JZP3507 / Jazz - LARVOL DELTA

Imipridones ONC201, ONC206, and ONC212 show potent killing and colony arrest of small-cell lung cancer cell lines (AACR 2026) - "The present findings suggest that SCLC may be highly sensitive to imipridones, particularly ONC212. Future works will aim to explore combination therapies and potential mechanisms including senescence induction, cell cycle alterations that may lead to reproductive arrest, metabolic changes, and alterations in growth and survival pathways in order to further characterize sensitivity and the colony arrest phenotype."

Preclinical • Lung Cancer • Oncology • Small Cell Lung Cancer • Solid Tumor • ATF4

Jazz Pharmaceuticals to Present Compelling...Pre-Clinical Data Advancing Oncology Research at AACR 2026 (PRNewswire) - "A poster presentation featuring preclinical data supporting the activity of JZP898 – currently in Phase 1 development – including evidence of tumor-localized interferon signaling and immune engagement in preclinical models. A presentation featuring preclinical research evaluating imiprodones, inclusive of dordaviprone (formerly ONC201) and JZP3507 (formerly ONC206), across renal cell carcinoma and small-cell lung cancer models, including combination approaches and comparative analyses to further characterize activity and mechanism."

Preclinical • Renal Cell Carcinoma • Small Cell Lung Cancer

Determining mechanisms of ONC212-resistance in uveal melanoma to develop combination therapy strategies (AACR 2026) - "ONC212-resistant clones exhibited higher IC50, and RI compared to parental cells and showed cross-resistance to other imipridones (ONC201, ONC206), suggesting shared mechanisms of resistance. Importantly, ONC201, the first imipridone was recently approved for therapy of midline gliomas. Therefore, lessons learned from this study may benefit patients acquiring resistance to ONC201 in future as well."

Combination therapy • Brain Cancer • Eye Cancer • Glioma • Melanoma • Ocular Melanoma • Oncology • Solid Tumor • Uveal Melanoma

ONC206 demonstrates potent anti-tumorigenic activity and is a potential novel therapeutic strategy for high-risk medulloblastoma. (PubMed, Neuro Oncol) - "Our results highlight ONC206 as a novel therapeutic option for patients with high-risk medulloblastoma and provide strong rationale for testing the efficacy of ONC206 in the treatment of these patients."

Journal • Brain Cancer • Medulloblastoma • Oncology • Pediatrics • Solid Tumor • CLPP

NCI-2021-00046: ONC206 for Treatment of Newly Diagnosed, Recurrent Diffuse Midline Gliomas, and Other Recurrent Malignant CNS Tumors (clinicaltrials.gov) - P1 | N=208 | Recruiting | Sponsor: Sabine Mueller, MD, PhD | Not yet recruiting ➔ Recruiting

Enrollment open • Brain Cancer • CNS Tumor • Diffuse Midline Glioma • Ependymoma • Glioma • Oncology • Solid Tumor

PNOC023: Open Label Phase 1 and Target Validation Study of ONC206 in Children and Young Adults with Newly Diagnosed or Recurrent Diffuse Midline Glioma (DMG), and Other Recurrent Primary Malignant Central Nervous System (CNS) Tumors. (clinicaltrialsregister.eu) - P1 | N=20 | Not yet recruiting | Sponsor: Prinses Maxima Centrum voor Kinderoncologie B.V.

New P1 trial • Brain Cancer • CNS Tumor • Diffuse Midline Glioma • Ependymoma • Glioma • Oncology • Solid Tumor

Study of ONC206 (JZP3507) in Advanced Pheochromocytoma and Paraganglioma (clinicaltrials.gov) - P2 | N=90 | Recruiting | Sponsor: Jazz Pharmaceuticals | Not yet recruiting ➔ Recruiting

Enrollment open • Oncology • Solid Tumor

In vitro modeling of nutritional and mitochondria-targeted therapies for osteosarcoma. (PubMed, bioRxiv) - "Current therapies are non-specific, involving primary tumor resection with DNA-damaging chemotherapies like methotrexate, doxorubicin, and cisplatin...We investigated the therapeutic potential in human osteosarcoma primary and metastatic cell lines of metabolic modulating drugs including metformin, cycloheximide, mitochondrial ETC inhibitors (antimycin A, metformin), dichloroacetate, and imipridones (ONC201, ONC206) on mitochondrial function and cell viability, individually and combined under various nutrient conditions across our lines...RNA-Seq transcriptome analysis revealed that effective nutrient and metabolic drug treatments triggered widespread regulatory changes in osteosarcoma cells involving increased translation/splicing with decreased mitochondrial processes such as cholesterol biosynthesis. These results demonstrate the utility of developing combined metabolic and chemotherapeutic treatments for osteosarcoma."

