microbicides a women’s health priority: why, what, & where we are polly f. harrison, ph.d....

MICROBICIDESA Women’s Health

Priority:Why, What, & Where We

Are

Polly F. Harrison, Ph.D.Director, Alliance for Microbicide Development

Drexel University College of MedicineInstitute for Women’s Health & Leadership

2007 Sex & Gender Research ForumPhiladelphia, PA – 10 January 2007

Q. WHY? A. The numbers

USA yearly: 40,000 HIV infections» unchanged for > 10 years

World 2006: 4.3 million new infections» 11,000 each day

~ 50% of 39.5 million adults living with HIV/AIDS are female

Sub-Saharan Africa: HIV/AIDS prevalence 3x higher in women 15-24 than same-aged men

Q. WHY? A. Social structure, culture, behavior . . .

Most HIV infections spread by unprotected sex Current HIV prevention male-controlled &/or contraceptive Women lack means to protect selves if partners do not

use male condoms or allow use of female condoms Abstinence &/or fidelity unlikely to protect women married

(or in steady partnerships of presumed trust) or the sexually abused

(Penalties for “insistence” can be severe)

Anthony Fauci, Congressional Presentation, 12/12/06

So, what DO we have to prevent HIV?

education/behavior mod

condoms, other barrier methods

treatment/preventing drug/alcohol abuse

clean syringes (e.g., needle exchange)

interrupting MTCT PrEP STD treatment ♂ circumcision Vaccination

MICROBICIDES

Microbicides for Prevention of HIV-1 Transmission

Shattock RJ and Moore JP. Nature Reviews Microbiology, vol. 1 Oct/2003

The Pipeline Concept

BUT . . . is it really a straight line ?

DHHS/NIH/NIAID/DAIDS

Chemistry, manufacturing, and controls (CMC)

Consumer manufacturing

R&D

In vitro validation

In vivovalidation

VirologyPharmacology

Toxicology

Preclinical Studies

Clinical Testing

SAFETY

Clinical Testing

EFFICACY

Marketing&

Distribution

Phase 4 Studies

Marketing

OTCProduct

Consumer

Pre-formulation & formulation

ACCEPTABILITY & USE

LONG STRAIGHT ROADLONG STRAIGHT ROAD

Conceptual “Best” Topical Microbicide ?

• Broad spectrum of activityAnti-HIV Other STIs No effect of/on seminal fluid/vaginal secretions

• Combination-compatibleDifferent targets Co-infections Excipients Other STIs Reproductive health

• Good in vivo safety profileVaginal microenvironment/flora Long-term use Reproduction/pregnancy

• No or little systemic absorption

• Long effect “window”/potential for coitus-disassociated use

• Compatible with

Condoms Barriers Other prevention strategies (vaccines, PrEP, …)

• AvailabilityCost Production General Access

• Easy use with high acceptability by women & menDHHS/NIH/NIAID/DAIDS

New Surface-active/Membrane Disruption Agents

H2C O (CH2)7CH3

CHO H

C O HH2

Octylglycerol (OG)

Invisible Condom”

Savvy™ (C31G)

CAP

Positive Attributes Challenges/Deficiencies

Low cost Low potency, narrow therapeutic index

Contraceptive

Activity against other STI’s (HSV 2, others)

“Surfactant stigma”

“Safe” profile in rectum (monkey model)

Active in lumen only;

coital-dependent use

PROs & CONs

Newer surfactant agents identified with low toxicity & contraceptive potential

Savvy trial, AID-funded, ongoing for contraception BUT HIV prevention trial halted

Lower toxicity than N-9, could replace N-9 as topical contraceptive ???

CAP being developed by CDC & NIH And … the “Chinese dilemma”

State of the Art

Acid/Buffering Agents


Restore/maintain vaginal acidity & ecology

Non-specific, thus low potency against HIV

Low local toxicity Coitally dependent

No systemic absorption

In vitro activity vs. acid-sensitive STI’s (BV, HSV2, HPV, Ct, GC)

Acidform, BufferGel

Contraceptive

State of the Art

May be used with cervical barriers for HIV & STI prevention

May replace N-9 for topical contraception

May be combined with other high-potency microbicides as combination products

Fusion Inhibitors

Carraguard

PRO 2000

CH2

SO3- Na+

n

Cellulose sulfate

PROs & CONs


Low cost Low potency vs. HIV

Low potential for resistance

Many have activity vs. other enveloped viruses (HSV2)

Undefined activity vs. other STIs

Contraceptive potential Coitally dependent

State of the Art

PRO 2000 in two effectiveness trials (HPTN 035 & MDP)

Cellulose sulfate in effectiveness studies (CONRAD, USAID)

Carraguard in late-phase effectiveness studies (Pop Council); data in 2007

May be considered as secondary actives for combination products

ART’s

Tenofovir

UC-781

MIV

TMC120

Molecular Structure of TMC120

Molecular Structure of TMC120

PROs & CONs


High potency No activity vs. other STI’s

Documented efficacy as therapeutics

Risk of ART-resistant virus

Cost?

