[Translation] A multicenter, randomized, double-blind, placebo-controlled Phase IIa trial to evaluate the efficacy and safety of ZM-H1505R (canonkevir) combined with entecavir (ETV) compared with ETV monotherapy in patients with chronic hepatitis B who have been receiving ETV monotherapy for at least 12 months

评估ZM-H1505R（卡农克韦）联合恩替卡韦（ETV）与ETV单药治疗相比在已经接受ETV单药治疗至少12个月的慢性乙型肝炎患者中的有效性和安全性。

[Translation]

To evaluate the efficacy and safety of ZM-H1505R (canonkevir) combined with entecavir (ETV) compared with ETV monotherapy in patients with chronic hepatitis B who have been receiving ETV monotherapy for at least 12 months.

Start Date11 Nov 2022

Sponsor / Collaborator

Shanghai Zhimeng Biopharma, Inc.Startup

NCT05484466

/ RecruitingPhase 2

A Phase IIa Study to Evaluate the Efficacy and Safety of ZM-H1505R in Combination With Entecavir (ETV) Compared With ETV Monotherapy in Patients With Chronic Hepatitis B Who Have Received ETV Monotherapy for at Least 12 Months

This is a multicenter, randomized, double-blind, placebo-controlled phase IIa study, designed to evaluate the efficacy and safety of ZM-H1505R in combination with Baraclude versus Baraclude monotherapy in adult CHB subjects with HBV DNA <2000 IU/mL but ≥ 50 IU/mL and who have received ETV (0.5 mg, once daily [QD)] monotherapy for at least 12 months.
The study is planned to enroll 90 adult CHB subjects who have received ETV monotherapy for at least 12 months and are still receiving ETV monotherapy (0.5 mg, QD) continuously. Eligible subjects will be randomized in a 1:1:1 ratio into 3 treatment groups. Both HBeAg positive and negative subjects will be included. There will be 20 HBeAg positive subjects and 10 HBeAg negative subjects in each treatment group.
After 48 weeks of treatment with the corresponding regimen, subjects will continue to take Baraclude 0.5 mg QD, as a monotherapy for a 12-week follow-up period for observation of efficacy and safety of ZM-H1505R.

Start Date11 Nov 2022

Sponsor / Collaborator

Shanghai Zhimeng Biopharma, Inc.Startup

[+1]

NCT05470829

/ CompletedPhase 1

A Multiple-center,Randomized,Double-blind,Placebo-controlled,Multiple-dose Study Among Chinese Healthy Subjects and Chronic Hepatitis B Patients to Evaluate Safety,Tolerability,Pharmacokinetics and Preliminary Pharmacodynamics of ZM-H1505R

This phase Ib study included two parts in which Part I was to evaluate the safety and bridge for PK among healthy Chinese subjects and Part II were about study among Chinese chronic hepatitis B virus-infected patients. Study of Part II was carried out following the safety assessment and racial difference evaluation in Part I.

Start Date27 May 2021

Sponsor / Collaborator

Shanghai Zhimeng Biopharma, Inc.Startup

100 Clinical Results associated with Cabocapavir

100 Translational Medicine associated with Cabocapavir

100 Patents (Medical) associated with Cabocapavir

Literatures (Medical) associated with Cabocapavir

01 Jan 2023·Gastro Hep Advances

Safety, Tolerability, and Pharmacokinetics of a Novel Human Hepatitis B Virus Capsid Assembly Modulator Canocapavir: A Randomized First-in-Human Study

Article

Author: Zhang, Zhijun ; Xia, Tian ; Hua, Bo ; Deng, Aiyun ; Guo, Ruoling ; Chen, Huanming ; Jin, Qiu ; Liu, Gang ; Liang, Bo ; Wang, Zhe ; Jiang, Xiuhong ; Lu, Hui

