Drug Discovery World Winter 2018/19 - Issue Summary
All of the articles in this edition of DDW are, in one way or another, aimed at improving the processes of selecting and progressing through development drug candidates which stand a good chance of achieving eventual regulatory approval within a shorter timeframe and at a lower cost than is currently the case.
The situation is summed up well by the authors of one of our articles who state that “in vitro systems that reflect human patients perfectly... would remove most of the bottlenecks and risks in drug discovery pipelines today”. The authors go on to point out that there is still some way to go before this “lofty goal” can be achieved, but they believe that the current ready availability of physiologically-relevant three-dimensional (3D) in vitro human models represents a significant step forwards and they address the various tissue engineering and 3D assay considerations involved using a 3D human model of non-alcoholic steatohepatitis as a case study.
The use of 3D cell culture systems to optimise clinical leads is also advocated by the authors of another article. They list a number of advantages which these cultures possess over 2D systems in that they have greater biological relevance when used, for example, in modelling for oncological, neurological and cardiovascular diseases. They should also allow more accurate early assessment of toxicity and metabolic liabilities. Together, these advantages should improve selection of compounds to enter development and reduce late stage, expensive failures.
The fact that traditional monolayers or suspension cultures can also be poorly predictive of relevant therapeutic effects of anticancer compounds has led to the growth of research into tumour-derived organoids – the subject of another article. The author points out that these organoids have the potential to be reliably predictive of eventual clinical efficacy. Previously, only small amounts could be produced in specialist laboratories using labour-intensive processes, but there are now emerging scalable bioprocessing technologies which could meet the growing demand for large scale production. The authors review the challenges that have to be overcome en route to this goal.
One of the causes of failures of drugs in development, be it due to issues with safety or with efficacy, is that most drugs display what is described in another article as their “promiscuity”, ie their tendency to interact with targets other than that associated with their therapeutic potential. The authors state that, on average, drugs can interact with 6- 28 other ‘off-target’ moieties. However, attitudes to this so-called polypharmacology are changing and, in appropriate cases, some drugs are now being designed deliberately to multi-target.
The effort devoted to this end is now called Systems Pharmacology and our authors provide their perspective on this. They admit that development of such drugs represents a “formidable challenge”, but state that significant progress has been made and suggest that a “new dawn” is breaking.
Articles reviewing technological advances in the world of drug discovery appear regularly in these pages. In this number we carry an article reviewing transdermal drug delivery (TDD) which is non-invasive compared with parenteral routes and, it is claimed, can give more controlled absorption and more uniform plasma concentrations than the oral route. Some drugs are already delivered by this route – nicotine patches being a familiar example – but there have been few real advances in the technology in the last two decades or so.
Now, however, the third generation of TDDs “is poised to make a significant impact on drug delivery”. The key to this system is that it disrupts the stratum cornea barrier thus allowing more effective delivery. The current development of an anti-migraine drug using such a novel TTD system is described.
Automated liquid handling systems now play an essential role in drug discovery laboratories. We include a report summarising the results from a roundtable meeting. The key products now available on the market are listed with technical details of each. It is stated that enhancements in the systems are resulting in improvements in the speed, accuracy and consistency of workflows.
We have a timely review of Good Laboratory Practice (GLP) requirements in the current drug discovery environment. The FDA GLP regulations were first issued in 1978 when non-clinical safety data emanated almost exclusively from in vivo studies.
This is in contrast to the situation today when in vitro and ex vivo test systems are increasingly used and the authors of our article pose the question ‘Which studies require GLP?’ In response they write, “with formal regulations in place, you’d think that the answer to this question would be simple. It is, and it isn’t”. There follows a detailed review of studies which apparently do, or do not, require GLP. The overall conclusion, given in the title to the article is “choosing the right CRO may save you time and money”.
As has been discussed on several occasions in earlier editions of DDW there is now a general realisation that no organisation, however large, can meet all the R&D requirements to provide a pipeline of significant new therapeutic entities. To some extent this has been addressed by collaborative arrangements with, for example, smaller companies providing leads and contract research organisations undertaking the clinical trials. Another initiative has been the development of pre-competitive collaborations between groups of companies to share information to, for example, avoid repeating approaches which have previously been shown, in another organisation, to be unsuccessful.
Another collaboration is The Pistoria Alliance which includes vendors, publishers and academic groups as well as science companies. We carry a report which summarises the opinions and conclusions from a recent discussion by the group which focused on the challenges and opportunities for leveraging non-clinical datasets in support of translational research. In particular, the Standard for Exchange of Nonclinical Data (SEND) format was discussed and was considered to provide “concise communication between the FDA, CROs and sponsors”.