ONC206 / Jazz - LARVOL DELTA

Preclinical analysis of ONC206 and ONC212 with lurbinectedin in pancreatic cancer (AACR 2025) - "Our group recently described lurbinectedin's potency as both a single agent and combinatorial agent with irinotecan and 5-fluorouracil in pancreatic cancer cell lines. Future studies will analyze whether a combination of lurbinectedin and ONC212 or lurbinectedin and ONC206, another imipridone and chemical analogue of ONC201, proves more efficient at killing pancreatic tumor cells in vitro. Our results are developing insights into novel combinatorial therapeutic regimens while investigating the molecular mechanisms underlying synergism."

Preclinical • Lung Cancer • Oncology • Pancreatic Cancer • Small Cell Lung Cancer • Solid Tumor

Imipridones (ONC201, ONC206 and ONC212) modulate MGMT and ClpX expression in DIPG cell lines (AACR 2025) - "Temozolomide (TMZ) is an oral alkylating agent that is generally well tolerated. We are going to test this mechanism of synergy and therapeutic efficacy in vivo by treating orthotopic DIPG mouse models with imipridones -/+ TMZ. Our results support further studies combining imipridones (ONC201, ONC206 and ONC212) with TMZ and RT as a reasonable and safe therapeutic option for DIPG."

Preclinical • Brain Cancer • CNS Tumor • Diffuse Intrinsic Pontine Glioma • Glioblastoma • Glioma • Malignant Glioma • Oncology • Solid Tumor • MGMT

Tumor treating fields with imipridone ONC206 in murine model of colorectal cancer [WITHDRAWN] (AACR 2025) - "Our ongoing studies further explore the effect of synergy on common pathways. Our results suggest an effective novel combination of Imipridone ONC206 and TTFields for the treatment of colorectal cancer."

Preclinical • Brain Cancer • CNS Tumor • Colorectal Cancer • Glioblastoma • Lung Cancer • Mesothelioma • Non Small Cell Lung Cancer • Oncology • Solid Tumor • ATF4 • DRD2

Dopamine receptor D2 and dopamine antagonism modulate the progression of small cell lung cancer (AACR 2025) - "To assess the therapeutic potential of DRD2, we utilized ONC206, a highly specific, orally bioavailable, and blood-brain barrier penetrating DRD2 antagonist...Integrated gene expression studies coupled with pathway analysis showed that DRD2 inhibition reduces SCLC growth and metastasis by inhibiting the cholesterol biosynthesis pathway. Altogether, our study provides strong preclinical rationale for targeting DRD2 via dopamine antagonism to attenuate SCLC growth and metastasis."

IO biomarker • Brain Cancer • Lung Cancer • Neuroendocrine Tumor • Oncology • Small Cell Lung Cancer • Solid Tumor • DRD2

Enhancing chemotherapy efficacy in pancreatic cancer synergistic effects of ONC206 and ONC212 with 5-FU through inhibition of p-ERK (AACR 2025) - "Resistance to chemotherapy, particularly 5-fluorouracil (5-FU), remains a major challenge in treating pancreatic ductal adenocarcinoma (PDAC). Our data demonstrate that combining 5-FU with ONC206 or ONC212 results in the inhibition of p-ERK, a critical node in the PDAC growth pathway. This synergy between 5-FU and the imipridone compounds ONC206 and ONC212 is a universal phenomenon in the tested human PDAC cell lines. Notably, ONC212 is more potent than ONC206, allowing for lower dosages, and in cases where ONC206 does not effectively inhibit p-ERK, ONC212 can be a more effective option Further studies are needed to elucidate the exact mechanism of this synergy, but these findings provide a promising foundation for developing novel combination therapies to improve PDAC treatment outcomes."

