Productive university, industry, and government relationships in preclinical drug discovery and development: considerations toward a synergistic lingua franca

Efficiency and productivity shortfalls conspire with subpar economic return to stigmatize the pharmaceutical industry and jeopardize its viability. This complex and costly innovation-to-commercialization failure, the formidable associated costs, and the relevance of various core competencies endemic to universities, the pharmaceutical industry, and government have been major drivers for establishing preclinical drug-discovery alliances involving these constituencies. Such cross-sector alliances have the potential to help restore at least some of the industry's former health by militating risk, enhancing productivity, and improving the quantity/quality of development candidates. This Editorial will highlight certain characteristics of pharma-industry and non-industrial settings that can jeopardize the effectiveness of these sectors for unified preclinical discovery campaigns capable of generating well-characterized drug candidates that merit human testing. Based on decades of research and development (R&D) and business experience spanning international big-pharma, biotechnology, and academic spheres, the author opines that a synergistic lingua franca is required among involved constituencies in order for such cross-sector discovery alliances to emerge as robust drug-discovery engines fueled by joint intellectual effort. Technology-transfer professionals, postdoctoral trainees, and consultants are discussed as resources for helping establish the university-industry-government triumvirate as a normative innovation network for preclinical drug discovery and development in the 21st century.     

Strategies for bringing drug delivery tools into discovery

The past decade has yielded a significant body of literature discussing approaches for development and discovery collaboration in the pharmaceutical industry. As a result, collaborations between discovery groups and development scientists have increased considerably. The productivity of pharma companies to deliver new drugs to the market, however, has not increased and development costs continue to rise. Inability to predict clinical and toxicological response underlies the high attrition rate of leads at every step of drug development. A partial solution to this high attrition rate could be provided by better preclinical pharmacokinetics measurements that inform PD response based on key pathways that drive disease progression and therapeutic response. A critical link between these key pharmacology, pharmacokinetics and toxicology studies is the formulation. The challenges in pre-clinical formulation development include limited availability of compounds, rapid turn-around requirements and the frequent un-optimized physical properties of the lead compounds. Despite these challenges, this paper illustrates some successes resulting from close collaboration between formulation scientists and discovery teams. This close collaboration has resulted in development of formulations that meet biopharmaceutical needs from early stage preclinical in vivo model development through toxicity testing and development risk assessment of pre-clinical drug candidates.     

The future of drug discovery: enabling technologies for enhancing lead characterization and profiling therapeutic potential

Technology often serves as a handmaiden and catalyst of invention. The discovery of safe, effective medications depends critically upon experimental approaches capable of providing high-impact information on the biological effects of drug candidates early in the discovery pipeline. This information can enable reliable lead identification, pharmacological compound differentiation and successful translation of research output into clinically useful therapeutics. The shallow preclinical profiling of candidate compounds promulgates a minimalistic understanding of their biological effects and undermines the level of value creation necessary for finding quality leads worth moving forward within the development pipeline with efficiency and prognostic reliability sufficient to help remediate the current pharma-industry productivity drought. Three specific technologies discussed herein, in addition to experimental areas intimately associated with contemporary drug discovery, appear to hold particular promise for strengthening the preclinical valuation of drug candidates by deepening lead characterization. These are: i) hydrogen–deuterium exchange mass spectrometry for characterizing structural and ligand-interaction dynamics of disease-relevant proteins; ii) activity-based chemoproteomics for profiling the functional diversity of mammalian proteomes; and iii) nuclease-mediated precision gene editing for developing more translatable cellular and in vivo models of human diseases. When applied in an informed manner congruent with the clinical understanding of disease processes, technologies such as these that span levels of biological organization can serve as valuable enablers of drug discovery and potentially contribute to reducing the current, unacceptably high rates of compound clinical failure.     

Medications development for substance-use disorders: contextual influences (dis)incentivizing pharmaceutical-industry positioning

Introduction: The significant contribution of substance-use disorders (SUDs) to the global-disease burden and associated unmet medical needs has not engendered a commensurate level of pharma-industry research and development (R&D) for novel SUD therapeutics invention. Analysis of contextual factors shaping this position suggests potential routes toward incentivizing R&D commitment for that purpose.

Areas covered: This article considers multiple primary factors that have consorted to disincentivize pharma industry’s operating in the SUD space: ill-understood pathology; variegated treatments and patient profiles; involved clinical trials; and – with particular reference to SUDs-negative cultural/business stigmas and shallow commercial precedent. Industry incentivization for SUD drug innovation requires progress on several fronts, including: translational experimental data and systems; personalized, holistic SUD treatment approaches; interactions among pharma, nonindustry constituencies, and the medical profession with vested interests in countering negative stereotypes and expanding SUD treatment options; and public–private alliances focused on improving SUD pharmacotherapy.

