Added Discovery Work

Even before clinical trials have been initiated, it's important to consider other ways in which the product could be used Fig. 4.36. Such consideration not only involves alternate indications for how the existing therapeutic could be used but also includes new formulations or constructs that may allow product expansion into new areas. The advantages of these product extensions are noted in figure 4.36, along with the example of alpha-interferon. Added preclinical work in pharmacology, ADME, or toxiciology may be required if the new indication or product form involves new diseases or substantially changes how the product will be used in humans.

An important component to the discovery and development process is a discussion of corporate partnerships (Fig. 4.37). Indeed, development partnerships today are more a matter of "when" than "if' [39-41]. This is in contrast with some of the concepts from the 1980s and early 1990s, when many organizations were hoping to become fully integrated pharmaceutical companies (FIPCos) capable of controlling all aspects of the drug development process (discovery through marketing). Today, even the largest pharma companies rely on in-licensing new targets or products as a means to expand their pipelines, 400 in 2003 and involving an important and growing amount of the research budget (see some examples on figure 4.14). Similarly, many companies have formed that specialize in various specific aspects of the drug discovery and development process ranging from target identification and validation to high-throughput screening (HTS), informatics, and databases. This diversification has led to a record number of partnerships, not only between pharma and biotech companies but also between multiple biotech companies [40, 41]. Some of these collaborations will result in one of the partners being acquired r Additional formulations and new indications can expand market for a therapeutic:

o Cost-effective way to generate new sales without requiring new drug discovery c Can create competitive advantages in marketplace o Can provide patent life extension r Each new indication requires new IND:

o Additional preclinical and toxicology studies may be required r Classic biologics example is alpha-interferon: c Initially approved for hairy cell leukemia in1986 o Has received at least 6 additional approvals o Product life has been extended by creation of PEG-Intron A®: Pegylated form provides a longer half-life and less frequent dosing 1 Other analogs also being developed

Fig. 4.36. Exploration of Additional Uses by the other, because the technology and/or products are deemed principal to the operation and success of the company.

Alliances and partnerships between pharma and biotech companies are now the norm for research operations, as can be observed by the list of the top six pharma company partners in 2003 (Fig. 4.38). The top 10 deals involve cancer, viral disease, the cardiovascular (CV) system and central nervous system (CNS). We already discussed the value to pharma, being targets, products, and technologies. The value to biotech is first the infusion of revenue to continue research and operations; up to $4 billion was promised to biotech from pharma in top 10 deals in the forms of, for example, up-front payments, mile-

r Driven by needs of large Pharma companies (expand targets, hits & unmet patient needs) and rapid expansion of new technologies r Many drug discovery companies now exist (more than 500):

c Tools - analysis, HTS, product systems, software, informatics c Databases - genome, proteome, combinatorial chemistry, biology o Examples - Millennium, Pharmacopeia, Albany Molecular r Partnerships for Pharma and Biotech: o Pharma-Biotech - nearly 400 in 2003 c Biotech-Biotech - more than 400 in 2003 $3.6B in 2003 - 15% growth - 5-10 % of all research $ spent r Acquisitions to bring in technology (M&A) - 128 in 2003

Fig. 4.37. Alliances in Discovery & Development

Source: King J. R&D Directions 2004; 10(2):28-39; Ernst & Young.

Resurgence: Global Biotechnology Report 2004

° Pharma: Astra-Zeneca, Aventis,

BMS, GSK, J&J, Merck ° Biotech: Millennium, Regeneron, TheraVax, Vertex

c $ 4.02 B (potential) in '03/'04 ^ Targets: Cancer, viral, CNS, CV ^ VALUE to Pharma? c New products c New targets k Value to Biotech? c Revenues: Milestones, research costs, royalties, sales c Development expertise c Access to sales and marketing stone achievement payments, and royalties. Biotech companies are very lean operations focused in research, such that the pharma can provide a staffing benefit in areas that are not yet ramped up for the biotech company (e.g., clinical research [clinical development] staff and operations), as well as marketing support to assist with the planning of product research, market research, and early launch preparation. The decision to form an alliance is based on a variety of factors beyond good science and product opportunity, so that it will be successful for both companies, large and small, pharma and biotech, established (structured and perhaps stodgy) and new (free-wheeling and chaotic at times). The two organizations have to fit together in some planning, financial, and operational framework. The seven issues in figure 4.38 addressing "how it (alliance) will work" must be dealt with effectively in order for both parties to benefit and products and sales to be the outcomes.

