The HIV Prevention Pipeline: A Future of Possibilities

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 BranchPrevention 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

CS

TFV TMC120

CCR5Integrase

Combinations

N9

BGSavvy

CarraguardPRO2000

UC78

Library of Compounds

>100,000 to 1,000,000

10

100

Lead(s)

1000

Prec

linic

alCl

inic

al

Product

Phase IPhase IIPhase IIIPhase IV

Formulation Manufacturing

Toxicology Pharmacology

Pipeline

Truvada

To Answer the Question I Need to Change Your Perception of What the HIV Prevention Pipeline Is

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Start by looking back!

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Prevention Clinical Trials: The Good, the Bad, and the Ugly

Trial Population, Regime, Drug Overall Efficacy (CI) Recalculation Comments

CAPRISA 004 Women, Vaginal BAT241% tenofovir gel

39% (6 to 60%)

Gel use:Low 28%Middle 38%High 57%

HSV-1 efficacy 51% (22% -70%)

iPrEx MSMTruvada , Oral, Daily

44% (15 to 63%)

FEM-PrEP Women Oral, Daily, Truvada

Stopped , no chance for efficacy determinationNo 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% Verified drug use77.9% (41 to 93%)

Female: 63.6% of HIV+ endpoint

HPTN052 Serodicordant couples Early ART CD4 350-550Late ART CD4 >250

96% (82 to 99%) Early ART superior 41% lower risk

VOICE Women DailyOral TDF or Truvada 1% Tenofovir Vaginal Gel

September 16, 2011 discontinue Oral Tenofovir armNovember 28, 2011 discontinue 1% Tenofovir gel armAugust 13, 2012 last subject out ---reporting Q1 2013

ASPIRE Phase III 3500 WomenSilicon Intravaginal Ring Dapivirine

Enrollment started July 24, 2012The Ring Study (IPM 027) 400 enrolled of 1650

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HIV Prevention in the Summer of 2012

Chinese Proverb/Curse: May You Live in Interesting Times!

June, 2010 July, 2011 2012

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Charles Darwin     “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.”

Charles Sanders Peirce (Father of Pragmatism)

“All the evolution we know of proceeds from the vague to the definite.” 

PreventionPipeline

AdherenceBasic

Research

Acceptability

Safety

Efficacy

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Evolution

The objective of the prevention pipeline must be to evolve a candidate to the safest, most effective and acceptable prevention strategy

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

DiscoveryPreclinical Virology

Preclinical Studies

(Critical Path)Clinical Studies

I II III

Implementation

Number of Compounds 100To

1,000,000

1 or 2

Cost of DevelopmentPer Compound

$ millions

$.01 to $1.00

Dollars versus Doability: Opposing Forces

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Determined by the properties of the inhibitor and delivery system

Federal, State and Local regulations may apply to specific activities

Code of Federal regulation (CFR) for GLP and GMP are primary determinates

FDA requirements• Virology• Toxicology• CMC

State, Federal and Local Regulations

Consumer preferences and needs

Complex Requirements

Chemistry, Manufacturing and Controls (CMC)

Implementation

R&D

In vitro Validation

In VivoValidation Preclinical Studies

Clinical Testing

SAFETY

Clinical Testing

EFFICACY

Supply Marketing Distribution

Phase IV Studies

OTCProduct

Consumer

Pre formulation + formulation

VirologyPharmacology

Toxicology

• Meet a desired outcome • Potential for advancement

• Cost of product• Ease of synthesis• Marketing outlook

• Long term safety• Profit and loss• Next generation products

Drug Developer Concerns

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Sustainability

100

10

Library of Compounds

>100,000 to 1,000,000

100

Library of Compounds

>100,000 to 1,000,000

10

100

Lead(s)

1000

Disc

over

yIte

rativ

e Sc

reen

Prec

linic

alCl

inic

al

Product

Phase IPhase IIPhase IIIPhase IV

Formulation Manufacturing

Toxicology Pharmacology

Initial Pipeline

Lead(s)

