A Phase I, Single-center, Open Label Clinical Study, to Evaluate the Pharmacokinetic Character of GLS4 Combined With RTV or TAF Alone or GLS4 and RTV and TAF Combination Administration in Healthy Subjects

The purpose of this study is to evaluate the drug-drug-interaction (DDI), pharmacokinetics (PK) and tolerability of GLS4/RTV combined with TAF in healthy subjects.

Start Date10 Jan 2021

Sponsor / Collaborator

Sunshine Lake Pharma Co., Ltd.

CTR20202147

/ CompletedPhase 1

评价甲磺酸莫非赛定/利托那韦两药联合或富马酸丙酚替诺福韦单药与甲磺酸莫非赛定/利托那韦/富马酸丙酚替诺福韦三药联合在健康受试者中的单中心、开放、药代动力学对比试验

[Translation] A single-center, open-label, pharmacokinetic comparative trial evaluating the combination of mofecillin mesylate/ritonavir or tenofovir alafenamide fumarate alone versus the combination of mofecillin mesylate/ritonavir/tenofovir alafenamide fumarate in healthy subjects

评估甲磺酸莫非赛定/利托那韦/富马酸丙酚替诺福韦三药联合与甲磺酸莫非赛定/利托那韦两药联合或富马酸丙酚替诺福韦单药相比药代动力学特征的变化，以及三药联合用药在健康受试者中的耐受性，为后续临床试验给药方案设计提供依据。

[Translation]

To evaluate the changes in pharmacokinetic characteristics of the three-drug combination of mofecillin mesylate/ritonavir/tenofovir alafenamide fumarate compared with the two-drug combination of mofecillin mesylate/ritonavir or tenofovir alafenamide fumarate alone, as well as the tolerability of the three-drug combination in healthy subjects, to provide a basis for the design of dosing regimens in subsequent clinical trials.

Start Date04 Jan 2021

Sponsor / Collaborator

Guangdong South China New Drug Creation Center

[+1]

ChiCTR2000038126

/ RecruitingPhase 1IIT

A Phase I, Single-center, Open Label Clinical Study, to Evaluate the Pharmacokinetic Character of GLS4 Combined With RTV or TAF Alone or GLS4 and RTV and TAF Combination Adimistration in Healthy Subjects

Start Date09 Oct 2020

Sponsor / Collaborator

The First Hospital of Jilin University

100 Clinical Results associated with Morphothiadine Mesylate

100 Translational Medicine associated with Morphothiadine Mesylate

100 Patents (Medical) associated with Morphothiadine Mesylate

Literatures (Medical) associated with Morphothiadine Mesylate

01 Mar 2025·Journal of Infection

Efficacy and safety of GLS4 with entecavir vs entecavir alone in chronic hepatitis B patients: A multicenter clinical trial

Article

Author: Gish, Robert G ; Zhang, Jie ; Zheng, Sujun ; Chen, Yunfu ; Yi, Yongxiang ; Yang, Dongliang ; Gong, Huanyu ; Niu, Junqi ; Zhao, Yingren ; Chen, Liang ; Zhang, Jiming ; Zhuang, Yulei ; Hu, Peng ; Lin, Shide ; Hou, Jinlin ; Zhang, Yingjun ; Tan, Youwen ; Kong, Fei ; Gao, Zhiliang ; Jin, Zhenjing ; Shang, Jia ; Mu, Mao ; Rao, Huiying ; Luo, Lin ; Lian, Jianqi ; Lu, Jiajie ; Zhang, Mingyuan ; Xie, Qing ; Xin, Yongning ; Wang, Maorong ; Gao, Haibing ; Han, Tao ; Xie, Wen ; Gao, Yanhang ; Wu, Chao ; Mao, Xiaorong

OBJECTIVESGLS4 is a first-in-class hepatitis B virus (HBV) capsid assembly modulator that inhibits HBV replication by interfering with assembly and disassembly of the virus nucleocapsid, this prospective, open-label, comparative, phase 2b trial evaluated the antiviral activity and safety of GLS4/ritonavir (RTV) combined with entecavir in hepatitis B e antigen-positive patients.METHODS250 CHB patients were enrolled, including treatment-naïve patients and those interrupted anti-HBV drugs for ≥ 6 months (Part A, n=125), and patients who had taken ETV for ≥1 year and had achieved viral suppression (Part B, n=125). Patients were randomly allocated to receive 120 mg GLS4/100 mg RTV plus 0.5 mg ETV or 0.5 mg ETV monotherapy for 96 weeks.RESULTSIn the mid-term, in Part A (n=122), greater least-squares mean (LSM) changes from baseline were observed in the GLS4/RTV plus ETV cohort than in ETV monotherapy cohort in HBV DNA (-6.28 vs -5.72 log10 IU/ml, p=0.0005), HBsAg (-0.87 vs -0.65 log10 IU/ml, p=0.0653), HBV pgRNA (-3.83 vs -1.91 log10 copies/ml, p<0.0001); The proportions of both HBV DNA and pgRNA negative patients were 17.3% (13/75, GLS4/RTV plus ETV) and 0% (0/30, ETV monotherapy). In Part B (n=123), greater mean LSM reductions in HBsAg (-0.17 vs -0.06 log10 IU/ml, p=0.0013), HBV pgRNA (-1.61 vs -0.28 log10 copies/ml, p<0.0001) were also observed in the GLS4/RTV+ETV cohort. the proportions of both HBV DNA and pgRNA-negative patients were 71.6% (48/67, GLS4/RTV plus ETV) and 18.9% (7/37, ETV monotherapy), respectively. No patients achieved HBsAg loss at week 48. GLS4/RTV + ETV were well tolerated, the most common adverse events were elevated alanine aminotransferase levels and hypertriglyceridemia, which were reversed by temporary GLS4/RTV discontinuation.CONCLUSIONSThe primary analysis at week 48 showed that the antiviral efficacy of GLS4/RTV with ETV was clearly superior to that of ETV monotherapy. GLS4/RTV with ETV was well tolerated; further studies evaluating its safety and efficacy are ongoing. (clinical trial identifier: NCT04147208).

