Overall Drug Discovery and
Development Process
Hypothesis
Generation
Commercialization
Candidate Development
Target
Identification
and
Validation
Assay
Development
Lead
Optimization
First
Human
Dose
Phase
IA
Phase
IB/II
Phase
III
Submit
Global
Global
Launch Optimization
Lead
Generation
Project
Sanction
Project Phase
Program
Sanction
Product
Decision
Program Phase
Product Phase
QSV
Goals
Lead
Optimization
Compound
Screening
Areas of Collaboration In Drug Development
Pre-Clinical
Development
Phase 1
Phase 3
Phase 4
Launch
FHD
Target ID
Target Validation
Phase 2
FED
Clinical Studies
- Consistent phenotyping
- Large-scale prospective trials
Biology of Disease
- Target ID
- MOA - Validation
Biomarkers - Synthesis - Application
Biobanks - Collection - Storage
Where Does this Fit into The NIH NCATs Effort?
Disease
Target
ID
Assay
Dev.
HTS
Probe
to
Lead
PreClinical
FDA
IND
Ph. I
Ph. II
Ph. III
FDA
Review
CER
Target Validation Space
NIH Supported
Basic Research
NIH Molecular Libraries
Initiative
TRND
RAID
NIH Clinical Center,
CTSAs
New NIH-FDA Partnerships
HMORN
PCORI
Target
Active
Key Definitions in Lead Generation
Active defines a "substance" that meets a threshold level of activity in a
primary screen
Associated with a HTS
Activity level defined by precedent and screen performance
Structure and purity of screening substance not confirmed
Hit
Hits provide a suggestive relationship of molecular structure and biological
activity to the target
Confirmed intrinsic activity (DR, IC50, EC50, etc) and characterization against secondary assays.
Confirmed structural identity and purity.
Meets pre-defined criteria for further assessment. Usually of limited potency/selectivity.
Provides starting point for SAR/structural hypotheses to improve biological potency/selectivity and drug-properties.
Rarely suitable for in vivo study or advanced mechanistic studies
Lead
A Lead represents a compound series derived from a Hit that demonstrates a
relationship between chemical structure and target-based activity in biochemical
and cell-based models. Compounds within the series have physicochemical
properties, potency and selectivity deemed appropriate for in vivo evaluation.
Common Characteristics
nM primary activity
Sub uM activity in cell based assays
10x selectivity for related targets
Enhanced solubility, chemical and metabolic stability, evidence of in vivo exposure
Lead Generation
Key Observations
High quality Leads are derived from high quality hits.
The key to finding high quality hits depends on a successful match of lead
generation strategies and technologies to a target. Broad screening of random
compounds is often not the most productive approach.
Optimizing quality hits into quality leads requires a relevant and validated
biological testing paradigm.
The quality of a testing paradigm in optimizing hits to leads is ultimately
limited by the quality of iterative ligand hypotheses (via SAR) tested against it.
Viable leads very rarely fall out of a single screening event with a fixed library.
Cross-functional discipline integration and team drug discovery experience
play a large role in successful lead discovery. Duplicating this outside of some
sort of portfolio optimization organization such as academia is likely to require
substantially longer timelines with lower success rates.
Hypothesis to Lead Generation
A collaborative enterprise among Discovery Scientists for:
the selection of valid targets for drug discovery,
the design and implementation of relevant screens and testing
paradigms that will enable compound discovery and
for industry, the identification and optimization of proprietary
molecules that demonstrate potential to be refined into drug
candidates.
Lead Discovery Science
Learning
Knowledge Based
Probabilistic
Technology
1996-1999
Dominant Influences
HTS Driven Hit Discovery
Combi-Chem
Maximum Diversity
Screen for Drug Promise
2000-2001
2004-2013
Dominant Influences
Target Validation Science Diversified Lead Generation
Bioinformatics
Strategies
Target Platforms
Computational Science
Target Drugability
Library Sciences
Quantitative Biology
Compound Quality
Assay Quality
Targeted Diversity
ADMET Profiling
Chemoinformatics
Structural Sciences
Receptor Panel Profiling
IP Strategies
Chemogenomics
Biological Flowschemes Systems Biology
Factored into Contemporary Lead Generation
Paradigm for Selection of Lead Generation Strategy
Triage of Targets
Little or No Discovery
Precedent
High Throughput Screening with
Maximal Diversity
Alternative Diversity (Natural Products)
Poor historical performance
Library and assay quality are key variables
Follow-up paradigm can be complex depending
on quality of diversity and target biology
Probabilistic
Target and
Gene Family Precedent
Gene Target Platforms
In Silico Hypothesis Generation
Computationally driven diversity
Targeted Libraries
Rational Design considering structural
biology and/or known ligands
Higher p(TS) of Hit identification
Not all targets benefit equally from this approach
Lead Generation Strategy
Knowledge Based
Using integrative approaches and data to identify targets and biomarkers
from publicly available GWAS data
Published SNP
strongly associated
with disease. Causal
gene not evident
Raw public SNP data with weaker
associations
Pathway information
eSNPs
Causal Networks
Other Informative
data
Candidate causal genes and
pathways of disease with human
evidence
DRUG TARGET OR BIOMARKER
Genetics: mouse & human
RNA: multiple tissues
eQTLs (SNP choice)
cQTLs
RNA-RNA correlations
Causality
Networks
What Level of Characterization and
Optimization defines a Viable Lead?