Journal • Preclinical • Oncology • Osteosarcoma • Pediatrics • Sarcoma • Solid Tumor

Preclinical efficacy of combinatorial B7-H3 CAR T cells and ONC206 against diffuse intrinsic pontine glioma. (PubMed, Neuro Oncol) - P1 | "B7-H3 CAR T cells combined with ONC206 is a feasible and efficacious multi-agent approach against multiple DIPG models."

Journal • Preclinical • Brain Cancer • CNS Tumor • Diffuse Intrinsic Pontine Glioma • Diffuse Midline Glioma • Glioma • Hematological Disorders • Hematological Malignancies • Metabolic Disorders • Oncology • Pediatrics • Solid Tumor • CD276 • GZMB • IFNL1 • IL2

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

First-in-human • 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

Study of ONC206 (JZP3507) in Advanced Pheochromocytoma and Paraganglioma (clinicaltrials.gov) - P2 | N=90 | Not yet recruiting | Sponsor: Jazz Pharmaceuticals

New P2 trial • Oncology • Solid Tumor

An agonist of mitochondrial CLPP, ONC206, overcomes mitochondrial dependencies and abates chemoresistance in triple negative breast cancer (SABCS 2025) - P1, P2 | "Approximately 50% of triple-negative breast cancer (TNBC) patients treated with neoadjuvant chemotherapy such as platinums (e.g., carboplatin, CRB), taxanes (e.g., docetaxel, DTX), and anthracyclines administered alone, in combination, sequentially, or with or without anti-PD1 agents, retain residual cancer burden (RCB)...ONC206, an analog of the first-in-class imipridone/dordaviprone/ONC201 with improved potency, is currently undergoing phase I clinical trials for CNS tumors (NCT04732065 and NCT04541082)...Collectively, our findings provide evidence that ONC206 disrupts mitochondrial dependencies in TNBC by driving excessive CLPP-mediated proteolysis, impairing OXPHOS, and activating mtUPR. This represents a novel and potentially promising therapeutic strategy to enhance chemotherapy response in TNBC."

Breast Cancer • Oncology • Solid Tumor • Triple Negative Breast Cancer

Combinatorial targeting of avapritinib-driven MAPK activation in pediatric high-grade glioma (SNO 2025) - "Combinatorial treatment of pHGG models with MEK (selumetinib, trametinib), ERK (ulixertinib) and integrated stress/ERK inhibitors (ONC201, ONC206) in vitro eradicated pERK activity. A patient with an un-resected PDGFRα-mutant pHGG treated with avapritinib and selumetinib prior to progression demonstrated complete and ongoing tumor regression (12 months+). Considering sustained MAPK activation identified in our study, dual avapritinib-MAPK targeted treatment may be an effective approach for PDGFRΑ-driven pHGG."

Clinical • Brain Cancer • CNS Tumor • Glioma • High Grade Glioma • Pediatrics • Solid Tumor • MCL1 • PDGFRA

Allosteric ClpP agonist ONC206 alters mitochondrial metabolism and stress response to elicit apoptosis in meningioma (SNO 2025) - "Imipridone ONC206, a derivative of dordaviprone (ONC201) with nanomolar potency, is an allosteric caseinolytic protease P (ClpP) agonist and dopamine receptor D2/3 (DRD2/3) antagonist, that is being evaluated in clinical trials that include central nervous system tumors...ONC206 also demonstrated superior potency in cell viability inhibition compared to sunitinib at equivalent concentrations...CRISPR/Cas9-mediated knockout of ClpP abrogates ONC206 sensitivity in meningioma cells and ONC206 effects on mitochondrial respiratory capacity. Our results indicate that ClpP agonism is directly involved in mediating the anti-cancer effects of potent novel agent ONC206 in meningioma."

