Principles of Translational Medicine: relationship between...

transcript

Principles of Translational Medicine:

relationship between animal and

human pharmacology

Compiled by: Endre Mikus PhD, CEO

Budapest, 21/10/2017

Outline

Definitions

Pre-Translation Medicine

Early Translational Medicine

Trends in recent Translational Medicine

Examples

Special aspects of biologics

Translational Medicine

Definition

„There is no clear definition of

translational medicine; it means

different things to different people.”

https://www.eupati.eu/non-clinical-

studies/translational-medicine/

Definition

„funding priorities that

emphasized multi-

disciplinary and trans-

disciplinary approaches

to translating discoveries

in one research paradigm

to another, ultimately

leading to improved

health outcomes.”

http://mscti.med.miami.edu/program/what-is-translational-research/

Pre-Translational Medicine

efficacysafety

Pre-Translational Medicine

Treat the symptoms with new drugs

Few disciplines: basic/applied/clinical

science not separated

Few and symptom similar animal models

Simple human trials

Not too much emphasis on toxicology

Easy registration

Disease=symptoms

The similarity in biology and symptoms

between the animal model and the human

disease.

The preclinical animal models predict

well drug effect on human:

Efficacy

Side effects/unwanted effects

Toxic effect.7

Old „paradigm” of pharmacology

„An animal sufficiently like humans…”

Assumption

Only few players e.g. doctors, chemists

Few disciplines

Common language, easy communication

Simple organisation chart

Low cost high return

Original PlayersPre-Translational Medicine

Outcome

New, effective natural origin

and synthetic drugs

Everybody was quite

happy with the

outcome. Until...

A bit later on...

Turned out

Efficacy is not enough

Safety is first

More tests and More investment

More disciplines More players

No more common language

Difficult communication

Concomitant

Serious cost increase in drug R&D

and hight attrition rate

.13 https://books.google.hu/books?id=fNMcCwAAQBAJ&pg=PA9&lpg=PA9&dq=drug+r%26d+disciplines+1960&source=bl&ots=IjMMzjgX-

y&sig=taA7ByYFJSy1hkHFLXvip5hk18U&hl=hu&sa=X&ved=0ahUKEwiv4ei4143XAhXJblAKHdFmC_MQ6AEIRjAG#v=onepage&q=drug%20r%26d%20disciplines%201960&f=false

Something was needed to help the

communication among disciplines and to

support the integration of the new

achivements of basic science into clinical

practice.

The Translational Medicine was

„The term translational medicine was introduced

in the 1990s but only gained wide usage in the

early 2000s.” https://www.britannica.com/topic/translational-medicine

„The preclinical animal models

predict well drug effect on human”:

Efficacy

Side effects/unwanted effects

Toxic effect

No real paradigm change

http://www.technewsdaily.com/4979-nih-translational-center-pharmaceutical-drugs-innovation.html

„I feel the tremor

in the force”

High attrition rate in drug R&D

Increasing development costs

Decreasing FDA approvalsPrice of drugs

Reasons for failure

http://www.nature.com/nrd/journal/v15/n12/full/nrd.2016.184.html?foxtrotcallback=true

The pre-clinical models/approaches were not

appropriate in respect of human use

CONCLUSION

WANTED because of the predictive value of his pharmacology models is approching to the zero

“Currently, nine out of ten

experimental drugs fail in

clinical studies because we

cannot accurately predict how

they will behave in people

based on laboratory and

animal studies.”http://cdn.intechopen.com/pdfs/42018/InTech-

Animal_models_in_drug_development.pdf

Significant differences

FACTORS HUMAN EXPERIMENTAL ANIMAL

Genetic background Heterogeneous, outbred,

Homogeneous, inbred, strains

Environment Diverse, full of stress,

pollutions, seasons

Well balanced, no stress, cleaned air,

standard temperature and

humidity, specific pathogen free

conditions

Food and beverages Different, complex Rodent chow, cleaned water

Age, scenescence Wide range Usualy young

Sex Both One of them preferred

Chronic disease

progression

Generaly low Accelerated

Disease phenotype Diverse Homogeneous

Origin of the disease Natural Arteficial

Anatomy/physiology Human Rodent

Treatment schedule Usually curative Usually preventive

Placebo/nocebo effect Significant Missing

Ortolog differences

Animal model scepticism

„Reuters quoted Francis Collins, Director of the NIH, as stating that:

“about half of drugs that work in animals may turn out to be toxic for

people. And some drugs may in fact work in people even if they fail

in animals, meaning potentially important medicines could be

rejected.”

http://cdn.intechopen.com/pdfs/42018/InTech-Animal_models_in_drug_development.pdf

Don’t mix!

