nesuparib (JPI-547) / Jeil - LARVOL DELTA

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

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

Onconic Therapeutics confirms up to 99.3% tumor reduction compared to non-treated control group in gastric cancer animal model [Google translation] (BioTimes) - "The announcement made in Chicago on the 29th newly disclosed the results of an animal model test in which patient-derived gastric cancer cells were transplanted, proving the excellent anticancer effect of nesuparib. In a mouse model transplanted with KATOIII gastric cancer cells with normal DNA repair function, the tumor size of the nesuparib monotherapy group was reduced by 57.2% compared to the non-administered control group (Vehicle). In addition, when administered in combination with the standard gastric cancer treatment Irinotecan, nesuparib showed a 92.4% tumor reduction. On the other hand, olaparib showed a 30.1% and 60.7% reduction in the monotherapy and combination groups, respectively, compared to the non-administered control group."

Preclinical • Gastric Cancer • Gastrointestinal Cancer

Nesuparib, a dual inhibitor of PARP and tankyrase, is efficacious in preclinical gastric cancer models by regulation of HIPPO and Wnt pathway (AACR 2025) - "To evaluate the impact of nesuparib on cell growth, half maximal inhibitory concentration (IC50) of nesuparib, Olaparib, and XAV939 in clonogenicity was compared in BRCA wild type gastric cancer cells. In addition, the combination of nesuparib with irinotecan showed stronger tumor growth suppression than the combination of Olaparib with irinotecan.In summary, these results suggest that nesuparib may exert anti-tumor efficacy in specific types of cancers with pro-cancerous signaling of the Wnt or Hippo pathway by the regulation of TNKS. This warrants a proof-of-concept of anti-tumor effect of nesuparib in gastric cancers and its potentials for clinical benefits."

Preclinical • Gastric Cancer • Oncology • Solid Tumor • AXIN1 • BRCA • CCND1 • MYC

Onconic Therapeutics Presents Abstract at AACR Showing 28-fold Higher Antitumor Effect of Nesuparib on Gastric Cancer Cells (BioTimes) - "Onconic Therapeutics...announced on the 31st that it will present the results of a non-clinical study on its next-generation dual inhibitor targeted anticancer drug candidate, Nesuparib, for gastric cancer at the American Association for Cancer Research (AACR) 2025, to be held in Chicago, Illinois, USA in late April....Unlike conventional PARP inhibitors that are effective only in HRD (homologous recombination deficient) cells, nesuparib exhibited a cancer cell growth inhibition effect in gastric cancer cell lines in which HR (homologous recombination) functions normally. This suggests that nesuparib has a mechanism to effectively block the proliferation and metastasis of gastric cancer cells by inhibiting TNKS activity and thereby inhibiting the expression of downstream genes of the Wnt and Hippo signaling pathways."

Preclinical • Gastric Cancer

PENELOPE: 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 (pMMR) Endometrial Cancer (clinicaltrials.gov) - P2 | N=92 | Recruiting | Sponsor: Yonsei University | Not yet recruiting ➔ Recruiting

Enrollment open • pMMR • Endometrial Cancer • Gynecologic Cancers • Gynecology • Oncology • Solid Tumor

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-pro (SGO 2025) - No abstract available

Clinical • Combination therapy • Metastases • P2 data • Oncology

Onconic Therapeutics’ nesuparib scores FDA orphan drug designation for gastric cancer (Korea Biomedical Review) - "Onconic Therapeutics...Nesuparib, has been granted Orphan Drug Designation (ODD) by the U.S. FDA for the treatment of gastric cancer, including gastroesophageal junction cancer."

Orphan drug • Gastric Cancer • Gastroesophageal Junction Adenocarcinoma

Study to Assess the Safety, Tolerability of JPI-547 in Combination With Modified FOLFIRINOX or Gemcitabine-nab-paclitaxel in Patients With Locally Advanced and Metastatic Pancreatic Cancer (clinicaltrials.gov) - P1 | N=30 | Recruiting | Sponsor: Onconic Therapeutics Inc. | Trial completion date: Sep 2026 ➔ Jun 2026

Trial completion date • Hepatology • Oncology • Pancreatic Cancer • Pancreatic Ductal Adenocarcinoma • Solid Tumor

Onconic Therapeutics to Present Preclinical Study Results of Next-Generation Targeted Anticancer Drug at AACR in April [Google translation] (BioTimes) - "Onconic Therapeutics...announced on the 13th that it will present the non-clinical results of its next-generation dual inhibitor targeted anticancer drug candidate, Nesuparib, as a poster at the American Association for Cancer Research (AACR) 2025 to be held in Chicago, Illinois, USA in April....At this conference, Onconic Therapeutics plans to present research results in new fields that go beyond the indications of existing PARP inhibitors, thereby confirming antitumor efficacy and dual mechanism of action of nesuparib, which can be used as a new targeted treatment in new indications, and once again prove its potential as an innovative treatment."

