H3B-6527 / Eisai - LARVOL DELTA

THE COMBINATION OF FGFR4 INHIBITOR H3B-5627 AND OXALIPLATIN PROMOTES DNA DAMAGE, CELL DEATH AND REDUCES TUMOR GROWTH IN VITRO AND IN PATIENT-DERIVED XENOGRAFT GASTRIC CANCER MODELS (DDW 2025) - "This study demonstrates that combining H3B-6527 with Oxaliplatin enhances DNA damage and disrupts key cell survival pathways, leading to greater cell death than either treatment alone."

Preclinical • Colorectal Cancer • Esophageal Cancer • Gastric Cancer • Oncology • Solid Tumor • CASP3 • CASP7 • FGFR4

Synergistic efficacy of FGFR4 inhibitor (H3B-6527) and oxaliplatin combination therapy in gastric cancer models (AACR 2025) - "This study demonstrates the synergistic efficacy of H3B-6527 and oxaliplatin in promoting apoptosis, enhancing DNA damage, and inhibiting tumor proliferation in gastric cancer models. These findings provide compelling evidence for the potential clinical application of this drug combination as a promising therapeutic strategy for gastric cancer patients, especially those with chemoresistance."

Clinical • Combination therapy • Preclinical • Gastric Cancer • Oncology • Solid Tumor • CASP3 • CASP7 • FGFR4

Targeting FGFR4 Abrogates HNF1A-driven Metastasis in Pancreatic Ductal Adenocarcinoma. (PubMed, bioRxiv) - "RNAi and two FGFR4 inhibiting modalities (H3B-6527 and U3- 1784) were utilized to demonstrate the efficacy of FGFR4 inhibiting agents at reducing HNF1A- driven metastasis...Importantly, FGFR4 is a targetable vulnerability and treatment with an FGFR4 blocking antibody reduces HNF1A-driven metastasis. These findings suggest that FGFR4 inhibitors could be an efficacious treatment for PDAC patients for the prevention or delay of metastatic tumor development."

Journal • Oncology • Pancreatic Cancer • Pancreatic Ductal Adenocarcinoma • FGFR4 • HNF1A

H3 Biomedicine Granted Orphan Drug Designation Of H3B-6527 For Treatment Of Hepatocellular Carcinoma (BioSpace) - "H3 Biomedicine...today announced that the U.S. Food and Drug Administration (FDA) has granted the company an orphan drug designation for H3B-6527, its first solid tumor clinical compound, for the treatment of patients with Hepatocellular Carcinoma (HCC)."

Orphan drug • Hepatocellular Cancer

EU/3/17/1902 - orphan designation for treatment of hepatocellular carcinoma (European Medicines Agency) - "On 23 August 2017, orphan designation (EU/3/17/1902) was granted by the European Commission to Eisai Europe Limited, United Kingdom, for N-{2-[(6-{[(2,6-dichloro-3,5-dimethoxyphenyl)carbamoyl](methyl)amino}pyrimidin-4-yl)amino]-5-(4-ethylpiperazin-1-yl)phenyl}prop-2-enamide (also known as H3B-6527) for the treatment of hepatocellular carcinoma."

Orphan drug • Hepatocellular Cancer

FIBROBLAST GROWTH FACTOR RECEPTOR-4 PROMOTES ANTIOXIDANT RESPONSE VIA ACTIVATION OF NUCLEAR FACTOR ERYTHROID 2-RELATED FACTOR-2 IN GASTRIC CANCER (DDW 2024) - "Pharmacologic inhibition of FGFR4 using H3B-6527, or its knockdown, decreased NRF2 with a remarkable reduction in the size and numbers of gastric cancer spheroids... Our findings suggest that the activation of NRF2 antioxidant response prevents accumulation of lethal high levels of ROS in response to H. pylori infection. The interaction between FGFR4 and P62 interfered with NRF2 binding to KEAP1, allowing it to escape KEAP1-dependent degradation mechanisms, leading to NRF2 accumulation and activation. The FGFR4-NRF2 signaling network may serve as a molecular vulnerability that can be targeted by FGFR4 inhibitors."

