ezurpimtrostat (GNS561) / Genoscience Pharma, Genfit - LARVOL DELTA

Combination of GNS561 and Trametinib in Patients With Advanced KRAS Mutated Cholangiocarcinoma (clinicaltrials.gov) - P1/2 | N=98 | Recruiting | Sponsor: Genfit | N=74 ➔ 98 | Trial completion date: Oct 2026 ➔ Jun 2028 | Trial primary completion date: May 2026 ➔ Dec 2027

Enrollment change • Trial completion date • Trial primary completion date • Biliary Cancer • Cholangiocarcinoma • Oncology • Solid Tumor • KRAS

GENFIT: Positive Phase 1b Data with GNS561 in Combination Therapy in Heavily Pretreated Patients with Cholangiocarcinoma (GlobeNewswire) - "The initial part of the Phase 1b study has been completed as planned, with 19 patients enrolled across four cohorts evaluating increasing doses of GNS561. A favorable safety and tolerability profile was observed, with no dose-limiting toxicities (DLT) reported, supporting continued clinical development. Continued signals of antitumor activity were also noted in this heavily pretreated population, with approximately half of patients achieving Stable Disease (SD) at Week 6, including one patient maintaining this status up to Week 30....GENFIT has decided to expand the Phase 1b study with additional cohorts at higher dose levels. This expansion, intended to further strengthen the clinical dataset, does not alter the planned transition to Phase 2, which remains on track for initiation in the second half of 2026. The recommended Phase 2 dose and study design are expected to be finalized over the summer."

P1 data • Trial status • Cholangiocarcinoma

CRISPR screen identifies autophagy inhibition (GNS561) as a PARP inhibitor (AZD5305) combination strategy in small cell lung cancer. (PubMed, Cancer Metab) - "Autophagy inhibition downstream of the mTOR pathway is a mechanism of PARPi sensitivity in SCLC. This suggests that a therapeutic combination of autophagy inhibition and PARPi is a promising treatment strategy in SCLC, paving the way for the adoption of novel treatments in this disease context."

Journal • Lung Cancer • Oncology • Small Cell Lung Cancer • Solid Tumor • TSC1 • TSC2

INHIBITION OF LYSOSOMAL DETOXIFICATION AND RECYCLING PATHWAYS IN ACUTE MYELOBLASTIC LEUKAEMIA (EHA 2026) - "Methods We studied a series of AML cell lines (HL-60, KASUMI1, KG1, MONOMAC 6, MOLM14, MV-4-11, K562), cultured in the presence of an ALDHA1 inhibitor (Dimate), in the presence of an autophagy inhibitor (GNS561-Ezurpimtrostat), as well as the Azacytidine-Venetoclax combination, and by combining these various inhibitors Results Most of the cell lines tested proved to be sensitive to the autophagy inhibitor at concentrations compatible with in vivo use, as they were relatively comparable to the results obtained in clinical trials in hepatocellular carcinoma. Cells. 2025 Jul 7; 14(13):1038."

Acute Myelogenous Leukemia • Hematological Malignancies • Hepatocellular Cancer • Leukemia • Solid Tumor • ALDH1A1 • mTOR • PPT1

A targeted drug conjugate derived from GNS561 and a Pt(II) moiety for PPT1-mediated lysosomal autophagy inhibition in triple-negative breast Cancer. (PubMed, Bioorg Chem) - "In vivo evaluations utilizing a MDA-MB-231 xenograft model demonstrated that GN-604 achieved superior antitumor potency to GNS561, cisplatin, or their co-administration. In summary, GN-604 emerges from this study as an encouraging bifunctional therapeutic modality tailored for the management of aggressive TNBC."

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

PARP and autophagy inhibition synergy in small cell lung cancer (AACR 2025) - "First-line treatment with platinum and etoposide chemotherapy—and radiotherapy for limited stage disease—produces good initial response, but most patients suffer treatment-resistant relapse within 2 years...Poly (ADP-ribose) polymerase (PARP) inhibitors (PARPi) effectively induce DNA damage in SCLC and have shown potential in this setting, but response is variable, so we aimed to identify mechanisms through which SCLC may be sensitized to PARPi therapy. CRISPR dropout screens were conducted using the Toronto KnockOut v1 (TKOv1) CRISPR library in the SBC5 and H82 SCLC cell lines, with the PARPi, olaparib, as the selection pressure...In wild-type cell lines, therapeutic mTOR activation with MHY1485 was validated by Western blot and therapeutic autophagy inhibition with chloroquine (CQ) or GNS561 was validated by Western blot after 3 hours starvation in EBSS medium... TSC1/2 knockdown sensitizes SCLC cell lines to PARPi in concordance with our model that mTOR downregulation..."

