Microbicide Update:What’s New, What’s Next?

Christine Mauck, MD

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

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

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

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

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

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

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

How do microbicides work?

Shattock RJ and Moore JP. Nature Reviews Microbiology, vol. 1 Oct/2003

Microbicides in clinical trials and their mechanism of action

MECHANISM OF ACTION CANDIDATE PHASE

Surfactant (viral disruption)

Savvy™ (C31G) 3

Entry/fusion inhibitors Carraguard® 3

Cellulose sulfate/CS (Ushercell) 3

PRO 2000 3

Invisible Condom™ 1/2

Cellulose acetate 1,2-benzenedicarboxylate (cellacefate/CAP)

1

VivaGel™/SPL7013 1

Vaginal defense enhancers

BufferGel® 2/2B

ACIDFORM™/Amphora™ 1

Replication inhibitors Tenofovir/PMPA gel 2

TMC120 1/2

UC-781 1

Uncharacterized Praneem polyherbal vaginal tablet 2

Combinations PC 815 (Carraguard® and MIV-150) 1Adapted from An Analytical Overview of the Microbicide Preclinical and Clinical Pipeline, Plescia, Finley, Harrison, des Vignes

5 Products Furthest AlongProduct/Developer

# to be enrolled

Location of trial Estimated end of follow-up

Carraguard®

Population Council

6,299 South Africa March 2007

BufferGel®

ReProtect, Inc.

3,220 Malawi, South Africa, United States, Zambia, and Zimbabwe

July 2008

PRO 2000Indevus Pharmaceuticals

.5% formulation

PRO 2000.5% & 2% formulations

9,673 S Africa, Tanzania, Uganda, Zambia March 2009

Cellulose sulfate Global Microbicide Project

2,574 Benin, Zimbabwe, India, South Africa, Uganda

February 2009

Family Health International

2,160 Nigeria February 2009

Savvy™Family Health International

2,142 Nigeria Stopped August 06

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)

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

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

Contraceptive studies of microbicides

Cellulose sulfate used alone – completed BufferGel used with Ortho All-Flex

diaphragm - completed Savvy used alone - underway

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

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

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)

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

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

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

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.Available at www.microbicide.org.

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

Development will require significant public money

Why aren’t 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?

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

ACKNOWLEDGMENTSACKNOWLEDGMENTS

♦ Alliance for Microbicide Development♦ Global Campaign for Microbicides♦ Certain slides courtesy of:

Sharon Hillier, PhD University of PittsburghJim Turpin, PhD, NIAID/DAIDSSalim Abdool Karim, MBChB, PhD, University of KwaZulu-Natal

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

Results Enrollment:

2022 women screened 200 enrolled

Disposition:

Completed study without becoming pregnant

82 (41%)

Became pregnant 18 (10%)

Discontinued early for gel-related reason: 14 ( 7%)

Discontinued early for other reasons 66 (33%)

Never used gel 18 ( 9%)

Lost to follow-up 2 ( 1%)

Females

Male partners

Age (mean) 26.6 yrs

29.0 yrs

Race (percent)

White, non-Hispanic 46% 48%

Hispanic 29% 25%

African American 21% 21%

Other 4% 6%

Education (% who attended college)

82% 74%

Ever used spermicide 27.5% NA

Demographics

Pregnancy Probabilities - CS

13.4

3.9

0

5

10

15

20

25

Typical use (6 months) Perfect use (6 cycles)

Cellulose sulfate

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

Pregnancy Probabilities – N-9

22.2

15.715.5

8.5

14

9.5

0

5

10

15

20

25

Typical use (6 months) Perfect use (6 cycles)

Advantage S (52.5 mg N-9)

Ortho Options Gel B (100 mg N-9)

Ortho Options Gel C (150 mg N-9)

Pregnancy Probabilities CS & N-9

22.2

15.715.5

8.5

14

9.5

13.4

3.9

0

5

10

15

20

25

Typical use (6 months) Perfect use (6 cycles)

Advantage S (52.5 mg N-9)

Ortho Options Gel B (100 mg N-9)

Ortho Options Gel C (150 mg N-9)

Cellulose sulfate

►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

Females

Male partners

% who liked the gel “OK” or “very much”

82% 84%

% who would either “recommend” or “strongly recommend” the gel to a friend or relative

73% 73%

% who said the gel is “the same,” “better,” or “much better” than other spermicides (of those who ever used spermicide)

89% 94%

Acceptability

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.

The end

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 method

5%

Study gel used alone but incorrectly

4%

Use of an alternative method alone 10%

Unprotected intercourse 4%

Coital acts

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 intercourse 125 (17%)

TOTAL 758 cycles