Translational MedicineFrom Drug Discovery and

Developmentto Clinical Trial:

Small Molecule vs Protein Product

Presented by

Ada Kung, Ph.D. DABT, MBA

Apr. 24, 2017

Expedient Solutions International, a drug

development and regulatory consulting company

• Alliance management leveraging on hands-on experience and

knowledge of both Greater China and US pharmaceutical/

biotechnology companies and CRO's

• Form strategic alliance with EPL/Aclairo in 2017

• Infrastructure planning including project management/

scheduling, budgeting design and planning/study or project

costing and analysis

• All aspects (preclinical, clinical, chemistry manufacturing, and

control, investigator’s brochure) of drug development of small

molecules, biologics, proteins, peptides, genetic & protein-

based vaccines and botanical products

• Project Management

• IND/NDA/BLA submissions to US FDA and China CFDA

•

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ESI Preclinical Development

• Toxicology, PK/Metabolism, Safety Pharmacology,

Genetic Toxicology, and efficacy modelings

• Preclinical GLP laboratory design and building per

AAALAC requirement

• Alliance with pathology, toxicology, and

pharmacology labs in China and U.S.

• Report writing in both English and Chinese

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What is Translational Medicine

• Turning Research into Medicines and

Treatment

• From Bench to Bed

• Bridging the gap between the discoveries at

the “Bench” and interventions and therapies

at the “Bedside”

• Research becomes an reality

4

New Drug Development Process

Drug DiscoveryPreclinical

DevelopmentClinical Development

In animal

studies

Multidisciplinary

research areas

In human

begins studies

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NEW DRUG

DEVELOPMENT

PROCESSDrug discovery

Multidisciplinary approaches

Pre-clinical

development

For Potential drug candidate

Cellular Biology

Pharmaceutical Organic Chemistry

Basic and Clinical pharmacology

Toxicology

Pharmaceutical Development

Analytical Research

Molecular Modeling

Regulatory sciences

Animal studies (in-vitro & in-vivo)

IND filing &

Approval

Clinical

developmentClinical trials

Human beings

Pharmacokinetics (ADME)

Pharmacodynamics (Receptors, enzymes and channels level etc)

Toxicological (Toxicokinetics and toxicodynamics)

Posological (Doses of drugs) NDA filing and

approval

New drug

continue use

Phase-I

Who

Volunteers, Terminal illness (20-80)

Why

Safety, PK, PD, Toxicology, dose

range

By Whom

Clinical Pharmacologists

Phase-II

Who

Selected patients (100-200)

Why

Efficacy, PK, PD, Dosage schedule

By Whom

Clinical Pharmacologists & clinical

investigators

Phase-III

Who

Large sample of patients

Why

Results confirmation of Phase I, II

By Whom

Clinical investigators

Phase-IV

Post-marketing

surveillance study

Who

Patients regular treatment

Why

Long term safety, efficacy under

actual conditions

By Whom

All physicians

Drug Discovery

新藥研發

Drug Value 1X

Pre-clinical Studies 臨床前試驗

Pharmacology藥理Toxicology 毒理PK/PD 藥物動力學/藥效

File IND

IND 申請

Phase I/II Clinical Trails

臨床試驗第一/二期

Process

Development

製程開發Cell Line 細胞株Upstream Process 上游製程Downstream Process下游製程

Formulation劑型

Analytical Science分析方法

Protein Characterization

蛋白質定性

Pre-clinical material supply

提供臨床前試驗藥品

Drug Value 2X

Drug Value 4X

Drug Value 5X

Drug Value 10X

Translational Medicine 轉譯醫學

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Drug Discovery - Development

(~$1B)• Years 0-3: Drug Discovery

• Years 4-5: Preclinical in vitro, in vivo

• Years 6-9: Clinical Trials

• Registration of the drug with USFDA

• Year 10+: Drug to market

• Year 10-11:Product Surveillance

• Phase IV : Observations/monitoring the product

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Tools in Translational Medicines

• Analytical and bioanalytical methods: Method

development and validation

• Biomarkers: The use of pharmacology and safety

biomarkers in early drug development

• Toxicology, DMPK, Pharmacology and

Biological effects: Translation of animal efficacy

and toxicity to human

• CMC

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Drug Discovery

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Target

Discovery

Informatics

& Functional

Genomics

Lead

Discovery

Medical

Chemistry

Cellular

& Molecular

Pharmacology

Preclinical

Development

Target

IdentificationBioinformatics

Assay

Development

Library

Development

In Vitro

Drug ActivityPK

Target

ValidationGenomks

HTP

Screening

Structure-Based

Drug Design

Cellular

Disease Model

In Vitro

Pharmacology

Assay

DevelopmentProteomks

Biochemistry

& Enzymology

Medical

ChemistryMOA

Tox/Safety

Pharmacology

Drug

Candidates

Drug Discovery Plan

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The New Discovery Process Poses