Gastric Cancer • Gastrointestinal Cancer • Infectious Disease • Oncology • Solid Tumor • FGFR4 • KEAP1 • TFF1

Fibroblast growth factor receptor-4 mediates activation of Nuclear Factor Erythroid 2-Related Factor-2 in gastric tumorigenesis. (PubMed, Redox Biol) - "Pharmacologic inhibition of FGFR4 using H3B-6527, or its knockdown, remarkably reduced the level of NRF2 with a reduction in the size and number of gastric cancer spheroids. Mechanistically, we detected binding between FGFR4 and P62 proteins, competing with NRF2-KEAP1 interaction, allowing NRF2 to escape KEAP1-dependent degradation with subsequent accumulation and translocation to the nucleus. These findings demonstrate a novel functional role of FGFR4 in cellular homeostasis via regulating the NRF2 levels in response to H. pylori infection in gastric carcinogenesis, calling for testing the therapeutic efficacy of FGFR4 inhibitors in gastric cancer models."

Journal • Gastric Cancer • Gastrointestinal Cancer • Infectious Disease • Oncology • Solid Tumor • FGFR4 • KEAP1

FXR AGONIST INDUCED INTESTINAL FGF15/19 REGULATES FXR SIGNALING IN LIVER IN LITHOCHOLIC ACID DIET-INDUCED ACUTE CHOLANGIOPATHY MOUSE MODEL. (AASLD 2023) - "The aim of this study is to determine effects and mechanisms of FXR agonists (GW4064 and obeticholic acid [OCA]) in the acute LCA mouse model of cholestasis. FXR agonists increase intestinal FGF19 by enhancing FXR binding to FGF19 promoter, that then induces hepatocyte bile exporters to decrease bile acid levels in hepatocytes, thus alleviating LCA mediated hepatocyte injury."

Preclinical • Cholestasis • Hepatology • ABCB1 • CYP27A1 • FGF19 • FGFR4 • GLI2 • IL6 • NR5A2

HIGH EXPRESSION OF FGFR4 PROMOTES GASTRIC CANCER THROUGH BINDING TO P62-KEAP1 AND NUCLEAR ACCUMULATION OF NRF2 (DDW 2023) - "Using H3B-6527, a selective FGFR4 inhibitor, we found a decrease of NRF2 in our in vitro and in vivo model after infection with H pylori... These findings demonstrated a novel functional role of FGFR4 in promoting gastric tumorigenesis via activation of the NRF2 antioxidant response. FGFR4 inhibitors represent a potential therapeutic strategy that calls for additional investigations in patients with gastric cancer."

Gastric Cancer • Gastrointestinal Cancer • Infectious Disease • Oncology • Solid Tumor • FGF19 • FGFR4 • KEAP1 • STAT3 • TFF1

Helicobacter pylori-induced FGFR4 mediates nuclear accumulation of NRF2 in gastric tumorigenesis (AACR 2023) - "We observed a reduction in NRF2 in our in vitro and in vivo models using H3B-6527, a specific FGFR4 inhibitor... These findings revealed that FGFR4 has a unique functional role in promoting gastric carcinogenesis by mediating accumulation and activation of the NRF2 antioxidant response. The use of FGFR4 inhibitors is a viable treatment option that warrants further research in patients with gastric cancer."

Gastric Cancer • Gastrointestinal Cancer • Oncology • Solid Tumor • FGF19 • FGFR4 • HMOX1 • KEAP1 • TFF1

Mechanisms of resistance toward FGFR4 inhibition in hepatocellular carcinoma (AACR-NCI-EORTC 2022) - "Materials and We established resistant cell lines following long-term exposure of Huh7 with BLU-554...In addition, the cells were also resistant to other FGFR4 inhibitors including FGF-401, H3B-6527 and erdafitinib... These data suggest the bypass activation of other RTK may contribute to acquired resistance of FGFR4 inhibition and potential combination strategy to overcome resistance. No"

Gastrointestinal Cancer • Hepatocellular Cancer • Oncology • Solid Tumor • FGF19 • FGFR4

Strategies to inhibit FGFR4 V550L-driven rhabdomyosarcoma. (PubMed, Br J Cancer) - "Our results pave the way for precision medicine approaches against FGFR4 V550L-driven RMS."

