[Translation] A prospective, randomized, positive parallel controlled, double-blind, double-dummy, multicenter phase III clinical trial of icariin soft capsules versus cinobucoid tablets as the first-line treatment for patients with complex disease, poor prognosis, composite biomarker positive, and unresectable hepatocellular carcinoma at baseline

主要目的：比较淫羊藿素组与华蟾素组受试人群的总生存期（OS）。次要目的：比较两组受试人群的9/12/18个月OS率、疾病进展时间（TTP）、无进展生存期（PFS）、客观缓解率（ORR）和疾病控制率（DCR）；比较两组受试人群的至生活质量恶化时间（TTD），包括健康相关生活质量/总体健康状况（HRQoL/GHS）、躯体功能、角色功能和症状；比较两组受试人群的安全性与耐受性；进行群体药代动力学（PopPK）探索研究，评估淫羊藿素给药后的药代动力学（PK）特征及其影响因素，并探索暴露与疗效的关系。探索性目的：在蛋白水平和基因组（DNA、RNA）水平上探索外周血生物标志物与临床疗效的相关性，支持受试者的伴随诊断以及精准治疗； PopPK研究中探索受试者基因组学信息，包括代谢酶尿苷二磷酸葡萄糖基转移酶（UGTs）的基因型，多药耐药相关蛋白2（MRP2）、多药耐药1（MDR1）、乳腺癌耐药蛋白（BCRP）、有机阴离子转运体3（OAT3）等转运体的基因型与PK特征的相关性；以及药物暴露水平与疗效的相关性。

[Translation]

Primary objective: Compare the overall survival (OS) of the subjects in the icariin group and the cinobucini group. Secondary objectives: Compare the 9/12/18-month OS rate, time to disease progression (TTP), progression-free survival (PFS), objective response rate (ORR) and disease control rate (DCR) between the two groups of subjects; Compare the time to quality of life deterioration (TTD) between the two groups of subjects, including health-related quality of life/general health status (HRQoL/GHS), physical function, role function and symptoms; Compare the safety and tolerability of the two groups of subjects; Conduct a population pharmacokinetic (PopPK) exploratory study to evaluate the pharmacokinetic (PK) characteristics of icariin after administration and its influencing factors, and explore the relationship between exposure and efficacy. Exploratory purpose: Explore the correlation between peripheral blood biomarkers and clinical efficacy at the protein level and genomic (DNA, RNA) level to support companion diagnosis and precision treatment of subjects; Explore the genomic information of subjects in PopPK studies, including the genotype of metabolic enzyme uridine diphosphate glucosyltransferase (UGTs), the correlation between the genotype of transporters such as multidrug resistance-associated protein 2 (MRP2), multidrug resistance 1 (MDR1), breast cancer resistance protein (BCRP), organic anion transporter 3 (OAT3) and PK characteristics; and the correlation between drug exposure level and efficacy.

Start Date01 Mar 2023

Sponsor / Collaborator

Beijing Shenogen Pharmaceutical Co., Ltd

[+1]

100 Clinical Results associated with Beijing Shenogen Pharmaceutical Co., Ltd

0 Patents (Medical) associated with Beijing Shenogen Pharmaceutical Co., Ltd

Literatures (Medical) associated with Beijing Shenogen Pharmaceutical Co., Ltd

01 Jul 2019·Cancer Research

Abstract CT148: Small molecule immune-modulator icaritin: Safety, durable survival and inflammation-immune biomarkers in advanced hepatocellular carcinoma

Author: Xu, Jianmin ; Meng, Kun ; Li, Shu ; Li, Qing ; Sun, Yan ; Liang, Jun ; Zheng, Limin ; Ye, Bin ; Qin, Shu-Kui ; Cheng, Ying

AbstractObjectives: Hepatocellular carcinoma (HCC) was characterized with high heterogeneity and immune “tolerogenic”. Despite of immune checkpoint inhibitors have demonstrated promising results with improved overall survival. Novel small molecule-based immune therapies with high safety profiles might be particularly needed for advanced HCC patients. The purpose of this Phase II study is to explore the safety, clinical activities and treatment associated inflammation-immune biomarkers of icaritin in advanced HCC.Methods: Major eligibility criteria include histologically confirmed unresectable, HCC patients with Child-Pugh Class A or B liver function. Total of 70 advanced HCC patients were enrolled and administrated with 600 mg b.i.d. Primary endpoints were TTP, and secondary endpoints were safety, OS, and DCR. Local disease control was defined as no progressive disease (PD) by RECIST. Kaplan-Meier analysis was utilized for OS assessment. Inflammation-Immune biomarkers NLR, PLR, cytokines, baseline expression of checkpoint/immune gene panel including PD-L1/L2, TIM3, IDO, HLA were evaluated by Nanostring and NGS technologies, retrospectively.Results: There was no ≥ grade III drug related AE observed in all enrolled 70 advanced HCC patients. Objective response evaluation in per-protocol population showed PR (1.6%), SD (32.8%) and PD (59.0%) and median overall survival (OS) 254day (95% CI, 172-296). DCR was achieved 34.4% (95% CI, 22.7-47.7%); Median OS for the PD-L1-positive (n=9) and negative (n=24) subgroups were 389 (95% CI, 80-522) vs. 286.5days (95%CI, 135-482), for IL-6-advantage (n=28) and disadvantage (n=16) subgroups were 328.5 (95% CI, 277-566) vs. 168 days (95% CI, 135-482), for IL-8 low (n=22) and high (n=22) subgroups were 475.5(95% CI, 309-NA) vs. 175days (95% CI, 135-295), respectively. Overall survival was significantly associated with patient genetic profiles such as neo-antigen, bacterial and viral DNA inserts.Conclusion: Icaritin has demonstrated its favorable clinical safety and preliminary immune-modulation efficacy. Potential baseline immune biomarkers to predict the improved OS were suggested including immune cell PD-L1 expression, low level peripheral IL-8, PLR, neoantigen and infection-associated genetic variations. Both safety and immune-response efficacy are warranted for the further Phase III validation.Citation Format: Shu-Kui Qin, Qing Li, Jianmin Xu, Jun Liang, Ying Cheng, Shu Li, Limin Zheng, Bin Ye, Kun Meng, Yan Sun. Small molecule immune-modulator icaritin: Safety, durable survival and inflammation-immune biomarkers in advanced hepatocellular carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr CT148.

