This study will be conducted to determine the effect of food on the relative bioavailability of H3B-6527 following administration of a H3B-6527 capsule with and without a meal.

Start Date27 Dec 2017

Sponsor / Collaborator

Eisai, Inc.

[+1]

NCT02834780 / CompletedPhase 1

An Open-Label Multicenter Phase 1 Study to Evaluate the Safety, Pharmacokinetics and Pharmacodynamics of H3B-6527 in Subjects With Advanced Hepatocellular Carcinoma

The purpose of this study is to determine the maximum tolerated dose (MTD) and recommended Phase 2 dose (RP2D) of H3B-6527, and to assess the safety, tolerability and pharmacokinetics of H3B-6527.

Start Date28 Dec 2016

Sponsor / Collaborator

H3 Biomedicine, Inc.

[+1]

100 Clinical Results associated with H3B-6527

100 Translational Medicine associated with H3B-6527

100 Patents (Medical) associated with H3B-6527

Literatures (Medical) associated with H3B-6527

01 Feb 2024·Redox biology

Fibroblast growth factor receptor-4 mediates activation of Nuclear Factor Erythroid 2-Related Factor-2 in gastric tumorigenesis

Article

Author: Zhang, Xing ; Cao, Longlong ; McDonald, Oliver G ; El-Gazzaz, Omar ; Chen, Zheng ; Bhat, Nadeem ; Xu, Zekuan ; Genoula, Melanie ; Maacha, Selma ; El-Rifai, Wael ; Soutto, Mohammed ; Zhu, Shoumin ; Chen, Xi Steven ; Lu, Heng ; Peng, Dunfa

Helicobacter pylori (H. pylori) is the leading risk factor for gastric carcinogenesis. Fibroblast growth factor receptor 4 (FGFR4) is a member of transmembrane tyrosine kinase receptors that are activated in cancer. We investigated the role of FGFR4 in regulating the cellular response to H. pylori infection in gastric cancer. High levels of oxidative stress signature and FGFR4 expression were detected in gastric cancer samples. Gene set enrichment analysis (GSEA) demonstrated enrichment of NRF2 signature in samples with high FGFR4 levels. H. pylori infection induced reactive oxygen species (ROS) with a cellular response manifested by an increase in FGFR4 with accumulation and nuclear localization NRF2. Knocking down FGFR4 significantly reduced NRF2 protein and transcription activity levels, leading to higher levels of ROS and DNA damage following H. pylori infection. We confirmed the induction of FGFR4 and NRF2 levels using mouse models following infection with a mouse-adapted H. pyloristrain. 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.

23 Nov 2022·British journal of cancer

Strategies to inhibit FGFR4 V550L-driven rhabdomyosarcoma

Article

Author: Szybowska, Patrycja ; Kostas, Michal ; Øy, Geir F ; Mælandsmo, Gunhild M ; Wesche, Jørgen ; Fletcher, Jonathan A ; Fiorito, Elisa ; Wiedlocha, Antoni ; Meza-Zepeda, Leonardo A ; Nakken, Sigve ; Singh, Sachin ; Haugsten, Ellen M

Abstract:

Background:

Rhabdomyosarcoma (RMS) is a paediatric cancer driven either by fusion proteins (e.g., PAX3-FOXO1) or by mutations in key signalling molecules (e.g., RAS or FGFR4). Despite the latter providing opportunities for precision medicine approaches in RMS, there are currently no such treatments implemented in the clinic.

Methods:

We evaluated biologic properties and targeting strategies for the FGFR4 V550L activating mutation in RMS559 cells, which have a high allelic fraction of this mutation and are oncogenically dependent on FGFR4 signalling. Signalling and trafficking of FGFR4 V550L were characterised by confocal microscopy and proteomics. Drug effects were determined by live-cell imaging, MTS assay, and in a mouse model.

Results:

Among recently developed FGFR4-specific inhibitors, FGF401 inhibited FGFR4 V550L-dependent signalling and cell proliferation at low nanomolar concentrations. Two other FGFR4 inhibitors, BLU9931 and H3B6527, lacked potent activity against FGFR4 V550L. Alternate targeting strategies were identified by RMS559 phosphoproteomic analyses, demonstrating that RAS/MAPK and PI3K/AKT are essential druggable pathways downstream of FGFR4 V550L. Furthermore, we found that FGFR4 V550L is HSP90-dependent, and HSP90 inhibitors efficiently impeded RMS559 proliferation. In a RMS559 mouse xenograft model, the pan-FGFR inhibitor, LY2874455, did not efficiently inhibit growth, whereas FGF401 potently abrogated growth.