Background and AimsCanocapavir (ZM-H1505R) is a small-molecule hepatitis B virus capsid assembly modulator with a novel pyrazole structure. This is the first-in-human study to investigate its safety, tolerability, and pharmacokinetics (PK) following oral administration in healthy subjects.MethodsThis was a randomized, double-blind, placebo-controlled study including single ascending dose (SAD) study with an additional crossover food-effect arm, and multiple ascending dose study. In SAD, 40 subjects, 8 in each cohort, were randomized in a 3:1 ratio to receive a single dose of 25, 75, 150, 300, and 450 mg of Canocapavir or placebo in fasted state. For food-effect study, subjects in the 150 mg cohort of SAD received a second dose (150 mg) of Canocapavir in the fed state after a 7-day washout period. In multiple ascending dose, 24 subjects, 8 in each cohort, were randomized in a 3:1 ratio to receive 75, 150, and 300 mg of Canocapavir or placebo once daily for 14 days. The safety and tolerability were assessed using vital signs, physical evaluation, electrocardiogram, laboratory investigations, and adverse events (AEs). Plasma PK parameters measured included area under the curves, C_max, C_min, T_max, and T_1/2.ResultsOral administration of single doses (25-450 mg) and multiple doses (75-300 mg) of Canocapavir was well tolerated. The most common AE seen was increased alanine aminotransferase. No dose dependency was observed in incidence and intensity of AEs. Mean plasma area under the curve and C_max of Canocapavir increased dose-proportionally. A significant margin was observed between plasma exposure of Canocapavir and its in vitro anti-hepatitis B virus activity. Food had an effect on its absorption.ConclusionThe safety and PK profile of Canocapavir support its further evaluation in chronic hepatitis B patients. The study was registered on ClinicalTrial.gov with the number NCT04220801.

Viruses

Canocapavir Is a Novel Capsid Assembly Modulator Inducing a Conformational Change of the Linker Region of HBV Core Protein

Author: Yu, Lin ; Xia, Tian ; Yang, Le ; Zheng, Yuan ; Wu, Yang ; Deng, Qiang ; Zhu, Yuanfei ; Zhang, Zhijun

Canocapavir is a novel antiviral agent with characteristics of core protein allosteric modulators (CpAMs) that is currently in a phase II clin. trial for treatment of hepatitis B virus (HBV) infection.Herein, we show that Canocapavir prevented the encapsidation of HBV pregenomic RNA and increased the accumulation of cytoplasmic empty capsids, presumably by targeting the hydrophobic pocket at the dimer-dimer interface of HBV core protein (HBc).Canocapavir treatment markedly reduced the egress of naked capsids, which could be reversed by Alix overexpression through a mechanism other than direct association of Alix with HBc.Moreover, Canocapavir interfered with the interaction between HBc and HBV large surface protein, resulting in diminished production of empty virions.Of particular note, Canocapavir induced a conformational change of capsids, with the C-terminus of HBc linker region fully exposed on the exterior of capsids.We posit that the allosteric effect may have great importance in the anti-HBV activity of Canocapavir, given the emerging virol. significance of HBc linker region.In support of this notion, the mutation at HBc V124W typically recapitulated the conformational change of the empty capsid with aberrant cytoplasmic accumulation.Collectively, our results indicate Canocapavir as a mechanistically distinct type of CpAMs against HBV infection.

BMC Medicine

Safety, tolerability, pharmacokinetics, and antiviral activity of the novel core protein allosteric modulator ZM-H1505R (Canocapavir) in chronic hepatitis B patients: a randomized multiple-dose escalation trial

Article

Author: Hua, Bo ; Chen, Huanming ; Mai, Jiajia ; Liang, Bo ; Deng, Aiyun ; Zhu, Xiaoxue ; Niu, Junqi ; Guo, Ruoling ; Zhang, Hong ; Ding, Yanhua ; Xia, Tian ; Chen, Hong ; Wu, Min ; Lu, Hui ; Wang, Zhe ; Jia, Haiyan ; Jiang, Xiuhong ; Li, Cuiyun ; Liu, Gang ; Li, Xiaojiao ; Liu, Jingrui ; Liu, Chengjiao ; Zhang, Zhijun ; Hu, Yue