Pharmacology animal model

Animal disease Human disease

Translational research helps in

differentation

Conclusion

Something must be done

Paradigm change is needed

Trends in recent Translational

Medicine

Rational drug R&D strategy is

needed...

We still don’t know enough about the human

molecular pathology.

We still don’t know enough about the

pharmacology animal model molecular

pathology.

Solution: we must increase our knowledge

Efficacious implementation of the achievements

of basic science to healthcare

Understand better the diseases

Understand better the animal models

Use the most appropriate animal models

Improve the communication among the disciplines

Decrease high attrition rate

Shorten development time

Predict early Succes/Failure

Patient stratification

Apply biomarkers; pre-clinical and clinical

Tasks of recent Translational

Medicine

New paradigm of drug R&D

Interact into the molecular

pathomechanism with new tools

Disease not only symptom

Molecular pathomechanism

Omic associations

Deeper information and better

understanding

The dark side of the drugs

We are not identical

„An animal sufficiently like

humans…” Not true

Pharmacology paradigm

change

The grandiose recognition

We are not identical

Recognition of patients

heterogeneity

„An animal sufficiently like

humans…” Not true

„Consequently, an animal model or a human

disease is by no means attempting to reproduce

the human disease with all its complexities in an

animal but rather to model specific aspects of a

disease.”

„Whenever using an animal model, it is thus of

utmost importance to define a specific question

and to ensure that the chosen model is fit-for-

purpose. „

NewHorizonsinTranslationalMedicine2(2014)5–11

Hypothesis

The predictive value of the animal models can be

increased by enriching our knowledge on the

molecular pathomechanism of human disorder and

preclinical animal models.

Knowing what molecular mechanism does make the

difference among the patient subgroups.

If the molecular pathomechanism is known and we

could find animal model where the same pathway in

the same way is impaired the predictive value would

increase.

However, it will not help „Commercial and Strategy”

failures. .31

New preclinical pharmacology

paradigm

Face validity: The similarity in biology and symptoms

between the animal model and the human disease.

Predictive validity: Demonstration that clinically

effective interventions demonstrate a similar effect in the

model.

Target validity: The target under investigation should

have a similar role in the disease model as in the clinical

situation. One classical example is the beta-3 adrenergic

receptor which has an important role in the energy

metabolism of rodents but not in humans.

.32 NewHorizonsinTranslationalMedicine2(2014)5–11

.33 NewHorizonsinTranslationalMedicine2(2014)5–11

Animal model validity scoring

https://www.fda.gov/drugs/developmentapprovalprocess/drugdevelopmenttoolsqualificationprogram/ucm284078.htm

Quality in specific pharmacology

Voluntary, GLP regulations

„For the purpose of this guidance, an animal

model is defined as a specific combination of an

animal species, challenge agent, and route of

exposure that produces a disease process or

pathological condition that in multiple important

aspects corresponds to the human disease or

condition of interest.”

FDA:Animal Model Qualification

Program

https://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guida

nces/UCM230597.pdf

ExampleSmall molecular weight

.36 https://www.frontiersin.org/articles/10.3389/fimmu.2015.00551/full

Inflammatory Bowel Disease

example

Genotype-Phenotype

AIM1. Better understanding of the molecular

pathomechanism

2. Development of new drugs and diagnostic tools

ExampleSearching for susceptibility genes and

associated molecular mechanisms

Genom Wide Association Studies (GWAS)Study specific genes with some overlapping with other study hits

The function of severeal genes are unknown

Few druggable targets

Example

.39 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4314302/

Drugs are categorized based on the mechanism of action.

Purple symbols indicate oral drugs.

IL, interleukin; TNF, tumor necrosis factor.

The therapeutic pipeline in ulcerative

colitis (UC)

The therapeutic pipeline in Crohn’s

disease (CD)

Példa

.40 http://www.cmghjournal.org/article/S2352-345X(15)00040-5/pdf

Most frequently used IBD animal

models

Genomics of IBD animal models

Comparison of the gene experession profile of different IBD animal models.

