Abstract
Introduction
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.
Methods
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.
Results
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.
Conclusion
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.
Trial registration
Clinicaltrials.gov identifier, NCT02662712.
Funding
Janssen Pharmaceutica.
This is a preview of subscription content, log in via an institution to check access.
Similar content being viewed by others
Change history
04 March 2020
In the original article Ninth and Tenth authors were incorrectly omitted from the author group. The correct author group is Joris Vandenbossche, Wolfgang Jessner, Maarten van den Boer, Jeike Biewenga, Jan Martin Berke, Willem Talloen, Loeckie De Zwart, Jan Snoeys, Koen Vandyck, John Fry, Jeysen Yogaratnam.
04 March 2020
In the original article Ninth and Tenth authors were incorrectly omitted from the author group. The correct author group is Joris Vandenbossche, Wolfgang Jessner, Maarten van den Boer, Jeike Biewenga, Jan Martin Berke, Willem Talloen, Loeckie De Zwart, Jan Snoeys, Koen Vandyck, John Fry, Jeysen Yogaratnam.
References
Polaris Observatory Collaborators. Global prevalence, treatment, and prevention of hepatitis B virus infection in 2016: a modelling study. Lancet Gastroenterol Hepatol. 2018;3:383–403.
Lavanchy D, Kane M. Global epidemiology of hepatitis B virus infection. In: Liaw YF, Zoulim F, editors. Hepatitis B virus in human diseases. Molecular and translational medicine. New York: Humana Press; 2016.
Nayagam S, Thursz M, Sicuri E, et al. Requirements for global elimination of hepatitis B: a modelling study. Lancet Infect Dis. 2016;16:1399–408.
Bourliere M. Hepatitis B treatment: could we extend the current treatment indication? Lancet Gastroenterol Hepatol. 2017;2:543–4.
Lam AM, Ren S, Espiritu C, et al. Hepatitis B virus capsid assembly modulators, but not nucleoside analogs, inhibit the production of extracellular pregenomic RNA and spliced RNA variants. Antimicrob Agents Chemother. 2017;61:e00680–17.
Woo ASJ, Kwok R, Ahmed T. Alpha-interferon treatment in hepatitis B. Ann Transl Med. 2017;5:159.
World Health Organization. Combating hepatitis B and C to reach elimination by 2030: An advocacy brief. Geneva: World Health Organization; 2016. http://apps.who.int/iris/bitstream/10665/206453/1/WHO_HIV_2016.04_eng.pdf?ua=1. Accessed 19 Feb 2019.
Bourne C, Lee S, Venkataiah B, Lee A, Korba B, Finn MG, Zlotnick A. Small-molecule effectors of hepatitis B virus capsid assembly modulators give insight into virus life cycle. J Virol. 2008;82:10262–10270.
Kakuda TN, Yogaratnam JZ, Westland C, et al. JNJ-64530440, a novel capsid assembly modulator: single- and multiple-ascending dose safety, tolerability and pharmacokinetics in healthy volunteers. EASL, Vienna, Austria, 10–14 April 2019; Poster FRI-180.
Berke JM. Capsid assembly modulator JNJ-56136379 prevents de novo infection of primary human hepatocytes with hepatitis B virus. AASLD, Boston MA, USA, November 11–15 2016; Abstract 234.
Berezhkovskiy LM. The connection between the steady state (Vss) and terminal (Vβ) volumes of distribution in linear pharmacokinetics and the general proof that Vβ ≥ Vss. J Pharm Sci. 2007;96:1638–52.
Van den Bergh A, Sinha V, Gilissen R, et al. Prediction of human oral plasma concentration-time profiles using preclinical data: comparative evaluation of prediction approaches in early pharmaceutical discovery. Clin Pharmacokinet. 2011;50:505–17.
Di L, Trapa P, Obach RS, et al. A novel relay method for determining low-clearance values. Drug Metab Dispos. 2012;40:1860–5.
European Association for the Study of the Liver (EASL). EASL 2017 Clinical Practice Guidelines on the management of hepatitis B virus infection. Hepatology. 2017;2017(67):370–98.
Acknowledgements
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.
Funding
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.
Authorship
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.
Disclosures
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 (ethisch.comite@uza.be). 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.
Data Availability
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.
Author information
Authors and Affiliations
Corresponding author
Additional information
Enhanced Digital Features
To view enhanced digital features for this article go to https://doi.org/10.6084/m9.figshare.8256479.
Rights and permissions
About this article
Cite this article
Vandenbossche, J., Jessner, W., van den Boer, M. et al. Pharmacokinetics, Safety and Tolerability of JNJ-56136379, a Novel Hepatitis B Virus Capsid Assembly Modulator, in Healthy Subjects. Adv Ther 36, 2450–2462 (2019). https://doi.org/10.1007/s12325-019-01017-1
Received:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s12325-019-01017-1