The effect of bulevirtide is maintained in difficult-to-treat hepatitis D

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

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

Both doses of bulevirtide demonstrated significant reductions in hepatic stiffness from baseline, and ALT normalization was greater at 24 and 48 weeks in the 2 mg and 10 mg groups, respectively, compared to controls:

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

“Treatment benefit was consistent across all subgroups, including those with cirrhosis of the liver,” Wedemeyer noted, and “importantly, the 10 mg dose of bulevirtide does not provide a benefit efficacy compared to the approved dose [in Europe] 2mg dose.”

In 2020, bulevirtide at a dose of 2 mg was conditionally approved in the EU for the treatment of chronic HDV based on phase II data. Developer Gilead has data submitted to FDA of the ongoing phase III trial (MYR301) for approval of the 2 mg dose.

Wedemeyer said bulevirtide was also well tolerated and safe, with no patients developing resistance. Milder to moderate injection site reactions and dose-dependent asymptomatic elevations in 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 bulevirtide 2 mg 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 judged to be procedure-related.

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

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 (which received a subcutaneous dose once daily for 144 weeks) or to a control group which received no treatment for 48 weeks followed by bulevirtide at a dose of 10 mg for 96 weeks. After that, all groups will be followed for a further 96 weeks without treatment.

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

Patients were stratified according to the presence (47%) or absence (53%) of compensated cirrhosis. The average age of the participants was about 42 years old, 57% were male and more than 80% were Caucasian. Most (60%) were receiving concomitant nucleoside/nucleotide analogues, and more than half were previously on interferon.

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

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

  • Zaina Hamza is a writer for MedPage Today, covering gastroenterology and infectious diseases. She is based in Chicago.

Disclosures

Funding for this study was provided by Gilead Sciences.

Wedemeyer did not report any disclosures.

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