Aim stated in the registry record

“This is a Phase 1, open-label, parallel-group study to evaluate the pharmacokinetics of GSK3228836 in participants with Child-Pugh B (CP-B) cirrhosis (moderate hepatic impairment), Child-Pugh A (CP-A) cirrhosis (mild hepatic impairment) and participants with normal hepatic function as healthy control.” (opens the source at this quote in a new tab)

Aim stated in the publication

“B-Assured (GSK Study 205871; NCT04971928) was a phase 1, multicenter, open-label study conducted to assess the effect of HI on the PK and safety of bepirovirsen.” (opens the source at this quote in a new tab)

Two United States centers, September 2021 to May 2022

“This was a phase 1, nonrandomized, open-label, parallel-group study conducted between September 7, 2021 and May 12, 2022 in 2 centers in the United States (Texas Liver Institute, UT Health San Antonio, San Antonio, TX, USA and Orlando Clinical Research Center, Orlando, FL, USA).” (opens the source at this quote in a new tab)

Study dates and status in the registry record

Field	Registry entry
Recruitment status	“Completed”
Study start (actual)	“2021-09-07”
Primary completion (actual)	“2022-05-12”
Study completion (actual)	“2022-05-12”
Other study identifiers	“205871”
Last update posted	“2022-09-27”

Two-part design with an interim decision rule

“This study was planned to be conducted in 2 parts, allowing a planned interim analysis following Part 1 (Figure 1). Part 1 was planned to be conducted in participants with moderate HI and Part 2 in those with mild impairment.” (opens the source at this quote in a new tab)
“It was decided that if no preset (or predefined) difference in PKs (area under the concentration-time curve from time 0 to infinite time [AUC0-∞] and Cmax geometric mean ratio [GMR] within a 0.5-1.5 range) was found in participants with moderate HI compared with HPs (Part 1) during the interim analysis, the findings would be applied to participants with mild HI (Part 2), thus eliminating the need to progress to Part 2 and thereby ending the study.” (opens the source at this quote in a new tab)

Matching of healthy participants

“Participants with moderate and mild HI were to be matched with HPs by gender, age (±10 years), race, and total body weight (±25%) in a 1:1 ratio.” (opens the source at this quote in a new tab)

Inclusion criteria and Child-Pugh classification

“Participants were male or nonpregnant female, at least 18 years of age, body weight >50 kg and body mass index within the range 19-40 kg/m2 (inclusive) at the time of signing the informed consent.” (opens the source at this quote in a new tab)
“To be classified as having cirrhosis, participants must have a Child-Pugh score of 7-9 (B/moderate; this group was planned to include at least 1 participant with a Child-Pugh score of 7, a score of 8, and a score of 9) or 5-6 (A/mild; this group was planned to include at least 1 participant with a Child-Pugh score of 5 and a Child-Pugh score of 6). Bepirovirsen is in development for the treatment of chronic HBV infection, but there was no requirement for participants in this PK study to have chronic HBV infection.” (opens the source at this quote in a new tab)

Key exclusion criteria

“Key exclusion criteria were myocardial infarction or acute coronary syndrome, stroke, or transient ischemic attack within the 12 weeks prior to enrollment; diagnosed or suspected HCC, malignancy within the past 5 years except for specific cancers that were cured by surgical resection (eg, skin cancer); and participants under evaluation for possible malignancy, a history/potential of vasculitis or other diseases that may be associated with vasculitis condition (eg, systemic lupus erythematosus, rheumatoid arthritis, relapsing polychondritis, and mononeuritis multiplex), and unstable cardiac function or diabetes.” (opens the source at this quote in a new tab)

