1Charles Oo

OPTIMIZING THE TRANSITION FROM

THE NONCLINICAL TO CLINICAL

PHASES IN DRUG DEVELOPMENT

Charles Oo, PharmD, PhD

ABCP, FCPcharlesoo@yahoo.com

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Schematic Stages of Pharmaceutical Research &

Development

Divided into Nonclinical Design/Discovery and Clinical Development

Identify a disease

Isolate

Target

& Validation

(~2-5 years)

Lead compound identification and optimization

(~2-5 years)

Cell –based

and animal

testing

(~1-3 years)

Formulation

& Scale-up

Human clinical trials (~2-15 years)

FDA approval

(~2-3 years)

Sales/Marketing

Nonclinical Design/

DiscoveryClinical

Development

In Silico prediction

Adapted from the Modern Method of Drug Discovery slides of Kumar PR

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Overview of Drug Development Strategies

With the recent technology and scientific progress, the pharmaceutical

industry has become quite proficient in rational drug design and

discovery at the nonclinical phase

However, application of rational drug development has not progressed

as quickly into clinical phase

The gap needs to be bridged, since clinical development represents at

least 70% of the total cost of drug development

Moreover, this situation is aggravated by a recently high attrition rate

Comprehensive understanding of the disease pathophysiology of

simpler nonclinical models is rare, while the development phase can

progress readily to the ‘complicated’ clinical stages with limited

disease insight. This exercise is analogy to throwing darts while being

blindfolded, hoping that one of the darts will stick

To be cost effective, multiple optimization and de-risking steps are

crucial and they should start early from the nonclinical phase

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Drug DiscoveryOne way to “discover” drugs

http://ccc.chem.pitt.edu/wipf/index.html

5Charles Oo *Adapted from Milligan PA et al, Clin Pharmacol Ther 2013

Target site exposure & binding*: Insufficient characterization of the

exposure–response relationship and binding (affinity and duration) at

target site before progressing to late-stage development;

Target site systems pharmacology*: Insufficient knowledge of the

treatment effect in the complex/interactive biological systems of

specific target population;

Translational predictability, or evidence-based verification:

Subsequent to insufficiencies of the above 2 items, low confidence on

predictability, and lacking evidence of detection of drug efficacy in

clinical trials

Team experience in assessing efficacy/safety benefits: Insufficient

prior learning with the primary endpoints (often due to “learning” of

the historically established endpoints from previous studies) by

project team.

Perceived Causes of Drug Failure

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Confidence in Target Site Exposure, Binding, and Pharmacology“Three Pillars of Survival”: target exposure (1), binding (2) and pharmacology

effects (3) in the in-vitro and in-vivo assessments in humans

Adapted from Morgan P, et al, Drug Discover Today 2012

Lo=low; Hi=high

Binding

confidence

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MEASURABLE

RESULTS

COMPOUND

APPLIED

Complex

perturbation

of

interacting

systems

What is the mechanism of

action?

Why are we seeing toxicity?

What is the target site? Which biomarkers can be used?

Endless questions in drug development........

Adapted from the Slide of Elliston KO “Systems Pharmacology: An Application of Systems Biology”, Genstruct Inc.

How best to capture efficacy

& safety in a clinical trial?

What is the ideal population?

What is the dosing regimen

for target exposure/binding?

How to translate findings from

nonclinical?

What evidences for drug effects?

What is the extent of change

and variability?

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Uniqueness of Each New Molecular Entity and its Systems

Pharmacology

Consider:

1. The distributive

hierarchy

(pharmacokinetics) of

drug molecule in

human body;

and

2. The propagation

schematics of drug

actions (efficacy and

safety;

pharmacodynamics) in

human body.

