Journal of Cardiovascular Translational Research

, Volume 3, Issue 5, pp 431–437

Cardiovascular Drug Discovery in the Academic Setting: Building Infrastructure, Harnessing Strengths, and Seeking Synergies

Authors

    • Sanford-Burnham Medical Research Institute at Lake Nona
  • Gregory P. Roth
    • Sanford-Burnham Medical Research Institute at Lake Nona
  • Daniel P. Kelly
    • Sanford-Burnham Medical Research Institute at Lake Nona
Article

DOI: 10.1007/s12265-010-9204-8

Cite this article as:
Gardell, S.J., Roth, G.P. & Kelly, D.P. J. of Cardiovasc. Trans. Res. (2010) 3: 431. doi:10.1007/s12265-010-9204-8

Abstract

The flow of innovative, effective, and safe new drugs from pharmaceutical laboratories for the treatment and prevention of cardiovascular disease has slowed to a trickle. While the need for breakthrough cardiovascular disease drugs is still paramount, the incentive to develop these agents has been blunted by burgeoning clinical development costs coupled with a heightened risk of failure due to the unprecedented nature of the emerging drug targets and increasingly challenging regulatory environment. A fuller understanding of the drug targets and employing novel biomarker strategies in clinical trials should serve to mitigate the risk. In any event, these current challenges have evoked changing trends in the pharmaceutical industry, which have created an opportunity for non-profit biomedical research institutions to play a pivotal partnering role in early stage drug discovery. The obvious strengths of academic research institutions is the breadth of their scientific programs and the ability and motivation to “go deep” to identify and characterize new target pathways that unlock the specific mysteries of cardiovascular diseases—leading to a bounty of novel therapeutic targets and prescient biomarkers. However, success in the drug discovery arena within the academic environment is contingent upon assembling the requisite infrastructure, annexing the talent to interrogate and validate the drug targets, and building translational bridges with pharmaceutical organizations and patient-oriented researchers.

Keywords

Drug DiscoveryCardiovascular DiseaseTherapeutic TargetSanford-Burnham Medical Research InstituteTranslational Research

Introduction

The impressive advances in cardiovascular therapeutics during the past several decades have had a major impact on human health and disease. Nevertheless, despite remarkable strides forward, cardiovascular disease continues to be the major contributor to morbidity and mortality in westernized societies. The pandemics of diabetes and obesity are fueling a staggering increase in the incidence of cardiovascular disease—and younger people are increasingly being victimized. Hence, there is still an urgent need for new and improved therapeutic agents to combat common diseases of the heart and vasculature such as heart failure, atherothrombotic vascular disease, hypertension, and cardiac arrhythmias. These common cardiovascular diseases are increasingly being viewed as heterogeneous disorders thus sparking keen interest in future therapies that are tailored to emergent disease subclassifications. For instance, optimal treatment of heart failure or vascular disease will require careful consideration of the specific etiologic factors (e.g., diabetes and hypertension) and other aspects of the pathophysiology that are linked to particular patient subgroups (i.e., personalized medicine).

What will be the source of the next generation of “game changing” cardiovascular drugs? The pharmaceutical industry faces steep challenges that have increasingly obstructed the discovery, development, and validation of innovative drugs. Declining research and development (R&D) productivity in the pharmaceutical industry has been the subject of many insightful critiques, but solutions to undo this stagnation have been elusive [14]. While “innovation malaise” in the pharmaceutical industry is not unique to the cardiovascular arena, this particular disease area has been especially vulnerable to “downsizing” during portfolio reviews and strategic reprioritization exercises. The pursuit of cardiovascular drugs, especially in the heart failure arena, has been simply viewed as “too risky” and “too expensive” given the large patient cohort sizes necessary to establish efficacy and safety. The enormity of the unmet medical need for new and improved therapeutic strategies for heart and vascular disease unveils an opportunity for non-profit research organizations to fill the innovation gap in collaboration with the pharmaceutical industry. In particular, efforts aimed at new target identification and validation must be sustained, even intensified, to sow the seeds for novel therapeutic approaches to stem the rising tide of cardiovascular disease.

