Reimbursement Review

Bulevirtide (Hepcludex)

Sponsor: Gilead Sciences Canada, Inc.

Therapeutic area: Chronic hepatitis delta virus (HDV) infection

This multi-part report includes:

Clinical Review

Pharmacoeconomic Review

Clinical Review

Abbreviations

Executive Summary

An overview of the submission details for the drug under review is provided in Table 1.

Table 1: Background Information of Application Submitted for Review

HDV = hepatitis delta virus; NOC = Notice of Compliance.

Introduction

Hepatitis delta is a rare, severe, and progressive liver disease caused by the hepatitis delta virus (HDV), an incomplete ribonucleic acid (RNA) virus that requires the hepatitis B virus (HBV) envelope to enter cells and replicate. HDV is considered the fastest progressing and most severe form of all viral hepatitis infections. HDV is a “satellite virus” and can only infect individuals with a concomitant HBV infection.^1,2 Chronic HDV infection is defined as an infection lasting 6 months or more.³ The likelihood of progression to chronic hepatitis depends on whether the initial infection with HDV occurred by HBV and HDV coinfection or superinfection. While less than 5% of patients progress to a chronic infection after coinfection, HDV infection becomes chronic in more than 80% of individuals with HBV and HDV superinfection.⁴

A 2024 study from the Polaris Observatory found that the adjusted prevalence of HDV in the population infected with HBV in Canada is approximately 3.0%.⁵ These estimates are consistent with a retrospective study conducted using data collected from patients seen by physicians in the Canadian HBV Network (9 clinics in 6 provinces across Canada), which reported an estimated rate of 4.8% (95% confidence interval [CI], 4.3% to 5.3%).⁶ Given that the prevalence of chronic HBV in Canada is estimated at 0.66%⁷ and the HBV diagnosis rate is 70%,⁵ the prevalence of HDV (both chronic and acute) is estimated at between 0.020%⁵ and 0.032% %,⁶ which equates to 2 to 3.2 per 10,000 population.

Key signs and symptoms of chronic HDV infection can range from nonspecific symptoms to rapidly progressing hepatitis. Symptoms may include fever, fatigue, loss of appetite, nausea, vomiting, abdominal pain, dark urine, clay-coloured bowel movements, joint pain, and jaundice.⁴ Chronic hepatitis usually exacerbates any pre-existing liver disease associated with HBV.⁸ Recovery is unlikely once a person has an infection, with the likelihood of recovery decreasing as the disease progresses. Only 35% of patients with acute infection, and even less (9.96%) with chronic infection, recover.⁹ For those who do not recover at the early stages of the disease, HDV infection is associated with an accelerated progression to fibrosis, early liver decompensation with cirrhosis, and increased risk of hepatocellular carcinoma (HCC), leading to greater liver-related mortality compared to HBV or hepatitis C virus (HCV).^10-12

Diagnosis of HDV generally involves 2 steps. The first step is detection of anti-HDV antibodies through an enzyme-linked immunosorbent assay to assess if a patient has ever been exposed to HDV. If the anti-HDV antibody test is positive, the patient is automatically tested for HDV RNA using reverse transcription-polymerase chain reaction (RT-PCR), to assess whether the HDV infection is active or chronic. Standard liver function tests are routinely performed if a patient already receives care for HBV; these assess the severity of a patient’s HBV and/or HDV disease. These liver function tests are done at initial diagnosis and to monitor treatment response.

According to the clinical experts consulted by Canada's Drug Agency (CDA-AMC) for this review, HDV occurs as a coinfection with HBV and is associated with a more aggressive liver disease, with a higher risk of cirrhosis, hepatic decompensation, and HCC. There are currently no approved treatments for chronic HDV in Canada.^13-15

The European Association for the Study of the Liver and the American Association for the Study of Liver Diseases (AASLD)^13-15 have indicated that pegylated interferon (PEG-IFN)-alpha has potential clinical benefit for patients with HBV and HDV coinfections. Of note, PEG-IFN-alpha is no longer used for HDV treatment in Canada due to its poor tolerability and limited accessibility. AASLD emphasized the importance of suppressing HBV replication in patients with chronic hepatitis D and elevated HBV DNA levels. Nucleoside (or nucleotide) analogues inhibit HBV DNA synthesis, but have no effect on HDV replication, which is independent of HBV. While guidelines vary on the use of nucleoside (or nucleotide) analogues for patients with HBV and HDV coinfections, they consistently highlight the lack of their efficacy against HDV.^13-16

The objective of this Clinical Review report is to review and critically appraise the clinical evidence submitted by the sponsor on the beneficial and harmful effects of bulevirtide monotherapy, administered once daily by subcutaneous injection at a dose of 2 mg, for the treatment of chronic HDV infection in adults with compensated liver disease.

Perspectives of Patients, Clinicians, and Drug Programs

The information in this section is a summary of input provided by the patient and clinician groups who responded to our call for input and from clinical experts consulted by for the purpose of this review.

Patient Input

CDA-AMC received a joint patient input submission from 2 organizations, Liver Canada and BC Hepatitis Network. Patient perspectives were gathered via an online survey conducted between February 21 and March 8, 2025, using social media. The 6 patients who responded to the survey, ranged in age from their 30s to their 60s, and were living with HDV or caring for someone with HDV living in Ontario, Alberta, or British Columbia. The patient groups described how receiving a diagnosis of HDV and experiencing disease-specific symptoms, including general physical and psychological symptoms, substantially impacts patients’ health-related quality of life (HRQoL). PEG-IFN is used off-label in Canada for the treatment of HDV. Patients with experience with PEG-IFN treatment highlighted the associated intolerable side effects, frequent travel to clinics for injections, and frequent blood tests for monitoring purposes. Patient respondents indicated a preference for treatments that require fewer injections and blood tests.

Patient respondents described stabilization of their liver disease as an important treatment outcome. Stabilization refers to slowed progression to liver fibrosis, cirrhosis, and liver cancer; improvement in decompensation events; and reduced need for a liver transplant. According to the patient input received for this review, chronic HDV is most common among newcomers and immigrants to Canada, who face multiple barriers to timely diagnosis. According to the patient input, these individuals are less likely to be screened for viral hepatitis, face limited access to routine care, and are more likely to experience fear and stigma related to hepatitis. Together, these barriers place individuals at higher risk for late diagnosis and advanced viral hepatitis–related liver disease. Patient respondents identified reflex testing for HDV among individuals with HBV as an important unmet need.

Clinician Input

Input From Clinical Experts Consulted for This Review

The clinical experts consulted by CDA-AMC for this review identified significant unmet needs in the management of chronic HDV infection in Canada, emphasizing the absence of approved or reimbursed therapies. The clinical experts indicated that although PEG-IFN was previously used off-label for the treatment of HDV, it is no longer used in clinical practice due to its poor tolerability, limited accessibility, and lack of feasibility for routine use. The clinical experts emphasized that currently available therapies for hepatitis B, including nucleoside (or nucleotide) analogues, are ineffective against HDV infection, which remains the primary driver of liver damage in individuals with coinfections. As a result, patients with HDV experience progressive liver disease without access to an effective treatment option. The clinical experts highlighted the need for a targeted therapy to reduce HDV viral load, normalize alanine aminotransferase (ALT) levels, potentially stabilize or improve liver fibrosis, and mitigate the risk of HCC and liver decompensation. This need is particularly urgent due to the aggressive nature of HDV infection and the associated risk of rapid progression to cirrhosis and HCC. The clinical experts noted that early initiation of bulevirtide is recommended to help mitigate the risk of progression to advanced liver disease. The clinical experts stated that bulevirtide would be used in combination with nucleoside (or nucleotide) analogues, such as tenofovir or entecavir, which are used to manage the HBV coinfection but are ineffective against HDV. The clinical experts identified individuals with compensated cirrhosis as the most in need of bulevirtide treatment but emphasized that all patients with chronic HDV require treatment due to the potential for rapid disease progression.

The clinical experts noted that the key outcomes used to determine response to treatment with bulevirtide include virologic response (i.e., undetectable HDV RNA or reduction in HDV RNA levels), biochemical response (i.e., normalization of ALT levels), and stabilization or improvement in liver fibrosis. According to the clinical experts, long-term outcomes such as improvements in portal hypertension, reduced progression to cirrhosis, and lower rates of HCC would also be clinically beneficial but were not assessed in trials. The clinical experts indicated that bulevirtide treatment should generally be discontinued in cases of progression to decompensated liver disease requiring transplant or the development of HCC, which requires other therapy. However, they emphasized that treatment decisions for patients with decompensated liver disease and those with HCC should be made on a case by case basis, as discontinuing HDV therapy could potentially worsen their condition. The clinical experts noted that discontinuation can be considered in the event of severe adverse reactions, such as allergy or significant injection site reactions, or if the patient experiences barriers to adherence to the daily injectable therapy. The clinical experts indicated that diagnosis of HDV infection, prescribing of bulevirtide, and monitoring of treatment response should be managed by clinicians with specialized expertise in hepatology or infectious diseases, given the complexity of HDV infection and the need for accurate interpretation of HDV RNA and ALT levels. The clinical experts also noted that the optimal duration of bulevirtide therapy remains uncertain for those patients with hepatitis infection that responds more slowly to treatment. According to the clinical experts, underdiagnosis of HDV is a significant issue in practice, largely due to the limited availability of HDV RNA testing and lack of routine screening, posing a barrier to timely treatment initiation. The clinical experts noted that systematic screening is lacking, particularly in individuals with HBV infection receiving care in the primary care setting.

Clinician Group Input

Ten clinicians from the Canadian Hepatitis B Network provided input. The Canadian Hepatitis B Network is a collaborative organization of health care professionals and researchers from across Canada with an interest in advancing excellence in the care of patients with hepatitis B, research into hepatitis B, and education. The clinician group stated that there is an unmet need for improved therapies for HDV and HBV coinfection. There are currently no Health Canada–approved treatments for HDV infection. HDV causes the most severe form of viral hepatitis in humans. HDV requires the HBV surface (or envelope) protein to infect the liver, and therefore can only infect people who have HBV. Individuals can acquire HBV and HDV at the same time or HDV can superinfect a patient with underlying chronic hepatitis B infection because of a shared route of transmission. The drug under review, bulevirtide, is a novel antiviral drug specifically targeting the binding of HDV (and HBV) to the liver-specific cell surface bile acid receptor, NTCP. Based on input received from the clinician group, patients with HBV and HDV coinfection and positive test results for HDV RNA are most likely to respond to the drug under review.

Patients with HDV coinfection are at substantial risk of liver disease and cirrhosis within 5 years of diagnosis, regardless of any disease characteristics. Patients best suited for treatment with the drug under review would be identified based on the clinical judgment of expert specialists in hepatology or infectious disease as well as by testing for HDV RNA. The clinician group highlighted that outcomes used in clinical practice are aligned with the outcomes typically used in clinical trials. A clinically meaningful response to treatment would be HDV RNA suppression, biochemical normalization, improvement in noninvasive fibrosis test results, and/or improvement in symptoms of liver disease decompensation (e.g., ascites, variceal bleeding). Based on input received from the clinician group, the criteria for discontinuing treatment include treatment failure, disease progression, and limited lifespan. The clinician group stated that the drug under review can be appropriately prescribed by a hepatology and infectious diseases specialist in a specialty clinic setting.

Drug Program Input

Input was obtained from the drug programs that participate in the CDA-AMC reimbursement review process. The following were identified as key factors that could potentially impact CDA-AMC recommending bulevirtide:

• relevant comparators

• consideration for initiation of therapy

• consideration for continuation or renewal of therapy

• consideration of discontinuation of therapy

• consideration for prescribing of therapy

• generalizability

• care provision issues

• system and economic issues.

The clinical experts consulted by CDA-AMC provided advice on the potential implementation issues raised by the drug programs.

Clinical Evidence

Systematic Review

Description of Studies

The sponsor-conducted systematic literature review (SLR) identified 1 pivotal, ongoing, phase III, randomized, open-label, parallel-group, multicentre trial (MYR301, N = 150). The primary objective of the MYR301 trial was to evaluate the efficacy and safety of bulevirtide at a dose of 2 mg for the treatment of chronic HDV infection in adults with compensated liver disease compared to delayed treatment with bulevirtide 10 mg after an observation period of 48 weeks. The secondary objectives of the trial included assessing the safety of bulevirtide and determining the optimal treatment duration. Patients were enrolled from 16 sites across 4 countries — Germany, Italy, Russia, and Sweden. The study includes a 4-week screening period, a 144-week treatment period, and a 96-week follow-up period. Following screening, patients were randomized using an electronic randomization system in a 1:1:1 ratio to receive delayed treatment with bulevirtide 10 mg after a 48-week observation period (N = 51), immediate treatment with bulevirtide 2 mg (N = 49), or immediate treatment with bulevirtide 10 mg (N = 50). This report primarily focuses on between-group comparisons of study end points up to week 48, specifically for bulevirtide at a dose of 2 mg, in line with the Health Canada indication. Data for the study group receiving immediate treatment with bulevirtide at a dose of 10 mg are not presented in this report because this dose is neither approved for use nor in use in clinical practice in Canada. Efficacy end points of interest to this review included combined response, undetectable HDV RNA or HDV RNA decrease of at least 2 log₁₀ IU/mL from baseline, change in liver stiffness from baseline, ALT normalization, undetectable HDV RNA, liver-related clinical events, HRQoL, and safety outcomes. The primary and secondary end points of the MYR301 trial were analyzed using data up to the cut-off date of September 30, 2022, with the database locked on June 8, 2023.

The mean age of patients was higher in the bulevirtide 2 mg group (44 years [SD = 9.0 years]) than in the delayed treatment group (41 years [SD = 7.5 years]). The proportion of male patients was larger in the bulevirtide 2 mg group (61.2%) than in the delayed-treatment group (51.0%). Nearly one-half of patients (47.3%) had cirrhosis at the time of randomization; in all cases, cirrhosis was classified as Child-Pugh Class A. All patients in both the bulevirtide 2 mg and the delayed-treatment group had HDV genotype 1 at baseline. A larger proportion of patients in the bulevirtide 2 mg group had cirrhosis with a Child-Pugh score of 6 points (30.4% versus 20.8% in the delayed-treatment group), HBV genotype D (95.9% versus 86.3% in the delayed-treatment group), and HBV DNA greater than or equal to the lower limit of quantification (LLoQ) (67.3% versus 52.9% in the delayed-treatment group). A total of 65.3% in the bulevirtide 2 mg group and 62.7% in the delayed-treatment group received oral anti-HBV treatment during the MYR301 trial; 54.7% of these patients had initiated this treatment before baseline. In addition, 53.1% of patients in the bulevirtide 2 mg group and 62.7% of patients in the delayed-treatment group had previously received interferon treatment. Most of the disease characteristics in the delayed-treatment group were similar at randomization at week 48, with a few notable exceptions. Specifically, the mean serum ALT level was higher at randomization (102 U/L [SD = 61.9 U/L]) than at week 48 (82 U/L [SD = 51.1 U/L]) and the mean liver stiffness was 15.3 kPa (SD = 8.95 kPa) at randomization and 16.1 kPa (SD = 11.84 kPa) at week 48.

Efficacy Results

Combined Response

Combined response at week 48 was a primary end point in the MYR301 trial. A combined response is defined as the simultaneous fulfillment of 2 conditions: undetectable HDV RNA (less than the lower limit of detection) or a decrease of at least 2 log₁₀ IU/mL from baseline, and ALT normalization. At week 48, 44.9% (95% CI, 30.7% to 59.8%) of patients in the bulevirtide 2 mg group compared to 2.0% (95% CI, 0.0% to 10.4%) of those in the delayed-treatment group achieved a combined response. The between-group difference in response rates was 42.9% (96% CI, 27.0% to 58.5%; P < 0.0001) in favour of the bulevirtide 2 mg group compared to the delayed-treatment group. The sensitivity analysis results, using the missing equals failure approach, were consistent with the primary analysis. Subgroup analyses of the primary end point, combined response at week 48, were conducted based on cirrhosis status. In the bulevirtide 2 mg group, the proportion of patients without cirrhosis who achieved a combined response was 53.8% (95% CI, 16.4% to 57.3%) compared to 34.8% (95% CI, 33.4% to 73.4%) of patients with cirrhosis. In the delayed-treatment group, 4.2% (95% CI, 0.1% to 21.1%) of patients with cirrhosis achieved a combined response compared to 0.0% (95% CI, 0.0% to 12.8%) of those without cirrhosis.

Undetectable HDV RNA at Weeks 24 and 48 After Scheduled End of Treatment

An undetectable HDV RNA at weeks 24 and 48 after scheduled end of treatment (sustained virologic response) was a secondary end point in the MYR301 trial; however, the results for this end point were not reported due to an insufficient follow-up period as the study is still ongoing.

Undetectable HDV RNA or HDV RNA Decrease by at Least 2 log₁₀ IU/mL at Week 48

A decrease in HDV RNA of at least 2 log₁₀ IU/mL or undetectable HDV RNA (virologic response) at week 48 was an additional secondary end point in the MYR301 trial. At Week 48, 73.5% (95% CI, 58.9% to 85.1%) of patients in the bulevirtide 2 mg group achieved a virologic response compared to 3.9% (95% CI, 0.5% to 13.5%) in the delayed-treatment group. The between-group difference in response rates was 69.5% (96% CI, 54.1% to 81.9%; P < 0.0001) in favour of the bulevirtide 2 mg group, compared to the delayed-treatment group. Subgroup analyses of virologic response were conducted based on cirrhosis status and concomitant treatment with HBV medication (ad hoc analysis). At week 48, 82.6% (95% CI, 61.2% to 95.0%) of the patients with cirrhosis in the bulevirtide 2 mg group and 8.3% (95% CI, 1.0% to 27.0%) of those in the delayed-treatment group had achieved a virologic response. Among patients without cirrhosis, the corresponding proportions were 65.4% (95% CI, 44.3% to 82.8%) and 0.0% (95% CI, 0.0% to 12.8%), respectively. At week 48, 78.1% (95% CI, 60.0% to 90.7%) of patients receiving concomitant HBV medication in the bulevirtide 2 mg group achieved a virologic response compared to 6.3% (95% CI, 0.8% to 20.8%) of those in the delayed-treatment group. Among the patients not receiving HBV medication, the proportions who achieved a virologic response were 64.7% (95% CI, 38.3% to 85.0%) and 0.0% (95% CI, 0.0% to 17.6%), respectively.

Change From Baseline in Liver Stiffness at Week 48

The change from baseline in liver stiffness assessed using FibroScan was a prespecified secondary end point for the week 48 analysis. At week 48, the least squares (LS) mean of change from baseline in liver stiffness was –3.06 kPa (95% CI, –4.67 kPa to –1.45 kPa) in the bulevirtide 2 mg group and 0.87 kPa (95% CI, −0.79 kPa to 2.53 kPa) in the delayed-treatment group. The between-group difference in LS means of change in liver stiffness was –3.93 (95% CI, –6.23 to –1.63; P = 0.0009) in favour of the bulevirtide 2 mg group. Subgroup analyses of the change in liver stiffness were conducted based on cirrhosis status. In the bulevirtide 2 mg group, the mean change from baseline in liver stiffness was –5.70 kPa (SD = 6.94 kPa) in patients with cirrhosis and –0.35 kPa (SD = 2.08 kPa) in patients without cirrhosis. In the delayed-treatment group, the mean change from baseline in liver stiffness was –0.20 kPa (SD = 4.00 kPa) in patients without cirrhosis and 1.78 kPa (SD = 10.1 kPa) in patients with cirrhosis.

Liver-Related Clinical Events

In the MYR301 trial, | █████████████ ███████████████ ███ ████████ ██ █ ███████ ██ ███ ███████████ █ ██ ██████ ██ ███ █ ███████ █████ █████████ ███ ██████████ ███████ ███ ███ ███ ██████████ ████ ███ ███████ ██████ █████████████ █ ███████ ████ █████████ ██ ███ ███████ █████████ █████ █████████ ███████████ █████ █ ████████ ███ ████ █████ █████████ ██ ███████████ ██ ██ ██████████.

Health-Related Quality of Life

The Hepatitis Quality of Life Questionnaire (HQLQ) was used to assess the quality of life of patients in the MYR301 trial. The HQLQ¹⁷ includes items from the Short Form (36) Health Survey (SF-36) and 4 hepatitis-specific health domain scores, including health distress, positive well-being, hepatitis-specific limitations, and hepatitis-specific health distress. Each domain is scored on a scale from 0 to 100, with higher scores indicating better HRQoL.

At week 24, compared to the delayed-treatment group, the LS mean differences in the bulevirtide 2 mg group were ███ (95% CI, ███ ██ ███) for the HQLQ physical component summary score, ███ (95% CI, ████ ██ ███) for the HQLQ mental component summary score, ████ (95% CI, ███ ██ ████) for the HQLQ health distress score, ███ (95% CI, ████ ██ ████) for the HQLQ positive well-being score| ███ (95% CI, ████ ██ ████) for the HQLQ hepatitis-specific limitations score, and ███ (95% CI, ████ ██ ████) for the HQLQ hepatitis-specific health distress score.

At week 48, compared to the delayed-treatment group, the LS mean differences in the bulevirtide 2 mg group were ███ (95% CI, ███ ██ ███) for the HQLQ physical component summary score, ███ (95% CI, ████ ██ ███) for the HQLQ mental component summary score, ███ (95% CI, ████ ██ ████) for the HQLQ health distress score, ███ (95% CI, ████ ██ ███) for the HQLQ positive well-being score, ███ (95% CI, ███ ██ ████) for the HQLQ hepatitis-specific limitations score, and ███ (95% CI, ███ ██ ████) for the HQLQ hepatitis-specific health distress score.

Undetectable HDV RNA

Undetectable HDV RNA (less than the LLoQ, target not detected) at week 48 was a key secondary end point in the MYR301 trial. At week 48, 12.2% (95% CI, 4.6% to 24.8%) of patients in the bulevirtide 2 mg group had undetectable HDV RNA compared to 0.0% (95% CI, 0.0% to 7.0%) of patients in the delayed-treatment group. The between-group difference in response rates was only calculated for the bulevirtide 10 mg group with the bulevirtide 2 mg group as the reference; this comparison is not relevant to this review. Subgroup analyses of the key secondary end point were conducted based on cirrhosis status and concomitant treatment with nucleoside (or nucleotide) analogues (ad hoc analysis). In the bulevirtide 2 mg group, 21.7% (95% CI, 7.5% to 43.7%) of patients with cirrhosis achieved undetectable HDV RNA, compared to 3.8% (95% CI, 0.1% to 19.6%) of those without cirrhosis. In the delayed-treatment group, 0.0% (95% CI, 0.0% to 14.2%) of patients with cirrhosis achieved an undetectable HDV RNA, compared to 0.0% (95% CI, 0.0% to 12.8%) of those without cirrhosis. Similarly, of the patients in the bulevirtide 2 mg group receiving concomitant HBV medication, 15.6% (95% CI, 5.3% to 32.8%) achieved undetectable HDV RNA compared to 5.9% (95% CI, 0.1% to 28.7%) of those not receiving HBV medication. In the delayed-treatment group, 0.0% of the patients achieved an undetectable HDV RNA, regardless of whether they were receiving concomitant HBV medication

ALT Normalization

ALT normalization at week 48 was a secondary end point in the MYR301 trial. At week 48, 51.0% (95% CI, 36.3% to 65.6%) of patients in the bulevirtide 2 mg group achieved ALT normalization compared to 11.8% (95% CI, 4.4% to 23.9%) of patients in the delayed-treatment group. The between-group difference in response rates was 39.3% (96% CI, 20.0% to 55.8%; P < 0.0001) in favour of the bulevirtide 2 mg group compared to the delayed-treatment group. Subgroup analyses of ALT normalization were conducted based on cirrhosis status and concomitant treatment with HBV medication. At week 48, 61.5% (95% CI, 40.6% to 79.8%) of patients without cirrhosis achieved ALT normalization compared to 39.1% (95% CI, 19.7% to 61.5%) of those with cirrhosis. In the delayed-treatment group, 7.4% (95% CI, 0.9% to 24.3%) of patients without cirrhosis achieved ALT normalization compared to 16.7% (95% CI, 4.7% to 37.4%) of patients with cirrhosis. Similarly, of patients in the bulevirtide 2 mg group who did not receive concomitant HBV medication, 52.9% (95% CI, 27.8% to 77.0%) achieved ALT normalization compared to 50.0% (95% CI, 31.9% to 68.1%) of those who received HBV medication. In the delayed-treatment group, 15.8% (95% CI, 3.4% to 39.6%) of patients who did not receive concomitant HBV medication achieved ALT normalization compared to 9.4% (95% CI, 2.0% to 25.0%) of those who received HBV medication.

Combined Response Over Time

The combined response at each study visit, an exploratory end point in the MYR301 trial, was analyzed exclusively using a missing equals failure approach. In contrast, the primary end point analysis incorporated a last observation carried forward (LOCF) approach to account for missing data due to COVID-19 pandemic-related restrictions at weeks 24 and 48. The combined response rates in the bulevirtide 2 mg group demonstrated consistent improvement over time: 34.7% (95% CI, 21.7% to 49.6%) at week 24, 44.9% (95% CI, 30.7% to 59.8%) at weeks 48 ███ ██, 55.1% (95% CI, 40.2% to 69.3%) at week 96, and 57.1% (95% CI, 42.2% to 71.2%) at week 144.

