1. Preclinical Development, an
overview:
do we need a change?
Carolina Salcedo, PhD
Director Pharmacology, SANIFIT
JORNADA TOX®
Barcelona, 1 de febrer de 2013
CERETOX
Photo: Can open innovation close the pharma productivity gap? By John McCulloch @ MaRS June 7, 2011
- Confidential - 1

2. Drug Discovery and Development
Target Lead
Candidate Preclinical Clinical
Discovery selection and Registration
selection Development Trials
optimization
From 1000nds to 1-3 1-3 1
3-5 years 400 M $
1 year
5-7 year 1B$
5-7 years
JORNADA TOX®
- Confidential - (Barcelona, 1 de febrer de 2013 - CERETOX) 2

3. Preclinical Development
Preclinical Package
1. Chemistry, manufacturing and controls
(CMC)
2. Efficacy
3. Safety
4. Toxicology
5. ADME & PK
6. Documentation : IB + IMPD
JORNADA TOX®
- Confidential - (Barcelona, 1 de febrer de 2013 - CERETOX) 3

4. Preclinical Development
Candidate Preclinical Clinical
selection Development Development
Exploratory toxicology Regulatory toxicology
Exploratory safety Regulatory safety
 Predict toxic/safety concerns  Provide a safety margin
 Select a candidate  Define the dose/concentration to start
human trials (NOAEL)
 Help in next step study designs
 Define max dose/concentration to be
dosed in humans
 Target organs/ Rescue treatments
 JORNADA TOX®
Obtain regulatory approval of clinical
- Confidential - (Barcelona, 1 de febrer de(IB, IMPD) 4
studies 2013 - CERETOX)

5. Critical tasks
Candidate Preclinical Clinical
selection Development Development
Exploratory toxicology Regulatory toxicology
General toxicity in Repeated dose toxicity
silico/ in vitro
Genotoxicity
Preliminar genotoxicity
Preliminary toxicity Local tolerance
in vivo Immunotoxicity
Reproductive/juvenile tox.
Additional/follow-up studies Carcinogenicity
Exploratory safety Regulatory safety
Off-target binding profile CNS
Preliminary CV safety Cardiovascular Follow-up studies
Preliminary CNS safety
Respiratory
Additional studies
JORNADA TOX®
- Confidential - (Barcelona, 1 de febrer de 2013 - CERETOX) 5

6. Exploratory toxicology&safety
Toxicology Assay Safety Assay
General Tox Citotox General Off -targets
Glutathion Depletion QT hERG
Phospholipidosis Purkinge
Phototox Guinea Pig ECG
Genotox Ames CNS Irwin
Micronucleus Others? Renal, GI
Special Tox LLNA
Topical irritation
In vivo Acute Tox
Repeated Dose Tox
Others Zebrafish
In silico DEREK, TOPAK,
OncoLogic, CASE
JORNADA TOX®
- Confidential - 6
(Barcelona, 1 de febrer de 2013 - CERETOX)

7. Regulatory safety&toxicology
EMA/FDA ICH guidelines:
• Guidelines are not recipes!
• Tailored to your compound
M3
S1- Carcinogenicity
S2 - Genotoxicity
S3- Toxicokinetics /PK
S4- Duration of chronc testing in animals
S5 -Reprotoxicity
S6 -Biotechnology
S7- Safety Pharmacology /QT
S8- Immunotoxicology
Toni Guzman !!!
JORNADA TOX®
- Confidential - (Barcelona, 1 de febrer de 2013 - CERETOX) 7

8. Regulatory safety&toxicology
The toxicological development plan depends on:
• Design of the clinical trial that will be supported:
duration, population
• Administration route
• Therapeutic indication
• Pharmacological target
• Exposure / Metabolism
The toxicological development plan need to answer:
• What is the maximal dose without adverse effects?
• What are the main targets of toxicity ?
• Are the effects reversible ? Monitorable ?
JORNADA TOX®
- Confidential - (Barcelona, 1 de febrer de 2013 - CERETOX) 8

9. Regulatory safety&toxicology
Are differences really due to the treatment?
• Dose response (and exposure response!)
• Consistency between sexes (not necessarily!)
• Consistency with other parameters and other available studies
• Artifacts possible?
• Anomalous values in vehicle group?
If they are related to the treatment, are they adverse?
• Exaggerated pharmacology or off-target effect?
• Magnitude of the difference compared to physiological range.
• Direct versus indirect effects. Feedback response effects. Stress-related
effects.
If they are adverse, are they relevant to humans???
JORNADA TOX®
- Confidential - (Barcelona, 1 de febrer de 2013 - CERETOX) 9

10. Safety margin
28d 28d Rat Dog Rat Human
In vitro Cell Animal Animal Rat No rodent Resp Cardio CNS Off- hERG Active Ph I
activity Model Model Tox Tox safety Safety safety targets (Pred)
105
MLD
104 LOAEL
NOAEL
Concentration (nM)*
103
EC50
ID50
IC50
102
HEC
Good
Tol &
IC50 pA2 Biomark
Kd
101
JORNADA TOX®
- Confidential - (Barcelona, 1 de febrer de 2013 - CERETOX)

