Bulevirtide

What is Bulevirtide?

Bulevirtide (Hepcludex, US nonproprietary name bulevirtide-gmod; original research code Myrcludex B) is a synthetic 47-amino-acid lipopeptide derived from the pre-S1 domain of the hepatitis B virus large envelope protein with N-terminal myristoylation. It is the first-in-class entry inhibitor for chronic hepatitis delta virus (HDV) infection — a defective satellite RNA virus that requires hepatitis B virus (HBV) co-infection to replicate and causes the most severe form of viral hepatitis. Bulevirtide binds the sodium taurocholate cotransporting polypeptide (NTCP, encoded by SLC10A1), the primary bile acid uptake transporter on hepatocyte basolateral membranes that doubles as the functional cellular receptor for HBV and HDV viral entry. By occupying NTCP, bulevirtide blocks viral attachment and entry into hepatocytes, halting the spread of HDV infection across the liver. The FDA granted accelerated approval to Hepcludex (bulevirtide-gmod) on May 22, 2026 — the first US-approved therapy for chronic HDV. The approved indication covers adults with chronic HDV infection without cirrhosis or with compensated cirrhosis, at a once-daily 8.5 mg subcutaneous dose. The approval was supported by Phase 3 MYR301 (NEJM 2023, PMID 37345876) and MYR204 (NEJM 2024, PMID 38842520) combination data, and came under accelerated-approval pathway based on surrogate endpoints (HDV RNA reduction plus ALT normalization) with a post-marketing requirement for long-term confirmatory outcomes. The European Medicines Agency previously granted conditional marketing authorization in July 2020 (full authorization in July 2023) at the 2 mg daily dose. The US 8.5 mg dose reflects label optimization based on the MYR301 dose-response analysis showing similar efficacy between 2 mg and 10 mg arms with the higher dose providing a safety margin in the broader US population. Bulevirtide is developed and commercialized by Gilead Sciences, which acquired the asset from MYR GmbH in March 2021.

What Bulevirtide Is Investigated For

Bulevirtide is the first US-approved therapy for chronic hepatitis delta virus (HDV) — a long-standing unmet need in hepatology, given HDV's classification as the most severe form of viral hepatitis and the absence of any FDA-approved option until May 22, 2026. The drug is a 47-amino-acid lipopeptide derived from the pre-S1 domain of HBV that blocks viral entry by binding the cellular receptor NTCP on hepatocytes. The strongest clinical evidence is the Phase 3 MYR301 trial (NEJM 2023, n=150, 1:1:1 to bulevirtide 2 mg/day, 10 mg/day, or delayed treatment): 45% of patients on 2 mg and 48% on 10 mg achieved the combined endpoint (HDV RNA ≥2 log10 decline or undetectable plus ALT normalization) at 48 weeks, versus 2% in the delayed-treatment arm (p<0.001). MYR204 (NEJM 2024) demonstrated additive efficacy when bulevirtide is combined with pegylated interferon-alpha-2a, providing an option for patients seeking higher response rates. The mechanism is mechanistically clean: NTCP receptor binding blocks new HDV-infected hepatocytes from forming, allowing the existing infected hepatocyte population to turn over without viral replenishment. Common side effects (≥10%) are injection-site reactions, headache, abdominal pain, fatigue, and pruritus, with asymptomatic elevations of bile acids and bilirubin as a documented on-target consequence of NTCP inhibition. The boxed warning specifies severe acute exacerbations of hepatitis D and B on discontinuation — patients require 6 months of hepatic monitoring after stopping, particularly those with compensated cirrhosis. Honest caveats: the accelerated-approval pathway requires a confirmatory long-term outcomes study; the 8.5 mg US dose is novel and differs from the 2 mg dose used in EU practice and most published trials; and bulevirtide does not cure HDV — discontinuation typically allows viral replication to resume from the residual infected hepatocyte pool.