32 known IBD successibility genes:TNF, IFN-, Lt, IL-6, IL-16, IL-18R1, IL-22,

CCR2, 7, CCL2, 3, 4, 5, 7, 11, 17, 20, CXCR3, CXCL1, 5, 10, Mmp3, 7,9, 14,

Timp1, Reg3, and Pap, S-100a8, S-100a9, Abcb1, and Ptgs2

2/32 upregulated genes in TNBS model

15/32 upregulated or downregulated in DSS model

30/32 are upregulated or downregulated in CD45RB transfer colitis model

Inflamm Bowel Dis 2007, 13:325-330

.42 Inflamm Bowel Dis

. 2009 June ; 15(6): 890–899

Gene expressin in

IL10-/- mice IBD model

Venn diagram illustration of gene expression similarity between DSS-induced colitis and ulcerative colitis (UC)

patient sample microarray data. A: 944 genes were upregulated at day 6 in DSS colitis compared with 876

upregulated genes from UC patients; 152 of these genes were similarly upregulated between both data sets. B: 665

genes were downregulated at day 6 during DSS colitis compared with 267 downregulated genes from UC patients;

22 of these genes were similarly downregulated between both data sets.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3026350/

Gene expressin in

DSS colitis model

Genes in the

pharmacology model

Susceptibility genes and

mechanisms in human diseases

Model 1

Model 2

Model 3

Model 4

-GWA studies

-other specific genomic

and/or omic approaches

Probably

predicted

value model

Model 1

Model 2

Model 3

Model 4

Genes in the

pharmacology modelSusceptibility genes and

Mechanisms in human diseases

Imaging

https://www.liverpool.ac.uk/translational-medicine/research/centre-for-preclinical-imaging/msot/

Rodent colonoscopy

DSS colitis model

Analogue with human biomarker

Biopsy option

Do not need to exterminate the animals; model progression

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1774595/pdf/gut05400950.pdf

cHS4I-hIL-1βP-Luc transgenic mice

Interleukin 1 beta (IL-1β)

contributes to the

development of

inflammatory bowel

disease (IBD) and is

correlated with the severity

of intestinal inflammation.

https://journal-inflammation.biomedcentral.com/track/pdf/10.1186/1476-9255-10-

16?site=journal-inflammation.biomedcentral.com

Rodent DSS colitis model

.49 https://www.researchgate.net/publication/282036993_CD4_T_cells_are_required_for_both_development_and_

maintenance_of_disease_in_a_new_mouse_model_of_reversible_colitis

Rodent colonoscopy

CD4+ transfer colitis model

.50 http://parts.igem.org/Part:BBa_K1993009

Rodent TNBS colitis model

MSC-mesenchymal stem cell

Homing efficiency of MSCs and illustrating their

distribution

Under IVIS Spectrum, MSCsCXCR4 exhibited enhanced capacities for targeted

migration to the bowels in IBD model.

.51https://www.researchgate.net/publication/287126056_Histamine_H2_Receptor-

Mediated_Suppression_of_Intestinal_Inflammation_by_Probiotic_Lactobacillus_reuteri/figures?lo=1

Rodent imaging

TNBS colitis model

Magnetic Resonance Imaging (MRI)

for mice

Magnetic resonance imaging is a radiological

tool used in the diagnosis of internal diseases in

soft tissue, such as the brain and heart.

http://www.mouseimaging.ca/technologies/mri.html

The 7-T, 40-cm MRI used to image multiple mice.

Micro-Computed Tomography (micro-CT)

for miceHigh-resolution X-ray computed tomography produces detailed three-dimensional images of soft tissue and bone structure. In the case of soft tissue, the highest resolutions are achieved with the help of a contrast agent, which increases the X-ray attenuation of the tissue of interest

Liver of mice vasculature

http://www.mouseimaging.ca/technologies/microct.html http://openi.nlm.nih.gov/detailedresult.php?img=3095598_pone.0019389.g004&req=4

bone-metastases

Single photon emission computed tomography - computed

tomography (SPECT-CT) imaging for mice

The primary use of the facility is for the development and validation of novel radiolabeled imaging ligands which can be used for tumor detection, cell tracking, diagnosis of autoimmune diseases or vulnerable plaque localization.

https://csb.mgh.harvard.edu/mouse_imaging/spect-ct

The system can be used with various isotopes, most

frequently 111In and 99mTc. The spatial resolution for the

SPECT system is approximately 1 mm.

