ONC206

Dual targeted investigational therapy for oncology

ONC206 is a dual targeted investigational therapy that is an agonist of the mitochondrial protease ClpP and an antagonist of the G protein-coupled receptor DRD2.  As a small molecule derivative of dordaviprone, ONC206 exhibits enhanced nanomolar potency while retaining safety, oral administration, and CNS penetration attributes. Downstream effects of dual target engagement in tumor cells include activation of the integrated stress response, altered mitochondrial bioenergetics, and inhibition of pro-survival Ras signaling that ultimately lead to cell death.

Potential target indications for ONC206 development include solid tumors beyond the lead indication of dordaviprone that are enriched for molecular vulnerabilities to its mechanism of action. Monotherapy efficacy has been observed across nonclinical models of difficult-to-treat CNS tumors (e.g. high-grade glioma and medulloblastoma) and non-CNS solid tumors (e.g. neuroendocrine, breast, and endometrial cancers).

Phase 1 trials are enrolling dose escalation cohorts that have explored multiple doses and schedules in adult and pediatric patients with CNS tumors. ONC206 has been well tolerated at doses delivering exposures that demonstrate efficacy in nonclinical models.