Presentations during the virtual 2020 annual meeting of the American Society of Clinical Oncology (ASCO), be held Friday, May 29 to Tuesday, June 2, 2020, highlight the clinical safety and efficacy of ONC201 across a number of clinical trials, age groups, and tumor types, including H3 K27M-mutant diffuse midline glioma.

ONCO201 is being developed by Oncoceutics. The company has received research grants from the National Cancer Institute (NCI), the U.S. Food and Drug Administration (FDA), The Musella Foundation, and the National Brain Tumor Society as well as support from a number of private and public partnerships.

The investigational agent is being evaluated in several Phase II clinical trials for a range of cancers that exhibit enrichment of predictive biomarkers associated with its mechanism of action.

Glioma, tumors that arise from glial cells, forms the tissue that surrounds and protects other nerve cells found within the brain and spinal cord. 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 this mutation can be found in tumors across the entire nervous system as well as across age groups, H3 K27M has a higher occurrence in midline brain locations, including the thalamus, brainstem, spinal cord. The mutation, which can occur in several different types of brain tumors, including astrocytoma, glioblastoma (GBM), and diffuse intrinsic pontine glioma (DIPG), is observed more frequently in younger patients.

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Chemotherapy has proven to be ineffective in some types of high-grade gliomas, such as DIPG, and is, as a result, not considered a curative option for any of these brain tumors. this has limited the standard treatment for the majority of patients to radiation and, when feasible, surgery.

To date, tumors with an H3 K27M mutation have no effective treatments. They are also associated with poor overall survival.

ONC201, a “founding member” of the imipridone class of small molecule, is an orally active small molecule selective antagonist of dopamine receptor D2 (DRD2) and ClpP agonist that is able to penetrate the blood-brain-barrier effectively. The drug acts as a bitopic antagonist of the G protein-coupled receptor (GPCR) dopamine receptor D2 (DRD2) and an allosteric agonist of the mitochondrial protease caseinolytic protease P (ClpP).

“The data presented at ASCO 2020 highlights the potential of ONC201 to address the substantial need for patients with H3 K27M-mutant glioma,” noted Lee Schalop, M.D., Chief Executive Officer of Oncoceutics.

“We are committed to build on this promising data and to help ensure that brain cancer patients benefit from the development of ONC201 and other new therapeutic options,” Schalop added.

Clinical efficacy
“We are encouraged by the clinical efficacy of ONC201 in a molecular subset of high-grade gliomas that have continued to be robust as the results grow and mature,” added Joshua Allen, Ph.D., Chief Scientific Officer of Oncoceutics.

Based on the reported durable tumor regression and clinical benefit FDA has granted Fast Track designation to ONC201 for the treatment of adult recurrent H3 K27M-mutant high-grade glioma.

During the 2020 virtual ASCO meeting a dedicated abstract will presented in which researchers discuss the rationale and design of the first-in-human clinical trial for ONC206, a second molecule being developed as another agent in Oncoceutics’ portfolio of imipridones entering clinical development.

ONC206 acts as a bitopic DRD2 antagonist and ClpP agonist. The investigational drug exhibits enhanced non-competitive effects, with high specificity, nanomolar potency, and disruption of DRD2 homodimers. Furthermore, in preclinical studies, the drug has demonstrated to be highly potent in the potential treatment of difficult-to-treat neuroendocrine tumors and high-grade gliomas. Downstream of target engagement, Oncoceutics’ ONC206 exhibits a mechanism of action similar to that of ONC201, involving activation of the integrated stress response and induction of TNF-related apoptosis-inducing ligand (TRAIL).

“We are further looking forward to the first clinical trial with ONC206 that offers new ways to address additional forms of cancers that lack effective treatments,” Allen concluded.

Other presentations
During the virtual ASCO meeting, expect a number of ONC201 and ONC206-related presentation

Abstract #TitleMeeting
2563Clinical experience of ONC201 in patients with recurrent H3 K27M-mutant spinal cord glioma.Abstract
3615Single-agent ONC201 in recurrent H3 K27M-mutant diffuse midline gliomaAbstract
3617Clinical efficacy of ONC201 in thalamic H3 K27M-mutant gliomaAbstract
3619ONC201 in previously irradiated pediatric H3 K27M-mutant glioma or newly diagnosed DIPGAbstract
TPS2576A first-in-human phase I single-agent dose-escalation, food effect, and dose-expansion study of oral ONC206 in recurrent and rare primary central nervous system neoplasms.Abstract
E16703Phase II study of ONC201 in pheochromocytoma-paragangliomas (PC-PG), medullary thyroid carcinoma (MTC), and other neuroendocrine tumors.Abstract
E14552Epidermal growth factor receptor expression as a molecular determinant of glioblastoma response to the dopamine receptor D2 antagonist, ONC201Abstract


Clinical trials
Phase 2 Study of ONC201 in Neuroendocrine Tumors – NCT03034200
ONC201 in Adults With Recurrent H3 K27M-mutant Glioma – NCT03295396
ONC201 in Pediatric H3 K27M Gliomas – NCT03416530
Expanded Access to ONC201 for Patients With H3 K27M-mutant and/or Midline High-Grade Gliomas – NCT03134131
Oral ONC201 in Recurrent GBM, H3 K27M Glioma, and Midline Glioma – NCT02525692

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