Post on 28-Dec-2015
Microbicide Science and Research Update
Jana Caylor Bowcut, MPHResearch Associate
Alliance for Microbicide Development
Global Campaign for Microbicides Pre-conferenceMicrobicides 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
Source: R. Shattock, St. George’s Hospital Medical School.
physiology of the vagina
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.
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
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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.)
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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
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.
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.
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.
clinical trial phases
Participants Length Purpose Phase 1 10-100 several mos. safety
Phase 2 ~200 6 mos. - 1 yr. expanded safety
Phase 3 300-30,000 1-4 yrs. effectiveness
*Additional phases are: Phase 1/2, Phase 2/2B and Phase 2/3
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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
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biopharmaceutical companies (~25) non-profit research entities (~38) public-sector entities worldwide (~5) entities doing supportive research (~36)
who is doing the work?
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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.
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the microbicide pipeline, by mechanism of action
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trends in microbicide research and development, 1996-2004
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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
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candidates in clinical trials
18TOTAL
Praneem Polyherbal
CarraguardTM, Cellulose sulfate/CS, EmmelleTM/dextrin-2-sulfate, SavvyTM/C-31G (PRO2000/5 will also be tested in an MRC-sponsored Phase 3 trial with EmmelleTM.)
1
4
2/3
3
BufferGelTM, PRO2000/522/2B
Lactobacillus crispatus suppository (CTV-05), Protected lactobacillus in combinationwith BZK
22
Invisible CondomTM11/2
AcidformTM/AmphoraTM, Cellulose acetate phthalate/CAP, Human monoclonal antibodies (C2F5, C2G12, C4E10), Lactin-V capsule, Polystyrene sulphonate/PSS, Tenofovir/PMPA, UC-781, VivaGel/SPL7013TM
81
MICROBICIDE CANDIDIATESTOTAL #PHASE
OVERVIEW OF MICROBICIDES IN CLINICAL TRIALS, FEBRUARY 2004
trials including evaluation for activity against non-HIV STIs
NAME PHASE 1 PHASE 2/2B PHASE 3
BufferGel “BV” “BV”, chlamydia, gonorrhea, HSV-2, syphilis, trich
Carraguard chlam, gonorrhea, HSV-2, syph, trich
Cellulose sulfate/CS
chlam, gonorrhea
Emmelle/D2S candida, chlam, gonorrhea, syphilis
PRO-2000/5 “BV”, chlamydia, gonorrhea, HSV-2, syphilis, trich
Savvy/C31G 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 OfficerFranka N. des Vignes, PhD Program OfficerTrisha L. Lamphear, MPH Research AssociateCecilia D. Fox Administrative AssociatePamela 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.
visit our website at:
www.microbicide.org
or contact the Alliance directly:8484 Georgia Avenue, Suite 940
Silver Spring, MD 20910tel: 301-587-9690; fax: 301-588-8390
email: info@microbicide.org
for more information