Virologic Response Over Time

The virologic response at each study visit, an exploratory end point in the MYR301 trial, was analyzed exclusively using a missing equals failure approach. The virologic response rates in the bulevirtide 2 mg group demonstrated improvement over time: 55.1% (95% CI, 40.2% to 69.3%) at week 24, 73.5% (95% CI, 58.9% to 85.1%) at week 48, █████ ████ ███ █████ ██ ██████ ██ ████ ██, 75.5% (95% CI, 61.1% to 86.7%) at week 96, and 73.5% (95% CI, 58.9% to 85.1%) at week 144.

Harms Results

Adverse Events

In the MYR301 trial, 83.7% of patients in the bulevirtide 2 mg group and 80.4% in the delayed-treatment group had experienced at least 1 adverse event (AE) by week 48. The most common AEs in the bulevirtide 2 mg group were headache (18.4% versus 0.0% in the delayed-treatment group), vitamin D deficiency (14.3% versus 25.5% in the delayed-treatment group), leukopenia (14.3% versus 19.6% in the delayed-treatment group), thrombocytopenia (10.2% versus 15.7% in the delayed-treatment group), and pruritus (12.2% versus 0.0% in the delayed-treatment group). The proportions of patients with grade 3 or higher AEs were 10.2% in the bulevirtide 2 mg group and 7.8% in the delayed-treatment group. Among patients in the bulevirtide 2 mg group, these grade 3 or higher AEs included depression (2.0% versus 0.0% in the delayed-treatment group), foot fracture (2.0% versus 0.0% in the delayed-treatment group), decreased neutrophil count (2.0% versus 0.0% in the delayed-treatment group), osteopenia (2.0% versus 0.0% in the delayed-treatment group), and thrombocytopenia (2.0% versus 5.9% in the delayed-treatment group).

At week 144, the proportion of patients who experienced at least 1 AE in the bulevirtide 2 mg group was 98.0%; 24.5% of patients in the bulevirtide 2 mg group experienced AEs that were grade 3 or higher. The most common AEs in the bulevirtide 2 mg group were vitamin D deficiency (44.9%), headache (20.4%), leukopenia (20.4%), thrombocytopenia (20.4%), lymphopenia (16.3%), and neutropenia (16.3%).

Serious Adverse Events

In the MYR301 trial, the proportions of patients who had experienced at least 1 serious adverse event (SAE) by week 48 were 4.1% in the bulevirtide 2 mg group and 2.0% in the delayed-treatment group. Most SAEs were experienced by 1 patient across the treatment groups. The SAEs in the bulevirtide 2 mg group included foot fracture (2.0% versus 0.0% in the delayed-treatment group), headache (2.0% versus 0.0% in the delayed-treatment group), hemiparesis (2.0% versus 0.0% in the delayed-treatment group), and depression (2.0% versus 0.0% in the delayed-treatment group). The SAEs in the delayed-treatment group included cholelithiasis (2.0% versus 0.0% in the bulevirtide 2 mg group) and COVID-19 (2.0% versus 0.0% in the bulevirtide 2 mg group).

At week 144, the proportion of patients who experienced at least 1 SAE in the bulevirtide 2 mg group was 6.1%, including esophageal varices (2.0%), foot fracture (2.0%), headache (2.0%), hemiparesis (2.0%), and depression (2.0%). Between weeks 48 and 144 (representing 96 weeks of treatment with bulevirtide at a dose of 10 mg), the proportion of patients who experienced at least 1 SAE in the delayed treatment group was 6.0%. These SAEs included COVID-19 (2.0%), urinary tract infection (2.0%), and plasma cell myeloma (2.0%).

Withdrawals Due to AEs

By week 144, there were no discontinuations due to treatment-related AEs in the MYR301 trial.

Mortality

By week 144, there were no deaths in either the bulevirtide 2 mg or the delayed-treatment group.

Notable Harms

In the MYR301 trial at week 48, 14.3% of patients in the bulevirtide 2 mg group and 9.8% in the delayed-treatment group had experienced at least 1 hepatic AE. The hepatic AEs in the bulevirtide 2 mg group included increased ALT (4.1% versus 7.8% in the delayed-treatment group), hyperbilirubinemia (4.1% versus 0.0% in the delayed-treatment group), increased blood bilirubin (4.1% versus 0.0% in the delayed-treatment group), increased aspartate aminotransferase (2.0% versus 5.9% in the delayed-treatment group), and hepatic pain (2.0% versus 0.0% in the delayed-treatment group). At week 144, the proportion of patients in the bulevirtide 2 mg group who had experienced at least 1 hepatic AE was 28.6%.

At week 48, 8.2% of patients in the bulevirtide 2 mg group and 5.9% in the delayed-treatment group had experienced at least 1 renal AE. The hepatic AEs in the bulevirtide 2 mg group included proteinuria (6.1% versus 3.9% in the delayed-treatment group) and urinary retention (2.0% versus 0.0% in the delayed-treatment group). At week 144, 98.0% of the patients in the bulevirtide 2 mg group had experienced at least 1 renal AE. At week 48, 10.2% of the patients in the bulevirtide 2 mg group versus 0.0% in the delayed-treatment group had experienced eosinophilia; at week 144, this proportion remained unchanged, at 10.2% of those in the bulevirtide 2 mg group. At week 48, 6.1% of patients in the bulevirtide 2 mg group versus 0.0% in the delayed-treatment group had experienced injection site reactions; at week 144, 20.4% of patients in the bulevirtide 2 mg group had experienced injection site reaction.

Critical Appraisal

Randomization in the MYR301 trial was performed using an appropriate methodology and stratification was prespecified. All efficacy and safety analyses were conducted using the full and safety analysis sets, respectively, and these analyses included all patients who were randomized and who had received at least 1 dose of bulevirtide after randomization. Some imbalances in baseline characteristics, likely due to small sample sizes, were observed; these may have hindered the achievement of true prognostic balance. Given the rarity of HDV and the challenges in recruiting patients into clinical trials, achieving large sample sizes is often not feasible. The open-label design of the MYR301 trial introduces a potential bias in the assessment of study outcomes; however, this bias was mitigated by blinding to treatment allocation the central laboratories employed for hematology and biochemistry assessment. Knowledge of the assigned treatment could have led to biases in the reporting and measurement of subjective outcomes, including patient-reported outcomes (e.g., HRQoL) and subjective AEs. However, the extent and direction of bias due to treatment knowledge is uncertain. Although there are always some concerns for risk of bias due to deviations from the intended interventions in open-label trials, there were relatively few protocol deviations, and these were balanced across the groups and therefore unlikely to have influenced the study results. Adherence to the interventions and study completion rates were generally high in the intervention groups of interest to this review, reducing concerns regarding deviations from the intended interventions that could have arisen due to the trial context.

According to FDA guidance,¹⁸ given that no drugs are currently approved for the treatment of HDV infection, a placebo-controlled trial is the preferred design for a phase III clinical trial. An alternative design could be a randomized controlled trial (RCT) in which patients are randomized to receive either the investigational drug (the immediate-treatment group) or placebo for a prespecified duration, followed by open-label treatment with the investigational drug for the deferred-treatment group.¹⁸ According to FDA guidance,¹⁸ a surrogate end point that provides evidence of both a decline in virologic replication and an improvement in associated liver inflammation, evident as a biochemical response, could reasonably predict clinical benefit. However, FDA guidance suggests that subsequent confirmation using clinical end points is required, and these should be collected as part of a long-term follow-up study. Based on the enrolled sample size, the MYR301 study was powered to test its primary and key secondary end points. Statistical analysis methods appear to be acceptable. Both interim analyses at weeks 24 and 48 were planned a priori. The risk of bias due to missing outcome data was considered to be low. The lack of adjustment for multiple comparisons for all but the primary and key secondary end points increases the risk of type I error, where false positives may be incorrectly identified as significant. Bulevirtide was favoured in the analysis, but there was uncertainty due to the small sample size, which increased the risk that prognostic balance was not achieved. The unadjusted comparisons and the decision not to stratify the analysis by cirrhosis due to the small sample size may introduce bias and reduce the accuracy of the estimated treatment effects. Subgroup analyses by cirrhosis status and prior use of nucleoside (or nucleotide) analogues were prespecified; however, they were descriptive and limited by small sample sizes. No definitive conclusions could be drawn about the effect of bulevirtide compared with delayed treatment on HRQoL due to risk of bias from assessors being aware of treatment assignments, as well as serious imprecision, with wide CIs that included both potential benefit and harm.

According to the clinical experts consulted by CDA-AMC, the inclusion and exclusion criteria of the MYR301 trial appropriately reflects the population with HDV who are eligible for bulevirtide therapy in clinical practice. While patients aged older than 65 years were excluded from the trial, the clinical experts emphasized that age alone should not preclude treatment with bulevirtide. The clinical experts noted that, in clinical practice, physicians are unlikely to delay treatment initiation for patients with HBV and HDV coinfection who present with advanced fibrosis, suggesting that earlier intervention may be clinically appropriate in such cases. Patients with HCV or uncontrolled HIV coinfection were excluded from the MYR301 trial. However, the clinical experts noted that in clinical practice, these coinfections can be sequentially managed, with HIV and HCV treated first, before initiation of HBV and HDV therapy. The clinical experts noted that although patients with creatinine clearance of less than 60 mL/min were excluded from the trial, those with moderate renal impairment may still be considered for treatment with appropriate monitoring. The clinical experts agreed that it is reasonable to expect that a significant proportion of patients treated for HDV in clinical practice will have cirrhosis, given that many are diagnosed at more advanced stages of the disease. The clinical experts also noted that patients with early-stage fibrosis (Meta-analysis of Histological Data in Viral Hepatitis [METAVIR] fibrosis stage 1 [F1] or fibrosis stage 2 [F2]) may be more likely to seek treatment to prevent disease progression. As a result, treatment in real-world settings may be initiated across a broader range of disease severity than is typically represented in clinical trials. Approximately 65% of patients in the MYR301 trial received concomitant oral anti-HBV therapy at baseline and this was balanced across the treatment groups. However, the clinical experts indicated that in clinical practice nearly all patients with HDV typically receive treatment with nucleoside (or nucleotide) analogues. The clinical experts noted that although HBV therapy may slow fibrosis progression, this is unlikely to affect the generalizability of the study, as improvements in both virologic and fibrosis outcomes were observed in patients who had previously received HBV therapy (54.7%) and progressed to advanced disease. According to the clinical experts, the surrogate outcomes used in the MYR301 trial — HDV RNA reduction or undetectability, ALT normalization, and changes in liver fibrosis — were appropriate for assessing treatment benefit. The clinical experts indicated that 48 weeks is a reasonable duration to assess efficacy in the MYR301 trial using these surrogate outcomes; however, longer-term follow-up would be required to assess hard clinical outcomes such as liver cancer, hepatic decompensation, or death, which are not expected to manifest within 1 year of treatment initiation. The MYR301 trial study population was drawn from several sites across 4 European countries, and no sites in Canada were included. The clinical experts indicated that overall, there are no major concerns with generalizing the findings from the trial to clinical settings in Canada.

Grading of Recommendations Assessment, Development and Evaluation Summary of Findings and Certainty of the Evidence

For pivotal studies and RCTs identified in the sponsor’s systematic review, Grading of Recommendations Assessment, Development and Evaluation (GRADE) was used to assess the certainty of the evidence for outcomes considered most relevant to inform expert committee deliberations, and a final certainty rating was determined as outlined by the GRADE Working Group. The selection of outcomes for GRADE assessment was based on the sponsor’s Summary of Clinical Evidence, consultation with clinical experts, and input received from patient and clinician groups and public drug plans. The following list of outcomes was finalized in consultation with expert committee members: combined response, virologic response, change from baseline in liver stiffness, HRQoL, and SAEs.

For the GRADE summary of findings for bulevirtide 2 mg versus delayed treatment, refer to Table 2.

Table 2: Summary of Findings for Bulevirtide 2 mg vs. Delayed Treatment for Patients With HDV Infection in the MYR301 Trial

CI = confidence interval; CDA-AMC = Canada's Drug Agency; HDV = hepatitis delta virus; HQLQ = Hepatitis Quality of Life Questionnaire; HRQoL = health-related quality of life; LLoQ = lower limit of quantification; LS = least squares; MID = minimal important difference; NR = not reported; RCT = randomized controlled trial; RNA = ribonucleic acid; SE = standard error; vs. = versus.

Note: Study limitations (which refers to internal validity or risk of bias), indirectness, imprecision of effects, and publication bias were considered when assessing the certainty of the evidence. All serious concerns in these domains that led to the rating down of the level of certainty are documented in the table footnotes.

^aCombined response was defined as undetectable HDV RNA (less than the LLoQ, target not detected) or HDV RNA decrease ≥ 2 log₁₀ IU/mL from baseline combined with ALT normalization.

^bIn the MYR301 study, patients were randomized in a 1:1:1 ratio to receive delayed treatment with bulevirtide 10 mg (N = 51), immediate treatment with bulevirtide 2 mg (N = 49), or immediate treatment with bulevirtide 10 mg (N = 50). Data related to immediate treatment with bulevirtide 10 mg are not included in this report, as this dose has not been approved and is not used in clinical practice in Canada.

^cDelayed treatment: Baseline at randomization to before the first dose of bulevirtide at week 48 or to early termination before week 48. From week 48 onwards, patients received bulevirtide 10 mg/day.

^dRated down 1 level for serious study limitations. Evidence from 1 trial with small sample size, raising concerns that prognostic balance may not have been achieved and the effect could be overestimated. An empirically derived MID was not identified for the between-group difference for this outcome. A difference of 20% between the groups was identified as a threshold of clinical importance for this outcome by the clinical experts consulted by CDA-AMC.

^eVirologic response was defined as undetectable HDV RNA or HDV RNA decrease ≥ 2 log₁₀ IU/mL from baseline.

^fIn the trial, statistical testing for this outcome was not adjusted for multiplicity. The results are considered as supportive evidence.

^gRated down 1 level for serious study limitations. Evidence from 1 trial with small sample size, raising concerns that prognostic balance may not have been achieved and the effect could be overestimated. An empirically derived MID was not identified for the between-group difference for this outcome. A difference of 30% between the groups was identified as a threshold of clinical importance for this outcome by the clinical experts consulted by CDA-AMC.

^hChange from baseline in liver stiffness was measured using FibroScan.

ⁱRated down 1 level for serious study limitations. Evidence from 1 trial with small sample size, raising concerns that prognostic balance may not have been achieved and the effect could be overestimated. There is no established MID for this outcome, and the clinical experts consulted by CDA-AMC could not provide a threshold of important difference. In the absence of a known threshold, the null was used.

^jRated down 1 level for serious risk of bias due to assessor knowledge of treatment assignment. Rated down 2 levels for very serious imprecision: CIs were wide and included potential for no difference and harm. There is no established MID for this outcome, and the clinical experts consulted by CDA-AMC could not provide a threshold of important difference. In the absence of a known threshold, the null was used.

^kRated down 1 level for serious risk of bias due to assessor knowledge of treatment assignment. Rated down 2 levels for serious imprecision. The effect may be unstable as it is informed by few events. There is no established MID for this outcome, and the clinical experts consulted by CDA-AMC could not provide a threshold of important difference. In the absence of a known threshold, the null was used.

Source: Clinical Study Report for MYR301.¹⁹ Details included in the table are from the sponsor’s Summary of Clinical Evidence.

Long-Term Extension Studies

No long-term extension study was submitted for this review.

Indirect Comparisons

Description of Studies

A sponsor-submitted indirect treatment comparison (ITC) evaluated bulevirtide 2 mg relative to other comparators, including PEG-IFN and best supportive care or nucleoside (or nucleotide) analogue therapy in patients with chronic HDV. The following outcomes were reported to address the objectives of the network meta-analysis (NMA): undetectable HDV RNA, undetectable HDV RNA or reduced by at least 2 log₁₀ IU/mL (virologic response), combined response, ALT normalization at weeks 24 and 48, and AEs and treatment discontinuations due to AEs at week 48. The Bayesian NMA was conducted using both fixed-effects and random-effects models.

Efficacy Results

Combined Response

At week 48, results from the fixed-effects models suggested that bulevirtide 2 mg results in a favourable improvement in the combined response compared with both PEG-IFN (risk difference = ███; 95% credible interval [CrI], ██ ██ ███) and nucleoside (or nucleotide) analogue therapy (risk difference = ███; 95% CrI, ███ ██ ███). The corresponding random-effects models also indicated that bulevirtide 2 mg demonstrated a favourable improvement in the combined response compared with both PEG-IFN and nucleoside (or nucleotide) analogue therapy (risk difference = ███; 95% CrI, ███ ██ ███) and nucleoside (or nucleotide) analogue therapy (risk difference = ███; 95% CrI, ███ ██ ███). The point estimates were comparable across both the fixed- and random-effects models. Sensitivity analysis of the combined response was not feasible at week 48 due to limited number of available studies.

Virologic Response

At week 48, results from the fixed-effects models indicated that bulevirtide 2 mg demonstrated a favourable improvement in the virologic response compared with both PEG-IFN (risk difference = ███; 95% CrI, ██ ██ ███) and nucleoside (or nucleotide) analogue therapy (risk difference = ███; 95% CrI, ██ ██ ██). However, the corresponding random-effects models yielded insufficient evidence to confirm a difference in the virologic response for the bulevirtide 2 mg group compared with the PEG-IFN or nucleoside (or nucleotide) analogue therapy groups. The point estimates were comparable across both the fixed-effects and random-effects models.

ALT Normalization

At week 48, results from the fixed-effects models indicated that treatment with bulevirtide 2 mg results in a favourable improvement in ALT normalization compared with both PEG-IFN (risk difference = ███; 95% CrI, ███ ██ ███) and nucleoside (or nucleotide) analogue therapy (risk difference = ███; 95% CrI, ███ ██ ███). The corresponding random-effects models yielded insufficient evidence to confirm a difference in the virologic response of patients in the bulevirtide 2 mg group compared with the PEG-IFN or nucleoside (or nucleotide) analogue therapy groups. The point estimates were comparable across both the fixed-effects and random-effects models.

Undetectable HDV RNA

At week 48, results from the fixed-effects models suggested that bulevirtide 2 mg results in a favourable improvement in achieving undetectable HDV RNA compared with the nucleoside (or nucleotide) analogue therapy group (risk difference = ███; 95% CrI, ██ ██ ███). However, there was insufficient evidence to confirm a difference in achieving undetectable HDV RNA in the bulevirtide 2 mg group compared with the PEG-IFN (risk difference = ███; 95% CrI, ████ ██ ██). The corresponding random-effects models yielded insufficient evidence to confirm a difference in achieving undetectable HDV RNA in the bulevirtide 2 mg group compared with the PEG-IFN or nucleoside (or nucleotide) analogue therapy groups.

Harms Results

There was insufficient evidence to confirm a difference between bulevirtide 2 mg and PEG-IFN or nucleoside (or nucleotide) analogue therapy in the rates of AEs, SAEs, or withdrawals due to AEs.

Critical Appraisal

The clinical experts consulted for this review noted that, in the absence of approved treatments for HDV, some of the regimens included in the NMA, such as PEG-IFN and nucleoside (or nucleotide) analogues, were appropriate comparators for bulevirtide. Although PEG-IFN can be used off-label to treat HDV, its use in clinical practice has become uncommon due to significant adverse effects, a global shortage, and limited availability in Canada. The clinical experts also noted that nucleoside (or nucleotide) analogues, which most patients receive use to manage HBV, have no direct effect on HDV. The clinical experts observed that several comparators included in the NMA analyses are not relevant to the context of HDV treatment in Canada, including bulevirtide plus tenofovir or PEG-IFN combined with adefovir, ribavirin, tenofovir, or entecavir. The literature search for the NMA was last updated by the sponsor in December 2021. The included studies were published between 2006 and 2019, and the treatment landscape has since evolved. An outdated literature search with possible omission of relevant or unpublished evidence can result in bias. The feasibility assessment for this NMA revealed considerable heterogeneity among the studies included in the analyses. There was considerable variation in the study design, treatment duration and duration of follow-up, regimen dosing, which may represent a potential source of heterogeneity. Several important disease-specific characteristics were not reported in some studies in the network, which limits the ability to assess heterogeneity between the studies, and not all outcomes were reported across all of the studies. The patient populations in the studies also varied, particularly in baseline characteristics such as age, presence of cirrhosis, HDV RNA levels, ALT levels, and treatment history. The numerous sources of heterogeneity, which cannot be adjusted for in the NMA, compromise the underlying transitivity assumption that must be met to draw valid conclusions. The network of interconnected studies was constructed using nucleoside (or nucleotide) analogues or delayed treatment as a common comparator.

The network of evidence was sparse (i.e., there were few studies contributing to several comparisons); in many cases, there was only 1 study per link, which was insufficient to reliably estimate between-study variances. Bayesian fixed-effects models were used as a base-case analysis, with a random-effects model for the exploratory analysis. When heterogeneity is present, the CrIs of the fixed-effects model may be narrower and less conservative than the random-effects model, underestimating the uncertainty arising from between-study variation. The results of the random-effects models for most outcomes were affected by important imprecision, precluding drawing a conclusion about which treatment may be favoured. The risk-difference models employed for the meta-analyses may have limitations in this context; specifically, the results of risk-difference meta-analyses can be influenced by the nonreporting of zero-event outcomes. These models also typically demonstrate lower statistical power and produce more conservative CIs compared to relative measures such as risk ratios, particularly when event rates are low.²⁰ No patient-reported quality of life data were evaluated, despite that HRQoL was considered an important end point for this review. The NMA evaluated the comparative safety of bulevirtide relative to PEG-IFN and nucleos(t)ide analogues; however, the wide CIs around these estimates indicate considerable uncertainty in the comparative safety outcomes.

Studies Addressing Gaps in the Evidence From the Systematic Review

SAVE-D Study

Description of Studies

SAVE-D was a multicentre, retrospective, real-world study (N = 244 patients) with the goal of addressing the gap in evidence on the effectiveness of bulevirtide treatment beyond 48 weeks in patients with cirrhosis with and without clinically significant portal hypertension. Patients with HDV-related cirrhosis who were starting bulevirtide monotherapy were consecutively enrolled in this study. Chronic HDV was defined as HDV RNA positivity for more than 6 months. Cirrhosis was defined either histologically (Meta-analysis of Histological Data in Viral Hepatitis [METAVIR] fibrosis stage 4 [F4]), noninvasively (liver stiffness of greater than 12.5 kPa), or clinically (nodular liver surface, splenomegaly, thrombocytopenia).

Efficacy Results

Of the patients who were enrolled, 244 (100%) had assessments available at baseline and 87 (36%) had assessments available at week 96.

Of the key efficacy results evaluated at week 96:

• Virologic response (HDV RNA ≥ 2 log₁₀ decline) rate was 79%.

• Undetectable HDV RNA rate was 48%.

• Biochemical response (ALT normalization < 40 U/L) rate was 64%.

• Combined response (HDV RNA ≥ 2 log₁₀ decline or undetectable, and ALT normalization) rate was 54%.

• The 96-week cumulative incidences of de novo HCC and decompensation were 3.0% and 2.8%, respectively.

Harms Results

Bulevirtide-related AEs were relatively mild, with a median bile acid increase from 15 μmol (interquartile range [IQR] = 9 μmol to 32 μmol) at baseline to 36 μmol (IQR = 19 μmol to 66 μmol) at week 96 (all time points versus baseline, P < 0.001) and mild and transient pruritis experienced by 24 patients (10%).

Critical Appraisal

This was a single-arm real-world study without a comparator, which means that comparative effectiveness conclusions relative to usual care could not be drawn. Further, the single-arm design precludes definitive conclusions. Major limitations of the SAVE-D study, which increased the uncertainty around effect estimates, were the lack of investigation into possible missing outcome data between weeks 24 to 96, posing a high risk of bias; limited generalizability to Canada; and lack of reported HRQoL outcomes.

MYR203 Study

Description of Studies

The MYR203 study was a multicentre, open-label, randomized, comparative, parallel-arm phase II study to assess the efficacy and safety of bulevirtide in combination with PEG-IFN-alpha versus PEG-IFN-alpha alone in the treatment of patients with chronic HBV and HDV coinfection. Each treatment arm had 15 patients. The interventions relevant to this review were bulevirtide 2 mg by subcutaneous injection as monotherapy compared with PEG-IFN-alpha alone.

Efficacy Results

The primary outcome of the study was HDV RNA response at week 72 (24 weeks posttreatment), defined as an HDV RNA value of less than the lower level of detection, equal to 10 IU/mL. Secondary outcomes were measured at 24 and 48 weeks, comprising of HDV RNA response, ALT normalization, combined response (negative HDV RNA and ALT normalization), and HDV RNA levels (log₁₀ scale). Liver fibrosis measured using FibroScan was an additional secondary end point.

At week 72 (24 weeks posttreatment), the primary efficacy end point of HDV RNA response was achieved by ███ ██████ ███ ███ ██ ██ ██████ ███ ███ ████ ███ ███ ████ ██ ██████ of the patients treated with PEG-IFN-alpha, and bulevirtide 2 mg, respectively. No patients (0 of 15 patients) treated with PEG-IFN-alpha only or with bulevirtide 2 mg only group achieved the HDV RNA response.