AbstractBackgroundHepatitis B virus (HBV) core protein-targeting antivirals (CpTAs) are promising therapeutic agents for treating chronic hepatitis B (CHB). In this study, the antiviral activity, pharmacokinetics (PK), and tolerability of ZM-H1505R (Canocapavir), a chemically unique HBV CpTA, were evaluated in patients with CHB.MethodsThis study was a double-blind, randomized, placebo-controlled phase 1b trial in Chinese CHB patients. Noncirrhotic and treatment-naive CHB patients were divided into three cohorts (10 patients per cohort) and randomized within each cohort in a ratio of 4:1 to receive a single dose of 50, 100, or 200 mg of Canocapavir or placebo once a day for 28 consecutive days.ResultsCanocapavir was well tolerated, with the majority of adverse reactions being grade I or II in severity. There were no serious adverse events, and no patients withdrew from the study. Corresponding to 50, 100, and 200 mg doses of Canocapavir, the mean plasma trough concentrations of the drug were 2.7-, 7.0-, and 14.6-fold of its protein-binding adjusted HBV DNA EC50 (135 ng/mL), respectively, with linear PK and a low-to-mild accumulation rate (1.26–1.99). After 28 days of treatment, the mean maximum HBV DNA declines from baseline were -1.54, -2.50, -2.75, and -0.47 log10 IU/mL for the 50, 100, and 200 mg of Canocapavir or placebo groups, respectively; and the mean maximum pregenomic RNA declines from baseline were -1.53, -2.35, -2.34, and -0.17 log10 copies/mL, respectively.ConclusionsCanocapavir treatment is tolerated with efficacious antiviral activity in CHB patients, supporting its further development in treating HBV infection.Trial registrationClinicalTrials.gov, number NCT05470829).

News (Medical) associated with Cabocapavir

27 Dec 2022

·www.core-biopharma.com

Zhimeng Biopharma Announces Dosing of First Subject in Phase II Clinical Trial of Its Novel HBV Capsid Assembly Modulator

Shanghai, China. December 27, 2022. Shanghai Zhimeng Biopharma, Inc. (“Zhimeng”), an innovation-driven biopharmaceutical company focused on the development of innovative drugs for the treatment of chronic hepatitis B and central nervous system diseases, announced dosing of the first participant in Phase II study of its novel HBV capsid assembly modulator Canocapavir (ZM-H1505R) in China/Hong Kong. Following the completion of a Phase Ia study of ZM-H1505R in the United States in 2021 and a Phase Ib study in China in 2022, Zhimeng initiated the Phase IIa trial of ZM-H1505R in China/Hong Kong in August 2022, which is a multicenter, randomized, double-blind, placebo-controlled study to evaluate the efficacy and safety of ZM-H1505R in combination with Entecavir (ETV) compared with ETV monotherapy in patients with chronic hepatitis B who have been receiving ETV monotherapy for at least 12 months. Zhimeng expects to receive the topline results from this trial in the middle of 2023.

Phase 2Phase 1

14 Jun 2022

·www.prnewswire.com

Zhimeng Biopharma will report positive phase 1b trial results on its HBV capsid inhibitor ZM-H1505R in the upcoming International Liver Congress

