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A Phase 3, Randomized Trial of Bulevirtide in Chronic Hepatitis D
Heiner Wedemeyer1, Soo Aleman1, Maurizia Rossana Brunetto1
1From Medizinische Hochschule Hannover, Excellence Cluster RESIST, and D-SOLVE Consortium (H.W., M.C.), Hannover, German Center for Infection Research (DZIF) Partner Site Hannover-Braunschweig, Braunschweig (H.W., M.C.), Clinical Pharmacology and Pharmacoepidemiology and DZIF Partner Site Heidelberg (A. Blank) and the Department of Internal Medicine IV (U.M.), Heidelberg University Hospital, Heidelberg, the Institute of Medical Virology (A. Berger, S.C.), the Department of Internal Medicine, University Hospital Frankfurt (S.Z.), DZIF (S.C.), and Fraunhofer Institute for Translational Medicine and Pharmacology ITMP (S.C.), Frankfurt, and Universitätsklinikum Hamburg-Eppendorf, Medizinische Klinik, and DZIF, Hamburg-Lübeck-Borstel-Riems, Hamburg (J.S.W.) - all in Germany; the Department of Infectious Diseases, Karolinska University Hospital, Karolinska Institutet, Stockholm (S.A.); the Department of Clinical and Experimental Medicine, University of Pisa, and the Hepatology Unit, Pisa University Hospital, Pisa (M.R.B.), the Division of Internal Medicine, University of Modena and Reggio Emilia, Modena (P.A.), and the Division of Gastroenterology and Hepatology, Foundation IRCCS Ca' Granda Ospedale Maggiore Policlinico, CRC "A. M. and A. Migliavacca" Center for Liver Disease, and the Department of Pathophysiology and Transplantation, University of Milan, Milan (P.L.) - all in Italy; M.F. Vladimirsky Moscow Regional Research and Clinical Institute (P.B.), National Medical Research Center of Tuberculosis and Infectious Diseases, Ministry of Health (V.C.), Sechenov University (V.C.), and the Clinic of Modern Medicine (T.S.), Moscow, the National Medical Research Center of Physiopulmonology and Infectious Diseases, Yekaterinburg (N.M.), Stavropol Regional Clinical Hospital, Stavropol (N.G.), Hepatolog, Samara (V.M.), and Southern Ural State Medical University, Chelyabinsk (O.S.) - all in Russia; and Gilead Sciences, Foster City, CA (D.M., V.S., Q.A., B.D., J.F., A.O., Y.L.).
Insights
Bulevirtide significantly reduced hepatitis D virus RNA and normalized alanine aminotransferase levels in patients with chronic hepatitis D. This treatment shows promise for managing this advanced liver disease.
Area of Science:
- Hepatology
- Virology
- Clinical Trials
Background:
- Coinfection with hepatitis D virus (HDV) accelerates liver disease progression in chronic hepatitis B patients.
- Bulevirtide is an inhibitor of HDV entry into hepatocytes.
Purpose of the Study:
- To evaluate the efficacy and safety of bulevirtide in patients with chronic hepatitis D.
- To assess the impact of bulevirtide on HDV RNA levels and liver enzyme normalization.
Main Methods:
- Phase 3 randomized trial involving patients with chronic hepatitis D.
- Patients received bulevirtide (2 mg or 10 mg daily) or no treatment for 48 weeks.
- Primary endpoint: undetectable HDV RNA or ≥2 log10 IU/mL decrease plus normalized alanine aminotransferase (ALT) at week 48.
Main Results:
- 45% and 48% of patients in the 2-mg and 10-mg bulevirtide groups, respectively, achieved the primary endpoint, versus 2% in the control group (P<0.001).
- ALT normalization occurred in 51% (2-mg) and 56% (10-mg) of patients, significantly higher than the control group (12%).
- No loss of hepatitis B surface antigen (HBsAg) observed; common adverse events included headache and fatigue. No serious treatment-related adverse events were reported.
Conclusions:
- Bulevirtide treatment for 48 weeks effectively reduced HDV RNA and normalized ALT levels in patients with chronic hepatitis D.
- The study supports bulevirtide as a potential therapeutic option for chronic hepatitis D.
- Further follow-up is ongoing to assess long-term efficacy and safety.
Background:
Coinfection with hepatitis D virus (HDV) accelerates the progression of liver disease associated with chronic hepatitis B. Bulevirtide inhibits the entry of HDV into hepatocytes.
Methods:
In this ongoing phase 3 trial, patients with chronic hepatitis D, with or without compensated cirrhosis, were randomly assigned, in a 1:1:1 ratio, to receive bulevirtide subcutaneously at 2 mg per day (2-mg group) or 10 mg per day (10-mg group) for 144 weeks or to receive no treatment for 48 weeks followed by bulevirtide subcutaneously at 10 mg per day for 96 weeks (control group). Patients will complete 96 weeks of additional follow-up after the end of treatment. The primary end point was a combined response at week 48 of an undetectable HDV RNA level, or a level that decreased by at least 2 log10 IU per milliliter from baseline, and normalization of the alanine aminotransferase (ALT) level. The key secondary end point was an undetectable HDV RNA level at week 48, in a comparison between the 2-mg group and the 10-mg group.
Results:
A total of 49 patients were assigned to the 2-mg group, 50 to the 10-mg group, and 51 to the control group. A primary end-point response occurred in 45% of patients in the 2-mg group, 48% in the 10-mg group, and 2% in the control group (P<0.001 for the comparison of each dose group with the control group). The HDV RNA level at week 48 was undetectable in 12% of patients in the 2-mg group and in 20% in the 10-mg group (P = 0.41). The ALT level normalized in 12% of patients in the control group, 51% in the 2-mg group (difference from control, 39 percentage points [95% confidence interval {CI}, 20 to 56]), and 56% in the 10-mg group (difference from control, 44 percentage points [95% CI, 26 to 60]). Loss of hepatitis B virus surface antigen (HBsAg) or an HBsAg level that decreased by at least 1 log10 IU per milliliter did not occur in the bulevirtide groups by week 48. Headache, pruritus, fatigue, eosinophilia, injection-site reactions, upper abdominal pain, arthralgia, and asthenia were more common in the 2-mg and 10-mg groups combined than in the control group. No treatment-related serious adverse events occurred. Dose-dependent increases in bile acid levels were noted in the 2-mg and 10-mg groups.
Conclusions:
After 48 weeks of bulevirtide treatment, HDV RNA and ALT levels were reduced in patients with chronic hepatitis D. (Funded by Gilead Sciences; MYR 301 ClinicalTrials.gov number, NCT03852719.).
