Microbicides A Scientific Update Ian McGowan MD PhD FRCP Center for Prevention Research David Geffen School of Medicine at UCLA

Overview Mucosal transmission of HIV infection The microbicide pipeline RT-Inhibitor microbicides Combination microbicides Formulation science Rectal microbicides Microbicides and PREP Microbicide development and the community

Mucosal Transmission of HIV Infection

Mucosal Targets for HIV Infection Shattock and Moore, Nat Rev Microbiol, 2003

Not Just the Mucosa…. HIV Increased virus replication and spread Afferent lymphatics Increased virus replication and spread Draining lymphoid tissue

The Microbicide Pipeline

Microbicide Mechanisms of Action Killing or inactivating pathogens Creating physical barriers Strengthening body’s natural defenses Preventing viral entry into cells Inhibiting viral replication

Viral Targets for Microbicides Shattock and Moore, Nat Rev Microbiol, 2003

Preclinical Microbicide Candidates Uncertain Defense Enhancers Entry / Fusion Inhibitors Ciclopiroxolamine Praneem polyherbal MucoCept HIV Lime Juice Acidform™ gel Cellulose sulfate Cellulose acetate Carraguard VivaGel Dextrin-2 sulfate Cyanovirin-N C85FL K5-N, OS(H) SAMMA Invisible condom Novaflux Porphyrins PSC Rantes BMS-806 BMS-378806 CMPD167 C52L Tobacco-derived antibodies / fusion proteins Anti-ICAM-1 Ab mAb B12, 2G12 mAb 2F5, 4E10 CD4 IgG2 T20 T-1249 SCH-C, D UK-427,857 TAK 779 AMD3100 SFD-1 Bicyclams Aptamers Membrane Disruption Replication Alkyl sulfates Savvy (C31G) Beta cyclodextrin Tenofovir TMC-120 UC-781 MIV-150 MC1220 C-731, 988

Microbicides in Clinical Trials Phase Membrane Disruption Defense Enhancers Entry Fusion Inhibitors Replication 1 AcidformTM Lime Juice Lactobacillus VivaGelTM Cellulose acetate PC-815 UC-781 TMC-120 1/2 Invisible CondomTM 2 (Praneem) Tenofovir 2/2B C31G BufferGelTM PRO-2000 (0.5% & 2%) 3 Carraguard® Cellulose Sulfate

RT-Inhibitor Microbicides

RT-Inhibitor Microbicides Phase Sponsor Tenofovir 2 Gilead Sciences UC-781 1 Biosyn, Inc. TMC-120 IPM/Tibotec MIV-150 (PC-815) (1) Population Council

The Issues Resistance Pharmacokinetics RT Combinations Seroconversion on study Exposure in chronically infected subjects Community implications Pharmacokinetics Plasma Tissue RT Combinations Possible synergy

HPTN-050 Group Category Tenofovir Dose N A1 Sexually abstinent HIV-negative 0.3% QD 12 A2 1.0% A3 BID A4 B C Sexually abstinent HIV-positive D Sexually active HIV-positive Mayer et al. AIDS 2006

HPTN-050 PK Mayer et al. AIDS 2006 HIV was detected in the plasma of 13/24 HIV+ women at Day 0 and 12/24 at Day 14, but in CVL of only 2 women at Day 0 and none at Day 14. No new resistance mutations evolved in plasma or CVL after 14 days of TFV gel use. No pt. had high level TFV mutations e.g K65R 3 women had plasma mutations associated with low level TFV resistance at Days 0 and 14 (M41L, L210M, +/- T215 I/Y), but 2 also had M184V, which would increase TFV susceptibility. Mayer et al. AIDS 2006

Resistance Issues What is the relationship between systemic absorption and the development of resistance? Will the risk be altered by the presence or absence or oral combination therapy? Could resistance occur during seroconversion? How should we assess resistance? What are the therapeutic implications?

The Geneva “Consensus” September 2004 RT-Microbicide studies should move ahead in HIV-1 seronegative populations. Studies in HIV-1 seropositive subjects are also important but should be considered with caution.