Expert opinion: Given the well-entrenched business stance whereby the prospect of future profits in major markets largely determines drug-company R&D investment trajectory, strategic initiatives offering substantial reductions in the risks and opportunity (i.e., time and money) costs associated with SUD drug discovery are likely to be the most potent drivers for encouraging mainstream industry positioning in this therapeutic area. Such initiatives could originate from front-loaded R&D operational and back-loaded patent, regulatory, marketing and health-care policy reforms. These may be too involved and protracted for the turbulent pharmaceutical industry to entertain amid its recent retrenchment from psychiatric/CNS diseases and intense pressures to increase productivity and shareholder value.     

Optimizing candidate selection--a vision in business limited conference. 1-2 December 1998, Basel, Switzerland

The pharmaceutical industry is faced with filtering hundreds of thousands of compounds to identify successful drug candidates. Given these numbers, how does the pharmaceutical industry identify optimal therapeutic agents rapidly, efficiently, economically and successfully, with the ultimate result of the patient receiving the best drug? The conference summarized the present and future requirements for evaluating emerging technologies, integrating that technology into a filter for large and growing numbers of compounds, building and linking diverse knowledge bases, and establishing predictive foundations that will optimize and accelerate drug discovery and development. Specific conference topics focused on organizational and management approaches as well as some of the major technologies and emerging techniques for supporting drug candidate selection and optimization. It is predicted that the pharmaceutical industry will be synthesizing and screening a million or more compounds for multiple therapeutic targets in the near future. Pulling together the resources of current and emerging technology, knowledge, and multidisciplinary teamwork, so that discovery and selection of successful drug candidates from this large pool of compounds can take place rapidly, is a significant challenge. This conference focused on the organizational issues and experimental tools that can provide for a shortening of discovery time, identification of current and future selection techniques and criteria, the linking of technologies and business strategies to reduce risk, and novel processes for optimizing candidates more quickly and efficiently. The conference was directed at industrial scientists involved in all stages along the drug discovery and development interface. This conference was well-attended, with approximately 100 participants.     

The role of early in vivo toxicity testing in drug discovery toxicology

The cost impact of late-stage failures of drug candidates has motivated the pharmaceutical industry to develop, validate, and implement a more proactive testing paradigm, including an emphasis on conducting predictive in vitro and in vivo studies earlier. The goal of drug discovery toxicology is not to reduce or eliminate attrition, as is often mis-stated as such, but rather to reprioritize efforts to shift attrition of future failing molecules upstream in discovery. This shift in attrition requires additional studies and investment earlier in the candidate evaluation process in order to avoid spending resources on molecules with soon-to-be-discovered development-limiting liabilities. While in silico and in vitro models will continually be developed and refined, in vivo preclinical safety models remain the gold standard for assessing human risk. For in vivo testing to influence early discovery effectively, it must: i) require low amounts of compound; ii) provide rapid results to drive decision-making and medicinal chemistry efforts; and iii) be flexible and provide results relevant to the development plan tailored to each target, drug class, and/or indication.     

Biomarkers,metabonomics, and drug development: Can inborn errors of metabolism help in understanding drug toxicity?

Application of "omics" technology during drug discovery and development is rapidly evolving. This review evaluates the current status and future role of "metabonomics" as a tool in the drug development process to reduce the safety-related attrition rates and bridge the gaps between preclinical and clinical, and clinical and market. Particularly, the review looks at the knowledge gap between the pharmaceutical industry and pediatric hospitals, where metabonomics has been successfully applied to screen and treat newborn babies with inborn errors of metabolism. An attempt has been made to relate the clinical pathology associated with inborn errors of metabolism with those of drug-induced pathology. It is proposed that extending the metabonomic biomarkers used in pediatric hospitals, as "advanced clinical chemistry" for preclinical and clinical drug development, is immediately warranted for better safety assessment of drug candidates. The latest advances in mass spectrometry and nuclear magnetic resonance (NMR) spectroscopy should help replace the traditional approaches of laboratory clinical chemistry and move the safety evaluation of drug candidates into the new millennium.     

