ONC201 - Selectively inducing cell death in brain and other cancers:
The development of ONC201 is focused on treating brain tumors with H3 K27M-mutations (sometimes referred to as H3 K28M or H3 K27-altered; H3 is sometimes referred to as histone H3, H3F3A, HIST1H3B, HIST1H3C, H3.3 or H3.1). The drug candidate has shown promising results in clinical trials for patients with brain tumors that have the H3 K27M-mutation, including significant tumor shrinkage and other clinical benefits.
ONC201 is the founding member of the imipridone class of anti-cancer small molecules which selectively targets Dopamine Receptor D2 (DRD2) and ClpP. ONC201-mediated cell death occurs via induction of the integrated stress response and upregulation of apoptotic factors, such as tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL). It is dosed orally and has been well-tolerated and shown clinical activity in Phase I and II trials for specific advanced cancers.
ONC201 has been shown to preferentially induce cell death in cancer cells by binding to and differentially altering activity of DRD2 and ClpP as shown schematically below.
CLINICAL TRIAL OPTIONSAdditional information about ONC201:
In November 2021, we reported data from the 50-patient cohort for the treatment of recurrent H3 K27M-mutant diffuse midline glioma at the Society for Neuro-Oncology (SNO) annual meeting. Dual reader blinded independent central review (BICR) determined an overall response rate (ORR) of 20% by RANO HGG. The median duration of response was 11.2 months in addition to the 8.3-month median time to response. Disease control rate was 40% and progression free survival (PFS) at six months was 35% and at 12 months was 30%. In addition, by best response of either HGG or LGG the ORR was 30%.
ONC201 was well tolerated. Based on clinical trials, the most common adverse events were mild to moderate headache, fatigue, nausea and vomiting. The most common adverse event that was considered related to ONC201 was fatigue. More severe adverse events (Grade > 3) occurred in <10% of the study subjects, and the majority of these events were considered not related to ONC201.
The ACTION clinical trial study planned for 4Q22 is a randomized, double-blind, placebo-controlled in newly diagnosed diffuse glioma patients whose tumor harbors an H3 K27M-mutation. The primary endpoint of the study is overall survival (OS) with alpha allocation to progression-free survival (PFS). The study will take place at up to 120 sites in North America, Europe and Asia Pacific.
ONC201 in brain and other CNS tumors:
The H3 K27M mutation is found in 50-90% of patients with diffuse midline glioma (DMG), including patients with tumors in the brainstem, thalamus, cerebellum and basal ganglia. The mutation is occasionally found in cortical locations outside of the midline. Overall, as many as 10% of patients with high-grade glioma (HGG) have the H3 K27M-mutation. The test for H3 K27M is often reflexively performed at diagnosis via locally or commercially available methods that include immunohistochemistry (IHC) staining or gene sequencing.
ONC201’s lead indication is focused on treating brain tumors with H3 K27M-mutations. This focus is based on both preclinical and clinical results that have shown the ability of single agent ONC201 to induce durable tumor regressions and clinical in patients with recurrent H3 K27M-mutant diffuse midline glioma.
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