A Phase 2b/3, Open-Label, Multicenter Trial Evaluating the Efficacy and Safety of Switching to Brelovitug for the Treatment of Chronic Hepatitis Delta Infection in Participants Receiving Bulevirtide (AZURE-3)

The primary objective is to evaluate the efficacy of switching from **bulevirtide** to treatment with **brelovitug** in patients with **chronic hepatitis delta infection** at Week 24. This objective addresses the clinical need to assess whether transitioning therapy can maintain or improve virological control in patients currently receiving bulevirtide treatment.

The secondary objectives include:

• To evaluate the **safety** and **tolerability** of switching from bulevirtide to treatment with brelovitug

• To characterize the efficacy of switching from bulevirtide to treatment with brelovitug

• To evaluate the **HDV clearance rates** after treatment in participants who do not rollover to the extended treatment protocol

This clinical trial enrolled a total of **10 participants** diagnosed with **chronic hepatitis D infection**. The study population included both **male and female** subjects aged **18 years and older**, comprising adults and elderly individuals. Participants were required to be currently receiving **bulevirtide treatment** for a minimum of 6 months prior to enrollment. All subjects were taking or willing to take **tenofovir disoproxil fumarate (TDF)**, **tenofovir alafenamide (TAF)**, or **entecavir (ETV)** at baseline and were expected to maintain stable antiviral therapy throughout the study duration. Eligible participants demonstrated detectable **HDV RNA** levels of at least 100 IU/mL at screening. The trial specifically excluded vulnerable populations and focused on patients with established chronic hepatitis D who had been on stable bulevirtide therapy, ensuring a homogeneous population for evaluating the efficacy of switching to brelovitug treatment.

This is a Phase 2b/3, open-label, multicenter clinical trial designed to evaluate the efficacy and safety of switching from bulevirtide to brelovitug (BJT-778) in participants with chronic hepatitis D infection. The trial employs an open-label design, meaning that both participants and investigators are aware of the treatment assignment. The study involves two investigational medicinal products: BJT-778, administered as a solution for injection via subcutaneous injection at a maximum daily dose of 300 mg for up to 96 weeks, and bulevirtide, used as a comparator, administered subcutaneously at a maximum daily dose of 2 mg for up to 24 weeks. Both products have been designated as orphan drugs for the treatment of this rare disease.

The primary objective is to evaluate the efficacy of switching from bulevirtide to brelovitug treatment at Week 24. The primary endpoint is the proportion of participants who achieve undetectable HDV RNA (below the lower limit of quantification, target not detected). Secondary endpoints include safety assessments such as the incidence and severity of treatment-emergent adverse events, the proportion of participants who permanently discontinue treatment due to adverse events, and changes from baseline in serum total bile salts. Additional efficacy endpoints assess virologic response, defined as HDV RNA decline of at least 2 log10 IU/mL from baseline or HDV RNA below the lower limit of quantification, normalization of ALT levels, and sustained virologic response at post-treatment follow-up weeks.

Eligible participants must be adults aged 18 years or older who have been receiving bulevirtide treatment for chronic hepatitis D infection for at least 6 months at the time of screening. Key inclusion criteria include HDV RNA levels of at least 100 IU/mL at screening and willingness to take or continue stable treatment with TDF, TAF, or ETV throughout the study duration. Participants must provide written informed consent prior to enrollment.

The study involves a screening visit to assess eligibility, followed by treatment visits at specified intervals including Weeks 24, 48, 72, and 96. Comparison with bulevirtide includes data collected through 24 weeks of treatment. Post-treatment follow-up visits are scheduled at 24 and 48 weeks after the end of treatment to assess sustained virologic response. The total duration of participant involvement extends up to 96 weeks of active treatment, with an additional follow-up period of up to 48 weeks. The overall trial is estimated to begin recruitment in February 2026 and conclude in March 2029. Conditions that may lead to early termination from the study include the occurrence of adverse events requiring permanent discontinuation of treatment, as determined by the investigator and participant in accordance with the study protocol.

**BJT-778** (brelovitug) is administered as the experimental medication in this clinical trial. The investigational product is supplied as a **solution for injection** and is administered via **subcutaneous injection**. The maximum daily dose is **300 mg**, with a maximum total dose of **28800 mg** over the course of treatment. The maximum treatment period is **96 weeks**. BJT-778 is designated as an **orphan drug** under the designation number EMA/OD/0000167926. The active substance is a protein-based compound classified as Protein - Other.

**Bulevirtide** serves as the **comparator treatment** in this trial. Participants receiving bulevirtide will be evaluated for switching to the experimental medication. Bulevirtide is formulated as a solution for injection and is administered via subcutaneous injection. The maximum daily dose is **2 mg**, with a maximum total dose of **336 mg**. The maximum treatment period for bulevirtide is **24 weeks**. This product holds orphan drug designation under the number EU/3/15/1500. The active substance of bulevirtide is also a protein-based compound.

The trial is designed as a **Phase 2b/3**, **open-label**, **multicenter** study evaluating the efficacy and safety of switching from bulevirtide to brelovitug for the treatment of **chronic hepatitis delta infection**. The primary objective is to evaluate the efficacy of switching from bulevirtide to treatment with brelovitug at **Week 24**. Both medications are administered subcutaneously, and neither product is formulated as a paediatric formulation.

Efficacy will be assessed through multiple parameters evaluating virologic and biochemical responses in participants with chronic hepatitis delta infection. The primary efficacy endpoint is the proportion of participants who achieve undetectable HDV RNA (below the lower limit of quantification, target not detected) at Week 24. Secondary efficacy endpoints include the proportion of participants achieving virologic response, defined as HDV RNA reduction of at least 2 log10 IU/mL from baseline or HDV RNA below the lower limit of quantification with target not detected, assessed at Weeks 24, 48, 72, and 96. Additional secondary endpoints include the proportion of participants achieving HDV RNA below the lower limit of quantification at these timepoints, as well as normal ALT levels alone and in combination with virologic response measures. Changes from baseline in HDV RNA and ALT levels will be evaluated. Post-treatment follow-up assessments will measure the proportion of participants who maintain undetectable HDV RNA at 24 and 48 weeks after treatment completion. Comparisons with bulevirtide treatment will include data through Week 24.