1. Microbicide Science and Research Update Jana Caylor Bowcut, MPH Research Associate Alliance for Microbicide Development Global Campaign for Microbicides Pre-conference Microbicides 2004 28 March 2004

2. Presentation Outline I. Biology of microbicides II. Methods of pre-clinical and clinical evaluation III.Overview of the microbicide pipeline

3. I. Biology of Microbicides

4. Source: R. Shattock, St. George’s Hospital Medical School. physiology of the vagina

5. vaginal defenses against HIV Vaginal pH- normal vaginal environment is acidic (pH ~4), which is destructive to HIV and many other STIs. Lactobacilli- naturally occurring bacteria that release a number of anti-microbial compounds (e.g. hydrogen peroxide, lactic acid) Natural immune defenses- epithelial cells, upon infection, synthesize anti-microbial molecules (defensins, cytokines) that recruit key immune cells

6. How will a microbicide work? Source: R. Shattock, St. George’s Hospital Medical School.

7. acid buffers- maintain an acidic vaginal pH vaginal defense enhancers- fortifies the natural immune defenses against infection (antibodies, lactobacilli, antimicrobial peptides) surface-active agents (“surfactants”)- inactivate or destroy viruses or bacteria by disrupting their outer envelopes or membranes. potential mechanisms of action for a microbicide Alliance for Microbicide Development

8. adsorption inhibitors- prevent entry into host target cells (coat the virus and/or target cell through charged interactions) entry/fusion inhibitors- prevent virus attachment and adhesion to, fusion with target cells. replication inhibitors- block viral replication multiple or uncharacterized mechanisms potential mechanisms of action for a microbicide (contd.) Alliance for Microbicide Development

9. combination microbicides A combination of 2 or more microbicides to produce an additive effect Benefits of combinations include: – maximizing activity – decreasing the potential for resistance – increasing the spectrum of STI activity – reducing the required concentration of expensive or potentially toxic agents Source: Rockefeller Report, The Science of Microbicides.

10. sexually transmitted infections 1) STIs (particularly ulcerative STIs) serve as cofactors in the HIV infection process 2) STIs are significant causes of morbidity and mortality. Many people are at much greater risk of STIs than HIV. 3) Many microbicides active against HIV have overlapping mechanisms of action against other STIs. Source: Rockefeller Report. The Science of Microbicides

11. II. Methods of pre-clinical and clinical evaluation

12. Main purpose is to ensure that the benefits outweigh the risks before a compound goes to clinical trials Extensive studies are conducted utilizing microbiology, pharmacology/toxicology, and chemistry, manufacturing and controls (CMC). pre-clinical methods of evaluation Source: Lard-Whiteford et al., 2004. Recommendations for the nonclinical development of topical microbicides for prevention of Human Immunodeficiency Virus transmission: An Update.

13. pre-clinical studies Cell-based assays: defines the full range of antiviral activity of the candidate drug substance Pharmacokinetic studies: carried out in animals to determine the extent to which a drug substance is absorbed, distributed, metabolized and excreted (ADME profile) General toxicology studies: designed to monitor the effects of a drug substance on general health and behavior, weight changes, food consumption, etc. (rodent and non-rodent species used) Source: Lard-Whiteford et al., 2004. Recommendations for the nonclinical development of topical microbicides for prevention of Human Immunodeficiency Virus transmission: An Update.

14. pre-clinical assays (contd.) Genetic toxicology studies: to evaluate the mutagenic potential of a candidate microbicide Vaginal irritation studies: a screening study (usually in rabbits) to determine the vaginal irritation potential of a drug substance. Safety pharmacology studies: if a compound has been shown to be absorbed systemically, the effects of the drug on the functions of the vital organs must be assessed. Source: Lard-Whiteford et al., 2004. Recommendations for the nonclinical development of topical microbicides for prevention of Human Immunodeficiency Virus transmission: An Update.

15. Reproductive toxicology studies: to determine the effect of the product on reproductive health and developing embryo/fetuses Carcinogenicity studies: carried out in rats and mice for 2 years to determine if there is evidence of tumorigenic effect. pre-clinical assays (contd.) Source: Lard-Whiteford et al., 2004. Recommendations for the nonclinical development of topical microbicides for prevention of Human Immunodeficiency Virus transmission: An Update.

16. clinical trial phases Participants LengthPurpose Phase 110-100 several mos. safety Phase 2 ~2006 mos. - 1 yr. expanded safety Phase 3300-30,0001-4 yrs. effectiveness *Additional phases are: Phase 1/2, Phase 2/2B and Phase 2/3 Alliance for Microbicide Development

17. methods of clinical evaluation How is safety assessed? How is efficacy assessed?