Many Challenges

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Biomarker and Molecular

Diagnostic Development

Building Disease KnowledgeInternal Focus on disease delivers

diagnostics which further refine disease

understanding

Building Target KnowledgeTarget validation molecule becomes

therapeutic molecule

Building Biomarker KnowledgeInternal Focus on disease delivers

molecular markers which support

clinical studies

Biologics

Based

Molecule

Delivery

1-2 years

Target Validation

Adapted from IBM Business consulting services

Define

Disease

Models

Target ID/

Molecule

Selection

Preclinical

PoC

Target/Molecule

PoC In Man

Drug Discovery Plan

• Bioavailability study in the rat (more animals with more time points)

• In Vitro Microsomal P450 inhibition and drug-drug interaction studies

• CaCO2 permeability study

• Plasma protein binding and red cell binding assay

• In vitro efficacy studies with and without the microsomal preparation

• Biomarker research

• Analytical and bioanalytical method development

• Single dose PK study (linear or non-linear PK potential)

• Tissue distribution study (may combine with the PK study)

• In vitro screening for cardio-toxicity, hepatotoxicity…..

• 7-day mammalian tox/toxicokinetics study in the rat; formulation not necessary for oral small molecule drugs

• Establish safety margin based on the efficacy and toxicity data

• Preformulation

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CYP 450 Interaction

• Liver is the major organ for drug metabolism / elimination

• Predominate enzyme system that metabolizes drugs is the

P450 (CYP450) family of enzymes which mediate oxidative

reactions, such as hydroxylations

• Could be used for species selection for animal toxicology

studies

– Select the animal species with the closest finger-print

metabolic profiles to human

• Could be used in the drug screening program: Select the drug

candidate that has the least adverse effect on the system

• Could be an useful tool in the combined drug therapy

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In vitro Toxicity Testings

• hERG for cardiovascular toxicity

• Hepatocyte for hepatotoxicity

• Ames tests for genotoxicity and

carcinogenicity potential

• Could be combined with Cytochrome P450

studies

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Biomarker

• What is a biomarker: “A characteristic that is

objectively measured and evaluated as an indicator

of normal biological processes, pathogenic

processes, or pharmacologic responses to a

therapeutic intervention.”

• Guidance for Industry (August, 2011)

– E16 Biomarkers Related to Drug or Biotechnology Product

Development: Context, Structure, and Format of

Qualification Submissions .

• Could be used as a surrogate end point for clinical

studies.

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Preformulation

• Formulation Research: explore different

vehicles and establish stability of the drug

candidate.

• Initial oral route of administration: suspension

for animal toxicology study

• Formulation components had been used in

the marketed drugs.

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Single Dose PK

• Animal Species: same as the projected

toxicology studies: the species with the

closest metabolic profiles to human.

• Wide enough dose range to reach saturable

PK

• Dose frequency for the toxicology study

based on the length of clearance half lives

• Ready for the determination of Bioavailability

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Bioavailability

• Definition : "Fraction of a dose of drug that is

absorbed from its site of administration and reaches,

in an unchanged form, the systemic circulation."

• Applied for mostly oral drugs, also any route of

administration other than the intravenous routes.

• In vitro CaCO2 permeability study

• In vivo single dose PK study: AUC of oral /AUC of IV

• If bioavailability is low, will need lots more drug and

thus costly

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7-Day Mammalian Toxicology in

the Rat• This is a pre-exploratory or pre-dose range

finding study

• No need to go any higher than 2,000 mg/kg

dose level

• To establish a safety margin

• To identify potential target organ of toxicity

• Get a preliminary idea of dose levels.

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Additional Consideration for

Proteins• Most drugs are administered intravenously

and no bioavailability study needed

(exception: Subcutaneous injection)

• CaCo2 permeability not needed

• In vitro Genotox may not needed: solubility

• Microsomal studies not needed

• Immunogenicity is a major concern

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Drug Development

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Drug Development

• Preclinical: Lead Optimization (Drug

Discovery) → Toxicology/Safety, Formulation,

Analytical Method Development/Validation,

PK/PD/ADME → Investigational New Drug

(IND)

• CMC (Chemistry, Manufacture, Control)

• Clinical Trials

• Regulatory Affairs

• Project Management

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Drug

Development

Stage 1

Stage 2

Stage 3

Stage 4

Stage 5

IND filing

Stage 1 (Initiation)

