Direct from Delhi: Microbicides2008 Comes to Sweet Home Chicago

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1 Direct from Delhi: Microbicides2008 Comes to Sweet Home Chicago Microbicide Pipeline Update Latifa Boyce Alliance for Microbicide Development

2 Outline Past: Where we ve been Present: Where we are Future: Where we are going

3 Pipeline: Microbicides2006 Cape Town, South Africa (23-26 April) Clinical Development (Ongoing) Discovery Virology Studies Phase 1 Phase 2 Phase 3 Development VivaGel / SPL7013 ACIDFORM / Amphora Lime Juice PC 815 UC-781 CAP (N=6) 1/2 Invisible Condom (N=2) Praneem polyherbal vaginal tablet Lactobacilli+ BZK TMC120 (N=3) 2/2B Carraguard PRO % & 2% Cellulose sulfate (CS) Savvy (N=4) BufferGel Tenofovir/ PMPA gel (N=2) Source: Alliance for Microbicide Development, April 2006

4 Pipeline: Microbicides2008 New Delhi, India (23-26 February) Clinical Development (Ongoing) Discovery Virology Studies Phase 1 Phase 2 Phase 3 Development VivaGel / SPL7013 UC-781 (0.1% & 0.25%) Dapivirine (TMC120) Ethanol in Emollient Gel (N=4) (N=0) PRO % (N=1) 1/2 (N=0) 2/2B BufferGel, PRO 2000 (0.5%) Tenofovir/ PMPA gel (1%) (N=2) Source: Alliance for Microbicide Development, March 2008

5 LONG STRAIGHT ROAD

6 Along the Microbicide Development Trail. The Journey Highs and lows Successes and failures PROGRESS has been made, nonetheless There is field-wide consensus we must continue the search for a safe and effective microbicide

7 Past Microbicide Efficacy Trials

8 Ongoing Microbicide Efficacy Trials

9 Field Transition: Early to Next Generation Microbicides Early Generation Examples N-9 Savvy Cellulose sulfate (CS) BufferGel PRO 2000 Characteristics Polyanions, Surfactants, Entry inhibitors, Vaginal defense enhancers Surface acting Target broad range of pathogens Coital dependant Next Generation Examples Tenofovir Dapivirine(TMC120) UC-781 PC-815 Characteristics Replication inhibitors Work inside cell to prevent HIV infection HIV specific (unless in combination) May or may not be coital dependant

10 Microbicidesin Development Lactin-V Invisible Condom NCp7 s GM Biotics(Osel) Free virus BufferGel DS007 (Merck L 644) Fusion Attachment PRO2000 SPL7013 (VivaGel) RANTES analogs Cyanovirin-N DS003 (BMS 793) DS001 (Merck 167) Maraviroc(Pfizer) S-DABO Dapivirine UC781 Tenofovir PC-815 Reverse Transcription Integration Pyrimidinediones(Samjin) Protein synthesis and assembly Early-generation compounds Next-generation compounds Budding Maturation

11 Microbicides2008 Clinical Trial Update Highlights & Lessons Learned Trials of Early Generation Products (completed or ongoing) Phase 3 Cellulose sulfate (CS) Phase 3 Carraguard HTPN 035 PRO 2000 (0.5%) BufferGel MDP 301 PRO 2000 (0.5% & 2%) Trials of Next Generation Products (ongoing or planned) CAPRISA 004 Tenofovir(gel) VOICE (Vaginal and Oral Interventions to Control the Epidemic) Tenofovir(oral and gel) IPM 009 Dapivirine(gel and ring)

12 Cellulose Sulfate (CS) Review:Trials of cellulose sulfate (Ushercell) lead by CONRAD were halted in 2007 after women who received the microbicidein one study became infected more frequently than those who received the inactive placebo gel. New:An investigation of CS using the substance on vaginal tissue samples revealed that CS may cause loss of tissue integrity by destroying proteins that bind cells together. This allows HIV to leak into the underlying tissues.

