IN-VIVO SAFETY – PRE IND DRUG DEVELOPMENT

EVERY STEP OF THE WAY

EVERY STEP OF THE WAY

Drug Development Boot Camp

Brian M. Roche, PhD, DSP, DABTExecutive Director of Global Safety PharmacologyCharles River - Ashland

General Principals

• Two Objectives:• Pharmacologically active• Safe for humans

• Goal of preclinical studies is to evaluate toxicity with respect to:• Target organs• Dose dependence• Relationship to exposure• Potential reversibility• Off-target effects• Evaluate toxic effects

• Outcomes are to estimate dose levels for IND toxicology and safety pharmacology studies.

Goals for IND program

For biopharmaceuticals and small molecules:

• Identify an initial safe dose and appropriate dose escalation scheme in humans

• Identify potential target organs of toxicity and determine whether such toxicity is reversible

• Identify appropriate species for toxicology assessment

• Identify parameters that are predictive of toxicity and can be clinically monitored

• Communicate risk

TYPICAL DRUG DEVELOPMENT FUNNEL

Discovery Exploratory Development

Idea DrugYears

Full Development

Phase I Phase II Phase III

0 155 10

Preclinical Pharmacology

250 compounds

Preclinical Tox & Safety

Drug Discovery5,000 to 10,000 compounds

Clinical Pharmacology& Safety, 5 compounds 1 compound

Discovery Lead OP Tox Safety Pharm Phase I

IND

•Clinical•High Throughput PK

IND Enabling Studies:

•Safety Pharmacology•CV

•CNS

•Respiratory

•GI

•Renal

•Dose Formulation Support

•Bioanalytical Support

IN-VIVO SAFETY – DRUG DEVELOPMENT PROCESS

•PK

•Dose range finder

•Tolerability studies

•Biodistribution

•Lead op tox

•Pharmacology

•Anesthetized preps

•LangendorffAssay

•Small animal Telemetry

•2nd species

1000 250 1-6

IND Enabling Studies:

•Toxicology•DFR

•14-28 Day

•Route of administration

•2 species

•Recovery

•Genetic Toxicology

•Dose Formulation Support

•Bioanalytical Support

GLP

PRIMARY PHARMACOLOGY• In vitro studies

• binding assays• Receptor binding affinity• Lead or safety panels

• In vivo studies• Single dose/activity in rodent/large animal• Multiple dose effects in large animal• Tolerability studies with safety endpoints

• Mechanism of action• Dose selection• Non-GLP

PHARMACOKINETICS AND TOXICOKINETICS

• ADME/DMPK• Metabolic and plasma protein binding studies

• CYP inhibition/induction

• Systemic exposure in the species used for repeat dose toxicology

• PK in test species and in-vitro biochemical data for potential drug interactions before Phase 3.

• Nonclinical testing of human metabolites only if exposures are greater than 10% of total drug exposure. Support Phase 3 clinical studies.

• Data integration• Interspecies scaling of in vitro and in vivo data to predict IND

and clinical performance

STATISTICAL FACTORS TO CONSIDER

False Positives

False Negatives

Discovery Lead OP Tox Safety Pharm Phase I

IND

•Clinical•High Throughput PK

IND Enabling Studies:

•Safety Pharmacology•CV

•CNS

•Respiratory

•GI

•Renal

•Dose Formulation Support

•Bioanalytical Support

IN-VIVO SAFETY – DRUG DEVELOPMENT PROCESS

•PK

•Dose range finder

•Tolerability studies

•Biodistribution

•Lead op tox

•Pharmacology

•Anesthetized preps

•LangendorffAssay

•Small animal Telemetry

•2nd species

1000 250 1-6

IND Enabling Studies:

•Toxicology•DFR

•14-28 Day

•Route of administration

•2 species

•Recovery

•Genetic Toxicology

•Dose Formulation Support

•Bioanalytical Support

GLP

SCENARIOS FOR SMALL AND LARGE MOLECULES

Study

New Chemical

Entity BioPharmaceuticalFollow-onBiologics Vaccines

Pharmacology Yes Yes Yes Yes

PK Yes Limited Mixed limited

Acute/DRFYes

(2 species)Yes

(1 or 2 relevant species)Yes

(1 species)

