Modeyso (dordaviprone) / Jazz - LARVOL DELTA

Small-Molecule Drugs in Pediatric Neuro-Oncology. (PubMed, Curr Oncol) - "This review provides a focused overview of several small-molecule agents under investigation or in early clinical use, including ONC201, tazemetostat, vorasidenib, CDK inhibitors, selinexor, and aurora kinase A inhibitors, among others. Despite encouraging preclinical and early-phase results, most agents face limitations due to study heterogeneity, lack of large-scale pediatric randomized trials, and challenges in drug delivery to the CNS. The review underscores the critical need for robust prospective clinical trials for the integration of these therapies into pediatric neuro-oncology care."

Journal • Review • Brain Cancer • CNS Tumor • Oncology • Pediatrics • Solid Tumor • AURKA

NCCN has published updates to the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Central Nervous System Cancers, Version 2.2025. (NCCN)

NCCN guideline • Glioma

Case Report: Application of ex-vivo drug sensitivity testing to identify personalized treatment options for an adolescent with diffuse midline glioma. (PubMed, Front Oncol) - "The patient then started a novel functional precision medicine (FPM)-guided two-drug combination of disulfiram, based on the DST results of this drug on the patient's tumor cells obtained at diagnosis, and ONC 201, the only drug that has advanced to a phase III clinical trial for H3K27M-DMG. Our case describes the feasibility and limitations of using DST of patient-derived tumor cells to identify potentially effective personalized and novel therapies for DMG, which should be evaluated for efficacy and safety in formal N-of-1 clinical trials settings. We discuss the benefits and risks of this approach, particularly considering its use in children, adolescents, and young adults with pediatric brain cancers."

Journal • Preclinical • Brain Cancer • Diffuse Midline Glioma • Glioma • Oncology • Pain • Pediatrics • Solid Tumor

Onco360 adds Modeyso (dordaviprone) to portfolio of Oncology and Rare Cancer therapies as a National Specialty Pharmacy Provider (GlobeNewswire) - "It is indicated for the treatment of adult and pediatric patients one year of age and older with diffuse midline glioma harboring an H3 K27M-mutation with progressive disease following prior therapy."

Commercial • Glioma

Jazz Pharmaceuticals to Host Modeyso (dordaviprone) Investor Webcast on August 27, 2025 (PRNewswire) - "Jazz Pharmaceuticals plc...to provide an overview of clinical data, patient need and commercialization strategy for Modeyso (dordaviprone)....Jazz senior management will provide an overview of Modeyso and commercial launch plans."

Clinical data • Launch US • Diffuse Midline Glioma

Testing for Safety and Colorectal Cancer Preventive Effects of ONC201 (clinicaltrials.gov) - P1 | N=36 | Recruiting | Sponsor: National Cancer Institute (NCI) | Not yet recruiting ➔ Recruiting | N=24 ➔ 36

Enrollment change • Enrollment open • Colorectal Cancer • Genetic Disorders • Oncology • Solid Tumor • BCL2

Effect of Severe Renal Impairment on Dordaviprone (ONC201) Pharmacokinetics. (PubMed, Drugs R D) - P1 | "Despite its minimal renal clearance, dordaviprone geometric mean AUC was increased by ~50% in severe RI participants, suggesting CYP3A4 activity may have been suppressed in these participants. The results of this study will be used to inform dordaviprone dosing in patients with RI."

Journal • PK/PD data • Brain Cancer • Glioma • Oncology • Renal Disease • Solid Tumor • CYP3A4

Assessing Cytochrome P450 Drug Interaction Risk for Dordaviprone Using Physiologically Based Pharmacokinetic Modeling. (PubMed, CPT Pharmacometrics Syst Pharmacol) - "The simulated increase in dordaviprone AUC and Cmax (4.6- and 1.7-fold) following administration of multiple doses of itraconazole was consistent with the observed values (4.4- and 1.9-fold). All PBPK-simulated changes in dordaviprone plasma exposure when administered with CYP3A4 moderate (erythromycin, fluconazole) and weak (cimetidine) inhibitors, and moderate (efavirenz) and strong (rifampicin) inducers were consistent with their CYP3A4 potency classification (AUC ratio = 2.68, 2.48, 1.42, 0.35, and 0.17, respectively). The simulated AUC and Cmax of probe substrates for CYP3A4 (midazolam), CYP2C8 (repaglinide) and CYP2D6 (desipramine) after coadministration with 625 mg dordaviprone were the same as those in the absence of dordaviprone (ratio = 1.0) and remained unchanged after a sensitivity analysis using 10-fold more potent inhibition constants. Due to changes in dordaviprone plasma exposure when co-administered with CYP3A4 inhibitors, dordaviprone dose adjustments..."