SHANGHAI, June 14, 2022 /PRNewswire/ -- Shanghai Zhimeng Biopharma announces that it will report the positive results obtained from a phase 1b study on its HBV capsid inhibitor ZM-H1505R in the International Liver Congress in June 22-26, 2022 (the EASL meeting). The recently completed phase 1b study was to evaluate the safety, tolerability, pharmacokinetics (PK), and preliminary antiviral activity of ZM-H1505R in a double-blind, randomized, placebo-controlled, dose escalating study in treatment-naïve chronic hepatitis B (CHB) patients. Patients were divided into three cohorts (10 patients each) and randomized within each cohort in a ratio of 4:1 to receive an ascending dose of 50, 100, or 200 mg of ZM-H1505R, or placebo once a day for 28 consecutive days. ZM-H1505R was safe and well tolerated within this dose range, with most AEs being mild to moderate in severity. No SAE was observed and there was no withdrawal due to AE. A proportional relationship was observed between dose and plasma exposure of ZM-H1505R. At day 28, the mean plasma Cmin were 2.73, 7.05, and 14.56 folds of its protein-binding adjusted HBV DNA EC50 for 50, 100, and 200 mg doses, respectively. Serum levels of HBV DNA and HBV pgRNA were significantly reduced from baselines after 28 days of treatment with ZM-H1505R. The mean maximal reductions from baselines in HBV DNA were -1.54, -2.50 and -2.75 log10 IU/mL, and in HBV pgRNA were -1.53, -2.35 and -2.34 log10 IU/mL in the 50, 100 and 200 mg cohorts, respectively. The mean maximal declines from baseline in HBcrAg were -0.61 and -0.51 log10 IU/mL in the 100 and 200 mg cohorts, respectively. "We are pleased to see the positive safety and preliminary efficacy results of ZM-H1505R from this phase 1b study." Commented Dr. Huanming Chen, CEO of Zhimeng Biopharma. "We believe that HBV capsid inhibitors such as ZM-H1505R will play an important role in further reducing the viruses in patients who have been treated with a NA for a long time but still have low levels of viremia. We are also confident that ZM-H1505R may become a component of a combination therapy for functional cure of CHB. With such promising results of ZM-H1505R, we will initiate a phase 2 trial in Q3 of 2022 to further evaluate its safety and efficacy". About ZM-H1505R ZM-H1505R is a small-molecule HBV capsid assembly modulator with a novel pyrazole structure currently being evaluated for the treatment of chronic hepatitis B (CHB). It is active against most HBV variants that show resistance to other HBV capsid modulators. About Zhimeng Biopharma Zhimeng Biopharma is a clinical-stage biopharmaceutical company committed to developing innovative drugs for the treatment of chronic hepatitis B (CHB) and severe neurological diseases with significant unmet medical needs. The company has recently announced the launch of the first-in-human phase I study of its novel TLR8 agonist, developed for CHB, in the US in March 2022; and the first-in-human phase I study of its novel small molecule, KCNQ2/3 selective opener, developed for the treatment of refractory epilepsy, in the US in May 2022. For more information, please visit: SOURCE Shanghai Zhimeng Biopharma, Inc.

CollaborateAntibodyInnovative DrugSmall molecular drug

12 Nov 2021

·www.core-biopharma.com

News Release from Shanghai Zhimeng Biopharma, Inc

Shanghai Zhimeng Biopharma announces the successful completion of its phase 1b clinical trial on its novel HBV capsid inhibitor ZM-H1505R. It was a randomized, double-blind, placebo-controlled trial to evaluate the safety, tolerability, pharmacokinetics, and preliminary efficacy against HBV in treatment naive chronic hepatitis B patients, in which subjects were orally dosed at 50 mg, or 100 mg and 200 mg of ZM-H1505R or placebo once daily for 28 days, followed by a 28-day of following up visits. In October, all dosing regimen had been successfully completed and the last patient had finished all scheduled follow-up procedures on November 9. The results of this study will be presented in EASL’s 2022 International Liver Congress. Dr. Huanming Chen, CEO of Zhimeng Biopharma commented that we are pleased to see the successful completion of this 1b trial. It is a great achievement made by our team toward our goal to develop a functional cure therapy for HBV. It also reflects the high efficiency and standard by which we conduct clinical trials. Reported on November 12, 2021

Phase 2Clinical ResultPhase 1siRNA

100 Deals associated with Cabocapavir

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Indication	Highest Phase	Country/Location	Organization	Date
Hepatitis B, Chronic	Phase 2	Hong Kong	Shanghai Zhimeng Biopharma, Inc.Startup	11 Nov 2022
Hepatitis B, Chronic	Phase 2	China	Shanghai Zhimeng Biopharma, Inc.Startup	11 Nov 2022

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Study	Phase	Population	Analyzed Enrollment	Group	Results	Evaluation	Publication Date


NCT05470829 (Pubmed)	Phase 1	Hepatitis B, Chronic	10	Canocapavir 50 mg	vxjgirfgkw(buxaarzdth) = xgdlzyrpje kemgmxapqc (yzuqwujrea )	-	16 Mar 2023
				Canocapavir 100 mg	vxjgirfgkw(buxaarzdth) = hvhmlxczgm kemgmxapqc (yzuqwujrea )
EASL2022	Not Applicable	Hepatitis B, Chronic	30	ZM-H1505R 50 mg	hmqfotaotc(hjgjewxsnl) = sleiqtykbn iyalqgyodc (wepahzntsq ) View more	-	25 Jun 2022
				ZM-H1505R 100 mg	hmqfotaotc(hjgjewxsnl) = lqoikqpshd iyalqgyodc (wepahzntsq ) View more

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