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Bulevirtide Plus pegIFNα Superior
to Bulevirtide Alone for Chronic HDV
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EASL Congress 2024, June 5-8, 2004, Milan
Mark Mascolini
Six months after the end of treatment, researchers reported in the New England Journal of Medicine that 10 mg of the HDV and HBV entry inhibitor bulevirtide daily plus 180 ug of pegylated interferon-alfa-2a (pegIFNα) weekly proved virologically superior to bulevirtide alone in people with chronic HDV infection [1]. At EASL 2024, researchers presented 48-week data confirming sustained virologic response to 10 mg of bulevirtide daily plus pegIFNα [2].
Bulevirtide, the first agent approved to treat HDV infection in Europe, thwarts binding of HBsAg-enveloped particles to cell entry receptors for both HBV and HDV [3]. Analysis of clinical trial data and combined clinical experience show that 2 mg of bulevirtide for 24 or 48 weeks alone or combined with pegIFNα lowers HDV load and drives alanine aminotransferase (ALT) into a normal range in a high proportion of people coinfected with HDV and HBV [3]. Combined bulevirtide and pegIFNα have synergistic activity when compared with either agent alone [3].
The phase 2b open-label MYR204 trial assessed 2 or 10 mg of subcutaneous bulevirtide once daily with or without pegIFNα compared with bulevirtide or pegIFNα alone for 48 weeks [2]. Researchers randomized (A) 25 people to pegIFNα (180 ug weekly) alone for 48 weeks, (B) 50 people to pegIFNα plus bulevirtide (2 mg subcutaneously daily) for 48 weeks then bulevirtide alone through week 96, (C) 50 people to pegIFNα plus bulevirtide (10 mg subcutaneously daily) for 48 weeks then bulevirtide alone through week 96, and (D) 50 people to bulevirtide alone (10 mg subcutaneously daily) for 96 weeks. The primary endpoint was undetectable HDV RNA 24 weeks after the end of treatment.
MYR204 enrolled 175 people with chronic HDV infection in France, Russia, Romania, and Moldova. Treatment arms did not differ substantially in age (overall average 41 years), sex (71% men), or race (87% white). One third of participants had compensated cirrhosis (average 13.1 kPa in liver stiffness). HDV RNA averaged, 5.3 log10 IU/mL and ALT 114 U/L. Almost half (48%) were taking a nucleos(t)ide, and 48% had already used interferon.
MYR204 investigators reported in the NEJM that 24 weeks after the end of treatment, proportions of participants with an undetectable HDV load were 17% in group A, 32% in group B, 46% in group C, and 12% in group D [1]. These results meant 10 mg of bulevirtide plus pegIFNα were virologically superior to bulevirtide alone.
At EACS 2024 MYR204 researchers reported that participants sustained these HDV RNA response rates through 48 weeks after the end of treatment: 25% (6 of 24) in arm A, 26% (13 of 50) in arm B, 46% (23 of 50) in arm C, and 12% (6 of 50) in arm D [2]. Response rates differed significantly between arms C and D (P = 0.0003), arms C and A (P = 0.0197), and arms B and D (P = 0.0283).
At week 48 ALT returned to a normal range in 42% in arm A, 38% in arm B, 46% in arm C, and 22% in arm D. A composite endpoint included undetectable HDV RNA or at least a 2-log (100-fold) drop in HDV RNA plus return to normal ALT. Proportions attaining that combined goal were 25% in arm A, 40% in arm C, and 8% in arm D (P < 0.05 arm C vs D). The investigators recorded HBsAg loss only in participants randomized to a bulevirtide group: 0% in arm A, 10% (5 of 500) in arm B, 4% (2 of 50) in arm C, and 2% (1 of 50) in arm D.
One person stopped bulevirtide because of a bulevirtide-related adverse event, and 3 people had bulevirtide-related serious adverse events after treatment ended. Leukopenia, neutropenia, and thrombocytopenia, mostly grade 1 or 2, were the most frequent adverse events.
The MYR204 team concluded that 10 mg of bulevirtide daily plus pegIFNα achieved the highest undetectable HDV RNA load rate at follow-up week 24 and sustained that advantage through week 48. They believe their findings position this combination as "a viable finite treatment option" for people with compensated chronic HDV infection.
A phase 3 trial of 2 or 10 mg of subcutaneous bulevirtide daily or delayed bulevirtide in 150 adults with or without compensated cirrhosis found that 45% in the 2-mg group, 48% in the 10-mg group, and 2% in the no-treatment control group attained a week-48 composite endpoint of undetectable HDV RNA or at least a 100-fold HDV RNA decline plus return to a normal ALT (P < 0.001 for either bulevirtide group versus the control group) [4].
Bulevirtide remains unlicensed in the United States.
References
1. Assalah T, Chulanov V, Lampertico P, et al. Bulevirtide combined with pegylated interferon for chronic hepatitis D. N Engl J Med. Published June 6, 2024. doi 10.1056/NEJMoa2314134. https://www.nejm.org/doi/full/10.1056/NEJMoa2314134
2. Assalah T, ChulanovV, Lampertico P, et al. 48-Week off-therapy efficacy and safety of bulevirtide in combination with pegylated interferon alfa-2a in patients with chronic hepatitis delta: final results from the phase 2b, open-label, randomized, multicentre study MYR204. Abstract GS-002.
https://www.nejm.org/doi/full/10.1056/NEJMoa2314134
3. Ferenci P, Reiberger T, Jachs M. Treatment of chronic hepatitis D with bulevirtide-a fight against two foes-an update. Cells. 2022;11:3531. doi: 10.3390/cells11223531. https://www.mdpi.com/2073-4409/11/22/3531
4. Wedemeyer H, Aleman S, Brunetto MR, et al. A phase 3, randomized trial of bulevirtide in chronic hepatitis D. N Engl J Med. 2023;389;22-32. doi 10.1056/NEJMoa2213429. https://www.nejm.org/doi/full/10.1056/NEJMoa221342
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