Author information

• ¹Department of Gastroenterology, Hepatology, and Endocrinology, Cluster of Excellence RESIST (EXC 2155), Hannover, Germany; Hannover Medical School, Hannover, Germany; German Center for Infection Research (DZIF) partner site, Hannover-Braunschweig, Braunschweig, Germany. Electronic address: wedemeyer.heiner@mh-hannover.de.
• ²MYR GmbH, Bad Homburg, Germany; Department of Infectious Diseases and Molecular Virology, Heidelberg University Hospital, Heidelberg, Germany.
• ³Hepatology Department, Moscow Regional Scientific Research, Clinic Institute MF Vladimirsky, Moscow, Russia.
• ⁴Department of Clinical Pharmacology and Pharmacoepidemiology, Heidelberg University Hospital, Heidelberg, Germany; German Centre for Infection Research, Heidelberg, Germany.
• ⁵H-Clinic, Moscow, Russia.
• ⁶Modern Medicine Clinic, Moscow, Russia.
• ⁷Clinic of the South-Ural State Medical University, Chelyabinsk, Russia.
• ⁸Reference Centre for Viral Hepatitis, Central Research Institute of Epidemiology, Moscow, Russia.
• ⁹Novosibirsk State Medical University, Novosibirsk, Russia.
• ¹⁰Medical Company Hepatology, Samara, Russia.
• ¹¹Stavropol State Medical University, Stavropol Regional Clinical Hospital, Stavropol, Russia.
• ¹²Department of Infectious Diseases, Physiology, Dermatology, and Venereology, Medical Institute of the North-Eastern Federal University MK Ammosov, Yakutsk, Russia.
• ¹³Gastroenterology and Dietology SM Riss, North-Western State Medical University, Mechnikov, Russia.
• ¹⁴Republican Clinical Infectious Diseases Hospital Professor AF Agafonov, Kazan, Russia.
• ¹⁵Infectious Clinical Hospital Number 1, Moscow City Department, Moscow, Russia.
• ¹⁶Department of Internal Medicine I, Goethe University Hospital Frankfurt, Frankfurt, Germany.
• ¹⁷Internal Medicine IV Gastroenterology, Heidelberg University Hospital, Heidelberg, Germany.
• ¹⁸Hannover Medical School, Hannover, Germany.
• ¹⁹University Hospital Hamburg-Eppendorf, Centre for Internal Medicine, Medical Clinic and Polyclinic, Hamburg, Germany; German Centre for Infection Research, Hamburg-Lübeck-Borstel-Riems, Germany.
• ²⁰Department of Infectious Diseases and Molecular Virology, Heidelberg University Hospital, Heidelberg, Germany; German Centre for Infection Research, Heidelberg, Germany.
• ²¹Clinical Pharmacology, Dr Margarete Fischer-Bosch-Institute, Stuttgart, Germany; University of Tuübingen, Tuübingen, Germany.
• ²²Clinical Pharmacology, Dr Margarete Fischer-Bosch-Institute, Stuttgart, Germany; Departments of Clinical Pharmacology, Biochemistry, and Pharmacy, University Hospital Tübingen, Tübingen, Germany.
• ²³MYR GmbH, Bad Homburg, Germany.
• ²⁴Department of Infectious Diseases and Molecular Virology, Heidelberg University Hospital, Heidelberg, Germany; German Centre for Infection Research, Heidelberg, Germany. Electronic address: stephan.urban@med.uni-heidelberg.de.

Abstract

Background: Bulevirtide is a first-in-class peptidic entry inhibitor for hepatitis B virus (HBV) and hepatitis D virus infection. In July, 2020, bulevirtide 2 mg received conditional marketing authorisation by the European Medical Agency for treatment of chronic hepatitis D virus infection. We investigated the antiviral activity of bulevirtide in patients chronically infected with HBV and hepatitis D virus.

Methods: MYR202 (ClinicalTrials.gov, NCT03546621; EudraCT, 2016-000395-13) was a multicentre, parallel-group, randomised, open-label, phase 2 trial. Adults (aged 18-65 years) with chronic hepatitis D virus infection, including patients with cirrhosis and patients who had contraindications to PegIFNα treatment or for whom treatment did not work, were eligible and were enrolled from four hospitals in Germany and 12 hospitals in Russia. Patients were randomly assigned (1:1:1:1) to receive 2 mg (n=28), 5 mg (n=32), or 10 mg (n=30) subcutaneous bulevirtide once per day with tenofovir disoproxil fumarate (TDF; 245 mg once per day orally) or TDF alone (245 mg once per day orally; n=30) for 24 weeks. Randomisation was done using a digital block scheme with stratification, consisting of 480 randomisation numbers separated into 30 blocks. The primary endpoint was undetectable hepatitis D virus RNA or 2 log₁₀ IU/mL or higher decline in hepatitis D virus RNA at week 24, which was analysed in the modified intention-to-treat population, including patients who received study medication at least once after randomisation. Hepatitis D virus RNA concentrations were monitored until week 48. Safety was assessed for all patients who received at least one dose of bulevirtide or TDF.

Findings: Between Feb 16, 2016, and Dec 8, 2016, 171 patients with chronic hepatitis D virus infection were screened; 51 were ineligible based on the exclusion criteria and 120 patients (59 with cirrhosis) were enrolled. At week 24, 15 (54%, 95% CI 34-73) of 28 patients achieved undetectable hepatitis D virus RNA or a 2 log₁₀ IU/mL or more decline in hepatitis D virus RNA (p<0·0001 vs TDF alone) with 2 mg bulevirtide, 16 (50%, 32-68) of 32 with 5 mg bulevirtide (p<0·0001), and 23 (77%, 58-90) of 30 with 10 mg bulevirtide (p<0·0001), versus one (4%, 0·1-18) of 28 with TDF alone. By week 48 (24 weeks after bulevirtide cessation), hepatitis D virus RNA concentrations had rebounded, with median changes from week 24 to week 48 of 1·923 log₁₀ IU/mL (IQR 0·566-2·485) with 2 mg bulevirtide, 1·732 log₁₀ (0·469-2·568) with 5 mg bulevirtide, and 2·030 log₁₀ (1·262-2·903) with 10 mg bulevirtide. There were no deaths associated with treatment. Three (9%) patients in the bulevirtide 5 mg group, two (7%) patients in the bulevirtide 10 mg group, and one (4%) patient in the TDF group had serious adverse events. Common treatment-emergent adverse events included asymptomatic bile salt increases and increases in alanine aminotransferase and aspartate aminotransferase.

Interpretation: Bulevirtide induced a significant decline in hepatitis D virus RNA over 24 weeks. After cessation of bulevirtide, hepatitis D virus RNA concentrations rebounded. Longer treatment durations and combination therapies should be investigated.

Funding: Hepatera LLC, MYR GmbH, and the German Centre for Infection Research, TTU Hepatitis.