Microbicides

Research Grid

Microbicide Research 2006-present	Description	Status	Partner
ANTIRETROVIRALS: TENOFOVIR - CONRAD and the International Partnership for Microbicides have licensed tenofovir from Gilead for continued clinical development.	Monkey and rabbit pharmacokinetic studies were conducted prior to initiating a pharmacokinetic study in women in March of 2007. A male tolerance study of tenofovir gel was carried out in 2006.	The pharmacokinetic clinical study in women conducted at Magee-Womens Research Institute (Pittsburgh), Advances in Health (Houston) and PROFAMILA (Dominican Republic) was completed in April 2008. Clinical supplies are being manufactured under CONRAD’s supervision for an ongoing Phase IIb clinical trial in South Africa.	International Partnership for Microbicides
ANTIRETROVIRALS: UC781 - CONRAD has licensed UC781 from Chemtura for development and public-sector marketing.	UC781 is a tight-binding non-nucleoside reverse transcriptase inhibitor (NNRTI) with excellent anti-HIV microbicidal properties, showing high potency alone and in drug combinations.	Safety studies were done in collaboration with CDC at Emory University in Atlanta and at Chulalongkorn University in Bangkok, Thailand and are in analysis. A male tolerance study was initiated by CONRAD at the California Family Health Councilin, Los Angeles, while a rectal safety study was launched at the University of California, Los Angeles, and a pharmacokinetic study commenced at the University of Pittsburgh.	CDC and NIH
PRECLINICAL EVALUATION: New and improved models to assess microbicide safety and efficacy.	An improved rabbit vaginal irritation (RVI) model that provides information on the pro-inflammatory potential of microbicide candidates has been developed. In combination with in vitro tests, this model will enhance the predictive power of preclinical evaluations. New markers of mucosal inflammation have been identified and assessed in preclinical studies and are currently being validated in clinical trials. Models to assess microbicide efficacy are also being developed.	The improved RVI is being used to evaluate microbicide candidates that failed in Phase III clinical trials and those that are currently in development. 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. Progress has also 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.	None
TESTING TRADITIONAL REMEDIES: CONRAD recently completed a trial of intravaginal lime juice.	This trial took place in response to reports of Nigerian women applying lemon or lime juice intravaginally around the time of intercourse, believing that it would protect them against vaginal acquisition of HIV and other sexually transmitted infections.	Among the observations were a dose-dependent pattern of symptoms, gross physical examination findings, colposcopic findings of deep epithelial disruption, and changes in some inflammatory markers that were consistent with a compromised vaginal barrier. The conclusion was that lime juice is unlikely to protect against HIV and may be harmful.	None
STUDYING THE MENSTRUAL CYCLE: A study that investigated the effects of the menstrual cycle on colposcopic findings on the cervix was conducted in Pune, India, in collaboration with the National AIDS Research Institute of the Indian Council of Medical Research.	It was concluded that the mean diameter of the largest visible blood vessel differed significantly between the estrogenic and progestogenic phases, and that such changes observed during the progestogenic phase in safety studies should be considered normal.	Completed	National AIDS Research Institute of the Indian Council of Medical Research
BIOMARKER RESEARCH: CONRAD and the Alliance for Microbicide Development organized a workshop on the state of the art of biomarker research in microbicide development in November 2006. Discussions focused on biomarkers of semen exposure, cervicovaginal inflammation and HIV infection.	This conference was the first of its kind and helped to identify gaps in knowledge, as well as studies and possible collaborations to resolve the gaps.	Proceedings have been published in Sexually Transmitted Diseases 36(3), 2009.	Alliance for Microbicide Development
INFLAMMATORY MARKERS: A study of inflammatory markers in women using vaginal products was begun at two sites.	In a random study, women are applying twice-daily a hydroxyethylcellulose-based "universal" placebo, 6% cellulose sulfate, or 4% nonoxynol-9 (Conceptrol®) gel for fourteen days. New safety endpoints are being studied that include soluble and cellular markers of inflammation in 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.	The degree of correlation between different methods of clinical assessment being used in the trial will be determined, as will the degree of correlation between the results of this clinical study and the results of the preclinical assessment of the same compounds.	None

Microbicide Research 2006-present

Description

Status

Partner

ANTIRETROVIRALS: TENOFOVIR - CONRAD and the International Partnership for Microbicides have licensed tenofovir from Gilead for continued clinical development.