Brain Cancer • CNS Tumor • Meningioma • Solid Tumor • ANXA5 • DRD2

ONC206 inhibits tumor growth and is a potential novel therapeutic strategy for refractory medulloblastoma (SNO 2025) - P1 | "Dordaviprone (ONC201) and its chemical derivative with nanomolar potency ONC206 induce apoptosis of cancer cells by activation of the mitochondrial caseinolytic protease P (ClpP). PDX-bearing mice also responded to ONC206, which led to a significant survival benefit (p-value range 0.003-0.047). Our results highlight ONC206 as a novel therapeutic option for patients with relapsed medulloblastoma and importantly, our results have paced the way for a clinical trial testing the efficacy of ONC206 in recurrent malignant brain tumors, including medulloblastoma (NCT04732065, PNOC23)."

Brain Cancer • Medulloblastoma • Oncology • Solid Tumor • ATF4 • CLPP

Combinatorial targeting of avapritinib-driven MAPK activation in pediatric high-grade glioma (WFNOS 2025) - "Combinatorial treatment of pHGG models with MEK (selumetinib, trametinib), ERK (ulixertinib) and integrated stress/ERK inhibitors (ONC201, ONC206) in vitro eradicated pERK activity. A patient with an un-resected PDGFRα-mutant pHGG treated with avapritinib and selumetinib prior to progression demonstrated complete and ongoing tumor regression (12 months+). Considering sustained MAPK activation identified in our study, dual avapritinib-MAPK targeted treatment may be an effective approach for PDGFRΑ-driven pHGG."

Clinical • Brain Cancer • CNS Tumor • Glioma • High Grade Glioma • Pediatrics • Solid Tumor • MCL1 • PDGFRA

Combinatorial targeting of avapritinib-driven MAPK activation in pediatric high-grade glioma (WFNOS 2025) - "Combinatorial treatment of pHGG models with MEK (selumetinib, trametinib), ERK (ulixertinib) and integrated stress/ERK inhibitors (ONC201, ONC206) in vitro eradicated pERK activity. A patient with an un-resected PDGFRα-mutant pHGG treated with avapritinib and selumetinib prior to progression demonstrated complete and ongoing tumor regression (12 months+). Considering sustained MAPK activation identified in our study, dual avapritinib-MAPK targeted treatment may be an effective approach for PDGFRΑ-driven pHGG."

Clinical • Brain Cancer • Pediatrics • Solid Tumor • MCL1 • PDGFRA

ONC206 demonstrates potent anti-tumorigenic activity and is a potential novel therapeutic strategy for high-risk medulloblastoma. (PubMed, bioRxiv) - P1 | "Dordaviprone (ONC201) and its chemical derivative with nanomolar potency, ONC206, induce apoptosis of cancer cells by activation of the mitochondrial caseinolytic protease P (ClpP). We also saw that ONC206 very significantly prolonged survival of medulloblastoma-bearing mice, both in genetically engineered mouse models and patient-derived xenografts. Our study provides a strong rationale for testing the efficacy of ONC206 in the treatment of patients with medulloblastoma and has set the stage for a clinical trial with this agent in pediatric patients with recurrent malignant brain tumors, including medulloblastoma ( NCT04732065 )."

Journal • Brain Cancer • Diffuse Midline Glioma • Glioma • Medulloblastoma • Oncology • Pediatrics • Solid Tumor • CLPP

Allosteric ClpP agonist ONC206 alters mitochondrial metabolism and stress response to elicit apoptosis in meningioma (WFNOS 2025) - "Imipridone ONC206, a derivative of dordaviprone (ONC201) with nanomolar potency, is an allosteric caseinolytic protease P (ClpP) agonist and dopamine receptor D2/3 (DRD2/3) antagonist, that is being evaluated in clinical trials that include central nervous system tumors...ONC206 also demonstrated superior potency in cell viability inhibition compared to sunitinib at equivalent concentrations...CRISPR/Cas9-mediated knockout of ClpP abrogates ONC206 sensitivity in meningioma cells and ONC206 effects on mitochondrial respiratory capacity. Our results indicate that ClpP agonism is directly involved in mediating the anti-cancer effects of potent novel agent ONC206 in meningioma."