At week 48, secondary end points between PEG-IFN-alpha and bulevirtide 2 mg differed by end point. HDV RNA response was achieved by the same number of patients 2 of 15 (13.3%; 95% CI, 1.7% to 40.5%) treated with PEG-IFN-alpha and bulevirtide 2 mg. ALT normalization was achieved by 4 of 15 (26.7%; 95% CI, 7.8% to 55.1%) and 11 of 15 (73.3%; 95% CI, 44.9% to 92.2%) of the patients treated with PEG-IFN-alpha and bulevirtide 2 mg, respectively. The combined response (HDV RNA decline and ALT normalization) was achieved by 1 of 15 (6.7%; 95% CI, 0.2% to 31.9%) and 2 of 15 (13.3%; 95% CI, 1.7% to 40.5%) of the patients treated with PEG-IFN-alpha alone and bulevirtide 2 mg alone, respectively.

For liver stiffness, there were no statistically significant differences in change from baseline between the group receiving bulevirtide alone and the group receiving PEG-IFN-alpha at any time point.

Harms Results

There were no deaths in the study and none of the AEs were suspected unexpected serious adverse reactions.

Critical Appraisal

While the MYR203 study was an exploratory phase II trial, the very small sample sizes (baseline, N = 15 per group) with all patients recruited from Russia, limits the generalizability of findings to patients in Canada. There was a risk of bias of missing outcome data when measuring its primary end point (HDV RNA response at 72 weeks), with a decline in sample sizes for the comparator PEG-IFN-alpha (N = 7) and bulevirtide 2 mg (N = 9) groups. In addition, HRQoL outcomes were not reported.

Conclusions

HDV is a rare and severe condition that is recognized as the most aggressive form of viral hepatitis. At the time of this review, bulevirtide is the only approved treatment of HDV in adults with compensated liver disease. Input from both patients and clinicians on this review highlighted a significant unmet need for new treatments that effectively treat and prevent the progression of HDV. The pivotal MYR301 phase III trial examined the efficacy and safety of bulevirtide 2 mg for the treatment of patients with chronic HDV with compensated liver disease, compared to patients in the delayed-treatment group who received a 10 mg dose of bulevirtide following a 48-week observation period. The MYR301 trial demonstrated moderate certainty evidence that treatment with bulevirtide 2 mg likely results in a clinically meaningful increase in achieving combined response, virologic response, and improvement in liver stiffness at week 48, compared to delayed treatment. No definitive conclusion can be drawn regarding the effects of bulevirtide treatment on HRQoL due to the potential bias from assessor knowledge of treatment assignment, and imprecision in the data, making the direction of effects unclear. Bulevirtide 2 mg was generally well-tolerated, and no major safety concerns were identified in the MYR301 trial. Beyond week 48, there is no direct comparative evidence between bulevirtide and the relevant comparators.

The MYR203 phase II trial provided evidence on the efficacy and safety of bulevirtide 2 mg as monotherapy versus PEG-IFN-alpha-2a alone in patients with HDV who had compensated liver disease. However, due to the limited sample size, study design limitations, and exploratory nature of the study, definitive conclusions cannot be drawn. The SAVE-D study was a real-world study that provided evidence on the efficacy of bulevirtide for up to 96 weeks in patients with HDV-related cirrhosis with and without clinically significant portal hypertension. However, the single-arm design of the SAVE-D study limits the ability to assess comparative effectiveness relative to usual care and to infer causality. Key limitations of both studies include a risk of bias from missing outcome data that contributes to uncertainty in the effect estimates, limited generalizability to patients in Canada, and no reporting of HRQoL outcomes, which patients considered important.

The results of the sponsor-submitted ITC suggested that, compared with PEG-IFN and best supportive care, bulevirtide may offer potential benefit in achieving combined response at week 48. However, the interpretation of the ITC is limited by several factors, including methodological limitations, between-trial heterogeneity, a sparse network, and small sample sizes, which preclude definitive conclusions on the comparative effects of bulevirtide. In addition, PEG-IFN is no longer used for treatment of HDV in Canada due to poor tolerability and limited accessibility. Given the considerable uncertainty in the sponsor-submitted ITC, no definitive conclusions can be drawn regarding the safety of bulevirtide compared to PEG-IFN and best supportive care.

Introduction

The objective of this report is to review and critically appraise the evidence submitted by the sponsor on the beneficial and harmful effects of bulevirtide 2 mg, administered once daily by subcutaneous injection, for the treatment of chronic HDV infection in adult patients with compensated liver disease.

Disease Background

The contents of this section were informed by materials submitted by the sponsor and input from clinical experts and have been validated and summarized by the review team.

Hepatitis delta is a rare, severe, and progressive liver disease caused by HDV, an incomplete RNA virus that requires the HBV envelope to enter cells and replicate. HDV is considered the fastest progressing and most severe form of all viral hepatitis infections. HDV is a “satellite virus” and can only infect individuals with a concomitant HBV infection.^1,2 Chronic HDV infection is defined as an infection lasting 6 months or more.³ The likelihood of progression to chronic hepatitis depends on whether the initial infection with HDV occurred due to HBV and HDV coinfection or superinfection. While less than 5% of patients progress to a chronic infection after coinfection, HDV infection becomes chronic in more than 80% of individuals with HBV and HDV superinfection.⁴

A 2024 study from the Polaris Observatory found the adjusted prevalence of HDV in the HBV-infected population in Canada to be approximately 3.0%.⁵ These estimates are consistent with the estimated rate of 4.8% (95% CI, 4.3% to 5.3%) reported by a retrospective study conducted using patient data collected by physicians in the Canadian HBV Network (9 clinics in 6 provinces across Canada).⁶ Given that the prevalence of chronic HBV in Canada is approximately 0.66%⁷ and the HBV diagnosis rate is approximately 70%,⁵ the prevalence of HDV (chronic and acute) infection is estimated to be 0.020%⁵ to 0.032%,⁶ which equates to 2 to 3.2 per 10,000 population (includes both chronic and acute HDV).

Key signs and symptoms of chronic HDV infection can range from nonspecific symptoms to rapidly progressing hepatitis. Symptoms may include fever, fatigue, loss of appetite, nausea, vomiting, abdominal pain, dark urine, clay-coloured bowel movements, joint pain, and jaundice.⁴ Chronic hepatitis usually exacerbates any pre-existing liver disease associated with HBV.⁸ Recovery is unlikely, and the likelihood of recovery decreases as the disease progresses. Only 35% of patients with acute infection, and even less (9.96%) with chronic infection, recover.⁹ For those who do not recover at the early stages of the disease, HDV infection is associated with an accelerated progression to fibrosis, early liver decompensation with cirrhosis, and increased risk of HCC, leading to greater liver-related mortality compared to HBV or HCV.^10-12

Diagnosis of HDV generally involves 2 steps. The first step is testing for anti-HDV antibodies through an enzyme-linked immunosorbent assay to assess if a patient has ever been exposed to HDV. If the anti-HDV antibody test is positive, meaning that the patient has been exposed to HDV, the patient is automatically tested for HDV RNA, using RT-PCR, to assess whether the HDV infection is active or chronic. Standard liver function tests are routinely performed to assess the severity of the HBV and HDV disease. These liver function tests are conducted at initial diagnosis and to monitor treatment response. Monitoring of response to HDV treatment involves several tests. Testing for HDV RNA through RT-PCR is required to determine whether to reinitiate treatment and to monitor treatment response. Bile acid tests are recommended to monitor for safety and assess adherence. All these monitoring tests are performed every 3 to 6 months. Both antibody and RNA tests are currently performed at the National Microbiology Laboratory in Winnipeg, Manitoba, and all other tests can be performed at outpatient labs or clinics.²¹

Standards of Therapy

The contents of this section were informed by materials submitted by the sponsor and input from clinical experts, and have been validated and summarized by the review team.

According to the clinical experts consulted by CDA-AMC for this review, HDV occurs as a coinfection with HBV and is associated with a more aggressive liver disease, with a higher risk of cirrhosis, hepatic decompensation, and HCC. There are currently no approved treatments for chronic HDV in Canada.^13-15 The Canadian Association for the Study of the Liver, the Association of Medical Microbiologists and Infectious Disease Canada, the European Association for the Study of the Liver, and AASLD^13-15 indicate that PEG-IFN-alpha has demonstrated some clinical benefit and is recommended as a potential treatment option for patients with HBV and HDV coinfection. AASLD further emphasizes the importance of suppressing HBV replication in individuals with chronic hepatitis D who have elevated HBV DNA levels. Nucleoside (or nucleotide) analogues are HBV polymerase inhibitors that primarily block HBV DNA synthesis, but do not directly suppress the production of the hepatitis B surface antigen (HBsAg), which is required by HDV for entry into hepatocytes.²² Although HDV requires coinfection with HBV, nucleoside (or nucleotide) analogues, which are effective against HBV, have no efficacy against HDV, as HDV replication is entirely independent of HBV replication.^1,15 While Canadian and international guidelines vary in their recommendations on the use of nucleoside (or nucleotide) analogues in patients with HBV and HDV coinfections, they consistently emphasize the lack of efficacy of nucleoside (or nucleotide) analogues against HDV.^13-16

The clinical experts indicated that, although there is limited evidence supporting the use of PEG-IFN-alpha for patients with HDV, response rates are generally low and the treatment is poorly tolerated. The clinical experts noted that, although PEG-IFN-alpha can be used off-label for the treatment of HDV, its use in clinical practice became uncommon due to significant adverse effects, a global shortage, and lack of availability in Canada.

According to the clinical experts consulted for this review, the therapeutic goals for chronic HDV infection include achieving undetectable or reduced HDV RNA, normalizing liver enzymes, improving liver function, and reducing the risk of decompensation, HCC, and liver-related mortality.

Drug Under Review

Key characteristics of bulevirtide are summarized in Table 3.

Bulevirtide has a Health Canada indication for the treatment of chronic HDV infection in adults with compensated liver disease, aligned with the reimbursement request. Bulevirtide has not been previously reviewed by CDA-AMC. The recommended dosage in adults is bulevirtide 2 mg once daily, administered by subcutaneous injection.²³ The optimal treatment duration has not been established. The sponsor has proposed that treatment be continued for as long as it is associated with clinical benefit. In all patients, the underlying HBV infection is managed simultaneously as clinically appropriate.

The HDV virion is assembly-deficient, requiring an envelope provided by HBV to enter host cells; as such, HDV is assumed to enter hepatocytes through the same mechanism as HBV.²⁴ The entry of both HBV and HDV into host cells requires the attachment of a surface protein found within the N-terminal myristoylated domain of the HBV envelope L-protein to NTCP, a hepatic bile salt transporter, followed by subsequent entry and membrane fusion.^25,26 Bulevirtide is a 47-amino acid, N-terminal myristoylated, HBV-L protein–derived, synthesized lipopeptide that acts as a potent, highly selective entry inhibitor of HDV. Bulevirtide blocks the entry of HBV and HDV into hepatocytes by binding to and inactivating NTCP.^23,26 By blocking the essential entry receptor, the de novo infection of liver cells is decreased, viral spread is inhibited, and the life cycle of HDV is disrupted. A reduction in the number of infected cells ultimately protects uninfected and newly formed hepatocytes from new infection and reinfection.^1,27 In contrast to directly acting antivirals, where viral production must be significantly reduced before the achievement of biochemical remission, treatment with entry inhibitors reduces the plasma levels of HDV RNA, due to a decline in the number of infected, virus-producing hepatocytes in the liver.

The drug under review is recommended for reimbursement by the following health technology assessment agencies: the National Institute for Health and Care Excellence (NICE) (England), the Scottish Medicines Consortium (Scotland), and the Haute Autorité de Santé (France). Bulevirtide has not been recommended by the All Wales Medicines Strategy Group (Wales). It is currently under review by the Pharmaceutical Benefits Advisory Committee and the Medical Services Advisory Committee (Australia). Bulevirtide has been approved by the following regulatory agencies: the European Medicines Agency (European Union), the Therapeutic Goods Administration (Australia), and the Medicines and Healthcare products Regulatory Agency (UK). It was not approved by the FDA (US) due to concerns about the manufacture and delivery of the therapy.²⁸

Table 3: Key Characteristics of Bulevirtide

HBV = hepatitis B virus; HDV = hepatitis delta virus; SC = subcutaneous; SC = subcutaneous.

^aHealth Canada indication.

Source: Gilead Sciences Canada Hepcludex clinical evidence and draft product monograph, Hepcludex (bulevirtide). Details included in the table are from the sponsor’s Summary of Clinical Evidence.

Perspectives of Patients, Clinicians, and Drug Programs

The full patient and clinician group submissions received are available in the consolidated patient and clinician group input document for this review on the project website.

Patient Group Input

This section was prepared by the review team based on the input provided by patient groups.

CDA-AMC received a joint patient input submission from 2 organizations, Liver Canada and BC Hepatitis Network.

Patient perspectives were gathered via an online survey conducted between February 21, 2025, and March 8, 2025, using social media. The 6 patients who responded to the survey ranged in age from their 30s to their 60s, and were living with HDV, in Ontario, Alberta, or British Columbia. Patients described how receiving a diagnosis of HDV and experiencing disease-specific symptoms, including general physical and psychological symptoms, substantially impacts their HRQoL. Caring for someone with HDV also leads to significant caregiver burden. All patients rated the importance of having access to new treatments for HDV as 5 out of 5 (where 5 is most important).

PEG-IFN is used off-label in Canada for the treatment of HDV. Patients with experience with PEG-IFN treatment highlighted the associated intolerable side effects, frequent need to travel to clinics for injections, and frequent blood tests for monitoring of response. Patients indicated a preference for treatments that require fewer injections and blood tests. One patient had experience with the drug under review through compassionate access from the manufacturer; they reported experiencing manageable side effects and rated their HRQoL at 4 out of 5 (where 5 is the best score), with improved liver test results and stabilization of liver disease.

Patients described stabilization of their liver disease as an important treatment outcome. Stabilization refers to slowed progression to liver fibrosis, cirrhosis, and liver cancer; improvement in decompensation events; and reduced need for a liver transplant. According to the patient input received for this review, chronic HDV is most common among newcomers and immigrants to Canada, who face multiple barriers to timely diagnosis. According to patient input, these individuals are less likely to be screened for viral hepatitis, face limited access to routine care, and are more likely to experience fear and stigma regarding hepatitis. Together, these barriers increase individuals’ risk for late diagnosis and advanced viral hepatitis-related liver disease. Patients identified reflex testing for HDV among individuals with HBV as an important unmet need. This diagnostic process occurs in 2 steps; the first step is an assay for anti-HDV antibodies, and if this is positive, the second step is a test for HDV RNA. This testing usually occurs in primary care, acute, or public health care settings or in hospitals. According to the patient input received, improving diagnosis rates allows earlier treatment initiation to stop the progression of liver disease before onset of liver cancer and/or liver failure.

Clinician Input

Input From Clinical Experts Consulted for This Review

All CDA-AMC review teams include at least 1 clinical specialist with expertise in the diagnosis and management of the condition for which the drug is indicated. Clinical experts are a critical part of the review team and are involved in all phases of the review process (e.g., providing guidance on the development of the review protocol, assisting in the critical appraisal of clinical evidence, interpreting the clinical relevance of the results, and providing guidance on the potential place of the drug in therapy). The following input was provided by 2 clinical specialists with expertise in the diagnosis and management of chronic HDV infection.

Unmet Needs

The clinical experts consulted by CDA-AMC for this review identified significant unmet needs in the management of chronic HDV infection in Canada, emphasizing the absence of approved therapies or access to reimbursed therapies. The clinical experts indicated that although PEG-IFN was previously used off-label, it is no longer used in clinical practice due to its poor tolerability, limited accessibility, and lack of feasibility for routine use. The clinical experts emphasized that currently available therapies for hepatitis B, including nucleoside (or nucleotide) analogues, are ineffective against HDV infection, which remains the primary driver of liver damage in individuals with HBV and HDV coinfection. As a result, patients with chronic HDV experience progressive liver disease without access to an effective treatment option. The clinical experts highlighted the need for a targeted therapy to reduce HDV viral load, normalize ALT levels, potentially stabilize or improve liver fibrosis, and mitigate the risk of HCC and liver decompensation. This need is particularly urgent due to the aggressive nature of HDV infection and the associated risk of rapid progression to cirrhosis and HCC.

Place in Therapy

According to the clinical experts consulted, bulevirtide would be used as a first-line therapy upon diagnosis of active chronic HDV infection in patients with chronic hepatitis B. The clinical experts noted that bulevirtide acts directly on the HDV replication cycle by preventing viral entry into hepatocytes. According to the clinical experts consulted, patients with detectable HDV RNA and elevated ALT levels were identified as appropriate candidates for treatment, as they are at an increased risk of disease progression in the absence of effective intervention. The clinical experts noted that early initiation of bulevirtide is recommended to help mitigate the risk of progression to advanced liver disease. The clinical experts stated that bulevirtide would be used in combination with nucleoside (or nucleotide) analogues, such as tenofovir or entecavir, which would be used to manage the HBV coinfection, but which are ineffective against HDV. The clinical experts further noted that PEG-IFN is no longer a viable option for the treatment of HDV infection due to its poor tolerability, lack of reimbursement, and limited availability, and therefore would not be considered before bulevirtide.

Patient Population

The clinical experts consulted by CDA-AMC identified individuals with compensated HDV-related liver disease as appropriate candidates for bulevirtide, and those with advanced fibrosis or cirrhosis most in need. The clinical experts indicated that treatment should be based on objective markers such as detectable HDV RNA and elevated ALT levels, rather than symptoms. The clinical experts noted that treatment response is most likely to occur in patients who do not have an immunocompromised condition, have lower baseline HDV RNA levels, and exhibit minimal fibrosis. Conversely, this treatment may be less suitable for patients with barriers to adherence to daily injectable therapy. According to the clinical experts, underdiagnosis of HDV is a significant issue in practice, largely due to the limited availability of HDV RNA testing and lack of routine screening, which pose barriers to timely treatment initiation. The clinical experts noted that systematic screening is lacking, particularly for individuals with HBV who are receiving care in the primary care setting. According to the clinical experts, HDV RNA testing is currently conducted at the National Microbiology Laboratory. The clinical experts emphasized the need for initiatives to establish local access to anti-HDV antibody testing and, ideally, HDV RNA testing as well. The clinical experts noted that noninvasive fibrosis assessment is adequate for evaluation and that liver biopsy is not necessary.

Assessing the Response Treatment

The clinical experts noted that the key outcomes used to determine response to treatment with bulevirtide include virologic response (i.e., undetectable HDV RNA or reduction in HDV RNA levels), biochemical response (i.e., normalization of ALT levels), and stabilization or improvement in liver fibrosis. The clinical experts noted that long-term outcomes such as improvements in portal hypertension, reduced progression to cirrhosis, and lower rates of HCC would also be clinically beneficial but were not assessed in trials. The clinical experts indicated that HDV should be monitored regularly, with liver enzyme and function tests and HDV RNA testing every 3 months and noninvasive fibrosis assessments (e.g., FibroScan) annually. According to the clinical experts, clinicians generally see patients in the clinic every 6 to 12 months, with routine bloodwork conducted every 3 to 6 months and ultrasounds for HCC screening every 6 months. These intervals were deemed appropriate for assessing treatment response and guiding decisions regarding continuation of therapy. The clinical experts emphasized that consistent monitoring of response is essential, as patients with HDV remain at high risk of disease progression even if their HBV is well controlled.

Discontinuing Treatment

The clinical experts indicated that bulevirtide treatment should be discontinued in cases of progression to decompensated liver disease requiring transplant or the development of HCC requiring other therapy. The clinical experts noted that discontinuation can be considered in the event of severe adverse reactions, such as allergy or significant injection site reactions, or if the patient experiences barriers to adherence to the daily injectable therapy. The clinical experts also noted that treatment with bulevirtide could be stopped after a period of consolidation if HDV RNA becomes undetectable, and that emerging information suggests that longer treatment duration may support sustained viral suppression. However, the clinical experts highlighted that treatment discontinuation is generally unlikely unless prompted by patient refusal, death, or the need for liver transplant.

Prescribing Considerations

The clinical experts indicated that the diagnosis of HDV infection, prescribing of bulevirtide, and monitoring of response should be managed by clinicians with specialized expertise in hepatology or infectious diseases, given the complexity of HDV infection and the need for accurate interpretation of HDV RNA and ALT levels. The clinical experts noted that bulevirtide is used in combination with nucleoside (or nucleotide) analogues such as tenofovir or entecavir, which are part of standard hepatitis B management and do not require special prescribing restrictions. The clinical experts indicated that treatment could be administered in outpatient or community settings, and with proper instruction, patients may be able to self-administer the medication; however, clinical oversight by a specialist remains essential for safe and effective treatment.

Additional Considerations

According to the clinical experts consulted by CDA-AMC, chronic HDV infection is rare in Canada, affecting approximately 1% to 2% of individuals with chronic hepatitis B; however, it is associated with more severe liver disease and faster disease progression. The clinical experts highlighted the lack of effective treatment options beyond nucleoside (nucleotide) analogue therapy for HBV, noting that PEG-IFN is poorly tolerated, has limited availability, and is no longer considered a viable option. In the clinical experts’ opinion, bulevirtide addresses a significant unmet medical need for this high-risk population. Despite the potential benefit of bulevirtide treatment, the clinical experts pointed out several remaining challenges, including limited access to systematic HDV screening, gaps in linkage to care, and the burden of managing a medication that requires daily injections. The clinical experts highlighted the need to ensure that patients have reliable access to injection-related supplies such as syringes and saline and receive proper education on how to administer the treatment safely and effectively. The clinical experts also noted that the optimal duration of bulevirtide therapy remains uncertain for patients with HDV that responds more slowly to treatment.

Clinician Group Input

This section was prepared by the review team based on the input provided by clinician groups.

Ten clinicians from the Canadian Hepatitis B Network provided input. The Canadian Hepatitis B Network is a collaborative organization of health care professionals and researchers from across Canada with an interest in advancing excellence in the care of patients with hepatitis B, research into hepatitis B, and education.

The clinician group stated that there is an unmet need for improved therapies for HDV and HBV coinfection. There are currently no treatments approved by Health Canada indicated for HDV. HDV causes the most severe form of viral hepatitis in humans. HDV requires the HBV surface (or envelope) protein to infect the liver and therefore can only infect people who have HBV. Patients with HDV are often young; yet they are at high risk of severe liver disease, liver failure, and liver cancer.

The clinician group stated that individuals can acquire HBV and HDV at the same time or HDV can superinfect a patient with underlying chronic HBV infection because of a shared route of transmission. The drug under review is a novel antiviral drug specifically targeting the binding of HDV (and HBV) to the liver-specific cell surface bile acid receptor, NTCP. Based on input received from the clinician groups, patients with HBV and HDV coinfection and who test positive for HDV RNA are most likely to benefit from treatment with the drug under review.

The clinician group noted that patients with HDV coinfections are at a high risk of liver disease and cirrhosis within 5 years of diagnosis, regardless of any disease characteristics. Patients best suited for treatment with the drug under review would be identified based on the clinical judgment of expert specialists in hepatology or infectious disease, as well as by testing for HDV RNA. No companion diagnostic test is required. The clinician group highlighted that outcomes used in clinical practice are aligned with the outcomes typically used in clinical trials. A clinically meaningful response to treatment would be HDV RNA suppression, biochemical normalization, improvement in noninvasive fibrosis test results, and/or improvement in symptoms of liver disease decompensation (e.g., ascites, variceal bleeding).

Based on input received from the clinician group, suggested criteria for discontinuing treatment were treatment failure (indicated as no HDV RNA decline or ALT normalization), disease progression, and limited lifespan. The clinician group stated that the drug under review can be appropriately prescribed by a hepatology and infectious diseases specialist in a specialty clinic setting.

Drug Program Input

The drug programs provide input on each drug being reviewed through the reimbursement review processes by identifying issues that may impact their ability to implement a recommendation. The implementation questions and corresponding responses from the clinical experts consulted by CDA-AMC for this review are summarized in Table 4.

Table 4: Summary of Drug Plan Input and Clinical Expert Response

ALT = alanine aminotransferase; CDA-AMC = Canada's Drug Agency; CDEC = Canadian Drug Expert Committee; CrCl = creatinine clearance; HBV = hepatitis B virus; HCC = hepatocellular carcinoma; HCV = hepatitis C virus; HDV = hepatitis delta virus; HRQoL = health-related quality of life; LLoD = lower limit of detection; PCR = polymerase chain reaction; PEG-IFN = pegylated interferon; RCT = randomized controlled trial; RNA = ribonucleic acid.

Clinical Evidence

The objective of this Clinical Review report is to review and critically appraise the clinical evidence submitted by the sponsor on the beneficial and harmful effects of bulevirtide at a dose of 2 mg administered by subcutaneous injection in the treatment of chronic HDV infection in adult patients with compensated liver disease. The focus is on comparing bulevirtide to relevant comparators and identifying gaps in the current evidence.

A summary of the clinical evidence included by the sponsor in the review of bulevirtide is presented in 3 sections with the CDA-AMC critical appraisal of the evidence at the end of each section. The first section, the systematic review, includes pivotal studies and RCTs selected according to the sponsor’s systematic review protocol. The assessment of the certainty of the evidence in this first section using the GRADE approach follows the critical appraisal of the evidence. The second section includes indirect evidence from the sponsor. The third section includes additional studies that were considered by the sponsor to address important gaps in the systematic review evidence.

Included Studies

Clinical evidence from the following are included in this review and appraised in this document:

• 1 pivotal RCT identified in systematic review

• 1 ITC

• 2 additional studies that address gaps in evidence.

Systematic Review

The contents of this section were informed by materials submitted by the sponsor, and have been validated and summarized by the review team.

Description of Study

Characteristics of the study included in the systematic review are summarized in Table 5.

