A First-in-Class Progesterone Receptor Antagonist For PR+ Metastatic Breast Cancer


APRISTOR OVERVIEW.  Apristor is an investigational New Chemical Entity (NCE) for PR+ breast and ovarian cancers. 

MECHANISM OF ACTION. Apristor is a type I progesterone antagonist that prevents PR monomer dimerization, inhibits ligand-induced phosphorylation, and prevents the association of PR with its co-activators, thus preventing PR-induced transcription.  The non-clinical efficacy of onapristone has been documented in multiple preclinical tumor models [Schneider 1992, Nishino 2009].  Studies have demonstrated clinical benefit from onapristone therapy in patients with endometrioid, breast, and ovarian cancer.

Progesterone, progesterone derivatives, and anti-progestins induce ligand-dependent conformational changes in the PR.  Based on in vitro characteristics such as DNA binding activity, onapristone has been defined as a type I progesterone antagonist, displaying relatively pure antagonistic properties and preventing binding of the antagonist-occupied PR to DNA at concentrations that are clinically achievable.

PR+ BREAST CANCER.  Approximately 60-70% of breast cancer patients express progesterone receptor (PR).  Apristor is a type I progesterone antagonist that prevents PR monomers from dimerizing. In turn, Apristor inhibits ligand and kinase-induced PR activation, which prevents PR from activating pro-cancer survival gene transcription programs. These properties are unique to Apristor within the antiprogestin class. The efficacy of Apristor has been documented in multiple preclinical tumor models, alone and in combination with other endocrine therapies, including aromatase inhibitors (AIs) and selective estrogen receptor degraders (SERDs). 



BREAST CANCER CLINICAL DATA.  Apiristor, in its short-acting form (Onapristone IR), has been administered to hundreds of healthy volunteers and cancer patients across Phase 1 through Phase 3 trials, including two Phase 2 trials in 120 patients with metastatic breast cancer [Robertson 1999, Jonat 2001].  In first line metastatic breast cancer, the drug demonstrated objective responses (tumor shrinkage) in over 50% of the treated patients. 

DEVELOPMENT OF APRISTOR.  To drive outcomes in hormonally-driven cancers, hormone receptor activity must be blocked continuously for 24 hours [McDonnell 2006].  Onapristone IR has a short half-life and blocks the progesterone receptor for only 2-4 hours.  To address the short half-life of Onapristone IR, Context Therapeutics has developed Apristor (Onapristone XR).  Apristor is an extended release version of Onapristone IR that has a 12 hour half-life and that provides 24 hour target coverage when administered orally twice per day.  Apristor therefore has the potential to surpass the clinical utility of the precedent compound, Onapristone IR [Cottu 2018].  Apristor is a New Chemical Entity (NCE) with patent protection through at least 2034.

COMPETITION.  Apristor is the only pure PR antagonist.  Competing antiprogestins are all dual agonist/antagonists, which results in poor durability of response due to agonist-mediated resistance. This may explain why existing antiprogestins, including mifepristone and ulipristal, have limited efficacy in cancer.



Sigma1 Inhibitor

A First-In-Class Sigma1 Inhibitor For Abiraterone-Resistant Prostate Cancer

Drug Discovery. Sigma1 is an intracellular protein that engages in client protein complex formation to regulate the quality control, transport, and activity of client proteins.  By therapeutically modulating Sigma1 stabilization of client proteins, client protein transport is altered, leading to positive or negative regulation of client protein signaling pathways. Many of these client proteins are validated disease targets but are generally considered undruggable through small molecule approaches.  Indirect modulation of client protein stability and transport through Sigma1 expands the universe of opportunities for new drug discovery and new treatments for patients.

Sigma1 Research Consortium.  Our strategy includes collaborating with academic and biopharmaceutical partners.  We have a flexible resource sharing program - our Sigma1 Toolkit - to enable the expedited transfer of our chemical library, reagents, and biomarker tools for groups interested in our core research areas and outside.