Endocrine Cancer • Lung Cancer • Neuroendocrine Carcinoma • Oncology • Small Cell Lung Cancer • Solid Tumor • TSC1

In Vivo Zebrafish Screening Identifies Potential Ototoxins Among Novel and Repurposed COVID-19 Therapeutics (ARO 2026) - "The secondary validation further confirmed 36 compounds as hair cell toxins, including drugs like nicotine, the anti-malarial drug quinine, and the anti-fibrotic agent ezurpimtrostat... We identified 36 compounds with potential ototoxic effects in our zebrafish screen. These compounds are now being evaluated for general cytotoxicity in zebrafish, with non-cytotoxic candidates advancing to rodent models to assess translational relevance in a mammalian system. Future studies will also incorporate inflammatory conditions to better mimic COVID-19 symptomology."

Preclinical • Brain Cancer • Infectious Disease • Novel Coronavirus Disease • Otorhinolaryngology • POU4F3

GENFIT: GNS561 Shows Promising Antitumor Activity in Combination Therapy (GlobeNewswire) - "The analysis evaluated 9 patients with measurable disease at baseline, 4 of them reaching tumor assessment at week 6. At this point, the combination therapy demonstrated: Disease stabilization observed in all 4 evaluated patients, who had all shown disease progression during previous treatment; Tumor shrinkage in a subgroup of patients with the best response showing a 20% reduction approaching the partial response (PR) threshold...Achieving disease control and tumor reduction in such heavily pretreated patient population with advanced CCA is a significant signal of antitumor activity.....Phase 1b dose escalation will continue as planned to confirm the activity signal, with new data for the next patient cohorts expected in 1Q26. These results will be used to establish the recommended Phase 2 combination doses, with completion expected in 1H26. Phase 2 initiation is targeted for 2H26."

P1 data • Trial status • Cholangiocarcinoma

PPT1 is a negative regulator of STING signaling in cancer cells and its inhibition reactivates immune surveillance in cold tumors. (PubMed, Proc Natl Acad Sci U S A) - "Treatment of preclinical prostate and ovarian cancer models expressing low levels of STING with the small molecule PPT1 inhibitor GNS561 enhanced STING expression and activation, leading to infiltration and activation of cytotoxic T cells that turned these tumors "hot" and reduced tumor growth, fibrosis, and dissemination without toxicity. Further analysis demonstrated that PPT1 is associated with reduced STING expression, CD8+ T cell numbers, overall survival, and immunotherapy outcomes in ovarian and prostate cancer patients. Thus, PPT1 inhibition may be a promising approach to activate STING and potentiate the effects of immunotherapy in cold tumors."

IO biomarker • Journal • Fibrosis • Genito-urinary Cancer • Immunology • Oncology • Ovarian Cancer • Prostate Cancer • Solid Tumor • CD8

Dual Regulation of Sprouty 4 Palmitoylation by ZDHHC7 and Palmitoyl-Protein Thioesterase 1: A Potential Therapeutic Strategy for Cisplatin-Resistant Osteosarcoma. (PubMed, Research (Wash D C)) - "GNS561 holds promise as an adjunctive therapy when combined with cisplatin, potentially overcoming resistance and improving efficacy, thereby enhancing the prognosis for OS patients. Future studies should further investigate the clinical potential of GNS561 and optimize OS treatment strategies."

Journal • Oncology • Osteosarcoma • Sarcoma • Solid Tumor • PPT1

GNS561 (ezurpimtrostat), a small basic lipophilic molecule, prevents lupus phenotype in a pristane-induced lupus mouse model. (PubMed, Br J Pharmacol) - "Altogether, this study highlights GNS561 as a promising investigational drug for systemic lupus erythematosus."

Journal • Preclinical • Immunology • Infectious Disease • Inflammation • Inflammatory Arthritis • Lupus • Nephrology • Rheumatology • Systemic Lupus Erythematosus

Novel Quinoline Substituted Autophagy Inhibitors Attenuate Zika Virus Replication in Ocular Cells. (PubMed, Virus Res) - "Thus, autophagy inhibitors have emerged as a potent therapeutic target to combat RNA viruses, with Hydroxychloroquine (HCQ) being one of the most promising candidates...These two compounds surpassed the antiviral efficacy of HCQ and other existing autophagy inhibitors, such as ROC-325, DC661, and GNS561...Furthermore, compounds GL-287 and GL-382 effectively inhibited the ZIKV-induced innate inflammatory response in ocular cells. Collectively, our study demonstrates the safe and potent antiviral activity of novel autophagy inhibitors against ZIKV."

