elraglusib (9-ING-41) / Actuate Therap - LARVOL DELTA

Mutational analysis and identification of potential biomarkers in patients with metastatic pancreatic cancer treated with the combination of the GSK-3 inhibitor elraglusib and gemcitabine/nab-paclitaxel in the 1801 Part 3B phase 2 study. (ASCO-GI 2026) - P2 | "Clinical Trial Registration Number: NCT03678883 The full, final text of this abstract will be available on Jan 05 at 05:00 PM EST."

Biomarker • Clinical • Metastases • P2 data • Gastrointestinal Cancer • Oncology • Pancreatic Cancer • Solid Tumor

Results from the randomized phase 2 study (1801 Part 3B) of elraglusib plus gemcitabine/nab-paclitaxel (GnP) versus GnP in previously untreated metastatic pancreatic ductal adenocarcinoma (mPDAC). (ASCO-GI 2026) - P2 | "Funded by Actuate Therapeutics, Inc Clinical Trial Registration Number: NCT03678883 The full, final text of this abstract will be available on Jan 05 at 05:00 PM EST."

Clinical • Metastases • P2 data • Gastrointestinal Cancer • Oncology • Pancreatic Cancer • Pancreatic Ductal Adenocarcinoma

Therapeutic Targeting of Epithelial Mesenchymal Cellular Plasticity in Pancreatic Cancer. (PubMed, Clin Cancer Res) - P2 | "GSK-3b blockade synergizes with FFX by modulating PDAC plasticity while promoting the development of a tumor suppressive immune microenvironment."

Journal • Oncology • Pancreatic Cancer • Pancreatic Ductal Adenocarcinoma • Solid Tumor • CD4 • CD8 • CEACAM6 • FN1 • TGFB1

Drug Repurposing for AML: Structure-Based Virtual Screening and Molecular Simulations of FDA-Approved Compounds with Polypharmacological Potential. (PubMed, Biomedicines) - "While targeted agents-such as LSD1 inhibitors, the BCL-2 inhibitor venetoclax, and IDH1 inhibitors-have provided clinical benefit, their efficacy is often limited by compensatory signaling and clonal evolution. This computational study supports the feasibility of a polypharmacology-based strategy for AML therapy by integrating epigenetic modulation, apoptotic reactivation, and metabolic correction within single molecular scaffolds. However, the identified compounds (Belumosudil, DB08512, and Elraglusib) have not yet demonstrated efficacy in AML models; further preclinical validation is warranted to substantiate these predictions and advance translational development."

FDA event • IO biomarker • Journal • Acute Myelogenous Leukemia • Hematological Disorders • Hematological Malignancies • Leukemia • Oncology • IDH1

Potential therapeutic GSK-3β inhibitor 9-ING-41 is active in combination with venetoclax in double-hit lymphoma (DHL). (PubMed, Cancer Biol Ther) - "Current therapies, including R-CHOP, show limited efficacy, necessitating novel strategies. The demonstrated single-agent efficacy and combination synergy with venetoclax support the potential of 9-ING-41 as a novel therapeutic strategy for DHL. These findings provide a proof-of-concept that may serve as a basis for future preclinical investigations in DHL."

Journal • Hematological Malignancies • High-grade B-cell lymphoma • Lymphoma • Oncology

Synergistic Killing Effect and Molecular Mechanism of Dual Targeting of Lymphoma By GSK-3 Inhibitor (9-ING-41) and BCL2 Inhibitor (ABT-199) (ASH 2024) - "Western blot revealed that the combination treatment modulated the expression of key proteins in the GSK-3 and WNT/β-Catenin pathways, indicating a potential mechanism for the observed synergistic effects.Conclusion : The combination of 9-ING-41 and ABT-199 demonstrates significant synergistic effects in inhibiting cell proliferation and inducing apoptosis in DHL cell lines. This dual targeting strategy presents a promising approach for improving treatment outcomes in DHL by modulating the GSK-3 and WNT/β-Catenin pathways."

