Drug discovery - Articles and news items
Industry news, News / 19 March 2013 / InvivoSciences Inc.
Torrey Pines Institute for Molecular Studies (TPIMS), a non-profit research institution and leader in advanced methods of drug discovery, and InvivoSciences Inc., an innovative company providing screening for first-in-class drug discovery, announced today a new collaboration to accelerate drug discovery in cardiac disease. Under the terms of the agreement, Torrey Pines Institute will work with InvivoSciences to screen the TPIMS collection of compounds in InvivoSciences’ 2012 Edison Award winning assay system. Financial terms of the deal were not disclosed. (more…)
Issue 6 2012 / 18 December 2012 / Terry McCann, TJM Consultancy
The average cost to a major pharmaceutical company of developing a new drug is over USD 6 billion1. Herper1 observes that the pharmaceutical industry is gripped by rising failure rates and costs, and suggests that the cost of new drugs will be reduced by new technologies and deeper understanding of biology. While the objectives of drug discovery don’t change, the methods and techniques by which pharmaceutical companies, biotechs and academia discover new drugs are evolving at a significant pace – and they need to.
Drug discovery scientists are all aiming to identify compounds and candidate drugs with ‘good’ properties that are safe and efficacious, as quickly and cheaply as possible. The standard approach of the last 20 years has been to identify a single molecule disease target, and then to identify a compound that interacts with and modulates this target with high specificity. However, there is now a growing realisation that this ‘one target – one drug’ approach doesn’t work well, and that screening huge libraries of compounds against one particular property of an isolated target is an inefficient way to discover potential drugs. Much of the innovation currently seen in drug discovery methodologies seeks to access and integrate more information – about targets, compounds, and disease phenotypes – to enable a more comprehensive and holistic approach to discovering ‘good’ drug candidates. This article does not try to crystal ball-gaze deep into the future, but rather to identify those trends in the adoption of new technologies and approaches that are gaining traction now, and that can be expected to become more prevalent in the next two to three years. (more…)
Issue 6 2012 / 18 December 2012 / D. Lansing Taylor, Director, University of Pittsburgh Drug Discovery Institute and Allegheny Foundation Professor of Computational and Systems Biology, University of Pittsburgh School of Medicine
The pharmaceutical industry has experienced a decade of turbulence driven by the ‘patent cliff’ as major revenue generators are lost to generic status, coupled to the absence of a sustainable pipeline of drug candidates in development that have a good chance of being approved and launched1,2. It is generally agreed that the lowest hanging drug discovery ‘fruit’ has been harvested and the industry is addressing diseases that are more complex. The current one target, one drug discovery and development paradigm continues to exhibit more than 90 per cent attrition mainly due to the lack of success in translating preclinical efficacy and safety data into successful human trials1. It has also become clear that efficient drug discovery and development requires a deeper understanding of the complexity of human biology early in the process3. The high attrition rates increase the costs and with the science indicating that precision therapeutics will replace the blockbuster model4, the challenge of drug discovery and development is even greater. The traditional business model of pharmaceutical companies working in silos is no longer sustainable.
A new vision of strategic collaborations
However, there is a new vision where strategic collaborations between pharmaceutical companies, government agencies, venture capital-backed biotechnology companies and academic medical centres will create a new breadth of approaches that have a good chance of increasing the innovation that has been stagnant in recent years5-8. Government funding agencies are increasing the emphasis on translational research, even in a period of funding pressures. (more…)
Issue 6 2012 / 18 December 2012 / Matthew A. Cooper and Reena Halai, Institute for Molecular Bioscience, the University of Queensland
In the journey of a molecule from its origins in a compound library to candidate drug status, a large variety of profiling must occur to define activity, selectivity, potency, adverse effects, pharmacology and in vivo efficacy. Advances in biophysical methods that can analyse drug interactions with a molecular target, a whole cell, or even ex vivo tissue have enabled many of these studies to be carried out without the need for reporter-based or ‘labelled’ assays. Label-free screening in high-throughput mode can be used as a pathway independent screening tool with whole cells, or in low-throughput mode with individual receptors to define interaction kinetics and thermodynamics. We highlight advances in optical and impedance-based biosensors, and examine their utility and suitability for various stages of the drug discovery process.
In the early to mid 20th century, drug discovery was a far more productive industry, and more drugs were launched per Pharma employee than today. The regulatory pathway that pre-empted the launch of a new drug was concise and easy to understand, and applications were dealt with expeditiously with a fraction of the supporting data required today. The process of discovery was also very different; it was driven largely by individuals in small teams who were prepared for serendipity, or by individuals with a very clear, defined hypothesis who drove rational drug design. Screening technologies could be summed up on one or two pages of a review; a dozen or so primary assays, some basic biochemistry to define ligand mode of action, perhaps some live cell work and a proof of concept demonstration in vivo. (more…)
Issue 6 2012 / 18 December 2012 / Sheraz Gul and Gesa Witt, European ScreeningPort GmbH
The histone deacetylase (HDAC) class of enzyme are a group of conserved enzymes known for their ability to remove acetyl groups from lysine residues on histone tails. Since aberrant HDAC enzyme expression is observed in various diseases, there is increasing interest in finding small molecules which function as HDAC enzyme inhibitors. This article reviews the various biochemical assays available for monitoring HDAC enzyme activity that have been validated for use in High Throughput Screening. The assays referred to are compatible with standard microtitre plates (96 and 384 well format) and make use of absorbance, luminescence and fluorescence detection methods.
