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Bulevirtide

Bulevirtide, sold under the brand name Hepcludex, is a first-in-class entry inhibitor antiviral medication used to treat chronic hepatitis delta virus (HDV) infection in adults and children aged 3 years and older weighing at least 10 kg with compensated liver disease, as confirmed by detectable HDV RNA in the blood.^[1] HDV is a defective satellite virus that requires co-infection with hepatitis B virus (HBV) for replication and is considered the most severe form of chronic viral hepatitis, accelerating progression to cirrhosis and hepatocellular carcinoma.^[2] The drug is administered as a daily 2 mg subcutaneous injection, either as monotherapy or in combination with nucleoside or nucleotide analogues active against HBV.^[1] Bulevirtide is a synthetic linear lipopeptide consisting of 47 amino acids, modeled on the pre-S1 domain of the HBV large envelope protein, which specifically binds to and blocks the sodium taurocholate cotransporting polypeptide (NTCP) receptor on hepatocytes—the primary entry point for both HDV and HBV into liver cells—thereby inhibiting viral attachment, internalization, and spread while reducing liver inflammation.^[2] Originally developed as Myrcludex B by the German biotechnology company MYR GmbH (later acquired by Gilead Sciences), it received orphan medicinal product designation from the European Medicines Agency (EMA) on June 19, 2015, and PRIME (Priority Medicines) eligibility on May 18, 2017, to expedite development for this unmet need affecting an estimated 10–25 million people worldwide.^[2] The EMA granted conditional marketing authorization on July 31, 2020, based on phase 2 data, with conversion to full authorization on July 18, 2023, following confirmatory phase 3 results; it has also been approved in the United Kingdom, Switzerland, Australia, and Canada but remains unapproved in the United States. The FDA issued a complete response letter in 2022 due to manufacturing concerns; a Biologics License Application for the 10 mg dose was submitted on September 22, 2025.^[1]^[3]^[4]^[5] In pivotal clinical trials, bulevirtide has shown significant antiviral activity against all HDV genotypes, with a dose-dependent reduction in HDV RNA levels and normalization of alanine aminotransferase (ALT). In the phase 2 MYR202 trial involving 90 patients with chronic HDV, 53.6% on 2 mg daily achieved a virologic response (≥2 log₁₀ IU/mL decline or undetectable HDV RNA) after 24 weeks, compared to 3.6% on tenofovir alone, alongside 42.9% ALT normalization versus 7.1%.^[2] The phase 3 MYR301 trial, a randomized study of 150 patients, reported combined responses (virologic improvement plus ALT normalization) in 45% on 2 mg and 48% on 10 mg at 48 weeks, versus 2% in untreated controls (P<0.001), with 12–20% achieving undetectable HDV RNA.^[6] Safety data from over 400 patients indicate mostly mild to moderate adverse events, including elevated bile salts (up to 39%), injection-site reactions, pruritus, headache, and gastrointestinal symptoms, with no treatment-related serious events or discontinuations due to toxicity in the phase 3 trial, though monitoring for bile acid elevations and potential flares upon discontinuation is required.^[1]^[6]

Medical uses

Indications

Bulevirtide is indicated for the treatment of chronic hepatitis delta virus (HDV) infection in plasma or serum HDV-RNA positive adults and pediatric patients aged 3 years and older weighing at least 10 kg with compensated liver disease.^[7] This approval addresses chronic HDV, which typically occurs as a co-infection with hepatitis B virus (HBV), as HDV is a satellite virus dependent on HBV for replication and propagation.^[7]^[6] The rationale for bulevirtide's use stems from the accelerated liver damage caused by chronic HDV infection, which progresses more rapidly to cirrhosis and hepatocellular carcinoma than HBV infection alone, representing a major unmet medical need due to the prior absence of approved specific antiviral therapies.^[6]^[1] As a first-in-class entry inhibitor, bulevirtide targets HDV entry into hepatocytes to suppress viral replication and mitigate liver inflammation.^[8]^[7] Patient selection is limited to individuals with stable liver function, such as those with Child-Pugh class A cirrhosis, excluding patients with decompensated cirrhosis, acute HDV infection, or unestablished safety in conditions like decompensated liver disease.^[7]^[9] During treatment, regular monitoring of HDV RNA levels, alanine aminotransferase (ALT), and liver function tests is required to evaluate virological and biochemical responses, as well as to detect any potential exacerbation upon discontinuation.^[7]^[6]