• Historical data

• Preliminary PK

• Potency/efficacy

• Safety margin

• Pre-formulation

• Analytical method

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Stage 2 (Month 1 & 2)

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•

•

•

2

Stage 3 (Month 3 & 4)

•

•

•

•

•

3

Stage 5 (Month 8 & 9)

•

•

•

•

5

Stage 4 (Month 5, 6, & 7)

•

•

•

•

4IND filing (Month 10)

•

•

6

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Stage 1 (Initiation)

• Review all background information and historical

data

• Lead selection and optimization (optional)

• Preliminary PK, potency (efficacy), safety margin

• Pre-formulation

• Analytical method development for

characterization and assay

• Open dialogue with FDA, e.g. Pre-IND meeting

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Guidance for Industry

• M3 Nonclinical Safety Studies for

the Conduct of Human Clinical Trials for

Pharmaceuticals. July 1997 ICH

• M3(R2) Nonclinical Safety Studies for the

Conduct of Human Clinical Trials and

Marketing Authorization for Pharmaceuticals

January 2010 ICH

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ICH Guidelines (S6): Preclinical Evaluation of

Biotechnology-Derived Pharmaceuticals

• Case-by-case, Science-based approach

• Product used in Pharm/Tox studies comparable to product for initial clinical studies: Formulated product vs API

• Biological Activity, Receptor binding, Cross- rereactivity in man & a range of animal species

• Animal Species: Pharmacologically active in vitro/in vivo: epitope or receptor expression; transgenic animals expressing human receptors or homologous proteins

• Number of animals (increases in frequency & monitoring duration)/Gender

• Administration/dose selection: Route/frequency approximates clinical use, Doses of multiples of human dose, PK, NOAEL, MTD/MFD

• Immunogenicity: Antibody titers, Antibody influence on PK/PD, complement activities and pathology

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Stage 2 (Month 1 & 2)

• Design protocols for 2-week pilot toxicity studies

(preferably in two different species).

• Audit and inspect preclinical CRO’s

• Start the preparation and protocol design for

safety pharmacology studies

• Continue on analytical method development and

formulation work

• Establish drug stability in the formulation

selected for the duration of toxicity studies.

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Animal Species

• Small Molecule:

– Microsomal metabolic profile comparable to man: Rat, Dog,

Monkey or Rabbit

• Protein Product:– mAb:

Cross-reactivities with the target cell and adverse effect as a result of undesirable binding to tissues

Immune complex formation (Pathology)

In vitro cell-based assay and in vivo efficacy

Immunohistochemistry

– Cytokine: Exhibit comparable pharmacologic effect as in man

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Dosing Regimen

• Duration, Frequency and Dose Level:

– approximates clinical design

– could be affected by PK/saturable PK and

clearance of the drug

Protein:

o Duration: could be limited by the antibody

formation against the protein drug (ADA)

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Dose Selection

• NOAEL to MTD

• Often given by oral route, soluble formulation

not necessary

• Alternate routes of intravenous administration:

Continuous vs Bolus

Protein

o Could be limited by the formulation concentration

(MFD vs MTD)

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Parameters to be Evaluated :

Proteins• Immunogenicity and anti-drug antibody titers

• Immunotoxicity:

– Inflammatory reactions at the injection site

– Distribution of surface antigen on target cells,

eg. CD4/CD8 ratios on T cells and CD20 for B cells

• Immune Function Assays: Natural killer cell activity,

Host resistance, Macrophage/Neutrophil function

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Parameters Potentially Affecting

the Immunogenicity• May lose efficacy

• Presence of protein aggregate potentially increases

immunogenicity

• Subcutaneous (vs iv) injection more likely induce

immunogenicity

• The presence of foreign protein (non-self)

• mAb targeted at cell bound epitope ~Immune stimulating protein

• Pegalation decreases immunogencity

• Impaired immune system in cancer patients

• Modified Fc may be less immunogenic

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Additional Considerations for

Study Design for Proteins• Recovery group:

– Evaluate reversibility (or the trend of reversibility) of toxicities or delayed

toxicities

– Allow more time for the antibody titer generation

• Metabolism and gene tox may not be needed

• Local tolerance (can be formulation)

• Case-by-case – Reproductive: Clinical indication & intended patient population: Tysabri for

MS

– Chronic and carcinogenicity: Generally inappropriate (growth factors)

• PK/TK

• Safety Pharm in one species

• Immune complex formation

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Other Issues with mAb &

Proteins Preclinical Development• Dose response may be threshold dose dependent

• Toxicity of excipient components

• Protein aggregates and degradation products

• Bioassay and cell-based assay for drug release, tertiary

structure, potency

• Exaggerated pharmacology vs frank toxicity

• Formulation may affect immunogenicity and bioavailability and

the selection of route of administration (sc vs iv)

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Stage 3 (Month 3 & 4)

• Initiate pilot toxicity study (including TK) in the rat and in the

non-human primate (or dog), two weeks apart.

