Transcript Document

The HIV Prevention Pipeline:
A Future of Possibilities
IRMA Webinar August 23, 2012
Jim A. Turpin, Ph. D.
Branch Chief
Preclinical Microbicide and Prevention Research Branch
Prevention Science Program
Division of AIDS, NIAID, NIH
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
If your particular candidate, delivery system or prevention strategy
is not presented--I apologize in advance
Today I Will Address the Question:
Do we currently have what it takes to create a
sustainable prevention pipeline?
DAIDS/PSP/PMPRB
To Answer the Question I Need to Change Your
Perception of What the HIV Prevention Pipeline Is
Pipeline
Library of
Compounds
>100,000 to 1,000,000
Combinations
1000
Integrase
100
CCR5
Truvada
10
UC78
CS
PRO2000
BG
Carraguard
Savvy
Preclinical
TMC120
Toxicology
Pharmacology
Formulation
Manufacturing
Clinical
Lead(s)
TFV
Phase I
Phase II
Phase III
Phase IV
Product
N9
DAIDS/PSP/PMPRB
Start by looking back!
DAIDS/PSP/PMPRB
Prevention Clinical Trials: The Good, the Bad, and the Ugly
Trial
Population, Regime, Drug
Overall Efficacy (CI)
Recalculation
Comments
CAPRISA 004
Women, Vaginal BAT24
1% tenofovir gel
39%
(6 to 60%)
Gel use:
Low
28%
Middle 38%
High 57%
HSV-1 efficacy 51%
(22% -70%)
iPrEx
MSM
Truvada , Oral, Daily
44% (15 to 63%)
FEM-PrEP
Women
Oral, Daily, Truvada
Stopped , no chance for efficacy determination
No safety issues reported
Partners in
PrEP
Serodicordant couples
Oral, Daily, TDF or Truvada
TDF: 62% (34 to 78%)
Truvada: 73% (49 to 85%)
TDF-2
Men (54%), Women (46%)
Oral, Daily, Truvada
63% (21 to 83%
HPTN052
Serodicordant couples
Early ART CD4 350-550
Late ART CD4 >250
96% (82 to 99%)
VOICE
Women Daily
Oral TDF or Truvada
1% Tenofovir Vaginal Gel
September 16, 2011 discontinue Oral Tenofovir arm
November 28, 2011 discontinue 1% Tenofovir gel arm
August 13, 2012 last subject out ---reporting Q1 2013
ASPIRE
Phase III 3500 Women
Silicon Intravaginal Ring Dapivirine
Enrollment started July 24, 2012
The Ring Study (IPM 027) 400 enrolled of 1650
DAIDS/PSP/PMPRB
Verified drug use
77.9% (41 to
93%)
Female: 63.6% of HIV+
endpoint
Early ART superior
41% lower risk
HIV Prevention in the Summer of 2012
June, 2010
July, 2011
Chinese Proverb/Curse:
May You Live in Interesting Times!
DAIDS/PSP/PMPRB
2012
Evolution
Charles Darwin
Charles Sanders Peirce (Father of Pragmatism)
“It is not the strongest of the species that
survives, nor the most intelligent that
survives. It is the one that is the most
adaptable to change.”
“All the evolution we know of proceeds from the
vague to the definite.”