The university is a major source of new discoveries for both disease pathology and potential product opportunities across the world. Research in the basic sciences is one of the three cornerstone missions of most universities, along with education and public service. The disciplines of research applicable to product discovery area of the industry are quite broad and are listed in Figure 4.39. Research laboratories at pharmaceutical and biotechnology companies need to stay abreast of the findings emanating from the university setting, which is accomplished in three ways: (1) scientific publications, (2) scientific presentations by university and company scientists at the major science meetings in all the basic research areas, and (3) research collaborations. At most companies, research groups have a budget that often includes grants to universities who have critical research underway that may advance the company's work. The company receives access to discoveries for disease pathogenesis, product leads

HOW to assess value?

° Product potential (Mkt, Ptnt) ° Product fit ° Organizational fit ^ Staff - PhD & MBAs ° Shared risk and costs ° Bio income ° Bio opportunity i HOW to make it work? o "Not invented here" syndrome c Scientific integration o Culture coordination c Division of work o Decision-making process o Progress /Follow-thru c Management of alliance

Fig. 4.38. Pharma-Biotech Alliances-Value & Process r University research (basic) scientists (many disciplines): o Medicinal chemists & Pharmaceutists (formulations) ° Disease processes (physiologists, biologists, geneticists) ° Protein chemists & Molecular biologists ° Pharmacokineticists & Pharmacologists r Access for company:

o Research network (expanded brain power) c Technologies c Disease targets ^ Product leads & candidates r Access for universities: c Grants o Patents o Publications

Fig. 4.39. Alliances in Discovery with Universities r Have well developed plan for target discovery & lead identification r Establish success criteria for making timely development decisions r Consider anticipated product label claims early, and design non-

clinical and clinical studies to address these claims r Conduct critical go/no-go experiments quickly r Maintain focus on target indication, but stay alert to other possibilities as well r Discovery and development decisions should be coordinated team effort, involving many departments within organization r Review benefits (and drawbacks) of collaboration regularly r Activity in humans is the goal - get there as quickly AND SAFELY as possible!

Remember - "In the field of observation, chance favors only the prepared mind" (Louis Pasteur)

Fig. 4.40. Key Success Factors in Discovery and candidates, disease targets, and new technologies that are created by university scientists. The university gains access to scientific and research expertise, financial support (that is, grants), patent opportunities (shared in some form with the company), product leads, possible postdoctoral training opportunities, and added publications from the collaboration. The collaboration between university and company researchers often starts with a discussion of their respective work, based on a recent public presentation or publication of a new study. If further details are needed, a confidentiality agreement is put in place to help protect both parties. If collaboration or funding appears mutually beneficial, a formal contract is created between the company and university that addresses the potential for new discoveries and patents, as well as the deliverables expected by the company from the university collaboration.

In summary, eight factors will be keys to success in discovery and early development, as shown on Figure 4.40. Excellence in governance and planning, which we discussed in earlier chapters, is also a necessity in the early research phases; five of the key eight factors, albeit in the research context, involve planning, decisions (criteria), focus (indications), reviews of work (regular), and team effort (decisions), in addition to the technical requirements of the experiments being done well and fast.

For your further education about discovery research and early development, you will find these 10 publications useful for more in-depth study (Fig. 4.41). Nature Reviews Drug Discovery is a particularly good source of review articles for discovery and product development.

r Bauer RJ, et al. 1999. Population pharmacokinetics and pharmacodynamics of the anti-CD11a antibody hu1124 in human subjects with psoriasis. Journal of Pharmacokinetics and Biopharmaceuticals 27:397-420.

r Dickson M and Gagnon JP. 2004. Key factors in the rising cost of drug discovery and development. Nature Reviews Drug Discovery 3:417-429.

r Hodgson J. 2001. ADMET - turning chemicals into drugs. Nature Biotechnology 19:722-726.

r Lindsay MA. 2003. Target discovery. Nature Reviews Drug Discovery 2:831838.

r Myers S and Baker A. 2001. Drug discovery - an operating model for a new era. Nature Biotechnology 19:727-730.

r Ng R. Drugs, From Discovery to Approval. Wiley-Liss, 2004.

r Reichert JM. 2003. Trends in development and approval times for new therapeutics in the United States. Nature Reviews Drug Discovery 2:695-702.

r Reichert J and Pavlou A. 2004. Monoclonal antibodies market. Nature Reviews Drug Discovery 3:383-384.

r Zambrowicz BP and Sands AT. 2002. Knockouts model the 100 best-selling drugs - will they model the next 100? Nature Reviews Drug Discovery 2:38-51.

r Special Issue - Drug Discovery. 2004. Science 303:1795-1822.

Fig. 4.41. Further Reading

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