Introduction


introduction A


s usual, several articles in this edition of DDW address what is described by the authors of one article as “increas- ing pressures on pharmaceutical companies to develop new, effective therapies across the board and keep the cost of develop- ment down”.


As has been discussed many times in these pages one obvious way of achieving that objective is to ensure, as far as possible, that leads entering development stand a good chance of proceeding to, and successfully emerging from, the later, and more costly, stages of development. Despite many improvements in the selection process for leads the attrition rate among compounds in clinical develop- ment remains high. However, the authors of the above article describe recently-developed in vitro human-based ADME and tox- icology methods which, they claim, if used throughout the discov- ery pipeline, could save both time and resource in the long run by more reliably providing information leading to the selection of compounds with high probability of success. A question which needs to be answered as early as possible regarding any potential new lead is how it will be metabolised in humans. A very important enzyme in this regard is CYP2D6, the enzyme encoded by the cytochrome P450-2D6 gene. It is involved in the metabolism of about a quarter of all commonly-used medi- cations. It activates some drugs and plays a role in the deactivation or excretion of others. Elucidating its function using existing methodologies has proved to be very difficult, but recently it has become apparent that the use of long-read sequencing may provide an answer and, as our author points out, should increase success rates in “matching the safest and most effective drug, at the right dose, to the right person”.


The authors of another article seek to demonstrate that User Experience (UX) Design could be incorporated usefully and seam- lessly into life science R&D and suggestions are made as to how this could be done. Essentially the point is made that while companies may use UX design externally for customers, marketing etc, they may not see the need to invest in their internal scientific software with consequent impact on the efficiency of their discovery team. The majority of new drugs currently being approved by regula- tory authorities are small molecules, but the author of another arti- cle states that biological drugs produced by living systems represent the largest class of drugs currently under development by the biotechnology and biopharmaceutical industries. They are struc- turally more complex, difficult to characterise and produce, but recent developments in, for example, processing and cellular sys- tems, have led to a better understanding and determination of their specificity. This, and other advances, have led to reduced cost and increased efficiency of production which is expected to increase by more than 300% in the next five years. Our author predicts that biologics are “the wave of the therapeutic future” and he states that “the time is right; the technologies are ready and the rewards are sweet, and the healthcare industry is finally catching up”. Over the last decade the treatment of cancers has improved markedly, largely due to the use of immunotherapeutic agents – also, of course, biologics – which stimulate the body’s own immune system to target and destroy tumours. There are now hundreds of antibody-based candidates in development but, as indicated by another of our authors, the traditional path of drug development


Drug Discovery World Summer 2017 used for small


molecules is far from being ideally suited to this class of large molecules.


This


applies especially to assessment, in pre- clinical studies, of their


safety. For


example, normal tis- sue may also be attacked by the stim- ulated immune sys- tem


leading to


autoimmune compli- cations. The author points out that it is probably too early to know the best prac- tice for this risk assessment but evalu- ation of antibody crossreactivity in a panel of 30+ organs is likely to remain a critical element in pre-clinical risk assessment.


Heterocyclic compounds play a vital role in the metabolism of all living organisms due, in large part, to the wide range of interactions they can be involved with. For similar reasons such compounds, especially nitrogen-containing ones remain a key part of the arma- mentarium of available anti-cancer drugs. In fact, as another author reports, about two-thirds of the anti-cancer drugs approved by the FDA in the first half of this decade were heterocycles. The author advocates that there should be a focus on heterocyclic com- pounds in compound screening collections thereby providing more leads to novel anti-cancer agents.


Antibiotic resistance is now generally accepted as being one of, if not the major issue facing healthcare systems around the world. Our author reports that the World Health Organisation estimates that 700,000 people will die worldwide each year from multi-drug resistant micro-organisms. Governments and commercial organisa- tions around the world are now investing in initiatives to identify new approaches to this problem which a far from simple one as demonstrated, for example, by the fact that a novel antibiotic class for use against Gram-negative infections has not been approved for use in the last 40 years – and this is not due to lack of effort! Various current approaches are described including the use of novel chemical entities, but also indirect therapeutics in which rather than killing the bacteria, there is a focus on blocking their virulence. Lysins, derived from bacteriophages (viruses which attack bacteria) are also being studied. We can only agree with our author who states that “innovative strategies to attack bacteria are being pursued, giving us hope that the tide may be ready to turn in the battle against antibiotic resistance”.


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  |  Page 69  |  Page 70  |  Page 71  |  Page 72