Delving into the Latest Updates on Fisogatinib with Synapse

Overview

Basic Info

Drug Type

Small molecule drug

Synonyms

Fisogatinib (USAN/INN), BLU-554, CS 3008

+ [1]

Target

FGFR4

Mechanism

FGFR4 antagonists(Fibroblast growth factor receptor 4 antagonists)

Therapeutic Areas

NeoplasmsDigestive System Disorders

Active Indication

Hepatocellular CarcinomaColorectal Cancer

Inactive Indication

Cholangiocarcinoma

Originator Organization

Blueprint Medicines Corp.

Active Organization

Cornerstone Pharmaceutical Co., Ltd

Blueprint Medicines Corp.

People's Liberation Army Air Force Military Medical University

Inactive Organization-

Drug Highest PhasePhase 1

First Approval Date-

Regulation-

Structure

Molecular FormulaC24H24Cl2N4O4

InChIKeyMGZKYOAQVGSSGC-DLBZAZTESA-N

CAS Registry1707289-21-1

Liver metastasis is the main cause of death in patients with colorectal cancer (CRC); thus, necessitating effective biomarkers and therapeutic targets for colorectal cancer liver metastasis (CRLM). Fibroblast growth factor 19 (FGF19) is a protumorigenic gene in numerous human malignancies. In this study, it is shown that FGF19 plays an indispensable role in CRLM. FGF19 expression and secretion are markedly correlated with liver metastasis and lower overall survival rates of patients with CRC. An in vivo metastasis model shows that FGF19 overexpression confers stronger liver-metastatic potential in CRC cells. Mechanistically, FGF19 exerts an immunomodulatory function that creates an environment conducive for metastasis in CRLM. FGF19 mediates the polarization of hepatic stellate cells to inflammatory cancer-associated fibroblasts (iCAFs) by activating the autocrine effect of IL-1α via the FGFR4-JAK2-STAT3 pathway. FGF19-induced iCAFs promote neutrophil infiltration and mediate neutrophil extracellular trap (NET) formation in liver metastatic niches via the production of complement C5a and IL-1β, which in turn accelerates the liver colonization of CRC cells. Importantly, targeting FGF19 signaling with fisogatinib efficiently suppresses FGF19-induced liver metastasis in a mouse model. In summary, this study describes the mechanism by which FGF19 regulates CRLM, thereby providing a novel target for CRLM intervention.

01 Jul 2023·Journal of hepatology

FGF19/FGFR4-mediated elevation of ETV4 facilitates hepatocellular carcinoma metastasis by upregulating PD-L1 and CCL2

Article

Author: Liu, Danfei ; Xia, Limin ; Sun, Mengyu ; Ji, Xiaoyu ; Chen, Xiaoping ; Zhang, Bixiang ; Wang, Yijun ; Liu, Bifeng ; Lin, Zhuoying ; Zhang, Zerui ; Liang, Huifang ; Xie, Meng ; Feng, Yangyang ; Huang, Wenjie ; Li, Yiwei ; Luo, Xiangyuan

BACKGROUND & AIMS:

Metastasis remains the major reason for the high mortality of patients with hepatocellular carcinoma (HCC). This study was designed to investigate the role of E-twenty-six-specific sequence variant 4 (ETV4) in promoting HCC metastasis and to explore a new combination therapy strategy for ETV4-mediated HCC metastasis.

METHODS:

PLC/PRF/5, MHCC97H, Hepa1-6, and H22 cells were used to establish orthotopic HCC models. Clodronate liposomes were used to clear macrophages in C57BL/6 mice. Gr-1 monoclonal antibody was used to clear myeloid-derived suppressor cells (MDSCs) in C57BL/6 mice. Flow cytometry and immunofluorescence were used to detect the changes of key immune cells in the tumour microenvironment.