The impact of parallel chemistry in drug discovery

With the application of parallel synthesis of single compounds to drug-discovery efforts, improvements in the efficiency of synthesis are possible. However, for improvements to occur in effective drug design - a critical requirement to increase productivity in the modern pharmaceutical industry - the implementation of in silico design hypotheses that incorporate comprehensive information on a target, including considerations of absorption, distribution, metabolism and excretion, is also necessary. Concomitantly, the use of automated methods of synthesis and purification is also required to improve drug design. Combining all of these elements allows the possibility to uncover unique insights into a biological target quickly and to therefore accelerate the rate of drug discovery.     

The new pre-preclinical paradigm: compound optimization in early and late phase drug discovery

The attrition rates of new chemical entities (NCEs) in preclinical and clinical development are staggeringly high. NCEs are abandoned due to insufficient efficacy, safety issues, and economic reasons. Uncovering drug defects that produce these failures as early as possible in drug discovery would be highly effective in lowing the cost and time of developing therapeutically useful drugs. Unfortunately, there is no single factor that can account for these NCE failures in preclinical and clinical development since factors, such as solubility, pKa, absorption, metabolism, formulation, pharmacokinetics, toxicity and efficacy, to name a few, are all interrelated. In addition, there are many problems in scaling-up drug candidates from the laboratory bench scale to the pilot plant scale. To address the problem of attrition rates of NCEs in preclinical and clinical development and drug scale-up issues, pharmaceutical companies need to reorganize their preclinical departments from a traditional linear approach to a parallel approach. In this review, a strategy is put forth to integrate certain aspects of drug metabolism/pharmacokinetics, toxicology functions and process chemistry into drug discovery. Compound optimization in early and late phase drug discovery occurs by relating factors such as physicochemical properties, in vitro absorption, in vitro metabolism, in vivo pharmacokinetics and drug scale-up issues to efficacy optimization. This pre-preclinical paradigm will improve the success rate of drug candidates entering development.     

Strategic applications of toxicogenomics in early drug discovery

Productivity issues facing the pharmaceutical industry are numerous, and the current challenges come in the face of an aging population and a demand for new and better medications. These challenges call for improvement in the drug discovery and development process, which paradoxically comes on the heels of remarkable scientific advances and in an era of great opportunity in medical science. Despite these advances, the pharmaceutical industry has yet to translate breakthroughs in new technologies, including genomics, into new drug therapies for unmet medical needs. The strategic application of toxicogenomics to the earliest stages of a drug discovery program offers a valuable opportunity to identify potential safety hurdles earlier than is the norm today. We propose that using genomics predictively (in vitro to predict outcomes in vivo and short-term studies in vivo to predict safety issues in longer studies) can assist in reducing inefficiency in the current paradigm, which is still heavily weighted on traditional endpoints from lengthy in vivo studies. Implementation of these strategies will assist in solving the current pharmaceutical pipeline productivity dilemma of long cycle times and unacceptable attrition rates in the preclinical drug discovery process.     

CYP Induction-Mediated Drug Interactions: in Vitro Assessment and Clinical Implications

Cytochrome P450 (CYP) induction-mediated interaction is one of the major concerns in clinical practice and for the pharmaceutical industry. There are two major issues associated with CYP induction: a reduction in therapeutic efficacy of comedications and an induction in reactive metabolite-induced toxicity. Because CYP induction is a metabolic liability in drug therapy, it is highly desirable to develop new drug candidates that are not potent CYP inducer to avoid the potential of CYP induction-mediated drug interactions. For this reason, today, many drug companies routinely include the assessment of CYP induction at the stage of drug discovery as part of the selection processes of new drug candidates for further clinical development. The purpose of this article is to review the molecular mechanisms of CYP induction and the clinical implications, including pharmacokinetic and pharmacodynamic consequences. In addition, factors that affect the degree of CYP induction and extrapolation of in vitro CYP induction data to in vivo situations will also be discussed. Finally, assessment of the potential of CYP induction at the drug discovery and development stage will be discussed.     

High-throughput screening-driven lead discovery: meeting the challenges of finding new therapeutics

The pharmaceutical industry faces a number of challenges that have cumulatively led to a decline in productivity, despite increasing levels of investment in research and development. It is in this context that some researchers and business analysts are questioning the value of the high-throughput screening (HTS) paradigm for the discovery of new therapeutics. While this criticism may be premature, significant changes are occurring in HTS-driven lead discovery to address the failure of drug candidates in the clinic. This article highlights some of these changes and their potential impact.     

