Safety and efficacy of bulevirtide in combination with tenofovir disoproxil fumarate in patients with hepatitis B virus and hepatitis D virus coinfection (MYR202): a multicentre, randomised, parallel-group, open-label, phase 2 trial.

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 log

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 log

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.

Informations de copyright

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Déclaration de conflit d'intérêts

Declaration of interests HW reports honoraria for speaking or consulting from Abbott, AbbVie, Bristol-Myers Squibb (BMS), Boehringer Ingelheim, Eiger, Gilead Sciences, Janssen, Merck Sharp & Dohme (MSD), MYR GmbH, Novartis, Novira, Roche, Roche Diagnostics, Siemens, and Transgene, and research support from Abbott, BMS, Gilead Sciences, Novartis, Roche Diagnostics, and Roche. KS and AA are employees of MYR GmbH. KS reports personal fees from MYR GmbH and research support from Hepatera during the conduct of the study. AB reports a research grant from MYR GmbH. VC reports honoraria for speaking and consulting from Gilead Sciences, BMS, AbbVie, and MSD and research support and personal fees from Gilead Sciences and AbbVie. BB reports a research grant from Hepatera. LA reports research support from the German Centre for Infection Research (DZIF), Hepatera, Roche, HUMABS BioMed, and Janssen. FAL reports a research grant from DZIF. MH reports grants from Robert Bosch Stiftung, Stuttgart, Germany. MS reports research grants from Robert Bosch Stiftung, Stuttgart, Germany and DZIF; research support from Gilead Sciences and Corat Therapeutics GmbH; honoraria for speaking from CED Services and Agena Bioscience; consulting for Hong Kong RIF 2018-2021; and being Editor-in-Chief for Pharmacogenetics and Genomics and for Drug Research. MC reports honoraria for speaking or consulting from AbbVie, BMS, Boehringer Ingelheim, Biogen, Gilead Sciences, Falk, Janssen, MSD, Roche, Roche Diagnostics, and Siemens. WEH reports research support from German Federal Ministry of Education and Research (grant number 01GK0702), MYR GmbH, and Hepatera. MD reports research grants from DZIF and from Hepatera; grants from Roche, HUMABS BioMed, and Janssen; and personal fees from Gilead Sciences outside the submitted work. SU reports honoraria for consulting or speaking or research grants from Gilead Sciences, Humabs, VirBio, Pepperprint, ENYO, Galapagos, MSD, Hepatera, and MYR GmbH; he is a patent holder and inventor on patents protecting bulevirtide. All remaining authors declare no competing interests.