MICROBICIDES A Women’s Health Priority: Why, What, & Where We Are Polly F. Harrison, Ph.D. Director, Alliance for Microbicide Development Drexel University College of Medicine Institute for Women’s Health & Leadership 2007 Sex & Gender Research Forum Philadelphia, PA – 10 January 2007

Q. WHY? A. The numbers l USA yearly: 40,000 HIV infections » unchanged for > 10 years l World 2006: 4.3 million new infections » 11,000 each day l ~ 50% of 39.5 million adults living with HIV/AIDS are female l Sub-Saharan Africa: HIV/AIDS prevalence 3x higher in women than same-aged men

Q. WHY? A. Social structure, culture, behavior... l Most HIV infections spread by unprotected sex l Current HIV prevention male-controlled &/or contraceptive l Women lack means to protect selves if partners do not use male condoms or allow use of female condoms l Abstinence &/or fidelity unlikely to protect women married (or in steady partnerships of presumed trust) or the sexually abused l (Penalties for “insistence” can be severe) Anthony Fauci, Congressional Presentation, 12/12/06

So, what DO we have to prevent HIV? l education/behavior mod l condoms, other barrier methods l treatment/preventing drug/alcohol abuse l clean syringes (e.g., needle exchange) l interrupting MTCT l PrEP l STD treatment l ♂ circumcision l Vaccination l 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 vivo validation Virology Pharmacology Toxicology Preclinical Studies Clinical Testing SAFETY Clinical Testing EFFICACY Marketing & Distribution Phase 4 Studies Marketing OTC Product Consumer Pre-formulation & formulation ACCEPTABILITY & USE

LONG STRAIGHT ROAD

Conceptual “Best” Topical Microbicide ? Broad spectrum of activity Anti-HIV Other STIs No effect of/on seminal fluid/vaginal secretions Combination-compatible Different targets Co-infections Excipients Other STIs Reproductive health Good in vivo safety profile Vaginal 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, …) Availability Cost Production General Access Easy use with high acceptability by women & men DHHS/NIH/NIAID/DAIDS

New Surface-active/ Membrane Disruption Agents H 2 CO (CH 2 ) 7 CH 3 C HOH C O H H 2 Octylglycerol (OG) Invisible Condom” Savvy™ (C31G) CAP

Positive AttributesChallenges/Deficiencies Low costLow 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

l Newer surfactant agents identified with low toxicity & contraceptive potential l Savvy trial, AID-funded, ongoing for contraception BUT HIV prevention trial halted l Lower toxicity than N-9, could replace N-9 as topical contraceptive ??? l CAP being developed by CDC & NIH l And … the “Chinese dilemma” State of the Art

Acid/Buffering Agents Positive AttributesChallenges/Deficiencies Restore/maintain vaginal acidity & ecology Non-specific, thus low potency against HIV Low local toxicityCoitally dependent No systemic absorption In vitro activity vs. acid- sensitive STI’s (BV, HSV2, HPV, Ct, GC) Acidform, BufferGel Contraceptive

State of the Art l May be used with cervical barriers for HIV & STI prevention l May replace N-9 for topical contraception l May be combined with other high-potency microbicides as combination products

Fusion Inhibitors Carraguard PRO 2000 Cellulose sulfate

PROs & CONs Positive AttributesChallenges/Deficiencies Low costLow potency vs. HIV Low potential for resistance Many have activity vs. other enveloped viruses (HSV2) Undefined activity vs. other STIs Contraceptive potentialCoitally dependent

State of the Art l PRO 2000 in two effectiveness trials (HPTN 035 & MDP) l Cellulose sulfate in effectiveness studies (CONRAD, USAID) l Carraguard in late-phase effectiveness studies (Pop Council); data in 2007 l 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 Positive AttributesChallenges/Deficiencies High potencyNo 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 l Tenofovir in evaluation as oral agent for HIV prevention l Tenofovir gel advancing into expanded Phase 2 testing (HPTN 059) l Several advancing in early clinical studies, some with sustained- release technology l Richest pipeline of products ready to move into effectiveness studies

