Drug Discovery World Winter 2017/18 - Issue Summary
A recurrent theme in recent numbers of Drug Discovery World has been the increasing necessity for large companies to form relationships with smaller companies, contract research organisations and academia in the search for new leads to potential novel, safe and effective medicines and to expedite their development.
That theme continues in this number with an article discussing the interdisciplinary integration which is necessary both within and between companies for these arrangements to work optimally. The author of the article suggests that historically there has been a so-called ‘silo mentality’ in pharmaceutical companies with ‘ineffective inter-departmental communication and poor organisational efficiency’. This can, and does, result in wastes of time, efforts and resources. He acknowledges that the silos are not there by design but result from poor management or flawed organisational structures. There are signs of an increasing recognition of this problem within the industry and organisational frameworks are being put in place which will facilitate collaboration and communication between specialist teams, whether they be internal or external to the company. INDiGO programmes, which eliminate walls between project teams, are discussed in the article.
Drug discovery alliance models are the subject of another article. Traditionally relationships between large companies and smaller partners have been focused on specific needs of the former and are usually one-way in nature. More recently, alliances have emerged in which more diverse organisations are involved and in which they are all true partners. Two such models are featured in which traditional players have been brought together in a way which, it is claimed, fully leverages the strength and diversity of each organisation.
The two articles discussed above suggest organisational changes which could improve productivity and efficiency in the drug discovery and development process. The remaining articles discuss technological advances which may also help in achieving the same end and the authors of another article state that “we are on the cusp of having previously unimaginable amounts of information about each target and many more targets to prosecute”. ‘Smart’ screens are now being developed but the information generated from them represents major challenges and the authors describe how their company was driven to making a major investment in rethinking its whole approach to screening, from where the compounds are stored to how rapidly they can be assessed and assayed. They describe this approach, which included the involvement of vendors, and state that “it is an approach that could be implemented by any organisation willing to make such a commitment”.
One of the reasons for the continuing high attrition rate among compounds in development is the failure of preclinical models to predict adverse effects or inadequacies in efficacy. In making this point the authors of another article herein state that the two-dimensional (2D) cell cultures which are widely used in drug research do not faithfully mimic the structural and functional properties found in vivo. They state that, in consequence, three-dimensional (3D) spheroidal cell culture models are gaining acceptance especially, as they describe with examples, some models which are now capable of being used in high throughput screening (HTS). Lack of this capability has, until recent developments, limited the usefulness of these 3D models.
Flow cytometry is a widely-used HTS platform, most commonly employed to date in the fields of immunology and haematology. Recent improvements in instrument automation and throughput now mean that the technique is becoming an increasingly attractive tool in drug discovery. Its advantages are that it enables large amounts of data to be collected from phenotypically- diverse live cell populations but, until recently, technical challenges around throughput and sample handling have meant that its use has been limited to relatively low-volume applications. However, instruments which are capable of handling micro- 384-well plates and screening tens of thousands of cells per second are now becoming commercially available. These are reviewed in another article.
Next-generation sequencing (NGS) has moved from the realms of research into those of clinical development, but this is not without its problems and challenges. These are the subject of another article which describes the way in which pre-competitive consortia are coming together with representatives from the pharma and diagnostic industries, technology service providers and regulators. These provide forums for the development of best practices in the development of appropriate approaches to the use and validation of these new technologies.
Another area in which there have been significant technological advances has been in the delivery of inhaled biologics. This is now the preferred route of administration for delivering biopharmaceuticals for the treatment of respiratory diseases. More than 40 such drugs are currently in development and in our article the additional considerations which are associated with their development – delivery route and biopharmaceuticals – are discussed. It is essential, for example, that there are appropriatelydesigned non-clinical safety studies prior to clinical assessment.
Therapeutic antibodies currently represent the fastest growing class of drugs, and in another article the authors discuss ‘new tools’ to enhance this pipeline. It is essential that analytical methods are available to monitor the level and distribution of these antibodies, both in animal models and in patients during clinical trials. This is made difficult by the fact that high levels of endogenous antibodies present in the serum have the potential to mask the therapeutic antibody molecule. This has necessitated the development of highly specific and sensitive reagents. Described in the article are anti-idiotypic reagents (anti-ID) – antigens, monoclonal antibodies, recombinant antibodies and antibody fragments and antibody alternatives – which must, to satisfy regulatory authorities, fulfil high quality standards for use in clinical settings. The authors consider that specifically selected anti-IDs can speed timescales in development and prevent down stream problems.
Dr Roger Brimblecombe PhD, DSc, FRCPath, FRSB