nesuparib (JPI-547) / Jeil - LARVOL DELTA

Nesuparib enhances anti-tumor efficacy with gemcitabine and nab-paclitaxel in BRCA wild type pancreatic cancer xenograft model (AACR 2026) - "We also observed that cyclinD1, β- Catenin, and RAD51 were decreased in Nesuparib with GnP treatment compared to the control or GnP treatment. Collectively, the data suggests that those molecular modulations are closely associated with the tankyrase inhibition by Nesuparib in BRCA wild-type model, and that combining Nesuparib with the standard chemotherapy further reduces cell proliferation and delays DNA repair compared to chemotherapy alone.Overall, our results suggest that combination with Nesuparib with GnP chemotherapy could be a novel and rational therapeutic option for pancreatic cancer treatment."

Preclinical • Oncology • Pancreatic Cancer • Pancreatic Ductal Adenocarcinoma • Solid Tumor • BRCA • CCND1 • MYBL2 • MYC • RAD51

UPR/ATF4/Noxa pathway overactivation through SERCA2 inhibition or ONC201 treatment combined with ABT-737 triggers apoptosis in chemoresistant ovarian cancer cells and patient-derived tumor organoids. (PubMed, Cell Death Dis) - "Ovarian cancer has a poor clinical prognosis due to chemoresistance following carboplatin/paclitaxel treatment...The therapeutic efficacy of these combinations was also proved in patient-derived tumor organoid models (PDTO), leading to their structural disintegration and reduced viability. Collectively, our study highlights that ABT-737, through BCL-xL inhibition and synergy with ER stress inducers, triggers ovarian cancer death, offering promising strategies for overcoming chemoresistance in relapsed ovarian cancer."

IO biomarker • Journal • Oncology • Ovarian Cancer • Solid Tumor • ATF4 • BCL2 • BCL2L1

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

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

TRAIL inducing drug, ONC201 prevents adenocarcinoma in transgenic KRASG12V mouse lung cancer model (AACR 2026) - "In conclusion, ONC201 demonstrated strong efficacy in preventing lung cancer in two preclinical mouse models and warrants further clinical development for the prevention of lung tumor in high risk populations. (Project funded 100% with Federal funds from NCI, NIH, DHHS, under Contract 75N91019D00020_75N91022F00003)"

Preclinical • Lung Cancer • Oncology • Solid Tumor • APAF1 • CCND1 • EGFR • FADD • KRAS • PCNA

Nesuparib (JPI-547), a dual tankyrase/PARP inhibitor, exhibits potent antitumor activity in small-cell lung cancer models by modulating Wnt and Hippo signaling pathways (AACR 2026) - "The research aimed to characterize the antitumor activity and mechanism of nesuparib compared with olaparib and irinotecan and assess the synergistic efficacy of nesuparib combined with irinotecan. Nesuparib (JPI-547), a dual TNKS1/2-PARP1/2 inhibitor, showed strong dose-dependent antitumor activity in BRCA wild-type SCLC. Combination with irinotecan produced a synergistic tumor-suppressive effect. Mechanistic studies indicated that nesuparib inhibited tumor growth by suppressing Wnt and Hippo signaling, supporting its potential as a novel therapeutic strategy for SCLC alone or with DNA-damaging agents."

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

Imipridone treatment activates canonical NFkB and inflammatory signaling in THP1 differentiated macrophages (IMMUNOLOGY 2026) - "Following differentiation, we treated the cells with 5µM or 2µM ONC201, 1.5µM or 0.75µM ONC206, or 0.1µM or 0.05µM ONC212 and collected lysates for western blot. Using the hallmarks gene set, we found that increased expression of genes associated with a baseline inflammatory, IFNα and IFNγ response were associated with patient radiographic response... We have identified a link between a more immunologically active TME and response to ONC201 in patients with DMG, and that changes in NFkB signaling occurred following imipridone treatment of the THP1 cell line. We will continue our analysis of changes in cytokine production through ELISA and luciferase reporter assays."