01 Nov 2024·Bioorganic & Medicinal Chemistry Letters

Design, synthesis and anti-HBV activity study of novel HBV capsid assembly modulators

Article

Author: Liu, Linyue ; Zhan, Peng ; Wang, Mei ; Chen, Yunfu ; Yang, Zechun ; Liu, Jun ; Xue, Peng ; Cai, Yuqing ; Xie, Yong ; Jia, Haiyong ; Liang, Minghui

Capsid assembly modulators (CAMs) have the potential to cure chronic hepatitis B, as demonstrated in clinical trials. Lead compounds NVR3-778 and 5a were found to exist in normal and flipped conformations through induced fit docking. Therefore, we designed and synthesized series I and II compounds by interchanging the amide and sulfonamide bonds of 5a to modify both the tolerance region and solvent-opening region. Among them, compound 4a (EC₅₀ = 0.24 ± 0.10 μM, CC₅₀ > 100 μM) exhibited potent anti-HBV activity with low toxicity, surpassing the lead compounds NVR3-778 (EC₅₀ = 0.29 ± 0.03 μM, CC₅₀ = 20.78 ± 2.29 μM) and 5a (EC₅₀ = 0.50 ± 0.07 μM, CC₅₀ = 48.16 ± 9.15 μM) in HepAD38 cells. Additionally, compared with the lead compound, 4a displayed a stronger inhibitory effect on HBV capsid protein assembly. Molecular dynamics (MD) simulations confirmed that the normal conformation of 4a had relatively stable conformation at different frames of binding modes. Furthermore, 4a showed better metabolic stability in human plasma than positive control drugs. Therefore, compound 4a could be further structurally modified as a potent lead compound.

01 Nov 2024·Acta Pharmaceutica Sinica B

Discovery of novel small molecules targeting hepatitis B virus core protein from marine natural products with HiBiT-based high-throughput screening

Article

Author: Ye, Jianyu ; Fu, Panpan ; Hua, Ting ; Wang, Mengxue ; Chen, Jieliang ; Jin, Yang ; Zai, Wenjing ; Luo, Gan ; Wang, Haiyu ; Hu, Kongying ; Yuan, Zhenghong ; Zhang, Yiqing ; Song, Xinluo ; Li, Xuwen ; Huang, Chao ; Liu, Jiangxia

Due to the limitations of current anti-HBV therapies, the HBV core (HBc or HBcAg) protein assembly modulators (CpAMs) are believed to be potential anti-HBV agents. Therefore, discovering safe and efficient CpAMs is of great value. In this study, we established a HiBiT-based high-throughput screening system targeting HBc and screened novel CpAMs from an in-house marine chemicals library. A novel lead compound 8a, a derivative of the marine natural product naamidine J, has been successfully screened for potential anti-HBV activity. Bioactivity-driven synthesis was then conducted, and the structure‒activity relationship was analyzed, resulting in the discovery of the most effective compound 11a (IC₅₀ = 0.24 μmol/L). Furthermore, 11a was found to significantly inhibit HBV replication in multiple cell models and exhibit a synergistic effect with tenofovir disoproxil fumarate (TDF) and IFNa2 in vitro for anti-HBV activity. Treatment with 11a in a hydrodynamic-injection mouse model demonstrated significant anti-HBV activity without apparent hepatotoxicity. These findings suggest that the naamidine J derivative 11a could be used as the HBV core protein assembly modulator to develop safe and effective anti-HBV therapies.

100 Deals associated with Morphothiadine Mesylate

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Indication	Highest Phase	Country/Location	Organization	Date
Hepatitis B, Chronic	Phase 3	China	Sunshine Lake Pharma Co., Ltd.	10 Dec 2021
Hepatitis B, Chronic	Phase 3	China	Guangdong South China New Drug Creation Center	10 Dec 2021

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