Analysis of liver biopsies reveals a strong intrahepatic reduction of HDV and inflammatory markers after treatment with Myrcludex B in combination with Tenofovir in chronic HBV/HDV infected patients

Myrcludex B (MyrB) is a first-in-class entry inhibitor, which blocks the HBV/HDV receptor sodium taurocholate co-transporter NTCP. While the results of the phase 2b clinical trial (MYR202) on chronically HBV/HDV co-infected individuals receiving MyrB daily in combination with TDF show a dose-dependent serum HDV RNA decline associated with improvements of biochemical activity and liver stiffness, here we investigated the impact of MyrB treatment in paired liver biopsies obtained at baseline (BL) and week 24. Methods 120 HBeAg-negative patients with chronic Hepatitis D were randomized in 4 treatment arms. TDF treatment (245 mg/day) started at least 12w prior to MyrB. MyrB was administered s.c. once daily at 2 (A), 5 (B) or 10 (C) mg for 24w. Patients in arm D received TDF alone. BL biopsies were available for 31 patients, paired liver biopsies for 22 patients. Virological parameters and expression of inflammatory genes were assessed by qPCR, RNA in situ hybridization (RNA-ISH) and immunohistochemistry. Results At w24, intrahepatic HDV RNA declined in all MyrB arms with median reductions from BL by 0.9log in A (n = 7), 1.1log in B (n = 5) and by 1.4log in C (n = 7). TDF treatment (D) showed modest HDV RNA reductions (0.3log IU/ml, n = 3). HBV infection levels declined only in some patients with the strongest median reduction of HBV pgRNA (0.9log) and total HBV DNA (0.6log) in group C. Of note, immunohistochemistry revealed a substantial and dose-dependent decrease of HDAg+ cells. The strong reduction of HDV replication was also confirmed by RNA-ISH on exemplary biopsy sections. Furthermore, transcriptional levels of proinflammatory cytokines (CXCL10, CXCL8, IL18, TGFB1) decreased in all MyrB treatment arms. The reduction was more pronounced in patients with intrahepatic HDVRNA decline of ≥1log. Conclusions Intrahepatic levels of HDV RNA and of HDAg+ cells strongly declined after 24 weeks of MyrB treatment in a dose-dependent manner. The concomitant reduction of ALT and inflammatory cytokines suggests that the drop of HDV infection can diminish liver inflammation. Because of the strong decline of intrahepatic HDV infection levels induced by blocking HDV entry and turnover, HDV clearance might be achievable upon prolonged treatment durations.