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Two different dosages of bulevirtide, an investigational first-in-class entry inhibitor, were safe and demonstrated superior responses compared with observation alone for patients with chronic hepatitis delta virus (HDV), a phase III trial showed.

In the 150-patient study, daily bulevirtide injections led to significantly greater week-48 combined virological and biochemical response at both the 2 mg (45%) and 10 mg (48%) dosages, when compared to a control group where treatment was delayed until week 48 (2%, P<0.001 for both), reported Heiner Wedemeyer, MD, PhD, of Hannover Medical School in Germany, at the European Association for the Study of the Liver.

Both bulevirtide doses demonstrated significant reductions in liver stiffness from baseline, and ALT normalization was superior at 24 and 48 weeks in both the 2-mg and 10-mg groups, respectively, versus controls:

• 24 weeks: 53% and 38% vs 6% (P<0.001 for both)
• 48 weeks: 51% and 56% vs 12% (P<0.001 for both)

"The treatment benefit was consistent across all subgroups, including those with liver cirrhosis," Wedemeyer noted, and "importantly, the bulevirtide 10-mg dose does not support an efficiency advantage over the approved [in Europe] 2-mg dose."

"As the most severe form of viral hepatitis, HDV presents a significant disease burden with high healthcare-related costs and until recently, no approved treatment options," Wedemeyer told MedPage Today.

In 2020, bulevirtide at the 2-mg dose was conditionally approved in the E.U. for treating chronic HDV based on phase II data. Developer Gilead has from the current phase III trial (MYR301) for approval of the 2-mg dose.

Wedemeyer said that bulevirtide was also well-tolerated and safe, without any patients developing resistance. More mild-to-moderate injection site reactions and dose-dependent asymptomatic elevations of total serum bile acids were observed in the 10-mg group, but both were less pronounced in the 2-mg group.

Most patients had an adverse event (AE), including 82% in the 2-mg bulevirtide group, 88% in the 10-mg group, and 77% in the control group, with grade 3/4 AEs occurring in 10%, 8%, and 6%, respectively. Serious AEs were rare (4%, 2%, and 2%, respectively), and none were deemed related to the intervention.

Common AEs of interest with bulevirtide included headache (18-20%), pruritus (12-16%), and fatigue (10-16%). No AEs led to treatment discontinuation, however, and no patients died during the study.

"I think that the overall message should be, 'so far, so good,' as the results obtained to date look promising for a disease that heretofore has lacked efficacious treatments," said Andrew Talal, MD, of the University at Buffalo in New York, who was not involved in this study.

Talal noted that the ability to judge bulevirtide's effectiveness will be more clear in about 2 years, when the trial is scheduled to conclude.

MYR301 is an ongoing open-label, multicenter phase III trial that enrolled 150 patients in Germany, Italy, Russia, and Sweden with chronic HDV. They were then randomized 1:1:1 to either the 2-mg or 10-mg bulevirtide groups (who received a once-daily subcutaneous dose for 144 weeks) or to a control group that received no treatment for 48 weeks followed by bulevirtide at the 10-mg dose for 96 weeks. After that, all groups will be followed for an additional 96 weeks without treatment.

The study's primary endpoint of combined virological and biochemical response was defined as undetectable HDV RNA (below the limit of detection) or a ≥2log₁₀ IU/ml decline from baseline and ALT normalization at week 48. Mean baseline HDV RNA was 5.05 log₁₀ IU/mL, and mean ALT values were 110.9 U/L.

Patients were stratified by the presence (47%) or absence (53%) of compensated cirrhosis. Mean participant age was about 42 years, 57% were men, and over 80% were white. Most (60%) were receiving concomitant nucleoside/nucleotide analogues, and over half were previously on interferon.

Across groups, mean liver stiffness at baseline was 14-15 kPa. At week 48, the least squares mean reductions in baseline kPa were -3.08 with the 2-mg bulevirtide dose, -3.17 with the 10-mg dose, and an increase of 0.88 in the control group (P=0.001 for both comparisons).

Wedemeyer reported that no patients in the study experienced hepatitis B surface antigen (HBsAg) loss, and that changes in HBsAg levels were minimal.

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