The 8th World Drug Discovery & Development Summit 2008
2nd & 3rd December 2008
Prague Congress Centre, Prague, Czech Republic
Speakers
Confirmed speakers include:
There is a significant drive within many pharmaceutical companies to expand their research activities outside their walls and create a network of alliances that cross the public and private sectors. But is this strategy working ? In this talk we'll take a look at what should be considered before establishing a cross-organisational alliance, focussing on specific examples of alliances between big pharma and the academic sector as examples of what works and where the pitfalls are. We'll also assess the factors involved in building a successful collaboration, and consider an interesting model of alliance management designed to optimise return on investment.
The benefit/risk ratio is the yardstick in drug development to judge the potential of new molecules to become viable medicines with benefit to patients. Hence preclinical Safety (including not only the classical toxicology disciplines, but also safety pharmacology, immunotoxicology, drug metabolism and pharmacokinetics) is an important dimension when comparing similar molecules prepared in lead optimization programs and helps to select molecules with superior chance for a successful development. New in silico or in vitro methods in most safety areas are available or are being developed today allowing to assess, in short time, series of compounds for major liabilities (e.g., genotoxicity, major organ toxicities, teratogenicity, immune system perturbations, drug-drug interaction potential). Modern early safety evaluation takes advantage of these new tools to build a testing strategy beginning with target assessment and extending to lead compound optimization and selection of clinical candidates. Starting with in silico techniques (query of databases for detecting structural alerts; modeling and simulation) and in vitro methods (enzymatic or cellular models, preferably with humanized cell lines) including -omics technologies (e.g., toxicogenomics, metabonomics), applied methods become more complex (e.g., minitox screen, in vivo imaging) as the selection of potential drug candidates in a project narrows. These testing paradigms are devised to support science-based decisions, are targeted to the nature of the molecule under consideration (small molecular weight NCE; biological; siRNA therapies) and take all available previous experience with a compound class or target into account. Today in vitro methods are not ready yet to replace in vivo testing entirely because results are often still qualitative in nature and limited by the uncertainty of extrapolation to a whole organism and the human species. However, they allow to focus necessary in vivo evaluations to the relevant questions, support selection of the most promising clinical candidates, help in refining study designs and overall allow to reduce the amount of required in vivo animal and human testing.
Dr Jacques Hamon
Head of In Vitro Safety Pharmacology Profiling, BaselNovartis Institutes for BioMedical Research
Switzerland
As clinical safety and toxicity are among the major causes of late drug failure, it is of high importance to identify potential drug liabilities early in the drug discovery process. Broad-scale in vitro safety pharmacology profiling of new chemical entities is one key element allowing a rapid assessment of off-target activities which may be responsible for adverse effects at a latter stage. What is the impact for compound success? How best to use in vitro safety profiling data in the drug discovery process? How important is compound promiscuity during lead optimization ? Can in silico tools be developed to guide the chemist even earlier? All these questions will be addressed and illustrated. Authors: Jacques Hamon, Laszlo Urban, Steven Whitebread, Dmitri Mikhailov, Josef Scheiber, Kamal Azzaoui, Andreas Bender
Lilly Discovery is exploring the use of cell based phenotypic and pathway assays to chemically interrogate complex biological systems composed of multiple or unknown biochemical components/pathways. Such Phenotypic Drug Discovery (PDD) approaches complement classical Target-directed Drug Discovery strategies. Potential advantages of PDD approaches include direct identification of cell active compounds, systematic inclusion of both known and unknown molecular components/mechanisms and interrogation of molecular targets in a relevant, cellular context. Concerns with cell based approaches include design of appropriate compound libraries, the statistical robustness and throughput of assays, and whether cellular assays can provide compound structure-activity relationships. This presentation is a status report on the use of PDD approaches at Eli Lilly and Company. Our experience to date indicates how multiplexed cellular imaging and the resulting compound activity fingerprints can be combined with advanced data analysis tools and computational hit expansion algorithms to identify compounds with known and novel mechanisms. Authors: Jonathan Lee, Jeff Sutherland, Tom Engler and Lou Stancato
Despite immense investments in pharmaceutical R&D, lack of drug efficacy and presence of drug toxicity are two major reasons limiting R&D productivity. Systems Biology, uses a new perspective (integration instead of reduction) to study complex interactions in biological systems. Through integrated analysis of Mining, Modeling, Manipulation, and Measurements, applied systems biology has shown several successes in addressing major hurdles in both drug efficacy and toxicity. Using case studies of atherosclerosis and drug-induced liver injury, this talk will present the applications of systems biology to key stages of drug R&D, its significant impact and future directions.
