Elsevier

Journal of Hepatology

Volume 65, Issue 3, September 2016, Pages 490-498
Journal of Hepatology

Research Article
Treatment of chronic hepatitis D with the entry inhibitor myrcludex B: First results of a phase Ib/IIa study

https://doi.org/10.1016/j.jhep.2016.04.016Get rights and content

Background & Aims

The therapeutic option for patients with chronic hepatitis delta virus infection (CHD) is limited to interferon alpha with rare curative outcome. Myrcludex B is a first-in-class entry inhibitor inactivating the hepatitis B virus (HBV) and hepatitis D virus (HDV) receptor sodium taurocholate co-transporting polypeptide. We report the interim results of a pilot trial on chronically infected HDV patients treated with myrcludex B, or pegylated interferon alpha (PegIFNα-2a) or their combination.

Methods

Twenty-four patients with CHD infection were equally randomized (1:1:1) to receive myrcludex B, or PegIFNα-2a or their combination. Patients were evaluated for virological and biochemical response and tolerability of the study drugs at weeks 12 and 24.

Results

Myrcludex B was well tolerated and no serious adverse event occurred. Although hepatitis B surface antigen levels remained unchanged, HDV RNA significantly declined at week 24 in all cohorts. HDV RNA became negative in two patients each in the Myrcludex B and PegIFNα-2a cohorts, and in five patients of the Myrcludex B + PegIFNα-2a cohort. ALT decreased significantly in the Myrcludex B cohort (six of eight patients), and HBV DNA was significantly reduced at week 24 in the Myrcludex B + PegIFNα-2a cohort. Virus kinetic modeling suggested a strong synergistic effect of myrcludex B and PegIFNα-2a on both HDV and HBV.

Conclusions

Myrcludex B showed a strong effect on HDV RNA serum levels and induced ALT normalization under monotherapy. Synergistic antiviral effects on HDV RNA and HBV DNA in the Myr-IFN cohort indicated a benefit of the combination of entry inhibition with PegIFNα-2a to treat CHD patients.

Lay summary

Myrcludex B is a new drug to treat hepatitis B and D infection. After 24 weeks of treatment with myrcludex B and/or pegylated interferon α-2a, HDV R NA, a relevant marker for hepatitis D infection, decreased in all patients with chronic hepatitis B and D. Two of eight patients which received either myrcludex B or pegylated interferon α-2a, became negative for HDV RNA, and five of seven patients who received both drugs at the same time became negative. The drug was well tolerated.

Graphical abstract

Figure adapted from Li W, Urban S. Entry of hepatitis B and hepatitis D virus into hepatocytes: Basic insights and clinical implications. J Hepatol 2016;64:S32-40.

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Introduction

The treatment of chronic hepatitis delta (CHD) infection is an area of unmet medical need. Hepatitis D virus (HDV), the causative agent of CHD, is a small, viroid-like single stranded, circular ribonucleic acid (RNA) virus, which acquires the envelope proteins from Hepatitis B virus (HBV) infected cells to assemble and disseminate [1], [2]. An estimated 15 to 20 million patients worldwide are infected with HDV via parenteral routes of infection, sexual transmission or contact with infectious blood. The prevalence of HDV is increasing, and there is presently no cure for CHD [3], [4], [5], [6], [7]. Co-Infections of HBV and HDV occur either simultaneously resulting in severe and occasionally fulminant hepatitis, with a high rate of HBsAg seroconversion and elimination of both viruses following recovery. Alternatively, HDV occurs as superinfection in individuals who already suffer from CHB. The clinical outcome of superinfection is characterized by a high rate of HDV chronification and worsening of the disease with accelerated progression to liver cirrhosis and hepatocellular carcinoma [3], [8].

Vaccination against HBV is the most effective way to protect against HDV and has helped to limit its prevalence in those countries where vaccination programs have been successfully implemented [7]. Current treatment options for CHD are sparse with no approved agents specifically addressing HDV replication. Currently approved drugs only indirectly interfere with virus replication by modulation of the immune system or by influencing the concurring HBV replication [2], [3], [8], [9], [10], [11]. In eligible patients, the first line therapy is treatment with pegylated interferon alpha (PegIFNα) for 12 months or longer, if tolerated. Sustained virological response has been observed to various extents in treated patients; however, response rates rarely exceed 25%. Longer treatment, combination or alternative treatment with nucleoside analogues such as adefovir, lamivudine, or entecavir did not increase response rates; only tenofovir showed some effect on HDV serum RNA in HIV co-infected patients with improvement in liver fibrosis [6], [10], [12], [13], [14], [15], [16], [17], [18]. Moreover, late relapses were demonstrated in patients who initially achieved sustained response to IFN therapy and who were HDV RNA negative 24 weeks after the end of treatment. This indicated that the virus could not be eliminated by this drug [11].