Adapted from Bai JPF, et al, Ann Rev Pharmacol Toxicol 53:451–73, 2013

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Simplistic Starting Point for Small Molecules

‘Sweet Spot’ in Molecular Mass–logP Space for ‘Drug-likeness

Ideal ’lean’ molecules

Riskier ‘obese’ molecules

‘Obese’ molecules need design strategies to improve pharmacokinetics, reduce target promiscuity & toxicity

Adapted from Hann MM et al, Nat Rev Drug Dis 11:355-365, 2012

FURTHER INFORMATION

CheMBL database:

https://www.ebi.ac.uk/chembl The Binding

Database: http://www.bindingdb.org

SCORPIO website:

http://scorpio.biophysics.ismb.lon.ac.uk

PDBCal data set: http://www.pdbcal.org

SUPPLEMENTARY INFORMATION

See online article: S1 (figure) ALL LINKS

ARE ACTIVE IN THE ONLINE PDF

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Two Remaining Hurdles in Drug Development:

Efficacy & Toxicity*

Strategy: improve the efficacy/toxicity ratio by starting from the ‘sweet spot’

Note:

Efficacy and toxicity hurdles

remain consistent in recent years

where pharmacokinetics (PK) hurdle is

essentially reduced

Adapted from an NIH White Paper by the QSP Workshop Group , 2011

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Multiple Parameters for Toxicity AssessmentSimilar parameters could also be applied to efficacy assessment

Source: Modi S. et al., Drug Discovery Today 17 (3/4):135-142, 2012

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The Success Rate of CNS Drug Development remains the

LowestTo facilitate CNS drug development, the following 4 cases are provided

● Potent activity: low to subnanomolar

● Highly selective

● Molecular weight <450

● Minimal hydrophobicity (clogP < 5)

● Number of H-bond donor < 3

● Number of H-bond acceptor < 7

● Number of rotatable bonds < 8

● H-bonds < 8

● pKa, neutral or basic with pKa 7.5–

10.5 (avoid acids)

● Polar surface area <60–70 A2

● >30-Fold margin between hERG IC50

and effective unbound plasma

concentration

● Metabolic stability: >80% remaining after

1 hour

● CYP enzyme inhibition:<50% at 30 M

● No significant CYP2D6 metabolism

● Not a potent CYP3A4 inducer

● Not an efficient P-glycoprotein substrate

(in vivo)

● Not a high-affinity serum albumin ligand

(Kd < 10 M)

● Aqueous solubility >60 g/ml

● Effective permeability >1x10-6cm/sec

Pajouhesh, NeuroRx, 2005

Case 1: Physicochemical attributes of a successful CNS

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Case 2:

Mean (range) of physical & chemical properties of

CNS and non-CNS drugs

Pajouhesh, NeuroRx, 2005

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Case 3

Some physicochemical properties vs. CNS penetration in mice

Bergstrom C, et al, Pharm Res 2012

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Case 4

Brain: Plasma ratio (C5min) vs. LogD in mice

For the dataset,

substrate penetration

via:

(●)-- passive diffusion

(Δ)-- active influx

(∇)-- active efflux

(□)-- high plasma

protein bound

The linear regression line

is for CNS transfer via

passive diffusion

Bergstrom C et al, Pharm Res 2012

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Summary of The Optimization Steps Establish a druggability database using internal and external sources,

including physicochemical properties and systems pharmacology

Implement earlier build-in attrition and de-risking processes, starting from the

nonclinical drug design/discovery phase

Enhance translational ability of in vitro systems/animal models by in-house

duplication, outside lab verification, and in using xenograft/transgenic cell-

lines/animals, and patient-derived induced pluripotent stem cells

Enhance team’s experience via therapeutic specialization, and continuous

education

Adopt cost-effective innovation in new technologies (eg, imaging, genomics,

micro-array/multiplex, virtual simulations)

Provide a formal, critical assessment of the benefits and risks at multiple

stages of drug development, to include

o Predictive biomarkers for both non-clinical and clinical phases

o Study target site exposure, binding sufficiency, and pharmacology at molecular

level in human disease condition

o In silico (computer) and in vivo correlation, and with evidence-based verifications

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Importance of A Smooth Transition

from Medicinal Chemistry, Preclinical Pharmacology, ADMET,

and Other Fields to Clinical Development

With smooth seamless transition:

facilitate early clinical development

starting from first-in-human study to

efficacy trial, drug registration and

marketing

Without smooth transition:

unguided, leading to higher risks

in clinical development

Adapt from http://ccc.chem.pitt.edu/wipf/index.html

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Questions and Comments?

Please forward to:

charlesoo@yahoo.com

THANK YOU!!!