Clinical • Oncology • Pancreatic Cancer • Pancreatic Ductal Adenocarcinoma • Solid Tumor • ATF4 • DRD2 • GPR132

Reduced severity of radiation esophagitis in mice following 2 weeks of ONC212 treatment [WITHDRAWN] (AACR 2025) - "Radiotherapy administered with curative intent or palliation in lung cancer, esophageal cancer, breast cancer or head and neck cancer is often associated with inflammation, debilitating esophageal injury, pain, difficulty swallowing, and dehydration. Our results provide a strategy with an orally bioavailable drug for treatment of severe esophagitis that is caused by therapeutic radiotherapy involving the esophagus. Additional directions for future research include studies of other TRAIL pathway agonists such as TRAIL itself, TLY012, or other imipridones including ONC201 or ONC206 effects on severity of radiation esophagitis."

Preclinical • Breast Cancer • Esophageal Cancer • Head and Neck Cancer • Lung Cancer • Oncology • Solid Tumor • CCL2 • CCL22 • CCL3 • CXCL12 • EGF • IGF1 • IL16

Pre-clinical efficacy of tumor treating fields and imipridones in glioblastoma and colorectal cancer cell lines (AACR 2025) - "We then treated cells with imipridones at the identified IC50 doses either alone or together with 200kHz TTFields and collected cell lysate after 72 hours.We found differences in AKT phosphorylation across our treatment conditions (control, ONC201, ONC206, ONC212, TTF, TTF + ONC201, TTF + ONC206, and TTF + ONC212). These findings are significant in guiding future in vivo experiments and offering insight on whether TTField and imipridone treatment can be further explored in clinical trials."

Preclinical • Brain Cancer • CNS Tumor • Colorectal Cancer • Glioblastoma • Lung Cancer • Mesothelioma • Non Small Cell Lung Cancer • Oncology • Solid Tumor

Imipridones ONC201, ONC206, and ONC212 promote immune-mediated cell death and anti-tumor activity in biliary tract cancer models in vitro (AACR 2025) - "Imipridones and MEK inhibitors exhibit potent antineoplastic effects in BTC cell lines. In RBE cells, half maximal inhibitory concentrations (IC50) were 2.53 μM (ONC201), 917 nM (ONC206), 46.99 nM (ONC212), and 5.94 μM (trametinib), while in HuCCT1 cells, they were 1.97 μM (ONC201), 1.06 μM (ONC206), 38.95 nM (ONC212), and 3.71 μM (trametinib). Imipridones (ONC201 and ONC212) with trametinib showed synergy in HuCCT1 cells."

Preclinical • Biliary Cancer • Biliary Tract Cancer • Oncology • Solid Tumor • DRD2

TRAIL-inducing imipridones ONC201, ONC206, and ONC212 demonstrate anti-neoplastic effects in colonic adenoma-derived organoids (AACR 2025) - "ONC206 and ONC212 demonstrated antineoplastic effects on adenoma-derived FAP and SSA organoids, with half maximal inhibitory concentrations (IC50) less than that of ONC201 in FAP and SSA organoids. As was noted in ONC201 studies, the mechanism of action of ONC206 and ONC212 appears to be mediated through modulation of multiple pathways including the TRAIL pathway (TRAIL and DR5 upregulation) and the integrated stress responses (ATF4 upregulation). Co-culture with NK cells revealed a significant increase in NK-mediated organoid cell death."

Colorectal Cancer • Oncology • Solid Tumor • ATF4

Elraglusib (9-ING-41), a glycogen synthase kinase-3β inhibitor in combination with imipridones for treatment of solid cancer (AACR 2025) - "Ovarian, GBM, pancreatic, and colorectal cancer cell lines were treated with the novel drug combination of elraglusib and imipridone ONC206...In pancreatic and colorectal cancer cell lines, synergy was also investigated and observed between elraglusib and imipridone ONC212...Our ongoing studies are exploring other potential mechanisms of synergy and effects on immune-mediated killing of cancer cells. Our results show a potentially effective new combination of Elraglusib and Imipridones that can be further developed for cancer treatment."