IO biomarker • Hematological Malignancies • High-grade B-cell lymphoma • Lymphoma • Oncology • ANXA5 • BCL6 • MYC

Redundancy of Glycogen Synthase Kinase 3 in Lymphoma Cell Viability, Proliferation, and the Cytotoxicity of Elraglusib (ASH 2023) - "The IC 50 of elraglusib remains similar despite a significant reduction in levels of GSK3, again suggesting that GSK3 is not its cytotoxic target. Importantly, elraglusib retains therapeutic potential in lymphoma however GSK3 is not a surrogate marker for its efficacy and additional studies are required to elucidate the mechanisms through which it mediates its cytotoxic effects."

Hematological Malignancies • Lymphoma • Non-Hodgkin’s Lymphoma • Oncology

Elraglusib, a glycogen synthase kinase-3β (GSK-3β) inhibitor, plus chemotherapy with or without immunotherapy in patients with recurrent, metastatic salivary gland carcinoma. (PubMed, Clin Cancer Res) - "The trial did not meet its primary endpoint, though 18% of non-ACC patients treated with immune priming followed by cisplatin plus elraglusib achieved response. Higher nGSK-3β expression was observed in tumor samples from responders."

IO biomarker • Journal • Adenoid Cystic Carcinoma • Hematological Disorders • Neutropenia • Oncology • Salivary Gland Cancer

The glycogen synthase kinase-3β inhibitor 9-ING-41 in combination with chemoimmunotherapy provides long-term survival in the Th-MYCN mouse model (AACR-NCI-EORTC 2025) - P1 | " Th-MYCN mice relapsed within 60 days following treatment with 2 consecutive daily doses of temozolomide/irinotecan (TEMIRI) or cyclophosphamide/topotecan (CYCLO/TOPO), in addition to 15µg 14G2a on day 1 and day 5. Pharmacokinetics of radiolabelled 14G2a confirmed that this regimen resulted in equivalent 14G2a serum levels in tumor-bearing Th-MYCN mice as observed for Dinutuximab in neuroblastoma patients... 9-ING-41 in combination with chemoimmunotherapy is highly potent, resulting in long-term tumor-free survival in the Th-MYCN mouse model of neuroblastoma. Our data suggests that 9-ING-41 at least in part works through modulating anti-tumour immunity, and we are currently investigating this further."

Combination therapy • Preclinical • Neuroblastoma • Oncology • Solid Tumor • MYCN

ENDOTHELIAL GLYCOGEN SYNTHASE KINASE 3β DELETION ATTENUATES MITOCHONDRIAL DYSFUNCTION, FERROPTOSIS, AND METABOLIC DYSFUNCTION-ASSOCIATED STEATOHEPATITIS IN MURINE MASH (AASLD 2025) - " Endothelial cell-specific Gsk3β knockout (Gsk3β△End) mice were generated by crossing Gsk3βfl/fl mice with mice expressing tamoxifen-inducible Cre recombinase under the regulation of the vascular endothelial cadherin promoter...Similar results were replicated in mice fed the FFC diet and treated with the GSK3 inhibitor elraglusib, suggesting that LSEC GSK3β modulate dendritic cell maturation... GSK3β inhibition in LSEC attenuates lipotoxic endotheliopathy via inhibiting ferroptosis and restoring mitochondrial function. Moreover, LSEC GSK3 inhibition attenuates proinflammatory myeloid cells hepatic infiltration likely by modulating dendritic cell maturation and reducing ICAM-1 expression. Hence, GSK3 inhibition could serve as a potential therapeutic strategy in human MASH."

Preclinical • Fibrosis • Hepatology • Immunology • Inflammation • Liver Cirrhosis • Metabolic Disorders • Metabolic Dysfunction-Associated Steatohepatitis • GSK3B • ICAM1 • TERC

9-ING-41 Combined With Retifanlimab, Plus Modified FOLFIRINOX for Patients With Advanced Pancreatic Adenocarcinoma (RiLEY) (clinicaltrials.gov) - P1 | N=12 | Recruiting | Sponsor: Anwaar Saeed | Not yet recruiting ➔ Recruiting | Initiation date: May 2025 ➔ Sep 2025 | Trial primary completion date: May 2027 ➔ Sep 2027

Enrollment open • Trial initiation date • Trial primary completion date • Oncology • Pancreatic Adenocarcinoma • Pancreatic Cancer

FOLFIRINOX + 9-Ing-41 + Losartan In Pancreatic Cancer (clinicaltrials.gov) - P2 | N=70 | Active, not recruiting | Sponsor: Colin D. Weekes, M.D., PhD | Recruiting ➔ Active, not recruiting

