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Translational feasibility of an oral, non-hormonal, male contraceptive pill

Award Number: R44HD100256
ORGANIZATION: NATIONAL INSTITUTE OF CHILD HEALTH AND HUMAN DEVELOPMENT
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 08/12/2019
PERIOD OF PERFORMANCE END DATE: 07/31/2022

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Translational feasibility of an oral, non-hormonal, male contraceptive pill - Unintended pregnancies account for almost one-half of total pregnancies in the US yearly, costing about $12 billion annually. One factor contributing to unintended pregnancies is the lack of an effective and safe oral, reversible male contraceptive drug. A promising approach for reversible suppression of spermatogenesis is antagonism of the retinoic acid receptor-alpha (RARα). Vitamin A-deprivation is well- known to block spermatogenesis and, based on knockout animal studies, RARα appears to be the major target of retinoic acid, the active form of Vitamin A. First-generation RARα-selective compounds inhibited spermatogenesis in mouse but were not orally bioavailable and were only moderately selective. The ideal drug should be orally-bioavailable with 100x specificity for RARα so that off-target effects potentially associated with antagonism of RARβ or RARα can be minimized. We have identified highly selective RARα antagonists that disrupt spermatogenesis in mice and have good oral bioavailability, potency, and other desirable drug-like properties. Our lead RARα antagonist OR-812 is 155-fold and >1,000-fold more potent at RARα than at RARβ and RARγ, respectively. Importantly, OR-812 disrupts spermatogenesis at oral doses of ~10 mg/kg following one week of treatment, without otherwise affecting the weight or appearance of the animals. In this two-year project, we propose to significantly de-risk translational development of OR-812 as a viable candidate for a male contraceptive by addressing these Specific Aims: 1) Identify a minimum efficacious dose (MED) for spermatogenesis inhibition by OR-812 following 45 days of oral dosing in mouse and establish reversibility within 2-4 months. 2) Determine the safety of OR-812 by non-GLP general toxicology in rat and find its NOAEL (No Observed Adverse Effect Level). 3) Confirm infertility following 45-day dosing of OR-812 and then restoration of fertility after a four-month recovery. The major project milestones are: (i) OR-812 has a good safety margin, a NOAEL that is >5x its MED for inhibition of spermatogenesis; and (ii) inhibition of fertility by OR-812 is reversible. Successful completion of this project will provide the data necessary for a pre-IND meeting with the FDA to elicit comments on Orphagen’s proposed IND-enabling pre-clinical study plan. With this information, we will apply for SBIR Phase III support to move OR-812 towards IND filing. Our long-term goal is to develop a non-hormonal male contraceptive that is safe, effective, and reversible. This would have significant social and economic impact by allowing men to share greater responsibility for contraceptive decisions.


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: 2023 ( Subtotal = $0 )
2023	2020	ORPHAGEN PHARMACEUTICALS, INC.	11558 SORRENTO VALLEY RD	SAN DIEGO	CA	92121	SAN DIEGO	USA	Child Health and Human Development Extramural Research	000	2	8/7/2023	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2020 ( Subtotal = $719,059 )
2020	2020	ORPHAGEN PHARMACEUTICALS, INC.	11558 SORRENTO VALLEY RD STE 4	SAN DIEGO	CA	92121	SAN DIEGO	USA	Child Health and Human Development Extramural Research	001	2	7/24/2020	NON-COMPETING CONTINUATION	$719,059
2020	2019	ORPHAGEN PHARMACEUTICALS, INC.	11558 SORRENTO VALLEY RD STE 4	SAN DIEGO	CA	92121	SAN DIEGO	USA	Child Health and Human Development Extramural Research	000	1	7/23/2020	NEW	$0
														Subtotal = $719,059

Issue Date FY: 2019 ( Subtotal = $1,093,784 )
2019	2019	ORPHAGEN PHARMACEUTICALS	11558 SORRENTO VALLEY RD STE 4	SAN DIEGO	CA	92121	SAN DIEGO	USA	Child Health and Human Development Extramural Research	000	1	8/12/2019	NEW	$1,093,784
														Subtotal = $1,093,784

Grand Total All Awards = $1,812,843

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Translational feasibility of an oral, non-hormonal, male contraceptive pill

Award Number: R44HD100256

ORGANIZATION: NATIONAL INSTITUTE OF CHILD HEALTH AND HUMAN DEVELOPMENT

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 08/12/2019

PERIOD OF PERFORMANCE END DATE: 07/31/2022

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