September 15, 2006 (Vol. 26, No. 16)

Benefits Abound for Both Businesses and Patients

In the 30 years since the founding of the first biotechnology company, the industry has evolved from focusing on research and innovating technology to commercializing products. Two significant drivers in this industrial transformation have been the premium placed by investors on late-stage clinical programs and the desire to reach the market as quickly and cost-effectively as possible.

In an effort to make themselves attractive investment candidates or to shorten the timeline from bench to bedside, many companies have responded by reducing their expenditures on research and preclinical activities, choosing instead to focus their financial and personnel resources on late-stage clinical development activities.

The scope of preclinical research is often being narrowed to encompass the minimum of safety, toxicology, and efficacy data necessary for filing an IND application rather than supporting a robust understanding of a target’s biology and its interactions with potential drugs.

This approach may provide some short-term improvement in the company’s bottom line, a transient increase in its valuation, or greater visibility associated with being a clinical development-stage company. However, it remains to be seen if this strategy creates long-term value for companies, shareholders, or patients.

Given the great interest in developing targeted therapies that address the underlying molecular mechanisms of disease, one might argue that understanding the biology of a target, its interactions with other targets and pathways, and its modulation by pharmacological agents is more critical today than at any other time in the history of medicine.

In fact, the high failure and attrition rates of product candidates entering clinical development suggest that the industry as a whole could be doing a much better job of screening for, optimizing, and evaluating drug candidates prior to initiating clinical development.

Even before compounds reach the drug-candidate stage, screening and optimization initiatives should be designed to address and provide information on drug-target interactions, drug interactions with competing or redundant targets, and a wide range of molecular markers of efficacy or toxicity.

Additionally, greater emphasis needs to be placed on using in vivo models for screening and optimizing compounds at the discovery stage. Such models are essential for a full understanding of how a compound modulates the target of interest, identifying off-target interactions that may result in unacceptable toxicities, and establishing a clinically relevant pharmacokinetic and pharmacodynamic profile.

Taken together, data gathered through target-focused screens and early in vivo studies enable a proactive approach that optimizes the pharmacology to match the biology. Ultimately, keeping both biology and clinical practice in mind throughout the entire drug discovery and development continuum can increase the likelihood that compounds reaching the development-candidate stage will have the safety and tolerability profiles and pharmaceutical characteristics necessary for successful clinical development.

Moving to a more biology-centric paradigm will clearly increase the cost of early-stage drug development. However, investments that give rise to higher quality development candidate compounds are likely to provide significant return over the long term.

Potential benefits of investing in expanded preclinical development activities include more rapid progress through Phase I trials, improved patient selection criteria that may result in increased response rates and/or fewer adverse events, trial designs that provide statistically relevant data with fewer patients or over a shorter period of time, and enhanced understanding of how to incorporate novel therapeutic approaches into standard clinical practice.


The discovery of XL880, a small molecule inhibitor of Met and the vascular endothelial growth factor receptor type-2 (VEGFR2), currently under development at Exelixis (, provides an example of how investing in extensive preclinical activities can streamline subsequent clinical development. XL880 was identified through a screening paradigm designed to select for compounds that potently inhibit both Met and VEGFR2 at nanomolar concentrations.

Extensive characterization of the two targets revealed that they play synergistic roles in promoting tumor growth and angiogenesis. Activation or overexpression of Met is a prevalent feature of a wide spectrum of human tumors, including papillary renal cell carcinoma, and is a negative prognostic indicator in patients with multiple myeloma, glioma, and certain other solid tumors.

The biology of the Met-signaling pathway suggested that inhibition of the target in cancer cells would inhibit downstream kinases, including ERK and AKT, and would increase apoptosis. This enabled the development of preclinical functional assays and biomarkers that could be used to assess the activity and potency of potential candidate compounds and provide additional validation of the target.

Extensive characterization and optimization allowed for the selection of a development candidate that demonstrated predictable pharmacokinetics and pharmacodynamics in vivo following single oral doses, efficacy, and acceptable safety and toxicity profiles.

The experience to date with XL880 suggests that there are tangible long-term benefits to investing in exhaustive discovery and preclinical research efforts. Although the ultimate test of any drug development strategy is approval and successful commercialization, the biological foundation on which XL880 is being developed already has improved the clinical timeline and identified a potentially faster path to the market.

By reducing the risk of clinical failure and potentially decreasing the size or duration of clinical trials, extensive investment in preclinical investigations will likely reduce overall clinical attrition and ultimately, drug development costs. Moreover, increasing the efficiency of clinical trials may result in earlier product approval and the establishment of a product-based revenue stream in a shorter time period than can be achieved with current paradigms.

This would allow increased investment in product candidates with a high chance of success, speed the availability of new drugs to patients with urgent medical need, and limit the exposure of patients in clinical trials to drugs from which they are not likely to benefit. At the end of the day, this is what the industry and patients we strive to help need to survive.

Michael Morrissey, Ph.D., is Phone: (650) 837-7000. E-mail: [email protected].

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