Microbicides

Research Grid

Microbicide Research	Description	Status
ANTIRETROVIRALS: TENOFOVIR GEL - CONRAD and the International Partnership for Microbicides have a co-exclusive license from Gilead for the development of 1% tenofovir gel as a microbicide.	Tenofovir is a nucleotide reverse transcriptase inhibitor (NRTI) that prevents viral replication in susceptible cells. CONRAD investigators and partners completed clinical trials studying the safety and pharmacokinetics of 1% tenofovir gel in women and tolerance in men. Tenofovir gel was being tested for expanded safety and microbicidal efficacy in clinical studies.	Pharmacokinetic studies demonstrated that tenofovir levels remained high for 24 hours following gel usage. CONRAD has supplied tenofovir gel for a number of clinical trials, the largest being CAPRISA 004, which showed tenofovir gel to be 39% effective in reducing a woman’s risk of becoming infected with HIV during sexual intercourse. CONRAD continues to supply tenofovir gel for a number of Microbicides Trial Network studies, including MTN-003, the Vaginal and Oral Interventions to Control the Epidemic (VOICE) trial, which is comparing oral tenofovir and tenofovir gel for the prevention of HIV. CONRAD will provide tenofovir gel for upcoming trials to confirm CAPRISA 004 results.
ANTIRETROVIRALS: UC781 GEL - CONRAD has licensed UC781 from Chemtura for development as a vaginal microbicide. CONRAD was developing UC781 with the intent to combine it with other microbicides.	UC781 is a tight-binding non-nucleoside reverse transcriptase inhibitor (NNRTI) with excellent anti-HIV microbicidal properties. UC781 gel was being tested for preclinical and clinical safety.	Studies of safety and pharmacokinetics in women, penile tolerance in men and rectal safety showed the single entity gel to be safe and well tolerated. Difficulties encountered combining UC781 with tenofovir and in alternative formulations led to a decision to discontinue all UC781 development in favor of pursuing other microbicide candidates.
PRECLINICAL EVALUATION: New and improved models to assess microbicide safety and efficacy are being developed.	An improved rabbit vaginal irritation (RVI) model that provides information on the proinflammatory potential of microbicide candidates has been developed. In combination with in vitro tests, this model will enhance the predictive power of preclinical evaluations. Models to assess microbicide efficacy are also being developed. New markers of mucosal inflammation have been identified and assessed in preclinical studies.	The improved RVI is being used to evaluate microbicide candidates that failed in Phase III clinical trials and candidates currently in development. Progress has been made toward establishing small animal models that are susceptible to HIV vaginal infection, and which will be useful for the early evaluation of microbicide efficacy. Low-dose, multiple-challenge R5/X4 SHIV and high-dose RT-SHIV vaginal infection models in monkeys have been developed to assess efficacy of advanced microbicide candidates. The newly identified markers of mucosal inflammation are currently being validated in clinical trials.
PRODUCT DEVELOPMENT: CONRAD’s product development scientists formulate the most promising microbicide candidates, either alone or in combination.	Tenofovir and UC781 were incorporated into a variety of formulations (i.e., as gels, intravaginal rings, films or fast-dissolve tablets). MIV-170 and other reverse transcriptase inhibitors are also being formulated.	Tenofovir and UC781 were successfully formulated into single entity gels. Testing of the two microbicides combined in a gel formulation in rabbits, however, showed the combination to be irritating, leading to a decision to discontinue development of UC781. Efforts are underway to formulate tenofovir in rings, fast-dissolve tablets and films, either alone or in combination with other microbicide candidates.
INFLAMMATORY MARKERS: CONRAD is engaged in efforts to identify and validate new clinical biomarkers of microbicide safety.	A study of inflammatory markers in women was conducted in which women applied the universal HEC placebo, cellulose sulfate (CS), or nonoxynol-9 twice daily for 14 days. New safety endpoints studied in this trial include soluble and cellular markers of inflammation in cervicovaginal lavage (CVL) fluid, biopsy specimens, and cytobrush specimens, as well as changes in pH, vaginal microflora, colposcopic findings, histopathological measures, and antiviral activity of the CVL supernatant.	Preliminary analysis showed that nonoxynol-9 was associated with an inflammatory pattern of results, while CS was not. After vaginal use, the anti-HIV effect of CS was still present in the CVL 8-18 hours after dosing. A new clinical study protocol to assess safety and efficacy will be developed for additional proprietary products.
INFLUENCE OF HORMONAL CONTRACEPTION ON MICROBICIDE SAFETY ENDPOINTS: CONRAD seeks to answer questions about the effects of hormonal contraception on vaginal immunity and HIV acquisition.	Two separate studies are planned by CONRAD, one retrospective and one prospective. A retrospective study will analyze swabs taken from women who participated in a 2004 clinical trial to link biomarkers of HIV acquisition and examine changes by contraceptive method. A prospective study will enroll 180 women desiring to start hormonal or intrauterine contraception and assess the effects of contraceptive methods on the persistence of tenofovir within the mucosa and changes in markers of mucosal safety following vaginal use of 1% tenofovir gel.	Analysis of cervicovaginal swabs is underway; results are expected by the end of 2011. The prospective study has begun enrolling participants; study completion and data analysis should be completed in 2012.
GEL IMAGING AND ACCEPTABILITY: Studies are needed to investigate whether assessing quantitative distribution of surrogate microbicides released from vaginal formulations can help inform the drug formulation process.	In an acceptability study, women will test the spreading gel and a bolus gel on hands and in the vagina and rate them on specific verified acceptability scales and dimensions, including leakage, application process, sexual pleasure, and potential for covert use. In a separate imaging study, the distribution, concentration and persistence of spreading gels through 24 hours after application will be assessed.	The imaging study is scheduled to begin in early January 2011, with results by the end of the year. The acceptability study is underway; results should be available in 2012. The imaging study will be conducted at Johns Hopkins University and the acceptability study at Brown University.
HIV INCIDENCE IN INDIA: High HIV incidence sites where future clinical trials of HIV prevention technologies, including microbicides, could be conducted need to be identified.	In collaboration with the Indian Council of Medical Research, six sites will enroll up to 9,000 sexually active high-risk women, aged 18-45 years. The planned analytical methods should allow investigators to determine whether a person who presents with HIV infection acquired his or her infection recently, which will enable identification of communities where the HIV incidence is high and HIV is spreading rapidly.	Study documentation is being finalized for study initiation in early 2011.