13 Carraguard Phase 3 Trial Results >6600 women 27 month of enrollment, 2 years of follow-up Study arms: CG + condoms versus Placebo + condoms Retentions and study power lower than desired Low adherence to product use and protocol observed Safety and acceptability of the product good Product ineffective at preventing transmission of HIV: No significant difference in HIV-seroconversionsand STI incidence observed in the Carraguard and placebo groups

14 Carraguard: Lessons Learned 1 st completed phase 3 trial of a microbicide(trial was not stopped early) Product showed strong safety profile before trial; during the trial it showed no harm to participants Adherence was a problem, but investigators were able to incorporate and test novel ways to improve adherence and its measurement, and better assess true adherence values Lessons learned form this trial can be incorporated into future trials

15 Ongoing Efficacy Trials of Early Generation Microbicides HPTN 035 Products PRO 2000 (0.5%) & BufferGel M2008 Update Self-reported adherence high Retention rates good Enrollment completed in July 2007 Trial completed in July 2008 Results expected early 2009 MDP 301 Products PRO 2000 (0.5%) M2008 Update 2% trial arm closed in February % arm is continuing Self-reported adherence high Retention rates good Recruitment completed in March 2008 Results expected late 2009

16 Early Generation Microbicides: Challenges & Lessons Learned Toxicity Irritation Adherence Unable to detect product s effect without sufficient compliance to product and study procedures

17 Next Generation Products Antiretroviral (ARV) Microbicides Nearly 70% of ongoing or planned microbicideclinical trials are testing ARV-based candidates 4 lead candidates: Tenofovir, Dapivirine, UC-781, and PC-815 May reduce the challenges encountered with trial participant adherence to product use since some of the ARV-based candidates are being designed to avoid coital-dependency These products are in testing with various application timeframes: 12 hours prior to sex, as pre-exposure prophylaxis (PrEP) 12 hours after sex, as post-exposure prophylaxis (PEP) Once daily Multiple formulations: Gels, rings, films, and oral pills.

18 Antiretroviral (ARV) Microbicides Class Drug Developer Development Stage NNRTI Dapivirine UC-781 PC-815 Pyrimidinediones S-DABO IPM CONRAD Population Council ImQuest Idenix Phase 1/2 Phase 1 Phase 1 NRTI Tenofovir* IPM / CONRAD Phase 1/2B CCR5 blocker Maraviroc* Merck L-167 Merck L-872 Merck L-882 RANTES analogs IPM IPM IPM IPM Mintaka Foundation gp41 binder Merck L-644 IPM gp120 binder BMS-793 Cyanovirin-N IPM Osel Zinc finger inhibitor NCp7 s ImQuest

19 Clinical Pipeline: ARV-Based Microbicides Clinical Trials Candidate Dapivirine (TMC120) ARV-Type Number of Clinical Trials Ongoing Planned NNRTI 1 8 PC-815 NNRTI 0 2 Tenofovir/PMPA gel NRTI 3 4 UC-781 NNRTI 5 0

20 Pipeline: ARV-Based Microbicides Research Candidate Demonstrated Properties () BMS793 gp120 binder Maraviroc CCR5 blocker M167, M872, M882 CCR5 blockers L 644 peptide gp41 inhibitor ZCM Combination with NNRTI MIV-150

21 Ongoing & Planned ARV Efficacy Trials Tenofovirgel CAPRISA 004 Phase 2B, ongoing since May 2007 Tenofovirgel / oral Tenofovir/ oral Truvada MTN 003, VOICE Phase 2B, planned late 2008 Dapivirinegel / ring / other IPM 009 Phase 3, planned late 2009

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23 Pipeline: Microbicides2010 Pittsburgh, PA, USA (23-26 May)???

24 Alliance for Microbicide Development 8484 Georgia Avenue, Suite 940 Silver Spring, Maryland Phone: Fax: Your one-stop shop to resources on microbicideresearch and development!

25 Thank You! AIDS Foundation of Chicago International Rectal MicrobicidesAdvocates (IRMA) International Partnership for Microbicides (IPM)