1. Microbicide Update: Whats New, Whats Next? Christine Mauck, MD

2. Learning objectives Describe what microbicides are and how they work List three benefits of microbicide in prevention of pregnancy and transmission of STIs Describe where microbicides are in the research pipeline and how soon the pubic will have access to use in the United States and abroad List two benefits of microbicides used with a diaphragm Indicate how health care providers can play a role in expediting public access to microbicides Describe in general terms the results of the CS contraceptive trial

3. What is a Microbicide? A topical product that reduces transmission of sexually transmitted infections (STIs) when applied either in the vagina or rectum Includes many forms Gels, creams, suppositories, films Sponge or vaginal ring that slowly releases the active ingredient Some of the microbicides being investigated prevent pregnancy and some do not

4. Why are microbicides important? Today's prevention options--condoms, mutual monogamy, and STI treatment--are not feasible for millions of people around the world, especially women. Married women in developing countries are among those at highest risk of contracting HIV. Many women do not have the social or economic power necessary to insist on condom use or to abandon partnerships that put them at risk. Because microbicides would not require a partner's cooperation, they would put the power to protect into the women's hand. Microbicides that are even 60 percent effective against HIV could avert at least 2.5 million infections over three years. From http://www.global-campaign.org/about_microbicides.htm

5. What would a perfect microbicide look like? Active against: HIV Other STIs Could be used in a combination product To have more than one mechanism of action against a specific STI To target multiple STIs Safe: Not inflammatory No deleterious effect on micro flora Safe for use in pregnancy No or little systemic absorption Long effect window Does not have to be used immediately before sex Adapted from: DHHS/NIH/NIAID/DAIDS

6. The perfect microbicide (continued) Compatible with Condoms Cervical barriers Seminal fluid/vaginal secretions Availability Cost Can be produced where needed Accessible Easy to use and acceptable

7. Laboratory Testing 2-6 Years Phase 3 (efficacy) 2 to 4 Years Simultaneous studies: HIV+, penile & rectal 10 or more years Phase 1 (safety) 1 to 6 Months Phase 2 (safety) Up to 2 Years 25 – 40 people 200-400 people 3,000-10,000 people From identified need to marketplace: Drug development

8. Microbicide pipeline As of August 2006: Over 30 microbicide candidates in preclinical development 14 microbicide candidates in clinical trials 5 in ongoing Phase 2/2b or Phase 3 trials

9. How do microbicides work? Shattock RJ and Moore JP. Nature Reviews Microbiology, vol. 1 Oct/2003

10. Microbicides in clinical trials and their mechanism of action MECHANISM OF ACTIONCANDIDATEPHASE Surfactant (viral disruption)Savvy (C31G) 3 Entry/fusion inhibitorsCarraguard ® 3 Cellulose sulfate/CS (Ushercell) 3 PRO 20003 Invisible Condom 1/2 Cellulose acetate 1,2-benzenedicarboxylate (cellacefate/CAP) 1 VivaGel/SPL70131 Vaginal defense enhancersBufferGel ® 2/2B ACIDFORM/Amphora1 Replication inhibitorsTenofovir/PMPA gel2 TMC120 1/2 UC-7811 UncharacterizedPraneem polyherbal vaginal tablet2 CombinationsPC 815 (Carraguard® and MIV-150)1 Adapted from An Analytical Overview of the Microbicide Preclinical and Clinical Pipeline, Plescia, Finley, Harrison, des Vignes

11. 5 Products Furthest Along Product/ Developer # to be enrolled Location of trialEstimated end of follow-up Carraguard ® Population Council 6,299South AfricaMarch 2007 BufferGel ® ReProtect, Inc. 3,220Malawi, South Africa, United States, Zambia, and Zimbabwe July 2008 PRO 2000 Indevus Pharmaceuticals.5% formulation PRO 2000.5% & 2% formulations 9,673S Africa, Tanzania, Uganda, ZambiaMarch 2009 Cellulose sulfate Global Microbicide Project 2,574Benin, Zimbabwe, India, South Africa, Uganda February 2009 Family Health International 2,160NigeriaFebruary 2009 Savvy Family Health International 2,142NigeriaStopped August 06