Microbicide Research

Description

Status

ANTIRETROVIRALS: TENOFOVIR GEL - CONRAD and the International Partnership for Microbicides have a co-exclusive license from Gilead for the development of 1% tenofovir gel as a microbicide.

Tenofovir is a nucleotide reverse transcriptase inhibitor (NRTI) that prevents viral replication in susceptible cells. CONRAD investigators and partners completed clinical trials studying the safety and pharmacokinetics of 1% tenofovir gel in women and tolerance in men. Tenofovir gel was being tested for expanded safety and microbicidal efficacy in clinical studies.

Pharmacokinetic studies demonstrated that tenofovir levels remained high for 24 hours following gel usage. CONRAD has supplied tenofovir gel for a number of clinical trials, the largest being CAPRISA 004, which showed tenofovir gel to be 39% effective in reducing a woman’s risk of becoming infected with HIV during sexual intercourse. CONRAD continues to supply tenofovir gel for a number of Microbicides Trial Network studies, including MTN-003, the Vaginal and Oral Interventions to Control the Epidemic (VOICE) trial, which is comparing oral tenofovir and tenofovir gel for the prevention of HIV. CONRAD will provide tenofovir gel for upcoming trials to confirm CAPRISA 004 results.

ANTIRETROVIRALS: UC781 GEL - CONRAD has licensed UC781 from Chemtura for development as a vaginal microbicide. CONRAD was developing UC781 with the intent to combine it with other microbicides.

UC781 is a tight-binding non-nucleoside reverse transcriptase inhibitor (NNRTI) with excellent anti-HIV microbicidal properties. UC781 gel was being tested for preclinical and clinical safety.

Studies of safety and pharmacokinetics in women, penile tolerance in men and rectal safety showed the single entity gel to be safe and well tolerated. Difficulties encountered combining UC781 with tenofovir and in alternative formulations led to a decision to discontinue all UC781 development in favor of pursuing other microbicide candidates.

PRECLINICAL EVALUATION: New and improved models to assess microbicide safety and efficacy are being developed.

An improved rabbit vaginal irritation (RVI) model that provides information on the proinflammatory potential of microbicide candidates has been developed. In combination with in vitro tests, this model will enhance the predictive power of preclinical evaluations.