Journal • PK/PD data • Brain Cancer • Glioma • Oncology • Solid Tumor

ONC201 in Adults With Recurrent H3 K27M-mutant Glioma (clinicaltrials.gov) - P2 | N=73 | Terminated | Sponsor: Chimerix | Active, not recruiting ➔ Terminated; The Sponsor terminated the study to prioritize enrollment in a randomized Phase 3 trial of ONC201 in an earlier setting. This decision was unrelated to any safety concerns with dordaviprone (ONC201).

Trial termination • Brain Cancer • Glioma • High Grade Glioma • Oncology • Solid Tumor

FDA grants accelerated approval to dordaviprone for diffuse midline glioma (FDA) - "...the Food and Drug Administration granted accelerated approval to dordaviprone (Modeyso, Jazz Pharmaceuticals, Inc.), a protease activator, for adult and pediatric patients 1 year of age and older with diffuse midline glioma harboring an H3 K27M mutation with progressive disease following prior therapy....Efficacy was evaluated in an integrated efficacy population of 50 adult and pediatric patients with recurrent H3 K27M-mutant diffuse midline glioma enrolled across five open-label, non-randomized clinical trials conducted in the U.S. (ONC006 [NCT02525692], ONC013 [NCT03295396], ONC014 [NCT03416530], ONC016 [NCT05392374], and ONC018 [NCT03134131])."

Accelerated approval • FDA approval • Diffuse Midline Glioma

PNOC022: Combination Therapy for the Treatment of Diffuse Midline Gliomas (clinicaltrials.gov) - P2 | N=360 | Recruiting | Sponsor: University of California, San Francisco | Trial primary completion date: Dec 2025 ➔ Dec 2027

Trial primary completion date • Brain Cancer • Diffuse Intrinsic Pontine Glioma • Diffuse Midline Glioma • Glioma • Oncology • Solid Tumor • BRAF

Combination of LowDose Epigenetic Modifiers and TIC10 for the Activation of Antitumor Immunity and Inhibition of Tumor Growth in Gastrointestinal Cancer. (PubMed, Cancer Med) - "LD-EMs remodeled the tumor microenvironment to an immune-promoting environment. Although TIC10 could suppress cell viability and induce cell apoptosis. A combination of LD-EMs and TIC10 indicated a rational strategy through complementary mechanisms."

Journal • Gastrointestinal Cancer • Gene Therapies • Oncology • Solid Tumor • CD8 • PTPRC

The therapeutic potential of repurposed mebendazole, alone and in synergistic combination with ONC201, in the treatment of diffuse midline glioma. (PubMed, Am J Cancer Res) - "Finally, one pair of ONC201-sensitive and ONC201-resistant DMG cell lines with acquired resistance showed same responsiveness to MBZ with similar values of IC50 and Emax. In conclusion, MBZ demonstrates high growth-inhibitory/proapoptotic activity, chemosensitization property to ONC201 and the ability to overcome ONC201 resistance in DMG cell cultures, proposing as a new low-toxicity therapeutic for DMG, with a potential to be used in second-line treatment and/or in combination protocols."

Journal • Brain Cancer • Diffuse Midline Glioma • Glioma • Oncology • Solid Tumor • ANXA5 • CASP3 • CDKN1A

Evaluation of the antineoplastic effects of imipridone derivatives in prostate cancer: Novel therapeutic opportunities (EACR 2025) - "However, the anticancer potential of its derivatives, ONC206 and ONC212, remains unexplored in the context of PCa. This study highlights ONC212 as a promising therapeutic candidate for targeting PCSCs, potentially improving PCa management by overcoming tumor resistance and recurrence."

Genito-urinary Cancer • Hematological Malignancies • Oncology • Prostate Cancer • Solid Tumor

ONC201 enhances the cytotoxic effect of cisplatin through ATF3/ATF4/CHOP in head and neck squamous cell carcinoma cells. (PubMed, Oncogenesis) - "The ability of ONC201 to overcome cisplatin resistance and its synergistic antitumor effects highlight its promise as a candidate for combination therapy. These findings support the translational potential of targeting the ATF3/ATF4/CHOP axis to improve outcomes in patients with cisplatin resistant HNSCC."