Brain Cancer • Diffuse Intrinsic Pontine Glioma • Diffuse Midline Glioma • Glioma • High Grade Glioma • Solid Tumor • ATF4 • GLI2 • IFNA1 • IFNG • IL1B • NLRP3

Onconic Therapeutics "Nesuparib Study Results Presented at American Association for Cancer Research" (News1 Korea) - "In in vitro small cell lung cancer cell experiments, nesuparib demonstrated up to 133 times stronger cancer cell growth inhibitory efficacy compared to the existing PARP inhibitor olaparib and approximately 25 times stronger efficacy compared to irinotecan, an anticancer drug used to treat small cell lung cancer....According to the abstract released this time, in in vitro experiments on pancreatic cancer cells without BRCA mutations, when nesuparib was administered in combination with Gemcitabine/nab-paclitaxel, a first-line standard treatment for pancreatic cancer, the number of surviving cancer cells was reduced by more than 70% compared to the Gemcitabine treatment group."

Preclinical • Pancreatic Cancer • Small Cell Lung Cancer

Onconic lands FDA orphan drug designation for nesuparib in small cell lung cancer (Korea Biomedical Review) - "The biological rationale for using nesuparib in small cell lung cancer is particularly strong due to the extreme genomic instability and replication stress caused by the loss of TP53 and RB1 genes."

Orphan drug • Small Cell Lung Cancer

To Evaluate the Safety and Tolerability of Study Drug as a Third-line and Beyond Therapy for Recurrent or Metastatic Gastric Cancer (clinicaltrials.gov) - P1/2 | N=49 | Not yet recruiting | Sponsor: Onconic Therapeutics Inc.

New P1/2 trial • Esophageal Cancer • Gastric Cancer • Gastroesophageal Junction Adenocarcinoma • Oncology • Solid Tumor

To Evaluate the Efficacy and Safety of JPI-547 in Combination With Bevacizumab as Maintenance Therapy in Relapsed Ovarian Cancer (clinicaltrials.gov) - P2 | N=81 | Not yet recruiting | Sponsor: Onconic Therapeutics Inc.

New P2 trial • Oncology • Ovarian Cancer • Solid Tumor • BRCA • BRCA1 • BRCA2 • HRD

Onconic Therapeutics announced on January 20 that the Ministry of Food and Drug Safety has approved the Phase 2 clinical trial plan (IND) for Nesuparib, its next-generation dual-targeted anticancer drug candidate, for the treatment of ovarian cancer. (The Asia Business Daily) - This clinical trial will enroll approximately 87 patients with ovarian cancer who have relapsed or developed resistance after previous PARP inhibitor therapy. The study aims to clinically validate the concept of 're-maintenance therapy,' which targets the treatment gap following existing maintenance therapy. Patient enrollment and dosing will take place at major tertiary hospitals in Korea, including Severance Hospital."

New P2 trial • Ovarian Cancer

Phase II randomized study of first-line carboplatin and paclitaxel in combination with pembrolizumab, followed by maintenance pembrolizumab alone or with nesuparib, in mismatch-repair proficient, advanced or recurrent endometrial cancer (PENELOPE). (PubMed, J Gynecol Oncol) - P2 | "Enrollment began in Q4 2024. ClinicalTrials.gov Identifier: NCT06502743."

Journal • Mismatch repair • P2 data • pMMR • Endometrial Cancer • Oncology • Solid Tumor

Small Molecule Activators of the Mitochondrial Protease ClpP Induce Senescence in Triple-Negative Breast Cancer Cells and Sensitize Cells to the Bcl-2 Inhibitor Venetoclax. (PubMed, Res Sq) - "We report that ONC201 and highly potent second generation ClpP agonists (TR-57, TR-107), promote induction of senescence in triple-negative breast cancer (TNBC) cell lines...By contrast, cells treated with the cell cycle inhibitor and senescence inducer, abemaciclib rapidly regained p-Rb and Myc expression and cell proliferation following washout...Combining a ClpP agonist with a PARP inhibitor (olaparib) produced an additive effect. In summary, we show that ClpP activators stably induce an irreversible senescence in a ClpP-dependent manner that synergizes with venetoclax in TNBC cells."