Journal • Oncology • Pediatrics • Rhabdomyosarcoma • Sarcoma • Solid Tumor • FGFR4 • PAX3

Combined inhibition of FGFR4 and VEGFR signaling enhances efficacy in FGF19 driven hepatocellular carcinoma. (PubMed, Am J Cancer Res) - "Using HCC relevant xenograft and PDX models, we show that Lenvatinib, an approved multi-kinase inhibitor, strongly enhanced the efficacy of FGFR4 inhibitor H3B-6527...This cell non-autonomous mode of action was further supported by strong in vivo combination efficacy with the mouse specific VEGFR2 antibody, DC101, which cannot cell-autonomously inhibit pathways in human xenografts. Mechanistic studies showed that the combination resulted in enhanced efficacy through increased anti-angiogenic and anti-tumorigenic activities. Overall, our results indicate that this combination can be a highly effective treatment option for FGF19 driven HCC patients, and provide preclinical validation of a combination that can be readily tested in the clinical setting."

Journal • Gastrointestinal Cancer • Hepatocellular Cancer • Oncology • Solid Tumor • FGF19 • FGFR4

H3B-6527-G000-101: Phase 1 Study to Evaluate the Safety, Pharmacokinetics and Pharmacodynamics of H3B-6527 in Participants With Advanced Hepatocellular Carcinoma (clinicaltrials.gov) - P1 | N=128 | Completed | Sponsor: H3 Biomedicine Inc. | Active, not recruiting ➔ Completed

Trial completion • Gastrointestinal Cancer • Hepatocellular Cancer • Hepatology • Liver Cancer • Oncology • Solid Tumor

[VIRTUAL] Indoxyl Sulfate Induces Cardiomyocyte Hypertrophy via FGF23-FGFR4 Signaling Pathway (KIDNEY WEEK 2021) - "Methods To induce LVH, 8-week-old-male C57BL/6J mice were fed high phosphorus diet after heminephrectomy for the induction of FGF23 and administrated with continuous subcutaneous dose of 100mg/kg IS per day for 4 weeks, and half of them were treated with continuous intraperitoneal administration dose of 7.5 mg/kg H3B-6527 (H3B), a fibroblast growth factor receptor 4 (FGFR4)- inhibitor...The mRNA levels of β-myosin heavy chain (βMHC), α-smooth muscle actin (αSMA), brain natriuretic peptide (BNP), polypeptide N-acetylgalactosaminyltransferase 3 (Galnt3), and FGF23 were significantly up-regulated (p < 0.05), but collagen I was not. Conclusion IS increased intact FGF23 protein expression and activated FGF23-FGFR4 signaling in cardiomyocyte, leading to LVH, and FGFR4 inhibition suppressed IS-induced LVH."

Chronic Kidney Disease • Nephrology • Renal Disease • FGF23 • FGFR4 • NPPB

H3B-6527-G000-101: Phase 1 Study to Evaluate the Safety, Pharmacokinetics and Pharmacodynamics of H3B-6527 in Participants With Advanced Hepatocellular Carcinoma (clinicaltrials.gov) - P1; N=128; Active, not recruiting; Sponsor: H3 Biomedicine Inc.; Trial completion date: Sep 2021 ➔ Dec 2021; Trial primary completion date: Feb 2021 ➔ Dec 2021

Clinical • Trial completion date • Trial primary completion date • Gastrointestinal Cancer • Hepatocellular Cancer • Hepatology • Liver Cancer • Oncology • Solid Tumor

A Phase I study of H3B-6527 in hepatocellular carcinoma (HCC) or intrahepatic cholangiocarcinoma (ICC) patients (pts). (ASCO 2019) - P1; "H3B-6527 is well tolerated and demonstrates early signs of clinical activity. Dose expansion on QD schedule and exploration of BID (twice daily) schedule is ongoing. Clinical trial information: NCT02834780"

Clinical • P1 data

[VIRTUAL] Phase I study of H3B-6527 in hepatocellular carcinoma (HCC) or intrahepatic cholangiocarcinoma (ICC). (ASCO 2021) - P1 | "H3B-6527 was well tolerated and demonstrated a favorable toxicity and safety profile and encouraging clinical activity in heavily pretreated HCC patients . Final trial results will be presented at conference."