12. Safety testing of microbicides Vaginal application in women: Once daily X 14 days then twice daily X 14 days Sexually abstinent then sexually active HIV-uninfected then HIV-infected Penile application in men: Once daily X 7 days HIV-uninfected then HIV-infected Rectal use – men and women Issue: assessment of irritation Colposcopy Soluble and cellular markers of inflammation (e.g. cytokines, SLIPI)

13. Efficacy testing of microbicides Issues: Lack of surrogate markers of protection Use of condoms Control arms: Condom only (no gel) Placebo (plus condom) Local incidence of disease P level needed Assumed efficacy Length of follow-up Management of women who become pregnant Development of resistance when using antiretroviral products Studies end up enrolling thousands of women and following them for at least one year

14. Microbicides and contraception There is a need for microbides that prevent pregnancy and HIV/STIs and those that prevent only HIV/STIs Cannot assess contraception and HIV/STI prevention in the same trial: Contraceptive trial requires no use of condoms HIV/STI trial requires condom counseling

15. Contraceptive studies of microbicides Cellulose sulfate used alone – completed BufferGel used with Ortho All-Flex diaphragm - completed Savvy used alone - underway

16. Microbicides and physical barriers Combining a physical barrier (e.g. diaphragm) with a microbicide has advantages: Should increase overall efficacy May concentrate formulation on target cells in cervix Replaces applicator Issues: Acceptability Irritation Cleaning & storage if barrier is reusable Disposal, environmental concerns & cost if single-use Examples: BufferGel used with the Ortho All-Flex diaphragm – phase 3 done Cellulose sulfate used with the new SILCS diaphragm – phase 3 about to start Cellulose Sulfate used with the Ortho All-Flex diaphragm – phase 1 done ACIDFORM used with the Ortho All-Flex diaphragm – phase 1 done BufferGel Duet (BufferGel used with a new diaphragm) – phase 1 done

17. Who is involved in microbicide development? Clinical trials: Phase 2/2b or 3 trials: Population Council – Carraguard Microbicide Trials Network – PRO 2000 & BufferGel Medical Research Council – PRO 2000 Global Microbicide Project (CONRAD) – Cellulose sulfate FHI – Savvy Others: CDC International Partnership for Microbicides

18. Microbicides Trial Network Funded by NIH Replaces HPTN that began in October 2001 Involves the University of Pittsburgh, University of Washington in Seattle, UCLA, and Family Health International Total funding of $285 million for the first year. Will conduct clinical trials to evaluate the safety and effectiveness of microbicides New trials Two ongoing trials (tenofovir and BufferGel)

19. Who else is involved in microbicide development? Funders Bill and Melinda Gates Foundation US Government NIH USAID CDC British government (Medical Research Council) Advocates Alliance for Microbicide Development Global Campaign for Microbicides

20. Alliance for Microbicide Development Global coalition of representatives from biopharmaceutical companies, nonprofit research institutions, health advocacy groups Authoritative source of information on microbicide research, development, funding Neutral objective convener of dialogue on key policy issues Educator about public health potential of microbicides Advocate for resources needed to develop them Trouble-shooter for the microbicide field www.microbicide.org

21. Global Campaign for Microbicides Broad-based, international effort to build support for increased investment into microbicides Goals are to: Raise awareness and mobilize political support for increased funding; Create a supportive policy environment for the development of new prevention technologies; and Ensure that the public interest and trial participants, users, and communities are protected. www.global-campaign.org/about.htm

22. Microbicide Development Strategy (MDS) Initiated by the Microbicide Donors Committee Year-long consultative process with key players in microbicide R&D Purpose: To take stock of the current status of the field, identify gaps, and build consensus on current R&D priorities Available at www.microbicide.org.

23. What does the development of a microbicide cost? Laboratory Testing Phase 1 (safety) Phase 2 (safety) Up to $13 Million Phase 3 (efficacy) Up to $50 Million

24. Development will require significant public money Why arent big pharmaceutical companies investing? Perceived low profitability Liability concerns Lack of in-house expertise Uncertain regulatory environment For the last 20 years, almost all funding for contraceptive R & D has come from governments and foundations Success with microbicides MUST depend on multidisciplinary, multisectoral partnerships & ADVOCACY What can you do to help?

