An animal model which another author claims is ‘revolutionising drug discovery’ is an inbred strain of mice known as C57BL/6 (Black 6 or B6 for short). This, he states, is the most important animal in modern research. It can be engineered and employed in increasingly complex applications. An example is its use in the growing field of immunooncology where it allows study of how the immune system interacts with a tumour in the context of a full content of immune cells. This is important knowledge in identifying and evaluating new therapeutic targets for immune-oncology.
The identification of previously unknown disease-specific receptors is the topic covered in another article where the authors suggest that advances in phenotype screening methodologies could allow that objective to be met while still meeting their basic role. They discuss specifically cDNA microarray technology which they claim has success rates “which far surpass other methodologies” and which has, therefore, been widely adopted across the industry and also attracted considerable interest from academic groups.
Advances which are being made in phenotype screening are also discussed by another author. She believes that the development of humanbased, physiologically-relevant in vitro systems should result in higher success rates among compounds which are selected for development. The systems should also provide information leading to discovery of novel mechanisms and to increased knowledge of disease biology.
The sequencing of the human genome in 2003 marked the beginning of a whole new era in medicine which has led to the discovery of many useful new therapies. However, another author cautions that genes alone cannot predict susceptibility to many complex diseases. There is, therefore, an increasing interest in so-called epigenetic mechanisms which do not alter the underlying DNA sequence. They are typically reversible and may be inherited or added in response to environmental factors. Our author describes technologies for mapping and measuring epigenetic biomarkers, many of which have already been identified for a wide range of serious and debilitating diseases. Collaborative ventures are already in place to develop multi-component treatment regimens which combine epigenetic drugs with other medicines. This approach is likely to attract more interest as, increasingly, we enter an era of personalised medicine.
We also carry a number of articles on developing technologies which, if their early promise is realised, will play a significant role in the future in drug discovery and development.
There is a discussion on the use of blockchain or distributed ledger technology (DLT) in drug discovery. In his introductory paragraph, the author gives a ‘good, relatively digestible definition or description of the technology’ and then goes on to describe potential usecases in R&D. He concludes that DLT is going to be a “major technological player in healthcare and drug discovery in the future” and states his belief that this future is not too far away.
The use of robots to automate high-volume repetitive tasks in a wide variety of industrial situations dates back to the early 1970s, since when the market has grown to a multibillion dollar level and on the way there have been significant technological advances. In another of our articles there is discussion as to how these advances could be used to improve the wide usage of robots in lab automation, specifically in drug discovery laboratories. The discussion focuses on a new generation of robots known as collaborative robots or ‘cobots’ which are designed to work alongside humans by sensing the presence of a person and adjusting their movement speed accordingly. The authors believe that for a variety of reasons, which they discuss, the use of these cobots should contribute to reducing the overall costs of drug discovery.
The increasing use of peptides as therapeutic agents – more than 100 are already in the market – has led to numerous attempts to devise methods of delivering them orally, thereby presumably increasing patient acceptability. The author of another article poses the question as to whether this is “a holy grail or quixotic quest”. He discusses the challenges that have to be met and potential means of overcoming them, some of which show early promise, but it appears that the jury is still out in regard to answering the author’s question and, in any event, some peptides will probably always remain difficult, if not impossible, to deliver orally.
There has been a long-held belief that nanomedicines, ie medicines delivered using such delivery systems as nanoparticles or liposomes, are not clinically practical. This, despite the advantages they offer in terms of stability, efficacy and lack of off-target effects. Their lack of popularity is largely based on the fact that traditional manufacturing methods are labour-intensive and hard to reproduce and to scale up. In another article the authors describe a new set of microfluidic systems which overcome these issues and which they state should “accelerate novel nanomedicines from the bench to the clinic”.
Dr Roger Brimblecombe PhD, DSc, FRCPath, FRSB