Table 5: Details of the Study Included in the Systematic Review

AE = adverse event; ALT = alanine aminotransferase; BLV = bovine leukemia virus; HBeAg = hepatitis B e-antigen; HBsAg = hepatitis B surface antigen; HBV = hepatitis B virus; HCV = hepatitis C virus; HDV = hepatitis delta virus; HQLQ = Hepatitis Quality of Life Questionnaire; LLoD = lower limit of detection; PCR = polymerase chain reaction; PEG-IFN = pegylated interferon; RNA = ribonucleic acid; SAE = serious adverse event; SC = subcutaneous; ULN = upper limit of normal.

Source: Clinical Study Report for MYR301.¹⁹ Details included in the table are from the sponsor’s Summary of Clinical Evidence.

The MYR301¹⁹ trial is an ongoing, phase III, randomized, open-label, parallel-group, multicentre trial (Figure 1). The primary objective of the MYR301 trial was to evaluate the efficacy of bulevirtide at a dose of 2 mg for the treatment of HDV infection in adults with compensated liver disease, compared with delayed treatment with bulevirtide at a dose of 10 mg after a 48-week observation period. The secondary objectives of the trial included assessing the safety of bulevirtide and determining the optimal treatment duration. Patients were enrolled from 16 sites across 4 countries — Germany, Italy, Russia, and Sweden. The study includes a 4-week screening period, a 144-week treatment period, and a 96-week follow-up period.

During the screening period, patients were evaluated for study eligibility in accordance with the study protocol. Following screening, patients were randomized using an electronic randomization system in a 1:1:1 ratio to receive delayed treatment with bulevirtide 10 mg after a 48-week observation period of (N = 51), immediate treatment with bulevirtide 2 mg (N = 49), or immediate treatment with bulevirtide 10 mg (N = 50). Randomization was stratified based on the presence of liver cirrhosis (yes or no). This was an open-label study, with central laboratories blinded to actual treatment allocation (except the laboratories for pharmacokinetic, immunogenicity, NTCP polymorphism, and resistance tests). The primary and secondary end points of the MYR301 trial were analyzed using data up to the cut-off date of September 30, 2022, with the database locked on June 8, 2023.

Data for the study group receiving immediate treatment with bulevirtide at a dose of 10 mg are not presented in this report as this dose has not been approved and is not in use in clinical practice in Canada. This report primarily focuses on between-group comparisons of study end points up to week 48, specifically for bulevirtide at a dose of 2 mg, in line with the Health Canada indication. The use of bulevirtide at a dose of 10 mg as a comparator beyond this period was considered inappropriate based on input from the clinical experts consulted by CDA-AMC that the use of the 10 mg dose would not align with clinical practice as this dose has not been approved by Health Canada.

The systematic review conducted by the sponsor also identified 2 supportive phase II RCTs (MYR202 and MYR203), but these were ineligible for inclusion in this systematic review section, which is limited to pivotal trials, phase III clinical trials, and phase IV clinical trials. The CDA-AMC review team decided against summarizing the MYR202 study in this report because it does not address a gap in the pivotal RCT evidence. The MYR202 study assessed the efficacy of 3 doses of bulevirtide in combination with tenofovir versus observation on background therapy with tenofovir in patients with chronic hepatitis D. The MYR203 phase II trial is summarized in the Studies Addressing Gaps in the Systematic Review Evidence section.

Figure 1: Study Design of the MYR301 Trial

BLV = bulevirtide; DT = delayed treatment; EOT = end of treatment; EOS = end of study; HDV = hepatitis delta virus.

^aPatients in the delayed-treatment group received bulevirtide 10 mg once daily for 96 weeks after receiving no treatment for HDV infection over a 48-week observation period.

Source: Clinical Study Report for MYR301.¹⁹ Details included in the figure are from the sponsor’s Summary of Clinical Evidence.

Populations

Inclusion and Exclusion Criteria

Patients were eligible for enrolment in the MYR301 trial if they were aged between 18 and 65 years and had chronic hepatitis D (i.e., positive serum anti-HDV antibody results or polymerase chain reaction [PCR]-detectable HDV RNA in serum or plasma for at least 6 months before screening). Additional eligibility criteria included positive PCR results for serum or plasma HDV RNA at screening; ALT levels greater than 1 times the upper limit of normal (ULN) but less than 10 times the ULN at screening; and serum albumin level greater than 28 g/L. Key exclusion criteria included decompensated cirrhosis, defined as a Child-Pugh hepatic insufficiency score greater than 7 points. Patients were also excluded from the MYR301 trial if they had current bleeding or ligation or a history of bleeding or ligation within the past 2 years. Additional exclusion criteria included coinfection with HCV or uncontrolled coinfection with HIV, a platelet count less than 60,000 cells/mm³, use of interferons within 6 months before screening, and creatinine clearance less than 60 mL/min.

Interventions

The MYR301 trial was designed to last for 240 weeks, including the 144-week treatment period and the 96-week off-treatment follow-up period.

In the bulevirtide 2 mg group, patients received bulevirtide 2 mg once daily via a single subcutaneous injection for 144 weeks.

In the delayed-treatment group, patients received bulevirtide 10 mg once daily, administered as 2 subcutaneous injections, for 96 weeks after a 48-week observation period with no active HDV treatment.

Bulevirtide was administered either by the patients at home or by designated personnel at the study site. Dose adjustments were not permitted in this study, and the use of rescue therapy was not applicable.

Concomitant Medications

Patients could receive nucleoside (or nucleotide) analogues at screening, during treatment, and during the follow-up period if required for the management of underlying chronic HBV infection, as indicated by current clinical practice guidelines.

Prohibited Medications

The following medications were prohibited in the MYR301 trial:

• systemic glucocorticosteroids (inhaled glucocorticosteroids were allowed)

• immunomodulatory drugs

• antiviral drugs for HBV and/or HDV treatment, apart from permitted nucleoside (or nucleotide) analogues and rescue therapy with bulevirtide for hepatitis exacerbation in the posttreatment period

• hematopoiesis-stimulating drugs

• sulfasalazine

• ezetimibe

• cyclosporine

• substrates of organic anion-transporting polypeptide

• irbesartan

• ritonavir.

Outcomes

A list of efficacy end points assessed in this Clinical Review report is provided in Table 6, followed by descriptions of the outcome measures. Summarized end points are based on outcomes included in the sponsor’s Summary of Clinical Evidence as well as any outcomes identified as important to this review according to the clinical experts consulted for this review and input from patient and clinician groups and public drug plans. With this in mind, the review team selected end points considered to be most relevant in informing expert committee deliberations and finalized this list of end points in consultation with members of the expert committee. The following efficacy end points were considered critical for expert committee deliberations and were assessed using GRADE: combined response; HDV RNA decrease of at least 2 log₁₀ IU/mL or undetectable HDV RNA; change from baseline in liver stiffness measured using FibroScan; and change in HRQoL from baseline. The remaining end points (undetectable HDV RNA, ALT normalization, liver-related clinical events, combined response over time, and virologic response over time) were summarized as supportive information. SAEs were also assessed using GRADE.

Table 6: Outcomes Summarized From the MYR301 Study

AE = adverse event; ALT = alanine aminotransferase; HDV = hepatitis delta virus; HQLQ = Hepatitis Quality of Life Questionnaire; LLoQ = lower limit of quantification; RNA = ribonucleic acid; SAE = serious adverse event.

Note: Combined response was defined as undetectable HDV RNA (less than the LLoQ, target not detected) or HDV RNA decrease ≥ 2 log₁₀ IU/mL from baseline combined with ALT normalization. Virologic response was defined as undetectable HDV RNA (less than the LLoQ, target not detected) or HDV RNA decrease ≥ 2 log₁₀ IU/mL. ALT normalization was defined as an ALT level within the normal reference range, assessed according to central laboratory criteria (≤ 31 U/L for females and ≤ 41 U/L for males in Russia, ≤ 34 U/L for females and ≤ 49 U/L for males in all other locations).

^aStatistical testing for these end points was adjusted for multiple comparisons (e.g., hierarchical testing).

^bThese end points were summarized because they were used to inform the health economics model.

Source: Clinical Study Report for MYR301.¹⁹ Details included in the table are from the sponsor’s Summary of Clinical Evidence.

The primary efficacy end point in the MYR301 trial was the combined response at week 48. Combined response was defined as meeting both of the following criteria: undetectable HDV RNA or decrease in HDV RNA of at least 2 log₁₀ IU/mL from baseline (virologic response) and normalization of ALT levels (biochemical response).

Undetectable HDV RNA was defined as HDV RNA levels less than the LLoQ, with the HDV RNA target not detected.

Virologic response was defined as undetectable HDV RNA or decrease in HDV RNA of at least 2 log₁₀ IU/mL from baseline.

ALT normalization was defined as an ALT level within the normal reference range, assessed according to central laboratory criteria (≤ 31 U/L for females and ≤ 41 U/L for males in Russia, and ≤ 34 U/L for females and ≤ 49 U/L for males in all other locations).

The change from baseline in liver stiffness was measured using FibroScan. FibroScan²⁹ is a noninvasive imaging tool that uses transient elastography to measure liver stiffness to provide a reliable estimate of liver fibrosis. It is considered the standard of care in clinical practice and is widely used in various chronic liver diseases, including HBV, HCV, and HDV. Liver stiffness values are reported in kilopascals, with higher values indicating more advanced fibrosis or cirrhosis.

Health-Related Quality of Life

The MYR301 trial used 3 tools to assess quality of life — the EQ-5D, the Fatigue Severity Scale, and the HQLQ. The clinical experts consulted for this review identified HQLQ as the most relevant questionnaire for evaluating disease-specific elements of quality of life in patients with chronic hepatitis D.

The HQLQ¹⁷ (Table 7) includes both the SF-36 items and 4 hepatitis-specific health domain scores. These hepatitis-specific domains include health distress (4 items), positive well-being (4 items), hepatitis-specific limitations (3 items), and hepatitis-specific health distress (4 items). The SF-36³⁰ is a self-administered questionnaire consisting of 36 items, which assess 2 main components: physical health and mental health. The physical component and the mental component summaries each contain 4 domains, which together evaluate the patient's overall HRQoL in relation to both physical and psychological aspects. Each domain is scored on a scale from 0 to 100, with higher scores indicating better HRQoL.

Table 7: Summary of Outcome Measures and Their Measurement Properties

ALT = alanine aminotransferase; HCV = hepatitis C virus; HQLQ = Hepatitis Quality of Life Questionnaire; HRQoL = health-related quality of life; SF-36 = Short Form (36) Health Survey; MID = minimal important difference; RCT = randomized controlled trial; SD = standard deviation; vs. = versus.

Statistical Analysis

Sample Size Determination

Based on findings from the earlier, phase II MYR202 trial,³² the expected response rates of the primary end point of combined response at week 48 for bulevirtide at 2 mg and 10 mg doses were at least 45%, while the conservative estimate for the response rate in the delayed-treatment group was 8% or less. With a sample size of 47 patients per treatment group, a 2-sided Fisher exact test at a 0.04 significance level would provide 97.8% power to detect this difference in response rates between the bulevirtide 2 mg and 10 mg groups and the delayed-treatment group. The overall power of simultaneously rejecting both null hypotheses would be 95.6%.

Multiplicity Adjustment

An interim analysis at week 24 and a primary analysis at week 48 were conducted to evaluate treatment efficacy of bulevirtide based on the primary end point. To account for the repeated analysis, the overall 2-sided significance level of 0.05 was allocated across the 2 time points: 0.01 for week 24 and 0.04 for week 48. At each analysis, the bulevirtide 10 mg (hypothesis 1) group and the bulevirtide 2 mg (hypothesis 2) group were compared to the delayed-treatment group at the corresponding adjusted significance level. Under this hierarchical procedure, the second hypothesis was tested only if the first null hypothesis was rejected. The key secondary end point was tested only if the null hypothesis for the primary end point was rejected. All other analyses were conducted with no adjustments for multiple comparisons.

Statistical Testing

Combined Response at Week 48

The primary analysis of the primary end point, combined response at week 24 and week 48, compared the rate difference between the bulevirtide 2 mg, bulevirtide 10 mg, and delayed-treatment groups. The proportions of patients who achieved the combined response were analyzed separately for the bulevirtide 2 mg and bulevirtide 10 mg groups compared with the delayed-treatment group. The difference in response rates was estimated with a 99% exact unconditional confidence interval (CI), calculated using the score statistic. The P values from 2-sided Fisher exact tests were also provided. The comparison of bulevirtide 2 mg treatment versus delayed treatment was considered significant only if the comparison of bulevirtide 10 mg treatment versus delayed treatment was significant. Response rates for each group were also presented with Clopper-Pearson 95% CIs.

Due to the anticipated low number of patients with response in the delayed-treatment group, the analysis was not stratified by cirrhosis or other covariates.

Undetectable HDV RNA at Week 48

The key secondary end point of the MYR301 trial, undetectable HDV RNA at week 48, was analyzed using the same methods as used for the primary end point. This test was to be performed only if the 2 null hypotheses for the primary end point at week 48 were rejected.

ALT Normalization at Week 48

The secondary end point, ALT normalization at week 48, was analyzed using the same methods as the coprimary end point. Exact unconditional CIs based on scores for the proportion differences were presented, with corresponding 95% CIs. For the within-group proportions, Clopper-Pearson 95% CIs were calculated.

Change From Baseline in Liver Stiffness at Week 48

For the change in liver stiffness from baseline at week 48, an analysis of covariance model was used to compare the LS means between the bulevirtide 2 mg and delayed-treatment groups as well as the bulevirtide 10 mg and delayed-treatment groups. The model accounted for treatment, region, presence of cirrhosis, and baseline liver stiffness as covariates. Nominal P values and 95% CIs for the LS mean differences were provided, along with the LS mean for each treatment group.

Descriptive statistics for liver stiffness and its change from baseline was presented by treatment group. Plots of means (with SDs) of change from baseline over time, including subgroup analysis by cirrhosis status, were also presented.

Health-Related Quality of Life

In the MYR301 trial, the exploratory outcome HRQoL was measured by change from baseline in the HQLQ and results are expressed as the change from baseline. The clinical experts consulted by CDA-AMC for this review identified the HQLQ as the most relevant disease-specific tool for assessing the HRQoL of patients with chronic hepatitis D.

HQLQ was analyzed using mixed-effects models for repeated measures for change from baseline with treatment, region, presence of cirrhosis, visit, and treatment by visit interaction as fixed effects and the baseline value as a covariate. The model was fitted using the restricted maximum likelihood approach. The LS mean, standard error, 95% CIs, and P values were reported for each domain of the HQLQ tool.

Combined response and virologic response at each visit were exploratory end points in the MYR301 trial.

Subgroup Analysis

In the MYR301 trial, efficacy end points were evaluated in the full analysis set (FAS) population across the following prespecified subgroups using descriptive statistics:

• cirrhosis status at randomization (presence versus absence)

• concomitant HBV treatment (yes versus no).

Sensitivity Analysis

A sensitivity analysis was performed on the FAS for the primary (combined response) and key secondary (undetectable HDV RNA) end points, where assessments made outside of the time window defined by plus or minus 30 days from the planned time point were considered as missing, regardless of whether the time deviation was related to COVID-19.

Handling of Missing Values

The LOCF approach was used to impute missing values for the combined response and undetectable HDV RNA in cases where the missing data were related to COVID-19 for the primary efficacy parameter. For all other instances, a missing equals failure approach was applied, where missing values are imputed as patients who showed no response. For HQLQ, for the observed case analysis, missing values were not imputed and remained missing.

For virology data in the MYR301 trial, the following imputation rules were applied:

• Values reported as less than the LLoQ with a note indicating “target not detected” were imputed as 0.

• Values less than the LLoQ without a “target not detected” note were:

  • Imputed as one-half of the LLoQ if the LLoQ was not equal to the lower limit of detection

  • Imputed as 0 if the LLoQ equals the lower limit of detection.

• Values greater than the upper limit of quantification were imputed as the upper limit of quantification.

• Nonmeasurable data were considered missing.

For log₁₀-transformed data, the following rules were applied:

• A value of 0 was imputed as 0 if the limit of detection was greater than 1.

• A value of 0 was imputed as the log₁₀ of one-half the limit of detection if the limit of detection was less than 1.

Table 8: Statistical Analysis of Efficacy End Points in the MYR301 Study

ALT = alanine aminotransferase; ANCOVA = analysis of covariance; HDV = hepatitis delta virus; NR = not reported; RNA = ribonucleic acid.

Source: Clinical Study Report for MYR301.¹⁹ Details included in the table are from the sponsor’s Summary of Clinical Evidence.

Analysis Populations

Table 9: Analysis Populations of the MYR301 Study

Source: Clinical Study Report for MYR301.¹⁹ Details included in the table are from the sponsor’s Summary of Clinical Evidence.

Results

Patient Disposition

Summary of patient disposition is presented in Table 10.

A total of 183 patients were screened for the MYR301 trial, and 150 were randomized. Eighteen percent of patients were unsuccessful in meeting the screening criteria. By week 144, 149 patients had received bulevirtide treatment, including 49 patients in the bulevirtide 2 mg group and 50 patients in the delayed-treatment group who started bulevirtide 10 mg at week 48. By week 48, the proportion of patients who discontinued the study was similar in both the bulevirtide 2 mg and delayed-treatment groups, with a 2.0% discontinuation rate in each group. The reason for discontinuation was withdrawal of consent (2.0%) in the bulevirtide 2 mg group and pregnancy (2.0%) in the delayed-treatment group. By week 144, the proportion of patients who discontinued the study was higher in the bulevirtide 2 mg group (8.2%) than in the delayed-treatment group (3.9%). In the bulevirtide 2 mg group, the reasons for discontinuation included withdrawal of consent (6.1%) and pregnancy (2.0%). In the delayed-treatment group, the discontinuations were due to pregnancy (2.0%) and death (2.0%). None of the patients in the MYR301 trial discontinued the study treatment.

Table 10: Summary of Patient Disposition in the MYR301 Study

FAS = full analysis set.

Note: One patient in the bulevirtide 2 mg group completed week 144 of the study and withdrew consent on the same day.

^aThe participants received bulevirtide at a dose of 10 mg from week 48 onwards.

Source: Clinical Study Report for MYR301.¹⁹ Details included in the table are from the sponsor’s Summary of Clinical Evidence.

Baseline Characteristics

Patient characteristics at the time of randomization (outlined in Table 11), are limited to those that are most relevant to this review or most likely to affect the outcomes or interpretation of the study results. The mean age was higher in the bulevirtide 2 mg group (44 years [SD = 9.0 years]) than in the delayed-treatment group (41 years [SD = 7.5 years]). The proportion of male patients was larger in the bulevirtide 2 mg group (61.2%) than in the delayed-treatment group (51.0%). Nearly one-half of the patients (47.3%) had cirrhosis at the time of randomization; all the cases of cirrhosis were classified as Child-Pugh Class A. All the patients in both the bulevirtide 2 mg and delayed-treatment groups had HDV genotype 1 at baseline. A larger proportion of the patients in the bulevirtide 2 mg group had a Child-Pugh score of 6 points (30.4% versus 20.8% in the delayed-treatment group), HBV genotype D (95.9% versus 86.3% in the delayed-treatment group), and HBV DNA greater than or equal to the LLoQ (67.3% versus 52.9% in the delayed-treatment group). Mean ALT levels were comparable in the bulevirtide 2 mg group (108 U/L [SD = 62.5 U/L]) and the delayed-treatment group (102 U/L [SD = 61.9 U/L]). A total of 32 patients (65.3%) in the bulevirtide 2 mg group and 32 patients (62.7%) in the delayed-treatment group received oral anti-HBV treatment during the MYR301 trial; 54.7% had initiated treatment before baseline. In addition, 26 (53.1%) of the patients in the bulevirtide 2 mg group and 29 (62.7%) of the patients in the delayed-treatment group had previously received interferon treatment.

Table 11: Summary of Baseline Patient and Disease Characteristics in the MYR301 Study (FAS)

ALT = alanine aminotransferase; FAS = full analysis set; HBeAg = hepatitis B e-antigen; HBsAg = hepatitis B surface antigen; HBV = hepatitis B virus; HDV = hepatitis delta virus; LLoQ = lower limit of quantification; RNA = ribonucleic acid; SD = standard deviation; TAF = tenofovir alafenamide; TDF = tenofovir disoproxil fumarate.

Notes: Baseline value was the last available value collected before or at the time of the first dose of bulevirtide in the bulevirtide 2 mg and bulevirtide 10 mg treatment groups and the last available value collected before or at randomization for the delayed-treatment group. For patients in the delayed treatment to bulevirtide 10-mg treatment group, baseline (i.e., value was the last available value collected before or at randomization for sex, race, and height, and the last available value collected before or at the time of the first dose of bulevirtide 10 mg at week 48 otherwise.

Racial categories used in the table are as reported in the source and may not align with Canada's Drug Agency inclusive language guidelines.

^aPatients received bulevirtide at a dose of 10 mg from week 48 onwards.

^bBody mass index = [weight (kg)/height (m)²] × 10,000.

^cChild-Pugh score and class are presented only for patients with cirrhosis. Percentages are based on the number of patients with cirrhosis and available Child-Pugh scores at baseline.

^dHBV genotyping was performed at the first positive test for HBV DNA, which could be postbaseline.

^eAnti-HBV medications are defined as oral medications with preferred names containing terms of tenofovir, tenofovir alafenamide, tenofovir disoproxil fumarate, tenofovir disoproxil, entecavir, adefovir, lamivudine, telbivudine, and adefovir dipivoxil.

Source: Clinical Study Report for MYR301.¹⁹ Details included in the table are from the sponsor’s Summary of Clinical Evidence.

Table 12 shows a summary of key disease characteristics assessed at randomization and the reset baseline at week 48 for patients randomized to the delayed-treatment group following a 48-week observation period, before receiving the first dose of bulevirtide 10 mg. This treatment group consisted of 50 patients who received at least 1 dose of the study treatment after week 48. For most disease characteristics, the summary statistics remained similar at randomization and week 48, with a few notable exceptions. Specifically, the mean serum ALT level was higher at randomization (102 U/L [SD = 61.9 U/L]) compared to week 48 (82 U/L [SD = 51.1 U/L]) and the mean liver stiffness was 15.3 kPa (SD = 8.95 kPa) at randomization and 16.1 kPa (SD = 11.84 kPa) at week 48.

Table 12: Resetting Baseline for Delayed-Treatment Group at Week 48 (FAS)

ALT = alanine aminotransferase; FAS = full analysis set; HBeAg = hepatitis B e-antigen; HBsAg = hepatitis B surface antigen; HBV = hepatitis B virus; HDV = hepatitis delta virus; RNA = ribonucleic acid; SD = standard deviation.

Notes: Baseline value was the last available value collected before or at randomization for the delayed-treatment group.

For patients in the delayed-treatment group receiving bulevirtide 10 mg, the baseline (i.e., reset baseline) value was the last available value collected before or at randomization for HBeAg and HDV and HBV genotypes, the last available value collected before the first dose of bulevirtide at week 48 for ALT levels, the last available value collected before or at week 48 for liver stiffness, and the last available value collected before or at randomization otherwise.

Source: Clinical Study Report for MYR301.¹⁹

Exposure to Study Treatments

Table 13 summarizes the extent of exposure and adherence to bulevirtide by week 144 in the MYR301 trial. The mean duration of study treatment exposure was ██████ █████ (SD = █████ █████) in the bulevirtide 2 mg group from baseline to week 144 and █████ █████ (SD = █████ █████) in the delayed-treatment group from weeks 48 to 144. The mean adherence rate was similar in the bulevirtide 2 mg and delayed-treatment groups (96.75% versus 97.83%, respectively). In the MYR301 trials, █████ of patients in the bulevirtide 2 mg group and █████ in the delayed-treatment group missed at least 1 dose of bulevirtide by week 144.

Table 13: Summary of Patient Exposure and Treatment Adherence in the MYR301 Study (SAS)

SD = standard deviation; SAS = safety analysis set.

Notes: Total duration of bulevirtide exposure (week) = (last dose date of bulevirtide – first dose date of bulevirtide + 1)/7, regardless of any temporary interruptions.

Total dose administered (mg) = sum of all doses administered as reported in the participant diary, which took participant-reported missed doses into consideration – sponsor identified missed doses.

Dose intensity (mg/week) = total dose administered / total duration of exposure.

If the calculated adherence rate was greater than 100%, the result was set to 100%.

Source: Clinical Study Report for MYR301.¹⁹ Details included in the table are from the sponsor’s Summary of Clinical Evidence.

Protocol Deviations

The proportion of patients with any important protocol deviation was higher in the delayed-treatment group than the bulevirtide 2 mg group (████ versus ████, respectively). The most common types of protocol deviation in both groups were related to █████ ████ ██████████████ █████ ██ ███ ███████ █████████ █████ ██████ ████ ██ ███ ███████████ | ██ ███████ ██████ ██████ ██ ███████ ███ █████ ███████████ █████ ██ ███ ███████ █████████ █████ ██████ ████ ██ ███ ███████████ | ██ ███████ ███ ███ ██ ██████████ ███████████ █████ ██ ███ ███████ █████████ █████ ██████ ████ ██ ███ ███████████ | ██ ██████.

Efficacy

Efficacy results are summarized in the combined response rates in the bulevirtide 2 mg group, which demonstrated consistent improvement over time: 34.7% (95% CI, 21.7% to 49.6%) at week 24, 44.9% (95% CI, 30.7% to 59.8%) at weeks 48 ███ ██, 55.1% (95% CI, 40.2% to 69.3%) at week 96, and 57.1% (95% CI, 42.2% to 71.2%) at week 144.