Efficacy
Adherence
Prevention
Pipeline
Basic
Research
Acceptability
Safety
The objective of the prevention pipeline must be to evolve a candidate to the
safest, most effective and acceptable prevention strategy
DAIDS/PSP/PMPRB
Evolution of the Prevention Pipeline
For pipelines the forces of evolution are also controlled
by the realities of the down-selection process inherent
in identifying and advancing lead candidates:
 Dollars versus doability--What can be accomplished with budgets
and makes sense to undertake
 Complex preclinical, clinical and regulatory requirements
 Need for Sustainability—continually deliver new and improved
prevention strategies
DAIDS/PSP/PMPRB
Dollars versus Doability: Opposing Forces
1 or 2
100
To
1,000,000
Number of Compounds
I
Discovery
$.01 to $1.00
DAIDS/PSP/PMPRB
Preclinical
Virology
Preclinical
Studies
(Critical Path)
II
III
Clinical Studies
Cost of Development
Per Compound
Implementation
$ millions
Complex Requirements
R&D
Supply
In vitro
Validation
In Vivo
Validation
Virology
Pharmacology
Toxicology
Preclinical Studies
Clinical
Testing
SAFETY
Clinical
Testing
Phase IV
Studies
Marketing
Distribution
OTC
Product
Consumer
EFFICACY
Pre formulation + formulation
Implementation
Chemistry, Manufacturing and Controls (CMC)
Determined by the
properties of the inhibitor
and delivery system
Code of Federal regulation
(CFR) for GLP and GMP are
primary determinates
State, Federal and
Local Regulations
Federal, State and Local
regulations may apply to
specific activities
FDA requirements
• Virology
• Toxicology
• CMC
Consumer preferences
and needs
Drug Developer Concerns
• Meet a desired outcome
• Potential for advancement
DAIDS/PSP/PMPRB
•
•
•
Cost of product
Ease of synthesis
Marketing outlook
• Long term safety
• Profit and loss
• Next generation products
Sustainability
Initial Pipeline
Discovery
Iterative Screen
Time
Targeted Expansion
Library of
Compounds
>100,000 to 1,000,000
Lead Expansion
Successful
New Target
Failure
1000
1000
100
100
New Limited
Synthesis
10
10
Clinical
Preclinical
Lead(s)
Toxicology
Pharmacology
Formulation
Manufacturing
Phase I
Phase II
Phase III
Phase IV
Product
Lead(s)
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
DAIDS/PSP/PMPRB
Library of
Compounds
>100,000 to 1,000,000
10
Lead(s)
Toxicology
Pharmacology
X
Toxicology
Pharmacology
Formulation
Manufacturing
Phase I
Phase II
Phase III
Phase IV
Product
However, we must not get lost in the complexity of the task
Drugs:
ARV/Non-ARV
Small Molecule
Peptide
Protein
Natural Products
Nucleic Acid
Other
Strategies
Systemic
Topical
Dosage Form:
Pills
Injectable
Implantable
Sustain. Release
Gels/films/tablet
DAIDS/PSP/PMPRB
Dosing:
Peri-Coital
Daily
Monthly
Quarterly
Longer?
Courtesy of Joe Romano
Our Question:
Do we currently have what it takes to create a
sustainable prevention pipeline?
To answer we must examine 2 critical
elements of the prevention pipeline:
1. Delivery systems
2. Candidates
DAIDS/PSP/PMPRB
We will look at:
Delivery systems
• Currently in clinical trials
• Next generation- in development
• The future
Candidates
• Now
• To 2015
• 2015 to 2020
• Emerging Candidates
DAIDS/PSP/PMPRB
Delivery Systems
Systems Currently in Clinical Trials (Phase I to III)
Vaginal gels
Silicon Rings
Oral
Tenofovir
Dapivirine
FACTS 001
Aspire
Rectal Gels
Truvada,
Maraviroc,
Maraviroc + FTC
Maraviroc + Dapivirine
HPTN 069
MTN 013/IPM 026
Tenofovir
CHARM, MTN 013
DAIDS/PSP/PMPRB
Injectable
TMC278 LA
BMGF
Next of Generation Delivery Systems In Development
Devices +/- Gels
Other gels
Vaginal Films
pH transition
Subliming Solid matrix
Segmented Rings
Rings with other polymers
DAIDS/PSP/PMPRB
Pod Rings
Injectables
Quick Dissolve Tablets
Some Thoughts on Rings
Where ?
Polymer
Options
Types of Rings
Matrix
Silicon
Ethyl Vinyl Acetate (EVA)
Polyurethanes
Barnhart et al.
Contraception, 2005 72:196
DAIDS/PSP/PMPRB
Reservoir
Further Thoughts on Rings
Segmented
Advantages
Johnson, et al. Eur. J. Pharm. Sci. 2010
39:203
 Release chemically
incompatible drugs
Pod (Versaring™)
 Control drug release
• Segmented-size of segment
• Pod-# of pods, size of pore
Pod
Baum et al. J. Pharm Sci 2012 101:2833
DAIDS/PSP/PMPRB
Pore
Some Thoughts on Vaginal Films
Water-soluble polymers designed to dissolve in the
vagina and release its active ingredient
Films Under Development:
PMPA
Dapivirine
Maraviroc
IQP0528
RC101
ADVANTAGES
 Precise and Reproducible dosage form
 Low unit dose cost (fractions of a penny/dose)
 Minimal leakage
 Can be used to deliver multiple active agents
 No applicator
 Scalable manufacturing process
(Listerine Pocket Paks >200,000 million units sold/yr.)
Courtesy of Lisa Rohan
DAIDS/PSP/PMPRB
Thoughts on Injectables
Very Exciting Development, But------Very Limited pipeline
• TMC278LA: (Janssen/BMGF)
NNRTI
• S-GSK1265744: (744 LA, Viiv)
Integrase inhibitor
Major strength of the injectible approach
• Long half-life---weeks to months
DAIDS/PSP/PMPRB
Lots of Delivery Options, But Will Women and
Men Use Them!
