An Analytical Report on the Investigational Drug: Telapristone Acetate (DB05253)

Executive Summary

Telapristone acetate, also known by its developmental code name CDB-4124 and proposed brand names Proellex and Progenta, is a synthetic, steroidal small molecule classified as a Selective Progesterone Receptor Modulator (SPRM).[1] Originally developed by the National Institutes of Health (NIH) and later advanced by Repros Therapeutics, it was investigated for the treatment of hormone-dependent gynecological conditions, primarily uterine fibroids and endometriosis, with additional exploration into its potential as an antineoplastic agent in early-stage breast cancer.[1]

The drug demonstrated significant clinical promise, driven by a potent antiprogestogenic mechanism of action. Unlike simple receptor antagonists, Telapristone acetate was found to function through a novel molecular pathway, globally reducing the binding of the progesterone receptor (PR) to chromatin and uniquely recruiting the transcriptional corepressor TRPS1 to mediate gene silencing.[4] This potent activity translated into compelling efficacy in clinical trials, particularly for uterine fibroids, where it produced substantial reductions in tumor volume, controlled heavy menstrual bleeding, and improved patient quality of life.[6]

However, the promising therapeutic profile of Telapristone acetate was ultimately overshadowed by a critical and insurmountable safety flaw: dose-dependent hepatotoxicity. During late-stage clinical development, serious adverse events involving elevated liver enzymes were observed, including cases that met the criteria for Hy's Law, a strong predictor of a drug's potential to cause fatal liver injury.[8] This safety signal led the U.S. Food and Drug Administration (FDA) to impose a full clinical hold on the oral formulation in August 2009, an order that was later downgraded to a partial hold but never fully lifted.[8]