The Basics of Drug Development Science Nothing to be scared of!
Or
Which Way to the Clinic?
IRMA Webinar September 28, 2010
Jim A. Turpin, Ph. D.
Preclinical Team Leader
Topical Microbicide Branch
Prevention Science Program
NIAID, Division of AIDS,
DHHS/NIH Required Disclaimer
The views expressed are those of the presenter and do not
necessarily reflect the official policies of the Department of Health
and Human Services (HHS), nor does mention of trade names,
commercial practices, or organizations imply endorsement by the
U.S. Government
DHHS/NIH/NIAID/DAIDS
Today's talk
Touch on the following :
What is drug development?
Basic Science behind drug development
Will use prevention and microbicides as a context for discussion
Everything I say can be applied to other drug development efforts
with appropriate modifications
A complex process but will take the 20,000 ft view
DHHS/NIH/NIAID/DAIDS
Definition
Lead or Candidate
A compound or proposed new chemical entity (NCE) with
properties or characteristics that make it appropriate for further
development
The terms can be applied interchangeably to any stage of the drug
development process
Emphasize that a selection (elimination) has occurred
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In a Nutshell
What is drug development?
Identifying candidates/leads for clinical testing that
will improve health or meet a medical need
To accomplish this we must integrate and balance:
 Scientific knowledge
 FDA Requirements
DHHS/NIH/NIAID/DAIDS
Drug Development: Opposing Forces
1 or 2
100,000
To
1,000,000
Number of Compounds
I
Discovery
Preclinical
Virology
$.01 to $1.00
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Preclinical
Studies
(Critical Path)
II
III
Clinical Studies
Cost of Development
Per Compound
Deployment
$ millions
Drug Development : Thy Name is Attrition
FACTOIDS
Average time from Discovery to Phase III trials : 12 years
Probabilities of Success
Discovery to Clinical Testing: ~11 %
Initial lead identification, i.e. screen random library
Chances of success ~ 1: 10,000 that a compound will go to clinical testing
Can raise to 1:100 to 1:1000 if working on a series of compounds
Clinical testing:
38% drop out in Phase I
60% percent drop out in Phase II
40% fail in Phase III
Of successful Phase III candidates only 23% are approved as drugs by the FDA
DHHS/NIH/NIAID/DAIDS
Where Do We Lose Candidates/Leads?
Ismail Kola & John Landis
Nature Reviews Drug Discovery 3, 711-716 (August 2004)
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Drug Development and the Pipeline Concept
Everyone talks about pipelines --Adjectives galore: robust, vibrant, sustainable
A pipeline is a way to describe and conceptualize a drug
development process involving many candidates/leads
DHHS/NIH/NIAID/DAIDS
Pipelines are Defined by Their Goal
Microbicides as the Example
Must protect healthy and HIV infected men and women when used
vaginally, penile and/or rectally without harm
Harm= any effect that increases infection susceptibility or changes
disease course for the worse, directly or indirectly
May be used episodically or continually by individuals for decades
Drug development strategy is used to identify suitable compounds
to meet the above requirements proactively and efficiently to
create a sustainable effort that:
Generates new candidates/leads
Eliminates the unsuitable
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The Drug Development Pipeline
Example: Microbicide Development
Preclinical
Virology
Discovery
Preclinical
Studies
(Critical Path)
Pilot
Studies
I
II
Clinical Studies
III
Deployment
Product recycled
In
Pipeline
Product Recycled
Into Discovery
Successful
Microbicide
Or
Microbicide
Strategy
LEAD
Lead Identification
And
Optimization
Product
Eliminated
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Drug Development
Multiple activities driven by Milestones that may occur
sequentially or simultaneously
Gantt Charts—A Tool of Industry
2
1
Preclinical
Virology
4
3
5
6 Years
7
8
9
10
S
Formulation
S
Pre/generic Formulation
Optimized Formulation
Manufacturing
S
Analytical Method Development
GMP Production
Clinical Batches
Pre Clinical Studies
S
(Acute Toxicology etc.)
Additional Toxicity studies
S
(Chronic Toc. , Repo. Etc.)