Translational Medicine links to

Systems Pharmacology

Translational medicine, special issues to be

addressed in the non-clinical development of

biological medicinal agents

Compiled by: Endre Mikus PhD, CEO

Budapest, 14/10/2017

Expected translational flowchart

„classical flowchart”

Molecular target and drug

candidate interaction

ResponseThe structure of molecular target

is species dependent

Rodent

Specific Pharmacology (therapeutic)

Safety pharmacology (side effects)

Toxicology

Biosimilar tests

human 100

dog 88 100

sheep 84 86 100

rabbit 76 77 75 100

mice 73 72 76 66 100

rat 72 72 72 68 89 100

guinea

75 76 72 72 74 72 100

human dog sheep rabbit mice rat guinea

The molecule under development interacts with both

human and rodent orthologue targets.

Challenge of Translational Medicine

Gap in the „classical” flowchart

Molecular target and drug

candidate NO interaction

ResponseThe structure of molecular target

is species dependent

Rodent

Specific Pharmacology (therapeutic)

Safety pharmacology (side effects)

Toxicology

Biosimilar tests

The molecule under development does not interact with

rodent orthologue target.

The molecule is human specific.

SOLUTION

Creation of arteficial systems

Working options 1/2

Searching for cross reacting animal species

Primate

Outbred , serious ethical considerations, expensive etc.

Only the 10% of the human specific antibodies show cross

reactivity with non-human homologue protein. Furthermore,

only the 10 % whithin this 10% show efficacy.http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2759500/pdf/mabs0105_0505.pdf

Surrogate/homolgue antibodyAn animal specific antibody is used in a preclinical phase for

pharmacodynamic, pharmacokinetic and toxicology studies.

Human transgene animalsThe human targeted protein is expressed in the rodents. The

human protein substitutes the rodent orthologue.

Working options 2/2

Humanised mice

Immuno-compromised animals with working

human genes, cell, tissues or even organs.

The Bicentennial Man

Humanised mouse

Both human and mouse immune cells are

present at the same time in the animals (!/?).

Immunogenicity if Biologics

Anti-drug antibodies (ADA) are produced during

protein therapy.

Immunogenicity to biologics represents a

significant hurdle in the continuing therapy of

patients in a number of disease settings.

Consequences:

Continuous decrease of potency

Systemic allergic hyperrection

Immunogenicity of Biologics

Immunogenicity

„Many biotechnology-derived pharmaceuticals

intended for humans are immunogenic in

animals.” Risk:underestimation safety and

toxicology concerns

„The induction of antibody formation in animals is

not predictive of a potential for antibody formation

in humans.”

.64 Guidance for Industry S6 Preclinical Safety Evaluation of Biotechnology-Derived Pharmaceuticals

Relevant preclinical models

are needed

Immunogenicity

Transgenic mice and xenograft

transplantation models have been generated.

Thank you for your attention

.67 http://www.scielo.br/scielo.php?script=sci_arttext&pid=S0100-879X2015000200096

Példa

Animal disease versus Pharmacology

animal model

Animal diseases occure when the animals

become ill. These illnesses can be similar to

human diseases, develop „spontaneously” and

can also be used for testing new chemical

entities.

Pharmacology animal model when scientists

make interventions on healthy animals to show

phenotypes similar to human diseases

Disease models

Mechanistic models

Task of Translatinal research

Definitions of disease

DISEASE=Genetic predisposition+environmental factors

Genetic predisposition is an inherited risk of developing

a disease or condition.

DISEASE=NOT HEALTHY

Objective and subjective symptoms

Dis-integration

Disease phenotypes,

personalised medicine

Hourglass perspective of disease evolutionsympmtoms are not enough any more

Symptom+biomarker

Biomarker

Grouping

Asthma, COPD

Functional GI

disorders, etc.