Components of a Biological Flowscheme
Primary Assays
Binding/ Functional Assays
Biochemical/Cellular
Selectivity/Cytotoxicity
In silico Filters
Active
In Vitro
Secondary Assays
Selectivity:subtype/target family
Complex Cellular Assays
ADMET Surrogates
Tox Surrogates
BioPharm Surrogates
Hit
SAR
Advanced In Vitro
Attribute Profiling
Tertiary Assays
ADME
Animal Models
Surrogate Activity
Efficacy Model
Toxicology
BioPharm
Lead
ADME
In Vivo Pharmacology
Toxicology
Clinical
Candidate
Lead Optimization
Optimize
Lead (molecules)
candidates are
identified through in
vitro and in vivo testing
Potency and selectivity
are enhanced
Lead
Optimization
Phase IA (Single dose safety studies)
Single dose studies
escalating/increasing
if well tolerated
Often can establish
MTD (maximally
tolerated dose)
Primary concern is to
establish safety
Phase
IA
Phase
Phase
IB
IB/II
Phase IB (Multidose Safety Studies)
Drug is administered in multiple
escalating doses to a relatively
small number of healthy
volunteers and/or patients to
determine safety, steady-state
PK and establish MTD for
subsequent studies
Increasing use of phase IB to
provide evidence of efficacy
and/or hitting biochemical
target (use of biomarkers and
surrogate endpoints).
Sometimes extends to POC
(proof of concept) small clinical
trials (also called IIa)
Phase
IB
Proof of Concept (POC)
Definition:
The Development Plan that defines the minimum number of experiments/studies that
provides the critical data that are required to fundamentally change (increase or
decrease) the p(TS) sufficiently to drive a Go/No Go Decision
Key parameters:
Clinical efficacy, receptor occupancy, safety and tolerability, drugability
Typically includes:
Small controlled study, <4 sites, <100 subjects/patients, short in duration (1-3 months)
Serves as a major investment decision and will therefore be reviewed and approved
by PMC with recommendation from the Program Team and PCAT II
Important Distinction:
While there are many opportunities for an Early Decision (Quick Kill) the key
defining element of the POC is that it significantly changes the p(TS) driving a
Go/No Go Decision
The Leading Edge: FAST Contracts
4/11/2013
FAST-AS: Autism spectrum
FAST-PS: Psychotic disorders spectrum
FAST-MAS: Mood-Anxiety spectrum
Similar language for all three solicitations
15
FAST Contract (Under Final Review)
Goals: Enhanced understanding of underlying
mechanisms and development of innovative treatments
Early phase clinical trials (FIH, POCM)
New compounds and repurposed drugs
Experimental medicine paradigm of Fast-fail trials
Aligned with RDoC: focus on fundamental
mechanisms that cut across traditional diagnostic
categories (e.g., working memory)
4/11/2013
16
Weighing priorities for targets & compounds
Robust pre-clinical data
Identifying top molecular targets
Clinical targets: e.g., RDoC domains/constructs
Receptor occupancy: PET ligand availability
Functional measures: e.g., EEG/ERPs, PPI
IND
Extant clinical data Phase I or beyond
4/11/2013
17
Phase II (Efficacy Studies in Patients)
Randomized, usually
placebo-controlled trial(s) in
which drug is administered at
either various fixed or
variable doses to establish
efficacy and further evaluate
safety in carefully selected
groups of patients (often
around 50 or less pts per arm)
Ideally, sufficient dose
ranging is provided to predict
right doses for pivotal
registration trials
Studies in this phase can
meet FDA pivotal efficacy
standards (e.g. ADHD)
Phase
II
Phase III (Registration Quality Trials)
Pivotal Efficacy:
At least two positive (usually
requires several to achieve)
Double blind safety & efficacy
data
Broader Safety Data (>1500pts):
Can be open to address:
Age & Gender
Duration (1 yr or more)
Special populations (especially if
PK issues)
Characterizing Response
Patients most likely to respond
Optimal dosing schedule
Switching treatments, etc.
Phase
III
Phase IV (Post-Marketing Studies)
Who? As larger and
larger real world
patients are studied who
benefits most?
What? Best way to use
drug in terms of timing,
titration or not, combing
with others,etc
Why? Differentiate
from existing drugs
interms of safety,
efficacy, ease of use..
Must. If FDA requires
monitoring for safety,
study in children, etc.
Phase IV
Typical Program Team
Market
Research,
Market
Planning
Discovery
Regulatory
Clinical
Pharmacology
Toxicology
Absorption,
Distribution,
Metabolism,
Excretion (ADME)
Quality
Assurance
CM&C
Regulatory
Therapeutic Area
Toxicology
Project
Leader
Medical MD/Clinical
Research Administrator
(CRA)
Program Team
Leader
Development
Project
Management
Clinical Trial
Material
Product
Develop- Process
ment
DevelopAnalytical
ment
Clinical Project
Management
Data
Management
Affiliate
Medical
Medical
Systems
Quality