Dr Thomas Metcalfe
Global Head of Personalized Healthcare PortfolioF. Hoffmann-La Roche Ltd.
Switzerland
The rapidly growing understanding of the molecular basis of disease pathology, aided by progress in genomics, genetics, and other “ ‘omic disciplines” provides us with numerous new insights into inter-patient difference and differences a more informative and accurate taxonomy of disease states. This understanding will allow us to devise new diagnostic tools and create more targeted medicines that are more effective and safer - this is what we understand as “personalised healthcare” (PHC) By taking the individual characteristics of patients and their diseases into account PHC has the potential to target medicines to those patients who are most likely to benefit from a therapy – thereby helping to avoid treating patients with medicines they are unlikely to benefit from and avoiding unnecessary exposure to the treatment’s potential side-effects. In some cases it will also be possible to identify patients who have a higher risk of suffering side-effects, allowing them to be treated with less risky therapies. This approach to healthcare promises many benefits: • Patients and physicians will benefit by being able to make safer, more efficacious and more rational therapy choices. The reduction of uncertainty related to the potential of response or risk from adverse events will likely improve patient compliance, duration of therapy and the patient-physician relationship. • Healthcare systems will benefit by reducing the burden of administering therapies to patients who have little or no chance of deriving benefit and by reducing the impact of avoidable adverse drug reactions. Whether or not this will lead to net cost savings by healthcare systems is difficult to say, as they will have to incur the cost of testing in order to reap these benefits – but PHC does represent a more rational and cost-effective approach to healthcare. • Drug companies also see some clear benefits from the PHC approach. The more rational use of medicines and the potential benefits for patients, physicians and healthcare systems means that it will be difficult for drug companies to register and market therapies which do not follow this approach. In addition, the PHC approach will likely allow many therapies to be developed which would not otherwise be developable. There is insufficient data to tell us whether or not PHC approaches will make drug discovery and development more efficient, but there are clear indications of the benefits of this approach in certain therapeutic indications. The systematic implementation within the drug discovery and development process requires new skills, competencies, infrastructures and processes and deep insights into the likely viability of a PHC approach in the targeted healthcare setting. This makes PHC approaches more suitable to certain healthcare settings and therapeutic areas than others.