Can deliver orally or vaginally

Some have poor systemic absorption

Extensive preclinical/clinical data available

Can modify to other delivery forms; possible use independent of coitus

State of the Art

Tenofovir in evaluation as oral agent for HIV prevention

Tenofovir gel advancing into expanded

Phase 2 testing (HPTN 059) Several advancing in early clinical studies,

some with sustained- release technology Richest pipeline of products ready to move

into effectiveness studies

CCR5 Antagonists

SCH-DN

O

N

F

F

F N O

N N

GSK-873140

AplavirocPfizer

Maraviroc (UK 427857)

SH-D

PROs & CONs


High potency vs. R5 HIV Safety/toxicity signals when agents used as therapeutics

Long-term binding to CD4 (up to 5 days)

Larger molecules (PSC-RANTES) may be expensive & difficult to formulate

Proven activity as HIV therapeutic

Concerns about selective pressure towards X4

Proof-of-concept in monkey model

Corporations inclined to allow access to product??

Small molecule scale-up

State of the Art

None yet in human trials as topical microbicides

PSC-RANTES being developed specifically for vaginal application; formulation challenges considerable

CCR5 antagonists developed as therapeutics have had safety signals which may limit further development as topical microbicides

GP120 Binders

Cyanovirin-N Dendrimers SPL

PROs & CONs


Activity against HSV 2 (dendrimer)

Difficult/expensive to formulate (cyanovirin)

Proof-of-concept in monkey model

(cyanovirin, rectally; dendrimers, vaginally)

Coitally-dependent use

Plant expression systems may increase availability

State of the Art

Dendrimers (SPL, VivaGel) in phase 1 clinical trials, beginning studies for STI prevention

Cyanovirin formulation complex, being considered for delivery through genetically-modified organisms

Cervical Barrier Delivery Systems

PROs & CONs


Provide protection of cervix – likely benefit for prevention of cervicitis

Higher unit cost ($.25) if used as applicator

Adaptable for use with different microbicide products

Difficulty with insertion

Familiar technology from contraceptive field

Environmental challenges with disposal

May “concentrate” formulation on target cells in cervix

Local/mechanical irritation

Replaces applicator

Current Status: Phase 1 acceptability of Duet completed

in early 2006 (N=24, CONRAD) Post-coital testing (phase 1) for SILCS

completed 2005The Future: SILCS moving to contraceptive

effectiveness study (CONRAD, USAID)

State of the Art

Sustained-release Delivery Systems: Rings

PROs & CONs


Increase compliance & acceptability

More exposure to drug, greater potential for toxicity

May be optimal method to deliver molecules active intra-cellularly

Difficulty in ring insertion & placement

Flexible platform for addition of antibacterial or contraceptive drugs

Optimal method for induction of resistance if patient seroconverts on product

Genetically-modified Bacteria

PROs & CONs


Potential for “continuous release” of molecules that bind HIV (CD4, cyanovirin)

“Competitive fitness” relative to endogenous flora

Extensive microbiological “proof-of-concept”

Concerns regarding genetically- modified organisms

Potential for use independent of coitus

Difficult to predict success in achieving sustained colonization

Nearly impossible to ensure delivery of therapeutic/prophylactic dose

Potential for inducing immune response (to organism or secreted protein)

Current Status: Lactobacillus Lactobacillus sCD4 & 17b hybrid protein

developed by Ed Berger, Chief, NIAID Laboratory of Viral Disease

Lactobacillus has been genetically modified to express sCD4 & 17b by Osel

Cyanovirin-N, an antiviral protein developed at NCI, has also been expressed in Lactobacillus

Some animal studies under way for Lactobacillus expressing these proteins

Genetically-modified Live Organism Vectors:

Lactobacillus

Current Status: E. coli Dean Hamer (NCI Biochemistry Lab) has

genetically engineered strain of E. coli to secrete an antiviral peptide in the gut

