Gastroenterology. 2019 Jan 5. pii: S0016-5085(18)35438-6. doi: 10.1053/j.gastro.2018.12.023. [Epub ahead of print]
Antiviral Activity, Safety, and Pharmacokinetics of Capsid Assembly Modulator NVR 3-778 in Patients with Chronic HBV Infection.
Yuen MF1, Gane EJ2, Kim DJ3, Weilert F4, Chan HLY5, Lalezari J6, Hwang SG7, Nguyen T8, Flores O9, Hartman G10, Liaw S11, Lenz O12, Kakuda TN13, Talloen W14, Schwabe C15, Klumpp K16, Brown N17.
Author information
1
Chair Professor, Department of Medicine, Queen Mary Hospital, University of Hong Kong, Hong Kong. Electronic address: [email protected].
2
Professor of Medicine, University of Auckland, Auckland, New Zealand.
3
Professor, Department of Internal Medicine, Hallym University, Chuncheon Sacred Heart Hospital, Gangwon-do, Republic of Korea.
4
Gastroenterologist, Waikato Hospital, Hamilton, New Zealand.
5
Professor, Department of Medicine and Therapeutics, Prince of Wales Hospital, The Chinese University of Hong Kong, Hong Kong.
6
Medical Director, Quest Clinical Research, San Francisco, CA, USA.
7
Professor, Department of Internal Medicine, CHA Bundang Medical Center, Gyeonggi-do, Republic of Korea.
8
Medical Director, Research and Education, Inc., San Diego, CA, USA.
9
Chief Scientific Officer, Novira Therapeutics, Doylestown, PA, USA.
10
Vice President of Chemistry, Novira Therapeutics, Doylestown, PA, USA.
11
Senior Director, Clinical Operations, Novira Therapeutics, Doylestown, PA, USA.
12
Compound Development Team Leader, Janssen Pharmaceutica NV, Beerse, Belgium.
13
Scientific Director, Clinical Pharmacology, Janssen Biopharma, South San Francisco, CA, USA.
14
Biostatistician (Senior Manager), Janssen Pharmaceutica NV, Beerse, Belgium.
15
Managing Director, Auckland Clinical Studies, Auckland, New Zealand.
16
Vice President, Discovery Research, Novira Therapeutics, Doylestown, PA, USA.
17
Chief Medical Officer, Novira Therapeutics, Doylestown, PA, USA.
Abstract
BACKGROUND & AIMS:
NVR 3-778 is a first-in-class hepatitis B virus (HBV) capsid assembly modulator that can inhibit HBV replication. We performed a proof-of-concept study to examine the safety, pharmacokinetics, and antiviral activity of NVR 3-778 in patients with chronic hepatitis B virus (HBV) infection.
METHODS:
We performed a phase 1 study in 73 HB e antigen (HBeAg)-positive patients with chronic HBV infection without cirrhosis. In a 2-part study (part 1 in New Zealand and part 2 in Hong Kong, Singapore, Taiwan, Korea, and the United States), patients were randomly assigned to groups that were given oral NVR3-778 (100 mg, 200 mg, or 400 mg daily or 600 mg or 1000 mg twice daily) or placebo for 4 weeks. Additional groups received combination treatment with pegylated interferon (pegIFN) and NVR3-778 (600 mg twice daily) or pegIFN with placebo.
RESULTS:
Reductions in serum levels of HBV DNA and HBV RNA were observed in patients receiving ≥1200 mg/day NVR 3-778. The largest mean reduction in HBV DNA was observed in the group given NVR 3-778 plus pegIFN (1.97 log10 IU/mL), compared with the groups given NVR 3-778 or pegIFN alone (1.43 log10 IU/mL and 1.06 log10 IU/mL, respectively). The mean reduction in HBV RNA was also greatest in the group given NVR 3-778 plus pegIFN (2.09 log10 copies/mL), compared with the groups given NVR 3-778 or pegIFN alone (1.42 log10 copies/mL and 0.89 log10 copies/mL, respectively). There was no significant mean reduction in HBsAg during the 4-week treatment period. There were no discontinuations and no pattern of dose-related adverse effects with NVR 3-778.
CONCLUSIONS:
In a phase 1 study of HBeAg-positive patients with chronic HBV infection without cirrhosis, NVR 3-778 was well tolerated and demonstrated antiviral activity. The agent reduced serum levels of HBV DNA and HBV RNA - to the greatest extent in combination with pegIFN. The observed reductions in HBV RNA confirmed the novel mechanism of NVR 3-778.