The leadership at the National Institutes of Health (NIH) has also recognized the perilous void created by the productivity crisis in the pharmaceutical industry. The NIH created the “Roadmap Initiative” (http://nihroadmap.nih.gov) which aims to foster high-risk, high-reward translational research in order to devise creative ways to more quickly advance discoveries to the clinic. The Roadmap Initiative is supported through the NIH Common Fund, which is designed to operate outside of the traditional NIH funding paradigm to promote innovative and transformative ideas in the field of chemical genomics and biomedical science. Academic research organizations, particularly non-profit research institutes such as the Sanford-Burnham Medical Research Institute (SBMRI; formerly the Burnham Institute for Medical Research), have responded to this health care threat and have undergone transformational changes to engage in the mission of drug discovery. The early experience at SBMRI will be used here to illustrate the practical strategies and challenges involved in the development of early drug discovery initiatives in the non-profit setting.

Building Drug Discovery Infrastructure

In 2009, SBMRI established a new research facility in the Lake Nona region of Orlando, Florida. The research focus of the “Lake Nona campus” is diabetes, obesity, and their cardiovascular complications. Importantly, the research infrastructure at the SBMRI-Lake Nona campus was specifically designed to expand and complement the tools, technologies, and talent for early stage drug discovery established recently at the SBMRI campus in La Jolla, California. The SBMRI drug discovery platform resides in the Conrad Prebys Center for Chemical Genomics (CPCCG). A 6-year $98 million grant from the NIH Roadmap Initiative coupled with a $10 million philanthropic gift launched the CPCCG. The CPCCG is one of four NIH-funded comprehensive centers chosen nationally to be a part of the Molecular Libraries Probe Program (MLP), which established the Molecular Libraries Probe Production Centers Network (MLPCN). The MLPCN offers academic institutes, non-profit organizations, and small biotechnology companies access to ultra high-throughput screening (uHTS) capabilities (see Box 1). The MLPCN is the curator of a small-molecule library (approximately 330,000 compounds) that can be used to screen for chemical probes to interrogate the functions of protein targets in either purified or cell-based systems. Overall, the CPCCG has access to nearly 1.1 million screening samples comprised of the NIH repository, internal small-molecule collections, known drugs and pharmacologically active agents, “rule of 3” fragments, and natural products.

SBMRI has assembled a screening and “hit-to-lead” technology platform, which is essentially unprecedented in the public, non-profit university and research institute sector. The uHTS system engineered by HighRes BioSolutions (http://www.highresbio.com/; Fig. 1) currently performs an average of 25 screening campaigns per year under the MLPCN directive. Since the inception of the MLP, the CPCCG has developed assays and screened against 76 biological targets, yielding 30 high quality probe molecules. Almost half of these screening campaigns are cell based, phenotypic pathway based, or high content assay formats. Approximately one third of the MLPCN assigned assays performed by the CPCCG have resulted from research endeavors by SBMRI investigators.
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Fig. 1

The ultra high-throughput platform for identification of molecular probes. Fully integrated, industrial scale uHTS robotic workstation in the Conrad Prebys Center for Chemical Genomics at SBMRI, Lake Nona. The uHTS facility has three robotic workstations, which enables multiple assays to be conducted simultaneously

The collective, NIH-sponsored MLPCN mission is not necessarily to launch a drug but rather to identify molecular tools to further understand the fundamental biology underlying disease states. The next step, an aspirational goal, is to then use the promising chemical biology findings as a foundation for a drug discovery campaign. Ideally, this will be enabled through close collaboration between the biotechnology/pharmaceutical sectors and research institutes/universities. However, as will be outlined below, the success of the early phase depends on the development of multi-disciplinary teams comprised of individuals with backgrounds in traditional basic research as well as drug discovery. Such teams must include biologists, chemists, pharmacologists, and physiologists, among others.

