Ian Cotgreave, SFT 2011-03-18 · Annual Meeting of the Swedish Society of Toxicology (SFT) Nobel Forum K lin k In tit t t Molecular Toxicology Global Safety Assessment AstraZeneca

Ian Cotgreave, SFT 2011-03-18

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Personal reflections on the future role(s) of “toxicologists” in drug discovery and developmentIan A Cotgreave

Annual Meeting of the Swedish Society of Toxicology (SFT)Nobel ForumK lin k In tit t t

Molecular ToxicologyGlobal Safety AssessmentAstraZeneca R+DSödertälje

Karolinska Institutet

[email protected]

18-03-2011

Format for the presentation

•Introduction to the current drug discovery/development paradigm.•An over-view of current definitions and roles for “t i l i t ”“toxicologists”.•Emerging demands on safety science from current attrition trends.•Challenges to toxicology and “toxicologists”:

• Front-loading (in silico, in vitro, in vivo methods) versus regulatory demands. Should we let go of traditions?

• New mechanisms, new methods and new tools, where will they fit?

• Is “Personalized Toxicology” possible as a natural part of “Personalized Medicine”?.

R&D | Innovative Medicines | Global Safety Assessment

• Mechanism-based translational risk assessment versus traditional regulatory toxicology, alternative or complement?

• Novel Therapeutic modalities, are we prepared?• Do we need to change the way we train toxicologists?

•Concluding remarks.

2 Name | Date


2

Forskningsprocessen inom läkemedels utveckling

Prekliniska studier Kliniska prövningar

KEMI/FARMAKO-

OG

IND* FAS I FAS II FAS III NDA** FAS IV

Discovery Development

LOGI

Sökande efteraktiva substanser

Toxikologi, effektstudier på olika djurslag

Myndighets-behandling

Effektstudier på friska försöks-personer

Patientstudier i begränsad skala

Jämförande studier på stort antal patienter

Myndighets-behandling

Fortsatta jämförande studier

50–150individer

100–200patienter

500–5 000patienter

Registrering, introduktion på marknaden**New Drug

ApplicationAnsökan om att få

k d fö

KUNSKAPS-

NIVÅ

KUNSKAPS-

NIVÅ

*Investigational New DrugAnsökan om att få ge ett nytt läkemedel till människa

R&D | Innovative Medicines | Global Safety AssessmentName | Date

8–12 år från idé till färdigt läkemedel

marknadsföra ett nytt läkemedel

2–4 år 2–6 mån 3–6 år 1–3 år

TIDSÅTGÅNG

So where does toxicology? fit in the R+D process? Regulatory toxicology versus ”front-loading” toxicology

År

1 162 3 4 5 6 7 8 9 10 11 12 13 14 15

Förstapatentansökan

Ansökan omklinisk prövning

Ansökan omregistrering

Explorativ forskning (Discovery) Läkemedelsutveckling (Development) Identifiering avIdentifiering avmåltavlor ochledsubstanser

Optimering avledsubstans

Test avterapikoncept

Klinisk utveckling Lansering

Kliniska prövningarFas I50-150personer

Fas II100-200personer

Fas III500-5 000personer

Fas IV, fortsatta studier

Forskningsstöd under livscykeln

Toxikologiska och farmakokinetiska studier(absorption, distribution, metabolism, utsöndring)

Farmaceutisk och analytisk utveckling

Processutveckling och tillverkning


Processutveckling och tillverkning

Registreringsarbete

Försäljning och marknadsföring (inkl planering och förberedelser)

Antal substanserUpp till 1 000 000 10-15 1-8 1-3 1

Name | Date


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So what kinds of ”toxicologists” do we have in the industry today?