Administration

Bulevirtide is administered as a subcutaneous injection for the treatment of chronic hepatitis delta virus infection in patients with compensated liver disease. The dosage is 2 mg once daily for adults (≥35 kg) and weight-based for pediatric patients: 1 mg (0.5 mL) for those weighing 10 to <25 kg, 1.5 mg (0.75 mL) for 25 to <35 kg, and 2 mg (1 mL) for ≥35 kg, administered every 24 hours with a tolerance of ±4 hours.^[7] The drug is provided as a lyophilized powder in single-dose vials, which must be reconstituted prior to use by adding 1 mL of sterile water for injection, followed by gentle swirling or rolling of the vial for up to 3 minutes until the solution is clear and free of particles or foam. The reconstituted solution has a concentration of 2 mg/mL and should be used immediately, or if necessary, stored for up to 2 hours at room temperature (not exceeding 25°C); it should not be refrigerated or frozen after reconstitution. Unreconstituted vials must be stored refrigerated at 2°C to 8°C and protected from light.^[7]^[10] Subcutaneous injections are typically performed in the upper thigh or lower abdomen, rotating sites to avoid irritation, though the back of the upper arm may be used with caregiver assistance; areas such as the knee, groin, navel, or sites with scars, bruises, or inflammation should be avoided. Patients can be trained for self-administration after receiving proper instruction from a healthcare professional. No oral formulation of bulevirtide is available.^[7]^[10] Treatment should be continued as long as there is clinical benefit, with discontinuation considered after at least 6 months of sustained HBsAg seroconversion if achieved, or upon loss of response. Combination therapy with ongoing nucleoside or nucleotide analogues for HBV suppression may be continued if applicable.^[7] No dose adjustments are required for patients with mild hepatic impairment (Child-Pugh class A); however, data are limited for moderate to severe hepatic impairment, decompensated cirrhosis, or renal impairment, and close monitoring is recommended in these populations, with use not recommended in decompensated liver disease.^[7]^[10]

Safety profile

Adverse effects

Bulevirtide treatment is generally well tolerated, with most adverse effects being mild to moderate in severity. In clinical trials, no treatment-related serious adverse events were reported, and there were no discontinuations due to adverse effects.^[6] Very common adverse effects, occurring in ≥1/10 of patients, include asymptomatic elevations in bile salts due to inhibition of the sodium taurocholate cotransporting polypeptide (NTCP), headache, pruritus, and injection site reactions such as erythema, pain, swelling, induration, rash, hematoma, or dermatitis.^[7] These injection site reactions affected 16% to 30% of patients in the phase 3 MYR301 trial, depending on the dose (2 mg or 10 mg daily), and were typically grade 1 or 2.^[6] Common adverse effects, occurring in ≥1/100 to <1/10 of patients, encompass eosinophilia (an elevation in white blood cell count), dizziness, nausea, fatigue, and arthralgia.^[7] In the phase 3 trial, fatigue was reported in 10% to 14% of treated patients and headache in 18% to 20%.^[6] Uncommon adverse effects, occurring in ≥1/1,000 to <1/100 of patients, include hypersensitivity reactions such as rash, itching, or swelling, potentially progressing to anaphylaxis.^[7] A notable serious effect, observed in <1% but highlighted in post-treatment monitoring, is potential exacerbation of hepatitis upon discontinuation, with alanine aminotransferase (ALT) elevations >5 times the upper limit of normal in up to 27% of patients in some studies.^[11] Management involves regular monitoring of bile acid levels and liver enzymes, particularly in patients with renal impairment where elevations may be more pronounced.^[7] Mild effects are typically managed symptomatically, such as with antihistamines or corticosteroids for injection site reactions or pruritus, while severe hypersensitivity requires immediate discontinuation.^[11] Safety data in pediatric patients (aged 3-17 years) are limited but suggest a similar profile to adults based on pharmacokinetic and tolerability studies; ongoing monitoring is recommended.^[12] Long-term data from phase 3 trials, including extensions up to 96 weeks, indicate that most adverse effects remain mild and reversible upon cessation, with no new safety signals or increased risk of malignancy observed.^[8] An integrated safety analysis across trials confirmed tolerability through 48 weeks, with bile acid elevations resolving post-treatment in the majority of cases.^[13]

