Delving into the Latest Updates on SYHA-1813 with Synapse

Overview

Basic Info

Drug Type

Small molecule drug

Synonyms

Target

Mechanism

CSF-1R antagonists(Colony stimulating factor 1 receptor antagonists), VEGFR antagonists(Vascular endothelial growth factor receptor antagonists)

Therapeutic Areas

NeoplasmsNervous System DiseasesDigestive System Disorders+ [5]

Active Indication

Solid tumorGliosarcomaBrain metastases+ [9]

Inactive Indication-

Originator Organization

Shanghai Runshi Pharmaceutical Technology Co., Ltd.

Active Organization

Shanghai Runshi Pharmaceutical Technology Co., Ltd.

Shanghai Institute of Materia Medica Chinese Academy of SciCSPC Megalith Biopharmaceutial Co., Ltd.

Inactive Organization-

Drug Highest PhasePhase 2

First Approval Date-

Regulation-

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This is an open-label, multi-center, multi-cohort, phase Ib/II clinical trial, divided into 8 cohorts according to tumor types. Cohorts 1-4 are SYHA1813 combined with different regimens, including safety run-in stage and cohort expansion stage. Cohorts 5-8 are SYHA1813 monotherapy and only include the expansion cohorts. The primary objective was to evaluate the safety and efficacy of SYHA1813 single agent or in combination with different regimens in unresectable locally advanced or metastatic solid tumors.

Start Date13 Nov 2024

Sponsor / Collaborator

Shanghai Runshi Pharmaceutical Technology Co., Ltd.

CTR20240525 / CompletedPhase 1

[14C]SYHA1813在中国成年健康受试者体内的物质平衡临床试验

[Translation] [14C] SYHA1813 substance balance clinical trial in Chinese healthy adult subjects

主要目的：1.定量分析男性健康受试者口服[14C]SYHA1813后排泄物中的总放射性，获得人体放射性回收率数据和主要排泄途径；2.考察男性健康受试者口服[14C]SYHA1813后在全血和血浆中的分配情况及血浆和全血（如适用）中总放射性的药代动力学特征；3.鉴定男性健康受试者口服[14C]SYHA1813后人体内的主要代谢产物，确定主要的生物转化途径，考察血浆中是否存在接近或高于药物总暴露量10%的代谢产物。次要目的：1.采用已验证的LC-MS/MS法定量分析血浆中SYHA1813和代谢产物M1及其他主要代谢产物（如适用）的浓度，获得SYHA1813和代谢产物M1及其他主要代谢产物（如适用）的药代动力学参数；2.评价[14C]SYHA1813单次给药后男性健康受试者的安全性。

[Translation]

Main objectives: 1. Quantitative analysis of the total radioactivity in the excreta of male healthy subjects after oral administration of [14C]SYHA1813, and obtaining the data on the recovery rate of human radioactivity and the main excretion pathway; 2. Investigate the distribution of [14C]SYHA1813 in whole blood and plasma and the pharmacokinetic characteristics of the total radioactivity in plasma and whole blood (if applicable) after oral administration of [14C]SYHA1813 to male healthy subjects; 3. Identify the main metabolites in the human body after oral administration of [14C]SYHA1813 to male healthy subjects, determine the main biotransformation pathways, and investigate whether there are metabolites in plasma that are close to or higher than 10% of the total drug exposure. Secondary objectives: 1. Quantitative analysis of the concentrations of SYHA1813 and metabolite M1 and other major metabolites (if applicable) in plasma using a validated LC-MS/MS method to obtain the pharmacokinetic parameters of SYHA1813 and metabolite M1 and other major metabolites (if applicable); 2. Evaluate the safety of male healthy subjects after a single dose of [14C]SYHA1813.

Start Date07 Apr 2024

Sponsor / Collaborator

Shanghai Runshi Pharmaceutical Technology Co., Ltd.

NCT06157918 / CompletedPhase 1

A Single-Center, Randomized, Open-label, Single-dose, 3-Sequence, 3-Period Rossover Design to Evaluate the Relative Bioavailability and Food Effect of SYHA1813 Oral Solution in Healthy Participants

This is a three-period crossover phase I study designed to evaluate the relative bioavailability, food effect, safety and tolerability of SYHA1813 oral solution in healthy participants.

Start Date20 Dec 2023

Sponsor / Collaborator

Shanghai Runshi Pharmaceutical Technology Co., Ltd.