• Drug project leaders:- Generalists covering regulatory toxicology demands (Toxicology

Project Leaders (TPLs))- Generalists covering early riks mitigation in drug projects (Discovery

toxicologists (DxTs))toxicologists (DxTs))

• Specialist support functions to in vivo toxicologicalresearch (Clinical, regulatory and exploratory):- Toxicologic Pathology.- Clinical Chemistry. - Reproductive Toxicology.- Genetic Toxicology.- Molecular Toxicology- QA

• Specialist functions supporting non in vivo toxicologicalh (Cli i l l t d l t )


research (Clinical, regulatory and exploratory)- Molecular Toxicology- Genetic Toxicology- Computational Toxicology

Name | Date

Have ”toxicologists” been doing a good job in this paradigm? What lessons can we learn via the attrition of our compounds due to toxicity?

• Predicting dose-dependent toxicity in and from animal studies has worked fairly well.studies has worked fairly well.

• Clinical experience often reveals surprises from:- collapsded safety margins- Ideosyncratic responses



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Phase Preclinical ‘Nonclinical’ Phase I

AZ

Phase I Phase I-III Phase I-III Phase III/ Marketing

Post-Marketing

Post-Marketing

Information: Causes of attrition

Causes of attrition

Dose-limiting ADRs

Serious ADRs

Causes of attrition

Causes of attrition

ADRs on label Serious ADRs Withdrawal from sale

Source: ABPI (2008) Car (2006) AstraZeneca (2000-2009)

Sibille et al. (1998)

ABPI (2008) Olson et al. (2000)

BioPrint® (2006)

Budnitz et al. (2006)

Stevens & Baker (2008)

Sample size: 156 CDs stopped

88 CDs stopped 14 CDs with dose-limiting ADRs

1,015 subjects

63 CDs stopped

82 CDs stopped

1,138 drugs 21,298 patients

47 drugs

Cardiovascular: 24% 27% 7% 9% 35% 21% 36% 15% 45%

24% 27% 7% 9% 35% 21% 36% 15% 45%

Hepatotoxicity: 15% 8% 0% 7% 29% 21% 13% 0% 32%

Haematology/BM: 3% 7% 0% 2% 3% 4% 16% 10% 9%

Nervous system: 12% 14% 71% 28% 2% 21% 67% 39% 2%

Immunotox; photosensitivity:

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

Gastrointestinal: 5% 3% 36% 23% 2% 5% 67% 14% 2%

Reprotox: 9% 13% 0% 0% 5% 1% 10% 0% 2%

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

Respiratory: 1% 2% 0% 0% 2% 0% 32% 8% 2%


Respiratory: 1% 2% 0% 0% 2% 0% 32% 8% 2%

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

Genetic tox: 5% 5% 0% 0% 0% 0% 0% 0% 0%

Carcinogenicity: 0% 3% 0% 0% 3% 0% 1% 0% 0%

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

Adapted from Redfern WS et al. SOT 2010 Poster 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.

7 Name | Date

So how should we respond to this in the coming generation?

1. Apply much more ”front-loaded” intellectual and practical scientific effort to ”de-risk” chemistries early and chaperoning the best compound into regulatory animal studies and humans.stud es and humans.

2. Accept and communicate risk, but avoid surprises.3. Respond more creatively to introducing modern molecular

risk assessment practices into the traditional scenario.4. Have the courage to apply ”breaking news” science in de-

risking proejcts.5. Foster much more pre-competitive collaboration between

pharma, universities and regulatory authorities.


Will this require new breeds of ”toxicologists”?

8 Name | Date


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Front-loading (in silico, in vitro, in vivo methods) versus current regulatory demands. Should we let go of our traditions?• The development of more complex modelling tools will

provide much more predictive power with respect to early de risking of projects de-risking of projects

- In silico methods- Cell-based models- Exploratory in vivo models

- So are these classed as toxicologist skills and should be fostered in the future?

R&D | Innovative Medicines | Global Safety Assessment9 Name | Date

In Silico Methods

“Those who cannot remember the past are condemned to repeat it”.