Combination therapy • Brain Cancer • CNS Tumor • Colorectal Cancer • Glioblastoma • Oncology • Ovarian Cancer • Pancreatic Cancer • Solid Tumor • BIRC5 • MCL1 • RELA • TNFA • TNFRSF10B

Allosteric ClpP agonist ONC206 alters mitochondrial metabolism, stress response, chromatin accessibility and cell cycle to elicit apoptosis in pheochromocytoma (AACR 2025) - "ONC206 also demonstrated superior cell viability inhibition and apoptosis induction in PC cell lines relative to temozolomide and sunitinib at equivalent concentrations. Accordingly, western blot showed ONC206 downregulated mitochondrial proteins (ClpX, SDHB), neuroendocrine markers (tyrosine hydroxylase, enolase-2, synaptophysin) and upregulated stress response (ATF4) in hPheo1 cells. Thus, ONC206 is a potent novel agent that is superior to SOC and dordaviprone that have shown clinical activity in PC-PG."

CNS Tumor • Endocrine Cancer • Oncology • Solid Tumor • ANXA5 • ATF4 • DRD2 • SDHB • SYP

Preclinical efficacy of combinatorial B7-H3 CAR T cell and ONC206 treatment in DIPG/DMG (AACR 2025) - P1 | "B7-H3 CAR T cells and ONC206 may have a combinatorial benefit. Therefore, future studies will continue to validate these findings, optimize dosing strategies, and assess immunocompetent DIPG models."

CAR T-Cell Therapy • Preclinical • Brain Cancer • CNS Tumor • Diffuse Intrinsic Pontine Glioma • Glioma • Hematological Malignancies • Oncology • Solid Tumor • ATF4 • CASP3 • CASP7 • CD276 • DRD2 • GZMB • IFNG • IFNL1 • IL2 • TNFA

Reduced EZH1/2 expression in imipridone-treated cells correlates with synergy following combinations with EZH1/2 or HDAC inhibitors in diffuse glioma and other tumors. (PubMed, Am J Cancer Res) - "Small molecule imipridones including ONC201, ONC206 and ONC212 have anti-cancer activity mediated in part through the integrated stress response, induction of TRAIL and its receptor DR5, and activation of mitochondrial caseinolytic protease ClpP with impaired oxidative phosphorylation...RNA-seq showed ONC201 and EHZ2i tazemetostat-treated cells have similar transcriptional profiles and share overlap of top regulated genes...ONC201 and EZH2i share similar targets and actions on tumors. Synergistic combinations of imipridones plus EZH1/2i or imipridones, EZH2i and HDACi merit further investigation."

Journal • Brain Cancer • Breast Cancer • CNS Tumor • Gastric Cancer • Gene Therapies • Genito-urinary Cancer • Glioma • Lung Cancer • Oncology • Prostate Cancer • Small Cell Lung Cancer • Solid Tumor • EZH2

Triple therapy slows glioblastoma growth and extends survival in preclinical study (Eurekalert) - "The study tested ONC201 and its analog ONC206 in combination with radiation therapy and the chemotherapy drug temozolomide (TMZ), a regimen referred to as IRT. This triple therapy slowed tumor growth and extended survival in a mouse model of glioblastoma, offering a potential new strategy for one of the most aggressive and treatment-resistant brain cancers."

Preclinical • Glioblastoma

Case Report: Rare intraventricular H3 K27-altered diffuse midline glioma in an adult. (PubMed, Front Oncol) - "The patient underwent two craniotomies, one laser interstitial thermal ablation (LITT), chemoradiotherapy, and bevacizumab and ONC206, through compassionate use. Their median survival is 10.5 months (ranges 1 - 24 months). This case report presents the clinical, radiological, pathological, and molecular characteristics of a 24-year-old white man diagnosed with a ventricular H3 K27-Altered diffuse midline glioma, highlighting the rare presentation, management, and outcomes."

