Pharmacokinetics, Safety and Tolerability of JNJ-56136379, a Novel Hepatitis B Virus Capsid Assembly Modulator, in Healthy Subjects
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Hepatitis B viral capsid assembly is an attractive target for new antiviral treatments. JNJ-56136379 (JNJ-6379) is a potent capsid assembly modulator in vitro with a dual mode of action. In Part 1 of this first-in-human study in healthy adults, the pharmacokinetics (PK), safety and tolerability of JNJ-6379 were evaluated following single ascending and multiple oral doses.
This was a double-blind, randomized, placebo-controlled study in 30 healthy adults. Eighteen subjects were randomized to receive single doses of JNJ-6379 (25 to 600 mg) or placebo. Twelve subjects were randomized to receive 150 mg JNJ-6379 or placebo twice daily for 2 days, followed by 100 mg JNJ-6379 or placebo daily for 10 days.
The maximum observed plasma concentration and the area under the curve increased dose proportionally from 25 to 300 mg JNJ-6379. Following multiple dosing, steady-state conditions were achieved on day 8. Steady-state clearance was similar following single and multiple dosing, suggesting time-linear PK. All adverse events (AEs) reported were mild to moderate in severity. There were no serious AEs or dose-limiting toxicities and no apparent relationship to dose for any AE.
JNJ-6379 was well tolerated in this study. Based on the safety profile and plasma exposures of JNJ-6379 in healthy subjects, a dosing regimen was selected for Part 2 of this study in patients with chronic hepatitis B. This is anticipated to achieve trough plasma exposures of JNJ-6379 at steady state of more than three times the 90% effective concentration of viral replication determined in vitro.
Clinicaltrials.gov identifier, NCT02662712.
KeywordsAntiviral activity Capsid assembly Hepatitis B virus Infectious diseases Phase 1
The authors would like to thank the participants of the study and acknowledge Hans Stieltjes and Freya Rasschaert (Janssen Pharmaceutica NV) whose contributions enabled the conduct and analysis of the study.
The investigator for this study, Dr. Maarten van den Boer, had direct clinical responsibility for subjects in this Phase 1 study and, as an author, has reviewed and approved this manuscript.
This study and the article processing charges were funded by Janssen Pharmaceutica. All authors had full access to all of the data in this study and take complete responsibility for the integrity of the data and accuracy of the data analysis.
Medical Writing and Editorial Assistance
Editorial support was provided by Andy Shaw, Lydia Travis and Ian Woolveridge of Zoetic Science, an Ashfield company, part of UDG Healthcare plc, and was funded by Janssen Pharmaceutica.
All named authors meet the International Committee of Medical Journal Editors (ICMJE) criteria for authorship for this article, take responsibility for the integrity of the work as a whole, and have given their approval for this version to be published.
Joris Vandenbossche is a Janssen employee and a Johnson & Johnson stockholder. Wolfgang Jessner was part of Janssen Pharmaceutica at the time of this study and is now employed by Roche Pharma Research & Early Development, Basel, Switzerland and a Johnson & Johnson and Roche stockholder. Maarten van den Boer is a Janssen employee and a Johnson & Johnson stockholder. Jeike Biewenga is a Janssen employee. Jan Martin Berke is a Janssen employee and a Johnson & Johnson stockholder. Willem Talloen is a Janssen employee and a Johnson & Johnson stockholder. Loeckie De Zwart is a Janssen employee and a Johnson & Johnson stockholder. Jan Snoeys is a Janssen employee and a Johnson & Johnson stockholder. Jeysen Z. Yogaratnam was a Janssen employee at the time of the study and has a patent application pending.
Compliance with Ethics Guidelines
This study was approved by the Ethics Committee, UZA, Wilrijkstraat 10, 2650 Edegem, Belgium (firstname.lastname@example.org). It was performed in accordance with the Helsinki Declaration of 1964, its later amendments and in compliance with Good Clinical Practice and applicable regulatory requirements. All volunteers provided written informed consent to participate in the study.
The data sharing policy of Janssen Pharmaceutical Companies of Johnson & Johnson is available at https://www.janssen.com/clinical-trials/transparency. As noted on this site, requests for access to the study data can be submitted through Yale Open Data Access (YODA) Project site at http://yoda.yale.edu.
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