Virologic Response Over Time

The virologic response at each study visit, an exploratory end point in MYR301, was analyzed exclusively using a missing equals failure approach. The virologic response rates in the bulevirtide 2 mg group demonstrated improvement over time: 55.1% (95% CI, 40.2% to 69.3%) at week 24, 73.5% (95% CI, 58.9% to 85.1%) at week 48, █████ ████ ███ █████ ██ ██████ ██ ████ ██, 75.5% (95% CI, 61.1% to 86.7%) at week 96, and 73.5% (95% CI, 58.9% to 85.1%) at week 144.

The results presented in Table 14 are for bulevirtide at a 2 mg dose compared to the delayed-treatment group, in accordance with the reimbursement request submitted by the sponsor.

Combined Response

The combined response at week 48 was a primary end point in the MYR301 trial. At week 48, 44.9% (95% CI, 30.7% to 59.8%) of patients in the bulevirtide 2 mg group and 2.0% (95% CI, 0.0% to 10.4%) of those in the delayed-treatment group achieved a combined response. The between-group difference in response rates was 42.9% (96% CI, 27.0% to 58.5%; P < 0.0001) in favour of the bulevirtide 2 mg group.

Missing data were minimal for the primary analysis. The sensitivity analysis results, using the missing equals failure approach, were consistent with the primary analysis. Subgroup analyses of the primary end point, combined response at week 48, were conducted based on cirrhosis status. In the bulevirtide 2 mg group, the proportion of patients without cirrhosis who achieved a combined response was 53.8% (95% CI, 16.4% to 57.3%) compared to 34.8% (95% CI, 33.4% to 73.4%) of patients with cirrhosis. In the delayed-treatment group, 4.2% (95% CI, 0.1% to 21.1%) of patients with cirrhosis achieved a combined response compared to 0.0% (95% CI, 0.0% to 12.8%) of those without cirrhosis.

Undetectable HDV RNA at Weeks 24 and 48 After Scheduled End of Treatment

An undetectable HDV RNA at weeks 24 and 48 after scheduled end of treatment (sustained virologic response) was a secondary end point in the MYR301 trial; however, the results for this end point were not reported due to an insufficient follow-up period as the study is still ongoing.

Undetectable HDV RNA or HDV RNA Decrease of at Least 2 log₁₀ IU/mL at Week 48

A decrease in HDV RNA of at least 2 log₁₀ IU/mL or undetectable HDV RNA (virologic response) at week 48 was an additional secondary end point in the MYR301 trial. At week 48, 73.5% (95% CI, 58.9% to 85.1%) of patients in the bulevirtide 2 mg group achieved a virologic response compared to 3.9% (95% CI, 0.5% to 13.5%) of patients in the delayed-treatment group. The between-group difference in response rates was 69.5% (96% CI, 54.1% to 81.9%; P < 0.0001) in favour of the bulevirtide 2 mg group. Missing data were minimal for the analyses.

Subgroup analyses for undetectable HDV RNA or HDV RNA decrease of at least 2 log₁₀ IU/mL were conducted based on cirrhosis status and treatment with concomitant HBV medication (ad hoc analysis). At week 48, the proportion of patients with cirrhosis who achieved a virologic response was 82.6% (95% CI, 61.2% to 95.0%) in the bulevirtide 2 mg group and 8.3% (95% CI, 1.0% to 27.0%) in the delayed-treatment group. Among patients without cirrhosis, the corresponding proportions were 65.4% (95% CI, 44.3% to 82.8%) and 0.0% (95% CI, 0.0% to 12.8%), respectively. At week 48, 78.1% (95% CI, 60.0% to 90.7%) of patients receiving concomitant HBV medication in the bulevirtide 2 mg group achieved a virologic response compared to 6.3% (95% CI, 0.8% to 20.8%) of those in the delayed-treatment group. Among those who were not receiving HBV medication, the corresponding proportions were 64.7% (95% CI, 38.3% to 85.0%) and 0.0% (95% CI, 0.0% to 17.6%), respectively.

Change From Baseline in Liver Stiffness at Week 48

The change from baseline in liver stiffness was a prespecified secondary end point for the week 48 analysis. At week 48, the LS mean of change from baseline in liver stiffness was –3.06 kPa (95% CI, –4.67 kPa to –1.45 kPa) in the bulevirtide 2 mg group and 0.87 kPa (95% CI, −0.79 kPa to 2.53 kPa) in the delayed-treatment group. The between-group difference in LS means of change in liver stiffness was –3.93 (95% CI, –6.23 to –1.63; P = 0.0009) in favour of the bulevirtide 2 mg group. Missing data were minimal for the analysis.

Subgroup analyses of the change in liver stiffness were conducted based on cirrhosis status. At week 48, in the bulevirtide 2 mg group, the mean change from baseline in liver stiffness was –5.70 kPa (SD = 6.94 kPa) in patients with cirrhosis and –0.35 kPa (SD = 2.08 kPa) in patients without cirrhosis. In the delayed-treatment group, the mean change from baseline in liver stiffness was –0.20 kPa (SD = 4.00 kPa) in patients without cirrhosis and 1.78 kPa (SD = 10.1 kPa) in patients with cirrhosis.

Liver-Related Clinical Events

██ ███ ██████ ██████ | █████████████ ████████████████ ███ ██████████ ████ ███ ███████ ██████ ███ ████████ ██ | ███████ ██ ███ ███████████ | ██ ██████ ████ ███ | ███████ █████ ███████████████ ███ ██ ██████████ ████████ █████████████ | ███████ ████ █████████ ██ ███ ███████ █████████ █████ █████████ ███████████ █████ | ████████ ███ ████ █████ █████████ ██ ███████████ ██ ██ ██████████.

Health-Related Quality of Life

At week 24, compared to the delayed-treatment group, the LS mean differences in the bulevirtide 2 mg group were ███ (95% CI, ███ ██ ███) for the HQLQ physical component summary score, ███ (95% CI, ████ ██ ███) for the HQLQ mental component summary score, ████ (95% CI, ███ ██ ████) for the HQLQ health distress score, ███ (95% CI, ████ ██ ████) for the HQLQ positive well-being score, ███ (95% CI, ████ ██ ████) for the HQLQ hepatitis-specific limitations score, and ███ (95% CI, ████ ██ ████) for the HQLQ hepatitis-specific health distress score.

At week 48, compared to the delayed-treatment group, the LS mean differences in the bulevirtide 2 mg group were ███ (95% CI, ███ ██ ███) for the HQLQ physical component summary score, ███ (95% CI, ████ ██ ███) for the HQLQ mental component summary score, ███ (95% CI, ████ ██ ████) for the HQLQ health distress score, ███ (95% CI, ████ ██ ███) for the HQLQ positive well-being score, ███ (95% CI, ███ ██ ████) for the HQLQ hepatitis-specific limitations score, and ███ (95% CI, ███ ██ ████) for the HQLQ hepatitis-specific health distress score. Missing data were minimal for the analyses.

Undetectable HDV RNA

Undetectable HDV RNA (less than the LLoQ, target not detected) at week 48 was a key secondary end point in the MYR301 trial. At week 48, 12.2% (95% CI, 4.6% to 24.8%) of patients in the bulevirtide 2 mg group had undetectable HDV RNA compared to 0.0% (95% CI, 0.0% to 7.0%) in the delayed-treatment group. The between-group difference in response rates was calculated only for the bulevirtide 10 mg group, with the bulevirtide 2 mg group as the reference; however, this comparison is not relevant to this review. Missing data were minimal for the analysis.

Subgroup analyses of the key secondary end point were conducted based on cirrhosis status and concomitant treatment with nucleoside (or nucleotide) analogues (ad hoc analysis). In the bulevirtide 2 mg group, 21.7% (95% CI, 7.5% to 43.7%) of patients with cirrhosis achieved undetectable HDV RNA compared to 3.8% (95% CI, 0.1% to 19.6%) of those without cirrhosis. In the delayed-treatment group, 0.0% (95% CI, 0.0% to 14.2%) of patients with cirrhosis achieved an undetectable HDV RNA compared to 0.0% (95% CI, 0.0% to 12.8%) of those without cirrhosis. Similarly, 15.6% (95% CI, 5.3% to 32.8%) of patients in the bulevirtide 2 mg group receiving concomitant HBV medication achieved undetectable HDV RNA compared to 5.9% (95% CI, 0.1% to 28.7%) of those not receiving HBV medication. In the delayed-treatment group, no patients achieved an undetectable HDV RNA, regardless of concomitant treatment with HBV medication.

ALT Normalization

ALT normalization at week 48 was a secondary end point in the MYR301 trial. At week 48, 51.0% (95% CI, 36.3% to 65.6%) of patients in the bulevirtide 2 mg group achieved ALT normalization compared to 11.8% (95% CI, 4.4% to 23.9%) in the delayed-treatment group. The between-group difference in response rates was 39.3% (96% CI, 20.0% to 55.8%; P < 0.0001) in favour of the bulevirtide 2 mg group. Missing data were minimal for the analysis.

Subgroup analyses of ALT normalization were conducted based on cirrhosis status and concomitant treatment with HBV medication. In the bulevirtide 2 mg group, 61.5% (95% CI, 40.6% to 79.8%) of patients without cirrhosis achieved ALT normalization compared to 39.1% (95% CI, 19.7% to 61.5%) of patients with cirrhosis. In the delayed-treatment group, 7.4% (95% CI, 0.9% to 24.3%) of patients without cirrhosis achieved ALT normalization compared to 16.7% (95% CI, 4.7% to 37.4%) of patients with cirrhosis. Similarly, 52.9% (95% CI, 27.8% to 77.0%) of patients in the bulevirtide 2 mg group who did not receive concomitant HBV medication achieved ALT normalization, compared to 50.0% (95% CI, 31.9% to 68.1%) of those who received HBV medication. In the delayed-treatment group, 15.8% (95% CI, 3.4% to 39.6%) of patients who did not receive concomitant HBV medication achieved ALT normalization, compared to 9.4% (95% CI, 2.0% to 25.0%) of those who received HBV medication.

Combined Response Over Time

The combined response at each study visit, an exploratory end point in MYR301, was analyzed exclusively using a missing equals failure approach. In contrast, the primary end point analysis incorporated an LOCF approach to account for missing data due to COVID-19 at weeks 24 and 48. The combined response rates in the bulevirtide 2 mg group demonstrated consistent improvement over time: 34.7% (95% CI, 21.7% to 49.6%) at week 24; 44.9% (95% CI, 30.7% to 59.8%) at weeks 48 ███ ██; 55.1% (95% CI, 40.2% to 69.3%) at week 96; and 57.1% (95% CI, 42.2% to 71.2%) at week 144.

Table 14: Summary of Key Efficacy Results From the MYR301 Study (FAS)

ALT = alanine aminotransferase; CI = confidence interval; FAS = full analysis set; HDV = hepatitis delta virus; HQLQ = Hepatitis Quality of Life Questionnaire; LLoQ = lower limit of quantification; LOCF = last observation carried forward; LS = least squares; NA = not applicable; NR = not reported; RNA = ribonucleic acid; SE = standard error; vs. = versus.

Note: Virologic response was defined as undetectable HDV RNA (less than the LLoQ, target not detected) or HDV RNA decrease ≥ 2 log₁₀ IU/mL; ALT normalization was defined as an ALT level within the normal reference range, according to central laboratory criteria (≤ 31 U/L for females and ≤ 41 U/L for males in Russia, and ≤ 34 U/L for females and ≤ 49 U/L for males in all other locations).

^aThe results for the delayed-treatment group were measured any time between baseline (at randomization) to before the patients in this treatment group received their first dose of bulevirtide at week 48 or early termination before week 48. From week 48 onwards, patients received bulevirtide 10 mg/day.

^bCombined response was defined as undetectable HDV RNA (less than the LLoQ, target not detected) or HDV RNA decrease ≥ 2 log₁₀ IU/mL from baseline combined with ALT normalization.

^cThe 95% CI for each group was based on the Clopper-Pearson exact method.

^dThe 99% and 96% exact unconditional CIs, based on the score statistic, were presented for the response rate difference at week 24 and week 48, respectively. For missing values related to COVID-19, the LOCF approach was used. Otherwise, the missing equals failure approach was used.

^eThe P value was based on the Fisher exact test.

^fThe analysis of the difference in the proportions of patients with response in the bulevirtide 10 mg group versus the bulevirtide 2 mg group was performed using Fisher exact test.

^gFor response rate difference, the 95% exact unconditional CI based on the score statistic was presented. For missing values related to COVID-19, the LOCF approach was used. Otherwise, the missing equals failure approach was used.

^hBaseline value was the last available value collected before or at the time of the first dose of bulevirtide for the bulevirtide 2 mg and 10 mg treatment groups. Baseline value was the last available value collected before or at randomization for the delayed-treatment group.

ⁱThe LS mean, SE, 95% CIs, and P values were based on the analysis of covariance model for change from baseline with treatment group, region, presence of cirrhosis, and baseline value as covariates.

^jLiver stiffness of 8.4 kPa at week 48 for 1 patient in the delayed-treatment group was added into the analysis.

^kP value was not adjusted for multiple comparisons.

^lThe baseline value was the last available value collected on or before first dose of study drug, or at or before randomization for the delayed-treatment group. The LS mean, SE, 95% CIs, and P values were based on the mixed-effects models for repeated measures for change from baseline with treatment, region, presence of cirrhosis, visit, and treatment by visit interaction as fixed effects and the baseline value as the covariate. The unstructured variance-covariance matrix was used. The Kenward-Roger method was used to estimate the degrees of freedom. Restricted maximum likelihoods were used to fit the model. Observed case: missing values remain missing.

^mBaseline value was the last available value collected before or at the time of the first dose of bulevirtide for the bulevirtide 2 mg, bulevirtide 10 mg, and delayed-treatment groups, and the last available value collected before or at randomization for the delayed-treatment group. The 95% CI was based on Clopper-Pearson exact method. For missing values, the missing equals failure approach was used.

Source: Clinical Study Report for MYR301.¹⁹ Details included in the table are from the sponsor’s Summary of Clinical Evidence.

Virologic Response Over Time

The virologic response at each study visit, an exploratory end point in MYR301, was analyzed exclusively using a missing equals failure approach. The virologic response rates in the bulevirtide 2 mg group demonstrated improvement over time: 55.1% (95% CI, 40.2% to 69.3%) at week 24; 73.5% (95% CI, 58.9% to 85.1%) at week 48; █████ ████ ███ █████ ██ ██████ ██ ████ ██; 75.5% (95% CI, 61.1% to 86.7%) at week 96; and 73.5% (95% CI, 58.9% to 85.1%) at week 144.

Harms

The key harm results in the safety analysis set from the MYR301 trial are summarized in Table 15.

Table 15: Summary of Harms Results From the MYR301 Study (SAS)

AE = adverse event; ALT = alanine aminotransferase; MedDRA = Medical Dictionary for Regulatory Activities; NR = not reported; SAE = serious adverse event; SAS = safety analysis set; TEAE = treatment-emergent adverse event.

Notes: AEs were coded according to MedDRA Version 26.0.

The AEs were allocated to periods based on event onset dates. For the bulevirtide 2 mg treatment group, TEAEs began on or after the study drug initiation and continued up to 30 days after permanent discontinuation of the study drug or led to premature study drug discontinuation. For the delayed-treatment group, treatment-emergent events began on or after the randomization date and before week 48, or up to the study discontinuation date if the patients discontinued the study before the week 48 visit, or else began on or after the randomization date and before the bulevirtide initiation date.

Source: Clinical Study Report for MYR301.¹⁹ Details included in the table are from the sponsor’s Summary of Clinical Evidence.

Adverse Events

At week 48, the proportions of patients who experienced at least 1 AE were 83.7% in the bulevirtide 2 mg group and 80.4% in the delayed-treatment group in the MYR301 trial. The most common AEs in the bulevirtide 2 mg group were headache (18.4% versus 0.0% in the delayed-treatment group), vitamin D deficiency (14.3% versus 25.5% in the delayed-treatment group), leukopenia (14.3% versus 19.6% in the delayed-treatment group), pruritus (12.2% versus 0.0% in the delayed-treatment group), and thrombocytopenia (10.2% versus 15.7% in the delayed-treatment group). The proportions of patients with AEs of grade 3 or higher were 10.2% in the bulevirtide 2 mg group and 7.8% in the delayed-treatment group. Among the patients in the bulevirtide 2 mg group, these AEs included depression (2.0% versus 0.0% in the delayed-treatment group), foot fracture (2.0% versus 0.0% in the delayed-treatment group), decreased neutrophil count (2.0% versus 0.0% in the delayed-treatment group), osteopenia (2.0% versus 0.0% in the delayed-treatment group), and thrombocytopenia (2.0% versus 5.9% in the delayed-treatment group).

At week 144, the proportion of patients in the bulevirtide 2 mg group who experienced at least 1 AE was 98.0%, including 24.5% of patients who experienced grade 3 or higher AEs. At week 144, the most common AEs in the bulevirtide 2 mg group were vitamin D deficiency (44.9%), headache (20.4%), leukopenia (20.4%), thrombocytopenia (20.4%), lymphopenia (16.3%), and neutropenia (16.3%).

Serious Adverse Events

At week 48, the proportions of patients who experienced at least 1 SAE were 4.2% in the bulevirtide 2 mg group and 2.0% in the delayed-treatment group in the MYR301 trial. Most SAEs were experienced by 1 patient across the treatment groups. The SAEs in the bulevirtide 2 mg group included foot fracture (2.0% versus 0.0% in the delayed-treatment group), headache (2.0% versus 0.0% in the delayed-treatment group), hemiparesis (2.0% versus 0.0% in the delayed-treatment group), and depression (2.0% versus 0.0% in the delayed-treatment group). The SAEs in the delayed-treatment group included cholelithiasis (2.0% versus 0.0% in the bulevirtide 2 mg group) and COVID-19 (2.0% versus 0.0% in the buvelirtide 2 mg group).

At week 144, 6.1% of patients in the bulevirtide 2 mg group experienced at least 1 SAE, including esophageal varices (2.0%), foot fracture (2.0%), headache (2.0%), hemiparesis (2.0%), and depression (2.0%). Between weeks 48 and 144 (representing 96 weeks of treatment with bulevirtide at a dose of 10 mg), 6% of patients in the delayed-treatment group experienced at least 1 SAE; these SAEs included COVID-19 (2.0%), urinary tract infection (2.0%), and plasma cell myeloma (2.0%).

Withdrawals Due to AEs

By week 144, there were no AE-related discontinuations in the MYR301 trial.

Mortality

By week 144, there were no deaths in either the buvelirtide 2 mg or the delayed-treatment group.

Notable Harms

At week 48, 14.3% of patients in the bulevirtide 2 mg group and 9.8% of patients in the delayed-treatment group had experienced at least 1 hepatic AE. In the bulevirtide 2 mg group these hepatic AEs included increased ALT levels (4.1% versus 7.8% in the delayed-treatment group), hyperbilirubinemia (4.1% versus 0.0% in the delayed-treatment group), increased blood bilirubin (4.1% versus 0.0% in the delayed-treatment group), increased aspartate aminotransferase (2.0% versus 5.9% in the delayed-treatment group), and hepatic pain (2.0% versus 0.0% in the delayed-treatment group). At week 144, the proportion of patients in the bulevirtide 2 mg group experiencing at least 1 hepatic AE was 28.6%.

At week 48, the proportions of patients experiencing at least 1 renal AE were 8.2% in the bulevirtide 2 mg group and 5.9% in the delayed-treatment group. The renal AEs in the bulevirtide 2 mg group included proteinuria (6.1% versus 3.9% in the delayed-treatment group) and urinary retention (2.0% versus 0.0% in the delayed-treatment group). At week 144, the proportion of patients in the bulevirtide 2 mg group experiencing at least 1 renal AE was 10.2%.

At week 48, 10.2% of patients in the bulevirtide 2 mg group versus 0.0% in the delayed-treatment group had experienced eosinophilia. At week 144, 10.2% of patients in the bulevirtide 2 mg group had experienced eosinophilia.

At week 48, 6.1% of patients in the bulevirtide 2 mg group versus 0.0% in the delayed-treatment group had experienced injection site reactions. At week 144, 20.4% of patients in the bulevirtide 2 mg group had experienced injection site reactions.

Critical Appraisal

Internal Validity

Randomization in the MYR301 trial was performed using an appropriate methodology and stratification was prespecified. An electronic randomization system was used, which typically has a low risk of bias. All efficacy and safety analyses were conducted using the full and safety analysis sets, respectively, and these analyses included all patients who were randomized and who had received at least 1 dose of bulevirtide after randomization. Some imbalances in baseline characteristics, likely due to small sample sizes, were observed in the MYR301 trial. These may have hindered the achievement of true prognostic balance. Specifically, imbalances in baseline characteristics could complicate the interpretation of treatment effects, as observed outcomes may be influenced by these baseline differences rather than the treatment itself. Given the rarity of HDV and the challenges in recruiting patients into clinical trials, achieving large sample sizes is often not feasible. The open-label design of the MYR301 trial introduces a potential bias in the assessment of study outcomes; however, this bias was mitigated by blinding to treatment allocation the central laboratories employed for hematology and biochemistry assessment. Knowledge of the assigned treatment could have led to biases in the reporting and measurement of subjective outcomes, including patient-reported outcomes (e.g., HRQoL) and subjective AEs. Physician’s knowledge of their patients’ assigned treatments may influence how they manage their patients, while patients' awareness of their assigned treatment may impact their likelihood of continuing in the study, which could have led to bias in favour of the intervention; however, the extent of such bias cannot be determined. Although there are always some concerns for risk of bias due to deviations from the intended interventions in open-label trials, there were relatively few protocol deviations, and these were balanced across the groups and therefore unlikely to have influenced the study results. Adherence to the interventions and study completion rates were generally high in the intervention groups of interest to this review, reducing concerns regarding deviations from the intended interventions that could have arisen due to the trial context.

The objective of the MYR301 trial was to assess the efficacy and safety of bulevirtide at a dose of 2 mg compared to the delayed-treatment group, where patients received bulevirtide at a dose of 10 mg after a 48-week observation period. According to FDA guidance,¹⁸ given that no drugs are currently approved for the treatment of HDV infection, a placebo-controlled trial is the preferred design for a phase III clinical trial. An alternative design could be an RCT in which patients are randomized to receive either the investigational drug (the immediate-treatment group) or placebo for a prespecified duration, followed by open-label treatment with the investigational drug for the deferred-treatment group.¹⁸ In this case, effectiveness would be demonstrated by a significant early improvement among participants in the investigational group compared with those in the placebo control. It is worth noting that the proportion of patients with response in the delayed-treatment group was expected to be low, as the patients in this group did not receive HDV treatment and only about 60% received HBV treatment. The third treatment group in the trial consisted of patients who received bulevirtide at a dose of 10 mg. The data for this group are not included in this report, as this dosage of bulevirtide is neither approved nor used in clinical practice in Canada.

All patients randomized to the delayed-treatment and bulevirtide groups received at least 1 dose of bulevirtide after randomization. The primary end point in the MYR301 trial was a combined response, that is, undetectable serum HDV RNA (defined as less than the LLoQ, target not detected) or HDV RNA decrease of at least 2 log₁₀ IU/mL, and ALT normalization. According to FDA guidance,¹⁸ a surrogate end point providing evidence of both a decline in virologic replication and an improvement in associated liver inflammation, as evident by biochemical response, could reasonably predict clinical benefit. However, FDA guidance suggests that subsequent confirmation using clinical end points is required and that these should be collected along with other long-term follow-up data. Although several liver-related clinical events were evaluated in the MYR301 trial, for example, cirrhosis development, decompensation of cirrhosis, and liver-related hospitalization, the study is ongoing and there has not been sufficient time to gather comprehensive data. As such, it remains uncertain whether the improvements observed in the surrogate end points evaluated in this trial will translate into meaningful benefits in clinical outcomes that patients consider to be important, or to what extent such benefits may be realized.

Based on the enrolled sample size, the study was powered to test its primary and key secondary end points. The analyses of primary and key secondary outcomes were conducted using the FAS population, which maintains randomization and minimizes the risk of bias by comparing groups that are randomized at baseline. Statistical analysis methods appear to be acceptable. Both interim analyses at weeks 24 and 48 were planned a priori. The lack of adjustment for multiple comparisons for all but the primary and key secondary end points increases the risk of type I error, where false positives may be incorrectly identified as statistically significant. Statistical analysis methods appear to be acceptable. Bulevirtide treatment outcomes were more favourable in the analysis with respect to a combined response, undetectable HDV RNA, virologic response, change in liver stiffness, and ALT normalization, but there was uncertainty in the true magnitude of the effect due to the small sample size, which increased the risk that prognostic balance was not achieved. The unadjusted comparisons and the decision not to stratify the analyses by cirrhosis due to the small sample size may introduce bias and reduce the accuracy of the estimated treatment effects. The long-term impact of treatment with bulevirtide 2 mg remains uncertain due to the relatively short 48-week duration of the comparison with usual care. A larger proportion of patients in the bulevirtide 2 mg group had a Child-Pugh score of 6 points (which is the borderline between Class A and Class B) compared to the delayed-treatment group. The clinical experts noted that this imbalance may increase the risk of AEs and disease progression in the bulevirtide 2 mg group; however, they highlighted that this should not impact the virological study outcomes. The clinical experts indicated that although liver stiffness was higher in the delayed-treatment group than in the bulevirtide 2 mg group, both at randomization and at week 48, this imbalance is unlikely to be clinically meaningful, as liver stiffness measurements can be affected by factors such as ALT levels and inflammation. Subgroup analyses by cirrhosis status and prior use of nucleoside (or nucleotide) analogues were prespecified; however, they were descriptive and were limited by small sample sizes, precluding any conclusions regarding the possibility of effect modification.

