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

Microbicide Update:
What’s New, What’s Next?
Christine Mauck, MD
Learning objectives
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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?
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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
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Some of the microbicides being investigated
prevent pregnancy and some do not
Why are microbicides important?
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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?
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Active against:
 HIV
 Other STIs
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Could be used in a combination product
 To have more than one mechanism of action against a specific STI
 To target multiple STIs
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Safe:
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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)
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Compatible with
 Condoms
 Cervical barriers
 Seminal fluid/vaginal secretions
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Availability
 Cost
 Can be produced where needed
 Accessible
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Easy to use and acceptable
From identified need to marketplace:
Drug development
Laboratory
Testing
2-6 Years
Phase 1
(safety)
Phase 2
(safety)
Phase 3
(efficacy)
1 to 6
Months
Up to 2
Years
2 to 4
Years
25 – 40
people
200-400
people
3,000-10,000
people
Simultaneous studies:
HIV+, penile & rectal
10 or more years
Microbicide pipeline
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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
Surfactant (viral disruption)
Savvy™ (C31G)
3
Entry/fusion inhibitors
Carraguard®
3
Cellulose sulfate/CS (Ushercell)
3
PRO 2000
3
Invisible Condom™
Vaginal defense enhancers
1/2
Cellulose acetate 1,2-benzenedicarboxylate
(cellacefate/CAP)
1
VivaGel™/SPL7013
1
BufferGel®
ACIDFORM™/Amphora™
Replication inhibitors
PHASE
2/2B
1
Tenofovir/PMPA gel
TMC120
UC-781
Uncharacterized
Praneem polyherbal vaginal tablet
Combinations
PC 815 (Carraguard® and MIV-150)
2
1/2
1
2
1
Adapted from An Analytical Overview of the Microbicide Preclinical and Clinical Pipeline, Plescia, Finley, Harrison, des Vignes
5 Products Furthest Along
Product/
Developer
# to be
enrolled
Location of trial
Estimated end
of follow-up
Carraguard®
6,299
South Africa
March 2007
3,220
Malawi, South Africa, United States,
Zambia, and Zimbabwe
July 2008
9,673
S Africa, Tanzania, Uganda, Zambia
March 2009
2,574
Benin, Zimbabwe, India, South Africa,
Uganda
February 2009
Family Health International
2,160
Nigeria
February 2009
Savvy™
2,142
Nigeria
Stopped August 06
Population Council
BufferGel®
ReProtect, Inc.
PRO 2000
Indevus Pharmaceuticals
.5% formulation
PRO 2000
.5% & 2% formulations
Cellulose sulfate
Global Microbicide Project
Family Health International
Safety testing of microbicides
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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
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Penile application in men:
 Once daily X 7 days
HIV-uninfected then HIV-infected
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Rectal use – men and women
Issue: assessment of irritation
 Colposcopy
 Soluble and cellular markers of inflammation (e.g. cytokines,
SLIPI)
Efficacy testing of microbicides
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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
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Studies end up enrolling thousands of women and
following them for at least one year
Microbicides and contraception
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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
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Cellulose sulfate used alone – completed
BufferGel used with Ortho All-Flex diaphragm completed
Savvy used alone - underway
Microbicides and physical barriers
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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
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Issues:
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Acceptability
Irritation
Cleaning & storage if barrier is reusable
Disposal, environmental concerns & cost if single-use
Examples:
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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
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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
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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
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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)
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Initiated by the Microbicide Donors Committee
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Year-long consultative process with key players in
microbicide R&D
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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.
What does the development of a
microbicide cost?
Laboratory
Testing
Phase 1
(safety)
Up to $13 Million
Phase 3
(efficacy)
$50
Up to
Million
Phase 2
(safety)
Development will require significant
public money
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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
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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
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
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
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Enrollment:
 2022 women screened
 200 enrolled
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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%)
Demographics
Females Male partners
Age (mean)
Race (percent)
White, non-Hispanic
Hispanic
26.6 yrs
29.0 yrs
46%
29%
48%
25%
African American
Other
Education (% who attended
college)
Ever used spermicide
21%
4%
82%
21%
6%
74%
27.5%
NA
Pregnancy Probabilities - CS
25
20
15
13.4
Cellulose sulfate
10
3.9
5
0
Typical use (6 months)
Perfect use (6 cycles)
How do these compare with N-9?
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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
25
22.2
20
15.7
15.5
15
14
Advantage S (52.5 mg N-9)
Ortho Options Gel B (100 mg N-9)
9.5
10
8.5
5
0
Typical use (6 months)
Perfect use (6 cycles)
Ortho Options Gel C (150 mg N-9)
Pregnancy Probabilities CS & N-9
25
22.2
20
15.7
15.5
15
14
Advantage S (52.5 mg N-9)
13.4
Ortho Options Gel B (100 mg N-9)
Ortho Options Gel C (150 mg N-9)
9.5
10
Cellulose sulfate
8.5
5
3.9
0
Typical use (6 months)
Perfect use (6 cycles)
Adverse events
►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.
Acceptability
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,” 89%
or “much better” than other spermicides
(of those who ever used spermicide)
94%
Conclusions of CS contraceptive trial
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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.
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CS gel is safe, with about three quarters of users
reporting no gel-related adverse events during 6
months of use.
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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
Coital acts
On average, there were 11.5 coital acts per cycle:
Study gel used alone as instructed
(“perfect use”)
Study gel used with an additional method
78%
Study gel used alone but incorrectly
Use of an alternative method alone
Unprotected intercourse
4%
10%
4%
5%
Cycles
Correct and consistent (“perfect”) gel use
Incorrect use of CS, use of an additional
contraceptive method, or use of an
alternative contraceptive method
Unprotected intercourse
TOTAL
343 (45%)
290 (38%)
125 (17%)
758 cycles