Journal • Head and Neck Cancer • Oncology • Oral Cancer • Solid Tumor • Squamous Cell Carcinoma • Squamous Cell Carcinoma of Head and Neck • ATF3 • ATF4 • DRD2

ONC201 Plus Weekly Paclitaxel in Patients With Platinum Refractory or Resistant Ovarian Cancer (clinicaltrials.gov) - P2 | N=62 | Recruiting | Sponsor: Ira Winer | Trial completion date: May 2026 ➔ May 2027 | Trial primary completion date: May 2025 ➔ May 2026

Platinum resistant • Trial completion date • Trial primary completion date • Fallopian Tube Cancer • Oncology • Ovarian Cancer • Peritoneal Cancer • Refractory Ovarian Cancer • Solid Tumor

Dose Optimization of ClpP Agonists Using an In Vitro Microfluidic Perfusion Platform and In Silico Pharmacokinetic-Pharmacodynamic Modeling. (PubMed, AAPS J) - "The imipridone, ONC201, is a ClpP agonist currently undergoing clinical evaluation across multiple cancer types, while additional analogs with improved potency and selectivity are in preclinical development...Moreover, we demonstrate that PK-PD model simulations using parameters derived from microfluidic perfusion datasets can successfully predict the anti-tumor efficacy of a ClpP agonist in a mouse tumor xenograft study. These studies support the translational relevance of the animal-alternative in vitro PK-PD platform and its utility to help guide dose optimization of ClpP agonists as cancer therapeutics."

Journal • PK/PD data • Preclinical • Breast Cancer • Oncology • Solid Tumor • Triple Negative Breast Cancer

Precision oncology in pediatric brain tumors: Real world experience from a middle income country. (ASCO 2025) - "Agents used included dabrafenib+trametinib (3), trametinib(3), bevacizumab (17), nimotuzumab (5), everolimus (1),ONC201 (2), ONC206 (1). Our experience with biologically targeted therapies in RR CNS tumors was promising with manageable toxicities. Further studies could explore TT in earlier treatment lines and/or as maintenance therapy."

Clinical • Real-world • Real-world evidence • Anaplastic Astrocytoma • Astrocytoma • Brain Cancer • Diffuse Midline Glioma • Glioma • High Grade Glioma • Medulloblastoma • Oncology • Pediatrics • Solid Tumor • BRAF • EZH2 • KIAA1549 • NF1 • NTRK

The gut microbiome in pediatric diffuse midline gliomas: Correlative study results from the PNOC022 trial. (ASCO 2025) - "This report focuses on the combination therapy arm involving dordaviprone and paxalisib, administered to patients (aged 2–39 years) who had completed standard-of-care radiation therapy (Cohort 2). Baseline high alpha-diversity in the gut microbiome is significantly associated with improved PFS and trended towards improved OS in pediatric patients with DMG in cohort 2 of PNOC022. Age-adjusted survival models reinforced its prognostic value for PFS and OS. These findings highlight the potential impact the gut microbiome has on outcomes and will be explored further and warrant our ongoing investigation in PNOC022."

Clinical • Brain Cancer • CNS Tumor • Diffuse Midline Glioma • Glioma • Oncology • Pediatrics • Solid Tumor

Efficacy and safety of dordaviprone (ONC201) in prospective clinical trials of adult and pediatric recurrent H3 K27M-mutant diffuse glioma patients. (ASCO 2025) - P1, P2 | "Another patient experienced a > 50% tumor regression (4.3-month TTR) that did not meet RANO PR criteria due to initiation of 2.5 mg dexamethasone post-baseline. In prospective clinical trials designed to evaluate ORR, single-agent dordaviprone response and safety in adult and pediatric recurrent H3 K27M-mutant diffuse glioma were similar to previously pooled analyses."

Clinical • Brain Cancer • CNS Tumor • Diffuse Midline Glioma • Glioma • Oncology • Pediatrics • Solid Tumor

Combination therapy of supercharged NK cells and ONC201 or ONC206 to target aggressive K27M brain tumor. (PubMed, Crit Rev Immunol) - "sNK cell-mediated cytotoxicity against K27M was significantly increased when sNK cells were combined with ONC201 and ONC206. This study suggests the potential use of sNK cells alone or in combination with ONC201 or ONC206 as therapeutic strategies in treating and preventing the recurrence of aggressive pediatric brain tumors."