For the primary and key secondary end points, the LOCF approach was used to address missing values related to COVID-19, while in other cases, missing data were treated as treatment failures (patients with no response). The missing equals failure approach was considered a conservative assumption of missing data. In contrast, the LOCF approach, which requires that the value is constant from the time that the data are missing to the time point analyzed, may not reflect the true trajectory of the outcome. The sensitivity analyses were conducted using a nonresponder imputation approach, and the results were consistent with those of the primary analyses. The risk of bias due to missing outcome data in the MYR301 trial is considered to be low. Although the imputation methods may not be perfect, the proportion of missing data was low across the relevant treatment groups and therefore does not raise concerns regarding the validity of the results. Important protocol deviations were reported for 8.2% to 9.8% of patients across the 2 treatment groups, with a comparable proportion between groups, and all deviations were identified before database lock. All the randomized patients were treated and only 2% in both the delayed-treatment and bulevirtide 2 mg groups had discontinued the study prematurely by week 48. The clinical experts noted that this discontinuation rate is not high, given the once daily subcutaneous dosing regimen.

Several patient-reported outcomes were assessed in the MYR301 trial. However, the clinical experts considered the HQLQ tool important for this review as it is liver-specific, includes domains related to mental health and fatigue, and is better supported by data in populations with liver disease. The HQLQ has been validated in patients with hepatitis C, but not in those with hepatitis D, leading to uncertainty regarding what would constitute a clinically relevant between-group difference. No definitive conclusions could be drawn about the effect of bulevirtide compared with delayed treatment on HRQoL due to risk of bias from assessors being aware of treatment assignments, as well as serious imprecision, with wide CIs that included both potential benefit and harm. No estimated minimal important differences were provided for the scales presented by the sponsor, resulting in uncertainty regarding what would constitute a clinically meaningful between-group difference. The risk of bias due to missing outcome data are considered low, given the limited extent of missing data. The analysis method for HRQoL outcomes relied on the likely implausible assumption that data were missing at random, and no sensitivity analyses were conducted to assess robustness to different missingness mechanisms.

External Validity

According to clinical experts, the inclusion and exclusion criteria of the MYR301 trial appropriately reflect the population of patients with HDV who would be eligible for treatment with bulevirtide in clinical practice. Given the rarity of the disease, a small sample size was anticipated and a larger trial may be infeasible. This review assessed the efficacy and safety of bulevirtide at a dose of 2 mg, which is the dose submitted for Health Canada approval, compared with delayed treatment.

The screening failure rate was about 18%. The clinical experts considered this to be fairly inclusive because screening failure rates of between 15% and 40% are common in hepatitis trials. According to the clinical experts consulted by CDA-AMC, the inclusion and exclusion criteria in the MYR301 trial were generally appropriate for the clinical trial setting. The clinical experts noted that while certain exclusion criteria are considered typical for clinical trials, they do not always reflect real-world practice, where treatment decisions are often based on individual clinical judgment and which may include patients typically excluded from trials. For example, while patients aged older than 65 years were excluded from the trial, the clinical experts emphasized that age alone should not preclude treatment with bulevirtide in clinical practice. The clinical experts noted that treatment decisions for older adults should be individualized based on comorbidities, functional status, and patient preferences. However, they acknowledged that bulevirtide treatment may not be appropriate for patients aged, for example, 80 years and older, if the potential burden outweighs the benefits. The clinical experts also noted that the 6-month requirement for a positive anti-HDV antibody assay or HDV RNA PCR result was appropriate within the trial context to confirm chronic HDV infection. The clinical experts also noted that, in clinical practice, physicians are unlikely to delay treatment initiation for patients with HBV and HDV coinfection who present with advanced fibrosis, suggesting that earlier intervention may be clinically appropriate in such cases. The clinical experts indicated that while the ALT level requirement was appropriate as a trial inclusion criterion to reflect active disease, it should not restrict treatment in clinical practice, particularly for patients with advanced liver disease who may have ALT levels in the normal reference range. Patients with HCV or uncontrolled HIV coinfection were excluded from the MYR301 trial; the clinical experts noted that in clinical practice these coinfections can be sequentially managed, with the HIV and HCV infections treated before initiation of HBV and HDV therapy. The clinical experts also noted that although patients with creatinine clearance of less than 60 mL/min were excluded from the trial, those with moderate renal impairment could still be considered for treatment with appropriate monitoring.

The clinical experts agreed that it is reasonable to expect that a substantial proportion of patients treated for HDV in clinical practice will have cirrhosis, given that many are diagnosed at more advanced stages of the disease. The clinical experts also noted that patients with early-stage fibrosis (fibrosis stage 1 [F1] or fibrosis stage 2 [F2]) may be more likely to seek treatment to prevent disease progression. As a result, treatment in real-world settings may be initiated across a broader range of disease severity than is typically represented in clinical trials. According to the clinical experts, although most patients in the MYR301 trial were white, reflecting the European trial site populations, this does not limit the generalizability of the findings to the population in Canada, as the virologic characteristics and treatment response are not expected to differ meaningfully across racial or ethnic groups. Approximately 65% of patients in the MYR301 trial received concomitant oral anti-HBV therapy at baseline and this was balanced across groups. However, the clinical experts indicated that this proportion is lower than expected in clinical practice, where nearly all patients with HDV are typically treated with nucleoside (or nucleotide) analogues. The clinical experts noted that although HBV therapy may slow the progression of fibrosis, this is unlikely to affect the generalizability of the study, as improvements in both virologic and fibrosis outcomes were observed in patients who had previously received HBV therapy (54.7%) and progressed to advanced disease.

According to the clinical experts, the surrogate outcomes used in the MYR301 trial — HDV RNA reduction or undetectability, ALT normalization, and changes in liver fibrosis — were appropriate for assessing treatment benefit. The clinical experts indicated that 48 weeks is a reasonable duration to assess efficacy in the MYR301 trial using these surrogate outcomes; longer-term follow-up would be required to assess hard clinical outcomes such as liver cancer, hepatic decompensation, or death, which are not expected to manifest within 1 year of treatment initiation. The clinical experts also identified undetectable HDV RNA at weeks 24 and 48 after the scheduled end of treatment (sustained virologic response) as an important outcome. The results for this end point were not reported, as the study is ongoing and the data are not yet available. The clinical experts noted that these outcomes align with standard measures in clinical trials and serve as meaningful indicators of disease activity and progression. The clinical experts indicated that in patients with HDV, fibrosis improvement is typically observed over a longer time frame. According to the clinical experts, liver stiffness measurements may be influenced by ALT levels and should therefore be interpreted with caution, and the absence of fibrosis improvement at week 48 does not diminish the clinical relevance of virologic response or overall treatment benefit. The HRQoL outcome was not formally compared between groups, limiting the ability to draw definitive conclusions about this important measure; the results are provided as supportive evidence. Safety data for bulevirtide 2 mg were reported up to week 144, which the clinical experts considered sufficient given the advanced disease status of patients who are at increased risk for AEs.

The MYR301 trial study population was drawn from several sites across 4 European countries, with no sites in Canada included. Nevertheless, the clinical experts indicated that there are no major concerns with generalizing the findings from the trial to clinical settings in Canada.

GRADE Summary of Findings and Certainty of the Evidence

Methods for Assessing the Certainty of the Evidence

For the pivotal RCT identified in the sponsor’s systematic review, GRADE was used to assess the certainty of the evidence for outcomes considered most relevant to inform expert committee deliberations, and a final certainty rating was determined as outlined by the GRADE Working Group:^33,34

• High certainty: We are very confident that the true effect lies close to that of the estimate of the effect.

• Moderate certainty: We are moderately confident in the effect estimate — The true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different. We use the word “likely” for evidence of moderate certainty (e.g., “X intervention likely results in Y outcome”).

• Low certainty: Our confidence in the effect estimate is limited — The true effect may be substantially different from the estimate of the effect. We use the word “may” for evidence of low certainty (e.g., “X intervention may result in Y outcome”).

• Very low certainty: We have very little confidence in the effect estimate — The true effect is likely to be substantially different from the estimate of effect. We describe evidence of very low certainty as “very uncertain.”

Following the GRADE approach, evidence from the RCT started as high certainty and could be rated down for concerns related to study limitations (which refers to internal validity or risk of bias), indirectness, imprecision of effects, and publication bias.

When possible, certainty was rated in the context of the presence of an important (nontrivial) treatment effect; if this was not possible, certainty was rated in the context of the presence of any treatment effect (i.e., the clinical importance is unclear). In all cases, the target of the certainty of evidence assessment was based on the point estimate and where it was located relative to the threshold for a clinically important effect (when a threshold was available) or to the null.

Results of GRADE Assessments

The GRADE assessments included an evaluation of the main outcomes considered important by clinicians, patient groups, and committee members. Table 2 presents the GRADE summary of findings for bulevirtide 2 mg versus delayed treatment in patients with chronic HDV infection.

Long-Term Extension Studies

No long-term extension study was submitted for this review.

Indirect Evidence

The contents of this section were informed by materials submitted by the sponsor and have been validated and summarized by the review team.

Objectives for the Summary of Indirect Evidence

The sponsor-submitted NMA³⁵ addressed the lack of head to head trial data comparing bulevirtide at a dose of 2 mg to the relevant comparators for the treatment of HDV. The indirect evidence is used to inform the pharmacoeconomic model.

The sponsor-submitted pairwise (direct) meta-analysis³⁶ was not summarized in this report because it involves pooling data from trials that directly compare treatments, which is generally preferable but not aligned with the focus of this review. Specifically, the analysis included studies like MYR301 and MYR202. The MYR202 study was excluded from this review due to its irrelevance to the treatment comparisons under evaluation.

Description of Indirect Comparisons

The sponsor-submitted ITC included a systematic review and an NMA evaluating the efficacy and safety of bulevirtide at a dose of 2 mg as monotherapy relative to other treatments available for chronic hepatitis D. The primary aim of the NMA was to evaluate the relative efficacy and safety of bulevirtide 2 mg versus comparators, including PEG-IFN and best supportive care, for patients with chronic hepatitis D.

Based on the prespecified eligibility criteria outlined in Table 16, the sponsor conducted a systematic review to identify studies investigating the efficacy of interventions used in the management of chronic HDV infection. A systematic review, which was informed by a predetermined protocol, was conducted to identify RCTs that investigated bulevirtide 2 mg or other relevant therapeutic regimens for patients with chronic hepatitis D who have compensated liver disease. Relevant treatments include PEG-IFN-alpha and interferon, as well as nucleoside (or nucleotide) analogue monotherapy or in combination with any included intervention. The methods used to conduct the systematic review, extract data, and assess study quality are shown in Table 16. The literature search was conducted as of January 2021 and was extended beyond March 30, 2021. Multiple databases were searched from inception through December 2021 to identify clinical trials. Study screening, study selection, and data extraction were conducted by 2 independent reviewers. Any discrepancies between the 2 reviewers were resolved by a third reviewer. Only studies published in English were included in this review. The assessment of the risk of bias of the included RCTs was performed at the study level using the NICE checklist.³⁷ The number of reviewers involved and whether they conducted assessments independently were not reported.

Table 16: Study Selection Criteria and Methods in the Sponsor-Submitted ITC

ALT = alanine aminotransferase; AASLD = American Association for the Study of Liver Diseases; CDA-AMC = Canada’s Drug Agency; CEA = cost-effectiveness analysis; CENTRAL = Cochrane Central Register of Controlled Trials; EASL = European Association for the Study of the Liver; ECCMID = European Congress for Clinical Microbiology and Infectious Diseases; G-BA = Gemeinsamer Bundesausschuss; HAS = Haute Autorité de Santé; HDV = hepatitis delta virus; HTA = health technology assessment; ICER = Institute for Clinical and Economic Review; ICTRP = International Clinical Trials Registry Platform; ISPOR = Professional Society for Health Economics and Outcomes Research; ITC = indirect treatment comparison; IQWiG = Institute for Quality and Efficiency in Health Care; NICE = National Institute for Health and Care Excellence; PBAC = Pharmaceutical Benefits Advisory Committee; RCT = randomized controlled trial, RNA = ribonucleic acid; SMC = Scottish Medicines Consortium.

Source: Sponsor-submitted direct meta-analysis³⁶ and network meta-analysis.³⁵ Details included in the table are from the sponsor’s Summary of Clinical Evidence.

ITC Design

The sponsor submitted a systematic review and an NMA to evaluate the relative efficacy and safety of bulevirtide 2 mg as monotherapy compared to other available treatments for chronic HDV infection. The objective of the NMA was to evaluate the relative efficacy and safety of bulevirtide 2 mg as a monotherapy versus interferon (in particular, PEG-IFN) and best supportive care in patients with chronic HDV infection. Of note, PEG-IFN is an off-label treatment of chronic HDV infection in Canada.

All the NMA efficacy outcomes were assessed at 2 time points: week 24 and week 48. If a study did not report data at these specific time points, data from the closest available time point were used. For example, the analysis at week 24 included data reported within a time window from week 24 to week 26.

The following outcomes were reported to address the objectives of the NMA: undetectable HDV RNA; HDV RNA undetectable or reduced by at least 2 log₁₀; combined response; ALT normalization at weeks 24 and 48; and AEs and treatment discontinuations due to AEs at week 48.

ITC Analysis Methods

For a summary of the analytical methods applied in the NMA, refer to Table 17.

Sponsor-Submitted NMA

NMA estimation was performed using Markov Chain Monte Carlo techniques, which require specifying prior distributions for model parameters. In all analyses, vague (noninformative) prior distributions were applied to the treatment-effect parameters, regardless of the model used.

The NMA was conducted within a generalized linear model framework, which has the flexibility of being able to accommodate the data structure in accordance with the guidelines of the NICE Decision Support Unit.³⁸ For continuous outcomes, a generalized linear regression model with a normal likelihood and identity link was employed, using the PEG-IFN monotherapy group as the comparator in all comparisons. Treatment effects were reported as mean differences with 95% CrIs. For binary outcomes, a generalized linear regression model with a binomial likelihood and logit link was used, and relative treatment effects were expressed as odds ratios with 95% CrIs.

The Bayesian NMA was conducted using both fixed-effects and random-effects models. For the primary analysis, the standard vague priors recommended in the NICE Decision Support Unit Technical Support Document 2³⁸ were applied. In cases where convergence issues arose ( such as networks with several single-study connections, outcomes with low event rates, or clinical heterogeneity in study characteristics), random-effects NMAs et al.³⁹ priors for between-study heterogeneity recommended by Turner were also explored. Choosing between fixed- and random-effects models was guided by the deviance information criterion (DIC).⁴⁰ When the difference in the DICs of the 2 models exceeded 3, the model with the lower DIC was considered to provide a better fit and was chosen as the preferred model for inference. If the difference in the DICs was less than 3, the fixed-effects model was preferred due to the limited number of contributing studies and the alignment of its results with those observed in trial-level and direct meta-analysis findings.

Convergence was assessed by examining the relevant parameters across iterations, visualizing the histories of chains, checking for overlapping chains, and evaluating Brooks-Gelman-Rubin statistics. To mitigate numerical instability, particularly in studies with zero-event cells or small sample sizes, continuity corrections were applied by adding 0.5 to the numerator and 1 to the denominator.³⁸ Studies with zero events in all arms that continued to impede convergence were excluded from the analysis. When convergence issues arose due to sparse data, single-study connections within the network, or clinical heterogeneity, random-effects NMAs incorporating informative priors were employed.³⁹ If these adjustments did not adequately resolve the convergence issues, an alternative NMA based on the risk-difference model was conducted.⁴¹ For any pair of treatments with both direct and indirect evidence, statistical tests were used to evaluate the null hypothesis that there is no inconsistency between these sources of evidence.

Imputation of Missing Values

For dichotomous outcomes, when only the percentage of patients with the outcome was reported and the number analyzed was not specified, the number of patients randomized was used as the denominator to calculate the number of events, in accordance with the intention-to-treat principle.

For continuous outcomes, when SDs were not reported, imputation methods were employed to derive missing SDs from available standard errors or 95% CIs. Consistent with the approach used for dichotomous outcomes, if the number of patients analyzed was not provided, the number of patients randomized was used for analysis in line with the intention-to-treat principle.

Assessing Heterogeneity

Various parameters were used to assess the qualitative heterogeneity of the patients recruited across the trials contributing to the NMA (Table 19). These parameters included mean age, sex, trial design, previous interferon treatment, ALT values at baseline, cirrhosis status, and presence of genotype HDV-1. The various trial designs and methodological aspects were also compared. As part of a heterogeneity assessment, statistical heterogeneity was presented for each outcome by means of I² statistics between available pairwise comparisons; according to the sponsor, an I² statistic greater than 75% indicates high levels of heterogeneity in pairwise comparisons.

Table 17: NMA Analysis Methods

ALT = alanine aminotransferase; HDV = hepatitis delta virus; NICE = National Institute for Health and Care Excellence; NAT = nucleoside (or nucleotide) analogue therapy; NMA = network meta-analysis; RCT = randomized controlled trial; RNA = ribonucleic acid; vs. = versus.

Source: Sponsor-submitted direct meta-analysis³⁵technical report. Details included in the table are from the sponsor’s Summary of Clinical Evidence.

NMA Results

Summary of Included Studies

Table 18 summarizes the 8 studies considered in the base-case of the NMA.

Table 18: Studies Considered for NMA Base-Case Analysis

NMA = network meta-analysis; PEG-IFN = pegylated interferon; p.o. = orally; SC = subcutaneous; TDF = tenofovir disoproxil fumarate; vs. versus.

Source: Sponsor-submitted NMA³⁵ technical report. Details included in the table are from the sponsor’s Summary of Clinical Evidence.

According to the sponsor, because standard interferon is no longer used in the UK for the treatment of hepatitis D, studies evaluating standard interferon were excluded from the base-case analysis. In addition, the NICE guideline for treatment of hepatitis B recommends a 48-week course of PEG-IFN-alpha-2a for individuals with HBV and HDV coinfections who exhibit significant fibrosis. However, a sensitivity analysis that included all standard interferon-alpha study results was conducted for all efficacy outcomes.

Studies Included in the NMA

An assumption was made in the NMA that nucleoside (or nucleotide) analogues, which are recommended for hepatitis B treatment and commonly used as concomitant medications in the treatment of hepatitis D (e.g., approximately 60% of patients in the MYR301 trial received concomitant antiviral treatment), have similar efficacy when used as monotherapy (tenofovir or adefovir) or in delayed treatment. Consequently, these treatments were grouped together under the common comparator, nucleoside (or nucleotide) analogue therapy, to create a combined network for analysis.

Table 19: Assessment of Homogeneity

HDV = hepatitis delta virus; NMA = network meta-analysis; PEG-IFN = pegylated interferon; RNA = ribonucleic acid.

Source: Sponsor-submitted NMA³⁵ technical reports. Details included in the table are from the sponsor’s Summary of Clinical Evidence.

The studies included in the NMA demonstrated heterogeneity across multiple domains, including baseline patient characteristics, trial design, treatment duration, and disease severity. Results of the homogeneity assessment undertaken by the sponsor are in Table 19.

Patients’ mean age ranged from 26.7 years in the Abbas et al. (2016) study⁵¹ to 44.0 years in the Niro et al. (2006) study.⁵⁰ The proportion of males ranged from 56.7% in the MYR203 study⁴⁷ to 77.5% in the Abbas et al. (2016) study.⁵¹ Baseline HDV RNA levels varied, with the lowest observed in the MYR203,⁴⁷ HIDIT-I,⁴⁸ and Abbas et al. (2016)⁵¹ studies (0.0 IU/mL) and the highest in the Niro et al. (2006)⁵⁰ and MYR201^44,45 studies (7.9 log₁₀ IU/mL and ███ █████ █████, respectively). Mean baseline ALT levels ranged from 79.0 U/L in the MYR203 study⁴⁷ to 144.0 U/L in the Niro et al. (2006) study.⁵⁰ Mean baseline HDV RNA levels varied from 0 log₁₀ IU/mL in the MYR203,⁴⁷ HIDIT-I,⁴⁸ and Abbas et al. (2016)⁵¹ studies to ███ █████ ████ in the MYR201 study.^44,45 Genotype 1 was the predominant HDV genotype across the included studies, although genotype data were not reported in the MYR201^44,45 or Niro et al. (2006)⁵⁰ studies.

The included studies differ in study phase (Ib/IIa, II, or III); this information was not reported in the HIDIT-I, Niro et al. (2006),⁵⁰ or Abbas et al. (2016)⁵¹ studies. Four studies had an open-label design (MYR201,^44,45 MYR202, MYR203,⁴⁷ MYR301¹⁹) and 1 was a double-blind trial (HIDIT-II⁴⁹); this information was not reported in the HIDIT-I,⁴⁸ Niro et al. (2006),⁵⁰ or Abbas et al. (2016)⁵¹ studies. Treatment duration ranged from 24 weeks (MYR201^44,45 and MYR202 studies) to 96 weeks (HIDIT-II⁴⁹ study), and the follow-up duration from 24 weeks in 6 trials to 96 weeks in 1 trial. Sample sizes ranged from 24 patients (MYR201 study^44,45) to 150 patients (MYR301 study¹⁹). Figure 2, Figure 3, Figure 4, Figure 9, Figure 10, Figure 11, and Figure 12 illustrate the network diagrams for the base-case analysis of the NMA.

Figure 2: Master Evidence Network for the Base-Case NMA Analysis

ADV = adefovir; BLV = bulevirtide; ETV = entecavir; NAT = nucleoside (or nucleotide) analogue therapy; NMA = network meta-analysis; PEG-IFN = pegylated interferon; RBV = ribavirin; TDF = tenofovir.

Source: Sponsor-submitted NMA³⁵ technical reports. Details included in the figure are from the sponsor’s Summary of Clinical Evidence.

Figure 3: NMA Network Diagram of Combined-Response Outcome at Week 24

BLV = bulevirtide; NAT = nucleoside (or nucleotide) analogue therapy; NMA = network meta-analysis; PEG-IFN = pegylated interferon; TDF = tenofovir.

Source: Sponsor-submitted NMA³⁵ technical reports. Details included in the figure are from the sponsor’s Summary of Clinical Evidence.

Figure 4: NMA Network Diagram of Combined-Response Outcome at Week 48

BLV = bulevirtide; NAT = nucleoside (or nucleotide) analogue therapy; NMA = network meta-analysis; PEG-IFN = pegylated interferon.

Source: Sponsor-submitted NMA³⁵ technical reports. Details included in the figure are from the sponsor’s Summary of Clinical Evidence.

Assessment of Risk of Bias

According to the sponsor, the methods of randomization and allocation concealment were adequate in 7 trials but unclear in the HIDIT-1 trial.⁴⁸ Only 1 study (HIDIT-II⁴⁹) used an adequate double-blind setting for conducting the trial. Of the remaining trials, 3 were open label, and 3 did not report the blinding information.^19,32,47 Most studies clearly reported patient withdrawals and employed appropriate analytical methods. The overall risk of bias was heterogeneous across the included studies, but none of the studies were considered to be outliers. Further, the risk of bias assessment did not identify any outlier high-risk study for the sensitivity assessment.

Efficacy Results

The Bayesian NMA was conducted using both fixed-effects and random-effects models. DIC was found to be comparable in the fixed-effects and random-effects models for all outcomes analyzed at all time points. For binomial outcomes (i.e., HDV RNA loss, HDV RNA loss or reduction by at least 2 log₁₀ IU/mL), ALT normalization, and combined response, the standard odds ratio model did not converge properly, leading to abnormally wide CrIs due to several single-study connections in networks and a low event rate (zero events). The convergence issue was resolved by the risk-difference model; hence it was selected as the preferred model for the binomial outcomes.

The results of the NMA are presented for the bulevirtide 2 mg as monotherapy versus PEG-IFN-alpha-2 and best supportive care consisting of nucleoside (or nucleotide) analogue therapy at weeks 24 and 48 (Table 20). According to the clinical experts consulted, these are the only 2 comparators identified as relatively appropriate for bulevirtide in patients with chronic HDV infection, given the lack of approved HDV treatments in Canada.

Combined Response

At week 24, results from the fixed-effects models (base-case analysis) indicated that bulevirtide 2 mg demonstrated a favourable improvement in the combined response compared with both PEG-IFN (risk difference = ███; 95% CrI, ███ ██ ████ and nucleoside (or nucleotide) analogue therapy (risk difference = ███; 95% CrI, ███ ██ ███). However, the corresponding random-effects models yielded insufficient evidence to confirm a difference in the combined response for the bulevirtide 2 mg group compared with the PEG-IFN or nucleoside (or nucleotide) analogue therapy groups. The point estimates were comparable across both the fixed-effects and random-effects models, but the 95% CrIs were wider in the random-effects models. By keeping all treatments separate in the base-case model (no nucleoside [or nucleotide] analogue therapy assumption), the results of the sensitivity analysis were consistent with the results from the fixed-effects models.

