Microbicide Science and Research Update Jana Caylor Bowcut, MPH Research Associate Alliance for...

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


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.)


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)


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.


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.)


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


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


biopharmaceutical companies (~25) non-profit research entities (~38) public-sector entities worldwide (~5) entities doing supportive research (~36)

who is doing the work?


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.


the microbicide pipeline, by mechanism of action


trends in microbicide research and development, 1996-2004


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


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: [email protected]

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