Aug01

FROM THE PIPELINE | Taking on a challenge – How an ambitious engineering goal led to an innovative MPT for HIV, HSV, and unintended pregnancy

Wednesday, 01 August 2018

FROM THE PIPELINE | Taking on a challenge – How an ambitious engineering goal led to an innovative MPT for HIV, HSV, and unintended pregnancy

It all started with the simple realization that women seeking protection against HIV also want to prevent unintended pregnancies. In general, they also prefer a combined method. Then followed the innovation challenge: Engineer a long-acting intravaginal ring that could release two chemically diverse drugs – one for HIV and herpes simplex virus (HSV) prevention, and one for contraception – at sustained, controlled, and yet extremely different release rates (up to 1000-fold) for 3 months; make it suitable and scalable for use in resource-limited countries, such as those of sub-Saharan Africa; and design it so women would want to use it. Even now it’s a daunting task. When this project began, 10 years ago, its feasibility was questioned by many, including our collaborators and ourselves. However, if successful, this challenge had strong potential to provide a truly game-changing MPT solution to a dire unmet need for women globally.

CONRAD, a not-for-profit global health research and development organization, took on the challenge in collaboration with Dr. Patrick Kiser at the University of Utah (now at Northwestern University) and with support from U.S. Agency for International Development (USAID) and National Institutes of Health (NIH). At the time, CONRAD was evaluating its tenofovir vaginal gel product in clinical trials, including a Phase IIb expanded safety and effectiveness study in South Africa (CAPRISA 004). This study demonstrated for the first time that a vaginal microbicide could reduce the acquisition of HIV and HSV when used consistently, before and after sex. If CONRAD could build on these promising results and take on the proposed MPT ring development challenge, it could improve the delivery method for tenofovir and expand microbicide method options for women around the world.

The outcome was a novel combination tenofovir/levonorgestrel ring, as well as a tenofovir-only ring, currently in expanded clinical development. These products are the result of a new, highly innovative, polyurethane reservoir ring technology which married state-of-the-art advancements in materials science, controlled drug delivery research, and medical device manufacturing to achieve our ambitious target product profile. Following extensive preclinical development, CONRAD conducted an intensive first-in-human clinical study (CONRAD 128) evaluating the safety, pharmacokinetics, pharmacodynamics, and acceptability of both rings after approximately one month of use in 50 women in the US and Dominican Republic.  Study results demonstrated no evidence of safety signals and achievement of pharmacologic benchmarks for both drugs.

With support from PEPFAR through USAID, an additional clinical study was initiated in late 2017 to evaluate the combination ring for longer use. The CONRAD 138 study is evaluating the tenofovir/levonorgestrel ring following 90 days of continuous use as well as an “interrupted use” regimen, in which the ring is removed for three days at the end of each month. This study, which is being conducted at the same clinical sites as CONRAD 128, will confirm that the MPT ring can meet benchmarks for the full-intended duration of use and will help to inform the acceptability and also the pharmacological forgiveness of the ring’s dosing regimen in the context of real world use when rings may be removed for menses or other reasons.

In collaboration with RTI International, CONRAD recently completed a socio-behavioral clinical study (Quatro) in South Africa and Zimbabwe focusing on assessing user acceptability and product preference of the ring compared with three other vaginal dosage forms. Results from this study will be available later this year and will inform ongoing product development efforts, such as this MPT ring, as well as other vaginal microbicide and MPT dosage forms that may better fit the needs of young women most at risk for HIV.

Future trials are planned with several partnering organizations to further advance the tenofovir and tenofovir/levonorgestrel MPT rings. CONRAD is partnering with the Microbicides Trial Network (MTN) to conduct a 90-day safety and pharmacokinetics study of the tenofovir-only ring (MTN 038). This study, to be conducted in 48 US women, is expected to start by early 2019.  CONRAD is also partnering with the CDC and USAID to conduct an expanded safety, acceptability, and adherence study of both rings in Kenyan women living in an HIV-endemic setting. These important collaborations illustrate the need for community contributions to the shared goal of improving MPT options available for HIV, HSV, and unintended pregnancy prevention.

Now, almost a decade after embarking on this development challenge, we have demonstrated initial proof of concept of this first-in-class MPT ring and have several ongoing and planned clinical trials underway.  However, this journey is far from over, and in order to truly provide this innovative prevention option to women, we still face the challenge of taking these rings to effectiveness trials and eventually to registration and market.  The challenge ahead may seem as daunting as the engineering one we initially set out to overcome, but its potential benefits for women, especially to those in greatest need around the world, will make the culmination of this grand challenge well worth the effort.

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About CONRAD
CONRAD is a not-for-profit biomedical research and development organization with a social mission to improve global health. A division of the Department of Obstetrics and Gynecology at Eastern Virginia Medical School, we are dedicated to improving sexual and reproductive health, particularly of young women in developing countries, through development of innovative user-centered technologies for the prevention of HIV, other sexually transmitted infections, unintended pregnancy, and other maternal and neonatal health disorders. Since its establishment in 1986 as a contraceptive R&D organization originally, CONRAD strives to bring its in-house pharmaceutical development and reproductive health R&D expertise to a wide international network of academic, governmental and industrial partners so that together we may innovate game-changing solutions to some of the world’s greatest unmet needs.  Learn more at www.conrad.org.

Acknowledgement
This project is made possible by the generous support of the American people through the United States Agency for International Development (USAID) under Cooperative Agreements to Eastern Virginia Medical School (EVMS)/CONRAD. The contents are the responsibility of EVMS/CONRAD and do not necessarily reflect the views of USAID or the U.S. Government.


About the Author

Meredith Roberts Clark

Meredith Clark, PhD is the Director of Preclinical Activities at CONRAD and Associate Professor in Obstetrics and Gynecology at the Eastern Virginia Medical School. She has over 10 years of experience in the research and development of MPTs and other drug delivery and biomedical innovations for improving sexual and reproductive health for women globally.

Kathleen Dietz

Kathleen Dietz is the Regulatory Manager at CONRAD. She has worked in regulatory for a decade and has experience with pharmaceutical products, medical devices and combination products across all stages of the regulatory lifecycle.

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