6.0

27

Understanding(Mechanisms(of(Adverse(Drug(ReacTons(

Centre)for)Drug)Safety)Science)

hip://www.liv.ac.uk/drug?safety))

!  pa'ent)morbidity)

!  pa'ent)mortality)

!  prohibit)effec've)therapy)

!  drug)airi'on)

!  drug)withdrawal)

)

Adverse)Drug)Reac'ons:)The)Problems)

6.0

28

CDSS)approach)to)improving)drug)safety)

Chemistry*of*the*Drug

Biology*of*the*System

Variability*of*the*Patient

Improving*Drug*Safety*Science

Safe*Drug*Design

Innovative*Use*of*Bioanalysis

Organ9directed*Toxicity

Predictive*Models

Mechanistic*Biomarkers

Role*of*the*Immune*System

Pharmacogeneticsof*ADRsHLA*Restriction

Chemical*Stress

Centre)vision)and)strategy)2014)?)2019)

Research)Programmes)

HypersensiTvity( Liver(Toxicity( GI(Toxicity(

Cross?Cu

mng)Scien

ce)

StraTfied(Medicine(

Biomarkers(

Bioanalysis(

Molecular(Chemistry(

Pa'ent)Popula'ons)of)Clinical)Importance)

InfecTon( Paediatrics( Cancer( InflammaTon(

InformaTcs(

Stem(Cells(and(Safety(Science(

Industry)Interac'ons)

Improved)benefit?risk)for)

new)and)exis'ng)

therapeu'cs)

6.0

29

CDSS)–)Working)with)Industry)

!  Collabora've)project)with)individual)industry)partner)

!  Non?compe''ve)large)scale)consor'a)

!  Contract)research)

!  Workshops)!  Tripartate)mee'ngs:)academia,)industry,)regulatory)authori'es)!  Gap)analysis)on)focused)issue)of)relevance)to)Industry))

!  ABPI?funded)Industry)Programme)Manager:)Alan)Norris) )) ) ) ) )(norrial@liv.ac.uk))

!  Inflamma'on)in)clinical)APAP)toxicity)(deleterious)in)vivo)?)Can)Acetyl?HMGB1)predict)outcome?)

Ac?HMGB1:)a)biomarker)for)outcome)based)on)mechanisms)

K182%185'(Acetyl)

K177+180'(Acetyl)K172'(Acetyl)

K173'(Acetyl)

COOHH2N

NuclearLocalization'sequence

Cytokinedomain

C106C45C23

SHSS

Disulfide Reduced'(Thiol)

QTRAP&5500&

Healthy volunteers

APAP-No ALI

APAP-ALI

0.001

0.01

0.1

1

10

100

Ace

tyla

ted

HM

GB

1 (n

g/m

l)

SurvivorsDied / Liver transplant

0.00 0.25 0.50 0.75 1.000.00

0.25

0.50

0.75

1.00

1 - Specificity

Sens

itivi

ty

Acetylated HMGB1ALT

DJ)Antoine)et)al)2012)J)Hepatol)

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30

))))))))))))))))))))))))))))))))))))))))))))Drug)approval)in)the)USA)

59)

•  Annual)New)Molecular)En'ty)(NME))&)New)Biologic)En'ty)(NBE))Approvals)vs.)R&D)Expenditures)in)2009)Dollars)

Report to the US President on “propelling innovation in drug discovery, development and evaluation”. US President’s Council of Advisors on Science and Technology (PCAST). September 25th 2012

The)problem)with)pharmaceu'cal)R&D:)

Phase Preclinical Non-clinical Phase I Phase I-III Phase I-III Phase III/ Approval

Post-Approval

Post-Approval

Post-Approval

Information: Causes of attrition

Causes of attrition

Serious ADRs Causes of attrition

Causes of attrition

ADRs on label Serious ADRs ADRs on label Withdrawal from sale

Source: ABPI (2008) Car (2006) Sibille et al. (1998)

ABPI (2008) Olson et al. (2000)

BioPrint® (2006)

Budnitz et al. (2006)

Tamaki et al., (2013)

Stevens & Baker (2008)

Sample size: 156 CDs stopped

88 CDs stopped

1,015 subjects

63 CDs stopped

82 CDs stopped

1,138 drugs 21,298 patients 106 approved drugs 2001-10

47 drugs

Cardiovascular: 24% 27% 9% 35% 21% 36% 15% 4% 45%

Hepatotoxicity: 15% 8% 7% 29% 21% 13% 0% 11% 32% Haematology/BM: 3% 7% 2% 3% 4% 16% 10% 8% 9%