Preclinical • Oncology

Study to Assess the Safety, Tolerability of JPI-547 in Combination With Modified FOLFIRINOX or Gemcitabine-nab-paclitaxel in Patients With Locally Advanced and Metastatic Pancreatic Cancer (clinicaltrials.gov) - P1 | N=30 | Recruiting | Sponsor: Onconic Therapeutics Inc. | Trial completion date: Dec 2024 ➔ Sep 2026 | Trial primary completion date: Dec 2024 ➔ Mar 2026

Trial completion date • Trial primary completion date • Hepatology • Oncology • Pancreatic Cancer • Pancreatic Ductal Adenocarcinoma • Solid Tumor

Study to Assess the Safety, Tolerability of JPI-547 in Combination With Modified FOLFIRINOX or Gemcitabine-nab-paclitaxel in Patients With Locally Advanced and Metastatic Pancreatic Cancer (clinicaltrials.gov) - P1 | N=24 | Recruiting | Sponsor: Onconic Therapeutics Inc. | Not yet recruiting ➔ Recruiting | Trial completion date: Aug 2023 ➔ Dec 2024 | Trial primary completion date: Aug 2023 ➔ Dec 2024

Combination therapy • Enrollment open • Metastases • Trial completion date • Trial primary completion date • Gastrointestinal Cancer • Hepatology • Oncology • Pancreatic Cancer • Pancreatic Ductal Adenocarcinoma • Solid Tumor

A Study to Evaluate the Efficacy and Safety of JPI-547 in Platinum-resistant, Advanced/Relapsed Ovarian Cancer Subjects Previously Treated With a PARP Inhibitor (clinicaltrials.gov) - P2 | N=58 | Active, not recruiting | Sponsor: Onconic Therapeutics Inc. | Not yet recruiting ➔ Active, not recruiting

Enrollment closed • Metastases • Oncology • Ovarian Cancer • Solid Tumor • BRCA1 • BRCA2

PENELOPE: 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 (pMMR) Endometrial Cancer (clinicaltrials.gov) - P2 | N=92 | Not yet recruiting | Sponsor: Yonsei University

New P2 trial • Endometrial Cancer • Gynecologic Cancers • Gynecology • Oncology • Solid Tumor

Efficacy of JPI-547, novel dual PARP inhibitor, in endometrial cancer cell line (AACR 2024) - "Cell viability assay for the drugs Olaparib and JPI-547 were assessed. JPI-547, a novel PARP inhibitor, showed good efficacy in PTEN mutation and PTEN-wild-type EEC cell lines than in conventional PARP inhibitor. The effect of reducing survival of ECC cell line with JPI-547 was confirmed with or without PTEN mutation. Further evaluation and in vivo experiments are needed to prove the efficacy of JPI-547 in EC."

Preclinical • Colorectal Cancer • Endometrial Cancer • Gynecologic Cancers • Oncology • Solid Tumor • DRD • PTEN • RAD51

Imipridones ONC201 and ONC212 exhibit anti-tumor activity in biliary tract cancers and synergy when combined with trametinib and olaparib in vitro (AACR 2024) - "Both ONC201 and ONC212 demonstrated antineoplastic effects in two BTC cell lines. Half maximal inhibitory concentrations (IC50) of ONC201 in RBE and HuCCT1 cell lines were 2.5uM and 2.0uM, respectively. The IC50 of ONC212 in RBE and HuCCT1 was 47nM and 39nM, respectively, which was similar to IC50s demonstrated with cytotoxic chemotherapy (gemcitabine IC50 = 7.57nM (RBE) and 9.84nM (HuCCT1))."

Preclinical • Biliary Cancer • Biliary Tract Cancer • Gastrointestinal Cancer • Oncology • Pancreatic Cancer • Pancreatic Ductal Adenocarcinoma • Solid Tumor • DRD2