• Pre-IND meeting– Documentation preparation.

– Request meeting and/or discussion with FDA

– Submit the document with all preliminary data to FDA to gain consent for

the GLP toxicity study design (hopefully before the start of GLP toxicity

studies)

• Receive results from the pilot toxicity studies and prepare for

the initiation of GLP toxicity studies.

• Protocol design for GLP toxicity studies finalized.

• Continue on analytical method development with validation of

the methods.

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Stage 4 (Month 5, 6, & 7)

• Pre-IND meeting with FDA

• Initiate the GLP toxicity studies in rodent and non-rodent (4-

week dosing + 4 week recovery or alternative study design as

agreed upon between sponsoring company and FDA); either

concurrently or one month apart.

• Continue on formulation development with stability studies

• Start genotox & safety pharmacology studies

• On-going GLP PK studies to support IND

• Start IND submission document preparation

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Stage 5 (Month 8 & 9)

• Develop clinical plan and protocols

• Review QA’ed data from CRO with the GLP toxicity studies

• Develop clinical plan and protocols and write investigator Brochure

• Validation of analytical methods completed to be used for the release of clinical materials

• Start looking for CRO’s for clinical trials

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IND Filing (Month 10)

• Submit IND

• Complete the one-month stability study for clinical materials and data to be included in the IND

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Toxicology Studies Post IND

Submission• Species and Route: same as pre-IND studies: small

molecules: rat/dog; protein and vaccine: rat/NHP

• Dosing Regimen and Duration: match the clinical

• Reproduction and Teratology: in 2 species toward mid and late Phase II clinical

• Start planning and initiating tox studies to support Phase III

– Chronic: 6 month rat and 9 month non-rodent

– Carcinogenicity: Rat or transgenic mouse model

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How to set the Clinical Starting Dose

Based upon the results from animal toxicity studies

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FDA Guidance

• Estimating the maximum safe starting dose in initial clinical

trials for therapeutics in adult healthy volunteers, July 2005:

HED

• S9 Nonclinical evaluation for anticancer pharmaceuticals,

March 2010

• Protein drugs:

• -No fixed alogrithm, case-by-case, and risk-benefit conditions

• -MABEL: Minimum Anticipated Biological Effect Level

• -PAD: Pharmacologically Active Dose

• -MRSD: Maximum Recommended Starting Dose

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Clinical Starting Dose for an

Anti-cancer Drug• STD: Severely Toxic Dose:

• Clinical Starting Dose:

– STD 10: At 1/10 of severely toxic dose if rodents

– HNSTD:

Highest dose level that does not produce evidence of

lethality, life-threatening toxicities or irreversible findings

1/6 HNSTD in non-rodent

• Need Safety Factor

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Chemistry Manufacturing

and Control

(CMC)

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CMC

Stage 3/4 (Month 3~7)

•QC release API

Extensive characterization of

reference standard

Final formulation selected

Start preparation of API and drug

product per GMP for clinical supply

Further validation of analytical

methods

Discuss preliminary data with FDA Lead Optimization Phase (Month -5~-1)

• Month -5 Start development of analytical methods Preliminary API stability Start biological screening of different analogs, if any

• Month -4 ~ -2 Initial characterization

• Month -2 ~ -1 Process transfer to GMP manufacturing Develop acceptance criteria for analytical methods Develop pre-formulation

• Month -1 Develop preclinical formulation for tox studies

1

Stage 2 (Month 1 & 2)

•Start pre-IND phase

Continue process optimization

Start tech transfer

•Pre-formulation stability study

Start analytical methods validation

Start pilot tox study and preparation

for pre-IND discussion Start preparing API per GM

2

Stage 5 (Month 8 & 9)

•Continue on analytical methods

validation

Continue API synthesis

•Start stability study of the

clinical materials (drug product)

5

3/4

IND filing (Month 10)

•All tasks completed and QC

release API and drug product

File IND

6

Stage 1

Stage 2

Stage 3

Stage 4

Stage 5

IND filing

45

Clinical Development

• Phase 1

– Usually healthy volunteers

• Phase 2

– Proof of principle

• Phase 3

– Confirmation of efficacy and safety

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Thank You!!!

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