Bulevirtide: First Approval

Connie Kang1 · Yahiya Y. Syed1

© Springer Nature Switzerland AG 2020

Abstract
Bulevirtide (Hepcludex®), a first-in-class entry inhibitor, is being developed by MYR GmbH for the treatment of chronic hepatitis delta virus (HDV) and chronic hepatitis B virus (HBV) infections. Bulevirtide was recently approved in the European Union (EU) for the treatment of chronic HDV infection in HDV RNA positive adult patients with compensated liver disease. This article summarizes the milestones in the development of bulevirtide leading to this first approval for chronic HDV.

Bulevirtide (Hepcludex®): Key points

An entry inhibitor that is being developed by MYR GmbH for the treatment of chronic HDV and HBV infec- tions.
Received its first approval on 31 July 2020 in the EU. Approved for use in chronic HDV infection in HDV
RNA positive adult patients with compensated liver disease.

1Introduction

Bulevirtide (Hepcludex®; formerly Myrcludex B) is a first-in-class entry inhibitor developed by MYR GmbH for the treatment of chronic HDV and HBV infections [1, 2]. Chronic HDV develops either as co-infection with HBV or as super-infection in patients with chronic HBV. HDV can accelerate hepatitis disease progression and lead to liver cir- rhosis and hepatocellular carcinoma [3]. With an increasing

Enhanced material for this AdisInsight Report can be found at https://doi.org/10.6084/m9.figshare.12806612 .
This profile has been extracted and modified from the AdisInsight database. AdisInsight tracks drug development worldwide through the entire development process, from discovery, through pre- clinical and clinical studies to market launch and beyond.
worldwide prevalence and no cure, treatment options for chronic HDV are an area of unmet need [3]. Bulevirtide inhibits the entry of HDV and HBV into human hepatocytes, leading to recovery and protection of naïve hepatocytes and potential virus eradication [2–4].
Bulevirtide was approved in July 2020 in the EU for the treatment of chronic HDV in HDV RNA positive adult patients with compensated liver disease [2, 5]. The approved dosage of bulevirtide is 2 mg once daily (every 24 h ± 4 h) by subcutaneous (SC) injection as monotherapy or coadministered with a nucleoside/nucleotide analogue for treatment of the underlying HBV infection. Though the optimal treatment duration is unknown, treatment should be continued as long as clinical benefit is evident. As no studies have been conducted with bulevirtide in patients with moderate or severe hepatic impairment, bulevirtide is not recommended in patients with decompensated liver disease [2]. Bulevirtide is currently undergoing phase III development for chronic HDV infection in Germany, USA, Sweden, Italy, Georgia and Russia [6]. The development program for chronic HBV infection is in phase II [6]. The drug is also in phase I stage for dyslipidaemia and in pre- clinical stage for non-alcoholic steatohepatitis and primary biliary cholangitis [6].

1.1Company Agreements

MYR GmbH has exclusive worldwide product rights for bulevirtide [7]. The University Hospital of Heidelberg out- licensed bulevirtide to MYR GmbH; both entities are collab-

*

[email protected]
orating for the development of bulevirtide [6]. MYR GmbH will also co-develop bulevirtide with Hepatera [7]. MYR

1 Springer Nature, Mairangi Bay, Private Bag 65901, Auckland 0754, New Zealand
GmbH has suplicensed the Commonwealth of Independent States rights for bulevirtide to Hepatera [6].

PIM Designation granted in the EU (Dec)

Phase I trial initiated (Jul 2011)

Orphan Drug status granted in the USA (Mar)
Orphan Drug status granted in the EU (Jun)
Breakthrough Therapy designation granted in the USA (Oct)

Approved in the EU (Jul)
Positive Opinion received in the EU (May)

PRIME eligibility granted in the EU (May)

2015 2016 2017 2018 2019 2020 2021 2022 2023

MYR202 (NCT03546621)
MYR203 (NCT02888106)

Phase II trials Phase III trial Phase IV trial
MYR204 (NCT03852433)
MYR301 (NCT03852719)
BuleDelta (NCT04166266)

Est Feb 2025 Est Nov 2025

Key milestones in the development of bulevirtide, focusing on its use in the treatment of chronic hepatitis delta virus. PRIME priority medicines, PIM promising innovative medicine

