Introduction


introduction A


s is usual, 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-dimen- sional (3D) in vitro human models represents a significant step for- wards 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 lia- bilities. Together, these advantages should improve selection of com- pounds 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 com- pounds 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 pro- vide 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 dis-


covery appear regularly in these pages. In this number we carry an arti- cle reviewing transdermal drug delivery (TDD) which is non-invasive compared with parenteral routes and, it is claimed, can give more con- trolled 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 devel- opment of an anti-migraine drug using such a novel TTD system is described.


Drug Discovery World Winter 2018/19 Automated liquid


handling systems now play an essential role in drug discovery labora- tories. We include a report summarising the results from a round- table 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 work- flows. We have a timely


review of Good Lab- oratory 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 con- trast 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 reg- ulations 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


DDWthere is now a general realisation that no organisation, however large, can meet all the R&D requirements to provide a pipeline of sig- nificant new therapeutic entities. To some extent this has been addressed by collaborative arrangements with, for example, smaller companies providing leads and contract research organisations under- taking 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 unsuccess- ful. Another collaboration is The Pistoria Alliance which includes vendors, publishers and academic groups as well as science compa- nies. We carry a report which summarises the opinions and conclu- sions 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”.


Dr Roger Brimblecombe PhD, DSc, FRCPath, FRSB 7


Page 1  |  Page 2  |  Page 3  |  Page 4  |  Page 5  |  Page 6  |  Page 7  |  Page 8  |  Page 9  |  Page 10  |  Page 11  |  Page 12  |  Page 13  |  Page 14  |  Page 15  |  Page 16  |  Page 17  |  Page 18  |  Page 19  |  Page 20  |  Page 21  |  Page 22  |  Page 23  |  Page 24  |  Page 25  |  Page 26  |  Page 27  |  Page 28  |  Page 29  |  Page 30  |  Page 31  |  Page 32  |  Page 33  |  Page 34  |  Page 35  |  Page 36  |  Page 37  |  Page 38  |  Page 39  |  Page 40  |  Page 41  |  Page 42  |  Page 43  |  Page 44  |  Page 45  |  Page 46  |  Page 47  |  Page 48  |  Page 49  |  Page 50  |  Page 51  |  Page 52  |  Page 53  |  Page 54  |  Page 55  |  Page 56  |  Page 57  |  Page 58  |  Page 59  |  Page 60  |  Page 61  |  Page 62  |  Page 63  |  Page 64  |  Page 65  |  Page 66  |  Page 67  |  Page 68