Conclusions:

Our results pave the way for precision medicine approaches against FGFR4 V550L-driven RMS.

02 Apr 2020·Xenobiotica; the fate of foreign compounds in biological systems

Correlation of thein vitrobiotransformation of H3B-6527 in dog and human hepatocytes with thein vivometabolic profile of¹⁴C-H3B-6527 in a dog mass balance study

Article

Author: Schindler, J. ; Nix, D. ; Smith, S. ; Smith, P. G. ; Rioux, N. ; Colombo, F. ; Lai, G. W.

1. H3B-6527 is an orally available covalent small molecule inhibitor of FGFR4 undergoing evaluation in adults with hepatocellular carcinoma. Absorption, metabolism, transport and elimination of H3B-6527 were investigated in vitro and in a ¹⁴C-H3B-6527 beagle dog mass balance study.2. Following intravenous dosing in dogs, unchanged ¹⁴C-H3B-6527 represents only 1.6% of the total dose in excreta. The low amount of radioactivity in the dog urine (4.9% of the administered dose), suggests that renal elimination is a minor pathway of clearance for H3B-6527. A majority of the radioactivity was observed in the feces up to 5 days after dose administration, suggesting that drug-related material was secreted in the bile, and that H3B-6527 clearance was mostly driven by metabolism.3. In vitro, H3B-6527 is a substrate of GSTs, CYP3A and P-glycoprotein.4. The major pathways of metabolism were similar in human and dog hepatocytes, and occurred via glutathione (GSH) conjugations and sequential hydrolysis, N-deethylation and hydroxylation.5. The metabolic profile of H3B-6527 was qualitatively similar in dog hepatocytes and plasma/excreta.