Single 300 mg subcutaneous dose

“In Part 1 of the study, participants attended the clinical research unit on day 1 and received a single dose of bepirovirsen 300 mg (2.0 mL) subcutaneously (2 injections of 150 mg [1.0 mL] each) into the upper arm, thigh, or abdomen.” (opens the source at this quote in a new tab)
“Due to the time-invariant PK and lack of accumulation observed with bepirovirsen, a single-dose study was selected to reduce participant exposure to the study drug while maintaining the ability to assess the impact of HI on bepirovirsen PKs.” (opens the source at this quote in a new tab)

Registered primary outcomes

“Area under the concentration-time curve (AUC) from time zero (pre-dose) extrapolated to infinite time [AUC(0-infinity)]” (opens the source at this quote in a new tab)
“Maximum observed concentration (Cmax)” (opens the source at this quote in a new tab)

Basis for the 0.5 to 1.5 geometric mean ratio thresholds

“The criteria defined were based on the fold-difference between the lowest and highest doses tested in patients with chronic HBV infection (150 and 450 mg, respectively) compared with the therapeutic dose (300 mg).” (opens the source at this quote in a new tab)

Need for a hepatic impairment study in the target population

“To our knowledge, no PK studies comparing healthy control and hepatically impaired participants have been conducted with ASOs, therefore it is difficult to predict bepirovirsen plasma exposure in this population. Hepatic impairment (HI) may alter the disposition of bepirovirsen by altering the drug concentration in plasma and liver and increasing free drug concentration, given that HI is associated with reductions in serum albumin concentrations.” (opens the source at this quote in a new tab)

Planned sample size

“The study aimed to enroll at least 24 participants, increased to approximately 48 participants if the study progressed to Part 2. A sample size of 12 PK-evaluable participants per group was selected based on the level of precision required for evaluation of PK parameters.” (opens the source at this quote in a new tab)

Participants screened and dosed

“A total of 30 participants were screened for the study, of whom 24 participants were assigned to receive active doses of bepirovirsen; 12 participants had moderate HI and 12 were matched healthy controls. No participants had chronic HBV infection.” (opens the source at this quote in a new tab)

Noncompartmental analysis and mixed effects model

“Noncompartmental plasma PK analysis was conducted, and a mixed effects analysis of covariance model was created for each endpoint. In Part 1, a binary variable indicating whether a participant was a healthy volunteer was included as a fixed effect and a participant matching variable was included as a random effect.” (opens the source at this quote in a new tab)

Protocol deviations and study populations

“Two participants did not complete the day 8 visit and none of the endpoint assessments were performed; however, these deviations did not exclude the participants from any study population.” (opens the source at this quote in a new tab)

Screen failures and completion of part 1

“Of the 6 participants who failed screening, 5 participants did not meet the inclusion/exclusion criteria for the study and 1 participant withdrew consent.” (opens the source at this quote in a new tab)
“Twenty-four participants (moderate HI, n = 12; HP, n = 12) received bepirovirsen and completed Part 1.” (opens the source at this quote in a new tab)
“Part 2 was omitted.” (opens the source at this quote in a new tab)

Demographics by group

Characteristic	Moderate hepatic impairment (N = 12)	Matched healthy controls (N = 12)
Age (years), mean (SD)	“59.9 (7.1)”	“60.9 (8.5)”
Female, n (%)	“5 (42)”	“5 (42)”
Weight (kg), mean (SD)	“88.6 (14.1)”	“84.9 (8.3)”
Hispanic or Latino, n (%)	“7 (58)”	“5 (42)”

Etiology of cirrhosis and concomitant medications

“All the participants with moderate HI received medications before and during the study for management of their health conditions whereas only 1 participant in the healthy control group used concomitant medications. The most common concomitant medications in the group with HI were furosemide (n = 8), spironolactone (n = 7), and lactulose (n = 6). In the HI group, 6 participants had alcohol-related cirrhosis, 3 participants had hepatitis C cirrhosis, and 3 participants had nonalcoholic fatty liver disease cirrhosis at baseline.” (opens the source at this quote in a new tab)

Geometric mean ratios, moderate hepatic impairment versus matched healthy controls