The CPCCG has established a variety of drug discovery resources that enable and facilitate “hit identification” and “hit-to-lead” advancement. External organizations and research investigators can access CPCCG resources through a variety of mechanisms, which include peer-reviewed NIH Roadmap funding strategies or direct contract-based research collaborations. The available services include the following:
  • Full-scale capabilities and technology to support uHTS using a broad diversity of assays (biochemical, cell based, and high content) and detection platforms (chemiluminescent, colorimetric, fluorescent absorbance, or emission including BRET, FRET, and FP) to screen diverse synthetic small molecule and natural product libraries;

  • Three fully integrated industrial-scale uHTS robotic modular workstations that automate the screening laboratory and have the capacity to conduct multiple assays simultaneously. The system is coupled with an identical single-arm instrument that is utilized for assay development and screening protocols;

  • Microscopy/high content screening (HCS) capabilities using novel algorithms for high-throughput image analysis;

  • Nuclear magnetic resonance (NMR)-based chemical fragment screening;

  • Label-free affinity selection-mass spectrometry screening;

  • Synthetic chemistry expertise and equipment to generate reference compounds and chemical probes and perform structure–activity relationship (SAR) optimization studies;

  • Adsorption/distribution/metabolism/excretion/toxicology (ADME/T) exploratory pharmacology assay capabilities for the assessment of “drug-like” properties and determination of dose–exposure relationships;

  • Highly integrated informatics infrastructure and efficient cheminformatic data mining capabilities;

  • Protein production facility to support target procurement;

  • NMR and X-ray crystallography platforms for elucidating ligand–protein interactions that can inform SAR campaigns;

  • Cell production facility for scale-up tissue culture.

The CPCCG medicinal chemistry team is comprised of over a dozen chemists ranging from newly minted postdoctoral associates through 20-year industry veterans who have shepherded bioactive small molecules through the preclinical and clinical development process. This team has fine tuned its hit set triage and “hit-to-lead” skills through exposure to diverse biological targets and related small molecule chemistries linked to MLPCN projects. The CPCCG chemistry infrastructure enables the iterative, systematic synthesis, analysis, and purification of single compounds, analog arrays, and libraries required for taking raw assay hits to lead status and then on to preclinical candidates. Several chemists have a background in natural product isolation and identification, which nicely complements the availability of over 150,000 natural product extracts and peak fraction libraries in the overall CPCCG screening tool set. The medicinal chemistry team works closely with the CPCCG exploratory pharmacology group so that physicochemical and ADME/T properties (in vitro and in vivo) of candidate molecules can be optimized in parallel with improved potency and selectivity.

It is important to emphasize that the requisite infrastructure for drug discovery must cover a wide array of expertise. “Drug hunting” is a highly specialized pursuit that requires practitioners who typically have training/experience acquired during stints in the pharmaceutical industry. Hence, the recruitment of former “drug hunters” to staff positions at the research institutes is crucial for success. The changing trends in the pharmaceutical industry, coupled with exciting opportunities to pursue early stage drug discovery in research institutes such as SBMRI, have created a new pool of talented individuals who are interested in making the career switch.

Harnessing Strengths: “Going Deep”

Successful drug discovery is facilitated by in-depth understanding of the molecular target and keen awareness of the pharmacological/toxicological consequences that arise from target engagement by the drug candidate. It is crucial to thoroughly profile (i.e., phenotype) the effects due to genetic manipulation of the target or dosing of agents that alter the activity of the target. However, the duress of timeline-driven business imperatives imposed by zealous portfolio managers has made rigorous characterization an elusive goal in the pharmaceutical industry. A powerful advantage of doing drug discovery in non-profit research arena is the freedom and desire to “go deep.” A research environment such as that existing at SBMRI fosters a “culture of science” where a premium is placed on solving the riddles of human biology and disease. Success is facilitated by the availability of technology cores such as analytical and functional genomics, transcriptomics, proteomics, and metabolomics. Consolidation of the expertise and technology in these fee-for-service research cores is a cost-effective means to generate experimental findings that are pivotal for target identification and validation.

Metabolomics (profiling of metabolites in the metabolic pathway network) is a prime example of how emerging technologies can shed light on the consequences of target engagement by drug candidates. The metabolomics core at SBMRI was formed as a partnership with the Stedman Center for Nutrition and Metabolic Research at the Duke University Medical Center. Mass spectrometry-based assay modules were established at the Lake Nona campus to measure acylcarnitines, amino acids, organic acids, and other metabolites in plasma and tissue samples. Together, these metabolite profiles serve as probes of intermediary metabolic pathways and provide powerful insight into biochemical pathways relevant to cardiovascular and metabolic diseases. Metabolomics is well suited to biomarker discovery, which is instrumental for all stages of the drug discovery and development path, especially as we aggressively pursue “personalized” therapeutic approaches. Indeed, metabolite profiles show great promise for defining signatures for the efficacy and potential toxicity of drug candidates, as well as for specific health and cardiometabolic disease states.

