Objective We examined the serological, virological (in serum and liver) and histological profiles in chronic hepatitis B virus (HBV) patients during and after completion of multiple dose (MD) ARC-520.
Design The present phase 1b study was a multidose, open-label extension cohort of patients that had received single dose ARC-520 in our previous study. Eight patients received 4–9 4 weekly doses of MD ARC-520 and entecavir. Liver biopsies were performed in six patients. Intrahepatic and serum HBV DNA, HBV RNA and viral antigens were measured.
Results All patients had 28.9–30.4 months of follow-up after the last MD. All three hepatitis B e antigen (HBeAg)-positive patients had profound reductions in hepatitis B surface antigen (HBsAg), HBeAg, hepatitis B core-related antigen and HBV RNA with two undergoing HBeAg seroconversion. One further achieved HBsAg seroconversion (anti-HBs level of 25.1 IU/L) and the remaining two had HBsAg reductions of −1.7 and −3.5 log IU/mL >30 months after MD. Among the five HBeAg-negative patients, four had modest HBsAg reduction >29 months after completion of MD and one achieved HBsAg seroconversion (anti-HBs level of 152.5 IU/L) and was negative for liver HBsAg staining. Entecavir was successfully stopped in this patient 12 months after HBsAg seroconversion. Temporally related alanine aminotransferase elevations preceded by HBsAg reductions were observed in three patients suggesting immune activation. HBcAg staining was negative in all six biopsied patients. Two patients with <10% HBsAg positive staining of hepatocytes had correspondingly low serum HBsAg levels of 1.5 and 11.5 IU/mL.
Conclusions MD ARC-520 therapy achieved sustained and profound reductions of viral antigens and HBV RNA. HBsAg seroclearance was achievable.
Trial registration number NCT02065336.
- hepatitis B
Data availability statement
All data relevant to the study are included in the article or uploaded as online supplemental information.
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M-FY and DK-HW contributed equally.
Contributors M-FY, BDG, JH, RC-LL, C-LL and L-YM performed the clinical trial; M-FY, DK-HW, TS, JH, CIW and BDG analysed the data; M-FY, TS, JH, RGG, BDG and CIW designed the studies; M-FY, DK-HW, CIW and BDG drafted the paper; M-FY, DK-HW, TS, CF, SAL, RC-LL, RGG, C-LL, JH, CIW, LYM and BDG critically revised the paper. All authors had access to the study data and had reviewed and approved the final manuscript, including the author list.
Funding This study was funded in full by Arrowhead Pharmaceutical. Award/grant number: not applicable.
Competing interests M-FY is advisory board member and received speaker’s fees from AbbVie, Janssen, Biocartis NV, Bristol Myers Squibb, Fujirebio Incorporation, Gilead Sciences, Merck Sharp and Dohme, Sysmex Corporation. M-FY does consulting for Aligos Pharmaceuticals, Assembly Biosciences, Arbutus Biopharma, Dicerna Pharmaceuticals, Clear-B Therapeutics, GlaxoSmithKline, Immunocore, Springbank Pharmaceuticals and also received research funding from Bristol Myers Squibb and Gilead Sciences. TS, JH, BDG, and CIW are employed by Arrowhead Pharmaceuticals and may hold stock. SL does consulting for Arrowhead Pharmaceuticals, Assembly Biosciences, Aligos Pharmaceuticals, Clear-B Therapeutics and GlaxoSmithKline. C-LL is on the Advisory Committees or Review Panels of: Bristol-Myers Squibb and Gilead Sciences. C-LL does consulting for Arrowhead Pharmaceuticals, Bristol-Myers Squibb, and Gilead Sciences. C-LL is on the Speaker’s Bureau for: Bristol-Myers Squibb and Gilead Sciences. RGG has had Grants/Research Support from Gilead Sciences and Merck & Co. RGG has performed as consultant and/or advisor to Akshaya Pharmaceuticals, Arbutus Biopharma, Arrowhead Pharmaceuticals, Bristol-Myers Squibb, ContraVir Pharmaceuticals, Enyo Pharma, Gilead Sciences, HumAbs BioMed, Ionis Pharmaceuticals, Merck & Co., Nanogen Biopharmaceutical and Novira Therapeutics. RGG has current activity with the Scientific or Clinical Advisory Boards of Arrowhead Pharmaceuticals, Merck & Co, ContraVir Pharmaceuticals, Gilead Sciences, Isis Pharmaceuticals, Enyo Pharma, HumAbs BioMed and Nanogen Biopharmaceutical. RGG is a member of the Speakers Bureau for Bristol-Myers Squibb, Gilead Sciences, and Merck & Co. RGG has stock options with Arrowhead Pharmaceuticals.
Provenance and peer review Not commissioned; externally peer reviewed.
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