Phase IPhase IIPhase IIIPhase IV

Formulation Manufacturing

Toxicology Pharmacology

10

Lead(s)

Phase IPhase IIPhase IIIPhase IV

Formulation Manufacturing

Toxicology Pharmacology

Product

Product

Lead(s)

1000

Product

Phase IPhase IIPhase IIIPhase IV

Formulation Manufacturing

Toxicology Pharmacology

New TargetTargeted Expansion Lead Expansion

10

Lead(s)

Toxicology Pharmacology

X

Successful Failure

Time

New LimitedSynthesis

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However, we must not get lost in the complexity of the task

Strategies

Systemic

Topical

Drugs:ARV/Non-ARVSmall Molecule

PeptideProtein

Natural ProductsNucleic Acid

Other

Dosing:Peri-Coital

DailyMonthlyQuarterlyLonger?

Dosage Form:Pills

InjectableImplantable

Sustain. ReleaseGels/films/tablet

Courtesy of Joe RomanoDAIDS/PSP/PMPRB

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

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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

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Delivery SystemsSystems Currently in Clinical Trials (Phase I to III)

Silicon Rings

Dapivirine Aspire

Maraviroc + Dapivirine MTN 013/IPM 026

Vaginal gels

Tenofovir FACTS 001

Rectal Gels

Tenofovir CHARM, MTN 013

Truvada,Maraviroc,Maraviroc + FTCHPTN 069

Oral Injectable

TMC278 LABMGF

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Next of Generation Delivery Systems In Development

Pod Rings

Vaginal Films

Segmented RingsRings with other polymers

Quick Dissolve Tablets

Other gelspH transitionSubliming Solid matrix

Devices +/- Gels

InjectablesDAIDS/PSP/PMPRB

Some Thoughts on Rings

Barnhart et al.  Contraception,  2005 72:196

Where ? Types of Rings

Silicon

Ethyl Vinyl Acetate (EVA)

Polyurethanes

PolymerOptions

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Matrix Reservoir

Johnson, et al. Eur. J. Pharm. Sci. 2010 39:203

Further Thoughts on RingsSegmented

Pod (Versaring™)

Baum et al. J. Pharm Sci 2012 101:2833

Pod

Pore

Advantages Release chemically

incompatible drugs

Control drug release • Segmented-size of segment• Pod-# of pods, size of pore

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Some Thoughts on Vaginal FilmsWater-soluble polymers designed to dissolve in the

vagina and release its active ingredient

ADVANTAGES Precise and Reproducible dosage form Minimal leakage No applicator Scalable manufacturing process     (Listerine Pocket Paks >200,000 million  units sold/yr.)

Low unit dose cost (fractions of a penny/dose)

Can be used to deliver multiple active agents

Courtesy of Lisa Rohan

Films Under Development:PMPADapivirineMaravirocIQP0528RC101

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Thoughts on Injectables

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

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Very Exciting Development, But-------

Optimizing for delivery device acceptability/adherence

FormulationScientist

Rheological parameters• Compatibility with drug• Viscosity• Osmolarity• Shearing • Stickiness• Mixing /miscibility • Color• Spreading • Coating• Adhesion to surfaces

BehavioralScientist

Perceptions• Leakage• Wetness• Sexual pleasure• Sexual comfort• Removal & disposal• Long residence • Application

Link Rheological

withWomen’s perception

Identify specific formulation characteristics that yield specific

women responses

Handling Intercourse

Lots of Delivery Options, But Will Women and Men Use Them!

Kate Morrow , Brown Univ. David Katz, UNC John Hayes, Penn. State. Univ.Greg Ziegler, Penn. State Univ.

Use Decisions

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The Future!