Yes (1 species;

rabbit)

Repeat dose tox w/TK

Yes (2 species; 1 nonrodent)

2 weeks to 9 months

Recovery Period

Yes (1 or 2 relevant species)

2 weeks to 6 monthsRecovery periodImmunogenicity

Local tolerance study Yes (1 species)

Yes (1 species)

Local toleranceimmunogenicity

Genotoxicity Yes No No NoSafety Pharmacology Yes Yes* No No*Preferred method is standalone assessment of safety pharmacology endpoints but may be considered for incorporation of SP endpoints in toxicology study design.

SCENARIOS FOR ANTI-CANCER PHARMACEUTICALS

Study TypeNCE

Advanced

NCEw/Increased Life

ExpectancyNBE

Advanced

NBEw/Increased Life

Expectancy

Pharmacology Yes Yes Yes Yes

PK Limited Limited Limited limited

Acute/DRFYes

(2 species)Yes

(2 species)Yes

(1 or 2 species)Yes

(1 or 2 species)

Repeat dose tox

Yeslimited TKRecovery

period

YesTK

Recovery period

Yeslimited TK

Recovery period

YesTK

Recovery periodImmunogenicity

Genotoxicity No No No No

Safety Pharmacology

Yes* – could be included in toxicity studies Yes

Yes* – could be included in toxicity

studies

Yes* – could be included in toxicity

studies

*Preferred method is standalone assessment of safety pharmacology endpoints but may be considered for incorporation of SP endpoints in toxicology study design.

Email:askcharlesriver@crl.com

Phone:877.CRIVER.1

THANK YOU

Charles River - Ashland

Backup Slides

EXAMPLE IND PACKAGE – NCEStudies GLP

Preclinical Pharmacology: In vitro Studies• Cloned Human Receptor Binding Affinity• PanLab (Cerep) Screen

NoNo

Preclinical Pharmacology: In vivo Studies• Activity in Rats• Single Dose Effects in Dogs• Single-Dose Effects in Pigs

NoNoNo

Preclinical Pharmacokinetics: In vitro Studies• Plasma Protein Binding• Comparative Microsomal Metabolism• Effects on Human Cytochrome P450• Efflux Transporter Substrate Study

YesYesYesNo

Preclinical Pharmacokinetics/Toxicokinetics: In vivo Studies in Rats• 7 Day Oral Gavage• 28 Day Oral Gavage• Freebase Toxicokinetics• ADME

NoYesNoYes

EXAMPLE IND PACKAGE – NCEStudies continued GLP

Preclinical Pharmacokinetics/Toxicokinetics: In vivo Studies in Dogs• TK Oral Study• TK IV Study• Single-Dose PK Study Oral and IV• Oral MTD• 28-Day TK• Freebase Toxicokinetics• ADME

NoNoYesNoYesNoYes

Safety Pharmacology: In vitro Studies• hERG• Langendorff isolated heart (guinea pig)

YesYes

Safety Pharmacology: In vivo Studies• Modified Irwin (rat)• Locomotor Activity (rat)• Intestinal Motility (rat)• Renal Function (rat)• Cardiovascular Range-Finding (dog)• Cardiovascular and Pulmonary Function (dog)

YesYesYesYesNoYes

EXAMPLE IND PACKAGE – NCE

Studies continued GLP

Single-Dose Toxicity in Mice and Rats• Acute IV Toxicity in Mice• Acute IV Toxicity in Rats• Acute Oral Toxicity in Mice• Acute oral Toxicity in Rats

YesYesYesYes

Repeat-Dose Toxicity in Rats and Dogs• 7-Day Dose Range Finding in Rats• 28-Day Toxicity in Rats• MTD in Dogs• 28-Day Toxicity in Dogs

NoYesNoYes

Genotoxicity• Ames Test• Chromosomal Aberration Assay (HPBL)• Mouse Micronucleus Assay

YesYesYes

17 EVERY STEP OF THE WAY17 EVERY STEP OF THE WAY

CASE STUDY DISCOVERY/LEAD OP/CANDIDATE SELECTION TO IND