Contraindications

Bulevirtide is contraindicated in individuals with known hypersensitivity to the active substance or to any of the excipients.^[7] This absolute contraindication stems from the potential for severe allergic reactions, where the risks clearly outweigh any therapeutic benefits.^[14] Use of bulevirtide is not recommended in patients with decompensated liver disease, including those classified as Child-Pugh B or C, as no studies have evaluated its safety or efficacy in this population, and underlying hepatic instability may exacerbate treatment-related risks such as bile salt elevations.^[7] Use with caution in patients with severe renal impairment (creatinine clearance <60 mL/min) or end-stage renal disease due to limited data; close monitoring of bile acid levels is recommended.^[10] Bulevirtide is also not indicated for acute hepatitis delta virus (HDV) infection or as monotherapy for hepatitis B virus (HBV) without concomitant HDV, as its approval is restricted to chronic HDV in compensated liver disease.^[7] In pregnant women, bulevirtide should be avoided unless the clinical need outweighs potential risks, given the absence of adequate human data despite no observed reproductive toxicity in animal studies; effective contraception is advised for women of childbearing potential during treatment and for at least one month after discontinuation.^[7] Breastfeeding should be discontinued during therapy, as it is unknown whether bulevirtide is excreted in human milk.^[14] Regarding drug interactions, no absolute contraindications exist, but co-administration with other sodium taurocholate co-transporting polypeptide (NTCP) inhibitors, such as cyclosporine, should be avoided to prevent enhanced inhibition and potential toxicity; monitoring is required with bile acid-binding resins or other interacting agents like rifampicin.^[7] These restrictions are grounded in bulevirtide's pharmacological profile as an NTCP entry inhibitor, which disrupts bile acid homeostasis and HBV/HDV uptake, leading to heightened risks in vulnerable populations where benefits do not justify potential harm.^[10]

Pharmacology

Mechanism of action

Bulevirtide is a synthetic lipopeptide that acts as an entry inhibitor for hepatitis B virus (HBV) and hepatitis D virus (HDV) by targeting the sodium/taurocholate cotransporting polypeptide (NTCP), a hepatocyte-specific receptor essential for viral attachment and uptake.^[2]^[6] Derived from the pre-S1 domain of the HBV large surface protein, bulevirtide mimics the viral attachment mechanism but competitively binds to NTCP with high affinity (IC₅₀ ≈ 140 pM), preventing the viruses from interacting with the receptor.^[15]^[6] The binding involves the myristoylated N-terminal region of bulevirtide, which anchors into a hydrophobic pocket on NTCP, while the peptide's "plug" (residues 2–20) and "string" (residues 21–47) domains occupy the transporter's translocation tunnel and extracellular loops, respectively, thereby blocking the viral pre-S1 domain from accessing the receptor.^[15]^[2] This interaction sterically occludes NTCP's viral binding sites, inhibiting HBV and HDV entry into hepatocytes and reducing de novo infections, but it does not interfere with intracellular viral replication or assembly of existing virions.^[15]^[6] Cryo-electron microscopy (cryo-EM) structures resolved in 2024 at 3.4 Å resolution reveal that bulevirtide buries approximately 2064 Å² of NTCP's surface area, with the myristoyl group inserting into transmembrane helices TM4 and TM5, and the peptide chain extending across extracellular loop 1 (ECL1) to disrupt the bile acid-binding pocket.^[15] These structural insights explain resistance mutations, such as NTCP variants G158R and S267F, which alter the binding interface and reduce bulevirtide affinity while also conferring natural protection against HBV/HDV infection.^[15] As a secondary effect, bulevirtide inhibits NTCP-mediated uptake of bile acids (IC₅₀ ≈ 195 nM), leading to elevated serum bile salt levels (up to 3-fold increase at therapeutic doses), which is an asymptomatic pharmacodynamic marker without direct antiviral activity inside infected cells.^[15]^[2]^[16]