Pre IND /IND
S
Clinical Trial Activities
Protocol Development
Phase I
S
Phase II
S
Phase III
S
S
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GO/NO GO Decisions
Intermediate GO/NO-GO Decisions
Drug Development and Pipelines are not Uni-Dimensional
Primary Path
Discovery
Iterative Screen
Time
Targeted Expansion
Path
Library of
Compounds
>100,000 to 1,000,000
Lead Expansion
Path
Successful
New Target
Failure
Library of
Compounds
>100,000 to 1,000,000
1000
100
New Limited
Synthesis
10
1000
Clinical
Preclinical
Lead(s)
Toxicology
Pharmacology
Formulation
Manufacturing
Phase I
Phase II
Phase III
Phase IV
Product
100
Lead(s)
Toxicology
Pharmacology
Formulation
Manufacturing
Phase I
Phase II
Phase III
Phase IV
Product
10
Lead(s)
Toxicology
Pharmacology
Formulation
Manufacturing
Phase I
Phase II
Phase III
Phase IV
Product
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100
10
10
Lead(s)
Lead(s)
Toxicology
Pharmacology
X
Toxicology
Pharmacology
Formulation
Manufacturing
Phase I
Phase II
Phase III
Phase IV
Product
The Challenge of the Basic Science of Drug
Development is
Finding the right needle in the right hay stack
And once it is found confirming the needle you found is
the one you were looking for
Doing all of this in sustainable fashion
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The Foundation of Drug Development is:
Scientific knowledge
We must understand the disease to be able to find
candidates/leads to prevent or treat it
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HIV drug development has to account for:
What we do not know
In HIV Infection
1. What form of the virus infects?
1. Cell –free
2. Cell-associated
3. Both
2. How does virus get to its target cells?
1. Micro-trauma
2. Translocation
3. Permeation
4. Cell capture
3. What is the first cell infected?
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HIV drug development must also account
for:
What we think we know
The data, models and observations we use to
describe the process of HIV transmission
and infection are subject to change as we learn more
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HIV Replication Cycle and Prevention Targets
Other Membrane targets
Rafts, lipids, etc.
Entry
X
Coreceptor
Attachment
X
Infectivity
X
X
X
Integrase
RNA
Integration
Translation
Transcription
Protease
Genomic RNA
Pr 160 gag/pol
Pr55gag
gp120/gp41
Immature Virion
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Reverse
Transcription
APOBEC 3G
Trim 5a
gp160
Target Tissues
Female Genital Tract
Cervix
Uterus
GI Tract
Anus
Vagina
Rectum
Introitus
Transition
Zone
DHHS/NIH/NIAID/DAIDS
Colon
Transition
Zone
Endocervix Ectocervix
Microbicides
Duration of Effectiveness?
Point
of no
return?
Haase
Nature Reviews
2010 464:217
DHHS/NIH/NIAID/DAIDS
Complex Microenvironment
1. Mucous
5. Innate defenses
2. pH
6. Target cell activation
3. Osmolarity
7. Distribution and coverage
4. Microbiota
Hendrix et al. Ann,.
Rev. Pharmacol.
Toxicol. 2009 49:349
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How do we decide what testing to do?
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First must ask:
What Are the Optimal “Drug” Characteristics
of a Candidate/Lead?
1. Ultimately driven by regulatory requirements to conduct clinical trials
2. FDA enforces regulations and provides guidance
3. No FDA guidance specific to microbicides
4. Most relevant FDA preclinical guidance is for antivirals:
Guidance for Industry Antiviral Product Development
http://www.fda.gov/OHRMS/DOCKETS/98fr/05d-0183-gdl0002-01.pdf
5. The needed properties can be divided into 4 general categories
1. Safety
3. Acceptability
2. Efficacy
4. Feasibility/Delivery
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Selected Properties of an Ideal Topical Microbicide
(FDA guidance)
Safety
Efficacy
Acceptability
Feasibility/Delivery
•
•
•
•
•
low in vitro toxicity and no systemic toxicity
Efficacy, In vitro --- In vivo (?)
Easily formulated and stable under likely storage conditions
Active in semen/seminal, cervicovaginal and rectal secretions
Low systemic uptake
• GMP and industrial scale production compatible
• Lack of effect on the microbiota: Lactobaclli
• Compatible with rectal use
• Acceptable to user
• Color, odor and taste compatible
• Overall ease of use- negotiable
• Does not negatively impact intercourse
• Compatible with condoms and other mechanical barriers
DHHS/NIH/NIAID/DAIDS
How do you Guidance into Drug Development?
