NIH Starts Clinical Trial with ONC206, a Next-Generation Imipridone

A first patient has been treated in a first-in-human clinical trial of the company’s next-generation imipridone ONC206, being developed by Oncoceutics, at the National Institutes of Health. The investigational drug is the second investigational agent in Oncoceutics pipeline to enter clinical trials.

The Phase I trial, for adults with recurrent primary central nervous system (CNS) neoplasms, is led by Mark Gilbert, MD, Chief of the Neuro-Oncology Branch, Center for Cancer Research (CCR), National Cancer Institute (NCI), and Brett Theeler, MD, Clinical Collaborator at the Neuro-Oncology Branch, CCR, NCI.

Imipridones
ONC206 is part of the family of small molecules drug candidates called imipridones, a novel class of compounds that selectively target G protein-coupled receptors (GPCR) for oncology.

These complex receptors form the largest family of receptors that reside on the surface of human cells and mediate many important physiological functions by binding to extracellular ligands and differentially controlling many signaling pathways inside cells.

The imipridone family of inhibitors also target mitochondria through activation of mitochondrial caseinolytic protease P (ClpP) reducing the function of essential pathways. These molecules offer a new mechanism for developing clinical therapie in a number of cancers and hematological malignancies.[1]

ONC206 possess the same core chemical structure as the company’s first-generation molecule ONC201, an orally active small molecule DRD2 antagonist and ClpP agonist in late-stage clinical development for H3 K27M-mutant glioma with additional indications under clinical investigation.

Gilbert’s laboratory has previously demonstrated that ONC206 exerts therapeutic effects in preclinical models of CNS tumors, including brain tumors, that currently have no effective treatment. Various studies have shown that imipridones reduce the proliferation of patient-derived xenograft and stem-like glioblastoma cell cultures in vitro. [2] The novel agent has also proven effective in several biomarker-enriched tumor types outside of the CNS that have been studied extensively by other research groups.

Preclinical studies
Preclinical studies suggest that the invesigational drug is likely to be orally bioavailable, penetrate the blood-brain barrier, demonstrate a well-tolerated safety profile, and selectively antagonize dopamine receptor D2 (DRD2).

While DRD2 is also targeted by ONC201, ONC206 exhibits distinct biological effects and chemical properties that position its clinical development in indications beyond those of the parent compound.

“I am excited to see next-generation imipridone ONC206 enter the clinic,” said Minesh Mehta, MD, Deputy Director and Chief of Radiation Oncology, Miami Cancer Institute and member of the board of directors of Oncoceutics.

“ONC206 has the potential to become an impactful new therapy for patients with untreatable CNS tumors and broadens the clinical utility of imipridones beyond its founding member, ONC201, which has already shown promise in helping patients,” Mehta added.

“Our study will evaluate the safety and clinical activity of ONC206 in patients with CNS malignancies,” Gilbert noted.

“This clinical trial was designed to incorporate biomarker information derived from our molecular studies of ONC206 in an effort to enable future patient selection,” he concluded.

Clibical trials
Phase I Study of Oral ONC206 in Recurrent and Rare Primary Central Nervous System Neoplasms – NCT04541082

Trial participation
For more information on trial participation and patient enrolling in this clinical study:

• Call the NCI’s toll-free number 1-800-4-Cancer (1-800-422-6237) (TTY: 1-800-332-8615),
• Email: NCIMO_Referrals@mail.nih.gov

Reference
[1] Carter JL, Hege K, Kalpage HA, Edwards H, Hüttemann M, Taub JW, Ge Y. Targeting mitochondrial respiration for the treatment of acute myeloid leukemia. Biochem Pharmacol. 2020 Oct 2;182:114253. doi: 10.1016/j.bcp.2020.114253. Epub ahead of print. PMID: 33011159.
[2] Ishida CT, Zhang Y, Bianchetti E, Shu C, Nguyen TTT, Kleiner G, Sanchez-Quintero MJ, Quinzii CM, Westhoff MA, Karpel-Massler G, Prabhu VV, Allen JE, Siegelin MD. Metabolic Reprogramming by Dual AKT/ERK Inhibition through Imipridones Elicits Unique Vulnerabilities in Glioblastoma. Clin Cancer Res. 2018 Nov 1;24(21):5392-5406. doi: 10.1158/1078-0432.CCR-18-1040. Epub 2018 Jul 23. PMID: 30037819; PMCID: PMC6214769.

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