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Bulevirtide With or Without PEG-IFN Shows 24-Week Activity Against Hep D
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EASL International Liver Congress, June 23-26, 2021
EASL: Bulevirtide Monotherapy at Low and High Doses in Patients With Chronic Hepatitis Delta: 24-Week Interim Data of the Phase 3 MYR301 Study - (06/24/21)
Mark Mascolini
Bulevirtide, a hepatitis D virus (HDV) entry inhibitor, lowered HDV load more than 100-fold when given alone for 24 weeks, and cut the load even more when given with pegylated interferon alfa-2A (PEG-IFN) [1]. Treatment with bulevirtide alone returned alanine aminotransferase (ALT) to normal more often than bulevirtide plus PEG-IFN in this 174-person randomized open-label trial.
Bulevirtide binds to the NTCP receptor on the surface of liver cells. Both HDV and HBV use NTCP to invade liver cells, so researchers are studying bulevirtide for both HDV and HBV infection [2]. HDV needs HBV envelope proteins to infect liver cells. The European Union has licensed bulevirtide for treatment of chronic HDV infection in HDV RNA-positive adults with compensated liver disease [2]. Some research ranks HDV as the most severe chronic viral hepatitis, and uncontrolled HDV infection may double or triple the death risk seen with HBV infection alone [3-5].
This multicenter, randomized, phase 2b trial (the MYR204 study) took place in France, Russia, Romania, and Moldova. For 48 weeks participants with chronic HDV infection receive (1) subcutaneous bulevirtide at a dose of 2 or 10 mg daily combined with PEG-IFN once weekly (50 participants receiving each dose), (2) PEG-IFN alone (24 participants), or (3) 10 mg of bulevirtide alone (50 participants). The still-unreported primary endpoint is undetectable HDV RNA 24 weeks after treatment stops. At the EASL International Liver Congress, researchers presented an interim analysis at treatment week 24 [1]..
Across the four treatment arms participants averaged about 40 years in age, about 70% were men, and about 85% Caucasian. One third of participants across study arms had cirrhosis. ALT averaged 107.5 and 112.6 U/L in the two combination therapy arms (2 mg and 10 mg bulevirtide plus PEG-IFN), 121.5 U/L in the PEG-IGN-only arm, and 118.4 U/L in the bulevirtide-only arm.
Serious adverse events arose in 4% and 2% in the combination arms (2 mg and 10 mg bulevirtide plus PEG-IFN), 8% in the PEG-IFN-only arm, and 2% in the bulevirtide-only arm. No adverse event led anyone to stop taking bulevirtide, while 4 people in the combination arms stopped PEG-IFN because of an adverse event. Injection-site reactions were rare and mostly mild in people taking bulevirtide.
Through 24 weeks, levels of hepatitis B surface antigen (HBsAg, a marker of current HBV infection) rose 0.074 log10 IU/mL in the PEG-IFN-only arm, fell 0.791 log10 in the bulevirtide-only arm, and fell 0.626 log10 and 0.324 log10 in the two combination arms (2 mg and 10 mg bulevirtide plus PEG-IFN). Number and proportions of people in each of those four arms with more than a 10-fold drop in HBsAg were 1 (4%), 0, 6 (12%), and 4 (8%).
HDV RNA levels fell in 24 weeks by median values of 2.01 log10 IU/mL in the PEG-IFN-only arm, 2.68 log10 in the bulevirtide-only arm, and 3.78 and 4.11 log10 in the combination therapy arms (2 mg and 10 mg bulevirtide plus PEG-IFN). Thus combination therapy controlled HDV RNA better than either monotherapy.
Researchers recorded 24-week virologic response (defined as at least a 100-fold drop in HDV RNA or undetectable HDV RNA) in 9 of 24 people (38%) in the PEG-IFN-only group, 36 of 50 (72%) in the bulevirtide-only arm, and 44 of 50 (88%) and 46 of 50 (92%) in the two combination therapy groups (2 mg and 10 mg bulevirtide plus PEG-IFN).
Through 24 weeks, 64% taking bulevirtide monotherapy reached a normal ALT, compared with 30% and 24% in the two combination therapy groups (2 mg and 10 mg bulevirtide plus PEG-IFN) and 13% in the PEG-IFN monotherapy group.
Defining efficacy as virologic response (defined above) and ALT normalization, the researchers determined 24-week efficacy rates of 13% with PEG-IFN monotherapy, 50% with bulevirtide monotherapy, and 30% and 24% with combination therapy (2 mg and 10 mg bulevirtide plus PEG-IFN).
In an ongoing phase 3 trial of bulevirtide (MYR301) also reported at this meeting, 150 people with chronic HDV infection received no treatment, 2 mg of bulevirtide daily, or 10 mg of bulevirtide daily for the first 48 weeks of a multiyear study [6]. After 24 weeks HDV RNA fell at least 100-fold in 55.1% receiving 2 mg of bulevirtide daily, 68% receiving 10 mg daily, and 4% receiving no treatment (P < 0.0001). Respective proportions reaching normal ALT at week 24 were 53.1%, 38%, and 5.9% (P < 0.0001).
References
1. Asselah T, Arama SS, Bogomolov P, et al. Safety and efficacy of bulevirtide monotherapy and in combination with peginterferon alfa-2a in patients with chronic hepatitis delta: 24 weeks interim data of MYR204 phase 2b study. EASL International Liver Congress, June 23-26, 2021. Abstract OS-2717.
2. Kang C, Syed YY. Bulevirtide: first approval. Drugs. 2020;80:1601-1605. doi: 10.1007/s40265-020-01400-1.
3. Wedemeyer H, Manns MP. Epidemiology, pathogenesis and management of hepatitis D: update and challenges ahead. Nat Rev Gastroenterol Hepatol. 2010;7:31-40. doi: 10.1038/nrgastro.2009.205.
4. Fattovich G, Giustina G, Christensen E, et al. Gut. Influence of hepatitis delta virus infection on morbidity and mortality in compensated cirrhosis type B. The European Concerted Action on Viral Hepatitis (Eurohep). 2000;46:420-426. doi: 10.1136/gut.46.3.420.
5. Romeo R, Del Ninno E, Rumi M, et al. A 28-year study of the course of hepatitis Delta infection: a risk factor for cirrhosis and hepatocellular carcinoma. Gastroenterology. 2009;136:1629-1638. doi: 10.1053/j.gastro.2009.01.052.
6. Wedemeyer H, Aleman S, Andreone P, et al. Bulevirtide monotherapy at low and high dose in patients with chronic hepatitis delta: 24 weeks interim data of the phase 3 MYR301 study. EASL International Liver Congress, June 23-26, 2021. Abstract LBP-2730.
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