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.