Monkey and rabbit pharmacokinetic studies were conducted prior to initiating a pharmacokinetic study in women in March of 2007. A male tolerance study of tenofovir gel was carried out in 2006.

The pharmacokinetic clinical study in women conducted at Magee-Womens Research Institute (Pittsburgh), Advances in Health (Houston) and PROFAMILA (Dominican Republic) was completed in April 2008. Clinical supplies are being manufactured under CONRAD’s supervision for an ongoing Phase IIb clinical trial in South Africa.

International Partnership for Microbicides

ANTIRETROVIRALS: UC781 - CONRAD has licensed UC781 from Chemtura for development and public-sector marketing.

UC781 is a tight-binding non-nucleoside reverse transcriptase inhibitor (NNRTI) with excellent anti-HIV microbicidal properties, showing high potency alone and in drug combinations.

Safety studies were done in collaboration with CDC at Emory University in Atlanta and at Chulalongkorn University in Bangkok, Thailand and are in analysis. A male tolerance study was initiated by CONRAD at the California Family Health Councilin, Los Angeles, while a rectal safety study was launched at the University of California, Los Angeles, and a pharmacokinetic study commenced at the University of Pittsburgh.

CDC and NIH

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

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

New markers of mucosal inflammation have been identified and assessed in preclinical studies and are currently being validated in clinical trials.

Models to assess microbicide efficacy are also being developed.

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

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.

Progress has also 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.

None

TESTING TRADITIONAL REMEDIES: CONRAD recently completed a trial of intravaginal lime juice.

This trial took place in response to reports of Nigerian women applying lemon or lime juice intravaginally around the time of intercourse, believing that it would protect them against vaginal acquisition of HIV and other sexually transmitted infections.

Among the observations were a dose-dependent pattern of symptoms, gross physical examination findings, colposcopic findings of deep epithelial disruption, and changes in some inflammatory markers that were consistent with a compromised vaginal barrier. The conclusion was that lime juice is unlikely to protect against HIV and may be harmful.

None

STUDYING THE MENSTRUAL CYCLE: A study that investigated the effects of the menstrual cycle on colposcopic findings on the cervix was conducted in Pune, India, in collaboration with the National AIDS Research Institute of the Indian Council of Medical Research.

It was concluded that the mean diameter of the largest visible blood vessel differed significantly between the estrogenic and progestogenic phases, and that such changes observed during the progestogenic phase in safety studies should be considered normal.

Completed

National AIDS Research Institute of the Indian Council of Medical Research

BIOMARKER RESEARCH: CONRAD and the Alliance for Microbicide Development organized a workshop on the state of the art of biomarker research in microbicide development in November 2006. Discussions focused on biomarkers of semen exposure, cervicovaginal inflammation and HIV infection.

This conference was the first of its kind and helped to identify gaps in knowledge, as well as studies and possible collaborations to resolve the gaps.

Proceedings have been published in Sexually Transmitted Diseases 36(3), 2009.

Alliance for Microbicide Development

INFLAMMATORY MARKERS: A study of inflammatory markers in women using vaginal products was begun at two sites.

In a random study, women are applying twice-daily a hydroxyethylcellulose-based "universal" placebo, 6% cellulose sulfate, or 4% nonoxynol-9 (Conceptrol®) gel for fourteen days. New safety endpoints are being studied that include soluble and cellular markers of inflammation in 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.

The degree of correlation between different methods of clinical assessment being used in the trial will be determined, as will the degree of correlation between the results of this clinical study and the results of the preclinical assessment of the same compounds.

None