100 Clinical Results associated with SYHA-1813

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100 Translational Medicine associated with SYHA-1813

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100 Patents (Medical) associated with SYHA-1813

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3

Literatures (Medical) associated with SYHA-1813

01 Dec 2023·Acta Pharmaceutica Sinica B

Preclinical and early clinical studies of a novel compound SYHA1813 that efficiently crosses the blood–brain barrier and exhibits potent activity against glioblastoma

Article

Author: Duan, Wenhu ; Kang, Zhuang ; Xie, Hua ; Feng, Fang ; Ding, Jian ; Li, Yan ; Zhan, Zhengsheng ; Su, Yi ; Shen, Yanyan ; Yao, Shanyan ; Wang, Caixia ; Zhang, Mengge ; Li, Mengyuan ; Liu, Yingqiang ; Sun, Yiming ; Zhang, Tao ; Lv, Yongcong ; Li, Wenbin ; Yang, Hanyu ; Tong, Linjiang ; Li, Shenglan ; Xue, Yaping ; Song, Peiran ; Yang, Xinying ; Geng, Meiyu ; Chen, Yi

Glioblastoma (GBM) is the most common and aggressive malignant brain tumor in adults and is poorly controlled. Previous studies have shown that both macrophages and angiogenesis play significant roles in GBM progression, and co-targeting of CSF1R and VEGFR is likely to be an effective strategy for GBM treatment. Therefore, this study developed a novel and selective inhibitor of CSF1R and VEGFR, SYHA1813, possessing potent antitumor activity against GBM. SYHA1813 inhibited VEGFR and CSF1R kinase activities with high potency and selectivity and thus blocked the cell viability of HUVECs and macrophages and exhibited anti-angiogenetic effects both in vitro and in vivo. SYHA1813 also displayed potent in vivo antitumor activity against GBM in immune-competent and immune-deficient mouse models, including temozolomide (TMZ) insensitive tumors. Notably, SYHA1813 could penetrate the blood-brain barrier (BBB) and prolong the survival time of mice bearing intracranial GBM xenografts. Moreover, SYHA1813 treatment resulted in a synergistic antitumor efficacy in combination with the PD-1 antibody. As a clinical proof of concept, SYHA1813 achieved confirmed responses in patients with recurrent GBM in an ongoing first-in-human phase I trial. The data of this study support the rationale for an ongoing phase I clinical study (ChiCTR2100045380).

01 Apr 2023·Investigational New Drugs

A phase I dose-escalation study of SYHA1813, a VEGFR and CSF1R inhibitor, in patients with recurrent High-Grade Gliomas or Advanced Solid Tumors

Article

Author: Li, Shenglan ; Kang, Zhuang ; Qiu, Jingbo ; Mao, Ying ; Zhang, Jing ; Lei, Ting ; Yang, Yang ; Li, Wenbin ; Su, Yangzhi ; Lin, Yi ; Wang, Haidan ; Li, Yongsheng

AbstractSYHA1813 is a potent multikinase inhibitor that targets vascular endothelial growth factor receptors (VEGFRs)/colony-stimulating factor 1 receptor (CSF1R). This study aimed to evaluate the safety, pharmacokinetics (PK), and antitumor activity of escalating doses of SYHA1813 in patients with recurrent high-grade gliomas (HGGs) or advanced solid tumors. This study adopted a combination of accelerated titration and a 3 + 3 design for dose escalation, with a starting dose of 5 mg once daily. The dose escalation continued at successive dose levels until the maximum tolerated dose (MTD) was determined. A total of 14 patients were enrolled and treated, including 13 with WHO grade III or IV gliomas and 1 with colorectal cancer. Two patients experienced dose-limiting toxicities (grade 4 hypertension and grade 3 mucositis oral) at 30 mg SYHA1813. The MTD was defined as 15 mg once daily. Hypertension (n = 6, 42.9%) was the most frequent treatment-related adverse event. Among evaluable patients (n = 10), 2 (20%) patients achieved partial response, and 7 (70%) had stable disease. The exposure increased with increasing doses within the studied dose range of 5 to 30 mg. Biomarker assessments demonstrated significant reductions in the levels of soluble VEGFR2 (P = .0023) and increases in the levels of VEGFA (P = .0092) and placental growth factor (P = .0484). The toxicities of SYHA1813 were manageable, and encouraging antitumor efficacy was observed in patients with recurrent malignant glioma. This study is registered with the Chinese Clinical Trial Registry (www.chictr.org.cn/index.aspx; identifier ChiCTR2100045380).

