Abstract

Background: Bulevirtide (BLV), a novel hepatitis delta virus (HDV) entry inhibitor, is approved in Europe for treatment of chronic hepatitis D (CHD). In clinical studies, virologic response (VR) was defined as undetectable HDV RNA or ≥2-log₁₀ IU/mL decline from baseline (BL). Optimal BLV monotherapy duration for CHD is unknown; it is also unclear whether continued therapy will benefit patients (pts) with early virologic nonresponse (NR) or partial response (PR). This integrated analysis evaluated continued BLV monotherapy in pts without VR after 24W.

Methods: Results from pts who completed BLV monotherapy for 96W in the Phase 3 (MYR301; NCT03852719) and Phase 2 (MYR204; NCT03852433) studies were included. NR and PR were defined as HDV RNA declines of <1 log₁₀ IU/mL and ≥1 but <2 log₁₀ IU/mL, respectively. Rates of biochemical response (alanine aminotransferase [ALT] within normal limits [WNL]) were compared.

Results: 141 CHD pts (47 BLV 2mg; 94 BLV 10mg) were evaluated. At BL 67% were male, 87% White, 43% had cirrhosis, 40% received concomitant nucleos(t)ide analogues, and 50% had prior interferon exposure. Mean (SD) HDV RNA was 5.2 (1.3) log₁₀ IU/mL; median (Q1, Q3) ALT was 94 (64, 136) U/L. At W24, 92/141 (65%) pts had VR (53 [58%] with ALT WNL), 34/141 (24%) had PR (19 [56%] with ALT WNL), and 15/141 (11%) had NR (2 [13%] with ALT WNL) (Table). 49 pts had NR or PR at W24. Of the 34 PR pts at W24, 25 (74%) had VR, and 24 (71%) had ALT WNL by W96. Of the 15 NR pts at W24, 7 (47%) had VR and 3 (20%) had PR by W96. A higher proportion of NR at W24 achieved VR at W96 among those receiving BLV 10mg (4/5, 80%) vs BLV 2mg (3/10, 30%). Among W24 NR or PR, the mean BL HDV RNA did not predict viral response at W96. Median (Q1, Q3) BL U/L ALT was higher in pts with NR (138 [112, 196]) vs VR (79 [53, 113]) and PR (95 [56, 150]) at W96. The mean (SD) log₁₀ IU/mL HDV RNA change at W96 among VR/PR/NR was −3.6 (1.1), −1.4 (0.3), and −0.2 (0.7) for VR, PR, and NR at W96. Median (Q1, Q3) U/L ALT change at W96 among VR/PR/NR was −48 (−73, −12), −42 (−83, −6), and −67 (−102, −33), respectively. Among all NR at W96, ALT declined >50% from BL in 7/11 (3/11 achieved ALT WNL).

Conclusion: Of 49 pts without VR at W24, the majority with PR and nearly half with NR were able to achieve VR at W96. ALT improved in all viral-response groups including those with NR. These results provide evidence for continuing BLV therapy despite early (24W) suboptimal virologic responses.