2Scientific Summary

2.1Pharmacodynamics

Bulevirtide is a synthetic lipopeptide consisting of 47 amino acids of the preS1 domain of the HBV large surface protein [4]. It binds to and competitively inhibits the sodium tauro- cholate co-transporting polypeptide (NTCP), which is a bile salt liver transporter that allows the entry of HDV and HBV into hepatocytes [2, 4]. This inhibition may help hepatocyte regeneration and prevent HDV/HBV reinfection in healthy hepatocytes, leading to a loss of infected hepatocytes from the liver [4].
Bulevirtide inhibited the spread of HBV in mice carrying HBV-infected human hepatocytes [8]. This was evidenced by the lack of increases in viraemia, antigen levels and the amount of HBV core antigen-positive human hepatocytes at week 6 following daily SC administration of bulevirtide [8]. Based on preclinical toxicological studies, there are no special risks with bulevirtide use in humans [2].

2.2Pharmacokinetics

Bulevirtide exhibited non-linear pharmacokinetics in healthy volunteers, following a two-compartment tar- get-mediated drug disposition model [4]. Bulevirtide
exposure increased disproportionally with increasing dose following SC and intravenous administrations; clearance and volume of distribution were reduced [2, 4]. Bioavailability was estimated to be 85% following SC administration [4]. Following bulevirtide 2 mg admin- istration, steady state is expected to be reached within the first weeks, with ≈ 2-fold accumulation ratios for maximum drug concentration (Cmax) and area under the curve (AUC) [2]. Time to Cmax (tmax) was 1–3 h over a bulevirtide dose range of 0.8–10 mg [4]. Increasing body height was linearly associated with an increasing amount of free binding partner (p < 0.001) [4]. Elimination is by a first-order process [4], and is thought to mainly involve target binding to NTCP (as bulevirtide was not found in the urine of healthy volunteers) [2]. Elimination half-life (t1/2) is 4–7 h [2].
In vitro, over 99% of bulevirtide is bound to plasma proteins and is not expected to have active metabolites [2]. Bulevirtide inhibited OATP1B1/3 transporters in vitro (albeit only at a concentration of ≥ 0.5 µM) and may interact with OATP1B1/3 substrates; close monitor- ing is recommended if concomitant therapy is required. Coadministration with NTCP inhibitors (e.g. sulfasala- zine) or NTCP substrates (e.g. atorvastatin) is also not recommended, as these drugs may affect bulevirtide pharmacokinetics [2].

Features and properties of bulevirtide

Alternative names HEPCLUDEX®; MyrB; Myrcludex-B; Myrcludex-B-MYR Pharma
Class Antihyperlipidaemics; Antivirals; Hepatoprotectants; Lipopeptides
Mechanism of action Entry inhibitor, sodium-bile acid co-transporter inhibitor
Route of administration Subcutaneous

Pharmacodynamics
Inhibits sodium taurocholate co-transporting polypeptide (NTCP), thereby preventing hepatitis D and B virus
entry into hepatocytes; inhibits viral spread in mice bearing HBV-infected human hepatocytes

Pharmacokinetics
Exhibits non-linear pharmacokinetics; ≈ 85% bioavailability; tmax 1–3 h; first-order elimination primarily via
target NTCP; elimination t1/2 4–7 h; coadministration with other NTCP-targeting drugs is not recommended

Adverse reactions
Most frequent Increased bile salts, injection site reactions ATC codes
WHO ATC code J05A-X28 (Bulevirtide)
EphMRA ATC code J5B1 (Viral hepatitis products)

Chemical name
N-Tetradecanoylglycyl-Thr-Asn-Leu-Ser-Val-Pro-Asn-Pro-Leu-Gly-Phe-Phe-Pro-Asp-His-Gln-Leu-Asp-Pro- Ala-Phe-Gly-Ala-Asn-Ser-Asn-Asn-Pro-Asp-Trp-Asp-Phe-Asn-Pro-Asn-Lys-Asp-His-Trp-Pro-Glu-Ala-Asn- Lys-Val-Gly-NH2

