Pharmacokinetics, Safety and Tolerability of JNJ-56136379, a Novel Hepatitis B Virus Capsid Assembly Modulator, in Healthy Subjects

Vandenbossche, Joris; Jessner, Wolfgang; Boer, Maarten van den; Biewenga, Jeike; Berke, Jan Martin; Talloen, Willem; Zwart, Loeckie de; Snoeys, Jan; Yogaratnam, Jeysen

doi:10.1007/s12325-019-01017-1

Cited by 25 publications

(41 citation statements)

References 9 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Capsid assembly modulators (CAMs) interrupt this process by binding to HBV core proteins and interfering with encapsidation of pgRNA and formation of viral nucleocapsids. There are a number of CAMs in clinical development, 6,7 including, ABI-H0731, 8 GLS4-JHS, 9 RO7049389, 10 JNJ-0440, 11 and JNJ-56136379 (JNJ-6379) [12][13][14] (more potent than NVR 3-778 15 ), each with the potential to counter HBV by blocking encapsidation of pgRNA and/or degrading capsids. However, it is not possible to evaluate the relative antiviral activity of these CAMs, as head-to-head clinical trials have not been conducted.…”

mentioning

confidence: 99%

JNJ-56136379, an HBV Capsid Assembly Modulator, Is Well-Tolerated and Has Antiviral Activity in a Phase 1 Study of Patients With Chronic Infection

et al. 2020

Self Cite

View full text Add to dashboard Cite

BACKGROUND & AIMS: JNJ-56136379 (JNJ-6379), a capsid assembly modulator that blocks hepatitis B virus (HBV) replication, was well tolerated and demonstrated dose-proportional pharmacokinetics in healthy participants in part 1 of its first clinical trial. In part 2, we have evaluated the safety, pharmacokinetics, and antiviral activity of multiple doses of JNJ-6379 in patients with chronic HBV infection. METHODS: We performed a double-blind study of 57 treatment-naïve patients with HB e antigen-positive or -negative (74%) chronic HBV infection without cirrhosis. Patients were randomly assigned to groups given JNJ-6379 at 25 mg (100 mg loading dose), 75 mg, 150 mg, or 250 mg or placebo daily for 4 weeks with an 8-week followup period. RESULTS: Twenty-three (56%) of 41 patients given JNJ-6379 had at least 1 adverse event (AE) during treatment, compared with 10 (63%) of 16 patients given placebo. No serious AEs were reported during the treatment period. Three patients (7%) given JNJ-6379 vs none given placebo had grade 3 AEs; of these, 1 patient (150 mg) also had an isolated grade 4 increase in the level of alanine aminotransferase that led to treatment discontinuation. JNJ-6379 exposure increased with dose, with time-linear pharmacokinetics. HBV-DNA and HBV-RNA decreased from baseline in patients receiving all doses of JNJ-6379, independently of viral genotype and HB e antigen status. On day 29, 13 (32%) of 41 patients had levels of HBV DNA below the lower limit of quantification. No clinically significant changes in levels of HB surface antigen were observed. CONCLUSIONS: In a phase 1 study of treatment-naïve patients with chronic HBV infection, all doses tested of JNJ-6379 were well tolerated, showed dose-dependent pharmacokinetics, and had potent antiviral activity in patients with CHB. The findings support a phase 2a study to evaluate JNJ-6379 ± nucleos(t)ide analogs in patients with chronic HBV infection, which is under way. Clinical-Trials.gov identifier: NCT02662712

show abstract

mentioning

confidence: 99%

JNJ-56136379, an HBV Capsid Assembly Modulator, Is Well-Tolerated and Has Antiviral Activity in a Phase 1 Study of Patients With Chronic Infection

et al. 2020

Self Cite

View full text Add to dashboard Cite

show abstract

“…Indeed, a high-throughput screen has been developed to rapidly identify potential CAMs (40). Importantly, several CAMs, such as NVR3-778, RO7049389, JNJ-0440, JNJ-6379, ABI-H0731, and AB-423, were well tolerated with favorable pharmacokinetics in healthy volunteers, and several of these compounds have showed antiviral properties in patients with CHB in early clinical trials (24,(41)(42)(43)(44)(45)(46).…”

Section: Discussionmentioning

confidence: 99%

“…NCT02662712) with JNJ-6739 has been conducted. The phase 1a part reported that single and multiple doses of JNJ-6379 were well tolerated in healthy adults, with dose-proportional pharmacokinetics (44). The 4-week phase 1b part in treatment-naive HBeAg-positive and -negative patients with CHB showed that all test doses of JNJ-6379 reduced serum HBV DNA, with a mean 2.70 log 10 reduction from baseline with the 250-mg once-daily dose (highest tested dose) and a mean 1.43 log 10 reduction from baseline in HBV RNA (24), which is expected from the MOA of JNJ-6739 in preventing encapsidation of HBV RNA.…”

Section: Discussionmentioning

confidence: 99%

Antiviral Properties and Mechanism of Action Studies of the Hepatitis B Virus Capsid Assembly Modulator JNJ-56136379