The histone deacetylase class of enzymes
The histone deacetylase (HDAC) class of enzymes are involved in many biological pathways1 and one of their best known properties is their ability to remove acetyl groups from lysine residues on amino-terminal histone tails2-4. Thus far, 18 HDAC enzymes have been identified which are divided into zinc dependent and NAD dependent enzymes5. The Class I HDAC enzymes include the zinc dependent HDACs 1, 2, 3, and 8 and consist of 350-500 amino acid residues6. The Class II HDAC enzymes are also zinc dependent but are larger, consist of about 1,000 amino acid residues7 and are subdivided into Class IIa (HDAC4, 5, 7, and 9) and Class IIb (HDAC6 and HDAC10) enzymes. The Class I and Class II HDAC enzymes can be inhibited by trichostatin A (TSA)8,9 and this inhibitor is often used as a reference to bench-mark their assays. The Class III HDAC enzymes are the sirtuin enzymes (SIRT1-7) and are NAD-dependent1,10. This class of enzymes is not sensitive to TSA but can be inhibited for example by nicotinamide. (more…)
Issue 5 2012 / 22 October 2012 / Bahija Jallal, Executive Vice President, Research & Development, MedImmune
The first biologic drug – infliximab (Remicade) – was launched in 1998 with initial sales of USD 500 million per annum. By 2010, Reuters’ top 10 drugs by sales included five biologics (Remicade, Enbrel, Humira, Avastin and Humira) generating around USD 34 billion in revenue, including USD 7.4 billion from Remicade1. Reuters have predicted that by 2014, these five will be joined in the top 10 by Herceptin, that their combined sales will be USD 47 billion per annum and that the three top-selling drugs in the world will be biologics1. It is fair to say then that biologics are transforming the landscape of the pharmaceutical industry – but how and why have these complex molecules achieved this?
Actually, the answer to the ‘why’ question is quite straightforward. They are safer and efficient in their target populations and their target populations are sometimes quite large and other times represent ‘new’ populations for therapy (i.e. there are no current therapeutic options for those patients). These factors combine to make biologics an attractive proposition for big Pharma.
Biologics are genetically-engineered proteins that mimic natural components of the immune system – including T-cells, interleukins, growth factors and interferons – and are highly specific for their targets. (more…)
Issue 4 2012 / 3 September 2012 / Pradeep Sharma and Katherine Fenner, Global DMPK, AstraZeneca R&D
Physiologically based pharmacokinetic (PBPK) models describe the different compartments (tissues) in the body linked via arterial and venous blood flow (Figure 1). The volume of each tissue and blood flows are available from literature data1-5 and PBPK models have been developed for many species including rat, mouse, dog, pig and human2,6,7. PBPK models can be applied to many aspects of the drug develop ment continuum, from drug discovery8 and into development including use in regulatory responses9.
PBPK modelling is becoming a tool of choice in the pharmaceutical industry for the prediction of pharmacokinetic parameters, drugdrug interactions (DDI) and tissue distribution from in vitro data. PBPK modelling was able to become a mainstream tool in the pharma – ceutical industry with advances in in vitro metabolism techniques along with the ability to predict tissue distribution parameters or Kp values for a number of classes of compounds10-13. These models usually assume that the liver and kidney are the only organs where elimination occurs and that blood flow to these organs limits the excretion rate. Recently, with advances in in vitro techniques to study transporter proteins, the input of these data in PBPK models is becoming more commonplace. (more…)
Issue 4 2012 / 3 September 2012 / David Cook & James Milligan, AstraZeneca
Ensuring patient safety during clinical trials is of paramount consideration with stringent monitoring built into trials (and beyond) and the design and interpretation of safety outcomes subject to a large amount of regulation. As a result, it is rare for clinical trials to produce extreme adverse drug reactions but it is also quite common for new medicines to fail in clinical testing due to unacceptable patient safety within a given indication. This is because once a new drug reaches clinical testing, its safety profile is already ‘locked in’, and clinical testing can only discover issues that already exist. The ideal way to ensure the safety of patients is to only progress new medicines into clinical testing which do not have unacceptable safety or tolerability issues. However, to reach this ideal means using learning in the clinic to influence design and development in the laboratory. In this short article, we discuss the practical challenges in doing this and in ‘translating’ patient safety observations such that they can impact on drug design and early development.