2.3Therapeutic Trials

Treatment with bulevirtide 2 mg plus tenofovir was associ- ated with a significantly (p < 0.0001 [9]) higher proportion of patients with undetectable HDV RNA or decrease by ≥ 2log10 from baseline to week 24 (primary endpoint) than tenofovir alone (53.6% vs 3.6% of patients, respectively) in the phase II MYR202 (NCT03546621) trial [2, 9]. MYR202 was a multicentre, open-label, randomized trial in patients with chronic HDV with liver cirrhosis, or who failed previous interferon therapy, or for whom such therapy was contraindi- cated (including history of interferon intolerance) [2]. Patients were randomized to bulevirtide 2 mg (n = 28), 5 mg (n = 32) or 10 mg (n = 30) once daily in addition to tenofovir, or to tenofovir alone (n = 28) for 24 weeks. At 24 weeks, alanine aminotransferase (ALT) normalization was achieved by signif- icantly (p ≤ 0.05) more bulevirtide 2 mg plus tenofovir recipi- ents (42.9%) than tenofovir recipients (7.1%). Significantly more bulevirtide 2 mg plus tenofovir recipients achieved the combined treatment endpoint, defined as undetectable HDV RNA or a ≥ 2log10 decline and ALT normalization, than teno- fovir recipients (21.4% vs 0%, respectively) [2].
In MYR202, at 12 weeks’ treatment-free follow up, the median HDV RNA in the bulevirtide 2 mg plus tenofovir arm had increased by 1.26 log (still - 0 .77 log below base- line) compared to no change in the tenofovir arm [10]. HDV RNA relapse was reported in 60% of HDV RNA responders in the bulevirtide 2 mg plus tenofovir arm [10].
In the 48-week MYR203 (NCT02888106) study, patients were randomized to bulevirtide 2 mg or 5 mg once daily plus PEG-INF-α-2a 180 µg, bulevirtide 2 mg alone or PEG-INF- α-2a 180 µg alone for 48 weeks (n = 15 in each arm) [11]. The efficacy profile of bulevirtide 2 mg in this small number

of patients was generally similar to that in the MYR202 study [2]. At week 48, serum HDV RNA was undetectable in more bulevirtide 2 mg plus PEG-INF-α-2a recipients (80% of patients [9]) than bulevirtide or PEG-INF-α-2a recipients (both 13.3%) [9, 11]. Hepatitis B surface antigen (HBsAg) levels declined (by > 1 log) or were undetectable in 46.7% of bulevirtide 2 mg plus PEG-INF-α-2a recipients [11]. No changes were seen in monotherapy recipients [11]. ALT nor- malization at week 48 was most frequent in patients who received bulevirtide only (73.3% of patients [9]) [9, 11].
Final MYR203 results at week 72 (24 weeks’ treatment- free follow-up) show bulevirtide 2 mg plus PEG-INF-α-2a remained effective in terms of the proportion of patients with undetectable serum HDV RNA (53.3% vs 0% of PEG-IFN- α-2a recipients [9]) [9, 11]. At week 72, ALT normalization was most frequently seen in bulevirtide 2 mg plus PEG- INF-α-2a recipients (53.8% [9]) [9, 11]). Six patients (40%) had > 1 log decline or undetectable HBsAg levels compared with 0% of monotherapy recipients [11].
The clinical proof of concept entry inhibition activity of bulevirtide was demonstrated in a randomized, open-label, pilot phase Ib/IIa study (MYR201HDV; NCT02637999) [3]. Patients with chronic HDV/HBV co-infection (n = 24) were administered bulevirtide 2 mg/day for 24 weeks followed by PEG-INF-α-2a for 48 weeks, bulevirtide 2 mg/day plus PEG-INF-α-2a for 24 weeks followed by PEG-INF-α-2a alone for a further 24 weeks, bulevirtide 2 mg/day only for 24 weeks, or PEG-INF-α-2a only for 48 weeks. A clinically relevant effect on HBsAg response was not seen at week 12 (primary endpoint), although HDV RNA decreased at week 24 in all patients. HDV RNA negativity was seen in five of seven bulevirtide plus PEG-INF-α-2a recipients, with ALT normalization occurring only in bulevirtide recipients [3].