Nervous system: 12% 14% 28% 2% 21% 67% 39% 20% 2% Immunotox;

photosensitivity: 7% 7% 16% 10% 11% 25% 34% 0% 2%

Gastrointestinal: 5% 3% 23% 2% 5% 67% 14% 21% 2% Reprotox: 9% 13% 0% 5% 1% 10% 0% 0% 2%

Musculoskeletal: 8% 4% 0% 5% 1% 28% 3% 3% 2% Respiratory: 1% 2% 0% 2% 0% 32% 8% 1% 2%

Renal: 6% 2% 0% 5% 9% 19% 2% 3% 0%

Genetic tox: 5% 5% 0% 0% 0% 0% 0% 0% 0% Carcinogenicity: 0% 3% 0% 3% 0% 1% 0% 0% 0%

Other: 4% 0% 0% 2% 4% 16% 2% 29% 2%

Adapted from Redfern WS et al. The Toxicologist 2010; 114 (S-1), 1081. 1-9% 10-19% >20% 0%

! ! !

The various toxicity domains have been ranked first by contribution to products withdrawn from sale, then by attrition during clinical development. Note general agreement between pairs of equivalent studies.

Side)effects:)Evidence,)prevalence,)occurrence)

6.0

31

Examples of how Preclinical Safety has contributed to the success of AZ products

2010(Revenues(ContribuTon(

▪  Renal)Toxicity)alert)in)humans)shown)to)be)due)to)inhibi'on)of)reuptake)not)toxicity.)

▪  Allowed)registra'on)

▪  QT.)Showed)mul'channel)effect)and)beier)than)other)an'psycho'cs)

▪  Cateracts)in)dogs)–)defined)mechanism))

▪  Influenced)labelling))

▪  Allowed)registra'on)

▪  Carcinoids)–)defined)mechanism) ▪  Allowed)registra'on)

▪  Uterine)tumours)–)showed)mechanism)is)rat)specific)

▪  Allowed)registra'on)

Impact(

N/A)

6.0)

5.3)

5.7)

USD)billions)

))

The)Problem)and)how)collabora'ons)can)help:)

•  Drug)Development)is)s'll))–  Cos'ng)to)much)–  Failing)to)frequently)in)all)stages)due)to)toxicity)–  Has)to)many)toxici'es)that)

•  Have)insufficient)transla'onal)understanding)–  Need)beier)biomarkers)

•  Emerge)late)in)development)•  Emerge)post)marke'ng)

•  CDSS)is)set)up)to)provide)non)compe''ve)and)integrated)collabora'ons)between)–  Academia)–  Research)Ins'tutes)–  Regulatory)Agencies)–  Government)–  Industry)

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32

Ximelagatran-induced ALT elevations: Biomarker discovery

•  Thrombin)inhibitor))developed)for)preven'on)of)venous)thromboembolic)events)and)stroke)

•  ~8%)of)pa'ents)included)in)long?term)studies)experienced)transient)ALAT)eleva'ons)(>3xULN))

•  No)pre?clinical)findings)indica'ng)hepatotoxicity)

•  Extensive)program)to)discover)biomarkers)that)predict)pa'ents)at)risk)

)

)Gene'c)predisposi'on))•  associa'on)with)HLADRB1*07,)but)gene'cs)alone)could)not)predict)DILI)

Sensi&vity*=**47%*Specificity*=**83%***

Protein)and)endogenous)metabolite)biomarkers)•  SBM)candidates)iden'fied)that)predict)ALT)eleva'ons)to)similar)extend)

Sensi&vity*=**36%*Specificity*=**84%**

•  Pyruvate/amino)acid)deprivia'on)hypothesis)(predisposi'on)and)treatment)effect))

•  Immune)hypothesis)(CSF1R)ectodomain)shedding)and)macrophage)ac'va'on,)treatment)effect))

Collabora'ons)to)understand)mechanism)of)ximelagatran?induced)ALT)eleva'ons)•  University)of)Helsinki,)Uni)Bonn,)Karolinska)Ins'tute)and)Liverpool)University)

)

)Kindmark)A)et)al,)Pharmacogenomics)J.)2008)Jun;8(3):186?95)Andersson)U)et)al,)Biomarkers.)2009)Dec;14(8):572?86)

Scandinavia)≈)14%)

E.)Asia)≈)0.9%)

Rest)of)Europe)≈)6%)