Download - Session 1-1 William Potter.pdf
-
8/10/2019 Session 1-1 William Potter.pdf
1/21
Project Phase
ProjectSanction
ProgramSanction
Program Phase
ProductDecision
Product Phase
Overall Drug Discovery and
Development Process
Target
Identification
and
Validation
Assay
Development
Lead
Generation
QSV
Goals
Hypothesis
GenerationCandidate Development Commercialization
Phase
III
Submit Global
LaunchGlobal
Optimization
LeadOptimization
FirstHuman
Dose
PhaseIA
PhaseIB/II
-
8/10/2019 Session 1-1 William Potter.pdf
2/21
Areas of Collaboration In Drug Development
Pre-ClinicalDevelopment
Phase 1 Phase 2 Phase 3
FHD
FEDLaunch
Compound
Screening
Lead
Optimization
Biology of Disease- Target ID
- MOA - Validation
Clinical Studies
- Consistent phenotyping
- Large-scale prospective trials
Biomarkers - Synthesis - Application
Phase 4
Target ID
Target Validation
Biobanks - Collection - Storage
-
8/10/2019 Session 1-1 William Potter.pdf
3/21
NIH Clinical Center,
CTSAsNIH Molecular Libraries
Initiative
TRND
FDA
Re-
view
Ph. IIIPh. IIPh. IDiseaseTarget
ID
Assay
Dev.HTS
Probe
to
Lead
Pre-
Clinical
FDA
IND
NIH Supported
Basic Research
CER
New NIH-FDA Partnerships
RAID
HMORN
PCORI
Where Does this Fit into The NIH NCATs Effort?
Target Validation Space
-
8/10/2019 Session 1-1 William Potter.pdf
4/21
Hits provide a suggestive relationship of molecular structure and biological
activity to the targetConfirmed 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 vivostudy or advanced mechanistic studies
Target
Active
Hit
Lead
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
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 vivoevaluation.
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 vivoexposure
-
8/10/2019 Session 1-1 William Potter.pdf
5/21
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 eventwith 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.
Lead GenerationKey Observations
-
8/10/2019 Session 1-1 William Potter.pdf
6/21
A col laborat ive enterpr is e among Discovery Scient ists for:
the selection of valid targetsfor drug discovery,
the design and implementation of relevant screens andtestingparadigmsthat will enable compound discovery and
for industry, the identification and optimization of proprietarymoleculesthat demonstrate potential to be refined into drugcandidates.
Hypothesis to Lead Generation
-
8/10/2019 Session 1-1 William Potter.pdf
7/21
2000-2001
Probabilistic Knowledge Based
Lead Discovery Science
1996-1999
Dominant I nf luences
HTS Driven Hit Discovery
Combi-Chem
Maximum Diversity
Screen for Drug Promise
Target Validation Science
Bioinformatics
Target Platforms
Target Drugability
Quantitative Biology
Assay QualityADMET Profiling
Structural Sciences
IP Strategies
Biological Flowschemes
2004-2013
Learning
Technology
Diversified Lead Generation
Strategies
Computational Science
Library Sciences
Compound Quality
Targeted DiversityChemoinformatics
Receptor Panel Profiling
Chemogenomics
Systems Biology
Dominant I nf luences
Factored into Contemporary Lead Generation
-
8/10/2019 Session 1-1 William Potter.pdf
8/21
Knowledge BasedProbabilistic
Lead Generation Strategy
Target and
Gene Family Precedent
Little or No Discovery
Precedent
High Throughput Screening with
Maximal Diversity
Alternative Diversity (Natural Products)
Triage of Targets
Gene Target Platforms
I n SilicoHypothesis Generation
Computationally driven diversity
Targeted Libraries
Rational Design considering structural
biology and/or known ligands
Paradigm for Selection of Lead Generation Strategy
Poor historical performance
Library and assay quality are key variables
Follow-up paradigm can be complex depending
on quality of diversity and target biology
Higher p(TS) of Hit identification
Not all targets benefit equally from this approach
-
8/10/2019 Session 1-1 William Potter.pdf
9/21
Using integrative approaches and data to identify targets and biomarkers
from publicly available GWAS data
Published SNP
strongly associatedwith disease. Causal
gene not evident
Candidate causal genes and
pathways of disease with human
evidence
DRUG TARGET OR BIOMARKER
Causal Networks
OtherInformative
data
eSNPs
Raw public SNP data with weaker
associations
Pathway information
Genetics: mouse & human
RNA: multiple tissueseQTLs (SNP choice)
cQTLs
RNA-RNA correlations
Causality
Networks
-
8/10/2019 Session 1-1 William Potter.pdf
10/21
What Level of Characterization and
Optimization defines a Viable Lead?
