A First-in-Class Progesterone Receptor Antagonist
ABOUT PR+ CANCERS
Over 100,000 patients with breast, ovarian, prostate, or uterine cancers die per year in the United States. For many of these patients, constitutive hormone signaling drives disease progression. This in turn makes the tumors ideal candidates for antihormonal therapy, and leads to poor response to chemotherapy or immunotherapy.
Apristor (onapristone xr) is a first-/best-in-class progesterone receptor (PR) antagonist for PR+ cancers. PR is an oncogene that is activated by progesterone, a carcinogenic hormone. Apristor was developed to address the potency and selectivity liabilities of mifepristone, an FDA approved mixed PR agonist/antagonist, that continues to be evaluated in PR+ cancers despite its drawbacks. Apristor is the only full PR antagonist in clinical development.
An estimated 35,000 patients in the United States currently have PR+ 2L mBCa, which represents a >$1.5 billion opportunity. There is a clear unmet need for a new treatment to replace or potentiate fulvestrant, an injectable antiestrogen, in 2L mBCa. Upon progression from first line antiestrogen or Cdk4/6 therapy, patients typically receive fulvestrant, which results in a 0-10% overall response rate (ORR) and a 3-4 month progression free survival (PFS). Investigators seek a therapeutic approach that will result in a clinically meaningful improvement in ORR and PFS compared to fulvestrant monotherapy.
The rationale for Apristor in 2L mBCa is driven by Phase 2 Apristor monotherapy data in 2L patients who have failed antiestrogen therapy as well as in preclinical models of antiestrogen and CDK4/6 resistance.
Apristor has been evaluated as a monotherapy in 1L mBCa, 3L+ ovarian, and 3L+ uterine cancer. Context seeks to expand upon these preliminary findings via Context-sponsored or Investigator Initiated Phase 2 trials.
APRISTOR DEVELOPMENT HISTORY:
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.