S1617 Elevations in Total Serum Bile Acids During Bulevirtide Treatment Show No Association With Adverse Events of Interest in Patients With Chronic Hepatitis Delta: An Integrated Safety Analysis of 48-Week Data

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Introduction: Bulevirtide (BLV) is a novel, first-in-class entry inhibitor of hepatitis delta virus that was conditionally approved for treatment of chronic hepatitis delta in the EU in July 2020. Elevations in total serum bile acids (BA) are expected with treatment, as BLV specifically binds to the sodium taurocholate cotransporting polypeptide receptor. Here, we present a 48-week integrated analysis of BA increases and safety from Phase 2 (MYR203 and MYR204) and Phase 3 studies (MYR301). Methods: Treatment-emergent adverse events (AEs) and serum BA were assessed during treatment with BLV 2 or 10 mg/d given subcutaneously. Symptoms potentially related to BA elevation (AEs of interest) were identified, including pruritus, skin disorders, eosinophilia, vitamin D decrease, cardiac events, and gallbladder disorders; on-treatment levels of BA were compared between patients with and without AEs of interest. Results: Of 179 patients, 64 and 115 on BLV 2 and 10 mg/d had 510 and 847 measurements of BA analyzed, respectively. Baseline (BL) demographics were similar between groups: mean (SD) age was 41 (8.9) years, 67% were male, 88% were White, 37% had compensated cirrhosis, mean (SD) HDV RNA was 5.3 (1.36) log10 IU/mL, median (Q1, Q3) HBsAg was 3.7 (3.5, 4.1) log10 IU/mL, median (Q1, Q3) BA was 10.3 (6.8, 16.3) μmol/L, and 52% had elevated ( >upper limit of normal [ULN] of 10 μmol/L) BA. On BLV therapy, median BA levels increased rapidly in a dose-dependent manner and remained stable over 48 weeks. Median (Q1, Q3) on-treatment BA levels were 18.4 (11.1, 30.0) and 42.0 (24.9, 78.9) μmol/L in BLV 2- and 10-mg/d groups. In the BLV 2-mg group, 22% of on-treatment BA values were within normal range (≤ULN) vs only 4% in the 10-mg group. Elevations in BA were asymptomatic and unrelated to any clinical sequelae. No notable differences in on-treatment BA levels between patients with and without reported AEs of interest and no cases of hypersensitivity or gallbladder disorders were reported. On-treatment BA levels were comparable between patients with and without concurrent increases in ALT (defined as ALT >3×ULN and >BL) and with and without compensated cirrhosis in each group (Figure 1). Conclusion: Asymptomatic dose-dependent elevations of BA levels observed over 48 weeks of treatment with BLV were not associated with AEs of interest, including pruritus, skin disorders, and eosinophilia. Although pruritus and eosinophilia are associated with BLV treatment, BA elevations do not appear to be the mechanism behind these AEs.Figure 1.: On-Treatment total serum bile acids in patients treated with BLV 2 and 10 mg with and without AEs of interest over 48 weeks. (1) System Organ Class of Skin and subcutaneous tissue disorders according to MedDRA v. 24.0; (2) System Organ Class of Cardiac disorders according to MedDRA v. 24.0; (3) Most common cardiac events were bradychardia (n = 8) and tachycardia (n = 3). The figure presents median and 5th, 25th, 75th, and 95th percentile values of all available on-treatment BA. AE, adverse events; BA, bile acids; BLV, bulevirtide; MedDRA, Medical Dictionary for Regulatory Activities.

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