Key clinical trials of bulevirtide

Drug(s) Indication Phase Status Location(s) Identifier Sponsor

Bulevirtide HDV, HBV, liver
cirrhosis
IV Ongoing
France
NCT04166266, ANRS-HD-
EP01, BuleDelta
Inserm-ANRS

Bulevirtide HDV infection III
Active, no longer recruiting
Multinational
NCT03852719, EudraCT2019-001213-17, MYR301
Hepatera, MYR GmbH

Bulevirtide, PEG-IFN-α
HDV infection II
Active, no longer recruiting
Multinational
NCT03852433, MYR204
Hepatera, MYR GmbH

Bulevirtide, PEG-IFN-α, tenofovir
HDV infection,
HBV infection
II
Recruiting Russia
NCT02888106, MYR203
Hepatera

Bulevirtide, tenofovir
HDV infection,
HBV infection
II
Completed Germany, Russia NCT03546621, MYR202
Hepatera, MYR GmbH,
Maxwell Biotech Group

Bulevirtide HDV infection,
HBV infection
I/II
Completed Unknown NCT02637999, MYR201HDV Hepatera, MYR GmbH

Bulevirtide HDV infection,
HBV infection
I
Completed Germany
EudraCT2010-022776-31
MYR GmbH

Bulevirtide HBV infection I/II Completed Russia NCT02881008, MYR201HBV Hepatera, Maxwell Bio-
tech Venture Fund

HBV hepatitis B virus, HDV hepatitis D virus, Inserm-ANRS French National Institute for Health and Medical Research-French National Agency for Research on AIDS and Viral Hepatitis, PEG-IFN-α peginterferon-alpha

2.4Adverse Events

Bulevirtide monotherapy or combination therapy was gener- ally well tolerated in clinical trials [2, 3, 10–14]. The most frequently reported adverse reactions (ARs) from the clinical trials were increased total bile salts and injection site reactions [2]. The AR of increased total bile salts was dose dependent, asymptomatic and reversible once treatment was discontinued. Increased ALT level was also a common AR; however, most were reported following treatment discontinuation and possibly associated with hepatitis exacerbation. The most common seri- ous AR was exacerbation of hepatitis following discontinuation of bulevirtide, potentially related to virologic rebound [2].
Within the MYR202 trial, bulevirtide therapy did not result in a specific adverse event (AE) pattern [10]. Increased total bile acid was reported as the most frequent AE. Increased bile salt levels returned to baseline levels at week 1 follow up after cessation of therapy. Two treatment- related serious AEs of hepatitis exacerbations were reported following bulevirtide treatment cessation [10].
In MYR203, by week 72, a higher proportion of AEs were considered related (possible, probably or certain) to PEG- IFN-α than bulevirtide therapy (534 vs 152 events) [9]. The most common AEs (incidence ≥ 40% of all study patients) were increased total bile salts, neutropenia, thrombocytope- nia, leukopenia and increased ALT. One bulevirtide plus PEG- IFN-α recipient experienced two serious AEs of proctitis and anal fistula. Both serious AEs were considered possibly related to PEG-IFN-α treatment and resolved after 5–11 days [9].
2.5Ongoing Clinical Trials

The MYR203 trial is still ongoing with two extension arms investigating high-dose (10 mg) bulevirtide administration as monotherapy and in combination with PEG-IFN-α. An open-label, randomized phase IIb trial (NCT03852433; MYR204) is evaluating bulevirtide in combination with PEG-INF-α-2a in patients with chronic HDV. An open-label, randomized phase III trial (NCT03852719; MYR301) is comparing high- versus low-dose bulevirtide in patients with chronic HDV. A prospective, multi-centre, non-comparative phase IV study (NCT04166266; BuleDelta) is evaluating the efficacy and safety of bulevirtide in patients with chronic HDV/HBV co-infection with either severe fibrosis injuries or moderate fibrosis injuries associated with persistently elevated ALT.

3Current Status

Bulevirtide received its first approval on 31 July 2020 in the EU for chronic HDV infection in plasma (or serum) HDV RNA positive adult patients with compensated liver disease [5].

Acknowledgements During the peer review process the manufac- turer of the agent under review was also offered an opportunity to review this article. Changes resulting from comments received were made on the basis of scientific and editorial merit.

Declarations

Funding The preparation of this review was not supported by any external funding.

Authorship and Conflict of interest Connie Kang and Yahiya Y. Syed are salaried employees of Adis International Ltd/Springer Nature, are responsible for the article content and declare no relevant conflicts of interest.
Ethics approval, Consent to participate, Consent to publish, Availability of data and material, Code availability Not applicable.

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