Journal • Brain Cancer • CNS Disorders • CNS Tumor • Diffuse Midline Glioma • Glioma • Oncology • Pain • Solid Tumor • Ventriculomegaly

Imipridones ONC201/ONC206 + RT/TMZ triple (IRT) therapy reduces intracranial tumor burden, prolongs survival in orthotopic IDH-WT GBM mouse model, and suppresses MGMT. (PubMed, Oncotarget) - P3 | "We show that ONC201 and ONC206 synergize with temozolomide (TMZ) and Radiotherapy (RT). By 231-days, the only surviving mice were in IRT group. Our results support investigation of ONC201/ONC206 in combination with RT/TMZ (IRT) in GBM or H3K27M mutated DG therapy."

Journal • Preclinical • Brain Cancer • CNS Tumor • Glioblastoma • Glioma • Oncology • Solid Tumor

ONC206-001: Phase I Study of Oral ONC206 in Recurrent and Rare Primary Central Nervous System Neoplasms (clinicaltrials.gov) - P1 | N=102 | Recruiting | Sponsor: Chimerix | Trial completion date: Feb 2025 ➔ Dec 2026 | Trial primary completion date: Sep 2024 ➔ Dec 2025

Trial completion date • Trial primary completion date • Anaplastic Oligoastrocytoma • Astrocytoma • Brain Cancer • CNS Tumor • Diffuse Midline Glioma • Embryonal Tumor • Ependymoma • Glioblastoma • Glioma • Gliosarcoma • Medulloblastoma • Meningioma • Oligodendroglioma • Oncology • Pilocytic Astrocytoma • Pleomorphic Xanthoastrocytoma • Rhabdoid Tumor • Sarcoma • Solid Tumor

Neuroendocrine prostate cancer drivers SOX2 and BRN2 confer differential responses to imipridones ONC201, ONC206, and ONC212 in prostate cancer cell lines. (PubMed, Am J Transl Res) - "The results suggest that treatment of castrate-resistant prostate cancer by imipridones may not be substantially affected by neuroendocrine differentiation as a therapy-resistance mechanism. The results support further testing of imipridones across subtypes of androgen-sensitive and castrate-resistant prostate cancer."

Journal • Preclinical • Brain Cancer • Castration-Resistant Prostate Cancer • CNS Tumor • Endocrine Cancer • Genito-urinary Cancer • Glioma • Neuroendocrine Tumor • Oncology • Prostate Cancer • Solid Tumor • CLPP • SOX2

Synergistic combination therapy with ONC201 or ONC206, and enzalutamide or darolutamide in preclinical studies of castration-resistant prostate cancer. (PubMed, Am J Cancer Res) - "Androgen receptor (AR) signaling is a target in prostate cancer therapy and can be treated with non-steroidal anti-androgens (NSAA) including enzalutamide, and apalutamide for patients with advanced disease. ONC201 and darolutamide demonstrated anti-tumor effects in vivo in the 22RV1 CRPC model. Our results prompt further translational and clinical studies with imipridones ONC201 or ONC206 in combination with enzalutamide or darolutamide for treatment of castrate resistant advanced or metastatic prostate cancer."

Journal • Preclinical • Castration-Resistant Prostate Cancer • Genito-urinary Cancer • Oncology • Prostate Cancer • Solid Tumor • ATF4

GABA production induced by imipridones is a targetable and imageable metabolic alteration in diffuse midline gliomas (SNO 2024) - "The imipridones ONC201 and ONC206 have emerged as promising therapies for DMG patients, but efficacy as monotherapy is limited...Importantly, the clinically translatable GABAB receptor antagonist SGS742 and the SOD1 inhibitor ATN-224 exacerbate oxidative stress and synergistically induce apoptosis in combination with imipridones in DMG cells...Collectively, we identify GABA as a unique metabolic adaptation to imipridones that can be leveraged for imaging drug-target engagement and for enhancing response to therapy. Clinical translation of our studies will enable precision therapy and imaging for DMG patients."