Physiological and metabolic assessment of targets and compounds in preclinical animal disease models is another critical component of the early drug discovery process. SBMRI has jointly developed the capabilities for rigorous cardiovascular and metabolic phenotyping so that the in vivo effects of candidate compounds and genetic manipulations of the targets can be assessed. The cardiometabolic phenotyping core focuses on rodent disease models (genetic, surgical, and diet induced), with emphasis on the use of mice. Combined with genomic and metabolomic profiling, this deep phenotyping approach can help define disease mechanisms and recognize compound efficacy and toxicity. The myriad of techniques/methodologies established at the SBMRI-Lake Nona campus for in-depth in vivo assessment of cardiometabolic drug targets and drug candidates include the following:
  • High-resolution ultrasound imaging;

  • Invasive and noninvasive hemodynamics;

  • Telemetric electrocardiogram and blood pressure monitoring in conscious freely roaming mice;

  • Exercise performance (treadmill apparatus);

  • Optical imaging;

  • Body composition determination (time-domain-NMR measurement of lean and fat mass);

  • Comprehensive Laboratory Animal Monitoring System for assessment of energy balance (food intake and indirect calorimetry);

  • Glucose homeostasis and insulin-sensitivity evaluation (including hyperinsulinemic/euglycemic clamp methodologies).

While the emerging strengths are considerable, research institutes such as SBMRI must avoid straying from the scope of their primary mission. The infrastructure and capabilities of non-profit research institutes are best suited to early stage drug discovery. Expanding the repertoire of expertise and capabilities beyond the pursuit of early stage drug discovery could lead to loss of focus and compromise the potential impact of their research discovery contributions. What should be the bounds of the “deliverables” of the non-profit research institutes? Listed below are several drug discovery aims that within the “sweet spot” of the non-profit arena
  • Show a desired pharmacological effect when the intended target is engaged with the “lead compound,”

  • Demonstrate that the observed pharmacological effects in preclinical animal models are relevant to human disease,

  • Identify a “lead compound” that is desirable from the perspective of chemical structure (“drug-like properties”) and patentability, and

  • Elucidate biomarker signatures that provide a sensitive “read-out” for target-related efficacy or toxicity.

Delivering as many of these aims as possible will create a solid foundation for an emerging drug discovery campaign and facilitate the “hand-off” to an industry partner with the expertise, resources, and working capital to advance the asset towards commercialization. In many cases, it is envisioned that even this early work will be conducted in partnership with industry as described below.

Seeking Synergies and Solutions: Finding the Right Partner

The changing trends in the pharmaceutical and biotechnology industries and the increased investment of non-profit research organizations in translational research have spawned the potential for natural symbiotic partnerships. There is growing reliance of the pharmaceutical industry on academic research institutions to accomplish the daunting task of early stage drug discovery. The number of phase I collaborative interactions doubled from 35 during 2000–2004 to 70 during 2005–2009 [5]. Likewise, the pharmaceutical industry is externalizing discovery activities at an increasing pace in order to tap into fresh ideas and harness the power of early stage innovative technologies.

In turn, non-profit research institutions must partner with the pharmaceutical industry for the resources and expertise that are essential for the downstream drug development process. Companies will increasingly forge alliances with research institutes—and vice versa—to bring novel therapeutic agents to the market. The biology is too complex, and the risks are too high. Partnership is essential. A research strategy based on teamwork and multi-disciplinary approaches is the sine qua non for success in the pharmaceutical industry. It is now being adopted by academic research institutions and embraced by the NIH.

