A phase 2, open-label, randomized, multiple-dose study evaluating Inarigivir in treatment-naïve patients with chronic hepatitis B.

Yoon J Kim, Nezam H Afdhal, Henry L Y Chan, Stephen A Locarnini, Kathy Jackson, Chelsea Macfarlane, Radhakrishnan P Iyer, Kwan Sik Lee, Jeong-Won Jang, Dong J Kim, Scott K Fung, Alnoor Ramji, Young S Lim, Susan Greenbloom, Won Kim, Carla S Coffin, Magdy Elkhashab, Wen-Juei Jeng, Chun-Jen Liu, Chi-Yi Chen, Man-Fung Yuen

Journal: Liver international : official journal of the International Association for the Study of the Liver 2023;43(1):77-89

PMID: 36300646

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Abstract

BACKGROUND/AIMS

Novel agents acting against hepatitis B virus (HBV) are needed to improve HBsAg seroclearance or termed as 'functional cure'. Inarigivir (retinoic acid-inducible gene I agonist) has immunomodulatory and direct antiviral actions against HBV. We aimed to determine the safety and efficacy of Inarigivir for the treatment of HBV infection.

PATIENTS/METHODS

80 treatment-naïve patients were randomized in 4 ascending dose cohorts to receive 12 weeks of Inarigivir 25, 50, 100, 200 mg or placebo in a ratio of 4:1. All patients were then given tenofovir for another 12 weeks.

RESULTS

Least squares (LS) mean reductions in HBV DNA from baseline increased with higher doses of Inarigivir (0.6116 in 25 mg and 1.5774 in 200 mg groups vs. 0.0352 in placebo group) (95% CI 0.9518-0.2011 and 1.921-1.1634 respectively). LS mean changes in HBV RNA and HBsAg from baseline ranged from -0.3856 to -0.5794 versus -0.1474 and -0.0956 to -0.1818 versus +0.0026 in Inarigivir-treated versus placebo groups respectively. During the tenofovir-treated period, LS mean reductions in HBsAg in the Inarigivir-treated groups ranged from 0.1709 to 0.3529 versus 0.1984 in the placebo group. Inarigivir-treated groups showed mean reductions in ALT from baseline between 23.3 and 33.8 versus 0.7 U/L in the placebo group. Treatment-emergent adverse events related to Inarigivir and placebo occurred in 4.7% and 6.3% patients respectively.

CONCLUSIONS

Twelve-week Inarigivir up to 200 mg dose was associated with a reduction of HBV DNA, HBV RNA and antigen levels. A trend for greater HBsAg reduction was observed in Inarigivir pre-treated patients after switching to tenofovir.

Address: Department of Medicine & State Key Laboratory of Liver Research, Queen Mary Hospital, School of Clinical Medicine, The University of Hong Kong, Pok Fu Lam, Hong Kong.; Division of Gastroenterology and Hepatology, Department of Medicine, Ditmanson Medical Foundation Chiayi Christian Hospital, Chiayi, Taiwan.; Department of Internal Medicine and Hepatitis Research Center, National Taiwan University College of Medicine and Hospital, Taipei, Taiwan.; Department of Gastroenterology and Hepatology, Chang Gung Memorial Hospital, Linkou Medical Center, Chang Gung University, Taoyuan City, Taiwan.; Toronto Liver Centre, North York General Hospital, University of Toronto, Toronto, Canada.; Cumming School of Medicine, University of Calgary, Calgary, Canada.; Department of Internal Medicine, Seoul National University College of Medicine, Seoul Metropolitan Government Boramae Medical Center Seoul, Seoul, South Korea.; Toronto Digestive Disease Associates, Woodbridge, Canada.; Gastrointestinal Research Institute, Vancouver, Canada.; Asan Medical Center, University of Ulsan College of Medicine, Seoul, South Korea.; Department of Internal Medicine and Liver Research Institute, Seoul National University College of Medicine, Seoul, South Korea.; Department of Medicine, University of Toronto, Toronto General Hospital, Toronto, Canada.; Hallym University College of Medicine, Chuncheon, South Korea.; Seoul St. Mary's Hospital, The Catholic University of Korea, Seoul, South Korea.; Gangnam Severance Hospital, Yonsei University Health System, Seoul, South Korea.; RIGImmune, Inc., New Haven, Connecticut, USA.; Spring Bank Pharmaceuticals, Hopkinton, Massachusetts, USA.; Victorian Infectious Diseases Reference Laboratory, Royal Melbourne Hospital, The Peter Doherty Institute for Infection and Immunity, Melbourne, Australia.; Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Prince of Wales Hospital, Sha Tin, Hong Kong.; Division of Gastroenterology and Hepatology, Beth Israel Deaconess Medical Center, Boston, Massachusetts, USA.

DOI: 10.1111/liv.15465

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MeSH Terms: Humans, Hepatitis B, Chronic, Hepatitis B Surface Antigens, DNA, Viral, Tenofovir, Antiviral Agents, Hepatitis B, Hepatitis B virus, Hepatitis B e Antigens, RNA, Treatment Outcome