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Nanotechnology

Ham, et al. Pharm. Res. 2009 26:502

Nanotechnology for Prevention Increasing Delivery Options

Drug in

Nanoparticles

Pictures courtesy of  Lisa Rohan 

Drug Drug-containingNanoparticles in:

Normal Tissue

Vaginal Lumen

Drug alone

Drug in

Nanoparticles

or

Vaginal Film

Vaginal Ring

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A new delivery platform Multiple types of drugs Combinations Time release

Biodegradable Potentially cost effective MPT compatible

Electrospun Nanofibers A Novel Approach for Delivery

Courtesy of Kim Woodrow, Univ. of WashingtonDAIDS/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?

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Candidates In Clinical Testing Next-Generation–to 2015

Tenofovir (TFV) NRTI, Gel

Dapavirine (TMC120)NNRTI, Ring

MaravirocCCR5, Oral, Ring

structural formula:structural formula:

Truvada Ring (pod)TFV Ring, Film, Tablet  Maraviroc Gel, FilmDapivirine gel      Film, RingIQP 0528 (NNRTI/Entry) Gel, RingTDF            Ring (pod)

Maraviroc + TFV Ring, GelDapivirine + TFV Ring, FilmMIV-150 (NNRTI) + Zn Gel (Carrageenan) IQP0528 + TFV Ring

InjectableTMC278LA Nano-LiquidS-GSK1265744 (744 LA) Liquid

Single

Combinations

+

TruvadaEmtricitabine +

Tenofovir Disoproxil Fumarate (TDF)Oral DAIDS/PSP/PMPRB

Candidate Sponsor CommentsRT Inhibitors

4’E-2FdA (NRTI) Michael Parniak(Univ. Pitt.)

Preclinical development, highly potent memory effect Film, Ring (pod)

Entry Inhibitors

BMS793 (DS003) IPMLicensed from BMS

gp120 Inhibitor, Preclinical developmentGel, Ring

Virucidal and Novel Mechanism

NCp7 inhibitors Ettore Appella(NCI)

Targets HIV NCp7, ejecting Zn from its Zn finger, protected 5 of 6 NHP as a gelRing

PD 404,182 A. M. Chomoun(Texas A&M)  

Unknown Mechanism of action -Virucidal

Immune Modulatory

Glycerol Monolaurate (GML)

Ashley Haase(Univ. Minn.)

Protected in Monkeys, Phase 1 completed Gel

In Development 2015-2020(Select small molecule inhibitors)

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Candidate Sponsor CommentsProtein 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 microbicideGel

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 developmentFilm, Ring (pod)

PIE12 trimer Michael Kay(Univ. Utah)

Highly potent HIV entry gp41 inhibitorRing

C5A Philippe Gallay(Scripps Research Inst.)

VirucidalSublimable 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

The Protein Microbicides –An Emerging Class

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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

antagonistsAbasic 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)

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Remaining Issues1 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

Live Bacteria Delivery Systems

Lagenaur et al. Mucosal Immunol. 2011 4:648Lactobacillus bioengineered to express the HIV entry inhibitor Cyanovirin-N (CV-N) protect 4 of 12 monkeys and reduce viral load in infected

Li et al. J. Acquir. Immune Defic. Syndr. 2011 58:379Bioactive CV-N was detected in rectal secretions after feeding monkeys with bioengineered Lactobacilli in yogurt

Recent advances in Lactobacillus delivered microbicides

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

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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

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But a Sustainable Pipeline is Not a Slam DunkSome 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 ?

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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.

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Acknowledgements

Lyric by Timbuk 3 –The future is so bright I gotta wear shades!

Jim Pickett and IRMA

For slides and discussions:Chelsea PolisJoe RomanoLisa Rohan Tom SmithChuck WiraKim Woodrow

The many investigators who are making the HIV Prevention Pipeline a reality

DAIDS/PSP/PMPRB

James Cummins Anabel LowryLeslie Marshall

Cherlynn Mathias

Hans Spiegel

PMPRB

Fulvia Veronese

PSP