Phase 2 Randomised Study of Bulevirtide as Monotherapy or Combined With Peg-IFNα-2a as Treatment for Chronic Hepatitis Delta

Abstract

Background and aim: Bulevirtide (BLV) leads to beneficial virologic and biochemical responses when given alone to treat hepatitis delta virus (HDV) infection, which causes the most severe form of chronic viral hepatitis. We evaluated 48 weeks of BLV monotherapy, BLV + tenofovir disoproxil fumarate (TDF) and BLV + pegylated interferon alfa-2a (Peg-IFNα-2a), with 24-week follow-up.

Methods: Ninety patients were enrolled into six arms of 15 each (A-F); 60 patients were included in the main randomisation (arms A-D), and 30 patients (arms E-F) were randomised to the extension phase: (A) Peg-IFNα-2a 180 μg once weekly (QW); (B) BLV 2 mg once daily (QD) + Peg-IFNα-2a 180 μg QW; (C) BLV 5 mg QD + Peg-IFNα-2a 180 μg QW; (D) BLV 2 mg QD; (E) BLV 10 mg QD + Peg-IFNα-2a 180 μg QW and (F) BLV 10 mg (5 mg twice daily) + TDF QD. The primary endpoint was undetectable HDV RNA at week (W)72.

Results: At W72, 53%, 27%, 7%, 7% and 33% of patients achieved undetectable HDV RNA in arms B, C, D, E and F, respectively, versus 0% in arm A. More arm B versus A patients had a > 1 log₁₀ IU/mL decline in or loss of hepatitis B surface antigen (HBsAg) at W72 (p = 0.017), including four patients with loss of HBsAg. Bile acid elevations were dose-dependent and reversible following the completion of BLV treatment.

Conclusions: BLV combined with Peg-IFNα-2a was well tolerated and resulted in high rates of HDV RNA undetectability off-treatment.

Trial registration: NCT02888106.

Keywords: HDV; Hepcludex; Myrcludex B; bulevirtide; entry inhibitor; pegylated interferon alfa.

FIGURE 1

Study schema and patient disposition. (A) Schema of randomised treatment groups included in the main study (arms A through D) and the study extension (arms E and F). The design consisted of a 4‐week screening period, a 48‐week treatment period and a 24‐week off‐treatment period. (B) Study disposition for arms A through E through week 72. BID, twice daily; BL, baseline; BLV, bulevirtide; NA, not applicable; Peg‐IFNα‐2a, pegylated interferon alfa‐2a; QD, once daily; QW, once weekly; TDF, tenofovir disoproxil fumarate.

FIGURE 2

Efficacy measures of (A) HDV RNA responses, (B) biochemical responses and (C) combined responses during the treatment and off‐treatment periods. (A) Percentages of patients achieving undetectable HDV RNA (HDV RNA response) at weeks 24, 48 and 72 by treatment group. (B) Percentages of patients achieving ALT normalisation (biochemical response) at weeks 24, 48 and 72 by treatment group. (C) Percentages of patients achieving the combined response of undetectable HDV RNA and ALT normalisation at weeks 24, 48 and 72 by the treatment group. All analyses are missing equal failure of the FAS. ALT, alanine aminotransferase; BID, twice daily; BLV, bulevirtide; EOFU, end of follow‐up; EOT, end of treatment; FAS, full analysis set; HDV, hepatitis delta virus; Peg‐IFNα‐2a, pegylated interferon alfa‐2a; TDF, tenofovir disoproxil fumarate.

FIGURE 3

(A) Serum HDV RNA and (B) serum ALT levels during the treatment and the off‐treatment periods. (A) Median (Q1, Q3) HDV RNA levels (log₁₀ IU/mL) by the treatment group. (B) Median (Q1, Q3) ALT levels by the treatment group. ALT, alanine aminotransferase; BID, twice daily; BL, baseline; BLV, bulevirtide; EOFU, end of follow‐up; EOT, end of treatment; HDV, hepatitis delta virus; Peg‐IFNα‐2a, pegylated interferon alfa‐2a; Q, quartile; TDF, tenofovir disoproxil fumarate.