MoleculesQ3 · CHEMISTRY

Enhanced Oral Absorption of Icaritin by Using Mixed Polymeric Micelles Prepared with a Creative Acid-Base Shift Method

Q3 · CHEMISTRY

ArticleOA

Author: Wang, Quntao ; Lu, Xin ; Tang, Cheng ; Yao, Hua ; Yin, Haiyan ; Chen, Xiaoming ; Ma, Xiaoping ; Yuan, Qipeng ; Meng, Kun ; Jin, Mingji

The purpose of this study was to develop mixed polymeric micelles with high drug loading capacity to improve the oral bioavailability of icaritin with Soluplus® and Poloxamer 407 using a creative acid-base shift (ABS) method, which exhibits the advantages of exclusion of organic solvents, high drug loading and ease of scaling-up. The feasibility of the ABS method was successfully demonstrated by studies of icaritin-loaded polymeric micelles (IPMs). The prepared IPMs were characterized to have a spherical shape with a size of 72.74 ± 0.51 nm, and 13.18% drug loading content. In vitro release tests confirmed the faster release of icaritin from IPMs compared to an oil suspension. Furthermore, bioavailability of icaritin in IPMs in beagle dogs displayed a 14.9-fold increase when compared with the oil suspension. Transcellular transport studies of IPMs across Caco-2 cell monolayers confirmed that the IPMs were endocytosed in their intact forms through macropinocytosis, clathrin-, and caveolae-mediated pathways. In conclusion, the results suggested that the mixed micelles of Soluplus® and Poloxamer 407 could be a feasible drug delivery system to enhance oral bioavailability of icaritin, and the ABS method might be a promising technology for the preparation of polymeric micelles to encapsulate poorly water-soluble weakly acidic and alkaline drugs.

MoleculesQ3 · CHEMISTRY

Preparation, Characterization, and In Vivo Evaluation of Amorphous Icaritin Nanoparticles Prepared by a Reactive Precipitation Technique

Q3 · CHEMISTRY

ArticleOA

Author: Yao, Hua ; Yin, Haiyan ; Tang, Cheng ; Jin, Mingji ; Kong, Junqiong ; Li, Fusu ; Chen, Xiaoming ; Meng, Kun ; Yuan, Qipeng ; Liang, Hao

Icaritin is a promising anti-hepatoma drug that is currently being tested in a phase-III clinical trial. A novel combination of amorphization and nanonization was used to enhance the oral bioavailability of icaritin. Amorphous icaritin nanoparticles (AINs) were prepared by a reactive precipitation technique (RPT). Fourier transform infrared spectrometry was used to investigate the mechanism underlying the formation of amorphous nanoparticles. AINs were characterized via scanning electron microscopy, X-ray powder diffraction, and differential scanning calorimetry. Our prepared AINs were also evaluated for their dissolution rates in vitro and oral bioavailability. The resultant nanosized AINs (64 nm) were amorphous and exhibited a higher dissolution rate than that derived from a previous oil-suspension formulation. Fourier transform infrared spectroscopy (FTIR) revealed that the C=O groups from the hydrophilic chain of polymers and the OH groups from icaritin formed hydrogen bonds that inhibited AIN crystallization and aggregation. Furthermore, an oral administration assay in beagle dogs showed that Cmax and AUClast of the dried AINs formulation were 3.3-fold and 4.5-fold higher than those of the oil-suspension preparation (p < 0.01), respectively. Our results demonstrate that the preparation of amorphous drug nanoparticles via our RPT may be a promising technique for improving the oral bioavailability of poorly water-soluble drugs.

100 Deals associated with Beijing Shenogen Pharmaceutical Co., Ltd

100 Translational Medicine associated with Beijing Shenogen Pharmaceutical Co., Ltd

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