Safety, pharmacodynamics, and antiviral activity of selgantolimod in viremic patients with chronic hepatitis B virus infection
Harry L.A. Janssen, Young‐Suk Lim, Hyung Joon Kim, Leonard Sowah, Cheng‐Hao Tseng, Carla S. Coffin, Magdy Elkhashab, Sang Hoon Ahn, Anh‐Hoa Nguyen, Diana Chen, Jeffrey J. Wallin, Simon P. Fletcher, Circe E. McDonald, Jenny C. Yang, Anuj Gaggar, Diana M. Brainard, Scott Fung, Yoon Jun Kim, Jia‐Horng Kao, Wan‐Long Chuang, Anna E. S. Brooks, P. Rod Dunbar
Abstract
Background & aimsNovel finite therapies for chronic hepatitis B (CHB) are needed, since current oral antivirals require prolonged treatment. This Phase 2 study (NCT03615066) evaluated safety, pharmacodynamics, and antiviral activity of selgantolimod (a toll-like receptor 8 agonist) with tenofovir alafenamide (TAF).MethodsViremic patients with CHB not receiving treatment were stratified by HBeAg status and randomized 2:2:1 to TAF 25 mg/day with selgantolimod 3 mg orally once weekly (QW), selgantolimod 1.5 mg QW, or placebo. Combination therapy continued until week (W)24, followed by TAF monotherapy until W48; patients then discontinued TAF and were followed until W96 (treatment-free follow-up [TFFU] period). The primary efficacy endpoint was the proportion with ≥1 log10 IU/mL HBsAg decline at W24.ResultsSixty-seven patients received study drug; 27 were followed during TFFU. Nausea, headache, vomiting, fatigue, and dizziness were the most common adverse events (AEs). Most AEs were Grade 1. Alanine aminotransferase (ALT) flares were not observed up to W48. Four patients experienced ALT and hepatitis flares during TFFU; all had HBV DNA increases. Selgantolimod increased serum cytokines and chemokines and redistributed several circulating immune cell subsets. No patients achieved the primary efficacy endpoint. HBsAg mean changes were −0.12, −0.16, and −0.12 log10 IU/mL HBsAg in the selgantolimod 3-mg, selgantolimod 1.5-mg, and placebo groups at W48, respectively; HBV DNA declined in all groups by ≥2 log10 IU/mL as early as W2, with all groups rebounding to baseline during TFFU. No HBsAg or HBeAg loss or seroconversion was observed throughout TFFU.ConclusionsSelgantolimod up to 3 mg was safe and well tolerated. Pharmacodynamics and antiviral activity in viremic patients support continued study of selgantolimod in combination CHB therapies.Impact and implicationsNovel therapeutics for chronic HBV infection are needed to achieve a functional cure. In this study, we confirmed the safety and tolerability of selgantolimod (formerly GS-9688, a toll-like receptor 8 agonist) when initiated with tenofovir alafenamide (TAF) over 24 weeks in patients infected with viremic chronic HBV. Overall, declines in HBsAg levels with selgantolimod treatment were modest; subgroup analysis indicated that patients with alanine aminotransferase (ALT) levels greater than the upper limit of normal had significantly greater declines compared with those with normal ALT levels (–0.20 vs –0.03 log10 IU/mL; p <0.001). These findings suggest a potential differential response to selgantolimod based on patients’ baseline HBV-specific immune response, which should be considered in future investigations characterizing the underlying mechanisms of selgantolimod treatment and in HBV cure studies using similar immunomodulatory pathways.Clinical trial numberNCT03615066.