Enrollment closed • Oncology • Pancreatic Adenocarcinoma • Pancreatic Cancer • Solid Tumor

Actuate Therapeutics Provides FDA with Updated Clinical Data Package to Support Planned Regulatory Interactions with FDA and EMA Over the Coming Months (GlobeNewswire) - "Actuate has amended its investigational new drug (IND) application with updated clinical data from its international randomized Phase 2 trial in first-line treatment of metastatic pancreatic cancer (Actuate-1801 Part 3B), which showed a statistically significant improvement in median overall survival with the combination arm of elraglusib plus gemcitabine/nab-paclitaxel (GnP) versus GnP alone. These data are intended to support planned regulatory submissions with the U.S. Food and Drug Administration (FDA) and the European Medicines Agency (EMA) beginning later this year and continuing into early 2026."

EMA filing • FDA filing • P2 data • Pancreatic Ductal Adenocarcinoma

ApoE4 Upregulates GSK-3β to Aggravate Alzheimer-Like Pathologies and Cognitive Impairment in Type 2 Diabetic Mice. (PubMed, CNS Neurosci Ther) - "Our findings suggest that ApoE4 exacerbates AD pathogenesis by activating GSK-3β. Furthermore, targeting GSK-3β may offer a promising therapeutic strategy to halt the progression from T2DM to AD, providing new insights into potential interventions for patients at risk."

Journal • Preclinical • Alzheimer's Disease • CNS Disorders • Cognitive Disorders • Diabetes • Inflammation • Metabolic Disorders • Type 2 Diabetes Mellitus • APOE • GSK3B

Actuate Therapeutics To Collaborate with Incyte Corporation and the University of Pittsburgh on Clinical Trial of Elraglusib in Combination with Retifanlimab and mFOLFIRINOX in Patients with Advanced Pancreatic Cancer (GlobeNewswire) - "'We are very excited to launch this study of elraglusib combined with retifanlimab and mFOLFIRINOX as a potentially synergistic, immune-modulatory approach for patients with advanced pancreatic cancer,' said Anwaar Saeed, MD, study principal investigator. 'While the first generation of immune checkpoint (PD-1, PDL-1, CTLA-4) inhibitors, including retifanlimab, has been transformative by targeting key immune pathways and restoring anti-cancer effector cells activity, this study explores complementary mechanisms - particularly those evoked by elraglusib - that may modulate additional checkpoints and work synergistically with existing inhibitors to deepen and broaden anti-tumor responses. A growing body of preclinical and clinical data suggests that elraglusib can stimulate NK/T-cell anticancer effector functions, enhance antigen presentation, and reduce myeloid-derived suppressor cells in the tumor. These effects have been observed in the context of emerging..."

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Actuate Therapeutics To Collaborate with Incyte Corporation and the University of Pittsburgh on Clinical Trial of Elraglusib in Combination with Retifanlimab and mFOLFIRINOX in Patients with Advanced Pancreatic Cancer (GlobeNewswire) - "Actuate Therapeutics...today announced the initiation of the Phase 1b trial of elraglusib in combination with Incyte’s PD-1 inhibitor, retifanlimab, and modified FOLFIRINOX (mFOLFIRINOX) as frontline therapy in advanced pancreatic adenocarcinoma. The trial is being conducted in collaboration with UPMC Hillman Cancer Center and Incyte Corporation....The Investigator-Initiated Phase 1b open-label, single-arm RiLEY (NCT06896188) trial, led by Anwaar Saeed, MD, Associate Professor of Medicine, and Chief of the Gastrointestinal Medical Oncology at UPMC Hillman Cancer Center, will initially enroll up to 12 patients with advanced pancreatic adenocarcinoma with an expansion plan based on interim efficacy results...In addition, elraglusib is being studied in a separate investigator initiated Phase 2 (NCT05077800) trial in combination with FOLFIRINOX and losartan in treatment-naïve mPDAC patients....Additional results from that study are expected in 2026."