Preclinical models of drug-induced liver injury (DILI) are often not predictive of chronic liver pathologies in man. Even the most dedicated systems cover only the obvious endpoints such as necrosis, apoptosis, phospholipidosis and metabolic induced toxicity, leaving other mechanisms of injury uninvestigated. Furthermore, animal models often fail to predict DILI. The complexity of DILI with its multiple causes (idiosyncratic vs iatrogenic) and mechanisms involving cross-talk between many different cell types are the cause of this unpredictability. As a result it is difficult to identify populations who may be susceptible to DILI and DILI is often not identified until a drug has reached market, resulting in late-stage drug withdrawals. There is therefore a need for better DILI prediction. Identification of biomarkers to predict drug safety and efficacy and the development of an improved in vitro system which encompasses the multiple mechanisms of DILI are therefore essential and will be discussed in this session
Five years ago most scientists did not consider low molecular weight fragments (MW = 120-250) with correspondingly low binding affinities of only mM to uM to be attractive starting points for drug discovery programs. However, today there is widespread acceptance that these fragments can be progressed into nM lead series and on into clinical candidates. A detailed structural understanding of the binding interactions between the fragment and its target protein utilizing X-ray crystallography or NMR is critical. An example from Astex’s laboratories of a fragment derived compound that is in oncology clinical trials will be discussed
Dr Dean J Welsch
Research Fellow, Indications Discovery UnitPfizer Global Research and Development
USA
In 2007 Pfizer created an Indications Discovery Unit (IDU) to add value to their extensive portfolio of development compounds by identifying and advancing opportunities for these compounds beyond their initial indications. This cross-therapeutic area team quickly defined a system to identify additional indications that employs both serendipity- and knowledge-based approaches. In the year since its inception the IDU has delivered value in several areas, including new product opportunities as well as the development of novel enabling tools. Importantly, that the success of this endeavor is largely a result of the highly-integrated nature of IDU collaborations, both with internal Pfizer and external partners, will be described. This presentation will use specific examples to highlight the progress, challenges, lessons learned, and potential future directions.
Dr Berthold Bödeker
Head, Cell Culture and Pilot Plants, Global Drug Discovery - Biotech DevelopmentBayer HealthCare AG
Germany
In the context of higher clinical failure rates and increasing number of compounds for biologics such as i.e. monoclonal antibodies or leukine muteins it becomes very important to efficiently manage technical development activities including clinical material production. Several strategies including bench marks used by big pharma and biotech companies as well as suited for biotech SMEs will be summarized focussing on lean processes, particularly in the early phase to clinical proof of concept (PoC). The pro and cons of such modern “back-loaded” development approaches compared to the classical continuous or front-loaded development will be discussed in detail.
Organic growth towards a “single-stop-shop” partner where clients can satisfy most of their needs, including computational design, chemical synthesis, biochemical and ADMET/PK profiling, drove NiKem Research activities and ensured success in the past seven years. However, technology platforms are not per se enough to be successful; grey-haired, well-trained medicinal chemists do have a unique capacity to translate ideas into clinical development candidates with greater chances to survive through development. Add to this “in house” profile a sustainable “hybrid” proposition, exploiting competitors from Asian countries to provide a 40% discount on prices in a highly productive NiKem-driven, IP-secure and quality-respectful scenario.
2007 speakers included:
Biomarker-based assays are already helping to identify cancer patients who are likely to experience a recurrence or respond to a particular medication. The discovery and validation of novel biomarkers will lead to more innovative diagnostic tools as well as allow for more efficient drug discovery programs. As part of FDA’s Critical Path initiative to speed development of new biomarkers and therapeutics, the FDA has issued guidances and concept papers on biomarkers, pharmacogenomic data submissions, and drug-device co-development. This talk is intended to provide some U.S. regulatory perspectives on current and future issues related to the discovery and use of biomarkers in drug development and patient management.
Innovative is the core of pharmaceutical R&D, and thus the major driver of the industry’s contribution to global healthcare and growth. While investing in both organic growth and gaining access to external innovation will drive the discovery of differentiated medicines, additional strategies will be required. One such strategy is the repositioning of drugs that have been tested in the clinic and did not meet the intended clinical endpoints. These otherwise safe drugs and their corresponding targets can now be repositioned to address new disease indications. This can be accomplished by applying both wet-lab and in silico-based applications, such as genetics, genomics, systems biology and chemogenomics. In my talk, I will exemplify how we have accomplished this, in partnership with our Biotech partner, GeneLogic.
Dr. Lawson will speak about innovation at UCB and the approach that is being taken in research to ensure continuing pipeline productivity. Balancing novelty at the level of the therapeutic target, therapeutic axis and the drug structures themselves is at the heart of this strategy.
