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

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

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

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

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

New P2b trial • Gastrointestinal Cancer • Hepatocellular Cancer • Oncology • Solid Tumor

GNS561-CL-I-Q-0211: Study of GNS561 in Patients With Liver Cancer (clinicaltrials.gov) - P1/2 | N=50 | Terminated | Sponsor: Genoscience Pharma | Trial completion date: Jan 2022 ➔ Apr 2022 | Recruiting ➔ Terminated; only phase 1b was completed and the phase 2 will be an another study, finally

Trial completion date • Trial termination • Biliary Cancer • Cholangiocarcinoma • Gastrointestinal Cancer • Hepatocellular Cancer • Hepatology • Liver Cancer • Oncology • Solid Tumor

Effect of Food and Formulation on the Pharmacokinetics, Safety, and Tolerability of GNS561 After One Single Dose (50 and 200mg) in Healthy Volunteers (clinicaltrials.gov) - P1 | N=27 | Not yet recruiting | Sponsor: Genoscience Pharma

New P1 trial • Gastrointestinal Cancer • Hepatology • Liver Cancer • Oncology • Solid Tumor

"GNS561 first effort proudly led by @MSKCancerCenter @MSK_DeptOfMed James Harding and @GABOUALFA is now published! Sadly did not lead far. Liver Cancer - https://t.co/sBf2W2r9YI @KargerPublisher" (@GABOUALFA)

Gastrointestinal Cancer • Hepatology • Liver Cancer • Oncology • Solid Tumor

GNS561 Exhibits Potent Antiviral Activity against SARS-CoV-2 through Autophagy Inhibition. (PubMed, Viruses) - "Autophagy-modulating compounds thus rapidly emerged as an attractive strategy to fight SARS-CoV-2 infection, including the well-known chloroquine (CQ). To confirm our findings, we used the K18-hACE2 mouse model and highlighted that GNS561 treatment led to a decline in SARS-CoV-2 virions in the lungs associated with a disruption of the autophagy pathway. Overall, our study highlights GNS561 as a powerful drug in the treatment of SARS-CoV-2 infection and supports the hypothesis that autophagy blockers could be an alternative strategy for COVID-19."

Journal • Infectious Disease • Novel Coronavirus Disease • Respiratory Diseases

"#GENOSCIENCEPHARMA out licenses rights of #GNS561 in Europe, US and Canada territories in #Cholangiocarcinoma https://t.co/iM8qBMIMT7" (@1stOncology)

Biliary Cancer • Cholangiocarcinoma • Gastrointestinal Cancer • Oncology • Solid Tumor