Commercial • P2 data • Trial status • Pancreatic Adenocarcinoma • Pancreatic Ductal Adenocarcinoma

RiLEY: 9-ING-41 Plus Retifanlimab and Gemcitabine/Nab-Paclitaxel in Patients With Advanced Pancreatic Adenocarcinoma (clinicaltrials.gov) - P2 | N=7 | Terminated | Sponsor: Anwaar Saeed | N=32 ➔ 7 | Active, not recruiting ➔ Terminated; Backbone chemo regimen of gemzar/abraxane no longer most favorable treatment for pancreatic cancer patients.

Enrollment change • Trial termination • Oncology • Pancreatic Adenocarcinoma • Pancreatic Cancer

9-ING-41 in Pediatric Patients With Refractory Malignancies. (clinicaltrials.gov) - P1 | N=40 | Terminated | Sponsor: Actuate Therapeutics Inc. | N=68 ➔ 40 | Trial completion date: Dec 2024 ➔ Jul 2025 | Recruiting ➔ Terminated | Trial primary completion date: Dec 2024 ➔ Jul 2025; The decision to conclude study was made to optimize the clinical study design and protocol to further evaluate the safety profile of elraglusib (9-ING-41) in pediatric and adult patients with refractory Ewings Sarcoma.

Enrollment change • Trial completion date • Trial primary completion date • Trial termination • Brain Cancer • Diffuse Intrinsic Pontine Glioma • Diffuse Large B Cell Lymphoma • Germ Cell Tumors • Glioma • Hematological Malignancies • Lymphoma • Meningioma • Neuroblastoma • Oncology • Pediatrics • Solid Tumor • AFP

Actuate Therapeutics Advances Clinical Program in Ewing Sarcoma After Positive Phase 1 Trial Demonstrates Complete and Partial Responses in Difficult-to-Treat Pediatric Sarcomas (GlobeNewswire) - P1 | N=40 | NCT04239092 | Sponsor: Actuate Therapeutics Inc.| "Actuate...announced the end of the Phase 1 portion of its clinical study evaluating elraglusib monotherapy or in combination with irinotecan, irinotecan plus temozolomide, or with cyclophosphamide plus topotecan in pediatric patients with refractory malignancies (Actuate-1902)...Of the ten (10) EWS patients enrolled, two (2) patients achieved complete responses by CT and/or complete metabolic responses (CR/CMR), while two (2) had confirmed stable disease. A partial response (PR) was also observed in one patient with a desmoplastic small-round-cell tumor (DSRCT), a small round cell sarcoma that forms in soft tissue...Actuate plans to further investigate elraglusib’s ability to positively change patients’ potential for successful treatment in a Phase 2 trial in pediatric, adolescent, and adult patients with relapsed/refractory Ewing Sarcoma....The Company expects to initiate the trial in 2026, subject to available funding."

New P2 trial • P1 data • Trial status • Ewing Sarcoma

Actuate Therapeutics Highlights Significant and Sustained Survival Benefit in Key Metastatic Pancreatic Cancer Patient Populations in Phase 2 Elraglusib Trial (GlobeNewswire) - P2 | N=350 | Actuate-1801 (NCT03678883) | Sponsor: Actuate Therapeutics Inc. | "Actuate Therapeutics, Inc...highlighted results from a pre-specified subgroup analysis of its Phase 2 (Actuate-1801 Part 3B) trial of elraglusib in combination with gemcitabine/nab-paclitaxel (GnP) in first-line metastatic pancreatic adenocarcinoma...Patients treated for at least one complete cycle (4 weeks) of therapy achieved a median overall survival (mOS) of 12.5 months in the elragusib/GnP arm, compared to 8.5 months in the control arm. The analysis showed a 43% reduction in the risk of death relative to control, highlighting the significant potential impact of early disease control by elraglusib. Improved outcomes were reported in the combination versus control arms, respectively: disease control rate (DCR): 53.4% vs 44.8%, overall response rate (ORR): 37.9% vs 29.3%, and median progression-free survival (PFS): 6.9 vs 5.6 months."