The development of recombinant DNA, large-scale cell culture technologies, advances in synthetic DNA and protein chemistry introduced a wide range of potential pharmaceutical products including cytokines, hormones, growth factors, and monoclonal antibodies for the diagnosis, prevention, and treatment of various diseases. Because of their complex structural and biological characteristics, different approaches to preclinical safety evaluation have been developed and in general, these approaches (i.e. case by case, science driven) have been successful. However, the adverse reactions experienced by the volunteers in the TGN1412 clinical trial prompted both industry and regulatory agencies to critically review the pre-clinical safety assessment as well as clinical practice for this clinical trial and in addition to review the ICHS6 guidance. The purpose of this talk is to present that analysis and to discuss how this event has impacted the pre-clinical safety assessment of biopharmaceuticals.
Metabolite profiling of biofluids and tissues has now achieved a considerable level of technical maturity, with analysis possible by a variety of different platforms. An advantage of metabolic profiling is that it enables the rapid determination of a subject’s metabolic phenotype, on readily accessed samples, allowing clinical interventions to be easily monitored. Practical difficulties encountered in humans included inter-individual variability and the difficulties associated with e.g. different diets etc. However, studies in animal models and human volunteers have demonstrated specific metabolic signatures for a range of diseases, and provided a firm foundation for ongoing study design for future clinical studies.
Small discovery companies (perhaps less than 100 employees), have a number of advantages over their larger counterparts. These can be summarised as fast decision making, empowerment and ownership at all levels of the organisation, ability to innovate rapidly and an obligation to succeed year-on-year. This creates a mindset focused on delivery and success, but absolutely requires freedom (to innovate), unhindered by large organisational bureaucracy. The major hindrance to such companies is they seldom have in-house expertise in all the disciplines required for successful drug discovery and development. This talk will be on how the focused small company, and its mindset, can be brought into larger R&D organisations, and how such a small unit can be successfully supported and complemented by R&D as a whole. Two models will be considered, the first being the purchase a small discovery company, and the second how to transform the silos within R&D into innovative research organisations
In the postgenomic era, recognition of the limitations of target-based drug discovery has led to the renaissance of a more holistic approach that involves the screening of test compounds for phenotypic changes elicited in mammalian cells and model organisms. This approach allows the identification of compounds with multiple cellular targets (‘polypharmacology’) and might better match the polygenic and multifactorial nature of many important diseases. The retrospective identification of the molecular targets underlying the observed phenotypic responses - termed target deconvolution – is important for elucidating biological mechanisms of disease and might also facilitate efficient progression of active compounds through drug development. The broad panel of experimental strategies applied for target deconvolution will be discussed
The development of molecularly targeted therapeutics has transformed drug discovery and development over the past 20 years. With this transformation come new challenges that were not as apparent in previous screening paradigms based on in vivo whole animal pharmacology. Approximately 50% of clinical candidates fail due to lack of efficacy or major safety hurdles. I will provide a number of examples of how these late stage risks can be mitigated by using a more holistic approach such as systems biology. Specifically, I will demonstrate the impact of an early cell based screen which predicts clinical hepatotoxicity and provide insight into how we can focus on efficacy early on in the value chain for the purpose of cytokine modulation in the context of inflammatory diseases.
Dr. Stefan Otto Mueller
Senior ToxicologistMerck KGaA
& Board certified and EUROTOX registered Toxicologist
Germany
Testing for the safety of a potential drug is a challenging task for the toxicologist in the pharmaceutical industry. The emerging new ‘omic-technologies have increased the possibilities but also the expectations to assess relevant and species-specific toxicities of drug candidates. Mueller will give examples on predictive models using global expression profiling. Furthermore, hepatocyte long-term culture models will be presented that have been successfully used to elucidate mechanisms of toxicities. These case studies exemplify how in vitro models can be used to extrapolate effects to humans and how ‘omic-technologies contribute to predictive toxicology.
Dr. Irina A. Antonijevic leads the Translational Research Group at Lundbeck Research USA with a focus on Depression and Anxiety. She will discuss the problems that the pharmaceutical industry faces today with regard to new drug development, particularly in Depression research. She will present how biomarkers can be used as a risk reduction strategy within drug development and also as a way to improve treatment outcomes in psychiatry. She will present some examples of how Lundbeck seeks to increase the odds of success in clinical development and what are critical prerequisites.