Despite the vast promise of academic–pharmaceutical partnerships in the drug discovery arena, success can be undermined by numerous challenges and pitfalls. It is necessary to preserve a “culture of science” that emphasizes the importance of deciphering disease mechanisms. Any retooling in the academic center with respect to technology and expertise to support drug discovery must not marginalize the basic discovery pursuits—the source of novel insight and the means to prized NIH funding. In addition, a secure intellectual property (IP) position in the drug discovery arena is imperative to exploit the therapeutic potential of the discovery and promote collaborative advancement of knowledge. Devising a plan for equitable sharing of IP between academic and pharmaceutical partners is crucial. The possible conflict of interest due to dreams of commercial rewards can also derail the pursuit of a deep understanding of the disease etiology. Finally, the pharmaceutical partner must embrace the fact that fundamental discovery and mechanistic studies are a wise investment, which serves as an engine for innovative ideas and novel therapeutic approaches.

Another synergy critical to drug discovery involves preclinical and patient-oriented research. Information gleaned from studies of human disease and insight gathered from preclinical investigations yield complementary and mutually advantageous information. Together, the two-way trafficking of information from “bench to bedside” and “bedside to bench” will serve to promote the development of drug candidates with promising therapeutic utility. Whereas the medical school environment is well suited for clinical research, novel partnerships with non-academic health systems may also prove to be valuable. For example, the newly formed partnership between SBMRI and the Florida Hospital system in Orlando has led to the formation of the Translational Research Institute for Diabetes and Metabolic Disease (TRI-MD). The mission of the TRI-MD is to expand our understanding of the human cardiometabolic disease cluster using highly phenotyped patient and control cohorts. The cadre of imaging and physiological assessments performed at the TRI-MD can provide a detailed picture of the clinical, physiological, and molecular perturbations that are associated with specific metabolic and cardiovascular disease states. Combined with “omics” profiling, the efficacy and toxicity associated with drug candidates can be rigorously determined. It is important to stress that this deep phenotyping of human subjects parallels closely the corresponding profiling of the animal models of human cardiometabolic disease. Building a highly coordinated bridge between the basic discovery and patient-oriented research will serve to devise and implement novel therapeutic solutions to the challenging unmet medical needs in the cardiovascular disease arena.

Conclusions

A dire need exists for innovative cardiovascular drug discovery research in order to front-load the drug discovery pipeline. Target identification and validation are no longer the eminent domain of the pharmaceutical industry, but rather have become an important mission of research organizations in the non-profit world. Figure 2 shows the three crucial elements for success (“Discovery Triad”): basic discovery research (“bench”), a translational bridge to patient-oriented discovery research (“bedside”), and a translational technology platform to realize the potential clinical utility of therapeutic agents/approaches. The pursuit of a deep understanding of disease mechanisms is within the “sweet spot” of non-profit research enterprises. This is especially powerful when close collaborations exist between basic scientists and patient-oriented researchers (i.e., the essence of translational research). Partnerships across academia and industry should also serve as a translational “bridge” for drug and biomarker discovery. However, clever ideas and novel insight are not sufficient to make a full impact. A highly sophisticated research infrastructure is needed to decipher the physiological and molecular changes that arise from genetic or pharmacologic perturbation of the drug target. The “omics” technologies (genomics, proteomics, and metabolomics) combined with physiological profiling and imaging modalities can provide a treasure trove of valuable insight. In addition to drug discovery, this deep phenotyping strategy can yield biomarkers that serve as surrogate read-outs for target engagement, therapeutic/toxicity effects, or a signal of disease progression. The biomarkers can also serve to guide the development of etiology-specific drugs for complex (and heterogeneous) cardiovascular diseases such as heart failure and atherosclerosis. Steering promising molecular targets to the early stage drug discovery platform can yield “chemical probes” for the selected targets that serve as experimental tools in the near term—and the leads for the drugs of tomorrow. The more “risk-tolerant” environment of non-profit research institutes coupled with the resources/capabilities of the “Discovery Triad” fosters creative attempts to identify innovative targets and evaluate their potential therapeutic utility—with the ultimate winner being patients who are suffering from the scourges of cardiovascular disease.
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Fig. 2

“The Discovery Triad”: (1) basic discovery research (“bench”), (2) patient-oriented discovery research (“bedside”)—both assisted by powerful common technologies—along with (3) early stage drug discovery platform. The key deliverable is novel insight into human disease mechanisms that trigger ideas for innovative and disease etiology-specific therapeutic strategies. In turn, the drug discovery platform will yield chemical probes to explore these innovative therapeutic strategies and serve as the leads for the drugs of tomorrow

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© Springer Science+Business Media, LLC 2010