P2 data • Pancreatic Ductal Adenocarcinoma

Actuate Therapeutics Reports Positive Biomarker and Machine Learning Data from Phase 2 Elraglusib Trial in First-Line Treatment of Metastatic Pancreatic Cancer at ASCO (GlobeNewswire) - P2 | N=350 | Actuate-1801 (NCT03678883) | Sponsor: Actuate Therapeutics Inc. | "Actuate...announced biomarker data from a recent poster presentation at the American Society of Clinical Oncology (ASCO) annual meeting from the Phase 2 (Actuate-1801 Part 3B) trial of elraglusib in combination with gemcitabine/nab-paclitaxel (GnP) in first-line metastatic pancreatic adenocarcinoma (mPDAC)...The analysis identified 7 biomarkers as uniquely significant predictors of favorable survival in the elraglusib-treated cohort, including one, CXCL2, with an inverse survival trend compared to the GnP control arm. This indicates that in patients not treated with elraglusib, high CXCL2 was unfavorable, but this trend is reversed with elraglusib treatment, highlighting the potential of elraglusib to favorably affect the immune microenvironment...Univariate analysis revealed strong predictive performance with CXCL2 emerging as a consistently reliable biomarker for survival..."

Biomarker • P2 data • Pancreatic Ductal Adenocarcinoma

Preliminary results from the randomized phase 2 study (1801 part 3B) of elraglusib in combination with gemcitabine/nab-paclitaxel (GnP) versus GnP alone in patients (pts) with previously untreated metastatic pancreatic ductal adenocarcinoma (mPDAC). (ASCO 2025) - P2 | "The preliminary results showed a statistically significant benefit for 1-yr OS and mOS and favorable trends for ORR and DCR with elraglusib/GnP over GnP, with manageable safety profile. The mOS for GnP is lower relative to MPACT and NAPOLI-3 but comparable to recent real-world meta-analyses, explained by advanced disease burden and higher mortality rate in the first 4 months in our study. Topline analysis (April 2025) and correlative biomarker analysis predictive for OS will be presented."

Clinical • Combination therapy • IO biomarker • Metastases • P2 data • Anemia • Fatigue • Neutropenia • Oncology • Pancreatic Cancer • Pancreatic Ductal Adenocarcinoma • IFNB1 • PD-L1

Machine learning and statistical prediction of overall survival (OS) from pre-dose plasma biomarkers in a randomized phase 2 trial (1801 Part 3B) of the GSK-3 inhibitor elraglusib in metastatic pancreatic ductal adenocarcinoma (mPDAC): Application toward patient enrichment. (ASCO 2025) - P2 | "Many CCSG biomarkers were identified as promising predictors of survival benefit in mPDAC patients treated with elraglusib+GnP. Both univariate statistical and multivariate ML approaches show predictive significance with high interpretability. The initial ML model is specific to elraglusib treatment, not GnP alone."

Biomarker • Clinical • IO biomarker • Machine learning • Metastases • P2 data • Patient Enrichment • Oncology • Pancreatic Cancer • Pancreatic Ductal Adenocarcinoma • IL18 • PD-L1

9-ING-41 Plus Carboplatin in Salivary Gland Carcinoma (clinicaltrials.gov) - P2 | N=35 | Active, not recruiting | Sponsor: Glenn J. Hanna | Trial completion date: Aug 2025 ➔ Apr 2027 | Trial primary completion date: Jun 2024 ➔ Feb 2025

Trial completion date • Trial primary completion date • Adenoid Cystic Carcinoma • Oncology • Salivary Gland Cancer

Actuate Therapeutics Presents Topline Elraglusib Phase 2 Data at ASCO 2025 Annual Meeting: Trial Meets Primary Endpoint of Median Overall Survival and Doubles 1-Year Survival in First-Line Treatment of Metastatic Pancreatic Cancer (GlobeNewswire) - P2 | N=350 | Actuate-1801 (NCT03678883) | Sponsor: Actuate Therapeutics Inc. | "The trial met its primary endpoint of improved median overall survival. Median overall survival (mOS) increased by almost three months (10.1 months vs 7.2 months, HR=0.63, log-rank p=0.01) with a 37% reduction in the risk of death and strong statistical significance, representing a clinically meaningful advance in the potential treatment of mPDAC. Patients receiving elraglusib with GnP achieved a 12-month survival rate in 44.1% of patients treated-double that of GnP alone (22.3%)....In addition to the improved mOS and one-year survival rate, a continued survival benefit was also observed at eighteen and twenty-four months (survival rates of 19.7% vs 4.4% and 13.8% vs 0% in the elraglusib/GnP combination arm vs the GnP arm, respectively)."

P2 data • Pancreatic Ductal Adenocarcinoma