The safety of the patient is a paramount consideration during the development and clinical testing of new drugs. Early clinical trials are set up to carefully consider the safety and tolerability of new pharmaceuticals and patient monitoring for safety continues throughout the later clinical testing phases and beyond. Prior to this, new pharmaceutical agents are subjected to a battery of preclinical tests and must overcome strict safety hurdles before a single patient receives a dose. (more…)
Issue 4 2012 / 3 September 2012 / Vikash Sinha, Clinical Pharmacology Leader, Janssen Research and Development
One of the important goals in preclinical and early clinical drug development is to reduce attrition rates and to improve our ability to pick winners and drop potential loser drug candidates. By being able to efficiently translate preclinical data and observations into possible clinical outcomes, one can make the drug development process more cost-effective. Identifying preclinical models – in silico, in vitro, in vivo – or assays that can best predict clinical observations is not trivial. It requires understanding of preclinical-to-clinical correlations and the success of translational science may vary depending on the therapeutic area where one is working. For example, anti-infectives or cancer therapeutic areas have validated biomarkers which can be useful in selecting the right drug candidate in early drug development.
However, it is extremely challenging to translate the preclinical pharmacological models into clinical signals for drugs in the neuroscience area. Selection of drug candidates with optimal pharmacokinetic (PK) parameters in early drug discovery is essential for convenient dosing regimens and effective therapy in patients. During drug discovery, considerable resources are required to assess the PK properties of potential drug candidates via in vivo and in vitro preclinical studies. (more…)
Issue 3 2012 / 10 July 2012 / Paul C. Guest, Department of Chemical Engineering and Biotechnology, University of Cambridge and Sabine Bahn
Department of Chemical Engineering and Biotechnology, University of Cambridge & Department of Neuroscience, Erasmus Medical Centre
Pharmaceutical companies are under increasing pressure to improve their efficiency and returns on drug discovery projects. This is a daunting task considering that the average drug costs approximately one billion US dollars to develop and takes around 12 years from initial discovery to reach the market1. In addition, approximately 70 per cent of drugs fail to recover their research and development costs and around 90 per cent fail to provide a satisfactory return on investment. Therefore, minimising risk is one of the most important aims in pharmaceutical discovery programs today.
There are now efforts to establish standard operating procedures to navigate through these problems and, at the same time, meet the regulatory demands. To facilitate this process, the regulatory health authorities have encour aged the incorporation of biomarkers into the drug discovery pipeline and the Food and Drug Administration (FDA) has called for efforts to modernise and standardise approaches for the delivery of more effective and safer drugs2.
Proteomics is the most applicable tech – nology for implementing biomarker app – roaches in drug discovery given that virtually all existing drug targets are proteins3. Proteomics is a systems approach for the global study of protein expression changes4. (more…)
Issue 2 2012 / 26 April 2012 / Luigi La Vecchia, Director of the Preparations Laboratories, Novartis Institute for Biomedical Research
In 2002, Novartis decided to create a new research centre in Cambridge, MA. This was accompanied by a significant increase in headcount in medicinal chemistry. Within two years, this resulted in a strongly increased demand for prep-scale synthesis which in turn led to priority issues and to prolonged turnaround times due to lack of resources in our Preparations Laboratories. In order to debottleneck time critical scale-up activities, the Preparations Laboratories was asked in 2004 to introduce outsourcing as an alternative option to an in-house increase of headcount.
Regarding the selection for outsourcing of projects, the following selection criteria should apply:
- ‘Easy’ projects with a good chance of success, i.e. well documented and few process steps
- Shorter time for critical requests
- Non-critical projects with regard to proprietary situation, giving us better control of quality and protection of know-how
In order to differentiate the individual com – panies from each other, the evaluation criteria outlined below were applied: (more…)
Issue 2 2012 / 26 April 2012 / Jayshree Mistry, Paul Lloyd, Kevin Oliver and Peter North, GlaxoSmithKline R&D and Duncan Judd, Awridian
This article describes the evolution of outsourcing within early drug discovery at GlaxoSmithKline (GSK), specifically for chemistry services applied to developing a compound from the screening hit through lead optimisation. It will touch on different business models, factors to consider when selecting potential CROs, the benefits of outsourcing and CRO management.
Although pharmaceutical companies have always outsourced some of their activities, the outsourcing of drug discovery research (Figure 1) has grown significantly over the last 10 years.
The enabling factors include a vast improvement in global communications, an opportunity to access talent outside of big pharma and to an increasing number of signatories to Trade Related aspects on Intellectual Property Rights (TRIPS). It is well recognised that drug discovery research is a costly and risky endeavour, estimated to be USD 800 million of the USD 1.8 billion cost of a new chemical entity1. There are many factors that can contribute to reducing these costs: reducing cycle times, minimising late stage failures and making better decisions are imperative, however the use of external flexible resources can also provide significant cost savings. Although outsourcing can facilitate drug discovery research outside of established pharma structures, it needs to be well managed to succeed. (more…)