Virtual Drug Development Nowadays, It Would Seem That There Is No Aspect of Drug Development That Cannot Be “Virtualised” - with Varying Degrees of Success

DRUG DEVELOPMENT Virtual drug development Nowadays, it would seem that there is no aspect of drug development that cannot be “virtualised” - with varying degrees of success. Dr John Hutchison, Vernalis The layman might be forgiven for associating the molecule, it is hoped that these techniques term “virtual” with computer-based technologies, will predict functional and other outcomes. as in “virtual reality”. Whilst this interpretation of Consequently, virtual techniques are marching the word has some relevance to pharmaceutical further and further down the screening cascade. R&D (particularly in research), in the context Two companies have made models available of drug development the term “virtual” has come which can simulate a drug’s metabolism and to describe a management philosophy rather than predict pharmacokinetics - namely the Camitro a new technology. Nonetheless, sophisticated Corporation and Navicyte, both based in computer-modelling techniques are making California. Simulations Plus Inc offers a product inroads into the process of R&D, so this is where which is believed to predict drug absorption from we will begin. the gastrointestinal tract, and a collaboration Virtual discovery and between scientists in the US, UK and New pre-clinical development Zealand has resulted in the creation of a virtual heart. It is claimed that this cardiac model can ... virtual The benefits of using “in silico” techniques for simulate certain pathological states and may be of techniques are compound screening in the drug discovery process value in predicting drug responsiveness in patients. are well established. The power of modelling Entelos PhysioLabs is also into commercialising marching arises from the ability to produce dynamic images disease models, having created simulations of further and of putative drugs and binding sites in a asthma, obesity and HIV, which they claim will further down three-dimensional form, whilst also factoring other reduce the failure rate in pharmaceutical R&D. influences such as surface charge. Huge numbers of Finally, the Physiome project (responsible for the the screening compounds contained within electronic libraries virtual heart) aims to create an entire virtual cascade can be screened for binding potential without the human body. Time will tell how predictive and bothersome task of actually making them. This has useful these models turn out to be, but it is clear greatly increased the speed and efficiency with that virtual technology - as it is understood by the which leads for conventional medicinal chemistry man on the street - will impact certain aspects of can be identified. This process is truly virtual in drug development and possibly improve our every sense of the word. decision-making in the early stages of a potential Beyond drug discovery, academic groups and drug’s life. others are also using virtual modelling techniques to recreate biological functions, including models Virtual development of enzymatic reactions, cellular responses and organ As indicated, “virtual development” embodies a function. In the same way that receptor modelling rather different concept and owes little to silicon might simulate the binding characteristics of a valley. In the context of drug development, the 94 Innovations in Pharmaceutical Technology DRUG DEVELOPMENT Figure 1. Three-dimensional representation of electrostatic surface potential (charge) of a potential drug. term “virtual” relates to the way the process is peaks and troughs. It is clear, therefore, that to set directed and managed, relying as it does on up a fully staffed “in-house” development group outsourcing. The choice of the word “virtual” to from scratch requires a huge investment, hundreds define this way of working is a bit misleading but, of staff and years of operation to become effective. emerging as it did in the early 1990s, was probably This is clearly never going to be a realistic prospect influenced as much by fashion as anything else. for a start-up company (although apparently it In the past, established pharmaceutical hasn’t stopped one or two from trying). Therefore, companies conducted most - if not all - of their if small companies are to engage in drug drug development in-house. Consequently, each development, a different approach is required. required the capability and infrastructure to Companies adopting a “virtual” approach work support all aspects of development including on the principle that operational tasks can be chemical development and primary manufacturing, contracted outside the company, whilst the analytical and bioanalytical chemistry, toxicology, strategic and project management functions are pharmaceutics and secondary manufacturing, retained within. This shortens the line of clinical development, regulatory affairs - and an command and provides a clearer delineation of array of support functions plus a management responsibility. In this pared-down environment, structure to control it all. Some large companies executive decisions may not be any more correct still operate exclusively in this way, although for but at least they stand a better chance of being most the trend is to use outsourcing to even out understood, acted upon and not constantly Innovations in Pharmaceutical Technology 95 DRUG DEVELOPMENT recycled through impenetrable layers of middle have also developed from small-scale beginnings managers. All the evidence points to a shortening into fully integrated pharma operations. of development time and cost. The extent to Looking at the more recent UK start-ups, which tasks are delegated outside varies between Vanguard Medica (now Vernalis) was one of the companies, but the outsourcing principle underlies first to identify itself as a “virtual development” the virtual development concept. To be effective, company, and for some time the phrase “Vanguard the “in-house team” has to be experienced Model” was used as a descriptor. Two new (functional head level in many cases) and the chemical entities (NCEs) have been approved in skill-base has to cover the full range of disciplines the last year or so, having been through the virtual engaged in development. development process - the anaesthetic chirocaine from Chiroscience (now part of Celltech Medeva) Factors influencing the growth of and frovatriptan from Vernalis. Consequently, the virtual development model is validated to the extent that it has delivered In the last decade or so, a number of forces have products and, in both cases, has done so more conspired to change the face of the pharmaceutical speedily than the industry average. However, as industry. R&D expenditure has increased whilst market conditions and investor sentiment have pricing and other regulations have squeezed changed during this decade, it is now unusual to To be effective, profitability, resulting in a wave of mergers, find small companies willing or able to undertake a the “in-house acquisitions and consolidations - a wave which full development through to registration. More continues with ever-larger players. This process often, small companies will undertake the earlier team” has to has had the effect, not surprisingly, of releasing stages (to so-called proof of principle in early be experienced experienced and talented industry personnel into patient studies, Phase IIa) and thenceforth seek partners for the more expensive later stages. ... and the the marketplace. Some have moved into contract research organisations (CROs), which initially Cambridge Antibody Technology (CAT) is an skill-base has sprang up in considerable numbers. Many of the example which has achieved success with its to cover the early CROs were focused on the provision of antibody-based platform technologies, and has a contract clinical research, but the market soon number of antibody products in development. Its full range of expanded to include other services such as contract development effort is directed at the early stages disciplines synthesis, analytical and preclinical functions, and (that is, up to Phase II ), whilst the more expensive engaged in in some cases sales and marketing. Phase III studies are conducted in collaboration Currently, there are few skills within the with partners. Whilst this is perhaps the norm, development industry that are not available in the contract there are some opportunities to take certain sector. At the same time, entrepreneurial research compounds all the way through, particularly for and development start-up companies were formed niche indications - as will be discussed later. in larger numbers, often based on ideas or Big pharma has experimented with the idea of technologies licensed from industry or from virtual development, as evidenced by Hoffman-La academic institutions. A symbiotic relationship Roche’s creation of Protodigm in 1996. Protodigm between early-stage pharma companies and employed only nine staff, representing one of contract organisations emerged - and thrives today the leanest of the virtual organisations, and with a number of operational alliances. Hence in demonstrated the cost-effectiveness of the virtual the 1990s, the environment was right for small principle during its life by improving development (in some cases very small) companies to take on times and reducing costs by approximately 25 development programmes which in the past would per cent compared with industry standards. have been the sole province of the pharmaceutical Protodigm now exists as an independent company, majors. To get some idea of the diversity of the

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