Pharmacokinetics

Bulevirtide is administered via subcutaneous injection, leading to rapid absorption with maximum plasma concentrations (C_max) achieved within 0.5 to 3 hours post-dose.^[10] The absolute bioavailability following subcutaneous administration is estimated at 48% for a 5 mg dose and 57% for a 10 mg dose, with modeling suggesting approximately 85% for clinical doses including 2 mg.^[2] At steady state with the recommended 2 mg daily dose, C_max is approximately 22 ng/mL and the area under the curve (AUC_0-24h) is 180 h·ng/mL, with about 2-fold accumulation and steady-state concentrations reached after approximately 14 days.^[10] Pharmacokinetics are nonlinear, following a two-compartment target-mediated drug disposition model due to binding to the sodium taurocholate co-transporting polypeptide (NTCP) receptor.^[7] Distribution of bulevirtide occurs primarily in the extracellular space, with an apparent volume of distribution ranging from 43 L to 133 L depending on dose and study conditions, which is smaller than total body water volume.^[10]^[2] The drug is highly bound to plasma proteins (>99%), primarily albumin, and its binding to NTCP on hepatocytes facilitates targeted liver distribution with limited penetration into the central nervous system.^[17]^[7] Metabolism of bulevirtide involves proteolytic degradation by peptidases into smaller peptides and amino acids, with no active metabolites formed and no significant involvement of cytochrome P450 enzymes.^[10] The myristoyl group attached to the peptide may undergo hydrolysis, but overall hepatic metabolism is minimal.^[2] Excretion of bulevirtide occurs mainly through receptor-mediated elimination via NTCP binding rather than renal or biliary routes, with no intact peptide detected in urine.^[7] The terminal half-life is 3 to 7 hours, though functional effects on NTCP receptor occupancy persist for over 24 hours.^[10] The apparent systemic clearance is approximately 12.8 L/h.^[10] The subcutaneous route avoids first-pass metabolism.^[2] In special populations, bulevirtide pharmacokinetics show no clinically relevant changes in mild hepatic impairment (Child-Pugh A), with no dose adjustment required.^[10] Data are limited for moderate or severe hepatic impairment and for renal impairment (no studies in patients with creatinine clearance <60 mL/min), though patients with severe renal dysfunction were excluded from clinical trials due to potential impacts on bile acid handling.^[2] No specific data exist for elderly patients (>65 years) or pediatric populations.^[7]