25. Support the Microbicide Development Act Barely 2% of the US budget for HIV/AIDS research is spent on microbicides. Three federal agencies support and/or implement microbicide R&D – NIH, CDC, Agency for International Development (USAID). But no one entity is in charge of coordinating everything. The Act would achieve better coordination and expanded resources for microbicide research at NIH, CDC and USAID. The Microbicide Development Act was introduced in the Senate in March 2005 and in the House in September 2005 You can take action by asking your congress person to support the act. Go to http://www.global-campaign.org/legislativeadvocacy.htm

26. ACKNOWLEDGMENTS Alliance for Microbicide Development Global Campaign for Microbicides Certain slides courtesy of: Sharon Hillier, PhD University of Pittsburgh Jim Turpin, PhD, NIAID/DAIDS Salim Abdool Karim, MBChB, PhD, University of KwaZulu-Natal

27. Cellulose Sulfate Contraceptive Trial Test product: CS gel – 3.5 ml used alone Site: California Family Health Council, Inc. Participants: 200 couples who did not desire a pregnancy, were at low risk for STIs, and agreed to use the study product as their primary means of contraception for six months Objectives: 6-month typical and perfect use pregnancy probabilities Consistency of use Safety Acceptability

28. Results Enrollment: 2022 women screened 200 enrolled Disposition: Completed study without becoming pregnant82 (41%) Became pregnant18 (10%) Discontinued early for gel-related reason:14 ( 7%) Discontinued early for other reasons66 (33%) Never used gel18 ( 9%) Lost to follow-up 2 ( 1%)

29. FemalesMale partners Age (mean)26.6 yrs29.0 yrs Race (percent) White, non-Hispanic46%48% Hispanic29%25% African American21% Other4%6% Education (% who attended college) 82%74% Ever used spermicide27.5%NA Demographics

30. Pregnancy Probabilities - CS

31. How do these compare with N-9? NIH/FHI N-9 study:* Most recent N-9 contraceptive study Done in U.S. Five arms: 3 gel arms 1 suppository arm 1 film arm # of women per arm averaged 297 6-month follow-up * Raymond et al. Contraceptive effectiveness and safety of five nonoxynol-9 spermicides: a randomized trial. Obstet Gynecol. 2004 Mar;103(3):430-9

32. Pregnancy Probabilities – N-9

33. Pregnancy Probabilities CS & N-9

34. 28.5% of women reported at least one gel-related adverse event during 6 months of use. Adverse events (percent of women ever experiencing the 5 most common gel-related events): Vulvovaginitis, unspecified 9.5% Urinary tract infection 7% Gel reaction 7% Spotting 5% Yeast infection 3.5% 78% of these adverse events were mild. Only one was severe (UTI requiring temporary interruption of gel). Only 1 gel-related male AE: mild reaction to study gel. Adverse events

35. FemalesMale partners % who liked the gel OK or very much82%84% % who would either recommend or strongly recommend the gel to a friend or relative 73% % who said the gel is the same, better, or much better than other spermicides (of those who ever used spermicide) 89%94% Acceptability

36. Conclusions of CS contraceptive trial CS gel is effective as a contraceptive: The 6-month cumulative probabilities of pregnancy in both typical and perfect use compare well with nonoxynol-9, the only contraceptive vaginal gel still approved for marketing in the U.S. CS gel is safe, with about three quarters of users reporting no gel-related adverse events during 6 months of use. CS gel is acceptable, with about three quarters of both women and men reporting liking it and being willing to recommend it to a friend.

37. The end

38. On average, there were 11.5 coital acts per cycle: Study gel used alone as instructed (perfect use) 78% Study gel used with an additional method5% Study gel used alone but incorrectly4% Use of an alternative method alone10% Unprotected intercourse4% Coital acts

39. Cycles Correct and consistent (perfect) gel use 343 (45%) Incorrect use of CS, use of an additional contraceptive method, or use of an alternative contraceptive method 290 (38%) Unprotected intercourse125 (17%) TOTAL758 cycles