Novel early clinical treatment approaches for CHD are currently being studied: lonafarnib, a prenylation inhibitor originally tested for its antineoplastic potency, affects the post-translational modification of the large HDV antigen and thereby interferes with the envelopment and release of the viral ribonucleoprotein [19], [20]. Recent clinical data revealed that lonafarnib dose-dependently reduced HDV serum RNA levels [21]. Another approach is based on intravenous administration of highly negatively charged nucleic acid polymers that interfere with the attachment of HBV/HDV to heparan sulfate proteoglycans [22]. This interaction is required prior to specific receptor binding. An additional effect of these drugs might be attributed to a putative effect on virus assembly [23], [24].

A promising approach used in our study aims at specific inhibition of the essential hepatic HBV and HDV virus receptor sodium taurocholate co-transporting polypeptide (NTCP) [25], by an optimized HBV envelope protein-derived lipopeptide, myrcludex B. This approach addresses a crucial and highly specific early step in the life cycle of HDV and HBV. According to its mode of action, myrcludex B blocks cccDNA formation and formation of HDV replicative intermediates in naïve or non-infected regenerated hepatocytes. Depending on the turnover dynamics of HDV and/or HBV infected cells (by either immune mediated cell killing, cytolytic effects of replicating HDV, or natural cell death) this would result in an overall decrease of infected cells. Thus, continuous administration of myrcludex B contributes to a decrease of the fraction of infected cells, which in the long-term may eventually lead to eradication of the infection [3], [4], [6], [8], [26], [27]. This principle that continuous entry inhibition even in an immune deficient animal model can lead to clearance of infection in the absence of any direct antiviral acting agents, has recently been proven in an animal model for hepatitis C virus (HCV) infection [28].

Myrcludex B is a myristoylated peptide of 47 amino acids derived from the preS1-domain of the HBV large surface (L-) protein. It efficiently blocks entry of HBV and HDV with IC50s of about 80 pM in primary human hepatocyte cultures, in cell lines, and in vivo in a humanized mouse model [26], [29], [30], [31], [32], [33], [34]. A first assessment on safety and pharmacokinetics of myrcludex B has been carried out in a dose escalating trial in healthy volunteers. The drug was excellently tolerated and pharmacokinetics followed a target mediated drug disposition [35]. In this paper we report the interim findings at week 24 of a pilot study in patients with CHB/CHD co-infection, who were subcutaneously (SC) treated with myrcludex B, PegIFNα-2a, or their combination.

Section snippets

Study design and setting

This pilot study was a sub-study of a phase Ib/IIa randomized, open-label clinical trial of daily myrcludex B vs. entecavir administration in patients with CHB. The study was registered and approved by the competent authority, the Russian Ministry of Health (registration and authorization number 736/November 29th 2013) and was approved by the Ethics Council of the Ministry of Health of the Russian Federation” (Ethics Council approval #73, November 19th 2013) and the Ethics Committee of the

Results

Eight patients were included in each cohort. Eight patients each at week 12 and 24 could be evaluated in the Myr cohort and the IFN cohort for all parameters except HDV RNA, because in both cohorts one patient each had no measurable HDV RNA at baseline in the central research laboratory. Seven patients only could be evaluated at week 12 and 24 in the Myr-IFN cohort because one patient terminated the study prior to week 12 due to a rash. Of the overall 24 patients at baseline, all were HBeAg

Discussion

Our study demonstrated for the first time the clinical ‘proof of concept’ of entry inhibition for CHD patients. As monotherapy myrcludex B was very well tolerated. The combination with PegIFNα-2a did apparently not increase the frequency or severity of the mainly hematological adverse events, which were mostly related to the PegIFNα-2a treatment. All patients with measurable HDV RNA in the Myr cohort experienced a decline of HDV RNA under myrcludex B monotherapy, with two of seven patients

Financial support

This clinical study was supported by Hepatera Ltd, Moscow, who was also legal sponsor of this study. Other partial funding came from Myr GmbH, Bad Homburg, the Bundesministerium für Bildung und Forschung (BMBF), “Innovative Therapieverfahren” and the “Deutsche Zentrum für Infektionsforschung (DZIF)” (German Center for Infection Research, DZIF TTU 05.901, TTU 05.804, TTU 05.904, TTU 05.704). AB has received personal funding from the Medical Faculty of the Heidelberg University. FAL is member of

Conflict of interest

SU is co-applicant and co-inventor of patents protecting myrcludex B. AA is employee of the Myr GmbH, Bad Homburg, partly funding this study.

Authors’ contributions

AB, SU, AA, and WEH analyzed the results and wrote the paper. PB, NV, MM, KK, and MP carried out the clinical study. TL carried out the virus kinetic modeling. MS and MH carried out the bile acid analytics. HW and FAL carried out HDV RNA and immunogenicity analytics. All authors significantly contributed to the manuscript.

Acknowledgements

The authors acknowledge the contributions of all volunteers, investigators, study personnel, the sponsor, the staff from data management (dataMatrix, St. Petersburg, Russia), and the analytical laboratory (Prolytik GmbH, Frankfurt, Germany). We are grateful to Katrin Schöneweiss and the technical assistance of Sarah Engelhardt, Franziska Schlund, and Markus König for analyzing samples. We thank the central diagnostic laboratory of the University Hospital Heidelberg and the Heidelberg Virology

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    These authors contributed equally as senior authors.

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