Primary Assays
Binding/ Functional Assays
Biochemical/Cellular
Selectivity/Cytotoxicity
In silicoFilters
Secondary AssaysSelectivity:subtype/target family
Complex Cellular Assays
ADMET Surrogates
Tox Surrogates
BioPharm Surrogates
Tertiary AssaysADME
Animal Models
Surrogate Activity
Efficacy Model
Toxicology
BioPharm
ADME
I n Vivo Pharmacology
Toxicology
I n Vitro
Advanced I n Vitro
Attribute Profiling
Active
Lead
Components of a Biological Flowscheme
Hit
SAR
Clinical
Candidate
-
8/10/2019 Session 1-1 William Potter.pdf
11/21
Lead Optimization
Lead (molecules)
candidates are
identified through invitro and in vivo testing
Potency and selectivity
are enhanced
LeadOptimization
Optimize
-
8/10/2019 Session 1-1 William Potter.pdf
12/21
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
PhaseIA
PhaseIB/II
PhaseIB
-
8/10/2019 Session 1-1 William Potter.pdf
13/21
Phase IB (Multidose Safety Studies)
Drug is administered in multipleescalating doses to a relativelysmall number of healthyvolunteers and/or patients todetermine safety, steady-state
PK and establish MTD forsubsequent studies
Increasing use of phase IB toprovide evidence of efficacyand/or hitting biochemical
target (use of biomarkers andsurrogate endpoints).Sometimes extends to POC(proof of concept) small clinicaltrials (also called IIa)
PhaseIB
-
8/10/2019 Session 1-1 William Potter.pdf
14/21
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,
-
8/10/2019 Session 1-1 William Potter.pdf
15/21
4/11/2013 15
The Leading Edge: FAST Contracts
FAST-AS: Autism spectrum FAST-PS: Psychotic disorders spectrum
FAST-MAS: Mood-Anxiety spectrum
Similar language for all three solicitations
-
8/10/2019 Session 1-1 William Potter.pdf
16/21
4/11/2013 16
FAST Contract (Under Final Review)
Goals: Enhanced understanding of underlyingmechanisms 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 fundamentalmechanisms that cut across traditional diagnosticcategories (e.g., working memory)
-
8/10/2019 Session 1-1 William Potter.pdf
17/21
4/11/2013 17
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 dataPhase I or beyond
-
8/10/2019 Session 1-1 William Potter.pdf
18/21
-
8/10/2019 Session 1-1 William Potter.pdf
19/21
Phase III (Registration Quality Trials)
Pivotal Efficacy: At least two positive (usually
requires several to achieve)
Double blind safety & efficacydata
Broader Safety Data (>1500pts):Can be open to address:
Age & Gender
Duration (1 yr or more)
Special populations (especially ifPK issues)
Characterizing Response Patients most likely to respond
Optimal dosing schedule
Switching treatments, etc.
PhaseIII
-
8/10/2019 Session 1-1 William Potter.pdf
20/21
-
8/10/2019 Session 1-1 William Potter.pdf
21/21
Program TeamLeader
MarketResearch,
MarketPlanning
Discovery Regulatory
ClinicalPharmacology
Therapeutic Area
Medical MD/ClinicalResearch Administrator
(CRA)
Toxicology
Absorption,Distribution,Metabolism,
Excretion (ADME)
ToxicologyProjectLeader
DevelopmentProject
Management
Clinical ProjectManagement
QualityAssurance
CM&CRegulatory
Clinical TrialMaterial
ProductDevelop-
mentProcessDevelop-
ment AnalyticalMedicalSystems
Quality
AffiliateMedical
DataManagement
Typical Program Team