11. Estimation of dose for FIH
If they are adverse, are they relevant to humans???
Monitorable, Reversible (Rescue treatment)
Jumping into human doses:
FDA Guidance for Industry: Estimating the Maximum Safe
Starting Dose in Initial Clinical Trials for Therapeutics in Adult
Healthy Volunteers
• Establish HED/MRSD based on NOAEL/MABEL
• Apply safety margin
• Define a escalation range
JORNADA TOX®
- Confidential - (Barcelona, 1 de febrer de 2013 - CERETOX) 11

12. However….are we doing well?
Jonathan Hitchcock, 2003 Pfizer
JORNADA TOX®
- Confidential - (Barcelona, 1 de febrer de 2013 - CERETOX) 12

13. The Attrition Problem
Pedro Cuatrecases, Drug discovery in jeopardy, 2006
• Productivity 1-2 drugs/10 reach market
• Budgets increase x30 since 1970 ($5billion
/year)
• Revolutionary scientific advances in last 20
years, offering new and innovative
opportunities
JORNADA TOX®
- Confidential - (Barcelona, 1 de febrer de 2013 - CERETOX) 13

14. The Attrition Problem
Angela Dunne, GSK, 2011
The attrition rate for drug discovery programs from target to
clinic is unacceptably high
–Causes a lack of new medicines to treat diseases of high unmet need
–Results in inefficiency of drug discovery organizations, requiring large target
portfolios to ensure sufficient medicine output
Significant contributors to attrition post-candidate are lack of
efficacy and/or toxicity
–Deployment of more physiological screens earlier in the drug discovery
process should make a significant impact in the overall attrition rate
JORNADA TOX®
- Confidential - (Barcelona, 1 de febrer de 2013 - CERETOX) 14

15. The Attrition Problem
Jim Kling, MSN Health & Fitness
FDA agency failed to catch serious side effects in a number of drugs before
they were approved, thus forcing embarrassing withdrawals
Drug Company Indication Why Expiration date
Vioxx Painkiller CV events 2004
Merck
Bextra Painkiller CV events 2005
Pfizer
Zelnorm IBS Heart problems 2007
Novartis
Tysabri MS Progressive multifocal 2005
Biogen Idec leukoencephalopathy
Neurospec Appendicities Life-threating side effects 2005
Palatin Thec. diagnosis
Cylert ADHA Liver failure 2005
Abbot
Permax Parkinson Blood backlow to aortic valves 2007
Valentant
Baycol Cholesterol Fatal rhabdomyolysis 2001
Bayer
Palladone Narcotic painkiller Sever effecst when taken with 2005
Purde Pharma alcohol
JORNADA TOX®
- Confidential - (Barcelona, 1 de febrer de 2013 - CERETOX) 15

16. The Attrition Problem: reasons (I)
• Patient population is heterogeneous. Differ at
genetic level with regard to drug transport,
metabolism, expression of disease, etc
• Early testing using tissues, cells, are just partially
predictive.
• Preclinical testing in animals models is modestly
predictive of effects in humans
• To many repeats, mainly in Discovery
• Marketing
• Management
JORNADA TOX®
- Confidential - (Barcelona, 1 de febrer de 2013 - CERETOX) 16

17. On track?
Candidate Preclinical Clinical
selection Development Development
Challenges Opportunities
Increasing predictability and regulatory acceptance Creating entirely new therapeutic
approaches (gene therapy,
of in silico / in vitro methods antibody therapy, stem cells).
Adding more knowledge to the drug discovery
process, so as to make success more certain :
Pharmacogenomics–Drugs and
dosage chosen based on genetic
Genomics, proteomics, metabonomics
composition –‘personalised medicine
Molecular toxicology
Transgenic animal models
Biomarkers Help pharmaceutical companies
Bioinformatics to get their programmes to fail
The only way to reduce costs and reduce time efficiently
to launch is by reducing repeats, at any stage.
- Confidential - JORNADA TOX® 17
(Barcelona, 1 de febrer de 2013 - CERETOX)

18. On track !
1. Olson H, 2000 : survey from 12 pharmaceutical companies with data
compiled from 150 compounds with 221 Human Toxicity (HT) events
reported. Positive HT concordance rate of 71% for rodent and
nonrodent species
2. 1991- 40% of attrition was due to poor PK/BA
Implementation of sophisticated panels of early in vitro ADME
2000 – a reduction to 10%
3. Fresh from the biotech pipeline 2011 (Jim Klings):
Drugs approvals were up in 2011, reversing the trend, thanks to
biologics
JORNADA TOX®
- Confidential - (Barcelona, 1 de febrer de 2013 - CERETOX) 18