Journal • Infectious Disease • Inflammation • Ocular Inflammation

ABE-LIVER: Ezurpimtrostat Autophagy Inhibitor in Association With Atezolizumab-Bevacizumab in First Line Treatment of Unresectable Hepatocellular Carcinoma (clinicaltrials.gov) - P2 | N=3 | Terminated | Sponsor: University Hospital, Grenoble | Phase classification: P2b ➔ P2 | N=196 ➔ 3 | Trial completion date: Dec 2025 ➔ Mar 2024 | Recruiting ➔ Terminated | Trial primary completion date: Jun 2025 ➔ Mar 2024; Study terminated due to recruitement issues

Enrollment change • Phase classification • Trial completion date • Trial primary completion date • Trial termination • Gastrointestinal Cancer • Hepatocellular Cancer • Oncology • Solid Tumor

Combination of GNS561 and Trametinib in Patients With Advanced KRAS Mutation Cholangiocarcinoma (clinicaltrials.gov) - P1/2 | N=74 | Recruiting | Sponsor: Genfit | Not yet recruiting ➔ Recruiting | Phase classification: P1b/2a ➔ P1/2 | Trial primary completion date: Jun 2025 ➔ May 2026

Combination therapy • Enrollment open • Metastases • Phase classification • Trial primary completion date • Biliary Cancer • Cholangiocarcinoma • Gastrointestinal Cancer • Oncology • Solid Tumor • KRAS

Ezurpimtrostat, A Palmitoyl-Protein Thioesterase-1 Inhibitor, Combined with PD-1 Inhibition Provides CD8 Lymphocyte Repopulation in Hepatocellular Carcinoma. (PubMed, Target Oncol) - "Ezurpimtrostat turns cold tumors into hot tumors and, thus, could improve T cell-mediated immunotherapies in liver cancer."

IO biomarker • Journal • Gastrointestinal Cancer • Hepatocellular Cancer • Hepatology • Liver Cancer • Oncology • Solid Tumor • CD8

Advances of Protein Palmitoylation in Tumor Cell Deaths. (PubMed, Cancers (Basel)) - "Central to our discourse are agents like Ezurpimtrostat (GNS561) and dimeric chloroquine (DC661), promising heralds in palmitoylation-targeted cancer therapy. Collectively, this review accentuates palmitoylation's transformative potential in oncology, foreshadowing groundbreaking therapeutic strategies and deepening our molecular comprehension of cancer dynamics."

Journal • Review • Tumor cell • Oncology

EZURPIMTROSTAT AUTOPHAGY BLOCKER, A PALMITOYL-PROTEIN THIOESTERASE 1 (PPT1) INHIBITOR, AND ATEZOLIZUMAB/BEVACIZUMAB TRIPLE COMBINATION REGIMEN ENHANCES ANTITUMOR EFFICACY IN HEPATOCELLULAR CARCINOMA (AASLD 2023) - P2b | "This study reports that GNS561 potentiates the anti-tumor effect of atezolizumab/bevacizumab combination emphasizing PPT1 inhibitors' therapeutic interest in combination with immunotherapy in HCC. This triple therapy is currently tested in the randomized phase 2 clinical trial ABE-LIVER, in first line setting in advanced HCC."

Clinical • Gastrointestinal Cancer • Hepatocellular Cancer • Oncology • Solid Tumor

Update on Autophagy Inhibitors in Cancer: Opening up to a Therapeutic Combination with Immune Checkpoint Inhibitors. (PubMed, Cells) - "GNS561, a PPT1 inhibitor, is a promising autophagy modulator as it has started a phase 2 clinical trial in liver cancer indication, combined with atezolizumab and bevacizumab, an assessment without precedent in the field. This approach paves a new road, leading to the resurgence of anticancer autophagy inhibitors as an attractive therapeutic target in cancer."

Checkpoint inhibition • Journal • Review • Gastrointestinal Cancer • Hepatology • Immune Modulation • Liver Cancer • Oncology • Solid Tumor

GENFIT Reports Full-Year 2022 Financial Results and Provides Corporate Update (GlobeNewswire) - "A Phase 1b/2a trial will evaluate GNS561 in patients with advanced KRAS mutated CCA. In the Phase 1b, patients will be enrolled to evaluate the safety and tolerability of GNS561 when given in combination with a MEK inhibitor, and to identify the recommended doses of the combination to be administered in the Phase 2a study. GENFIT targets to screen the first patient towards the end of the second quarter of 2023."