CCR5 Antagonists SCH-D GSK Aplaviroc Pfizer Maraviroc (UK ) SH-D

PROs & CONs Positive AttributesChallenges/Deficiencies High potency vs. R5 HIVSafety/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 l None yet in human trials as topical microbicides l PSC-RANTES being developed specifically for vaginal application; formulation challenges considerable l CCR5 antagonists developed as therapeutics have had safety signals which may limit further development as topical microbicides

GP120 Binders Cyanovirin-NDendrimers SPL

PROs & CONs Positive AttributesChallenges/Deficiencies 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 l Dendrimers (SPL, VivaGel) in phase 1 clinical trials, beginning studies for STI prevention l Cyanovirin formulation complex, being considered for delivery through genetically-modified organisms

Cervical Barrier Delivery Systems

PROs & CONs Positive AttributesChallenges/Deficiencies 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: l Phase 1 acceptability of Duet completed in early 2006 (N=24, CONRAD) l Post-coital testing (phase 1) for SILCS completed 2005 The Future: l SILCS moving to contraceptive effectiveness study (CONRAD, USAID) State of the Art

Sustained-release Delivery Systems: Rings

PROs & CONs Positive AttributesChallenges/Deficiencies 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 Positive AttributesChallenges/Deficiencies 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 l Lactobacillus sCD4 & 17b hybrid protein developed by Ed Berger, Chief, NIAID Laboratory of Viral Disease l Lactobacillus has been genetically modified to express sCD4 & 17b by Osel l Cyanovirin-N, an antiviral protein developed at NCI, has also been expressed in Lactobacillus l Some animal studies under way for Lactobacillus expressing these proteins Genetically-modified Live Organism Vectors: Lactobacillus

Current Status: E. coli l Dean Hamer (NCI Biochemistry Lab) has genetically engineered strain of E. coli to secrete an antiviral peptide in the gut l HIV C-peptide binds to gp 41 l Capacity of this genetically-modified organism to colonize mouse gut following ampicillin treatment documented l Similar model studies with SHIV challenge under way Genetically-modified Live Organism Vectors: E. coli

Combination Products Positive AttributesChallenges/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

l Broad diversity of mechanisms of action l Each has significant strengths & challenges l Near-term pipeline of molecules ready to enter Phase 1 testing is modest, must be expanded rapidly l 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 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 Carraguard® Cellulose sulfate/CS PRO & 2% (N=3) Tenofovir/PMPA 1% gel BufferGel & PRO % (N=2/3) TOTAL TRIALS 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 DHHS/NIH/NIAID/DAIDS

Challenges in Microbicide Trials Lack of surrogate markers/correlates of protection/measures of biological activity, so only meaningful effectiveness studies those with HIV infection as endpoint Lack of surrogate markers/correlates of protection/measures of biological activity, so only meaningful effectiveness studies those with HIV infection as endpoint Adherence to protocol, pregnancy rates: Adherence to protocol, pregnancy rates: effects on time on product ?? Study procedures: time on follow-up Study procedures: time on follow-up Ethical requirements Ethical requirements Study power Fx of above + baseline incidence Study power Fx of above + baseline incidence

Microbicide Pipeline Is Distinctive... BUT NOT UNIQUE !! Like many (most?) “global health products” funded by: Governments NGOs Small to very small (virtual?) pharmas Philanthropies DHHS/NIH/NIAID/DAIDS Success MUST depend on multidisciplinary, multisectoral partnerships & ADVOCACY

Acknowledgments PPT-Sharers: Ward Cates, FHI Anthony Fauci, MD, NIAID Sharon Hillier, PhD, U. Pittsburgh Jim Turpin, PhD, NIAID/DAIDS Salim Abdool Karim, MBChB, PhD, U. KwaZulu-Natal Database Compilers & Monitors: Staff, Alliance for Microbicide Development DHHS/NIH/NIAID/DAIDS And our funders...

More acknowledgments Franka N. des Vignes, PhD Deputy Director Betsy Finley, MPH Writer, Research Associate Carolyn Plescia, MPH Writer, Research Associate Lois Holston Administrative Associate The work of the Alliance has been made possible by the dedication of its participants & contributions from the l Bill & Melinda Gates Foundation l CONRAD the William and Flora Hewlett Foundation International Partnership for Microbicides l John M. Lloyd Foundation Moriah Fund Rockefeller Foundation and the generosity of private contributors.