Brain Cancer • Meningioma • Solid Tumor • ANXA5 • DRD2

ONC206 inhibits tumor growth and is a potential novel therapeutic strategy for refractory medulloblastoma (WFNOS 2025) - P1 | "Dordaviprone (ONC201) and its chemical derivative with nanomolar potency ONC206 induce apoptosis of cancer cells by activation of the mitochondrial caseinolytic protease P (ClpP). PDX-bearing mice also responded to ONC206, which led to a significant survival benefit (p-value range 0.003-0.047). Our results highlight ONC206 as a novel therapeutic option for patients with relapsed medulloblastoma and importantly, our results have paced the way for a clinical trial testing the efficacy of ONC206 in recurrent malignant brain tumors, including medulloblastoma (NCT04732065, PNOC23)."

Brain Cancer • Medulloblastoma • Oncology • Solid Tumor • ATF4 • CLPP

Jazz Pharmaceuticals Showcases New Clinical and Translational Data for Modeyso (dordaviprone) in H3 K27M-mutant Diffuse Midline Glioma at SNO 2025 (PRNewswire) - "The presentations will feature both clinical and preclinical research evaluating Modeyso (dordaviprone), as well as new preclinical data featuring JZP3507 (formerly ONC206) in central nervous system (CNS) tumors....Key presentations include: (i) New translational research characterizing potential molecular pathways associated with sensitivity to dordaviprone and exploring how targeted combination strategies may help to enhance response; (ii) Preclinical data evaluating how dordaviprone may influence the tumor immune environment to inform future research on rational immunotherapy combinations."

Clinical data • Preclinical • Diffuse Midline Glioma

IMIPRIDONES ONC201/ONC206 AND RADIOTHERAPY REMODEL THE TUMOR-IMMUNE MICROENVIRONMENT IN DIFFUSE MIDLINE GLIOMAS (SIOP 2025) - "However, the rise in Tregs under combination therapy suggests a compensatory immunosuppressive response. These findings highlight the urgent need to recognize how standard treatments like chemotherapy and RT can unintentionally undermine anti-tumor immunity—emphasizing the importance of integrating immunomodulatory strategies into future therapeutic approaches for DMG."

Brain Cancer • CNS Disorders • Diffuse Midline Glioma • Glioma • Oncology • Pediatrics • Solid Tumor • PTPRC

Allosteric ClpP agonist ONC206 alters mitochondrial metabolism, stress response and chromatin accessibility to elicit apoptosis in pheochromocytoma (NANETS 2025) - "ONC206 demonstrated superior cell viability inhibition and/ or apoptosis induction in PC lines relative to dordaviprone, temozolomide, sunitinib and belzutifan at equivalent and/or therapeutically relevant concentrations. CONCLUSIONS ONC206 is a potent novel agent that is superior to SOC and dordaviprone in PC. ClpP mediates response and acquired resistance to ONC206 in PC."

Oncology • Solid Tumor • ANXA5 • CLPP • DRD2 • SDHB

Trial-in-Progress: A Phase 2 Study of ONC206 in Patients with Advanced Pheochromocytoma and Paraganglioma (NANETS 2025) - "This small molecule is a potent derivative of dordaviprone that was previously reported to induce responses in patients with PCPG. Total anticipated enrollment is 90 patients. RESULTS N/A CONCLUSIONS N/A"

Clinical • Metastases • P2 data • CNS Tumor • Oncology • Solid Tumor • DRD2

Combination of the First-in-Class Imipridone ONC201 and Standard Anticancer Therapies as a Rational Approach for Therapeutic Benefit. (PubMed, Curr Issues Mol Biol) - "ONC206 and ONC212, are more potent analogs of ONC201 and exhibit similar characteristics. In this review, we discuss the therapeutic potential of ONC201 and its analogs using combination strategies across different cancers."

Journal • Review • Brain Cancer • Diffuse Midline Glioma • Glioma • Oncology • Solid Tumor