“When a single dose of bepirovirsen was administered to participants with moderate HI, geometric least squares (LS) mean AUC0-∞ was lower than in matched healthy controls with geometric LS mean ratio (90% CI) of 0.69 (0.59, 0.82; Figure 2 and Table S3). The geometric LS mean Cmax was lower in participants with moderate HI compared with matched healthy controls with a geometric LS mean ratio (90% CI) of 0.67 (0.52, 0.85).” (opens the source at this quote in a new tab)
“The CL/F and Vz/F estimates were higher in participants with moderate HI with geometric LS mean ratios (90% CI) of 1.44 (1.22, 1.70) and 1.64 (1.24, 2.19) than in matched healthy controls, respectively (Figure 2 and Table S3).” (opens the source at this quote in a new tab)

Plasma PK parameters by group (geometric mean)

Parameter	Moderate hepatic impairment (N = 12)	Matched healthy controls (N = 12)
AUC0-∞ (h × μg/mL)	“75.1”	“108.9”
Cmax (μg/mL)	“6.57”	“9.83”
t1/2 (hour)	“232.2”	“204.9”
CL/F (L/h)	“4.00”	“2.75”
Vz/F (L)	“1338”	“814.2”
Tmax (hour), median (min, max)	“4.0 (3.0, 12.0)”	“5.1 (4.0, 8.1)”

Decision not to proceed to part 2

“Data from the planned interim analyses of Part 1 showed the GMRs of both total plasma AUC0-∞ and the Cmax of bepirovirsen between participants with moderate HI and matched healthy controls were between 0.5 and 1.5, therefore the study did not continue to Part 2; data from Part 1 are presented herein.” (opens the source at this quote in a new tab)

Hepatic impairment statement in the prescribing information

“There is a 33% reduction in Cmax and a 31% reduction in AUC0-∞ in participants with moderate hepatic impairment (Child-Pugh Class B) but without HBV infection when compared to participants with normal hepatic function.” (opens the prescribing information at this quote)

Adverse events and adverse events of special interest

“A total of 6 (25%) participants experienced AEs, 3 from each group (Table S4). The most common AE was injection-site erythema, which was reported in 4 participants: 3 in the healthy control group and 1 in the HI group. All other AEs were reported in 1 participant each in the HI group. There were no deaths reported in the study and all AEs were mild in intensity and not serious.” (opens the source at this quote in a new tab)
“Five (21%) participants experienced injection-site reactions that were considered drug-related AEs by investigators. No clinically significant bleeding, ALT increases, vascular inflammation and complement activation, or renal injury were reported.” (opens the source at this quote in a new tab)

Immunogenicity

“Two (8%) participants were positive for antibepirovirsen antibodies at baseline, of which 1 participant was positive for antibepirovirsen antibodies posttreatment. There were no PK or safety concerns identified in these participants.” (opens the source at this quote in a new tab)

Summary: study limitations

B-Assured dosed 24 participants (12 with moderate hepatic impairment and 12 matched healthy controls) with a single 300 mg dose, and no participant had chronic HBV infection; the 12 participants with impairment had alcohol-related, hepatitis C, or nonalcoholic fatty liver disease cirrhosis. Part 2 in mild impairment was omitted, and the Part 1 findings were to be applied to participants with mild impairment. Unbound bepirovirsen was not measured. The prescribing information contraindicates bepirovirsen in chronic hepatitis B patients with cirrhosis of any Child-Pugh class.

Limitations stated by the investigators

“The limitations to the present study included the fact that no participants had hepatitis B-induced cirrhosis; however, it is unclear whether the etiology of HI alters the drug PKs and disposition.” (opens the source at this quote in a new tab)
“Considering that the difference between participants with HI and HPs was not deemed clinically relevant, the outcome of unbound levels of bepirovirsen was not evaluated in this study.” (opens the source at this quote in a new tab)