Acta Pharmacologica Sinica

Discovery of a novel BTK inhibitor S-016 and identification of a new strategy for the treatment of lymphomas including BTK inhibitor-resistant lymphomas

Article

Author: Huang, Yu-Qing ; Duan, Wen-Hu ; Song, Pei-Ran ; Zhang, Tao ; Tang, Hao-Tian ; Chen, Yi ; Wan, Zhi-Peng ; Tong, Lin-Jiang ; Xue, Yu ; Feng, Fang ; Huang, Ge-Ge ; Song, Zi-Lan ; Shi, Wen-Hao ; Xie, Hua ; Ding, Jian ; Fang, Yan ; Li, Yan ; Zhang, Ao ; Zhan, Zheng-Sheng

Bruton's tyrosine kinase (BTK) has emerged as a therapeutic target for B-cell malignancies, which is substantiated by the efficacy of various irreversible or reversible BTK inhibitors. However, on-target BTK mutations facilitating evasion from BTK inhibition lead to resistance that limits the therapeutic efficacy of BTK inhibitors. In this study we employed structure-based drug design strategies based on established BTK inhibitors and yielded a series of BTK targeting compounds. Among them, compound S-016 bearing a unique tricyclic structure exhibited potent BTK kinase inhibitory activity with an IC₅₀ value of 0.5 nM, comparable to a commercially available BTK inhibitor ibrutinib (IC₅₀ = 0.4 nM). S-016, as a novel irreversible BTK inhibitor, displayed superior kinase selectivity compared to ibrutinib and significant therapeutic effects against B-cell lymphoma both in vitro and in vivo. Furthermore, we generated BTK inhibitor-resistant lymphoma cells harboring BTK C481F or A428D to explore strategies for overcoming resistance. Co-culture of these DLBCL cells with M0 macrophages led to the polarization of M0 macrophages toward the M2 phenotype, a process known to support tumor progression. Intriguingly, we demonstrated that SYHA1813, a compound targeting both VEGFR and CSF1R, effectively reshaped the tumor microenvironment (TME) and significantly overcame the acquired resistance to BTK inhibitors in both BTK-mutated and wild-type BTK DLBCL models by inhibiting angiogenesis and modulating macrophage polarization. Overall, this study not only promotes the development of new BTK inhibitors but also offers innovative treatment strategies for B-cell lymphomas, including those with BTK mutations.

100 Deals associated with SYHA-1813

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R&D Status

10 top R&D records.

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Indication	Highest Phase	Country/Location	Organization	Date
Solid tumor	Phase 2	-	CSPC Megalith Biopharmaceutial Co., Ltd.	-
Brain metastases	Phase 1	CN	Shanghai Runshi Pharmaceutical Technology Co., Ltd.	26 May 2021
Colorectal Cancer	Phase 1	CN	Shanghai Runshi Pharmaceutical Technology Co., Ltd.	26 May 2021
Giant Cell Tumor of Tendon Sheath	Phase 1	CN	Shanghai Runshi Pharmaceutical Technology Co., Ltd.	26 May 2021
High grade glioma	Phase 1	CN	Shanghai Runshi Pharmaceutical Technology Co., Ltd.	26 May 2021
Kidney Neoplasms	Phase 1	CN	Shanghai Runshi Pharmaceutical Technology Co., Ltd.	26 May 2021
Lung Cancer	Phase 1	CN	Shanghai Runshi Pharmaceutical Technology Co., Ltd.	26 May 2021
Stomach Cancer	Phase 1	CN	Shanghai Runshi Pharmaceutical Technology Co., Ltd.	26 May 2021
Thyroid Cancer	Phase 1	CN	Shanghai Runshi Pharmaceutical Technology Co., Ltd.	26 May 2021

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Clinical Result

Indication

Phase

Evaluation

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Study	Phase	Population	Analyzed Enrollment	Group	Results	Evaluation	Publication Date


ChiCTR2100045380 (SYHA1813, ESMO2024)	Phase 1	Recurrent Glioblastoma	38	SYHA1813 10mg	rfdtrhpowg(lbneqxhdxl) = TRAEs ≥ grade 3 occurred in more than 2 patients were hypertension (28.9%) and decreased platelet count (10.5%) skfszntgby (joafgpgave ) View more	Positive	15 Sep 2024
ChiCTR2100045380 (SYHA1813, ESMO2024)	Phase 1	Recurrent Glioblastoma	38	SYHA1813 15mg		Positive	15 Sep 2024
ChiCTR2100045380 (ESMO2023) Manual	Phase 1	Meningioma	11	SYHA1813 15mg or 20mg	(ibpofwziol) = fwqkndchde qrbrlqdxix (dtsoexmxpk, 16.8 - 76.6) View more	Positive	21 Oct 2023
ChiCTR2100045380 (Pubmed)	Phase 1	HR-positive/HER2-low Solid Tumors \| Recurrent Malignant Glioma	14	SYHA1813	(yevlgpzpnr) = lokrdzhmni wukyjqimre (eemshugosn ) View more	-	08 Mar 2023
ChiCTR2100045380 (ESMO2022) Manual	Phase 1	HR-positive/HER2-low Solid Tumors \| Recurrent Malignant Glioma	14	SYHA1813 5 mg/15 mg/30 mg	(aigxajbzdz) = The dose-limiting toxicities (DLTs) were grade (G) 4 hypertension (n = 1) and G3 mucositis oral (n =1) at 30 mg. zzsjshslzy (udoxywrbmz ) View more	Positive	10 Sep 2022