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

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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

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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 (now part of 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 Fulcrum Pharma Developments, offering drug virtual approach and philosophy, it is worth development services on a contract basis. It has looking at some examples - although the following recently announced an agreement with Xenova, does not purport to be an exhaustive list which another biopharmaceutical player, to develop would be beyond the scope of this feature. products in oncology. More recent entrants onto the virtual Virtual development companies development scene in the UK include Arachnova Many adolescent biopharmaceutical companies Ltd, which specialises in identifying and (that is, those now in their teens and beyond) have developing new therapeutic uses for existing been through the virtual stage (in some cases before products, and DevCo, which licenses-in CNS the term was coined) and now - by virtue of organic projects from other pharmaceutical companies. growth and consolidation - more resemble Larger pharma companies may release compounds conventional pharmaceutical companies. Celltech for development outside if they no longer fall Medeva and its subsumed companies would fall within their therapeutic focus, and occasionally into this category. In the US, Genentech and Biogen merger activity can release products or candidate

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A symbiotic drugs where there is duplication. Where the provider, Quintiles, which acts as a partner for relationship originator company wishes to retain downstream both the development and commercialisation rights to its compounds, an alliance with a virtual of products. The company clearly has global between company can provide an “off balance sheet” vehicle aspirations having opened offices in the UK and early-stage which permits projects to be continued without New Zealand. pharma impacting the originator’s profit and loss account. New entrants are still joining the virtual The collaborative approach, which involves company parade - a recent example being the aptly companies and cost- and risk-sharing, is attractive to many named Virtual Drug Development Company. contract small cap investors who are more sensitised to This group intends to concentrate on early stage organisations the natural attrition of compounds during clinical research in cancer, and hopes to make use development now than they were ten years ago. of the various regulatory mechanisms in the US emerged - and Not surprisingly, the US has not been backward to fast-track drugs destined for serious and thrives today in coming forward with virtual approaches to drug life-threatening disease indications. The company development. The more established biotechnology has formed a variety of alliances, including one with a number companies have gone beyond the point at which with the aforementioned Fulcrum, presumably to of operational they could be considered virtual. Of the more exert leverage on development opportunities on alliances recent players, the Medicines Company (founded both sides of the Atlantic. It is likely that further in 1996) is unusual in that it takes compounds at a collaborations along these lines will emerge as later stage of development. Based near Boston, the smaller players seek to find synergies. company specialises in late-stage development and Investment in areas of high unmet medical commercialisation; it has one cardiovascular need is attractive to a number of smaller product (bivalirudin) in the registration process companies, even if the eventual market (defined by and a number of others in the later stages. The patient population) is relatively small. Legislation company has 61 employees worldwide and has in the US permits fast-tracking during the entered into a strategic alliance with the service development of drugs for serious or life-

Figure 2. The Virtual Development Organisation.

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threatening conditions, and Orphan Drug operation to create an integrated R&D function. an alliance legislation now in place in Europe as well as the US I am sure that a variety of strategies will be played with a virtual provides assistance and incentives for companies to out with varying degrees of success, but one thing develop drugs for rare diseases. These conditions can be assured - the sector will never be dull. company can very often fall below the radar screen of the provide an “off pharmaceutical majors, but provide an interesting balance sheet” opportunity for the smaller players. By way Dr John Hutchison was awarded a of example, Cephalon, an established US PhD in physiology by the University vehicle which biotechnology player, has built a successful of Liverpool in 1980, and permits projects business out of developing a treatment for subsequently studied clinical narcolepsy, a rare sleep disorder. to be continued medicine at he University of without The prospects for virtual development Leicester. After four years in in the future hospital medicine, he joined the impacting the The is constantly evolving, pharmaceutical industry working in originator’s but it seems that the virtual approach to development the department of clinical pharmacology at . profit and loss will survive so long as there are start-ups wishing Over the next ten years he held a number of posts in account to conduct drug development, and it is quite drug development within Fisons and Astra, eventually likely that the pharmaceutical majors will continue heading up Astra’s experimental medicine function. to pursue more aggressive outsourcing policies and Since then, he has managed development operations hence virtualise some aspects of their operations. in two small companies, firstly Cerebrus and more No doubt economics, rather than anything else, recently Vernalis. Dr Hutchison is a Member of the will drive the move in this direction but Royal Society of Physicians (London) and a Fellow of the savings are plain. The smaller “drug the Faculty of Pharmaceutical Medicine. development” boutiques cannot afford to stand still either, and the challenge that faces them all is how to secure a supply of quality drug development Acknowledgment candidates. One solution, and indeed the route The author would like to thank Debbie Porter for followed by Vernalis, is to acquire a drug discovery her help in preparing this article.

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