IO biomarker • Journal • Breast Cancer • Metabolic Disorders • Oncology • Solid Tumor • Triple Negative Breast Cancer • CHEK2 • LMNB1 • MYC • TP53BP1

JEIL PHARMACEUTICAL said on the 17th that its subsidiary Onconic Therapeutics received approval from the Ministery of Food and Drug Safety for an investigational new drug (IND) application for phase 1b–2 clinical trials of the next-generation anticancer drug candidate 'Nesuparib' in patients with relapsed or metastatic gastric cancer (Chosun Biz) - "The purpose of this trial is to evaluate the safety, tolerability, and efficacy of a combination therapy of Nesuparib and the conventional chemotherapeutic agent irinotecan. It is scheduled to be conducted at major tertiary hospitals in Korea....Nesuparib has begun dosing patients in a phase 2 clinical trial for pancreatic cancer, and an investigator-initiated phase 2 trial in endometrial cancer in combination with Merck's immuno-oncology therapy 'Keytruda' is also underway."

New trial • Trial status • Endometrial Cancer • Gastric Cancer • Pancreatic Cancer

Onconic Therapeutics…reported that its investigational dual-target therapy nesuparib (JPI-547) demonstrated strong preclinical efficacy in pancreatic cancer, not only in BRCA2-deficient cells but also in HRD-negative and RNF43-mutated Wnt-addicted tumors… (Korea Biomedical Review) - "According to the published data, nesuparib exhibited similar tumor-suppressing effects at one-tenth of the concentration of olaparib in BRCA2-deficient pancreatic cancer cells, while also achieving higher tumor growth inhibition in animal models. Notably, efficacy was also confirmed in HRD-negative cells. The drug demonstrated significant activity in pancreatic cancer cells with RNF43 mutations that rely on Wnt signaling, suppressing both the Wnt/β-catenin and YAP oncogenic pathways."

Preclinical • Pancreatic Cancer

Onconic Therapeutics announced on the 29th that it has received approval from the Ministry of Food and Drug Safety for a phase 2 clinical trial plan (IND) for locally advanced and metastatic pancreatic cancer of the next-generation anticancer drug candidate Nesuparib. (Maeil Business Newpaper)

New P2 trial • Pancreatic Cancer

JPI-547, a Dual Inhibitor of PARP/Tankyrase, Shows Antitumor Activity Against Pancreatic Cancers with Homologous Recombination Repair Deficiency or Wnt-Addiction. (PubMed, Int J Biol Sci) - "JPI-547 outperformed most PARP inhibitors, with a half-maximal inhibitory concentration approximately 10-fold lower than that of olaparib. PDAC cells reliant on Wnt signaling due to pathogenic RNF43 mutations showed increased susceptibility to JPI-547 without altering homologous recombination repair efficiency. JPI-547 disrupts the Wnt/β-catenin pathway in RNF43-mutated cells and inhibits the oncogenic YAP pathway, highlighting its multifaceted therapeutic potential in PDAC with HRD or Wnt-addiction."

Journal • CNS Disorders • Oncology • Pancreatic Cancer • Pancreatic Ductal Adenocarcinoma • Psychiatry • Solid Tumor • BRCA2 • HRD • RNF43

Onconic Therapeutics announced on the 18th that it will submit a clinical trial plan (IND) to the Ministry of Food and Drug Safety and recruit phase 2 clinical patients for patients with advanced and metastatic pancreatic cancer. (Maeil Business Newpaper)

New P2 trial • Pancreatic Cancer

Onconic Therapeutics Requests Change to Nesuparib Clinical Trial Plan [Google translation] (HIT News) - "The company has submitted an application for approval (change approval) for a Phase 1b/2 gastric cancer trial of its anticancer drug candidate, nesuparib (JPI-547), to the Ministry of Food and Drug Safety. This trial will assess DLT in Phase 1b to determine the appropriate combination dose and then proceed to Phase 2 with that dose."