P1 data • Biliary Cancer • Cholangiocarcinoma • Fatigue • Gastrointestinal Cancer • Hepatocellular Cancer • Oncology • Solid Tumor • FGF19 • FGFR4

H3 Biomedicine Announces Presentation of Four Abstracts at the 2021 American Society of Clinical Oncology (ASCO) Annual Meeting (Businesswire) - "H3 Biomedicine Inc....today announced the presentation of four posters providing updated investigational data on its H3B-6545 clinical program for breast cancer and its H3B-6527 clinical program for hepatocellular carcinoma at the 2021 American Society of Clinical Oncology (ASCO) Annual Meeting, being held virtually June 4–8, 2021....Updated results from both studies will be presented at ASCO."

Clinical data • P1 data • P1/2 data • Breast Cancer • Gastrointestinal Cancer • Hepatocellular Cancer • Oncology

FGF19/FGFR4 signaling axis confines and switches the role of melatonin in head and neck cancer metastasis. (PubMed, J Exp Clin Cancer Res) - "Our study gains novel mechanistic insights into melatonin-mediated modulation of FGF19/FGFR4 signaling in HNSCC, demonstrating that activating this molecular node confines the role of melatonin in suppressing metastasis and even triggers the switch of its function from anti-metastasis to metastasis promotion. The blockade of FGF19/FGFR4 signaling would have great potential in improving the efficacy of melatonin supplements in cancer treatment."

Journal • Head and Neck Cancer • Oncology • Oral Cancer • Solid Tumor • Squamous Cell Carcinoma • Squamous Cell Carcinoma of Head and Neck • Tongue Carcinoma • ATF4 • FGF19 • FGFR4 • PERK • VIM

Phase 1 Study to Evaluate the Safety, Pharmacokinetics and Pharmacodynamics of H3B-6527 in Participants With Advanced Hepatocellular Carcinoma (clinicaltrials.gov) - P1; N=128; Active, not recruiting; Sponsor: H3 Biomedicine Inc.; Recruiting ➔ Active, not recruiting; Trial completion date: Dec 2020 ➔ Sep 2021; Trial primary completion date: Jun 2020 ➔ Feb 2021

Clinical • Enrollment closed • Trial completion date • Trial primary completion date • Gastrointestinal Cancer • Hepatocellular Cancer • Hepatology • Liver Cancer • Oncology • Solid Tumor

H3B-6527: Recommended P2 dose in P1/2 trial (NCT02834780) in HCC in mid-2018 (36th Annual J.P. Morgan Healthcare Conference, H3 Biomedicine)

Trial status • Hepatocellular Cancer • Oncology

H3B-6527: Recommended P2 dose in P1/2 trial (NCT02834780) in HCC in mid-2018 (36th Annual J.P. Morgan Healthcare Conference, H3 Biomedicine)

Trial status • Hepatocellular Cancer • Oncology

H3B-6527: "FGFR4 target engagement confirmed in patients from first 2 cohorts: Increases in plasma FGF19 observed in 3/3 patients at 300 mg dose level and 1/2 patients at the 600 mg dose level" (36th Annual J.P. Morgan Healthcare Conference, H3 Biomedicine)

P1 data • Hepatocellular Cancer • Oncology

H3B-6527: "FGFR4 target engagement confirmed in patients from first 2 cohorts: Increases in plasma FGF19 observed in 3/3 patients at 300 mg dose level and 1/2 patients at the 600 mg dose level" (36th Annual J.P. Morgan Healthcare Conference, H3 Biomedicine)

P1 data • Hepatocellular Cancer • Oncology