George Santayana: Life of Reason, Reason in Common Sense, Scribner's, 1905, page 284

”The Nintendo generation are the teachers now!”


g

Ian Cotgreave: SFT Annual meeting 2011


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Computational Toxicology………Exploiting data & methods from all corners of AZ to address safety issues earlier in drug discovery


Safety-Directed Drug

Design

Molecular Understanding of Adverse Events

Clinical Understanding of Adverse Events

Scott BoyerName | Date

….Developing tools for better utilization of internal and external unstructured data.

=



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Computational Predictive Toxicology – How?In vivo:

ScorecardCompound:>100 gm

Time: MonthsAnimals: Many

ScorecardCompound:>100 gm

Time: MonthsAnimals: Many


Animals: ManyAnimals: Many

Name | Date

In vitro:

ScorecardCompound: 5 mg

ScorecardCompound: 5 mgp g

Time: DaysAnimals: None

p gTime: Days

Animals: None



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In silico:

ScorecardCompound: NoneTime: SecondsAnimals: None

ScorecardCompound: NoneTime: SecondsAnimals: NoneAnimals: NoneAnimals: None


In vitro models

1. Molecular techniques

EpiVax (US) and Retrogenix (UK)Direct binding/association between LMW-drugs and specific HLA-molecules

Two-hybrid ligand fishingFor off-target binding

drugs and specific HLA molecules



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2. Cell models: Stem CellshESC and iPSC-derived screening tools


iPSCs are pluripotent and can form cells of all germ layers


•Toxicology most focused on hepatocytes and cardiomyocytes

18 Name | Date


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Human variability in response: Are iPSCs the answer for liver?

• Variability in phases 0-III in bioactivation and detoxification.• Variabiltiy in toxicicty mechanism expression in DILI.• Variability in predosposition for DILI• Variability in predosposition for DILI.• IPSc techniques offer cloning and modelling of Genotypic

variances in: - CYPs, UGTs, MRPs etc- mitochondrial function- apoptotic regulators- hormonal responses- In fat metabolism


IMI (Eu/Pharma: ”Mega-Call”: Patient-derived Stem cells in drug discovery)

• A partnership between the EU Commission and 15 major pharma• Focussed on deriving iPSC from patients for:

- Safety/DMPK Screening. - Target validationTarget validation.- Disease modelling.- Includes build of independent CRO facilities and associated

infrastructure.- Has a budget of 100 million Euros.

• Being finalized now and due for emission during Q2



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Induced pluripotent stem cells: A stem cell breakthrough.

F:\Science Day l 2010\stemcell br


http://www.tv.com/video/WizGdIzkMLN03MaY2ah3Qg6jB9qQIAVK/stem-cell-breakthrough?o=cbs

Name | Date

Animal models

1. ”Humanized” mice, Not just CYPs, but such as hHLA

Drug HLA association Toxicity Reference

AstraZenecaHuman HLA-transgenic mouse model developedfor Ximelagatran treatment.

Drug HLA association Toxicity Reference

Abacavir B*5701 Skin Mallal, 2002Allopurinol B*5801 Skin Hung, 2005

Carbamazepine B*1502 Skin Chung, 2004

NevirapineDRB1*0101Cw8, B14

LiverSkin

Martin, 2005Littera, 2006

Fl l illi B*5701 Li D l 2009


Flucloxacillin B*5701 Liver Daly, 2009

Ximelagatran DRB1*0701 Liver Kindmark, 2008


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2. Disease models

Zucker Obese ratsNon-obese diabetic mice


Zebra fish with renal disease

New mechanisms, new methods and tools, where will they fit?

1. Mechanisms: Stress response (not just oxidative stress, heat shock, shear stress etc…..)

Depiction of PKR as transducer of “ribotoxic stress” response. ”ER stress response”ribotoxic stress response.