History & Discovery

Bulevirtide's story begins with the long-standing puzzle of how hepatitis B and D viruses recognize and enter hepatocytes. The pre-S1 domain of HBV's large envelope protein had been understood for decades to mediate cellular entry, but the cellular receptor remained unidentified until Yan and colleagues at the National Institute of Biological Sciences in Beijing identified NTCP (sodium taurocholate cotransporting polypeptide, SLC10A1) as the functional HBV and HDV entry receptor in their 2012 eLife paper (PMID 23150796). The discovery transformed HBV/HDV drug development by revealing that the bile acid transporter on hepatocyte basolateral membranes was the target. Myrcludex B, a synthetic lipopeptide corresponding to residues 2–48 of the pre-S1 domain with N-terminal myristoylation, was developed in parallel at Heidelberg University and the German Center for Infection Research as the first synthetic competitor at the NTCP entry site. Pre-clinical work demonstrated sub-nanomolar inhibition of viral entry and acceptable safety, and the molecule entered clinical development under MYR GmbH, a Heidelberg-based biotech spinoff. Early Phase 1 and Phase 2 trials (MYR202, MYR203) established proof-of-concept for chronic HDV — a population where no approved therapy existed and only off-label pegylated interferon-alpha provided low response rates (~25%) with substantial tolerability burden. The European Medicines Agency granted conditional marketing authorization for Hepcludex (bulevirtide) in July 2020 at the 2 mg daily subcutaneous dose, the first regulatory approval for any HDV therapy worldwide. Gilead Sciences acquired MYR GmbH in March 2021 for approximately €1.15 billion cash plus up to €300 million in milestones, taking over global development and commercialization. The Phase 3 MYR301 trial published in NEJM in 2023 (Wedemeyer et al., PMID 37345876) demonstrated 45% combined response at the 2 mg dose and 48% at the 10 mg dose versus 2% in the delayed-treatment arm at 48 weeks (n=150). MYR204 (Asselah et al., NEJM 2024, PMID 38842520) demonstrated additive efficacy when bulevirtide is combined with pegylated interferon-alpha-2a. The EMA upgraded the conditional approval to full marketing authorization in July 2023. The US regulatory path was less smooth. The FDA issued a Complete Response Letter in 2022 over manufacturing and delivery-device concerns, requiring Gilead to address CMC issues and reformulate. Final 144-week MYR301 follow-up presented in May 2025 supported durable response and post-discontinuation undetectability in subsets of patients with longer treatment exposure. The FDA granted accelerated approval to Hepcludex (US nonproprietary name bulevirtide-gmod) on May 22, 2026 at the 8.5 mg once-daily subcutaneous dose — different from the 2 mg EU dose — making it the first US-approved therapy for chronic HDV. The label covers adults with chronic HDV infection without cirrhosis or with compensated cirrhosis, and carries a boxed warning for severe acute hepatitis D and B exacerbations on discontinuation, particularly in cirrhotic patients. Gilead estimates 40,000–80,000 affected individuals in the US. The accelerated-approval pathway requires a post-marketing confirmatory outcomes study to characterize long-term clinical event reduction.

How It Works

Hepatitis D virus needs to attach to a specific door on liver cells to get inside and infect them. That door is a protein called NTCP, which normally lets the liver absorb bile acids. Bulevirtide is a synthetic copy of the part of hepatitis B that normally binds to NTCP — but instead of letting HBV/HDV in, it sits in the doorway and blocks new viruses from entering. The existing infected cells eventually die off without spreading the infection, gradually reducing the viral load.

