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:

ClpP=caseinolytic protease P; DRD2=Dopamine receptor D2; ATF4=activating transcription factor 4;
CHOP=C/EBP-homologous protein; ERK=extracellular-regulated kinase; AKT=protein kinase B

ClpP agonism

• ClpP normally degrades misfolded proteins in mitochondria
• ONC201 modifies ClpP conformation, promoting excess degradation of specific mitochondrial proteins important for cancer cell viability

DRD2 antagonism

• DRD2 is a G protein-coupled neuroreceptor that regulates Ras signaling
• ONC201 antagonizes DRD2, inhibiting Ras signaling pathways

H3 K27M sensitivity

• H3 K27M reduces methylation of histone H3, altering gene expression and increasing sensitivity to ONC201

Additional information on 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.

Neuro-Oncology and H3 K27M-mutations

Neuro-oncology is a category that includes all tumors of the brain and spinal cord, such as astrocytoma, glioma, ependymoma, and glioblastoma. Gliomas are tumors which arise from glial cells, forming the tissue that surrounds and protects other nerve cells found within the brain and spinal cord. The term H3 K27M refers to a specific mutation in genes that encode for proteins called histone H3, which occurs in a subset of these tumors. While the mutation can be found in tumor locations across the nervous system and across age groups, H3 K27M has a higher occurrence in midline brain locations (thalamus, brainstem, spinal cord) and in younger patients. The mutation can occur in several different types of brain tumors, including tumors that were traditionally called glioblastoma (GBM) or diffuse intrinsic pontine glioma (DIPG). Tumors with this mutation have no effective treatments after radiation and are associated with poor overall survival. Standard treatment for many patients consists of radiation and, when feasible, surgery. Chemotherapy is not curative for any of these brain tumors and has proven ineffective in clinical trials of some types of high-grade gliomas where the H3 K27M-mutation is found, such as DIPG.

About ONC201 in H3 K27M-mutant gliomas

In November 2021, leading investigators that work with ONC201 reported data from a 50-patient cohort for the treatment of H3 K27M mutant glioma at the 2021 Society for Neuro Oncology (SNO) Annual Meeting. The oral presentation highlighted the best of an overall response rate 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’s clinical activity against brain cancer is enabled by the drug’s ability to cross the blood brain barrier and achieve therapeutic concentrations within tumors. In clinical trials, ONC201 has been well-tolerated in patients.

ONC201 in other cancers

In collaboration with several universities, ONC201 is being evaluated in tumor types that are generally enriched for specific predictive biomarkers or microenvironments. The Cleveland Clinic evaluated ONC201 in neuroendocrine tumors in a Phase II clinical trial. Tumor regressions in response to single agent ONC201 have been observed in patients with advanced paragangliomas, which are adrenal-related tumors that can secrete dopamine and exhibit elevated DRD2 expression. 

References: 

1. Feng J, et al. The H3.3 K27M mutation results in a poorer prognosis in brainstem gliomas than thalamic gliomas in adults. Hum Pathol. 2015 Nov;46(11):1626-32. doi: 10.1016/j.humpath.2015.07.002. Epub 2015 Jul 15. PMID: 26297251.
2. Wierzbicki K, et al. Targeting and Therapeutic Monitoring of H3K27M-Mutant Glioma. Curr Oncol Rep. 2020 Feb 6;22(2):19. doi: 10.1007/s11912-020-0877-0. Erratum in: Curr Oncol Rep. 2020 Apr 16;22(5):47. PMID: 32030483; PMCID: PMC7501595.
3. Hoffman LM, et al. Clinical, Radiologic, Pathologic, and Molecular Characteristics of Long-Term Survivors of Diffuse Intrinsic Pontine Glioma (DIPG): A Collaborative Report From the International and European Society for Pediatric Oncology DIPG Registries. J Clin Oncol. 2018 Jul 1;36(19):1963-1972. doi: 10.1200/JCO.2017.75.9308. Epub 2018 May 10. PMID: 29746225; PMCID: PMC6075859.
4. Prabhu VV, et al. ONC201 and imipridones: Anti-cancer compounds with clinical efficacy. Neoplasia. 2020 Dec;22(12):725-744. doi: 10.1016/j.neo.2020.09.005. Epub 2020 Oct 23. PMID: 33142238; PMCID: PMC7588802.
5. Allen JE, et al. Dual inactivation of Akt and ERK by TIC10 signals Foxo3a nuclear translocation, TRAIL gene induction, and potent antitumor effects. Sci Transl Med. 2013 Feb 6;5(171):171ra17. doi: 10.1126/scitranslmed.3004828. PMID: 23390247; PMCID: PMC4535715.
6. Madhukar NS, et al. A Bayesian machine learning approach for drug target identification using diverse data types. Nat Commun. 2019 Nov 19;10(1):5221. doi: 10.1038/s41467-019-12928-6. PMID: 31745082; PMCID: PMC6863850.
7. Ishizawa J, et al. Mitochondrial ClpP-Mediated Proteolysis Induces Selective Cancer Cell Lethality. Cancer Cell. 2019 May 13;35(5):721-737.e9. doi: 10.1016/j.ccell.2019.03.014. Epub 2019 May 2. PMID: 31056398; PMCID: PMC6620028.