Chemistry

Properties

Bulevirtide is a synthetic 47-amino acid lipopeptide derived from the pre-S1 domain of the hepatitis B virus large surface protein.^[2] Its molecular formula is C₂₄₈H₃₅₅N₆₅O₇₂, and it has a molecular weight of approximately 5399 Da.^[18] The compound is formulated as the acetate salt to enhance its pharmaceutical utility.^[2] Bulevirtide exhibits poor solubility in water, with solubility reported at about 1 mg/mL in 50% acetic acid and approximately 7 mg/mL in carbonate buffer at pH 8.8; it is stable in solution within a pH range of 6-8.^[2] The commercial formulation is a lyophilized powder for solution for injection, containing mannitol as the primary excipient and no preservatives; it is reconstituted with sterile water for injection to yield a clear solution at approximately 2 mg/mL, with a pH of about 9.0 and osmolality around 300 mOsm/kg.^[7] For stability, unopened vials should be refrigerated at 2-8°C and protected from light, with a shelf life of 3 years; freezing must be avoided, and the reconstituted solution remains stable for up to 2 hours at room temperature (25°C).^[7] Bulevirtide is produced through solid-phase peptide synthesis, featuring myristoylation at the N-terminal glycine residue, followed by purification to achieve high purity suitable for clinical use.^[2]

Structure

Bulevirtide is a synthetic lipopeptide consisting of 47 L-amino acids derived from amino acid positions 2–48 of the pre-S1 domain of the hepatitis B virus (HBV) large surface protein, specifically based on genotype D sequence with a Gln46Lys substitution for enhanced activity.^[2]^[15] Its amino acid sequence is N-myristoyl-Gly-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, with the C-terminus amidated.^[2] A critical modification is N-terminal myristoylation, where a 14-carbon saturated fatty acid (myristic acid) is attached to the glycine residue via an amide bond, promoting membrane association; the peptide is linear and lacks disulfide bonds for stability.^[2]^[19] In its three-dimensional conformation, as revealed by a 2024 cryo-electron microscopy (cryo-EM) structure at 3.4 Å resolution bound to the sodium taurocholate cotransporting polypeptide (NTCP), bulevirtide adopts an extended, non-helical form divided into three functional parts: the myristoylated N-terminal glycine anchors into the lipid bilayer and interacts with NTCP transmembrane helices TM4 and TM5; a globular "plug" domain (Gly²–Asp²⁰) wedges into the NTCP translocation tunnel to occlude the central binding pocket; and a flexible "string" domain (Pro²¹–Gly⁴⁸) drapes across the extracellular surface, binding to extracellular loop 1 (ECL1) and further blocking access.^[15] This architecture enables bulevirtide to sterically hinder both viral entry and bile salt transport through NTCP.^[15] Bulevirtide, formerly known as Myrcludex B, represents a optimized analog of the natural HBV pre-S1 lipopeptide, with no stereoisomers due to its composition of standard L-amino acids.^[2] For a visual representation of its molecular formula (C₂₄₈H₃₅₅N₆₅O₇₂) and connectivity, refer to PubChem compound ID 134687648.^[19]

