Ann. N.Y. Acad. Sci. ISSN 0077-8923

ANNALS OF THE NEW YORK ACADEMY OF SCIENCESIssue: Animal Models: Their Value in Predicting Drug Efficacy and Toxicity

Have animal models of disease helped or hinderedthe drug discovery process?

Ann Jacqueline HunterOI Pharma Partners Ltd. Weston, Herts, United Kingdom

Address for correspondence: Ann Jacqueline Hunter, Ph.D. OI Pharma Partners Ltd, Red Sky House, Fairclough Hall, HallsGreen, Weston, Herts SG4 7DP, UK

Animal models have played an important role in target validation, screening of compounds for efficacy andoptimization of pharmacokinetic properties and toxicological testing. However, new paradigms for drug discoveryand development will require a greater emphasis on animal models of mechanism.

Keywords: drug discovery; preclinical models

Over the past decade there has been a realizationthat the current model for drug discovery and de-velopment is becoming more unsustainable. This isreflected in the fact that the costs of drug discoveryand development have doubled over the past decade,yet new medicine approvals have remained static.The major reasons for compound failure are lack ofefficacy in patients and unexpected toxicity.1,2 Thefailure of positive data in animal models of diseaseto translate into meaningful data in the clinic hasled researchers and others to question the validity ofthese models. This has been especially true for areassuch as the central nervous system (CNS), where an-imal models are perceived to be less predictive of thehuman condition, although recent data on failuresin phase II trials across therapeutic areas does notnecessarily show that the CNS is worse than someother therapeutic areas.3

In the past, many of the animal models that pre-dicted the efficacy of compounds in the clinic weresymptomatic in nature, for example, models wherethe effects on blood pressure were measured, andchemically induced seizures in normal mice wereused to study the effects of anti-convulsants. Diseasemodels did exist, such as those for cancer, strokeand pain, and these were used for screening, al-though they were not necessarily more predictivethan the symptomatic models. With the advent ofthe completed human genome sequence, there wasan enormous rise in the number of genetic models

of disease, primarily in mice, as well as a focus ondeveloping new models of disease based on humanphysiology. However, these advances in model de-velopment have not made a significant increase inimproving the rate of success in phase II proof-of-concept studies. So what can we do to better utilizeanimal models to develop new medicines, especiallyfor the treatment of complex diseases?

There are actually very few models of human dis-ease in animals that faithfully reproduce all aspectsof the human pathophysiology and symptomatol-ogy. This is not surprising, as most human diseasesare highly heterogenous. There are many good mod-els of particular aspects of a disease, for example, anindividual pathological feature or symptom. Thisdoes not devalue a model, providing the limita-tions in terms of extrapolating any findings to thewhole patient population are recognized and ac-knowledged. An example is the G39A SOD trans-genic mouse model of ALS, which uses a mutationthat is responsible for only a very small percentageof ALS patients.4 Although the model is relativelyrapid and mimics the symptomatology and someaspects of the pathology, key pathological changesare missing. Even with this very specific model, thereare important differences between laboratories interms of measurements, reproducibility and drugeffects. Significant variability between experimentswithin a lab can also occur, and positive effectsin this model have failed to translate into clinical

doi: 10.1111/j.1749-6632.2011.06375.xAnn. N.Y. Acad. Sci. 1245 (2011) 1–2 c© 2011 New York Academy of Sciences. 1

Animal models and drug discovery Hunter

benefit.5 Perhaps of greater concern is thatmolecules that failed to work in this ALS modelhave not progressed to the clinic, and this is alsotrue in other areas where there is great variability inthe disease models, for example, multiple sclerosis(MS).

For all disease models, whether surgically or phar-macologically induced or genetic, there needs to beclarity around the pathology that is being modeledin the animal and how it relates to the human condi-tion. For example, in stroke research the ability of adrug to produce neuroprotection relies on the strokemodel having sufficient collateral blood flow in thecompromised infarcted area for the compound to beable to reach the cells and halt cell death. Likewise,such neuroprotective compounds should only betaken into clinical populations where there is a per-fusion/diffusion mismatch, that is, in patients whohave a compromised area that is still salvageable.6

It is also important that the right molecules aretaken into the clinic—some failures that have beenattributed to a failure of a particular animal modelmay actually have been due to the fact that the com-pound tested clinically had not been demonstratedfor target exposure, target engagement, and/or phar-macological activity at the target. Where there is of-ten little or no agreement across researchers aboutwhich is the most appropriate animal model for adisease, it can be hard to estimate the required ex-posure at the target for activity based on the diseasemodels. This is because the concentrations (expo-sures) of a compound in preclinical models requiredfor efficacy can differ across the various models used,even when these models are carried out in the samelaboratory. This complexity makes it difficult to ex-trapolate the exposures necessary for efficacy in hu-man patients.7

With the advent of more target validation in hu-mans through genetic and other studies, it is timelyto embrace new models of drug development: oneswhere animal models still play a key role, but wherethere is more focus on animal models of mecha-nism, rather than animal models of disease. Whatdo I mean by a model of mechanism? For example,if a compound is thought to have potential in MS,say via blocking the influx of leukocytes into the

brain and hence suppressing neuroinflammation,then demonstrating that the compound causes thisblockade in animals might alone be sufficient forprogression to humans. Demonstrating that suchblockade of influx happens in phase I studies in theclinic should give confidence to move the moleculeinto phase II studies. Hence, would there be anyneed to show an effect in the mouse experimen-tal autoimmune encephalomyelitis (EAE) model ofMS? Such a mechanistic approach is frequently usedwith antibodies where there is no activity at therodent target, as there are few primate models ofdisease. Ideally, the focus should be on developingmechanistic in vivo assays that can be translated tohumans—assays that can demonstrate that a com-pound affects the target mechanism, give an un-derstanding of the exposures required for efficacyon the mechanism, allow comparison of pharma-codynamics with pharmacokinetics, and hopefullyadvance molecules to the clinic more rapidly.

Conflicts of interest

A.J.H. is an ex-employee and shareholder of Glaxo-SmithKline PLC; a nonexecutive director and share-holder with Proximagen Group PLC; and CEO andowner of OI Pharma Partners Ltd.

References

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2. Paul, S.M., D.S. Mytelka, C.T. Dunwiddie, et al. 2010. Howto improve R&D productivity: the pharmaceutical industry’sgrand challenge. Nat Rev Drug Discov. 9: 203–214.

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4. Montes, J., C. Bendotti, M. Tortarolo, et al. 2008. Translationalresearch in ALS in Animal and Translational models for CNSdrug discovery, Vol 2. R.A. McArthur & F. Borsini, eds.: 267–297. Academic Press.

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7. Valenzanoa, K.J., L.G. Tafesseb, G. Leeb, et al. 2005. Pharmaco-logical and pharmacokinetic characterization of the cannabi-noid receptor 2 agonist, GW405833, utilizing rodent modelsof acute and chronic pain, anxiety, ataxia and catalepsy. Neu-ropharmacology 48: 658–672.

2 Ann. N.Y. Acad. Sci. 1245 (2011) 1–2 c© 2011 New York Academy of Sciences.