Optimizing for delivery device acceptability/adherence
Formulation
Scientist
Rheological parameters
• Compatibility with drug
• Viscosity
• Osmolarity
• Shearing
• Stickiness
• Mixing /miscibility
• Color
• Spreading
• Coating
• Adhesion to surfaces
Behavioral
Scientist
Link
Rheological
with
Women’s perception
Identify specific formulation
characteristics that yield specific
women responses
Handling
DAIDS/PSP/PMPRB
Intercourse
Use
Decisions
•
•
•
•
•
•
•
Perceptions
Leakage
Wetness
Sexual pleasure
Sexual comfort
Removal & disposal
Long residence
Application
Kate Morrow , Brown Univ.
David Katz, UNC
John Hayes, Penn. State. Univ.
Greg Ziegler, Penn. State Univ.
The Future!
Nanotechnology
DAIDS/PSP/PMPRB
Nanotechnology for Prevention
Increasing Delivery Options
Drug
Drug
in
Nanoparticles
Drug-containing
Nanoparticles in:
Vaginal Film
or
Normal Tissue
Drug alone
Drug
in
Nanoparticles
Vaginal Ring
Vaginal
Lumen
Ham, et al. Pharm. Res. 2009 26:502
DAIDS/PSP/PMPRB
Pictures courtesy of
Lisa Rohan
A Novel Approach for Delivery
Electrospun Nanofibers




A new delivery platform
Multiple types of drugs
Combinations
Time release
 Biodegradable
 Potentially cost effective
 MPT compatible
Courtesy of Kim Woodrow, Univ. of Washington
DAIDS/PSP/PMPRB
Our Question:
Do we currently have what it takes to create a
sustainable prevention pipeline?
We have delivery systems
Do we have the candidates?
DAIDS/PSP/PMPRB
structural formula:
Candidates
In Clinical Testing
Next-Generation–to 2015
Single
Tenofovir (TFV)
NRTI, Gel
Dapavirine (TMC120)
NNRTI, Ring
Maraviroc
CCR5, Oral, Ring
+
Truvada
Emtricitabine +
Tenofovir Disoproxil Fumarate (TDF)
Oral
Truvada
TFV
Maraviroc
Dapivirine gel
IQP 0528 (NNRTI/Entry)
TDF
Ring (pod)
Ring, Film, Tablet
Gel, Film
Film, Ring
Gel, Ring
Ring (pod)
Combinations
Maraviroc + TFV
Dapivirine + TFV
MIV-150 (NNRTI) + Zn
IQP0528 + TFV
Ring, Gel
Ring, Film
Gel (Carrageenan)
Ring
Injectable
TMC278LA
Nano-Liquid
S-GSK1265744 (744 LA) Liquid
DAIDS/PSP/PMPRB
In Development 2015-2020
(Select small molecule inhibitors)
Candidate
Sponsor
Comments
RT Inhibitors
4’E-2FdA (NRTI)
Michael Parniak
(Univ. Pitt.)
Preclinical development, highly potent
memory effect
Film, Ring (pod)
Entry Inhibitors
BMS793 (DS003)
IPM
Licensed from BMS
gp120 Inhibitor, Preclinical development
Gel, Ring
Virucidal and Novel Mechanism
NCp7 inhibitors
PD 404,182
Ettore Appella
(NCI)
Targets HIV NCp7, ejecting Zn from its Zn
finger, protected 5 of 6 NHP as a gel
Ring
A. M. Chomoun
Unknown Mechanism of action -Virucidal
(Texas A&M)
Immune Modulatory
Glycerol Monolaurate
(GML)
DAIDS/PSP/PMPRB
Ashley Haase
(Univ. Minn.)
Protected in Monkeys, Phase 1 completed
Gel
The Protein Microbicides –An Emerging Class
Candidate
Sponsor
Comments
Protein Microbicides (Ready for clinical testing)
5P12 RANTES
Mintaka Foundation
(Geneva Switzerland)
CCR5 inhibitor, Phase 1 in progress?
Gel
Griffithsin
K. Palmer
(Univ. Louisville)
Entry inhibitor: Preclinical development, Plant produced microbicide
Gel
Anti-HIV mAb (4E10, VRC01)
Deborah Anderson
(Boston Univ. Med. School)
Plant produced broadly neutralizing HIV monoclonal antibodies:
Mapp Biopharmaceuticals and Reprotect collaborating
Duet + Film, Ring (pod)
Protein Microbicides (Formulated)
RC101 (retrocyclin)
Alex Cole
(Univ. Florida)
Entry inhibitor: Preclinical development
Film, Ring (pod)
PIE12 trimer
Michael Kay
(Univ. Utah)
Highly potent HIV entry gp41 inhibitor
Ring
C5A
Philippe Gallay
(Scripps Research Inst.)