New P1/2 trial • Biliary Cancer • Biliary Tract Cancer • Cholangiocarcinoma • Gastrointestinal Cancer • Oncology • Solid Tumor

Genoscience Pharma receives FDA Orphan Drug Designation for ezurpimtrostat to treat HepatoCellular Carcinoma (HCC) (Genoscience Press Release) - "Genoscience Pharma...today announces that its lead candidate, ezurpimtrostat...has been granted Orphan Drug Designation (ODD) by the US Food and Drug Administration (FDA) for the treatment of HepatoCellular Carcinoma (HCC)....ODD qualifies ezurpimtrostat for a potential seven years of market exclusivity after approval....We have recently launched our phase 2b clinical trial using ezurpimtrostat in conjunction with the standard atezolizumab/bevacizumab treatment. We are looking forward to sharing the intermediate results in 2024.”"

Orphan drug • P2b data • Gastrointestinal Cancer • Hepatocellular Cancer • Oncology • Solid Tumor

[PREPRINT] Targeting PPT1 with ezurpimtrostat sensitives liver tumor to immunotherapy by switching cold into hot microenvironments (bioRxiv) - “Herein, we revealed that inhibition of PPT1 using ezurpimtrostat, a safe anticancer drug in humans, decreased the liver tumor burden by inducing the penetration of lymphocytes within tumors when combined with anti-programmed death-1 (PD-1). Inhibition of PPT1 potentiates the effects of anti-PD-1 immunotherapy by increasing the expression of major histocompatibility complex (MHC)-I at the surface of liver cancer cells and modulates immunity through recolonization and activation of cytotoxic CD8+ lymphocytes.”

Preclinical • Preprint • Gastrointestinal Cancer • Liver Cancer • Oncology • Solid Tumor

ABE-LIVER: Ezurpimtrostat Autophagy Inhibitor in Association With Atezolizumab-Bevacizumab in First Line Treatment of Unresectable Hepatocellular Carcinoma (clinicaltrials.gov) - P2b | N=196 | Recruiting | Sponsor: University Hospital, Grenoble | Not yet recruiting ➔ Recruiting

Enrollment open • Gastrointestinal Cancer • Hepatocellular Cancer • Oncology • Solid Tumor

IMMUNONCOVID: Prospective Study in Patients With Advanced or Metastatic Cancer and SARS-CoV-2 Infection (clinicaltrials.gov) - P2 | N=19 | Completed | Sponsor: Centre Leon Berard | Active, not recruiting ➔ Completed | N=219 ➔ 19

Enrollment change • Trial completion • Hematological Disorders • Infectious Disease • Novel Coronavirus Disease • Oncology • Respiratory Diseases • Solid Tumor • IL6

FDA Grants GENFIT’s GNS561 Orphan Drug Designation for the Treatment of Cholangiocarcinoma (GlobeNewswire) - "GENFIT...announced that the U.S. Food and Drug Administration (FDA) has granted Orphan Drug Designation to GNS5611 (ezurpimtrostat), a novel clinical-stage autophagy/PPT1 inhibitor, for the treatment of cholangiocarcinoma....GNS561 (ezurpimtrostat) is a PPT-1 (Palmitoyl Protein Thioesterase-1) inhibitor that blocks autophagy....A Phase 2 trial is expected to start in the fourth quarter 2022, with a first patient visit expected in the first quarter 2023."

New P2 trial • Orphan drug • Biliary Cancer • Biliary Tract Cancer • Cholangiocarcinoma • Gastrointestinal Cancer • Oncology • Solid Tumor

First-In-Human Effects of PPT1 Inhibition Using the Oral Treatment with GNS561/Ezurpimtrostat in Patients with Primary and Secondary Liver Cancers. (PubMed, Liver Cancer) - P1/2 | "Based on a favorable safety profile, exposure, and preliminary signal of activity, oral GNS561 RP2D was set at 200 mg BID. Studies to evaluate the antitumor activity of GNS561 in hepatocarcinoma cells and intrahepatic cholangiocarcinoma are to follow NCT03316222."

Journal • P1 data • Biliary Cancer • Cholangiocarcinoma • Colorectal Adenocarcinoma • Colorectal Cancer • Fatigue • Gastrointestinal Cancer • Gastrointestinal Disorder • Hepatocellular Cancer • Hepatology • Liver Cancer • Oncology • Pancreatic Adenocarcinoma • Pancreatic Cancer • Solid Tumor