Drug discovery approaches can principally be grouped into target- and function-based approaches, where the aims, respectively, are to develop a target selective drug or a drug that produces a specific biological effect, irrespectively of its mode-of-action. Most analyses of drug discovery approaches focus on screening capacity and productivity, whereas the strategic implications of choice of drug discovery approach on market position and ability to maintain market exclusivity are rarely considered. However, a comparison of approaches from the market position perspective indicates that the functional approach may superior for the development of novel, innovative treatments.
Ark is a specialist healthcare group with operations in the UK and Kuopio- Finland. The development of Cerepro® started in the mid-1990s in Kuopio, under Professor Seppo Yla-Herttuala. Robert Shaw is Ark’s Technical Director, spending 70% of his time in Kuopio - Finland. Robert manages Ark’s gene-therapy product development, and the supply of Ark’s products. Dr. Minna Nokelainen is Ark’s Manufacturing Development Director, responsible for all aspects of process/analytical development and scale-up for Ark’s gene therapy applications. Robert and Minna will explain the development of Cerepro®, its control and state of regulatory review with EMEA. Cerepro® has been submitted to the EMEA under the CTD procedure and the supply of product to a phase 3 clinical trial has now completed.
Despite rigours preclinical and clinical examinations drug induced liver injury is an unresolved problem and the most common reason for drug withdrawal from the market. In fact, drug induced liver injury accounts for more than 50% of the cases of acute liver failure in the US today. Serious limitations in our current knowledge on mechanisms of hepatotoxicity hampered the development of suitable test systems and an identification of individuals at risk of suffering undue drug effects. Medical progress in an understanding of drug induced liver disease has been achieved through application of genomic sciences. In my presentation I will focus on the pathogenesis and clinical consequences of drug induced liver injury and will discuss two prominent examples to illustrate the power of the new approaches in rational drug development as to prevent undue toxicity of drugs.
Drug-induced liver injury (DILI) is the most common reason why drugs are not approved or are removed from the market after they have been approved (http://dilin.dcri.duke.edu/). Jinghai (Jim) Xu and colleagues applied systems biology approaches to predict drug-induced hepatotoxicity. Using text mining, researchers constructed a database of both marketed and “safe” drugs and those that failed mainly due to toxicity reasons. Using a combination of high content biology and primary cells, they have assembled an experimental database that is rich in toxicological and pharmacokinetics context. Using multivariate analysis, the researchers derived a decision-tree algorithm that can identify a significant number of toxic drugs with minimal false positives. The result is a rational approach towards early toxicity screening and prediction, and a significant return on investment. They are now applying this systems biology approach in other areas of drug-induced toxicity.
Cellular Technology Limited (CTL) has been providing contract research services to government laboratories, major pharmaceutical companies, and academic institutions for nearly a decade. Based on its strong academic roots, CTL established the scientific foundations for introducing ELISPOT analysis as a T cell diagnostic tool, including the development of the first automated ELISPOT reader system. CTL pioneered the transition of the ELISPOT technology from a basic research tool to a GLP compliant immune monitoring technology. The U.S. Food & Drug Administration (FDA) has recently encouraged the use of ELISPOT for immune monitoring. In its relative short history, CTL has been chosen repeatedly to serve as a reference laboratory, including the Immune Tolerance Network, and currently, the Sabin Vaccine Institute's Cancer Vaccine Consortium. In addition, we have been awarded multiple contracts by the U.S. National Institutes of Health (NIH) for the development and validation of human and animal models for infectious diseases and BioDefense applications. Furthermore, CTL has optimized, qualified, and validated test methods for its clients in various test systems, including, but not limited to human, monkey, mouse, rat, rabbit, and pig. This has provided CTL a wealth of expertise encompassing a wide range of assay types in a regulated and non-regulated environment, and high throughput mode.