Models to assess microbicide efficacy are also being developed.

New markers of mucosal inflammation have been identified and assessed in preclinical studies.

The improved RVI is being used to evaluate microbicide candidates that failed in Phase III clinical trials and candidates currently in development.

Progress has been made toward establishing small animal models that are susceptible to HIV vaginal infection, and which will be useful for the early evaluation of microbicide efficacy. Low-dose, multiple-challenge R5/X4 SHIV and high-dose RT-SHIV vaginal infection models in monkeys have been developed to assess efficacy of advanced microbicide candidates.

The newly identified markers of mucosal inflammation are currently being validated in clinical trials.

PRODUCT DEVELOPMENT: CONRAD’s product development scientists formulate the most promising microbicide candidates, either alone or in combination.

Tenofovir and UC781 were incorporated into a variety of formulations (i.e., as gels, intravaginal rings, films or fast-dissolve tablets). MIV-170 and other reverse transcriptase inhibitors are also being formulated.

Tenofovir and UC781 were successfully formulated into single entity gels. Testing of the two microbicides combined in a gel formulation in rabbits, however, showed the combination to be irritating, leading to a decision to discontinue development of UC781. Efforts are underway to formulate tenofovir in rings, fast-dissolve tablets and films, either alone or in combination with other microbicide candidates.

INFLAMMATORY MARKERS: CONRAD is engaged in efforts to identify and validate new clinical biomarkers of microbicide safety.

A study of inflammatory markers in women was conducted in which women applied the universal HEC placebo, cellulose sulfate (CS), or nonoxynol-9 twice daily for 14 days. New safety endpoints studied in this trial include soluble and cellular markers of inflammation in cervicovaginal lavage (CVL) fluid, biopsy specimens, and cytobrush specimens, as well as changes in pH, vaginal microflora, colposcopic findings, histopathological measures, and antiviral activity of the CVL supernatant.

Preliminary analysis showed that nonoxynol-9 was associated with an inflammatory pattern of results, while CS was not. After vaginal use, the anti-HIV effect of CS was still present in the CVL 8-18 hours after dosing. A new clinical study protocol to assess safety and efficacy will be developed for additional proprietary products.

INFLUENCE OF HORMONAL CONTRACEPTION ON MICROBICIDE SAFETY ENDPOINTS: CONRAD seeks to answer questions about the effects of hormonal contraception on vaginal immunity and HIV acquisition.

Two separate studies are planned by CONRAD, one retrospective and one prospective. A retrospective study will analyze swabs taken from women who participated in a 2004 clinical trial to link biomarkers of HIV acquisition and examine changes by contraceptive method. A prospective study will enroll 180 women desiring to start hormonal or intrauterine contraception and assess the effects of contraceptive methods on the persistence of tenofovir within the mucosa and changes in markers of mucosal safety following vaginal use of 1% tenofovir gel.

Analysis of cervicovaginal swabs is underway; results are expected by the end of 2011. The prospective study has begun enrolling participants; study completion and data analysis should be completed in 2012.

GEL IMAGING AND ACCEPTABILITY: Studies are needed to investigate whether assessing quantitative distribution of surrogate microbicides released from vaginal formulations can help inform the drug formulation process.

In an acceptability study, women will test the spreading gel and a bolus gel on hands and in the vagina and rate them on specific verified acceptability scales and dimensions, including leakage, application process, sexual pleasure, and potential for covert use. In a separate imaging study, the distribution, concentration and persistence of spreading gels through 24 hours after application will be assessed.

The imaging study is scheduled to begin in early January 2011, with results by the end of the year. The acceptability study is underway; results should be available in 2012. The imaging study will be conducted at Johns Hopkins University and the acceptability study at Brown University.

HIV INCIDENCE IN INDIA: High HIV incidence sites where future clinical trials of HIV prevention technologies, including microbicides, could be conducted need to be identified.

In collaboration with the Indian Council of Medical Research, six sites will enroll up to 9,000 sexually active high-risk women, aged 18-45 years. The planned analytical methods should allow investigators to determine whether a person who presents with HIV infection acquired his or her infection recently, which will enable identification of communities where the HIV incidence is high and HIV is spreading rapidly.

Study documentation is being finalized for study initiation in early 2011.