HIV C-peptide binds to gp41

Capacity of this genetically-modified organism to colonize mouse gut following ampicillin treatment documented

Similar model studies with SHIV challenge under way

Genetically-modified Live Organism Vectors:E. coli

Combination ProductsPositive Attributes Challenges/Deficiencies

Combinations proven therapeutic approach for

HIV treatment

Formulation complexity enormous

Lower risk of “break-through” infections

Current FDA regulatory pathway requires combination products to be evaluated as A vs. B vs. A+B

Lower risk of ART resistance developing

Huge trials, difficult to power to detect differences between A vs. A+B

Slow-release technology possible

Expensive/complex licensing issues

Broad diversity of mechanisms of action Each has significant strengths & challenges Near-term pipeline of molecules ready to

enter Phase 1 testing is modest, must be expanded rapidly

Must better define TARGET for each active & whether can successfully deliver ACTIVE to that target

Summary: State of the Art

Acidform/Amphora

PC815

UC-7781

VivaGel

(N=4)

Discovery Preclinical Virology

Preclinical Studies

Current Clinical Studies

1 2 3

Carraguard

Cellulose sulfate (CS)

PRO 2000 (0.5 & 2%) (N=3)

Tenofovir/PMPA 1% gel

BufferGel &PRO2000 (0.5%)

(N=2 or 3)

Praneem tablet

(N=1)

Invisible

Condom

TMC120

(N-2)

• Vaginal defense enhancers 5• Surface –active /membrane

disruption agents 2• Entry/fusion inhibitors 21• Replication inhibitors 1• Combinations 5• Uncharacterized mechanism 1

TOTAL “35”

Discovery/early preclinical 31

Advanced preclinical 4

NO FEWER THAN 38 DIFFERENT ORGANIZATIONS INVOLVED !!

1/2 2/2B

Preclinical Development

OVERVIEW: The Microbicide Pipeline

Acidform/Amphora

PC815

UC-781

VivaGel

(N=4)

Clinical Studies

1 2 3

Carraguard®

Cellulose sulfate/CS

PRO2000 0.5 & 2%

(N=3)

Tenofovir/PMPA 1% gel

BufferGel & PRO2000 0.5%

(N=2/3)

TOTALTRIALS

12

Praneem tablet

(N=1)

Invisible

Condom

TMC120

(N=2)

TOTAL IN

PRECLINICAL DEVELOPMENT

“35+”

1/2 2/2B

Preclinical Development

The Microbicide Pipeline – The Clinical Part


Challenges in Microbicide Trials

• Lack of surrogate markers/correlates of Lack of surrogate markers/correlates of protection/measures of biological activity, so protection/measures of biological activity, so only meaningful effectiveness studies those only meaningful effectiveness studies those with HIV infection as endpointwith HIV infection as endpoint

• Adherence to protocol, pregnancy rates: Adherence to protocol, pregnancy rates:

effects on time on product ??effects on time on product ??• Study procedures: time on follow-upStudy procedures: time on follow-up• Ethical requirementsEthical requirements• Study power Fx of above + baseline incidenceStudy power Fx of above + baseline incidence

Microbicide Pipeline Is Distinctive . . .Microbicide Pipeline Is Distinctive . . .

BUT NOT UNIQUE !! Like many (most?) “global health products” funded by:

• Governments• NGOs • Small to very small (virtual?) pharmas• Philanthropies


Success MUST depend on multidisciplinary, multisectoral partnerships & ADVOCACY

AcknowledgmentsAcknowledgments

• PPT-Sharers:Ward Cates, FHIAnthony Fauci, MD, NIAIDSharon Hillier, PhD, U. PittsburghJim Turpin, PhD, NIAID/DAIDSSalim Abdool Karim, MBChB, PhD,

U. KwaZulu-Natal• Database Compilers & Monitors:Staff, Alliance for Microbicide Development


And our funders . . .

More acknowledgments

Franka N. des Vignes, PhD Deputy DirectorBetsy Finley, MPH Writer, Research AssociateCarolyn Plescia, MPH Writer, Research AssociateLois Holston Administrative Associate The work of the Alliance has been made possible by the

dedication of its participants & contributions from the

Bill & Melinda Gates Foundation CONRAD

• the William and Flora Hewlett Foundation

• International Partnership for Microbicides John M. Lloyd Foundation

• Moriah Fund

• Rockefeller Foundation

and the generosity of private contributors.

microbicides a women’s health priority: why, what, & where we are polly f. harrison, ph.d....

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