Bulevirtide Monotherapy Is Safe and Well Tolerated in Chronic Hepatitis Delta: An Integrated Safety Analysis of Bulevirtide Clinical Trials at Week 48

Abstract

Background and aims: The safety and tolerability of bulevirtide (BLV), a novel entry inhibitor of hepatitis delta virus, were evaluated in an integrated analysis of clinical trial results from patients with chronic hepatitis delta (CHD).

Methods: Week 48 on-treatment clinical and laboratory results from two Phase 2 trials (MYR203 [NCT02888106] and MYR204 [NCT03852433]) and one Phase 3 trial (MYR301 [NCT03852719]) were pooled (N = 269). Patients were grouped as follows: BLV 2 mg (n = 64), BLV 10 mg (n = 115), pegylated interferon-alfa (n = 39) and control (n = 51). The control group consisted of patients assigned to the delayed treatment group in Study MYR301.

Results: Adverse events (AEs) that occurred more frequently with BLV 2 mg and BLV 10 mg versus control included increased total bile acid levels (20% and 17% vs. 0%), injection-site reactions (16% and 20% vs. 0%), headache (16% and 17% vs. 0%), pruritus (11% and 10% vs. 0%) and eosinophilia (9% and 4% vs. 0%). Increases in total bile acid levels were observed with BLV without clear correlation with AEs, such as pruritus, eosinophilia or vitamin D deficiency. Grade 3 or 4 study drug-related AEs occurred in a higher proportion of patients receiving pegylated interferon-alfa (51%) than with BLV 2 or 10 mg (3% and 4%, respectively). There were no serious AEs related to BLV, and no patients discontinued BLV due to an AE. Neither hepatic decompensation nor death occurred.

Conclusions: BLV monotherapy was safe and well tolerated through 48 weeks of treatment in patients with CHD.

Trial registration: NCT02888106, NCT03852433 and NCT03852719.

Keywords: Hepcludex; antiviral agent; bulevirtide; hepatitis B virus; hepatitis D virus; safety.

FIGURE 1

Bulevirtide integrated safety analysis. Study arms pooled for the Week 48 safety analysis set are shown; data from the 24‐week treatment‐free follow‐up period of MYR203 were included for certain analyses of the adverse event of interest and total bile acids elevation. ^aTotal N of study patients treated. ^bIn combination with tenofovir disoproxil fumarate. BLV, bulevirtide; Peg‐IFNα, pegylated interferon‐alfa; SoC, standard of care. Primary report of MYR204 published as Asselah et al. [20]; primary report of MYR301 published as Wedemeyer et al. [15].

FIGURE 2

Total bile acid levels at baseline and on treatment. (A) Box plot of baseline total bile acids (μmol/L) from patients who underwent treatment with BLV 2 and 10 mg or delayed treatment (control). The baseline total bile acid value is the last available value collected prior to the first dose of the study drug. (B) Box plot of total bile acids (μmol/L) from on‐treatment visits for the BLV 2‐mg and 10‐mg treatment groups and the delayed‐treatment group (control). For both box plots, the horizontal lines within the shaded boxes represent the medians. The shaded boxes represent the interquartile ranges (25%–75%). The box plot whiskers represent the maximums and minimums. An outlier bile acids value for one participant in the BLV 10‐mg group at Week 8 with a value of 611.9 μmol/L was excluded from the box plot. All on‐treatment visits in Studies MYR203, MYR204 and MYR301 up to Week 48 were included. BLV, bulevirtide; Q1, first quartile; Q3, third quartile; ULN, upper limit of normal.

FIGURE 3

Total bile acids (μmol/L) by visit and treatment group. Data expressed as median (Q1, Q3). This analysis included on‐treatment data from MYR203, MYR204 and MYR301 and follow‐up data from MYR203. The dotted horizontal line represents the ULN. The baseline value was the last available value collected prior to the first dose of the study drug. For patients in the Study MYR301 delayed‐treatment group, the baseline value was the last available value collected at or prior to randomisation. The control group in this figure corresponds to the MYR301 delayed‐treatment group. BL, baseline; BLV, bulevirtide; Q1, first quartile; Q3, third quartile; ULN, upper limit of normal.

FIGURE 4

Relationship of total bile acid levels with AEs of interest. For the box plots, the horizontal lines within the shaded boxes represent the medians. The shaded boxes represent the interquartile ranges (25%–75%). The box plot whiskers represent the 5th and 95th percentiles. (A) Box plots of the total bile acid levels in patients with and without AEs of interest (BLV 2 and 10 mg combined). (B) Mean change in total bile acid levels over time in patients with and without pruritus. ^aN represents individual records of on‐treatment bile acid level values. ^bIdentified by system organ class term according to MedDRA v. 24.0. ^cMost common cardiac events were bradycardia (n = 8) and tachycardia (n = 3), all asymptomatic, Grade 1–2. AE, adverse event; BL, baseline; BLV, bulevirtide; MedDRA, Medical Dictionary for Regulatory Activities.

FIGURE 5

Liver test abnormalities while on treatment. On‐treatment data from MYR203, MYR204 and MYR301 are included in (A) and (B). Baseline and on‐treatment data from MYR203, MYR204 and MYR301 are included in Panel (C). (A) Lower incidence of liver test abnormalities with BLV. (B) eDISH plot of maximum TBL and ALT levels. (C) eDISH plot of baseline compared to Week 48 TBL and ALT levels. The control group in (A) and (B) corresponds to the MYR301 delayed‐treatment group. The BLV group in (A) and (B) included patients who received BLV 2 or 10 mg as monotherapy. The BL value was the last available value collected prior to the first dose of the study drug. For patients in the study MYR301 delayed‐treatment group, the BL value was the last available value collected at or prior to randomisation. ALT, alanine aminotransferase; AST, aspartate aminotransferase; BL, baseline; BLV, bulevirtide; eDISH, evidence of drug‐induced serious hepatotoxicity; Peg‐IFNα, pegylated interferon‐alfa; TBL, total bilirubin; ULN, upper limit of normal.