The Role of the Algorithm
Algorithm: A set of rules or steps that results in achieving
the right answer in the shortest period of time
Algorithms and the Basic Science of Drug Development
1. Use best assays to pick the best candidates/leads
2. Basic Science driven
3. May include approaches to address gaps in knowledge
4. In Prevention---everyone has one
5. Tailored to the objectives and goals of the individual drug
development program
DHHS/NIH/NIAID/DAIDS
Finding Candidates/Leads:
NIAID Screening Algorithm
Objective:
Proof-of –feasibility as a proposed microbicide candidate
Primary Assays
CD4-dependent CCR5-tropic
1) Cell-associated HIV-1 transmission assay
2) Cell-free HIV-1 entry assay
TI <10 (colorless compound) or
TI <50 (colored compound)
Stop testing
TI >10 (colorless)
or >50 (colored)
TI <10 (colorless compound) or
TI <50 (colored compound)
Confirmatory Assays
Repeat of primary assays for confirmation of results
Stop testing
TI >10 (colorless)
or >50 (colored)
Secondary Mechanistic Assays
2) CD4-dependent CXCR4-tropic assays
a) HIV-1 cell-associated transmission assay
1) CD4-dependent CCR5-tropic fusion assay
b) HIV-1 entry assay
c) HIV-1 fusion assay
3) CD4-independent (ME-180) assay
Most highly ranked compounds
Specialized Assays
1)
2)
3)
4)
Human cervical explant model
Human PBMC clade panel testing
Combination drug assays
Specialized toxicity assays (Vybrant™ and LIVE/DEAD®)
DHHS/NIH/NIAID/DAIDS
Antimicrob Agents Chemother. 2008 52:1768-81.
Algorithms Addressing FDA Requirements
CONRAD Algorithm
IPM Algorithm
Courtesy of Gustavo Doncel
Courtesy of Joe Romano
Preclinical Testing Algorithm for Multi-Purpose Drug Candidates
Compound
CV Safety
Efficacy
HIV
In vitro
• X4/R5, CF/CA, LA/CI, clades
• Cell lines, pri cells, explants
• Env factors (pH, SP, CVS, F)
• Resistance
Animal Models
• Humanized mice
• NHP (S/M Dose)
Other STPs
In Vitro / Ex vivo
Models
• FRT epithelial cells
• Immune cells
• CV explants
• Lactobacilli
Endpoints
• Cell viability and multiplication
• Epithelial integrity/permeability
• Inflammatory mediators
• Innate factors and antiviral activity
• Enhancement of infection
• HD, TV, CA, BV
Animal Models
• HSV, CT, NG
Contraception & Other
Repro Health Benefits
In vitro
• Sperm viab, motil, function
Animals Models
• Rabbit/monkey
In Vitro
Models
• Epithelial cell monolayer
• Dual chamber/explant
Endpoints
• Absorption
• [API/active metabolite]
• Inhibition of target
Animal Testing
In vitro
• HSV, CT, NG
Pharmacokinetics /
Pharmacodynamics
Animal Testing
Models
• Refined RVI
• Mouse safety/HSV susceptibility
• NHP
Endpoints
• Histopathology
• Epithelial integrity
• Inflammation
• Immune response
• Enhancement of infection
DHHS/NIH/NIAID/DAIDS
Models
• Rabbit, rodent, NHP
– PK alone or w/ safety
– PK + efficacy (ex vivo/in vivo)
Endpoints
• [Drug] in CV mucosa, plasma,
CVS
• [Active metab] in target cells
• Inhibition of target/infection
• ADME
Common Themes?
Safety and Activity
 Safety- In vitro cytotoxicity
 Activity---Efficacy
 Effect in Ex Vivo Tissue Model (Explants)--Safety and Efficacy
 Animal Model--Efficacy
 FDA required testing—Safety (Critical Path)
DHHS/NIH/NIAID/DAIDS
Tenofovir (TFV, PMPA)
NRTI
UC781
NNRTI
Dapivirine (TMC120)
NNRTI
Lets Develop a Microbicide Candidate!
VivaGel™ (SPL7013)
Entry
DHHS/NIH/NIAID/DAIDS
Maraviroc
CCR5
Microbicide Candidate?