DIAGNOSIS

Symptom

Pre-Translational

Translational

Not only phenotype matters

End of symptom hegemony

The Word of Biomarkers arrived?

http://basdai.com/research2.htm http://basdai.com/research2.htm

http://ocw.tufts.edu/Content/19/CourseHome/302560/302572

Task of Translational research

Analysing problems making solutions

The new achivements of genomics, proteomics and

epigenetics have to be applied both in pre-clinical and

clinical pharmacology in order to syncronise preclinical

pharmacology with clinical trial protocols.

BIOMARKERS

We need words

http://sciclips.wordpress.com/2012/01/09/cancer-theranostics-potential-applications-of-cancer-biomarker-database/

Biomarkers are the words

used by Translational

research

"a characteristic that is objectively measured and

evaluated as an indicator of normal biologic

processes, pathogenic processes, or

pharmacologic responses to a therapeutic

intervention."

early diagnosis

patient stratification

and monitoring of treatment responses

The official NIH definition of a biomarker

Biomarkers in the bench and in the clinic

.75 http://www.profactproteomics.com/services.html

Where do the biomarkers come from?

.76 http://www.eusem.com/main/CH/pot

Task of Translational research

Genotype-Phenotype relationships

Genomics

Let we start with „easy”!

Gaucher’s disease

the genotypes are known

monogenic disorders

Genotype Phenotypes

Gaucher’s disease

The mutation of a single gene induces several phenotypes

The disease arises due to genetic mutations. More than 300 genetic mutations have

been found to be associated with Gaucher’s disease.

Gaucher’s disease is a common lysosomal storage disease that results from inherited mutations in the gene encoding acid-glucosidase

http://www.sciencedirect.com/science/article/pii/S1096719204002240

Glucocerebrosidase gene-deficient

Let we see a bit harder example!

Chronic obstructive pulmonary disease (COPD)

GenotypePhenotypes

Genome-Wide Association Study…

…is an examination of many common genetic variants in different individuals to see if any variant is associated with a trait.

GWAS typically focus on associations between single-nucleotide polymorphisms (SNPs) and traits like major diseases.

Better understanging

New tharepeutic targets

Patient subpopulations

Personalised medicine

Realionship among other

diseases

Biomarkers

Several phenotypes

Diagnosis is based on pulmonary function

measurementsThe diagnosis of COPD is highly depending on which guidelines are

used for defining the disease (Respiratory Research 2007, 8:89)

Following 3887 individual spirometry study

10.2% fulfilled NICE COPD

14 % fulfiled GOLD COPD

21.7 % fulfilled ERS

Chronic obstructive pulmonary disease

(COPD)

Genotype-Phenotype realtionship

Studies of genotype–phenotype correlations

reveal significant genotypic heterogeneity

among clinically similar patients, and vastly

different phenotypes among patients with the

same mutations.

Increasing number of published GWAS studies

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3169525/figure/pgen-1002269-g001/

How the animal models could approach

to the human pathology?

Animal

models

Pathology

Pharmacology model

development

Animal diseases as potential

pharmacology models

Genomics in animals diseases

Animal diseases as models for human

diseases

Noninsulin-dependent diabetes mellitus (NIDDM), with

mild obesity

Otsuka Long-Evans Tokushima Fatty (OLETF) rats

Chronic Obstructive Pulmonary Disease

Heaves on horses

Atopic Dermatitis

Canine atopic dermatitis in the West Highland White Terrier

Scott syndrome is a rare hereditary bleeding disorder

Canine Scott syndrome

Genomics in animal models

Comparison of the gene expression changes in experimental colitis models

Of 32 genes that are known to change transcriptional activity in IBD:TNF, IFN-,

Lt, IL-6, IL-16, IL-18R1, IL-22, CCR2, 7, CCL2, 3, 4, 5, 7, 11, 17, 20, CXCR3,

CXCL1, 5, 10, Mmp3, 7,9, 14, Timp1, Reg3, and Pap, S-100a8, S-100a9, Abcb1,

and Ptgs2

2/32 are upregulated in TNBS,

15/32 are upregulated or downregulated in DSS

30/32 are upregulated or downregulated in the CD45RB transfer colitis.

Inflamm Bowel Dis 2007, 13:325-330

The genetic modification of laboratory

mouse strains produces quite homogeneous

genotype-phenotype relationship.

Genotype-Phenotype relationship

Animal

https://www.ncbi.

nlm.nih.gov/pmc/

articles/PMC2692

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