Ark is a specialist healthcare group with operations in the UK and Kuopio- Finland. The development of Cerepro® started in the mid-1990s in Kuopio, under Professor Seppo Yla-Herttuala. Dr. Minna Nokelainen is Ark’s Manufacturing Development Director, responsible for all aspects of process/analytical development and scale-up for Ark’s gene therapy applications. Robert and Minna will explain the development of Cerepro®, its control and state of regulatory review with EMEA. Cerepro® has been submitted to the EMEA under the CTD procedure and the supply of product to a phase 3 clinical trial has now completed.
Mammalian cell line expression systems are currently the most important workhorses for the expression of glycosylated biopharmaceuticals such as monoclonal antibodies (mAbs). Looking back over the last two decades, target biology, product quality and improvement of yield have been the main drivers for improvements in biopharmaceutical production. Overall a significant progress in such fields have been documented. During the past six years the development speed as a new driving force for innovation has emerged. However, regardless of which strategy is followed, cell line development still takes 30-50 % of the overall time necessary to prepare the first clinical material. Therefore, there is still a strong need to further shorten the timelines. The presentation will outline different opportunities to improve development time lines for glycosylated proteins.
Quintiles have conducted more First in Man and Exploratory Medicine studies than any other CRO. They are proud of the way trials are conducted, their volunteer safety record, quality and the speed of our delivery. Quintiles has unrivalled experience in First Dose in Man studies with over 250 New Chemical Entities (NCEs) and Biologics investigated. They have conducted over 700 Phase I/IIa development studies in the last 7 years across 18 therapeutic areas, so have learnt a lot about the potential pitfalls companies may face and potential strategies to counter them.
Imaging biomarkers applied effectively can dramatically increase the efficiency of the drug development process. These biomarkers can be used to accurately assess target engagement and for advanced PK/PD modeling in both pre-clinical and clinical studies. Nevertheless, translating pre-clinical results to clinical trials is one of the biggest challenges in drug development. Of key importance to successfully bridge the gap is to minimize the difference between the two stages. Therefore, the development of a consistent imaging protocol and a single set of biomarkers in preclinical and clinical studies will greatly increase the chances of a smooth transition. This workshop session discusses decisions that need to be made when incorporating non-invasive imaging to improve the transition from pre-clinical to clinical.
Imaging biomarkers applied effectively can dramatically increase the efficiency of the drug development process. These biomarkers can be used to accurately assess target engagement and for advanced PK/PD modeling in both pre-clinical and clinical studies. Nevertheless, translating pre-clinical results to clinical trials is one of the biggest challenges in drug development. Of key importance to successfully bridge the gap is to minimize the difference between the two stages. Therefore, the development of a consistent imaging protocol and a single set of biomarkers in preclinical and clinical studies will greatly increase the chances of a smooth transition. This workshop session discusses decisions that need to be made when incorporating non-invasive imaging to improve the transition from pre-clinical to clinical.
As Vice President Imaging Technologies, Bioscan Inc., Dr. Haemisch is responsible for the technological development and enhancement of Bioscans Pre-clincial Imaging product line. After receiving his Ph.D. in solid state physics from Wuerzburg University Dr. Haemisch started his career in 1993 with General Electric Medical Systems as the Product Manager for PET in Europe. In 1997 he was hired by ADAC Laboratories and later became Global Product Manager for PET at their headquarters in Milpitas, California. Already during that time he started to investigate the possibilities of applying medical imaging technology to fundamental biological and drug research. When ADAC got acquired by Philips Medical Systems in 2001, Dr. Haemisch started a pre-clinical instruments product line at Philips. During this time he also concluded his studies as an Executive Masters of Technology Management at Wharton School/University of Pennsylvania. In June 2006 he joined Bioscan Inc. in order to fully focus on pre-clinical imaging technology. Dr. Haemisch also co-authored several books on imaging technology.