At week 48, results from the fixed-effects models indicated that bulevirtide 2 mg demonstrated a favourable improvement in the combined response compared with both PEG-IFN (risk difference = ███; 95% CrI, ██ ██ ███) and nucleoside (or nucleotide) analogue therapy (risk difference = ███; 95% CrI, ███ ██ ███). The corresponding random-effects models also indicated that bulevirtide 2 mg demonstrated a favourable improvement in the combined response compared with both PEG-IFN and nucleoside (or nucleotide) analogue therapy (risk difference = ███; 95% CrI, ███ ██ ███) and nucleoside (or nucleotide) analogue therapy (risk difference = ███; 95% CrI, ███ ██ ███). The point estimates were comparable across both the fixed-effects and random-effects models. Sensitivity analysis of the combined response was not feasible at week 48 due to the limited number of available studies.

Virologic Response

At week 24, results from the fixed-effects models (base-case analysis) demonstrated that bulevirtide 2 mg resulted in a favourable improvement in the virologic response compared with nucleoside (or nucleotide) analogue therapy only (risk difference = ███; 95% CrI, ███ ██ ███).The corresponding random-effects models yielded insufficient evidence to confirm a difference in the virologic response for the bulevirtide 2 mg group compared with the PEG-IFN or nucleoside (or nucleotide) analogue therapy groups. By keeping all treatments separate in the base-case model (no nucleoside [or nucleotide] analogue therapy assumption), by excluding 2 studies based on the heterogeneity assessment, and by including 2 studies irrespective of HDV RNA reduction definition, the results of the sensitivity analyses were consistent with the results from the fixed-effects models.

At week 48, results from the fixed-effects models indicated that bulevirtide 2 mg demonstrated a favourable improvement in the virologic response compared with both PEG-IFN (risk difference = ███; 95% CrI, ██ ██ ███) and nucleoside (or nucleotide) analogue therapy (risk difference = ███; 95% CrI, ██ ██ ██). However, the corresponding random-effects models yielded insufficient evidence to confirm a difference in the virologic response between the bulevirtide 2 mg group and the PEG-IFN or nucleoside (or nucleotide) analogue therapy groups. The point estimates were comparable across both the fixed-effects and random-effects models.

ALT Normalization

At week 24, results from the fixed-effects models indicated that bulevirtide 2 mg demonstrated a favourable improvement in ALT normalization compared with both PEG-IFN (risk difference = ███; 95% CrI, ███ ██ ███) and nucleoside (or nucleotide) analogue therapy (risk difference = ███; 95% CrI, ███ ██ ███). Similarly, the corresponding random-effects models indicated a favourable improvement in ALT normalization compared with both PEG-IFN (risk difference = ███; 95% CrI, ███ ██ ███) and nucleoside (or nucleotide) analogue therapy (risk difference = ███; 95% CrI, ██ ██ ███). The point estimates were comparable across both the fixed-effects and random-effects models. By keeping all treatments separate in the base-case model (no nucleoside [or nucleotide] analogue therapy assumption), the results of the sensitivity analyses were consistent with the results from both the fixed-effects and random-effects models.

At week 48, results from the fixed-effects models indicated that bulevirtide 2 mg demonstrated a favourable improvement in ALT normalization compared with both PEG-IFN (risk difference = ███; 95% CrI, ███ ██ ███) and nucleoside (or nucleotide) analogue therapy (risk difference = ███; 95% CrI, ███ ██ ███). The corresponding random-effects models yielded insufficient evidence to confirm a difference in the virologic response for the bulevirtide 2 mg group compared with the PEG-IFN or nucleoside (or nucleotide) analogue therapy groups. The point estimates were comparable across both the fixed-effects and random-effects models.

Undetectable HDV RNA

At week 24, both fixed-effects and random-effects models yielded insufficient evidence to confirm a difference in achieving undetectable HDV RNA in the bulevirtide 2 mg group compared with the PEG-IFN or nucleoside (or nucleotide) analogue therapy groups. By keeping all treatments separate in the base-case model (no nucleoside [or nucleotide] analogue therapy assumption), including standard interferon studies in the base-case analysis, and removing 2 studies based on the heterogeneity assessment, the results of the sensitivity analyses were consistent with the results from both the fixed-effects and random-effects models.

At week 48, results from the fixed-effects models indicated that the bulevirtide 2 mg group demonstrated a favourable improvement in achieving undetectable HDV RNA compared with the nucleoside (or nucleotide) analogue therapy group (risk difference = ███; 95% CrI, ██ ██ ███). However, there was insufficient evidence to confirm a difference in achieving undetectable HDV RNA in the bulevirtide 2 mg group compared with the PEG-IFN group (risk difference = ███; 95% CrI, ████ ██ ██). The corresponding random-effects models yielded insufficient evidence to confirm a difference in achieving undetectable HDV RNA in the bulevirtide 2 mg group compared with the PEG-IFN or nucleoside (or nucleotide) analogue therapy groups.

Table 20: Summary of NMA Efficacy Outcomes of Bulevirtide

CrI = credible interval; HDV = hepatitis delta virus; NAT = nucleoside (or nucleotide) analogue therapy; NMA = network meta-analysis; PEG-IFN = pegylated interferon; RNA = ribonucleic acid.

Note: Results in bold reported 95% CrIs that excluded the null (redacted).

Source: Sponsor-submitted NMA³⁵ reports. Details included in the table are from the sponsor’s Summary of Clinical Evidence.

Safety Outcomes

There was insufficient evidence to confirm differences between bulevirtide at a 2 mg dose and treatment with PEG-IFN or nucleoside (or nucleotide) analogue therapy in the rates of AEs, SAEs, or withdrawals due to AEs.

Table 21: Summary of NMA Results for Safety Outcomes of Bulevirtide at Week 48

AE = adverse event; CrI = credible interval; NAT = nucleoside (or nucleotide) analogue therapy; NMA = network meta-analysis; OR = odds ratio; PEG-IFN = pegylated interferon; SAE = serious adverse event; vs. = versus.

Source: Sponsor-submitted NMA³⁵ reports. Details included in the table are from the sponsor’s Summary of Clinical Evidence.

Critical Appraisal of NMA

The systematic review conducted to identify potentially relevant studies for the ITC was methodologically robust; the sponsor employed a comprehensive literature search strategy, conducted study selection and data extraction in duplicate, and provided a list of excluded studies along with justifications for their exclusion. However, the ITC report did not state whether the risk of bias and feasibility assessments were carried out by a single or by multiple assessors, which has implications for the risks for bias and errors in these processes. The study inclusion and exclusion criteria in this NMA were not provided, which reduced the potential to assess heterogeneity. The sponsor’s risk of bias assessment did not identify any studies with a high risk of bias, but the Cochrane Risk of Bias tool v.2.0 was not used as intended because the appraisals were performed at the study level, as this methodology does not take into account that risk of bias can vary depending on the effect estimate being evaluated, particularly for such domains as performance, detection, attrition, and reporting bias.⁵²

The clinical experts consulted for this review noted that, in the absence of approved treatments for HDV, some regimens included in the NMA, such as PEG-IFN and nucleoside (or nucleotide) analogues, were relatively appropriate comparators for bulevirtide. Although PEG-IFN can be used off-label to treat HDV, its use in clinical practice has become uncommon due to significant adverse effects, a global shortage, and limited availability in Canada. The clinical experts also noted that nucleoside (or nucleotide) analogues are used to manage HBV but have no direct effect on HDV. The clinical experts observed that several comparators included in the NMA analyses are not relevant to the context of HDV treatment in Canada, including bulevirtide plus tenofovir or PEG-IFN combined with adefovir, ribavirin, tenofovir, or entecavir. The inclusion of these therapies in the network could increase heterogeneity; however, given that inclusion or exclusion criteria of the included trials were not reported, this could not be comprehensively assessed.

The literature search for the NMA was last updated by the sponsor in December 2021. The included studies were published between 2006 and 2019, and the treatment landscape has since evolved. An outdated literature search with the possible omission of relevant or unpublished evidence can result in bias. The feasibility assessment for this NMA revealed considerable heterogeneity among the studies in the analyses. Although the definitions of most end points were consistent across the trials, the definition of undetectable HDV RNA differed in 2 studies in the NMA. In addition, there was considerable variation in study design, treatment duration, duration of follow-up, and regimen dosing. These sources of heterogeneity cannot be adjusted for in the NMA. Although the I² statistic was used to assess the heterogeneity, it does not fully capture the complexity of between-study variability, so the true potential for important between-study heterogeneity is uncertain.⁵³ Several important disease-specific characteristics were not reported in some studies in the network, and the patient populations in the included studies varied, particularly in baseline characteristics such as age, presence of cirrhosis, HDV RNA levels, ALT levels, and treatment history. These numerous sources of heterogeneity compromise the underlying transitivity assumption that must be met to produce valid conclusions from the NMA. Not all outcomes were reported across all the studies included in the NMA. The network of interconnected studies was constructed using nucleoside (or nucleotide) analogues or delayed treatment as a common comparator. The clinical experts consulted for this review considered this approach relatively appropriate, as most patients with HBV and HDV coinfection receive nucleoside (or nucleotide) analogues for the management of HBV. The results of the sensitivity analysis that retained all treatments as separate in the base-case model (i.e., without the nucleoside [or nucleotide] analogue therapy assumption) were consistent with those from the fixed-effects and random-effects models for all outcomes at week 24; however, corresponding results were not reported for week 48.

The network of evidence was sparse (i.e., there were few studies contributing to several comparisons); in many cases, there was only 1 study per link, which is insufficient to reliably estimate between-study variances. Bayesian fixed-effects models were used as a base-case analysis, with a random-effects model for the exploratory analysis. When heterogeneity is present, the CrIs of the fixed-effects model may be narrower and less conservative than the random-effects model, underestimating the uncertainty arising from between-study variation. The results of the random-effects models for most outcomes were affected by important imprecision, precluding drawing a conclusion about which treatment may be favoured. In addition, the assumptions of the fixed-effects model (e.g., a single true effect size, or no between-study heterogeneity) are likely less realistic than those of the random-effects model (e.g., assumes variation in effect sizes across studies). The point estimates for efficacy outcomes were comparable in the fixed-effects and random-effects models. Statistical tests were used to evaluate the null hypothesis that there is no inconsistency between direct and indirect evidence for the same treatment comparisons. However, these tests may have limited power to detect incoherence when it exists. The sponsor noted that a common challenge with binomial outcomes was model nonconvergence, often due to single-study effects and the presence of zero-event data. As a result, risk-difference models were employed for the meta-analyses, but their use may be limited in this context; specifically, the results of risk-difference meta-analyses can be influenced by the nonreporting of zero-event outcomes. In addition, these models typically demonstrate lower statistical power and produce more conservative CIs compared to relative measures such as risk ratios, particularly when event rates are low.²⁰

No patient-reported quality of life data were evaluated, despite that HRQoL was considered an important end point for this review. The wide CIs around the estimates of the safety of bulevirtide relative to PEG-IFN and nucleoside (or nucleotide) analogues indicate considerable uncertainty in the comparative safety outcomes.

Studies Addressing Gaps in the Systematic Review Evidence

The contents of this section were informed by materials submitted by the sponsor and have been validated and summarized by the review team.

Two studies submitted by the sponsor were summarized to address gaps in the systematic review evidence (Table 22). The SAVE‑D study was summarized to provide evidence of the effectiveness of bulevirtide beyond 48 weeks. The MYR203 study was summarized to provide direct evidence of the efficacy of bulevirtide monotherapy compared to IFN-alpha alone.

Of note, the sponsor also included real-world cohort evidence from the Canadian HBV Network registry as part of the submission; however, it is not summarized in this report. A poster of the study⁵⁴ was submitted to CDA-AMC. The sponsor was unable to provide additional documentation in a format that allowed completion of a detailed review and appraisal of the data.

Table 22: Summary of Studies Addressing Gaps in the Systematic Review Evidence

ALT = alanine aminotransferase; CI = confidence interval; HCC = hepatocellular carcinoma; HDV = hepatitis delta virus; IQR = interquartile range; PEG-IFN = pegylated interferon; RNA = ribonucleic acid; vs. = versus.

Sources: Details included in the table are from Degasperi et al. (2025),⁵⁵ and the MYR203 Clinical Study Report.

Description of Studies

This section summarizes the SAVE-D and MYR203 studies.

SAVE-D Study Design and Objectives

The aim of the SAVE-D study was to evaluate effectiveness, safety, and clinical outcomes of bulevirtide monotherapy in a large real-life cohort of patients with chronic hepatitis D and cirrhosis. Results were reported for up to 96 weeks. Details of the SAVE-D study are shown in Table 23.

Table 23: Details of the SAVE-D Study

ALT = alanine aminotransferase; EASL = European Association for the Study of the Liver; HCC = hepatocellular carcinoma; HDV = hepatitis delta virus; RNA = ribonucleic acid; vs. = versus.

Source: Degasperi et al. (2025).⁵⁵

Populations

Consecutive patients with HDV-related cirrhosis starting bulevirtide 2 mg monotherapy between September 2019 and February 2023 were enrolled in this multicentre retrospective study. Patients were enrolled from centres in Austria, France, Germany, Greece, and Italy. Chronic HDV was defined as HDV RNA positivity for more than 6 months. Cirrhosis was defined either histologically (Meta-analysis of Histological Data in Viral Hepatitis [METAVIR] fibrosis stage 4 [F4]), noninvasively as liver stiffness measurement (LSM) greater than 12.5 kPa, or clinically (nodular liver surface, splenomegaly, thrombocytopenia). Exclusion criteria were not reported.

Interventions

Bulevirtide 2 mg was self-administered as subcutaneous injections every 24 hours.

Outcomes

Clinical and virologic responses were collected at treatment baseline and every 24 weeks thereafter. The primary and secondary end points are summarized in Table 23.

Statistical Analysis

Categorical variables were reported as frequencies (using percentages) while continuous variables were reported as medians (with range). To compare categorical variables, chi-square or Fisher exact tests were used, while continuous variables were analyzed using Student t tests, Mann-Whitney U tests, or Kruskal-Wallis tests, as appropriate. All tests were conducted as 2-sided using a significance level of 0.05.

For continuous variables that were assessed at multiple time points, repeated measures analysis of variance was used, and the Bonferroni correction was applied to address the issue of multiple testing. The Kaplan-Meier method was used to calculate cumulative incidences of liver-related events and mortality. Follow-up duration was measured from baseline to the date of a liver-related event, death, or latest follow-up.

Results

Patient Disposition

Patient baseline characteristics are summarized in Table 24. Median age was 49 years (IQR = 40 years to 58 years). Almost two-thirds (61%) of patients were males, 82% were white, 10% had HIV coinfection, and 94% had HDV genotype 1. Of the total cohort (N = 244), 95% had compensated cirrhosis Child-Pugh Class A in 24% of patients, while the remaining 11 patients had Child-Pugh Class B7 cirrhosis at the start of treatment with bulevirtide. Cirrhosis was diagnosed based on liver stiffness measurements in 158 patients (65%), clinical signs in 45 (18%), and histological findings in 41 (17%).

Most patients showed features of advanced liver disease in terms of severity of portal hypertension: 54% of patients had esophageal varices (37% on prophylaxis) and 15% had a history of previous decompensation (ascites 12%, bleeding 3%). Median spleen size was 15 cm (IQR = 12 cm to 17 cm), median platelet count was 94 multiplied by 10³/mm³ (IQR = 67 × 10³/mm³ to 145 × 10³/mm³), and median liver stiffness was 18.3 kPa (IQR = 13.0 kPa to 26.3 kPa). Fourteen patients (6%) had active HCC at the start of bulevirtide treatment; 58% had a history of previous IFNa treatment; and 92% were receiving nucleoside (or nucleotide) analogue therapy for HBV (55% tenofovir disoproxil fumarate, 32% entecavir, 3% tenofovir alafenamide, 2% other).

Upon starting bulevirtide treatment, median ALT values were 80 U/L (IQR = 55 U/L to 130 U/L) and 8% of patients had ALT levels in the normal reference range. Median quantitative HBsAg values were 3.8 log₁₀ IU/mL (IQR = 3.4 log₁₀ IU/mL to 4.1 log₁₀ IU/mL) and 93% of patients had HBV that was hepatitis B e-antigen negative. Median HDV RNA levels were 5.4 log₁₀ IU/mL (IQR = 4.1 log₁₀ IU/mL to 6.5 log₁₀ IU/mL).

Table 24: Baseline Characteristics of Patients in the SAVE-D Study

ALT = alanine aminotransferase; AST = aspartate aminotransferase; BMI = body mass index; GGT = gammaglutamyltransferase; HBeAg = hepatitis B e-antigen; HBsAg = hepatitis B surface antigen; HBV = hepatitis B virus; HCC = hepatocellular carcinoma; HCV = hepatitis C virus; HDV = hepatitis delta virus; IFN = interferon; IQR = interquartile range; NUC = nucleoside (or nucleotide) analogue therapy; RNA = ribonucleic acid.

^aAvailable for 82 patients.

^bAll patients with undetectable HIV RNA.

^cAll patients with undetectable HCV RNA.

^dChild-Pugh A6 in 59 patients (24%); Child-Pugh B7 in 11 patients (5%).

^eEsophagogastroduodenoscopy results were available for 169 patients (69%), of whom 62 (37%) received prophylaxis.

^fAscites experienced by 30 patients (12%), bleeding experienced by 7 patients (3%).

^gActive HCC experienced by 14 patients (6%).

^hAccording to local laboratory assessments, median HBV DNA was 1.4 log₁₀ IU/mL (IQR = 1.0 to 1.5 log₁₀ IU/mL).

Source: Degasperi et al. (2025).⁵⁵

Efficacy

Of the enrolled patients, 244 (100%) had assessments available at baseline, 242 (99%) at week 24, 209 (86%) at week 48, 164 (67%) at week 72, and 87 (36%) at week 96.

After initiating bulevirtide 2 mg/day monotherapy, median HDV RNA declined from 5.4 log₁₀ IU/mL (IQR = 4.1 log₁₀ IU/mL to 6.5 log₁₀ IU/mL) at baseline to 2.4 log₁₀ IU/mL (IQR = 0.7 log₁₀ IU/mL to 3.8 log₁₀ IU/mL) at week 96 (P < 0.001 for all time points versus baseline), with a median decline of 2.5 log₁₀ IU/mL (1.3 log₁₀ IU/mL to 3.7 log₁₀ IU/mL) and 2.7 log₁₀ IU/mL (1.6 log₁₀ IU/mL to 4.1 log₁₀ IU/mL) at weeks 48 and 96, respectively (Figure 5).

Figure 5: HDV RNA Levels During Bulevirtide Monotherapy in the SAVE-D Study

HDV = hepatitis delta virus; IQR = interquartile range; pts = points; RNA = ribonucleic acid; vs. = versus.

Source: Degasperi et al. (2025).⁵⁵

Virologic response was achieved by 53% of patients at week 24, 65% at week 48, 67% at week 72, and 79% at week 96. Rates of HDV RNA undetectability at the same time points were 17%, 28%, 38%, and 48%, respectively (Figure 6).

Median ALT values declined from 80 U/L (IQR = 55 U/L to 130 U/L) at baseline to 39 U/L (IQR = 29 U/L to 53 U/L) at week 24 and stayed less than the ULN until week 96 (P < 0.001 for all time points versus baseline).

Biochemical response was achieved by 54% of patients at week 24, 61% at week 48, 61% at week 72, and 64% at week 96. For additional thresholds of biochemical response (ALT < 1.5 × ULN; ALT < 2.0 × ULN), rates of ALT normalization increased to 96% and 98%, respectively, at week 96 (Figure 7).

Rates of combined response were 33% at week 24, 44% at week 48, 46% at week 72, and 54% at week 96 (Figure 6). The proportion of patients with less than 1 log₁₀ IU/mL HDV RNA decline from baseline progressively decreased over time, from 22% at week 24, to 19% at week 48, 14% at week 72, and 10% at week 96. Despite the suboptimal virologic response, a biochemical response was achieved by 33% of these patients at week 24 and 36% at week 48, while only 2 out of 8 patients (25%) with less than 1 log₁₀ IU/mL decline at week 96 had ALT levels in the normal reference range. Overall, 31%, 30%, and 35% of patients with less than 1 log₁₀ IU/mL HDV RNA decline had a greater than 50% decrease in ALT levels compared to baseline at weeks 24, 48, and 72, respectively.

Figure 6: Effectiveness of Bulevirtide Treatment in the SAVE-D Study

HDV = hepatitis delta virus; pts = points; RNA = ribonucleic acid.

Source: Degasperi et al. (2025).⁵⁵

Figure 7: Achievement of ALT Normalization According to Different ALT Thresholds in the SAVE-D Study

ALT = alanine aminotransferase; pts = points; ULN = upper limit of normal.

Source: Degasperi et al. (2025).⁵⁵

Harms

During bulevirtide treatment, median bile acid levels increased from 15 μmol/L (IQR = 9 μmol/L to 32 μmol/L) at baseline to 37 μmol/L (IQR = 21 μmol/L to 73 μmol/L) at week 24, 41 μmol/L (IQR = 18 μmol/L to 82 μmol/L) at week 48, 39 μmol/L (IQR = 17 μmol/L to 66 μmol/L) at week 72, and 36 μmol/L (IQR = 19 μmol/L to 66 μmol/L) at week 96 (at all time points versus baseline, P < 0.001) (Figure 8). Mild and transient pruritus was experienced by 24 patients (10%); of the 24 patients, 19 (79%) experienced pruritus in the first 24 weeks of treatment. Bile acid levels at the time of pruritus onset were increased in all patients (37 μmol/L [IQR = 17 μmol/L to 94 μmol/L]), without any significant difference compared to patients without pruritus at the same time point. Injection site reactions were experienced by 7 patients (3%); a grade 3 maculopapular rash with mild eosinophilia experienced by 1 patient at treatment week 24 (and who had achieved a viral response at the time of event), leading to bulevirtide discontinuation with complete recovery.⁵⁵

Figure 8: Serum Bile Acid Levels During Bulevirtide Monotherapy From Baseline up to 96 Weeks in the SAVE-D Study

IQR = interquartile range; vs. = versus.

Source: Degasperi et al. (2025).⁵⁵

MYR203 Study Design and Objectives

The MYR203 trial was a multicentre, open-label, randomized, comparative, parallel-arm phase II study to assess the efficacy of bulevirtide as a monotherapy or in combination with PEG-IFN-alpha or tenofovir compared with PEG-IFN-alpha alone. Patients were randomized into 6 treatment groups, 2 of which were considered relevant to the current review: group A, where patients received PEG-IFN-alpha 180 mcg, and group D, where patients received bulevirtide 2 mg. The study results were to be used to select the optimal treatment regimen for bulevirtide in the next phase.

Populations

Adults (aged 18 to 65 years) with chronic hepatitis B (hepatitis B e-antigen positive or negative) and presence of HBsAg and anti-HDV antibodies for at least 6 months before screening were eligible to participate in the study. Requirements included a positive test result for HDV RNA during screening and ALT levels greater than or equal to 1 times the ULN but less than 10 times the ULN. Patients were not included if they had received antiviral therapy to treat chronic hepatitis B, anticancer therapy, or immunomodulatory therapy during the previous 6 months or needed concomitant treatment with glucocorticosteroids and drugs with myelotoxic effect. Patients were also not included if they had HCV or HIV coinfections, an oncological disease, decompensated liver disease in the current or past medical history, signs of medication-induced or alcohol-induced liver impairment, or other medical conditions associated with chronic liver disease.

Interventions

Patients were randomly assigned in equal numbers to 1 of the 6 treatment groups: 2 mg bulevirtide plus PEG-IFN-alpha, 5 mg bulevirtide plus PEG-IFN-alpha, 10 mg (10 mg once daily) bulevirtide plus PEG-IFN-alpha, 10 mg (5 mg twice a day) bulevirtide plus tenofovir disoproxil fumarate, 2 mg bulevirtide alone, and PEG-IFN-alpha alone. All the groups received the assigned study treatment for 48 weeks, after which the durability of the viral response was assessed over a follow-up period of 24 weeks. This was an open-label study, where neither the patients nor the investigators were blinded to the assigned treatment.

Outcomes

The outcomes summarized from the MYR203 trial are presented in Table 25.

Table 25: Summary of MYR203 Study Outcomes

ALT = alanine aminotransferase; HDV = hepatitis D virus; RNA = ribonucleic acid.

Note: tatistical testing for these end points was adjusted for multiple comparisons (e.g., hierarchical testing).

Source: Sponsor’s Summary of Clinical Evidence.

Statistical Analysis

Statistical models used along with the end point reported as found in Table 26. No adjustment factors, methods to handle missing data, or sensitivity analyses were performed.

Table 26: Statistical Analysis of Efficacy End Points in the MYR203 Study

HBV = hepatitis B virus; HDV = hepatitis delta virus; RNA = ribonucleic acid; vs. = versus.

Source: Sponsor’s Summary of Clinical Evidence.

Sample Size and Power Calculation

The primary end point was undetectable HDV RNA, assessed using PCR, at week 72, to justify the minimum size of the treatment groups.

The sample size calculation was carried out according to the method described by Chow et al.⁵⁶ using the TrialSize package for the R programming language. The results from the 24-week treatment period in the MYR201 study were used: in the PEG-IFN-alpha therapy group (PEG-IFN-alpha 180 mcg for 48 weeks), the proportion of participants with undetectable HDV RNA, assessed using PCR, was 29% (2 of 7 participants), and in the combined-therapy group (bulevirtide 2 mg plus PEG-IFN-alpha 180 mcg for 24 weeks, followed by PEG-IFN-alpha 180 mcg for 24 weeks), the proportion of participants with undetectable HDV RNA, assessed using PCR, was 71% (5 of 7 participants). It was expected that 5 clinical study groups would demonstrate efficacy comparable to the MYR201 substudy combined-therapy results. Based on these assumptions and a significance level of 0.10, having a group size of 15 would make it possible to reach at least 60% power in the study.

