Introduction


introduction I


t has become increasingly apparent in the last decade or so that the traditional processes used in drug discovery and development organisations in the search for new therapeutic agents are no longer


fit for purpose. As is pointed out by the author of one of the articles in this edition of DDW, there are now more than 1,500 drugs approved by the Food and Drug Administration (FDA), meaning that the easiest disease targets are now adequately covered. With these ‘low hanging fruits’ having been plucked, there remain many less accessible ones to still be harvested. Our author cites, in particular, multicausal diseases including cancers, metabolic and psychiatric disorders. He discusses the ‘cutting-edge technologies’ which have been, or are being, developed to meet these challenges and mentions, for example, advances in microscopy and cellular models and the use of in vitro and in silico models in predictive toxicology. These should lead to more efficient and safer therapies based on either small or large molecules. The other articles in this number of DDWall deal with essentially the


same topic, ie attempts to increase the efficiency of the drug discovery and development process, from a variety of organisational and techno- logical points of view. In one article, the authors point out that in the late 1990s many independent companies developed, and offered to pharmaceutical companies, ‘innovative’ tools, technologies and plat- forms (TTPs), but these do not appear to have resulted in much, if any, significant productivity enhancement. More recently, there have been attempts to amalgamate platform technologies within start-up and early-stage drug development companies in order to increase numbers of candidates in drug development pipelines and to increase the value of the companies. A case study of one such attempt is presented and the conclusion of our authors is that, despite some unresolved questions, the paradigm is ‘here to stay’. Another relatively new approach described in these pages is the use


of human stem cells in drug discovery. Whereas previously such cells were seen primarily as regenerative materials in cell therapies, the use of induced pluripotent stem cells (iPSCs) in disease modelling and human cell-based screening assays is now becoming more common and a number of commercially-available stem cell technologies are described. The authors state that disease models based on stem cells will play an increasingly important role in delivering the promise of person- alised medicine. The next generation of innovations are, they claim, set to overcome current challenges and ‘a new frontier in drug discovery awaits’. Functional genomic screening is playing an increasingly important


role in the identification and validation of new biological targets for precision medicines. This increase has been fuelled by the discovery of CRISPR-Cas9 systems which have enabled therapeutic opportunities to be identified for diseases other than cancer which was the focus previ- ously. Authors of another article state that ‘it is an exciting time to be a gene editing scientist’ and they describe the way in which coupling of phenotypic analysis to CRISPR-based screening should enable leads to be identified, even in complex areas such as neurodegenerative disease. A relatively untapped source of potentially-useful therapeutic


biomolecules is represented by cellular RNAs, which play a crucial role in disease progression. New technologies, including the CRISPR-Cas9 genome editing technology referred to in the previous paragraph, will facilitate the search for therapeutic candidates from this source. A few RNA-based therapies have already received regulatory approval and are on the market for the treatment of, for example, AMD, Duchenne muscular dystrophy and spinal muscular atrophy. As further advances are made in RNA therapeutic design and delivery technologies, it is


Drug Discovery World Fall 2018


anticipated that fur- ther RNA-based thera- peutics will emerge. Although in vitro


assays have improved greatly over the years, the use of animal mod- els still forms an essen- tial part of the pre- clinical evaluation of a potential new drug. Increasingly, genetical- ly-engineered animal models (GEMs) are being used. However, as is pointed out by one of our authors, ‘intellectual property around GEMs can feel a bit like a minefield’. She quotes cases in which lawsuits have been filed and where multimillion dollar payments have changed hands in order to settle the disputes. Thorough due diligence is, therefore, essential and the author lists a number of questions that a drug developer should ask when contemplating obtain- ing a GEM or other research tool from a non-profit organisation. In the last decade or so there have undoubtedly been significant


advances, some of which are discussed above, in drug design, but the cost and time involved from bench to bedside remain unacceptably high and are increasing. We include an article describing how the MD Anderson Cancer Center is addressing this issue by ‘making patients a priority’. A long list of lessons learned so far is headed by the statement ‘focus on your patients... their survival is your bottom line’. The steps taken include collaborations with biopharm companies and there appears to be a willingness to do more, although it is acknowledged that some of the lessons learned are not translatable to pharmaceutical companies with their focus on the bottom line or to smaller academic centres which lack the advantages of scale of major cancer centres such as MD Anderson. There has been a substantial increase in the use of botanical supple-


ments in recent years associated with increased interest in alternative health approaches. This raises a concern that there may be undesirable or unacceptable interactions between these products and prescribed or OTC medicines. There have been, for example, reports of botanical extracts and/or phytochemical constituents inhibiting the cytochrome P450 enzyme. The authors of one of our articles undertook a study using the sandwich cultured human hepatocytes in vitro model to study the effects of co-treatment of Schisandra spenanthera (claimed to have anti-oxidant, anti-inflammatory, antibacterial, etc activities) with the sedative midazolam. Results were consistent with findings from clinical studies which have shown a 52% decrease in midazolam clearance when co-administered with S.spenanthera. The authors suggest that this hepatic model could be used routinely to predict clinically-relevant botanical-drug interactions.


Dr Roger Brimblecombe PhD, DSc, FRCPath, FRSB 7


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