Zhou H et al. Toxicol. Sci. 2003;74:335-344


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Mechanisms: Epigenetics


2. Mechanisms: New molecular entities

Small non-coding RNAs: miRNA


”Vault” RNAs


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2. New methods and tools: Imaging

Bioluminescence New bioluminiscence model measuresCD8+ T-cell function in the liver.

PET imaging


Distribution ofA neurotoxinin the brain

NMR (MRI) imagingImaging human liver for pathophysiology



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Emerging methods: Carbon dating of cell turnover

”Half lives” of human cardiomyocytes have been Measured accurately

”Human cell carbon datingConsortium”

“By the time a halt was called to above ground nuclear testing in 1963, levels of carbon-14 in the atmosphere had doubled beyond natural background levels, says Frisén. Since the halt, this has halved every 11 years. By taking this into account, one can see detectable changes in levels of carbon-14 in modern DNA, he says. "Most molecules of the cell will turn over all the time. But DNA is a material that does not exchange carbon after cell division, so it serves as a time capsule for carbon " Frisén says”


a time capsule for carbon, Frisén says .

O Bergmann et al. Science 2009;324:98-102

Applications in toxicology in the future?

Personalized Health Care and Safety

• Will it be possible to individualise t f h i k “Id assessment of human risk: “Ideosyncracy

“and “Personalised toxicology”?• The development of mechanistically-

validated biomarkers of human toxicity



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Variability in Adverse Drug Reactions

• Why do a few people get a side effect while others don’t?• Some side effects seem like an overdose (excessive pharmacologic effect)• Others are very rare and seemingly random (“idiosyncratic”)• Some of this variability in human drug responses caused by people’s genetic

differences but not alldifferences but not all

Type A (intrinsic) Type B (idiosyncratic)

PredictableUsually dose dependent

High morbidityLow mortality

Responds to dose reduction

UnpredictableRarely dose dependent

Low morbidityHigh mortality

Responds to drug withdrawal


pRelatively common (75% of ADRs)

p gVery rare

Name | Date Ina Schuppe-Koistinen

Enable personalized healthcareStratify patient groups

based on their likelihood for

ImpactImpact

Enable launch of drugs thatotherwise would have failed

Safety Biomarkers (SBMs) can add value in three areas:

based on their likelihood foradverse drug reactions (ADRs)

Identify projects with safety liability earlyIdentify compounds with weak safety profiles and

elevated risk for causing future ADR,within a compound family early

Enable more competitivelaunches

R d l l f t i t

Increased safety for trialsubjects

Potential to stop compounds with safety issues early


Increase patient safetyUse common toxicity SBMs to

monitor clinical trials and discoverOrgan toxicity while damage is still

reversible

Reduce level of uncertaintyat key decision points

Reduce level of late stagesafety related attrition

32 Name | Date Ina Schuppe-Koistinen


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Sim and Ingelman-Sundberg, TiPS in press

33 Name | Date

PHC Based on Genetic Differences in Metabolism


• topoisomerase inhibitor for treatment of colon cancer (Pfizer) • glucouronidation by UGT1A1• slow metabolizers with ”*28 variant” recieve larger than expected dose• dosed for each patient according to genotype

34 Name | Date

Ina Schuppe-Koistinen


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Other kinds of biomarkers: What types of new DILI biomarkers are needed?

- New biomarker(s) should be more sensitive and specific for detection of DILI and give mechanistic information about the injury.

• Predicitive DILI biomarkers that signal liver injury before ALT has increased in patients.

• Prognostic DILI biomarkers that follow the development of injury and signal if a patient is recovering or developing acute liver failure.

• Susceptibility biomarkers for patient stratification to select patients at risk

R&D | Innovative Medicines | Global Safety Assessment35 Name | Date Ina Schuppe-Koistinen

Safety Biomarker Development Process within AZ

AZ TechnologiesPGx

OmicsRegulators

SBMDiscovery

SBM Qualification

SBM Assay Validation

SBM

ImagingCandidate SBMs

From literature

ConsortiaPSTC/IMI

Regulators


GSA Patient Safety/PHC

Ina Schuppe-Koistinen


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Mechanism-based translational risk assessment versus traditional regulatory toxicology, alternative or complement?