Combination Microbicides

Combination Microbicides Rhesus macaque challenge model BMS-378806 Binds to gp120 CMPD167 Binds to CCR5 C52L Inhibits gp41 mediated fusion Veazey et al. Nature 2005

CMPD167 [5.0 mM] $$$$$$$$ Veazey et al. Nature 2005 Group Infection No Infection CMPD167 [5.0 mM] + BMS-378806 [5.5 mM] + C52L [1.5 mM] + + + BMS-378806 [2.0 mM] + C52L [1.5 mM] + + + + + + CMPD167 [5.0 mM] + BMS-378806 [2.0 mM] CMPD167 [1.0 mM] + C52L [1.5 mM] + + + + + + CMPD167 [5.0 mM] + C52L [1.5 mM] + + CMPD167 [5.0 mM] + Mannan [50 mg ml-1] BMS-378806 [5.5 mM] Challenge delay [2-6 h] BMS-378806 [5.5 mM] CMPD167 [5.0 mM] Challenge delay [2-12 h] CMPD167 [5.0 mM] CMPD167 [1.0 mM] Mannan [50 mg ml-1] Controls CMPD167 [5.0 mM] $$$$$$$$ Veazey et al. Nature 2005

Formulation Science

Formulation Innovation First generation of formulations were not optimized for vaginal or rectal use 2nd generation products being developed on the basis of: Stability Rheological properties Absorption Local environment (rectum vs. vagina) Acceptability Broader range of delivery systems Gels, foams, films, suppositories, and rings

Imaging Where the Product Goes Charles Lacey MD, & Craig Hendrix MD

TMC120 Vaginal Rings                                                           Malcolm et al., Journal of Antimicrobial Chemotherapy, 2005

Rectal Microbicides

Why Develop Rectal Microbicides? Anal intercourse (AI) is the primary risk factor for HIV transmission among MSM. The prevalence of AI among the heterosexual population is underappreciated and represents a significant risk for HIV transmission. Much AI is unprotected. The rectal mucosa is highly vulnerable to HIV infection. Based on the N-9 experience, vaginal products may not be suitable for rectal administration.

Prevalence of AI International Studies South Africa: Lane T, Pettifor A, Pascoe S, Fiamma A, Rees H. Heterosexual anal intercourse increases risk of HIV infection among young South African men. AIDS. 2006 Jan 2;20(1):123-5. Ramjee G GE. Prevalence of HIV Among Truck Drivers Visiting Sex Workers in KwaZulu-Natal, South Africa. Sex Transm Dis 2002; 29:44-9 Anal sex was practiced by 42% of the men and only 23% of these men reported condom use during anal sex China: Liu H, Xie J, Yu W, Song W, Gao Z, Ma Z, Detels R. J Acquir Immune Defic Syndr Hum Retrovirol. 1998 Sep 1;19(1):80-8. Peru: Caceres C, Oss V, Marin B, Hudes E, al e. Young People and the structure of sexual risks in Lima. AIDS 1997;11((suppl 1)):S67-77.

Prevalence of Anal Receptive Sex Population N Prevalence of AI Reference MSM in EXPLORE study 4295 48 – 54% Koblin et al. 2003 High risk women 1268 32% Gross M et al. 2000 College students 210 20% Civic D 2000 US Survey 15 – 44 years NSFG 12,571 35-40% Mosher WD et al. 2005 Californian residents 3545 6-8% Erickson PI et al. 1995

US HIV Infection by Transmission Category* (2004) (%) MSM contact 18,203 47 IDU 5,962 15 MSM + IDU 1,372 4 High Risk Heterosexual contact 12,683 33 Other / not identified 335 1 Total 38,553 This slide shows the distribution of transmission categories for HIV/AIDS cases diagnosed in 2004 in 35 areas with confidential name-based HIV infection surveillance. Approximately 47% of the 38,553 HIV/AIDS cases diagnosed in 2004 among adults and adolescents were attributed to male-to-male sexual contact. An additional 4% of were attributed to male-to-male sexual contact and injection drug use. Injection drug use accounted for 15% of HIV/AIDS diagnoses, and high risk heterosexual contact accounted for another 33%. The following 35 areas have had laws or regulations requiring confidential name-based HIV infection surveillance since at least 2000: Alabama, Alaska, Arizona, Arkansas, Colorado, Florida, Idaho, Indiana, Iowa, Kansas, Louisiana, Michigan, Minnesota, Mississippi, Missouri, Nebraska, Nevada, New Jersey, New Mexico, New York, North Carolina, North Dakota, Ohio, Oklahoma, South Carolina, South Dakota, Tennessee, Texas, Utah, Virginia, West Virginia, Wisconsin, Wyoming, Guam and the US Virgin Islands. The data have been adjusted for reporting delays and cases without risk factor information were proportionally redistributed. * CDC data from 35 areas with HIV surveillance

