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Human placental biodisposition of novel antiherpesviral drugs, amenamevir and pritelivir, using ex vivo and in vitro experimental models

Award Number: R01HD107428
ORGANIZATION: NATIONAL INSTITUTE OF CHILD HEALTH AND HUMAN DEVELOPMENT
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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ABSTRACT Genital herpes simplex virus (HSV) infections in pregnancy pose a risk for perinatal transmission of the virus to neonates, and HSV infections in the newborns are associated with severe morbidity and mortality. A standard treatment of HSV infections with nucleoside analogs such as acyclovir does not eliminate asymptomatic viral shedding and is ineffective against acyclovir-resistant HSV strains. Amenamevir and pritelivir, the helicase-primase inhibitors, represent novel antiherpesviral medications that were developed to circumvent the limitations of the nucleoside analogs. Both novel drugs completed Phase II clinical trials in treatment of genital herpes in men and nonpregnant women and demonstrated superiority over placebo and standard treatments. While amenamevir is currently indicated for the treatment of herpes zoster in Japan, pritelivir received an FDA Breakthrough Therapy designation and has entered a Phase III clinical trial. Pregnant women infected with genital herpes could benefit from amenamevir and pritelivir in suppressive or episodic treatments to prevent the transmission of HSV to neonates. The first step to determine the potential use of the novel drugs in pregnancy is to obtain preclinical data on their placental biodisposition. The focus of the proposed investigation is to determine the biodisposition of amenamevir and pritelivir by human placenta using ex vivo and in vitro experimental models. Meanwhile, assessing fetal safety for amenamevir and pritelivir, as well as their effect on placental function, is imperative in clinical development of these novel drugs for their potential use in pregnancy. While existing data from toxicity studies in animal models suggest a favorable reproductive and developmental safety profile for amenamevir, assessment of potential developmental hazards of pritelivir remains to be conducted. The specific aims are to 1) Determine the extent of bidirectional transfer of amenamevir and pritelivir across term human placenta ex vivo, the distribution of these drugs in the placental tissue and maternal and fetal circuits, and their effect on placental viability and functional parameters; 2) Determine the role of placental efflux membrane transporters in the placental disposition of amenamevir and pritelivir; and 3) Determine potential embryo-fetal developmental toxicity of pritelivir in mice. This work will provide the preclinical data needed to determine potential use of amenamevir and pritelivir in the treatment of newly acquired and reactivated genital herpes in pregnancy as well as in HSV suppressive therapy during pregnancy. Amenamevir and pritelivir could be effective alternative treatments to manage genital herpes in pregnancy to reduce the risk of mother-to-neonate HSV transmission in women with asymptomatic presentation of genital herpes at the time of delivery and for those with inadequate response to standard treatment with nucleoside analogs.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2024 ( Subtotal = $24,526 )
2024	2024	UNIVERSITY OF TEXAS MEDICAL BRANCH AT GALVESTON	301 UNIVERSITY BLVD	GALVESTON	TX	77555	GALVESTON	USA	Child Health and Human Development Extramural Research	000	2	11/22/2023	SUPPLEMENT FOR EXPANSION	$24,526
														Subtotal = $24,526

Issue Date FY: 2023 ( Subtotal = $418,754 )
2023	2023	UNIVERSITY OF TEXAS MEDICAL BRANCH AT GALVESTON	301 UNIVERSITY BLVD	GALVESTON	TX	77555	GALVESTON	USA	Child Health and Human Development Extramural Research	001	2	7/28/2023	NON-COMPETING CONTINUATION	$418,754
2023	2022	UNIVERSITY OF TEXAS MEDICAL BRANCH AT GALVESTON	301 UNIVERSITY BLVD	GALVESTON	TX	77555	GALVESTON	USA	Child Health and Human Development Extramural Research	000	1	7/27/2023	NEW	$0
														Subtotal = $418,754

Issue Date FY: 2022 ( Subtotal = $418,754 )
2022	2022	UNIVERSITY OF TEXAS MEDICAL BRANCH AT GALVESTON	301 UNIVERSITY BLVD	GALVESTON	TX	77555	GALVESTON	USA	Child Health and Human Development Extramural Research	000	1	8/11/2022	NEW	$418,754
														Subtotal = $418,754

Grand Total All Awards = $862,034

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Human placental biodisposition of novel antiherpesviral drugs, amenamevir and pritelivir, using ex vivo and in vitro experimental models

Award Number: R01HD107428

ORGANIZATION: NATIONAL INSTITUTE OF CHILD HEALTH AND HUMAN DEVELOPMENT

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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