There is currently great effort to form very large public-private partnership (PPP)consortia to develop the use of private partnership (PPP)consortia to develop the use of alternatives to animals to better predict human risk. These are founded on:

- Definition of toxicity pathways and biomarkers of these.- Definition of the trans-species relevance of these pathways

and markers (translatability).- Development of new test paradigms to model acute and

chronic toxicity in responces to foreign chemicals.


Here are two examples from differing angles…

37 Name | Date

Through a Memorandum of Understanding, research, develop, validate and translate innovative chemical testing methods that characterize toxicity pathways

•Research, develop, validate and translate innovative chemical testing methods that characterize toxicity pathways.•Research ways to use new tools to identify chemical induced biological activity mechanisms.•Prioritize which chemicals need more extensive toxicological evaluation.•Develop models that can be used to more effectively predict how chemicals will affect biological responses. •Identify chemicals, assays, informatic analyses, and targeted testing needed for the innovative testing methods.


•Plan to have nearly 10,000 chemicals under study at NCGC by the third quarter of FY2010. •Conduct 50 or more ToxCast™ high-throughput screening assays on this enlarged chemical library every year for the next several years. •Be able to provide the data generated from the innovative chemical testing methods to risk assessors to use when making decisions about protecting human health and environment.

38 Name | Date


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European Cosmetics Industry co-funds unique research initiative launched by the European Union’s Health Programme under the 7th Framework Programme (FP7): “Towards innovative, non-animal safety testing methods of chemicals and ingredients of cosmetic products”

•Project SCR&Tox, “Stem Cells for Relevant Efficient Extended and Normalized Toxicology”.•Project HeMiBio, “Hepatic Microfluidic Bioreactor”. •Project DETECTIVE, “Detection of endpoints and biomarkers of repeated dose toxicity using in vitro systems”.•Project COSMOS, “Integrated In Silico Models for the Prediction of Human Repeated Dose Toxicity of COSMetics to Optimise Safety”.

testing methods of chemicals and ingredients of cosmetic products


p y p y•Project NOTOX, “Predicting long-term toxic effects using computer models based onsystems characterization of organotypic cultures “.•Project ToxBank, “Supporting Integrated Data Analysis and Servicing of Alternative Testing Methods in Toxicology”.

Novel therapuetic modalities

The future of the pharmaceutical industry holds new therpeutic modalities which will pressurize the role of the ”toxicologist”



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1. Cell therapies in regenerative medicine

E:\Science Day 2010\regenerated


However, the risks for serious adverse reactions are many!



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2. Scaffolds and materials in regenerative medicineExample: ”Nanomaterial” A new field of toxicology emerging


3. Molecular biological therapeuticsSiRNA

Humanised antibodies

Aptomers



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Concluding remarks

1. So is there a future for ”toxicologists” in the pharmaceutical industry?

2. Yes, with particular focus on early prediction of human risk and de-risking of drug projects, before major investment decisions are made.

3 But the term ”toxicologist” covers a multitude of scientific 3. …But the term toxicologist covers a multitude of scientific skills and contributions.

4. Therefore the traditional view of the ”toxicologists” contribution to drug discovery and development should change.

5. This is driven both by the changing needs in prediction of risk and in the rapid expansion of relevant scientific areas.

6. Perhaps we should introduce the idea of ”cloud toxicologists” = multiple skill sets all contributing to solve a common prediction paradigm.


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It is critical that the training of ”toxicologists” in the future must adapt rapidly to these changing demands and rapidly evolving scientific possibilities.

Documents

Ian Cotgreave, SFT 2011-03-18 · Annual Meeting of the Swedish Society of Toxicology (SFT) Nobel Forum K lin k In tit t t Molecular Toxicology Global Safety Assessment AstraZeneca