18. “safety” testing “Safety” refers to the absence of significant adverse events related to microbicides use in the study population “Safety” does NOT mean “keeping participants safe from infection” Source: Global Campaign for Microbicides

19. “Efficacy” and “Effectiveness” Efficacy is the maximum ability of a drug or treatment to produce a result – Measured by reduction in infections with “perfect use” of product Effectiveness is the ability of drug or treatment to produce a result under conditions of “typical use” – Measured by reduction in infections averaged across all users Source: Global Campaign for Microbicides

20. How is “safety” assessed? macroscopic naked- eye inspection of the cervicovaginal region is used to determine presence of lesions and/or disrupted blood vessels. colposcopy- detects epithelial damage not visible to the naked-eye (necessary for Phase 1, possibly for Phase 2, but not Phase 3) systemic toxicity is assessed by measuring plasma or serum levels and pharmacokinetics Source: International Regulatory Issues in Microbicide Development. Preliminary report from a WHO Consultation. 4-6 March, 2002.

21. How is “effectiveness” assessed? Phase 3 Trial Endpoints: Reduction of HIV incidence Reduction of STI incidience Contraceptive effectiveness-- Safety endpoints--systemic and local genital safety are assessed Behavioral endpoints--condom use dynamics, changes in sexual practices Frequency of product use

22. III. the microbicide pipeline

23. the microbicide database -the pipeline is monitored using the Microbicide Research and Development Database (MRDD) the MRDD can be accessed at www.microbicide.org Alliance for Microbicide Development

24. biopharmaceutical companies (~25) non-profit research entities (~38) public-sector entities worldwide (~5) entities doing supportive research (~36) who is doing the work? Alliance for Microbicide Development

25. the microbicide “pipeline” 62 candidate microbicides – 44 in pre-clinical development – 18 in clinical development* * With  HIV incidence as primary endpoint; other trials have contraceptive efficacy &  non-HIV STIs as primary endpoints; some products in > 1 clinical trial phase. Alliance for Microbicide Development

26. the microbicide pipeline, by mechanism of action Alliance for Microbicide Development

27. trends in microbicide research and development, 1996-2004 Alliance for Microbicide Development

28. candidate microbicides with STI activity Treponema pallidum: 2 Hepatitis B: 3 Haemophilus ducreyi: 4 Human Papillomavirus: 7 Trichomonas vaginalis: 7 Candida albicans: 14 Chlamydia trachomatis: 15 Neisseria gonorrhea: 17 Herpes Simplex Virus: 20 Alliance for Microbicide Development

29. candidates in clinical trials 18TOTAL Praneem Polyherbal Carraguard TM, Cellulose sulfate/CS, Emmelle TM /dextrin-2-sulfate, Savvy TM /C- 31G (PRO2000/5 will also be tested in an MRC-sponsored Phase 3 trial with Emmelle TM.) 1414 2/3 3 BufferGel TM, PRO2000/5 22/2B Lactobacillus crispatus suppository (CTV-05), Protected lactobacillus in combinationwith BZK 22 Invisible Condom TM 11/2 Acidform TM /Amphora TM, Cellulose acetate phthalate/CAP, Human monoclonal antibodies (C2F5, C2G12, C4E10), Lactin-V capsule, Polystyrene sulphonate/PSS, Tenofovir/PMPA, UC-781, VivaGel/SPL7013 TM 81 MICROBICIDE CANDIDIATESTOTAL #PHASE OVERVIEW OF MICROBICIDES IN CLINICAL TRIALS, FEBRUARY 2004

30. trials including evaluation for activity against non-HIV STIs

31. conclusions We’ve come a long way – pipeline growing/changing (new targets, combinations) – bigger, more varied financial base – new scientists, peer-reviewed articles 1973-91 = 7; 2000-02 = 232+ – bigger, more integrated advocacy base Please contact the Alliance if you are involved in or know of work that is not represented in the database.

32. acknowledgments Polly F. Harrison, PhD Program Officer Franka N. des Vignes, PhD Program Officer Trisha L. Lamphear, MPH Research Associate Cecilia D. Fox Administrative Associate Pamela Norick Senior Legislative and Policy Adviser The work of the Alliance has been made possible by the dedication of its participants and contributions from the: William and Flora Hewlett Foundation, International Partnership for Microbicides, Moriah Fund, Rockefeller Foundation, Bill and Melinda Gates Foundation through the Global Microbicide Project, and the generosity of private contributors.

33. visit our website at: www.microbicide.org or contact the Alliance directly: 8484 Georgia Avenue, Suite 940 Silver Spring, MD 20910 tel: 301-587-9690; fax: 301-588-8390 email: info@microbicide.org for more information