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 rests primarily on the Phase 3 MYR301 trial (NEJM 2023, PMID 37345876), with supporting data from the monotherapy arm of the Phase 2b MYR204 trial — 50 participants given 8.5 mg once daily for 96 weeks. The pegylated-interferon combination MYR204 also studied is not part of the US approval; interferon appears in the label only as a baseline characteristic of the enrolled population. Approval came under the accelerated pathway on surrogate endpoints (HDV RNA reduction plus ALT normalization), with a confirmatory post-marketing requirement attached. In the EU, the European Commission previously granted conditional marketing authorization in July 2020 on EMA's recommendation (converted to a standard authorization in July 2023) at the 2 mg daily dose. The 8.5 mg US dose is not a third dose: the FDA label records that the MYR301 protocol specified 10 mg and that a later dose-recovery study found the delivered dose was in fact 8.5 mg. The US label therefore describes the trial's higher-dose arm by its measured delivered amount, while the EU label continues to use the genuinely lower 2 mg dose MYR301 ran alongside it. 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 elevation of total bile salts as the documented on-target consequence of NTCP inhibition — it appeared in every treated participant in MYR301, peaked by week 8 and resolved after discontinuation. 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 US label's 8.5 mg is the MYR301 higher-dose arm restated as its measured delivered amount rather than a new dose, while the EU's 2 mg is the genuinely lower of the two the trial compared; 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 Commission, on EMA's recommendation, granted conditional marketing authorization for Hepcludex (bulevirtide) on 31 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 conditional EU authorization was converted to a standard marketing authorization on 18 July 2023. The US regulatory path was less smooth. The FDA issued a Complete Response Letter on 27 October 2022 citing concerns over the manufacture and delivery of bulevirtide; Gilead said at the time that no new safety or efficacy studies had been requested. The final 144-week MYR301 results, published in J Hepatol in 2026, added 96 weeks of post-treatment follow-up and showed that virologic response fell from 73-92% at the end of treatment to 30-33% afterwards. 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 — the MYR301 higher-dose arm restated as its measured delivered amount, and higher than the 2 mg dose the EU authorised — making it the first US-approved therapy for chronic HDV (approval framed as a milestone in a Lancet Microbe August 2026 editorial, PMID 42586109). 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. That structure describes steric occlusion rather than allostery: bulevirtide forms a plug lodged in the bile-salt transport tunnel of NTCP plus a string that covers the receptor's extracellular surface. It inhibits viral entry at sub-nanomolar concentrations while only partially inhibiting bile-salt transport, which is why the on-target bile-salt 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. The 144-week publication (Wedemeyer J Hepatol 2026, PMID 41966308) does not soften it much: it showed response rates roughly halving after discontinuation, which sharpens rather than answers the question of what treatment does to liver-related outcomes. The required confirmatory study is observational, comparing treated patients against a historical control group, with study completion due February 2033 and the final report June 2034.
• 02Optimal treatment duration — the FDA label states plainly that it is unknown and that treatment should continue as long as it is associated with response. The 144-week data give the first concrete predictor of durable off-treatment control (consecutive weeks of HDV RNA undetectability before stopping), but no threshold has been validated, and nothing identifies in advance who will reach it. Real-world response-guided evidence from the Austrian cohort (Schwarz JHEP Rep 2026, PMID 41903606) is beginning to inform this question.
• 03Combination with pegylated interferon — MYR204 demonstrated additive efficacy, but the optimal combination regimen, sequencing, and treatment-duration framework remains to be clarified. Response-guided combination protocols are emerging from real-world European experience but have not been formally tested in a randomized post-approval program.
• 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

Monitoring & Measurement

Common Questions

Who Bulevirtide Is NOT For

Drug & Supplement Interactions

The honest headline is that the FDA label anticipates no clinically meaningful drug interactions. Section 7.1 states that no CYP-enzyme or transporter-mediated inhibition or induction by bulevirtide is anticipated at clinically relevant concentrations, and because bulevirtide is cleared by peptide catabolism rather than hepatic metabolism, other drugs are not expected to alter its exposure either. This is worth stating explicitly because the opposite claim circulates widely. Bulevirtide does inhibit NTCP and the hepatic transporters OATP1B1 and OATP1B3 in vitro, with IC50 values the label gives as 0.32 µM, 0.5 µM and 8.7 µM respectively, and that in-vitro profile has been extrapolated on many sites into warnings about statins, valsartan, sulfasalazine, methotrexate and irinotecan. The label reaches the opposite conclusion — it states that no clinical interaction is expected for OATP1B or NTCP substrates at clinically relevant bulevirtide concentrations — and none of those drugs is named anywhere in it. Treat transporter-substrate warnings attributed to the bulevirtide label as unsourced. 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