Considering the exploratory nature of the study, the number of arms calculated could be considered sufficient to draw conclusions about the optimal dosing schedule to be used in clinical studies of the next phases.

Patient Disposition

Table 27: Patient Disposition in the MYR203 Study

PEG-IFN = pegylated interferon.

Notes: Percentages are based on the number of patients who were randomized within each treatment group except group A.

Patients are presented in the treatment groups as treated (i.e., actual treatment).

^aPercentages are based on the number of patients who prematurely withdrew from each treatment group.

Source: MYR203 Clinical Study Report.

Patient Characteristics

Table 28: Patient Demographic and Baseline Characteristics in the MYR203 Study (SAS)

BMI = body mass index; n/nmiss = number of patients with evaluable data/number of patients with missing data; PEG-IFN = pegylated interferon; Q1 = first quartile; Q3 = third quartile; SAS = safety analysis set; SD = standard deviation.

Notes: Percentages are based on the number of patients in each treatment group.

Racial categories used in the table are as reported in the source and may not align with Canada's Drug Agency inclusive language guidelines.

Source: MYR203 Clinical Study Report.

Efficacy

Other Secondary Efficacy End Point: Degree of Liver Fibrosis

At baseline, the mean liver stiffness was 11.01 kPa (SD = 4.66 kPa) in the PEG-IFN-alpha group (group A) and 13.78 kPa (SD = 5.09 kPa) in the bulevirtide 2 mg group (group D). There were no statistically significant differences in the change from baseline between the group receiving bulevirtide alone (group D) and the PEG-IFN group (group A) at any time point. Similar results were observed when the analyses were performed on the per-protocol analysis set population.

Table 29: Key Efficacy Outcomes in the MYR203 Study (FAS)

ALT = alanine aminotransferase; CI = confidence interval; HBsAg = hepatitis B surface antigen; HDV = hepatitis delta virus; FAS = full analysis set; LLoD = lower limit of detection; LS = least squares; NA = not available; PEG-IFN = pegylated interferon; RNA = ribonucleic acid; SD = standard deviation.

^aHDV RNA response was defined as an HDV RNA value less than the LLoD, where LLoD = 10.

^bProportions, as percentages, are based on the number of patients analyzed in each treatment group.

^cCIs calculated using the Clopper-Pearson (exact) method for within-group proportions and exact unconditional method for difference in proportions.

^dFisher exact test was used for the comparison of respective the bulevirtide group and PEG-IFN-alpha-2 only group.

^eFor the FAS, patients were analyzed as randomized (i.e., planned treatment).

^fP values were not adjusted for multiple testing using Bonferroni correction.

^gALT normalization was defined as ALT value within the normal reference range.

^hCombined response was defined as HDV RNA response and ALT normalization.

ⁱA mixed-effects model for repeated measures was used to test null hypotheses of no difference compared to the control group.

^jThe model included log₁₀-transformed data for all postbaseline visits for the dependent variable and was adjusted for baseline HDV RNA (log₁₀- transformed), treatment group, analysis visit, the interaction between treatment group and analysis visit.

Source: MYR203 Clinical Study Report.

Harms

For a summary of the key harms data in the MYR203 study, refer to Table 30.

Table 30: Key Harms Data in the MYR203 Study (SAS)

AE = adverse event; ALT = alanine aminotransferase; GGT = gammaglutamyltransferase; MedDRA = Medical Dictionary for Regulatory Activities; NA = not available; PEG-IFN = pegylated interferon; SAE = serious adverse event; SAS = safety analysis set.

Notes: Adverse events are coded according to MedDRA Version 21.1.

Percentages are based on the number of patients in each treatment group.

For the SAS, patients were analyzed as treated (i.e., actual treatment).

Source: Table 35, Table 39, and Table 42, MYR203 Clinical Study Report.

Critical Appraisal

SAVE-D Study

Internal Validity

SAVE-D was a multicentre retrospective real-world study (n = 244 patients) with the goal of addressing the gap in evidence on the effectiveness of treatment with bulevirtide beyond 48 weeks in patients with cirrhosis with and without clinically significant portal hypertension. SAVE-D was a single-arm real-world study without a comparator, which means that conclusions could not be drawn about the effectiveness of bulevirtide treatment relative to usual care. Further, the single-arm design does not allow for causal conclusions.

The consecutive enrolment of new patients in the SAVE-D study helped minimize selection bias. The authors also correctly applied Bonferroni adjustment for multiple testing to reduce the risk of type I errors when comparing repeated measures analysis of variance for continuous variables at different time points. There was a potential risk of bias in the measurement of outcomes because HDV RNA quantification was performed locally using different assays with different limits of quantification and detection. This variability could impact the HDV RNA undetectability rates. As a function of the real-world, retrospective design, there was potential for underreporting of bulevirtide-related AEs and liver-related events. The SAVE-D study did not investigate missing outcome data, including possible informative censoring of patients between weeks 24, 48, 72, and 96. The sample sizes declined from 244 (100%) at baseline, to 87 (36%) at week 96, posing a high risk of bias due to missing outcome data, particularly after week 24. The open-label administration of bulevirtide meant that patients’ knowledge of their treatment could lead to more favourable outcomes and fewer SAEs. In addition, even though the AEs reported were relatively mild, patients who remained in the study represent a healthier subgroup who were better able to tolerate any AEs, potentially skewing the results. The authors reported confounders at baseline but did not assess time-varying exposure to other confounding viral conditions (e.g., HCV or HIV infection) after enrolment, which could impact concomitant treatment (e.g., nucleoside [or nucleotide] analogue) and study outcomes. Other statistical methods could have been used to adjust for time-varying confounders.

External Validity

Recruitment for SAVE-D occurred across 46 centres in Austria, France, Germany, Greece, and Italy, allowing generalizability to populations in these countries, but this limit generalizability to the patient population in Canada. Most of the study participants were white (82%), and 95% had cirrhosis classified as Child-Pugh Class A. The authors acknowledged the prevalence of the HDV-1 genotype in the European setting, which could limit generalizability to the context in Canada. The absence of comparators in this study meant there was no assessment of comparative effectiveness or causal inference of bulevirtide relative to usual care. Out of the outcomes patients deemed important, the SAVE-D study did not report HRQoL outcomes.

MYR203 Study

Internal Validity

The MYR203 study was an exploratory phase II trial that was susceptible to various risks of bias. The small sample sizes in each randomized group (n = 15), increased the risk that true prognostic balance was not achieved as was evidenced by the imbalance in baseline characteristics between groups, potentially leading to the overestimation of the beneficial effects of bulevirtide. A larger percentage of patients in the PEG-IFN-alpha group (33.3%) than in the bulevirtide alone group (13.3%) withdrew prematurely from the study. The relatively large percentage of missing data poses a risk of bias for this open-label study.

By week 72, there was a risk of bias due to missing outcome data evidence in a decline in patients remaining in the analysis set: 46% in the PEG-IFN-alpha group and 60% in the bulevirtide group alone. The sponsor used a missing equals failure approach that assumes that patients with missing data had a negative outcome. Sensitivity analyses were conducted using complete cases, which assumes that data are missing completely at random. The sponsor did not demonstrate that the 2 assumptions, missing equals failure and missing completely at random, are valid. Therefore, there is likely a risk of bias due to missing outcome data, the magnitude and direction of which are uncertain.

The open-label design can also pose a risk of bias in the measurement of AE outcomes. The authors did not apply any methods to adjust for multiple testing, increasing the likelihood of type I errors for statistically significant results. The small sample sizes also meant that the effect estimates for many end points were subject to high levels of uncertainty due to imprecision (with 95% CIs spanning the null).

External Validity

All the patients enrolled in the MYR203 study were from Russia, which limits the generalizability to patients in Canada. The exclusion of patients who had previously received antiviral therapy for the treatment of chronic hepatitis B and patients with HCV or HIV coinfections improved the internal validity but limited external validity. The comparator group used in this study was PEG-IFN, which is limited in use in Canada due to the adverse effects and drug availability issues, further limiting the generalizability of this study. HRQoL outcomes were not measured in the MYR203 trial despite this being an important outcome for patients with HDV infection. The use of very small sample sizes greatly limits the generalizability of the findings of bulevirtide as an effective therapy for HDV infection.

Discussion

Summary of Available Evidence

The MYR301 trial was an ongoing, phase III, randomized, open-label, parallel-group, multicentre study (N = 150). The objective of the MYR301 trial was to evaluate the efficacy and safety of bulevirtide at a dose of 2 mg for treating chronic HDV infection in adults with compensated liver disease, compared to delayed treatment with a 10 mg dose of bulevirtide following a 48-week observation period. The trial comprises a 4-week screening period, a 144-week treatment period, and a 96-week follow-up period. Patients were randomized to receive delayed treatment with bulevirtide 10 mg after an observation period of 48 weeks, immediate treatment with bulevirtide 2 mg, or immediate treatment with bulevirtide 10 mg. The mean age of patients was 42 years (SD = 8.4 years). Nearly one-half of the patients (47.3%) had cirrhosis at the time of randomization; all the cases of cirrhosis were classified as Child-Pugh Class A. During the MYR301 trial, 60.7% of patients received oral anti-HBV treatment and 56.0% of patients had a history of prior interferon treatment.

In the absence of direct comparative evidence of bulevirtide versus other relevant comparators, the sponsor conducted an NMA. The objective of the NMA was to evaluate the relative efficacy and safety of bulevirtide 2 mg as a monotherapy versus PEG-IFN and best supportive care, consisting of nucleoside (nucleotide) analogue therapy in patients with chronic HDV infection who had compensated liver disease, given the lack of approved treatments for HDV. Fixed-effects and random-effects models were applied within a Bayesian framework to assess combined response, virologic response, ALT normalization, and HDV RNA loss at weeks 24 and 48.

Two additional studies that address gaps in the evidence from the systematic review are summarized in this report. SAVE-D is a multicentre, retrospective, single-arm, real-world study (N = 244). The objective of the SAVE-D study was to evaluate the efficacy of treatment with bulevirtide 2 mg for up to 96 weeks in patients with HDV-related cirrhosis with and without clinically significant portal hypertension, and to explore predictors of treatment and the drug’s impact on hard outcomes. The study end points included virologic, biochemical, and combined responses, undetectable HDV RNA, suboptimal response, safety outcomes, liver-related complications, and harms. Most patients in the SAVE-D study presented with features of advanced liver disease in terms of severity of portal hypertension, with 54.0% experiencing esophageal varices and 15.0% with a history of previous decompensation. The MYR203 trial was a multicentre, open-label, randomized, comparative, parallel-arm phase II trial that provided direct comparative evidence for the efficacy and safety of bulevirtide 2 mg as monotherapy and PEG-IFN alone in the treatment of patients with chronic hepatitis D who had compensated liver disease, after 48 weeks of treatment. The study outcomes included HDV RNA response at weeks 24, 48 ███ ██, ALT normalization, combined response, liver fibrosis, and HDV RNA levels at weeks 24 and 48, and harms. The mean age of patients was 36.8 years (SD = 7.7 years). In the MYR203 trial, 45.6% of patients had a history of prior medication use, and 63.3% received concomitant medication during the study.

Interpretation of Results

Efficacy

HDV, a rare and rapidly progressing disease, is considered the most severe form of viral hepatitis. HDV occurs as a coinfection with HBV and is associated with a significantly higher risk of cirrhosis, hepatic decompensation, and HCC. There are currently no established consensus guidelines for the management and treatment of HDV infection in Canada. At present, bulevirtide is the only treatment specifically indicated for HDV treatment. This highlights the ongoing need for effective therapies that can both treat and prevent HDV infection. The current standard of care includes nucleoside (or nucleotide) analogues, which are effective against HBV but not HDV, and PEG-IFN-alpha, which can be used off-label for treating HDV. However, the clinical experts consulted for this review indicated that PEG-IFN-alpha is now rarely used in clinical practice due to its adverse effects, the global shortage, and limited availability in Canada. The optimal duration of bulevirtide therapy has not been established, and clinical experts have noted that the optimal duration remains uncertain for patients who demonstrate a slower response to treatment.

The evidence from the pivotal MYR301 trial addressed treatment outcomes deemed important by both patients and clinicians. Input from the patient group emphasized key priorities, namely slowing disease progression, reducing decompensation events and the need for a liver transplant, improving HRQoL, and having treatments that require fewer injections and blood tests. Similarly, input from the clinician group and clinical experts consulted by CDA-AMC highlighted that the most important treatment goals for patients with HDV are achieving HDV RNA suppression and biochemical normalization and stabilizing or improving liver fibrosis. The clinical experts noted that long-term outcomes such as improvements in portal hypertension, reduced progression to cirrhosis, lower rates of HCC, and liver-related mortality would also be clinically beneficial but were not measured in the MYR301 trial. Therefore, results from the analyses of the following outcomes measured in the MYR301 trial were summarized and assessed using GRADE: combined response, virologic response, change from baseline in liver stiffness, HRQoL, and SAEs. In addition, ALT normalization, undetectable HDV RNA, change from baseline in combined response, liver-related clinical events, change from baseline in virologic response were included in the report as supportive information. An undetectable HDV RNA after scheduled end of treatment (sustained virologic response) was identified by clinical experts as an important outcome; however, the results for this end point were not reported, as the study is still ongoing.

According to the clinical experts consulted for this review by CDA-AMC, although the use of a delayed-treatment group in patients with aggressive disease could raise ethical concerns, the trial design was deemed acceptable by regulatory authorities due to the absence of an established treatment for HDV at the time. The clinical experts also noted that the delayed-treatment group effectively served as the best available standard of care or placebo comparator for the MYR301 trial. The clinical experts indicated that the inclusion of a delayed-treatment group in the trial provided valuable insight into the natural progression of HDV and helped contextualize the benefits of early intervention. Data from the group receiving immediate treatment with bulevirtide 10 mg are not presented in this report because this dose is neither approved for use nor used in clinical practice in Canada. The focus of this report is on between-group comparisons of study end points up to week 48, specifically regarding the 2 mg bulevirtide dose, consistent with the Health Canada indication. The clinical experts indicated that using bulevirtide at the 10 mg dose as a comparator beyond week 48 was inappropriate because 10 mg is not a Health Canada–approved dose and is not expected to be used in clinical practice.

Evidence from the MYR301 trial demonstrated with moderate certainty that, compared with delayed treatment, treatment with bulevirtide 2 mg results in a clinically meaningful increase in achieving combined response at week 48. The point estimate for the between-group differences exceeded the 20% threshold the clinical experts had suggested, and the 95% CIs did not include trivial effects; this suggests favourable outcomes for bulevirtide 2 mg rather than for delayed treatment. The certainty of evidence was considered moderate due to imprecision, including potential for treatment overestimation due to the small sample size. Given the rarity of the disease, the small sample sizes observed in the MYR301 trial were expected and a larger trial may be infeasible. The clinical experts consulted considered the combined response an appropriate surrogate measure for assessing treatment benefit and noted that surrogate markers are routinely used in clinical trials, including those evaluating HDV therapies. According to the clinical experts, a reduction in HDV RNA levels of at least 2 log₁₀ or achievement of undetectable HDV RNA (virologic response) are both considered indicative of a meaningful antiviral effect that may slow or halt disease progression. Normalization of ALT levels was also identified by the clinical experts as a clinically relevant biochemical marker of treatment response.

In addition to the combined response, individual component outcomes, virologic response and ALT normalization, were reported in the MYR301 trial, with both end points demonstrating a benefit of bulevirtide over delayed treatment at week 48. The point estimate for the between-group difference for the virologic response exceeded the threshold of 30% that the clinical experts had suggested, and the 95% CIs did not include trivial effects; these results favour treatment with bulevirtide 2 mg over delayed treatment. The certainty of evidence was considered moderate due to imprecision and there was potential for overestimating the treatment effect due to the small sample size. The secondary outcome in the MYR301 trial, the proportion of patients with ALT normalization at week 48, also supported the clinical benefit of bulevirtide over delayed treatment for chronic HDV infection. For undetectable HDV RNA at week 48, a secondary outcome in the trial, the between-group difference in response rates was calculated using the bulevirtide 2 mg group as the reference and the 10 mg group as the comparator; however, this comparison is not relevant to this review.

The clinical experts stated that measuring liver stiffness using FibroScan is the preferred method for assessing fibrosis in clinical practice. Improvement in fibrosis was identified by the clinical experts as a relevant and meaningful surrogate, although improvements require longer observation periods, from 1 to 3 years. Evidence from the MYR301 trial demonstrated with moderate certainty that, compared with delayed treatment, bulevirtide 2 mg likely results in improvement in liver stiffness at week 48. The clinical experts could not provide a threshold for a clinically meaningful between-group difference for this outcome. Subgroup analyses by cirrhosis status and prior use of nucleoside (or nucleotide) analogues were prespecified; however, the results were descriptive and limited by small sample sizes and should not be used to infer effect modification.

HRQoL is an important outcome to patients and clinicians and was assessed as an exploratory outcome using the HQLQ scale scores. The clinical experts noted that the HQLQ is a liver-specific instrument that captures aspects of mental health and fatigue and has been validated in the context of liver disease. For the HQLQ mental and physical component summary scores, the HQLQ positive well-being score, the HQLQ hepatitis-specific limitations score, and the HQLQ hepatitis-specific health distress score, there is very low-certainty evidence for a benefit when compared with delayed treatment at weeks 24 and 48. The very low certainty of evidence was attributed to risk of bias from assessors being aware of treatment assignments, as well as serious concerns for imprecision, with wide CIs that included both the potential for no difference and harm. There was insufficient information to allow for conclusions on the long-term efficacy of bulevirtide for patients with HDV. The clinical experts highlighted that long-term clinical end points such as reduced incidence of HCC or decreased episodes of hepatic decompensation are rarely captured within the assessment time frames of pivotal trials but are nevertheless important for long-term evaluation of treatment benefit.

Overall, there are no major concerns with the generalizability of the MYR301 trial results. According to the clinical experts consulted by CDA-AMC, patients enrolled in the trials were considered to have more severe disease than those typically seen in clinical practice. The clinical experts indicated that trial inclusion and exclusion criteria are more restrictive than the selection criteria that would typically be applied in clinical practice. For instance, patients aged older than 65 years, those with moderate renal impairment, or those with HCV or HIV coinfections, who would be eligible to receive bulevirtide in clinical practice, were excluded from the MYR301 trial. Clinical expert input also indicated that the proportion of patients with HBV and HDV coinfection who receive HBV therapy is higher in clinical practice than the proportion in the trial.

The aim of the sponsor-submitted ITC was to assess the efficacy and safety of bulevirtide 2 mg compared with best supportive care (nucleoside [or nucleotide] analogue therapy) and PEG-IFN, both of which were identified by the clinical experts as relatively appropriate comparators in the absence of approved treatments for HDV. The clinical experts indicated that while PEG-IFN was previously used, its use has largely declined in clinical practice due to poor tolerability, safety concerns (particularly in patients with advanced liver disease), and limited availability in Canada. The clinical experts also noted that nucleoside (or nucleotide) analogues are used to manage HBV but have no direct effect on HDV. According to the clinical experts consulted, several comparators included in the NMA analyses are not relevant to the context in Canada, including bulevirtide plus tenofovir or PEG-IFN combined with adefovir, ribavirin, tenofovir, or entecavir. The results of fixed-effects models suggested that bulevirtide showed potential advantage over PEG-IFN in achieving the combined response, virologic response, and ALT normalization at week 48. In contrast, the random-effects model showed benefit of bulevirtide over PEG-IFN only for the combined response. Similarly, compared to nucleoside (or nucleotide) analogue therapy, fixed-effects models indicated potential benefits of bulevirtide in achieving combined response, virologic response, ALT normalization, and undetectable HDV RNA at week 48, while the random-effects model demonstrated a benefit for combined response only. The CDA-AMC review team considered the results of the random-effects models to be more relevant, as the fixed-effects models assumed that effects are identical across studies, which is unlikely. Overall, substantial uncertainty remains regarding these relative effects due to several limitations: a large degree of clinical and methodological heterogeneity across studies, a sparse network, small sample sizes, imprecision, and assumptions made in the analysis that cannot be fully verified. No patient-reported quality of life data, which was considered an important end point for this review, were evaluated.

Two additional studies that addressed gaps in the evidence from the systematic review are summarized in this report: MYR203 and SAVE-D. However, due to the sample size and study design limitations of these studies and the exploratory nature of the MYR203 study, definitive conclusions cannot be drawn from them. The SAVE-D study was a single-arm study, which limits the ability to assess comparative effectiveness relative to usual care and for inferring causality. Key limitations of both studies were a risk of bias from missing outcome data that contribute to uncertainty in the effect estimates, limited generalizability to patients in Canada, and no reporting of HRQoL outcomes, which patients considered to be important.

Harms

According to the clinical experts consulted by CDA-AMC for this review, bulevirtide 2 mg was generally well-tolerated by the patients in the MYR301 trial, and no major safety concerns were identified. The clinical experts noted that most of the AEs would be expected and considered manageable in routine clinical practice. Common AEs, including lymphopenia, fatigue, eosinophilia, and injection site reactions, are considered manageable in clinical practice and are consistent with the underlying disease severity in the trial population, which included a high proportion of patients with cirrhosis. In particular, the experts noted that thrombocytopenia observed shortly after treatment initiation was likely a reflection of advanced liver disease rather than a direct effect of the drug. Overall, the proportion of patients in the MYR301 trial who experienced SAEs was low, with similar rates observed across treatment groups. The evidence is very uncertain about the effect of bulevirtide 2 mg on SAEs at week 48 when compared with delayed treatment. No treatment discontinuations due to AEs were reported by week 48. The clinical experts emphasized the importance of closely monitoring hepatic and renal function, particularly in light of the underlying comorbidities commonly present in the target patient population. The sponsor-submitted ITC evaluated the comparative safety of bulevirtide relative to PEG-IFN and nucleoside (or nucleotide) analogues; however, the wide CIs around these estimates indicate considerable uncertainty in the comparative safety outcomes.

Other Considerations

According to the clinical experts consulted for this review, HDV testing is not systematically conducted among individuals with HBV infection. The clinical experts emphasized the need for increased health care provider education and recommended the implementation of reflex testing in provincial or local laboratories when individuals test positive for HBsAg. The clinical experts also indicated that treatment with bulevirtide can be challenging for patients because of the need to reconstitute drugs and the associated supply requirements, which can be costly given the daily administration and chronic nature of the disease. At present, HDV testing is likely confined to hepatology specialists and is performed opportunistically rather than as part of routine screening. The clinical experts noted that initiating treatment with bulevirtide and monitoring response should be conducted by clinicians experienced in managing viral hepatitis because of the complexity of treatment, which involves daily injections, and the need for patient counselling; however, they acknowledged that access to such specialists may be difficult in certain regions, particularly rural areas.

Conclusion

HDV is a rare and severe condition that is recognized as the most aggressive form of viral hepatitis. At the time of this review, bulevirtide is the only approved treatment for HDV in adults with compensated liver disease. Input from both patients and clinicians highlighted a substantial unmet need for new treatments that effectively treat and prevent the progression of HDV. The pivotal MYR301 phase III trial compared the efficacy and safety of a 2 mg dose of bulevirtide in the treatment of patients with chronic HDV with compensated liver disease, with a 10 mg dose of bulevirtide following a 48-week observation period (the delayed-treatment group). The MYR301 trial demonstrated moderate certainty evidence that treatment with bulevirtide 2 mg likely results in a clinically meaningful increase in achieving combined response, virologic response, and improvement in liver stiffness at week 48 compared with delayed treatment. No definitive conclusion can be drawn regarding the effects of bulevirtide treatment on HRQoL due to the potential bias from assessor knowledge of treatment assignment, and imprecision in the data, making the direction of effects unclear. Bulevirtide 2 mg was generally well-tolerated, and no major safety concerns were identified in the MYR301 trial. There is no direct comparative evidence beyond week 48 between bulevirtide and the relevant comparators.

The MYR203 phase II trial provided evidence on the efficacy and safety of bulevirtide 2 mg as monotherapy versus PEG-IFN-alpha-2a alone in patients with HDV infection and compensated liver disease. However, due to the limited sample size, study design limitations, and its exploratory nature, definitive conclusions cannot be drawn from the MYR203 trial. The SAVE-D study was a real-world study with the objective of providing evidence on the efficacy of treatment with bulevirtide for up to 96 weeks in patients with HDV-related cirrhosis with and without clinically significant portal hypertension. However, the single-arm design of the SAVE-D study limits the ability to assess comparative effectiveness relative to usual care and to infer causality. Key limitations of both studies include a risk of bias from missing outcome data that contribute to uncertainty in the effect estimates, limited generalizability to patients in Canada, and no reporting of HRQoL outcomes, which were deemed important by patients.

The results of the sponsor-submitted ITC suggest that, compared with PEG-IFN and best supportive care, bulevirtide may have potential benefit in achieving combined response at week 48. However, the interpretation of the ITC is limited by several factors, including methodological limitations, between-trial heterogeneity, a sparse network, and small sample sizes, which preclude definitive conclusions on the comparative effects of bulevirtide. In addition, PEG-IFN is no longer used for HDV treatment in Canada due to its poor tolerability and limited accessibility. Given the considerable uncertainty in the sponsor-submitted ITC, no definitive conclusions can be drawn regarding the safety of bulevirtide compared to PEG-IFN and best supportive care.

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