Journal • Review • Brain Cancer • Diffuse Intrinsic Pontine Glioma • Glioma • High Grade Glioma • Oncology • Pediatrics • Solid Tumor • IFNG

Jazz Pharmaceuticals Announces First Quarter 2025 Financial Results and Updates 2025 Financial Guidance (PRNewswire) - "Key Highlights: Submitted sNDA for Zepzelca in combination with atezolizumab (Tecentriq) as maintenance therapy in 1L ES-SCLC based on the potentially practice-changing results from the Phase 3 IMforte trial. Data from trial to be presented at the 2025 ASCO Annual Meeting in June 2025; Acquisition of Chimerix added dordaviprone to late-stage pipeline, representing near-term commercial opportunity; PDUFA target data of August 18, 2025...Commercial Updates: (i) Rylaze/Enrylaze (asparaginase erwinia chrysanthemi (recombinant)-rywn): Rylaze/Enrylaze net product sales decreased 8% to $94.2 million in 1Q25 compared to 1Q24. This decrease was driven by headwinds from an update to Children's Oncology Group (COG) pediatric treatment protocols for acute lymphoblastic leukemia made in mid-2024 that impacted timing of asparaginase administration."

FDA filing • PDUFA • Sales • Acute Lymphocytic Leukemia • Diffuse Glioma • Small Cell Lung Cancer

Comparative study of the anti-tumour effects of the imipridone, ONC201 and its fluorinated analogues on pancreatic cancer cell line. (PubMed, Sci Rep) - "The site of the fluorination influenced the mechanism of apoptotic action of these compounds. Overall, TBP-134 showed superior efficacy, making it a promising candidate for structural optimization within the imipridone family to develop more effective, selective treatments for pancreatic tumours."

Journal • Preclinical • Oncology • Pancreatic Adenocarcinoma • Pancreatic Cancer • Pancreatic Ductal Adenocarcinoma • Solid Tumor

Jazz Pharmaceuticals Showcases Transformative Data at ASCO 2025, Highlighting Advances in Small Cell Lung Cancer, HER2+ Gastroesophageal Cancer and Diffuse Glioma (PRNewswire) - "Key presentations include: (i) An oral abstract of the Phase 3 IMforte trial, which showed statistically significant and clinically meaningful survival benefit (progression-free survival (PFS) and overall survival (OS) for the combination of Zepzelca and atezolizumab (Tecentriq) for extensive-stage small cell lung cancer (ES-SCLC) patients receiving treatment in the first-line maintenance setting; (ii) A rapid oral abstract of four-year follow-up data, including new OS and translational biomarker data, from an ongoing Phase 2 trial of Ziihera in combination with chemotherapy for the first-line treatment of HER2-positive advanced or metastatic gastroesophageal adenocarcinoma (mGEA); (iii) An oral abstract of efficacy and safety data from a Phase 2 trial of dordaviprone (ONC201), from the recently completed Chimerix acquisition, in prospective clinical trials of adult and pediatric recurrent H3 K27M-mutant diffuse glioma patients."

Clinical data • Gastroesophageal Junction Adenocarcinoma • Glioma • Small Cell Lung Cancer

Can Focused Ultrasound Overcome the Failure of Chemotherapy in Treating Pediatric Diffuse Intrinsic Pontine Glioma Due to a Blood-Brain Barrier Obstacle? (PubMed, Pharmaceuticals (Basel)) - "A patient-derived xenograft DIPG model exposed to high-intensity focalized ultrasound (HIFU) or low-intensity focalized ultrasound (LIFU) combined with MBs was treated with doxorubicin, panobinostat, olaparib, ONC201 (Dordaviprone®) and anti-PD1. This review reports pre-clinical and clinical studies performed to demonstrate the usefulness of FUS in patients with DIPG treated with some chemotherapy. The papers reviewed were published in PubMed until the end of 2024 and were found using a combination of the following keywords: diffuse intrinsic pontine glioma (DIPG), DIPG H3K27-altered, blood-brain barrier and BBB, focused ultrasound (FUS) and radiotherapy (RT)."

Journal • Review • Brain Cancer • CNS Disorders • CNS Tumor • Diffuse Intrinsic Pontine Glioma • Diffuse Midline Glioma • Glioma • Oncology • Pediatrics • Solid Tumor