UK HIV Infection by Transmission Category Heterosexual subcategories Sex between men This slide shows the total number of diagnoses of HIV in individuals infected through sex between men and women, broken down by sub-category of probable country of infection as well as exposure. Numbers of cases are shown on the vertical axis and the year of diagnosis on the horizontal axis. The vast majority of those infected through sex between men and women, have been infected in Africa with large increases in recent years. Other increases include those infected in the Caribbean and Europe. Individuals infected through sex between men and women in the UK, the majority will have had a partner infected abroad mainly Africa, but there are some with partners also infected in the UK – about 20 per year and rising. These individuals will have had heterosexual contact with “high risk” partners in other words; partner(s) who were men who have sex with men and injecting drug users. Reporting delay will mean that numbers particularly for recent years, will continue to rise. Furthermore, reports indicating heterosexual exposure but with insufficient information to sub-categorize and cases reporting heterosexual exposure in the UK with no evidence of “high risk” partners, are followed up by a research nurse in order to clarify exposure details. Data on the breakdown of the heterosexual transmission by sub-category of probable country of infection and exposure is updated every three months and published on the HPA website in a set of quarterly surveillance tables – the data behind this slide can be found in Tables?

Rectosigmoid Anatomy

Modeling Rectal Microbicide Efficacy 0.5 1.5 1 2 Efficacy 0.2 0.4 0.6 0.8 R No microbicide use 10% microbicide use 30% microbicide use 50% microbicide use R R Adapted from Breban et al. (In Press)

Rectal Safety Assessment Vaginal Microbicide (Cellulose sulfate) Animal Toxicology Phase 1 Rectal Safety Rectal Microbicide (Product X) Combination Microbicide (Tenofovir) Preclinical Evaluation Cell lines Explant studies Animal models Animal toxicology Human studies Phase 1 Phase 2 Phase 2B/3

Rectal Safety of Vaginal Microbicides Candidate Murine Primate Explant Human N-9 +++ Buffergel Neg ? C31G Carraguard Cellulose sulfate PRO 2000 SPL7013 Octylglycerol PMPA TMC120 UC781

Where to Protect and What to Measure? Hendrix et al., 2004

HPTN-056 Study Groups Group 1 Group 2 Group 3 Group 4 HIV-1 negative / anal receptive (N = 4) Group 2 HIV-1 negative / not anal receptive (N = 4) Group 3 HIV-1 positive / anal receptive + plasma viral load > 10,000 (N = 4) Group 4 HIV-1 positive / anal receptive + plasma viral load < 50 (N = 4)

HPTN 056 Study Design Week - 2 + 2 + 4 Screening Baseline Week 2 + 2 + 4 Screening Baseline Week 2 Week 4 Consent Physical Anoscopy Rectal GC/CH HIV Ab CD4 / Viral load Sigmoidoscopy Intestinal biopsy at 10cm and 30cm Cell isolation and flow cytometry Tissue cytokines Rectal immunoglobulins Tissue / rectal secretion viral load

Microbicides and PREP

PREP – The Key Issues Availability of efficacy data for PREP Long term safety in seronegative subjects Tissue PK profile at site of infection Potential for differential resistance patterns Animal studies of PREP inconclusive TDF – negative TDF / FTC - positive Consumer preference Cost

Microbicide Development and the Community

Regulatory Challenges Kaplan et al. Science. 2004

Community Resistance Mills et al., BMC Int Health Hum Rights 2005

Grant et al. Science. 2005

Phase 3 Study of Savvy in Ghana "The reason we decided to stop the trial was that the group of women who volunteered to participate had such a low incidence of HIV that there was no way for this study to show whether use of Savvy, compared with a placebo gel, would prevent HIV or not," Leigh Peterson FHI

A New Network?

MTN Clinical Trials Portfolio

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