Berke

Dehertogh

Vergauwen

et al. 2020

Antimicrob Agents Chemother

Self Cite

View full text Add to dashboard Cite

Capsid assembly is a critical step in the hepatitis B virus (HBV) life cycle, mediated by the core protein. Core is a potential target for new antiviral therapies, the capsid assembly modulators (CAMs). JNJ-56136379 (JNJ-6379) is a novel and potent CAM currently in phase II trials. We evaluated the mechanisms of action (MOAs) and antiviral properties of JNJ-6379 in vitro. Size exclusion chromatography and electron microscopy studies demonstrated that JNJ-6379 induced the formation of morphologically intact viral capsids devoid of genomic material (primary MOA). JNJ-6379 accelerated the rate and extent of HBV capsid assembly in vitro. JNJ-6379 specifically and potently inhibited HBV replication; its median 50% effective concentration (EC50) was 54 nM (HepG2.117 cells). In HBV-infected primary human hepatocytes (PHHs), JNJ-6379, when added with the viral inoculum, dose-dependently reduced extracellular HBV DNA levels (median EC50 of 93 nM) and prevented covalently closed circular DNA (cccDNA) formation, leading to a dose-dependent reduction of intracellular HBV RNA levels (median EC50 of 876 nM) and reduced antigen levels (secondary MOA). Adding JNJ-6379 to PHHs 4 or 5 days postinfection reduced extracellular HBV DNA and did not prevent cccDNA formation. Time-of-addition PHH studies revealed that JNJ-6379 most likely interfered with postentry processes. Collectively, these data demonstrate that JNJ-6379 has dual MOAs in the early and late steps of the HBV life cycle, which is different from the MOA of nucleos(t)ide analogues. JNJ-6379 is in development for chronic hepatitis B treatment and may translate into higher HBV functional cure rates.

show abstract

“…Another phase I trial, by Zhao et al [ 98 ], evaluated the safety, tolerability, and pharmacokinetics of GLS4 (a novel HBV capsid assembly inhibitor), with or without ritonavir (used to enhance plasma levels of GLS4) and was found to have acceptable tolerability and sustained higher than proposed effective plasma trough concentration, when used in combination[ 98 ]. A phase I double-blind, RCT of 30 healthy adults, by Vandenbossche et al [ 99 ], looked into the safety, tolerability, and pharmacokinetics of JNJ-56136379 (a novel HBV capsid assembly modulator), showed it to be well-tolerated, with a more than three times the 90% effective plasma concentration required to inhibit viral replication[ 99 ].…”

Section: Hepatitis B Treatmentmentioning

confidence: 99%

Advances in treatment and prevention of hepatitis B

Shah¹,

Aloysius²,

Sharma³

et al. 2021

WJGPT

View full text Add to dashboard Cite

Chronic hepatitis B (CHB) continues to contribute to worldwide morbidity and mortality significantly. Scientists, clinicians, pharmaceutical companies, and health organizations have dedicated substantial Intellectual and monetary resources to finding a cure, increasing immunization rates, and reducing the global burden of CHB. National and international health-related organizations including the center for disease control, the national institute of health, the American Association for the study of liver disease (AASLD), The European association for the study of the Liver (EASL), The Asia Pacific association for the study of the Liver (APASL) and the world health organization release periodic recommendations for disease prevention and treatment. Our review of the most recent guidelines by EASL, AASLD, APASL, and Taiwan Association for the Study of the Liver revealed that an overwhelming majority of cited studies were published before 2018. We reviewed Hepatitis B-related literature published 2018 onwards to identify recent developments and current barriers that will likely direct future efforts towards eradicating hepatitis B. The breakthrough in our understanding of the hepatitis B virus life cycle and resulting drug development is encouraging with significant room for further progress. Data from high-risk populations, most vulnerable to the devastating effects of hepatitis B infection and reactivation remain sparse. Utilization of systems approach, optimization of experimental models, identification and validation of next-generation biomarkers, and precise modulation of the human immune response will be critical for future innovation. Within the foreseeable future, new treatments will likely complement conventional therapies rather than replace them. Most Importantly, pragmatic management of CHB related population health challenges must be prioritized to produce real-world results.

show abstract

Pharmacokinetics, Safety and Tolerability of JNJ-56136379, a Novel Hepatitis B Virus Capsid Assembly Modulator, in Healthy Subjects

Cited by 25 publications

References 9 publications

JNJ-56136379, an HBV Capsid Assembly Modulator, Is Well-Tolerated and Has Antiviral Activity in a Phase 1 Study of Patients With Chronic Infection

JNJ-56136379, an HBV Capsid Assembly Modulator, Is Well-Tolerated and Has Antiviral Activity in a Phase 1 Study of Patients With Chronic Infection

Antiviral Properties and Mechanism of Action Studies of the Hepatitis B Virus Capsid Assembly Modulator JNJ-56136379

Advances in treatment and prevention of hepatitis B

Contact Info

Product

Resources

About