Bulevirtide is a 47-amino-acid synthetic lipopeptide derived from the pre-S1 domain (residues 2–48) of the hepatitis B virus large envelope protein (L-HBsAg), with N-terminal myristoylation that enables membrane association. The myristoyl group and the specific pre-S1 sequence together confer high-affinity, sub-nanomolar binding to NTCP (sodium taurocholate cotransporting polypeptide, encoded by SLC10A1) — the primary bile acid uptake transporter on hepatocyte basolateral membranes and, as established by Yan and colleagues in eLife 2012 (PMID 23150796), the functional cellular receptor for HBV and HDV viral entry. Under normal physiology, NTCP imports sodium-coupled bile acids from sinusoidal blood into hepatocytes for biliary secretion. HBV and HDV exploit NTCP as an entry point: the pre-S1 domain of HBV's envelope protein binds NTCP, triggering endocytosis of the virion. HDV, as a defective satellite virus, packages itself in HBV's envelope and uses the same entry pathway. Bulevirtide's lipopeptide structure occupies the NTCP binding pocket with much higher affinity than the bile acids the transporter normally handles — Liu and colleagues (Nature Communications 2024, PMID 38509088) published a cryo-EM structure of the bulevirtide-NTCP complex that visualized the binding interaction. The mechanism is allosteric in nature with respect to bile acid transport: bulevirtide inhibits viral entry at sub-nanomolar concentrations but only partially inhibits bile acid transport, which is why the on-target side effect of bile acid and bilirubin elevation is typically asymptomatic rather than producing overt cholestasis. Because bulevirtide blocks new viral entry rather than directly clearing existing infection, the therapeutic effect develops over time as infected hepatocytes turn over without viral replenishment. Allweiss and colleagues (J Hepatol 2024, PMID 38340811) demonstrated in human liver biopsies that bulevirtide treatment reduces the number of HDV-infected hepatocytes, providing direct histologic evidence of the on-treatment effect. The mechanism explains both the gradual onset of efficacy (months of treatment required for full response) and the boxed warning for severe hepatitis flare on discontinuation: stopping the drug allows the residual HBV reservoir to resume HDV propagation, occasionally producing rebound viremia and immune-mediated liver injury, particularly in compensated cirrhosis where reserve is limited.

Evidence Snapshot

Research Gaps & Open Questions

What the current literature has not yet settled about Bulevirtide:

• 01Long-term clinical outcomes (liver decompensation, HCC, transplant, mortality) — the post-marketing confirmatory study required under accelerated approval will be definitive.
• 02Optimal treatment duration — durable post-discontinuation response in subsets is encouraging but the criteria predicting which patients achieve sustained response are not established.
• 03Combination with pegylated interferon — MYR204 demonstrated additive efficacy, but the optimal combination regimen, sequencing, and treatment-duration framework remains to be clarified.
• 04Decompensated cirrhosis and HCC — not yet studied at scale; an unmet need given that HDV accelerates progression to these stages.
• 05Pediatric efficacy and safety — limited data; HDV in children is uncommon but not absent.
• 06HIV/HCV co-infection — limited data, though these populations are clinically common.
• 07Combination with next-generation HBV therapies — once-curative HBV regimens emerge, the optimal pairing with bulevirtide for HDV will become an active question.

Forms & Administration

Once-daily subcutaneous injection (Hepcludex/bulevirtide-gmod) — US-approved dose is 8.5 mg SC daily; EU-approved dose is 2 mg SC daily. Supplied as a powder for reconstitution. Administered by the patient at home after training. Concomitant HBV nucleos(t)ide analog therapy (entecavir, tenofovir disoproxil fumarate, or tenofovir alafenamide) is the standard backbone — bulevirtide alone does not treat HBV.

Dosing & Protocols

The ranges below reflect protocols commonly discussed in the literature and by clinicians — not a prescription. Actual dosing for any individual should be determined by a qualified healthcare provider who knows the patient.

Hepcludex is FDA-approved and prescription-only. The doses described reflect the approved US and EU labels. Bulevirtide is not a curative therapy for HDV — it suppresses viral replication during treatment, and discontinuation can trigger viral rebound and severe hepatitis flare in some patients.

Timeline of Effects

Common Questions

Who Bulevirtide Is NOT For

Drug & Supplement Interactions

Bulevirtide inhibits NTCP and other hepatic organic anion transporting polypeptides (OATPs). Substrates of these transporters may have increased plasma exposure when co-administered: HMG-CoA reductase inhibitors (statins — particularly rosuvastatin, atorvastatin, simvastatin), angiotensin receptor blockers (valsartan), sulfasalazine, methotrexate, and irinotecan are among the clinically relevant categories. The FDA label provides specific guidance on dose adjustment or monitoring for these combinations. Concomitant HBV nucleos(t)ide analogs (entecavir, tenofovir disoproxil fumarate, tenofovir alafenamide) are the standard combination and do not have problematic interactions. Pegylated interferon-alpha-2a combination is the basis of the MYR204 regimen and is generally well-tolerated, though additive cytopenias and constitutional symptoms apply.

Safety Profile

Legal Status

Regulatory status changes over time. Verify current local rules with a qualified professional.

Myths & Misconceptions