Efficacy and safety of GLS4 with entecavir vs entecavir alone in chronic hepatitis B patients: A multicenter clinical trial - 05/03/25

Doi : 10.1016/j.jinf.2025.106446

Mingyuan Zhang ^a,^b,^c , Yanhang Gao ^a,^b,^c,^⁎ , Fei Kong ^a,^b,^c , Haibing Gao ^d , Yongxiang Yi ^e , Chao Wu ^f , Yongning Xin ^g , Sujun Zheng ^h , Jiajie Lu ⁱ , Tao Han ^j , Yingren Zhao ^k , Peng Hu ^l , Xiaorong Mao ^m , Qing Xie ⁿ , Jie Zhang ^o , Jinlin Hou ^p , Zhiliang Gao ^q , Jianqi Lian ^r , Liang Chen ^s , Jia Shang ^t , Wen Xie ^u , Mao Mu ^v , Zhenjing Jin ^w , Maorong Wang ^x , Shide Lin ^y , Huiying Rao ^z , Dongliang Yang ^aa , Huanyu Gong ^ab , Lin Luo ^ac , Yunfu Chen ^ac , Yulei Zhuang ^ac , Yingjun Zhang ^ac , Robert G. Gish ^ad,^ae , Youwen Tan ^af,^⁎ , Jiming Zhang ^ag,^⁎ , Junqi Niu ^a,^b,^c,^⁎
^a Department of Hepatology, Center of Infectious Diseases and Pathogen Biology, The First Hospital of Jilin University, Changchun 130021, China
^b Jilin Provincial Key Laboratory of Metabolic Liver Diseases, Jilin University, Changchun 130021, China
^c China-Singapore Belt and Road Joint Laboratory on Liver Disease Research, Changchun 130021, China
^d Infectious Disease Hospital, Mengchao Hepatobiliary Hospital, Fujian Medical University, Department of Infectious Diseases and Liver Diseases, 350028 Fuzhou, China
^e The Second Hospital of Nanjing, Hepatology Department, 210003 Nanjing, China
^f Nanjing Drum Tower Hospital, 210003 Nanjing, China
^g Qingdao Municipal Hospital, Department of Gastroenterology, 266000 Qingdao, China
^h Beijing YouAn Hospital, Capital Medical University, 100071 Beijing, China
ⁱ West China hospital Sichuan University, 610041 Sichuan, China
^j Tianjin Third Central Hospital, 300170 Tianjin, China
^k The First Affiliated Hospital of Xi’an Jiao Tong University, 710061 Xian, China
^l The Second Affiliated Hospital of Chongqing Medical University, 400010 Chongqing, China
^m The First Hospital of Lanzhou University, 730030 Lanzhou, China
ⁿ Ruijin Hospital Affiliated to The Shanghai Jiao Tong University Medical School, 200062 Shanghai, China
^o Shanghai Putuo District Central Hospital, 200062 Shanghai, China
^p Nanfang Hospital, Southern Medical University, Department of Infectious Diseases, 510515 Guangzhou, China
^q The Third Affiliated Hospital of Zhongshan University, 510405 Guangzhou, China
^r The Second Affiliated Hospital of Air Force Military Medical University, 710038 Xian, China
^s Shanghai Public Health Clinical Center, 201508 Shanghai, China
^t Henan Provincial People’s Hospital, 450003 Henan, China
^u Beijing Ditan Hospital, 100015 Beijing, China
^v The Affiliated Hospital of Guizhou Medical University, 550004 Guizhou,China
^w The Second Hospital of Jilin University, Hepatology Department, 130041 Changchun, China
^x Chinese PLA 81 Hospital, 210003 Beijing, China
^y Affiliated Hospital of Zunyi Medical University, 563099 Zunyi, China
^z Peking University People’s Hospital, 100044 Beijing, China
^aa Union Hospital College Huazhong University of Science and Technology, 430023 Wuhan, China
^ab The Third Xiangya Hospital of Central South University, 410000 Hunan, China
^ac The State Key Laboratory of Anti-Infective Drug Development (NO. 2015DQ780357), Sunshine Lake Pharma Co, Ltd, 523871 Dongguan, Guangdong, China
^ad Robert G. Gish Consultants, LLC, San Diego, CA, USA
^ae Hepatitis B Foundation, Doylestown, PA, USA
^af Zhenjiang Third People’s Hospital, Hepatology Department, 212003 Zhenjiang, China
^ag Huashan Hospital, Fudan University, Department of Infectious Diseases, 200040 Shanghai, China

^⁎Correspondence to: Department of Hepatology, First Hospital of Jilin University, Changchun 130021, Jilin, China.Department of Hepatology, First Hospital of Jilin UniversityChangchunJilin130021China^⁎⁎Correspondence to: Department of Hepatology, The Third Hospital of Zhenjiang Affiliated Jiangsu University, Zhenjiang 212000, Jiangsu, China.Department of Hepatology, The Third Hospital of Zhenjiang Affiliated Jiangsu UniversityZhenjiangJiangsu212000China^⁎⁎⁎Correspondence to: Department of Infectious Diseases, Jing' An Branch of Huashan Hospital, Fudan University, 200040 Shanghai, China.Department of Infectious Diseases, Jing' An Branch of Huashan Hospital, Fudan UniversityShanghai200040China

Summary

Objectives

GLS4 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.

Methods

250 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.

Results

In 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.

Conclusions

The 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).

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Highlights

•	GLS4+Nuc significantly suppressed HBV DNA and induced a rapid reduction in HBV pgRNA.
•	GLS4 +Nuc was well tolerated over 48 weeks in HBV patients.
•	This is by far the largest-scale clinical study on CpAM towards HBV.

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Abbreviations : HBV, NUCs, ETV, CHB, cccDNA, pol-pgRNA, CpAM, RTV, HBsAg, HBeAg, peg-IFN, pgRNA, ALT, ULN, AST, HBsAb, HBeAb, HBcAb, HBcrAg, PBMC, AEs, ECG, LLOQ, LSM, TDF

Keywords : Chronic hepatitis B, GLS4, Antiviral treatment, Capsid inhibitor, PgRNA

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Vol 90 - N° 3

Article 106446- mars 2025 Retour au numéro

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Efficacy and safety of GLS4 with entecavir vs entecavir alone in chronic hepatitis B patients: A multicenter clinical trial - 05/03/25

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