Brain Cancer • CNS Tumor • Diffuse Midline Glioma • Glioma • Oncology • Solid Tumor • ATF4 • SOD1

Deuterium metabolic imaging interrogates the histone H3K27M mutation and provides an early readout of response to therapy in diffuse midline gliomas (SNO 2024) - "Radiation is standard of care and the imipridones ONC201 and ONC206 have emerged as promising therapies for DMG patients. Collectively, our studies link the H3K27M mutation with elevated glycolysis and identify [6,6'-2H]-glucose as a safe, orally administered contrast agent for visualizing the metabolically active lesion and for imaging early response to therapy in DMGs in vivo. Clinical translation of our studies will provide physicians with a much-needed tool to determine whether DMG patients are responding to standard and experimental therapies under development."

Brain Cancer • CNS Tumor • Diffuse Midline Glioma • Glioma • Oncology • Solid Tumor • PFKFB3 • PGK1 • SLC16A3 • SLC2A1

Allosteric mitochondrial ClpP agonist ONC206 alters stress response, metabolic and epigenetic profiles to elicit anti-cancer efficacy in high-grade gliomas (SNO 2024) - "Dordaviprone (ONC201) is a dopamine receptor D2/3 (DRD2/3) antagonist and allosteric ClpP agonist that has demonstrated durable responses in recurrent H3 K27M-mutant glioma patients. These ClpP mutations recapitulated resistance and, conversely, wildtype ClpP overexpression restored sensitivity. Thus, allosteric ClpP agonism is a key determinant of ONC206 activity in HGG by altering stress response, metabolic, and epigenetic profiles."

Clinical • Brain Cancer • CNS Tumor • Glioma • Malignant Glioma • Oncology • Solid Tumor • Targeted Protein Degradation • ATF4 • CLPP • DRD2

ONC206, an imipridone derivative, demonstrates anti-colorectal cancer activity against stem/progenitor cells in 3D cell cultures and in patient-derived organoids. (PubMed, Pharmacol Rep) - "Collectively, our findings demonstrate that ONC206 is an effective anticancer molecule capable of targeting CCSCs, which may represent a novel therapeutic strategy that can overcome CRC resistance and recurrence."

Journal • Preclinical • Colorectal Cancer • Hematological Disorders • Oncology • Solid Tumor

Chimerix Reports Third Quarter 2024 Financial Results and Provides Operational Update (GlobeNewswire) - "ONC206:...The two Phase 1 dose escalation trials conducted in partnership with the Pacific Pediatric Neuro-Oncology Consortium (PNOC) and the National Institutes of Health (NIH) have enrolled over 80 pediatric and adult patients with unselected CNS tumors, with no dose limiting toxicity observed to date...The company expects to assess any objective responses in the first half of 2025, allowing sufficient time for response onset and confirmation in current and future dose cohorts."

Enrollment status • P1 data • CNS Tumor • Oncology • Solid Tumor

Neuroendocrine Prostate Cancer Drivers SOX2 and BRN2 Confer Differential Responses to Imipridones ONC201, ONC206, and ONC212 in Prostate Cancer Cell Lines. (PubMed, bioRxiv) - "The results support the idea that treatment of castrate-resistant prostate cancer by imipridones may not be significantly impacted by neuroendocrine differentiation as a therapy-resistance mechanism. The results support further testing of imipridones across subtypes of androgen-sensitive and castrate-resistant prostate cancer."

Journal • Preclinical • Brain Cancer • Castration-Resistant Prostate Cancer • CNS Tumor • Endocrine Cancer • Genito-urinary Cancer • Glioma • Neuroendocrine Tumor • Oncology • Prostate Cancer • Solid Tumor • CLPP • SOX2