Virucidal
Sublimable Solid Matrix
Protein Microbicides (In development)
Peptide Triazoles
Irwin Chaikin
(Drexel Univ.)
Entry inhibitor
DARPins
Melissa Robbiani
(Population Council)
Bio-optimization of naturally occurring ankyrin repeat proteins,
inhibit HIV entry by binding to Env. Design alternative to antibodies
DAIDS/PSP/PMPRB
ON THE HORIZON
OR
AT THE FAR EDGE OF KNOWN SPACE
Bioengineered microbicides
 Endogenous (vaginal, GI tract) bacteria expressing protein
microbicides
Immunomodulation as a prevention strategy
 TLR and other pattern recognition receptor inhibitors and
antagonists
Abasic Phosphorothiolate 2’ Deoxyribose 14-mer (PDB)
Antiviral and Anti-inflammatory (Peter Katsikis, Drexel Univ.)
Genetic microbicides
 siRNAs (multiple investigators)
 Adenovirus vector delivered microbicides
(Wayne Marasco, Harvard Medical School)
DAIDS/PSP/PMPRB
Live Bacteria Delivery Systems
Recent advances in Lactobacillus delivered microbicides
Lagenaur et al. Mucosal Immunol. 2011
4:648
Li et al. J. Acquir. Immune Defic. Syndr.
2011 58:379
Lactobacillus bioengineered to
express the HIV entry inhibitor
Cyanovirin-N (CV-N) protect 4
of 12 monkeys and reduce viral
load in infected
Bioactive CV-N was detected in
rectal secretions after feeding
monkeys with bioengineered
Lactobacilli in yogurt
Remaining Issues
1 Immunotoxicity: Unknown
in Humans if there will be immune responses to prevention
protein in the bioengineered bacteria and/or loss of tolerance to endogenous bacteria
2 Colonization: Will bioengineered bacteria stably colonize without some environmental
advantage, e.g. antibiotic pre-treatment
3 Regulatory Requirements: Genetically Modified Organism (GMO)
4 Human Trials: Unique trial designs will be needed to assure environment control and
removal of GMO and restoration of normal microbiome in subjects
DAIDS/PSP/PMPRB
Our Question:
Do we currently have what it takes to create a
sustainable prevention pipeline?
We have delivery systems
We have the candidates
DAIDS/PSP/PMPRB
The Answer
Do we currently have what it takes to create a
sustainable prevention pipeline?
YES—we have the necessary depth and
numbers of delivery systems and
prevention drug candidates to create a
sustainable prevention pipeline
DAIDS/PSP/PMPRB
But a Sustainable Pipeline is Not a Slam Dunk
Some Additional Challenges
1. What criteria(s) must the delivery system and candidate meet (down-selection) to
advance to clinical testing?
• Delivery formats (Gel, Film, Ring, Tablet, Injectable, Oral )
• Candidates
2. Do any of our options hold the key to global acceptability/adherence or will we
need a range of delivery systems to satisfy needs and how will we manage this?
3. With devices now allowing combinations of biophysically diverse compounds, how
do we manage the potential proliferation of combination strategies?
4. Roll-out and beyond challenges—How do we
• Maintain supplies of drug and vehicles?
• Manage the ecological and biological impact of non-biodegradable delivery
devices that may contain residual drug ?
DAIDS/PSP/PMPRB
Final Thoughts and Take Home Messages
One of our greatest prevention challenges in the next
decade will not be that we lack options, but
prioritizing to advance the best prevention options
The prevention field is positioned to not only
optimally deliver prevention strategies, but to also
provide a range of delivery choices to men and
women
The prevention pipeline is not static and limited to
only “here and now candidates”, the door is open and
the infrastructure is there for continued evolution of
HIV prevention strategies.
DAIDS/PSP/PMPRB
Acknowledgements
Jim Pickett and IRMA
For slides and discussions:
Chelsea Polis
Joe Romano
Lisa Rohan
Tom Smith
Chuck Wira
Kim Woodrow
PMPRB
James Cummins
Anabel Lowry
Leslie Marshall
Cherlynn Mathias
Hans Spiegel
PSP
Fulvia Veronese
The many investigators who are making the HIV Prevention Pipeline a reality
Lyric by Timbuk 3 –The future is so bright I gotta wear shades!
DAIDS/PSP/PMPRB