Development and regulation

Research history

Bulevirtide, originally known as Myrcludex B, emerged from research in the 2000s focused on the pre-S1 domain of the hepatitis B virus (HBV) large surface protein, led by Stephan Urban at Heidelberg University Hospital and supported by the German Center for Infection Research (DZIF).^[20] Urban's group identified the critical role of the myristoylated pre-S1 peptide in HBV attachment to hepatocytes as early as 2002 in duck HBV models, with human applications advancing through studies showing specific binding to differentiated hepatocytes. Between 2008 and 2012, this work culminated in the recognition of the peptide as a high-affinity binder to the sodium taurocholate cotransporting polypeptide (NTCP), the HBV/HDV entry receptor, enabling targeted inhibition of viral entry.^[21] Preclinical development validated bulevirtide's efficacy in blocking HDV entry using animal models, including woodchucks susceptible to HDV and humanized mice engrafted with human hepatocytes to mimic HBV/HDV infection. In these models, subcutaneous administration of the myristoylated peptide prevented intrahepatic virus spreading and reduced viremia without toxicity, supporting its advancement to clinical testing.^[22] MYR GmbH, which licensed the compound, initiated phase 1 trials in 2015 to assess safety, pharmacokinetics, and tolerability in healthy volunteers and HBV/HDV patients, confirming a favorable profile with no serious adverse events at doses up to 10 mg daily.^[23] Key clinical trials advanced bulevirtide's evaluation for chronic HDV. The phase 2 studies MYR202 and MYR203, conducted from 2016 to 2018, tested subcutaneous doses of 2 mg, 5 mg, and 10 mg daily as monotherapy or with pegylated interferon in patients with compensated chronic HDV, demonstrating significant HDV RNA reductions (≥2 log IU/mL in up to 50% of participants at 24 weeks) and biochemical improvements without virologic breakthroughs upon cessation. Building on this, the phase 3 MYR301 trial (2018–2021) randomized 150 adults with compensated chronic HDV to 2 mg bulevirtide, 10 mg bulevirtide, or placebo for 48 weeks, meeting its primary endpoint of combined virologic response (HDV RNA undetectable or ≥2 log reduction) and alanine aminotransferase normalization in 45% of the 2 mg group versus 2% on placebo.^[6] Post-approval research has focused on long-term efficacy and real-world application. Extensions of the MYR301 trial to 144 weeks, with data reported in 2025, showed undetectable HDV RNA rates of 29% in the 2 mg arm and 50–52% in the 10 mg arms, alongside ongoing ALT normalization in over 50% of participants and no disease progression.^[24] Real-world evidence from European compassionate use programs, involving 114 patients with advanced HDV since 2020, corroborates these findings, with HDV RNA suppression in 58% at 24 weeks and improved liver function in cirrhotic cases.^[25] MYR GmbH drove early development from preclinical stages through phase 3, culminating in European conditional approval in 2020, after which Gilead Sciences acquired the company for up to €1.45 billion to expand global access.^[26] Regulatory challenges included a 2022 U.S. FDA complete response letter citing manufacturing and delivery issues, which Gilead addressed through process improvements without requiring new efficacy data.^[3]

Approvals

Bulevirtide, marketed as Hepcludex by Gilead Sciences, received conditional marketing authorization from the European Medicines Agency (EMA) on July 31, 2020, for the treatment of chronic hepatitis delta virus (HDV) infection in adults with compensated liver disease.^[1] This authorization was based on phase 2 clinical data demonstrating virologic response, with the obligation to confirm benefits through ongoing studies. In July 2023, the European Commission converted this to full marketing authorization following positive results from the phase 3 MYR301 trial, solidifying its status as the first approved therapy for this indication in the European Economic Area.^[27] Beyond the EU, bulevirtide has gained approvals in several regions. Health Canada issued a Notice of Compliance on August 8, 2025, authorizing Hepcludex for chronic HDV in adults with compensated liver disease.^[4] In Switzerland, Swissmedic granted marketing authorization on February 5, 2024, after prior orphan drug designation in March 2021.^[28] The Therapeutic Goods Administration (TGA) in Australia approved it on July 30, 2024, for the same indication in adults, with subsequent Pharmaceutical Benefits Scheme listing recommended in August 2025 to improve access.^[29] In the United States, bulevirtide remains unapproved as of November 2025. Gilead submitted a Biologics License Application (BLA) in December 2021, but received a Complete Response Letter (CRL) on October 27, 2022, citing deficiencies in chemistry, manufacturing, and controls without raising safety or efficacy concerns. A new BLA for bulevirtide 10 mg was submitted on September 22, 2025, and is currently under FDA review.^[3]^[30] The approved labeling specifies bulevirtide as monotherapy for chronic HDV in adults with compensated liver disease, reflecting its orphan drug status across multiple jurisdictions—including the EU (designated in 2015), US, and Switzerland—due to the rarity of HDV, which affects an estimated 12-15 million people globally among those with chronic hepatitis B.^[31]^[32] Post-approval commitments include ongoing monitoring for antidrug antibodies (ADA), which have shown low incidence in clinical studies (detected in a minority of patients via ELISA, with no clear impact on efficacy or safety).^[7] In the EU, pricing is approximately €8,500-13,500 per month, with Gilead offering patient assistance programs to facilitate access in approved regions.^[33]^[34]

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