RESULTS:

ETV4 expression was positively related to higher tumour-node-metastasis (TNM) stage, poor tumour differentiation, microvascular invasion, and poor prognosis in human HCC. Overexpression of ETV4 in HCC cells transactivated PD-L1 and CCL2 expression, which increased tumour-associated macrophage (TAM) and MDSC infiltration and inhibited CD8⁺ T-cell accumulation. Knockdown of CCL2 by lentivirus or CCR2 inhibitor CCX872 treatment impaired ETV4-induced TAM and MDSC infiltration and HCC metastasis. Furthermore, FGF19/FGFR4 and HGF/c-MET jointly upregulated ETV4 expression through the ERK1/2 pathway. Additionally, ETV4 upregulated FGFR4 expression, and downregulation of FGFR4 decreased ETV4-enhanced HCC metastasis, which created a FGF19-ETV4-FGFR4 positive feedback loop. Finally, anti-PD-L1 combined with FGFR4 inhibitor BLU-554 or MAPK inhibitor trametinib prominently inhibited FGF19-ETV4 signalling-induced HCC metastasis.

CONCLUSIONS:

ETV4 is a prognostic biomarker, and anti-PD-L1 combined with FGFR4 inhibitor BLU-554 or MAPK inhibitor trametinib may be effective strategies to inhibit HCC metastasis.

IMPACT AND IMPLICATIONS:

Here, we reported that ETV4 increased PD-L1 and chemokine CCL2 expression in HCC cells, which resulted in TAM and MDSC accumulation and CD8⁺ T-cell inhibition to facilitate HCC metastasis. More importantly, we found that anti-PD-L1 combined with FGFR4 inhibitor BLU-554 or MAPK inhibitor trametinib markedly inhibited FGF19-ETV4 signalling-mediated HCC metastasis. This preclinical study will provide a theoretical basis for the development of new combination immunotherapy strategies for patients with HCC.

01 Feb 2023·Investigational new drugs

A phase Ib/II study of BLU-554, a fibroblast growth factor receptor 4 inhibitor in combination with CS1001, an anti-PD-L1, in patients with locally advanced or metastatic hepatocellular carcinoma

Article

Author: Liu, Baorui ; Xu, Chen ; Shen, Jie ; Zhu, Sihui ; Zhou, Mingzhen

OBJECTIVE:

Targeted therapy combined with immunotherapy has become the main treatment option for hepatocellular carcinoma (HCC). This trial assessed the safety and efficacy of fibroblast growth factor receptor 4 inhibitor (BLU-554) in combination with the anti-PD-L1 monoclonal antibody (CS1001) in patients with locally advanced or metastatic HCC.

PATIENTS AND METHODS:

This Phase Ib/II trial enrolled patients with locally advanced or metastatic HCC who were FGF19-positive. The patients were intravenously administered with CS1001 (1200 mg) every three weeks and orally administered with BLU-554 (600 mg) daily. The primary endpoint was objective response rate (ORR), as assessed according to RECISTv1.1.

RESULTS:

Four patients were treated with BLU-554 combined with CS1001. The trial revealed a 50% ORR and 100% DCR. The main adverse reactions that were attributed to BLU-554 in combination with CS1001 were diarrhoea, liver function impairments and skin rashes. Only one patient had immune-related adverse reactions.

CONCLUSION:

Preliminary data showed that BLU-554 in combination with CS1001 is safe and effective for treatment of patients with locally advanced or metastatic HCC.

100 Deals associated with Fisogatinib

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External Link

KEGG	Wiki	ATC	Drug Bank
D11737	-	-	DB16167

R&D Status

10 top R&D records.

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Indication	Highest Phase	Country/Location	Organization	Date
Hepatocellular Carcinoma	Phase 2	CN	Cornerstone Pharmaceutical Co., Ltd	27 Nov 2019
Cholangiocarcinoma	Phase 1	US	Blueprint Medicines Corp.	-
Colorectal Cancer	Preclinical	CN	People's Liberation Army Air Force Military Medical University	22 Feb 2023

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Clinical Result

Indication

Phase

Evaluation

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Study	Phase	Population	Analyzed Enrollment	Group	Results	Evaluation	Publication Date


NCT02508467 (Pubmed) Manual	Phase 1	FGF19 positive Neoplasms FGF19 Positive	115	Fisogatinib (FGF19-positive)	lomqxitpmn(xheewrklur) = most adverse events were manageable, grade 1/2 gastrointestinal events, primarily diarrhea, nausea, and vomiting. oczbydxfbe (qsgaadpadr )	Positive	01 Dec 2019
				Fisogatinib (FGF19-negative)