Project Summary
Our twelve years of research has led to the discovery of triptonide (TN) as a promising non-
hormonal male contraceptive agent (Nature Communications, 2021, 12:1253). In addition to its
excellent potency and proven oral bioavailability, TN does not cause discernable toxic effects in
either mice or monkeys at its minimum effective dose. All available data strongly suggest that
TN is worth further investment to develop it as a viable non-hormonal male contraceptive drug
candidate. Taking advantage of the R61/R33 funding mechanism, we propose to conduct
several Investigational New Drug (IND)-enabling studies to collect data required by the FDA for
official IND application. Specifically, we will conduct non-GLP toxicity and safety pharmacology
studies to identify the maximum tolerated dose (MTD) followed by a six-month repeat dose
toxicity study using MTD and minimum effective doses (MED) in male Sprague-Dawley rats in
the R61 phase. In addition, deep learning-based pathological and RNA-seq-based
transcriptomic analyses will also be performed. The data will not only guide and corroborate the
GLP-compliant toxicity and safety pharmacology studies proposed in the R33 phase, but also
provide molecular insights for any potential phenotypes observed. In the R33 phase, we will
work with Pharmaron Inc. to perform non-GLP toxicity studies in dogs, in vitro secondary
pharmacology, and GLP-compliant repeat-dose toxicity and safety pharmacology studies all as
part of a package of studies intended to move triptonide into a Phase I clinical trial.