News (Medical) associated with H3B-6527

30 Apr 2021

·www.globenewswire.com

Advanced Liver Cancer Drug Pipeline Prospers with an Inrush

Los Angeles, USA, April 29, 2021 (GLOBE NEWSWIRE) -- Advanced Liver Cancer Drug Pipeline Prospers with an Inrush of Pharma Companies and Emerging Novel Therapies A comprehensive analysis of 50+ key companies and 50+ emerging therapies enriching the Advanced Liver Cancer Pipeline Landscape. DelveInsight’s ‘Advanced Liver Cancer Pipeline Insights’ report provides a holistic view of the pipeline therapies that are under development in pre-clinical as well as clinical stages of development and growth prospects across the Advanced Liver Cancer domain. Some of the key highlights from the Advanced Liver Cancer pipeline report are: In the News Got queries? Want to know more? Request for Sample @ Advanced Liver Cancer Clinical Trial Analysis and Pipeline Insights Advanced Liver Cancer Pipeline Activity: At a Glance Reach out @ Advanced Liver Cancer Pipeline: Novel therapies and emerging technologies Advanced Liver Cancer Pipeline Agent Assessment The Advanced Liver Cancer Pipeline report lays down holistic coverage of active pipeline assets segmented by Stage, Product Type, Route of Administration, Molecule Type, Target, and Indications of various drugs. By Product Type By Stage By Molecule Type By Route of Administration By Mechanism of Action By Targets By Stage and Route of AdministrationBy Stage and Product Type For more information on emerging drugs, visit Advanced Liver Cancer Pipeline: Emerging Therapies and Trends Scope of the Report Coverage: GlobalKey Players: Siranomics, Novartis, Yiviva, Eisai, CAS Lamvac Biotech, Benhealth Biopharmaceutical, Chia Tai Tianqing Pharmaceutical, Surface Oncology, Zai Lab (Shanghai), Can-Fite Biopharma, Suzhou Zelgen Biopharmaceuticals, Innovent Biologics, SignalRX Pharmaceuticals, Carsgen Therapeutics, Shanghai Henlius Biotech, Jiangsu HengRui Medicine, Leap Therapeutics, Eureka Therapeutics, and many more.Key Advanced Liver Cancer Pipeline Therapies: STP 705, PDR001, YIV-906, H3B 6527, Plasmodium Immunotherapy, Activated CIK, AK105 Injection, SRF 388, MGD013, Namodenoson, SHR-1210, ET140203, PLM60, INC280, Donafenib, IBI308, SF1126, CAR-GPC3 T Cells, HLX10, and many more. Have a walkthrough of the report @ Advanced Liver Cancer Emerging Pipeline Key Questions Answered Need to clarify something? Get in touch @ Advanced Liver Cancer Drug Pipeline Insights Table of Contents Visit to know more of what’s covered @ Advanced Liver Cancer Emerging Therapies Other Insightful Reports Liver cancer IncidenceRead about the rising global burden of Liver Cancer. Excessive Daytime Sleepiness MarketGet a comprehensive analysis of epidemiology, pipeline therapies, and kye companies including Bioprojet Pharma/Harmony Biosciences, Axsome Therapeutics, Jazz Pharmaceuticals, BenevolentAI Bio, and many others. Bevacizumab Biosimilars InsightCoverage of about 40+ companies and 40+ marketed and pipeline drugs in Bevacizumab Biosimilars landscape. Pegfilgrastim Biosimilar InsightComprehensive insights about 20+ companies and 20+ marketed and pipeline drugs in Pegfilgrastim Biosimilars landscape. Different Types of Alternative MedicineKnow more about the state of Alternative Medicine in Healthcare and their changing landscape. Adeno-Associated Virus (AAV) Vectors in Gene TherapyAnalysis of emerging therapies and key companies including Pfizer (previously Sangamo Biosciences), NightstaRx Ltd, a Biogen Company, MeiraGTx, Neurocrine Biosciences/ Voyager Therapeutics, Roche (previously Spark Therapeutics)/Pfizer, Sangamo Therapeutics, Freeline Therapeutics, Spark Therapeutics, Asklepios Biopharmaceutical (Actus Therapeutics), Audentes Therapeutics, Roche/Sarepta Therapeutics, Horama S.A., MeiraGTx UK II Ltd, RegenxBio, Sangamo Therapeutics, Amicus Therapeutics, Amicus Therapeutics, and several others. Angelman Syndrome MedicationsA rich analysis of emerging drug therapies and key companies such as GeneTX Biotherapeutics, LLC, Ultragenyx Pharmaceutical Inc, Hoffmann-La Roche, Ovid Therapeutics Inc., Biogen, and others involved in the Angelman Syndrome market. Get in-depth knowledge of the healthcare and pharma world through DelveInsight's Competitive Intelligence Services and Business Solutions. About DelveInsight DelveInsight is a leading Business Consultant and Market Research firm focused exclusively on life sciences. It supports Pharma companies by providing comprehensive end-to-end solutions to improve their performance. Get hassle-free access to all the healthcare and pharma market research reports through our subscription-based platform PharmDelve. For more insights, visit Pharma, Healthcare, and Biotech News

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100 Deals associated with H3B-6527

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R&D Status

10 top R&D records.

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Indication	Highest Phase	Country/Location	Organization	Date
Advanced Hepatocellular Carcinoma	Phase 1	US	H3 Biomedicine, Inc.	28 Dec 2016
Advanced Hepatocellular Carcinoma	Phase 1	US	Eisai, Inc.	28 Dec 2016
Advanced Hepatocellular Carcinoma	Phase 1	BE	H3 Biomedicine, Inc.	28 Dec 2016
Advanced Hepatocellular Carcinoma	Phase 1	BE	Eisai, Inc.	28 Dec 2016
Advanced Hepatocellular Carcinoma	Phase 1	CA	H3 Biomedicine, Inc.	28 Dec 2016
Advanced Hepatocellular Carcinoma	Phase 1	CA	Eisai, Inc.	28 Dec 2016
Advanced Hepatocellular Carcinoma	Phase 1	FR	Eisai, Inc.	28 Dec 2016
Advanced Hepatocellular Carcinoma	Phase 1	FR	H3 Biomedicine, Inc.	28 Dec 2016
Advanced Hepatocellular Carcinoma	Phase 1	IT	H3 Biomedicine, Inc.	28 Dec 2016
Advanced Hepatocellular Carcinoma	Phase 1	IT	Eisai, Inc.	28 Dec 2016

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Study	Phase	Population	Analyzed Enrollment	Group	Results	Evaluation	Publication Date


NCT02834780 (ASCO2021)	Phase 1	Hepatocellular Carcinoma \| Intrahepatic Cholangiocarcinoma	128	H3B-6527 po daily (QD)	bulpnwzaqa(ujuekxxixr) = 45.8% cdzkvqzbbw (ktftwarqbn ) View more	Positive	28 May 2021

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