 Safety- In vitro Cytotoxicity
– Safety = cytotoxicity--Usually determined simultaneously with efficacy
– General guidelines (any cytotoxicity is a concern)
• No toxicity Cell lines, Primary cells, i.e. PBMCs
• No toxicity on genital and GI epithelial cells
• No toxicity to endogenous H2O2 producing Lactobacilli
DHHS/NIH/NIAID/DAIDS
Microbicide Candidate?
 Activity in:
• General anti-HIV activity
• Is the mechanism of action compatible with microbicide
use?
• Effect of:
• Cervical mucous/secretions and/or GI and secretions
• Semen/Seminal fluid
• Environmental pH
• Inhibits multiple HIV clades/subtypes of virus
• Resistance
• How quickly generate
• Effect on antiviral activity
• Cross Resistance
• Severity
• Combinations with other candidates or drugs
DHHS/NIH/NIAID
Microbicide Candidate?
• Effect in Ex Vivo Tissue Model
– First chance for tissue exposure to unformulated
or formulated microbicide
• Toxicity
– Metabolic viability—MTT assay
– Histology
• Activity
Tissue on support matrix
– Inhibition of HIV replication
Microbicide
Virus
Wash
DHHS/NIH/NIAID/DAIDS
Microbicide Candidate?
• Animal model testing (efficacy)
• Humanized mice
• NHP
•Role of efficacy
• Researcher--argument for “Biological Plausibility”
• FDA--optional but preferred to be active
DHHS/NIH/NIAID/DAIDS
Microbicide Candidate?
SAFETY: The Critical Path
Studies required by FDA
International Conference on Harmonization (ICH)
guidance are also used
Goal of the Critical Path:
Prepare for testing in humans by looking for any issues
that will affect safety and/or feasibility
DHHS/NIH/NIAID/DAIDS
Critical Path: Translation from Preclinical to
Clinical Testing?
Preclinical Studies
General Preclinical Virology







Antiviral activity
Toxicity Cell lines/Primary cells
Range of Action--Subtypes
Mechanism of Action
Resistance
Combination
Relevant Matrices
Preformulation
↓GLP
Lab
 Effect on Lactobacilli
 Effect of Matrices
–Seminal Plasma
–Cervical fluid
–Mucin
 Other STIs
 Cervical Explants
 NHP iVag transmission
 Rabbit Vaginal/Rectal Irritation testing
 Systemic Absorption by iVag or iR.
 Penile Irritation
Chemistry Manufacturing and Control (CMC)
Must be carried out in
accordance with the CFR
for GLP and GMP studies
GMP
Unformulated
Active Pharmaceutical
Ingredient (API)
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PK and Toxicology GLP
 Condom Compatibility GLP
Animal GLP
Formulation
 Stability
 Sterility
 Release
Microbicide Specific
Formulated
Gel or Ring
Stability, Sterility, Purity, Packaging
Systemic Absorbance?
iVag. or iR.
.
Yes







No
Genotoxicity
Acute Toxicity
Maximum tolerated dose (MTD)
Chronic Toxicity, 90+ days
PK and Metabolites (ADME)
Carcinogenesis
Reproductive toxicology
–Seg. I Reproductive performance
–Seg. II Teratology
–Seg. III Perinatal/Post natal
 Dermal/systemic Hypersensitivity
 Dermal/ systemic Photosensitivity
 Others, if applicable-Lung, CNS, Heart etc.
Applicator GMP
Selection Compatibility
Acceptability
Filling
Take Home Messages
Drug development is a process
The process is controlled by multiple factors
• FDA regulations and guidances
• Basic science of HIV infection
• Evolving knowledge of what might work
The basic science of drug development is a process to
select the candidate(s) with the best chance of success
DHHS/NIH/NIAID/DAIDS
AND FINALLY:
Jim Turpin’s slightly twisted final thoughts on the
Basic Science of Drug Development
 A challenge --not for the faint-hearted
 Must embrace the Zen of Candidate Reduction
It is never too early or late to eliminate a candidate
and if you do-- kill it dead---put a stake through its heart, and
bury it at midnight at a crossroads –No Regrets Allowed
 The process is ever evolving—flexibility of mind is good!
 Seems complicated but the roadmap is there, just gotta follow it
 Sometimes its one of the most rewarding things you can do because
it can change the world
DHHS/NIH/NIAID/DAIDS
Thank You
Questions?
Timbuk3 –The future is so bright I gotta wear shades!
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