Download How is “safety” - Global Campaign for Microbicides

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
Presentation Outline
I.
Biology of microbicides
II.
Methods of pre-clinical and clinical
evaluation
III. Overview of the microbicide pipeline
I. Biology of Microbicides
physiology of the vagina
Source: R. Shattock, St. George’s Hospital Medical School.
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
How will a microbicide work?
Source: R. Shattock, St. George’s Hospital Medical School.
potential mechanisms of action for a
microbicide



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.
Alliance for Microbicide Development
potential mechanisms of action for a
microbicide (contd.)




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
Alliance for Microbicide Development
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.
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
II. Methods of pre-clinical and clinical
evaluation
pre-clinical methods of evaluation
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).
Source: Lard-Whiteford et al., 2004. Recommendations for the nonclinical development of topical
microbicides for prevention of Human Immunodeficiency Virus transmission: An Update.
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.
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.
pre-clinical assays (contd.)

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.
Source: Lard-Whiteford et al., 2004. Recommendations for the nonclinical development of topical
microbicides for prevention of Human Immunodeficiency Virus transmission: An Update.
clinical trial phases
Participants
Length
Purpose
Phase 1
10-100
several mos.
safety
Phase 2
~200
6 mos. - 1 yr.
expanded safety
1-4 yrs.
effectiveness
Phase 3
300-30,000
*Additional phases are: Phase 1/2, Phase 2/2B and Phase 2/3
Alliance for Microbicide Development
methods of clinical evaluation

How is safety assessed?

How is efficacy assessed?
“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
“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
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.
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
III. the microbicide pipeline
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
who is doing the work?




biopharmaceutical companies
non-profit research entities
public-sector entities worldwide
entities doing supportive research
(~25)
(~38)
(~5)
(~36)
Alliance for Microbicide Development
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
the microbicide pipeline, by mechanism
of action
Devices (2)
Uncharacterized
Mechanisms (6)
Acid Buffers (3)
Vaginal Defense
Enhancers (8)
Replication
Inhibitors (5)
Surfactants (6)
Entry & Fusion
Inhibitors (21)
Adsorption
Inhibitors (11)
Alliance for Microbicide Development
trends in microbicide research and
development, 1996-2004
25
20
15
10
5
0
1996
2001
2003
2004
Acid Buffers
Vaginal Defense Enhancers
Surfactants
Adsorption Inhibitors
Entry & Fusion Inhibitors
Replication Inhibitors
Multiple Mechanisms
Uncharacterized Mechanisms
Devices
Alliance for Microbicide Development
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
candidates in clinical trials
OVERVIEW OF MICROBICIDES IN CLINICAL TRIALS, FEBRUARY 2004
PHASE
TOTAL #
MICROBICIDE CANDIDIATES
1
8
AcidformTM/AmphoraTM, Cellulose acetate phthalate/CAP, Human monoclonal
antibodies (C2F5, C2G12, C4E10), Lactin-V capsule, Polystyrene
sulphonate/PSS, Tenofovir/PMPA, UC-781, VivaGel/SPL7013TM
1/2
1
Invisible CondomTM
2
2
Lactobacillus crispatus suppository (CTV-05), Protected lactobacillus in
combinationwith BZK
2/2B
2/3
2
1
BufferGelTM, PRO2000/5
Praneem Polyherbal
3
4
CarraguardTM, Cellulose sulfate/CS, EmmelleTM/dextrin-2-sulfate, SavvyTM/C31G (PRO2000/5 will also be tested in an MRC-sponsored Phase 3 trial with
EmmelleTM.)
TOTAL
18
trials including evaluation for activity
against non-HIV STIs
NAME
PHASE 1
PHASE 2/2B
BufferGel
“BV”
“BV”, chlamydia,
gonorrhea, HSV-2,
syphilis, trich
chlam, gonorrhea,
HSV-2, syph, trich
Carraguard
Cellulose
sulfate/CS
chlam, gonorrhea
Emmelle/D2S
candida, chlam,
gonorrhea, syphilis
PRO-2000/5
Savvy/C31G
PHASE 3
“BV”, chlamydia,
gonorrhea, HSV-2,
syphilis, trich
chlamydia
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.
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.
for more information
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: [email protected]