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Humanised Studies

As personalised medicine grows in importance, we look at the possibility of using fresh, functional human tissues, and the potential of it better predicting drug safety and efficacy in R&D.

It has been 12 years since the term ‘personalised medicine’was coined following the mapping of the human genome; however, with exception of a small number of cancer therapies, the expected flow of drugs has not yet materialised. Pharmacogenomics now appears to represent only a part of the process towards achieving this goal and having moved towards proteomics on the assumption that protein expression – not gene expression – is the key factor determining drug sensitivity, is a critical part of the picture being missed once again? A true prediction of drug effects in individual patients, for the majority of diseases and chronic ailments, will require investigations that stretch from genomic level through to detailed human pharmacology at the organ/system level.This article will examine whether the next 10 years could see the use of fresh, functional human tissues playing a greater role in predicting human safety and efficacy as part of a stratified medicines approach.

Human Tissue Research in Drug Development

Pathology departments have been storing tissue specimens since the 1800s; however, it wasn’t until mid-1980s before ‘tissue banking’ really took off, and since the year 2000 there has been an explosion, both in the number of banked samples and the number of organisations collecting, storing and processing such samples. Biobanks even made Time magazine’s list of the top 10 influential technologies of the next decade (1).The pharma industry, however, has only just started to view human tissues as something greater than a tool to aid target discovery and validation.The increased emphasis on the use of biomarkers in decisionmaking means that the collection and analysis of human tissues remains important through lead selection and optimisation; can involve functional demonstrations of human efficacy and safety using living tissues during preclinical studies; and continues into the clinic with biopsies and serum biomarkers allowing longitudinal validation for both commercial and regulatory purposes.

The increased importance of such human tissues to decision-making is also apparent from demands for improved specimen quality and standardised collection procedures. Since the National Cancer Institute flagged up concerns in 2006 about the wide range of protocols and practices employed in obtaining and storing tissue samples, efforts have accelerated on this front and many countries have implemented legislation that clarifies procedures for tissue collections (2).

The earliest successes have been in cancer, where human tissue research has been of great importance for many years, for example, in the development of trastuzumab (Herceptin, Genentech) that targets breast cancer cells overexpressing the HER-2 gene. Key to the success of this discovery was the link between a poor prognosis for patients with breast cancer and the presence of HER-2 over-expression, which occurs in only 20 to 25 per cent of breast cancers. More recently, Amgen used a biomarker strategy to identify that Vectibix was effective only in the 60 per cent of patients without a mutation of the KRAS gene. These examples highlight the benefit of better target selection as part of a stratified medicine approach.

Drivers for the Increased Use of Human Tissues

Since Kola and Landis published their landmark review of clinical attrition rates in 2004, which highlighted that lack of efficacy was the greatest cause of clinical failure, Phase 2 attrition rate has barely improved (3). A more recent and insightful analysis by Paul et al has demonstrated that Phase 2 and 3 attrition rates actually appear to be increasing, as new drug targets are pursued and greater risk-benefit ratios are demanded by regulators (4). They calculated that, based on an average cost-to-market for a new chemical entity (NCE) of $1.78 billion, a reduction in Phase 2 attrition rate from 66 to 50 per cent would reduce the average cost to around $1.28 billion; unsurprisingly, new predictive methods are urgently being sought (4).

Perhaps the greatest reason cited for the high Phase 2 attrition rate is an over-dependence on animal models of disease, which, in turn, is driving a search for human tissue samples that more accurately reflect the human disease and can be used in predictive tests of drug efficacy. In simple terms, human tissue-based data will drive decision-making, and if the strategy proves successful, it will drive down Phase 2 attrition and lead to a plateau in the spiralling costs of drug development. 



Fresh Human Tissues Predict Efficacy and Safety

Figure 1 shows the process by which fresh, functional tissues can be used in non-clinical pharmacokinetic and pharmacodynamic (PK/PD) studies. Tissues are obtained from surgery, transplant networks, or in some cases, post mortem; where the post mortem interval is sufficiently short. Such tissues are not in short supply; however, it is a major challenge to achieve the necessary patient consent, collection and distribution of tissues in a timeframe to allow rapid analysis while the tissue remains viable, and therefore such operations are often active 24/7 to run experiments at short notice. Nonetheless, the power of such data lies in the translation to clinical parameters, for example in vitro measures of the vascular component of blood pressure regulation, inotropic effects on the heart, and measurements of gastrointestinal permeability. The studies resemble a small clinical trial: patients are ‘recruited’ by defining the acceptance criteria for tissue specimens and comparisons can then be made between different patient groups. Groups of patients identified during target validation can then be followed into functional studies during lead optimisation or preclinical safety studies.

Moreover, longitudinal studies using clinical biopsies can follow the same biomarkers into Phase 1 and 2 studies to support proof-of-concept. Perera et al tracked the beneficial effects of hormone-replacement therapy on microvascular function using in vitro measurements of endothelial responses in resistance arteries isolated from gluteal biopsies (5). Comparisons were made between control subjects (where endothelial responses are normal) and women with type 2 diabetes (where endothelial responses are compromised) before and after receiving six months of continuous combined hormonereplacement therapy (HRT), after which endothelial responses were restored to control levels.This powerfully highlighted the beneficial vascular effects of the treatment that would not have been picked up simply from measurements of mean arterial blood pressure.

A similar process can be followed in other organs and tissues; for example, for investigations in psoriasis, skin biopsies created from residual surgical skin can allow up to 60 test conditions in a sample from a single patient. This allows testing of various compounds or formulations for efficacy and absorption such as cytokine production and epidermal hyperplasia (see Figure 2). The same protocols can then be conducted in a smaller number of biopsies obtained from patients with psoriasis, bridging the gap between non-clinical and clinical studies.



Conclusion

Fresh, functional human tissues are likely to become a valued part of the drive towards personalised medicine by better prediction of drug safety and efficacy in discrete groups of patients.The full benefit of such functional tests will be realised when they are combined with the current uses of static human tissues to improve both target selection and non-clinical proof of efficacy and safety.

References

  1. Parks A, Biobanks – 10 ideas changing the world
  2. Hede K, New biorepository guidelines raise concerns, JNCI 98 (14): pp952- 954, 2006
  3. Kola I and Landis A, Can the pharmaceutical industry reduce attrition rates? Nature Reviews Drug Discovery 3: pp711-715, 2004
  4. Paul SM et al, How to improve R&D productivity: the pharmaceutical industry’s grand challenge, Nature Reviews Drug Discovery 8: pp203-214, 2008
  5. Perera M et al, Hormone replacement therapy can augment vascular relaxation in postmenopausal women with type 2 diabetes, Human Reproduction 17 (2): pp497-502, 2002

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David Bunton is co-founder and CEO of Biopta Ltd. After graduating from the University of Glasgow with an Honours degree in Physiology, he undertook a PhD in Pharmacology at Glasgow Caledonian University, which led immediately to his appointment as a Lecturer in Physiology and Pharmacology. David was also a consultant to the Diabetes Education and Training Unit at Glasgow Caledonian and has numerous publications in respiratory and vascular pharmacology, including a number of reviews on the state of the art in human tissue research. He is a member of the British Pharmacological Society and Safety Pharmacology Society, and is an active contributor to the drive towards greater use of human tissues in drug development having co-organised the 2009 human tissue conference at the House of Lords. Email: davidbunton@biopta.com
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