New P1/2 trial • Gastric Cancer • Gastrointestinal Cancer

Onconic Secures Australian Patent for Dual-target Anticancer Drug Nesuparip (Business Korea) - "Onconic Therapeutics announced on July 28 that its dual-target anticancer drug candidate 'nesuparib' has obtained a use patent as a treatment for PARP inhibitor-resistant cancer in Australia. The patent will remain in effect until May 18, 2042...Meanwhile, this patent has been filed in 21 countries including Australia, Eurasia, and South Africa, and the company is also pursuing enhancement of technological value through securing a global intellectual property portfolio."

Patent • Endometrial Cancer • Gastric Cancer • Gastrointestinal Cancer • Ovarian Cancer • Pancreatic Cancer

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

Celltrion and Onconic team up on ovarian cancer combo with dual-target PARP drug (Korea Biomedical Review) - "Korean biotech Onconic Therapeutics is teaming up with biosimilar giant Celltrion to develop a new treatment option for relapsed ovarian cancer, combining Onconic’s dual-mechanism small molecule nesuparib with Vegzelma, Celltrion’s bevacizumab biosimilar already approved in major markets for colorectal and breast cancers."

Commercial • Ovarian Cancer

PENELOPE: A randomized phase II trial of first-line carboplatin and paclitaxel in combination with pembrolizumab, followed by maintenance pembrolizumab with or without nesuparib, in patients with newly diagnosed advanced or recurrent MMR-proficient endometrial cancer. (ASCO 2025) - P2 | "Two landmark phase III RCTs, NRG-GY018 and RUBY, proved that the addition of pembrolizumab or dostarlimab to standard chemotherapy resulted in significantly longer progression-free survival (PFS) than with chemotherapy alone in patients with advanced or recurrent endometrial cancer...Although the phase III DUO-E trial demonstrated elongated PFS from paclitaxel/carboplatin plus durvalumab followed by maintenance durvalumab with or without olaparib in patients with advanced or recurrent endometrial cancer, this trial is not designed to prove that addition of olaparib maintenance provides extra survival benefits...Primary endpoint is investigator-assessed PFS (RECIST 1.1) of arm B vs. arm A, and key secondary endpoints are overall survival, overall response rate, disease control rate, duration of response, and safety. Enrollment began in Q4 2024."

Clinical • Combination therapy • Metastases • P2 data • Endometrial Cancer • Oncology • Solid Tumor

An open-label, dose-finding, phase Ib study to assess the safety, tolerability of nesuparib (JPI-547), a dual inhibitor of PARP/TNKS, in combination with modified FOLFIRINOX (mFOLFIRINOX) and gemcitabine-nab-paclitaxel (GemAbraxane) in patients with locally advanced and metastatic pancreatic cancer. (ASCO 2025) - P1 | "Current maintenance therapy with the PARP inhibitor, olaparib, benefits only patients with germline BRCA1/2 mutations (Approximately 5-7 % of PDAC cases)...Arm A includes mFOLFIRINOX chemotherapy with biweekly oxaliplatin (65 mg/m²), leucovorin (400 mg/m²), irinotecan (135 mg/m²), and 5-FU (2,400 mg/m²)...Enrollment began in Q1 2022. ClinicalTrials.gov ID: NCT05257993"

Clinical • Combination therapy • Metastases • P1 data • Oncology • Pancreatic Cancer • Pancreatic Ductal Adenocarcinoma • Solid Tumor • BRCA • BRCA1 • BRCA2 • HRD