Patented inhibitors of p53–Mdm2 interaction (2006 – 2008)

Importance of the field: Induction of apoptosis by reactivation of p53 in cancer cells is an emerging therapeutic concept for the treatment of cancer. The discovery and design of novel small molecules that block the p53–Mdm2 protein interaction, thereby activating p53, has provided interesting drug candidates that have currently entered clinical trials or are at the preclinical development stage.

Areas covered in this review: A selection of the interesting patents focusing on small molecule inhibitors of the p53–Mdm2 interaction, recorded from 2006 until 2009, is presented together with a review of the related structural chemistry space.

What the reader will gain: Readers will rapidly gain an overview of the majority of patented scaffolds of small molecule inhibitors of the p53–Mdm2 protein–protein interaction and learn about current limitations and properties of these compounds.

Take home message: The discovery p53–Mdm2 protein–protein interaction inhibitors have delivered new potential options for a targeted cancer therapy with drug-like, non-toxic small molecules. If successful, this approach could gain considerably more attention in the pharmaceutical industry by targeting a variety of validated intracellular protein–protein interactions.     

The role of early in vivo toxicity testing in drug discovery toxicology

The cost impact of late-stage failures of drug candidates has motivated the pharmaceutical industry to develop, validate, and implement a more proactive testing paradigm, including an emphasis on conducting predictive in vitro and in vivo studies earlier. The goal of drug discovery toxicology is not to reduce or eliminate attrition, as is often mis-stated as such, but rather to reprioritize efforts to shift attrition of future failing molecules upstream in discovery. This shift in attrition requires additional studies and investment earlier in the candidate evaluation process in order to avoid spending resources on molecules with soon-to-be-discovered development-limiting liabilities. While in silico and in vitro models will continually be developed and refined, in vivo preclinical safety models remain the gold standard for assessing human risk. For in vivo testing to influence early discovery effectively, it must: i) require low amounts of compound; ii) provide rapid results to drive decision-making and medicinal chemistry efforts; and iii) be flexible and provide results relevant to the development plan tailored to each target, drug class, and/or indication.     

Metabolism and toxicity of drugs. Two decades of progress in industrial drug metabolism

The science of drug metabolism and pharmacokinetics (DMPK) has developed significantly over the past 20 years, and its functional role in today's pharmaceutical industry has matured to the point where DMPK has become an indispensable discipline in support of drug discovery and development. While contributions to the lead optimization phase of discovery efforts have been particularly noteworthy in helping to select only the best drug candidates for entry into development, it should be recognized that the scope of DMPK spans the continuum of discovery through clinical evaluation and even into the post-marketing phase; as such, the breadth of DMPK's involvement is almost unique in contemporary pharmaceutical research. This perspective summarizes notable advances in the field, many of which have been made possible by technological developments in areas such as molecular biology, genetics, and bioanalytical chemistry, and highlights the critical nature of key partnerships between Drug Metabolism, Medicinal Chemistry, and Safety Assessment groups in attempting to advance drug candidates with a low potential for causing adverse events in humans. Finally, some speculative predictions are made of the future role of DMPK in pharmaceutical research, where current advances in our mechanistic understanding of the molecular processes that control the absorption, disposition, metabolism, elimination, and toxicity of drugs and their biotransformation products will combine to further enhance the impact of DMPK in drug discovery and development.     

Drug discovery and development: lessons from an undeveloped drug

In this article, drug discovery and preclinical development paradigms, as employed in today’s pharmaceutical companies, are discussed. The antimalarial drug, artemisinin, is given as an example of a compound that is unlikely to be developed by a modern pharmaceutical company, yet is a safe and effective drug for the treatment of a deadly disease. It is argued that the use of prespecified charts, listing undesired properties to deselect molecules may lead to missed opportunities in bringing best-in-class medications to patients. Implementation of systems pharmacology, disease progression and pharmacokinetic/pharmacodynamic models are proposed. These models offer a superior approach in selecting the best drug candidates with the highest chance of success of entry into the market.     

Drug discovery and development: lessons from an undeveloped drug

In this article, drug discovery and preclinical development paradigms, as employed in today's pharmaceutical companies, are discussed. The antimalarial drug, artemisinin, is given as an example of a compound that is unlikely to be developed by a modern pharmaceutical company, yet is a safe and effective drug for the treatment of a deadly disease. It is argued that the use of prespecified charts, listing undesired properties to deselect molecules may lead to missed opportunities in bringing best-in-class medications to patients. Implementation of systems pharmacology, disease progression and pharmacokinetic/pharmacodynamic models are proposed. These models offer a superior approach in selecting the best drug candidates with the highest chance of success of entry into the market.