Preclinical development (C. Salcedo)

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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

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Registration

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Clinical Trials

Drug Discovery and Development

Preclinical Development

Candidate selection

Lead selection and optimization

Target Discovery

3-5 years

1 year

5-7 years

5-7 year

JORNADA TOX® (Barcelona, 1 de febrer de 2013 - CERETOX)

400 M $

1 B $

From 1000nds to 1-3 1-3 1

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Preclinical Package

1. Chemistry, manufacturing and controls (CMC)

2. Efficacy

3. Safety

4. Toxicology

5. ADME & PK

6. Documentation : IB + IMPD

JORNADA TOX®

(Barcelona, 1 de febrer de 2013 - CERETOX)

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Provide a safety margin

Define the dose/concentration to start human trials (NOAEL)

Define max dose/concentration to be dosed in humans

Target organs/ Rescue treatments

Obtain regulatory approval of clinical studies (IB, IMPD)

Predict toxic/safety concerns

Select a candidate

Help in next step study designs

Clinical Development


Candidate selection

Exploratory toxicology

Exploratory safety

Regulatory toxicology

Regulatory safety



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Additional/follow-up studies


Critical tasks

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Candidate selection

Exploratory toxicology

Exploratory safety

Regulatory toxicology

Regulatory safety

Genotoxicity

Repeated dose toxicity

Reproductive/juvenile tox.

Carcinogenicity

Local tolerance

Cardiovascular

CNS

Respiratory

Follow-up studies

Additional studies

General toxicity in silico/ in vitro

Preliminar genotoxicity

Preliminary toxicity in vivo

Off-target binding profile

Preliminary CV safety

Immunotoxicity

Preliminary CNS safety


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Exploratory toxicology&safety

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Toxicology Assay

General Tox Citotox

Glutathion Depletion

Phospholipidosis

Phototox

Genotox Ames

Micronucleus

Special Tox LLNA

Topical irritation

In vivo Acute Tox

Repeated Dose Tox

Others Zebrafish

In silico DEREK, TOPAK, OncoLogic, CASE


Safety Assay

General Off -targets

QT hERG

Purkinge

Guinea Pig ECG

CNS Irwin

Others? Renal, GI

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Regulatory safety&toxicology

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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 !!!


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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®



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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®



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105

104

103

102

101

Co

nc

en

tra

tio

n (

nM

)*

In vitro

IC50

Kd

Cell

activity

pA2

IC50

Animal

Model

Animal

Model

EC50 ID50

28d

Rat

Tox

28d

No rodent

Tox

MLD

LOAEL

NOAEL

Human

Active

(Pred)

HEC

Off-

targets

hERG Rat

Resp

safety

Dog

Cardio

Safety

Rat

CNS

safety

Ph I

Good Tol &

Biomark


Safety margin

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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


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Jonathan Hitchcock, 2003 Pfizer

However….are we doing well?


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• 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

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Pedro Cuatrecases, Drug discovery in jeopardy, 2006

The Attrition Problem

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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



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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 Merck

Painkiller CV events 2004

Bextra Pfizer

Painkiller CV events 2005

Zelnorm Novartis

IBS Heart problems 2007

Tysabri

Biogen Idec

MS Progressive multifocal

leukoencephalopathy

2005

Neurospec

Palatin Thec.

Appendicities

diagnosis

Life-threating side effects 2005

Cylert

Abbot

ADHA Liver failure 2005

Permax

Valentant

Parkinson Blood backlow to aortic valves 2007

Baycol

Bayer

Cholesterol Fatal rhabdomyolysis 2001

Palladone

Purde Pharma

Narcotic painkiller Sever effecst when taken with

alcohol

2005

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• 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

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The Attrition Problem: reasons (I)


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Candidate selection

On track?


Challenges

Increasing predictability and regulatory acceptance

of in silico / in vitro methods

Adding more knowledge to the drug discovery process, so as to make success more certain :

Genomics, proteomics, metabonomics Molecular toxicology Transgenic animal models Biomarkers Bioinformatics

The only way to reduce costs and reduce time to launch is by reducing repeats, at any stage.

Opportunities

Creating entirely new therapeutic approaches (gene therapy, antibody therapy, stem cells).

Pharmacogenomics–Drugs and dosage chosen based on genetic composition –‘personalised medicine

Help pharmaceutical companies to get their programmes to fail efficiently

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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

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Preclinical development (C. Salcedo)

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