Study 219239 relative bioavailability of vial and prefilled syringe
30 evidence topics · 4 sources
Objective
Aim stated in the publication
“The current study was designed to evaluate the relative bioavailability of bepirovirsen when delivered via SC injection from a vial (HCP‐administered) or by a PFS SSD (HCP‐ or self‐administered) in healthy adult participants. Safety and tolerability were assessed as a secondary objective.” (opens the original PMC page at this quote in a new tab)View highlighted excerpt for this quote
Location and study date
Study dates and status in the registry record
| Field | Registry entry |
|---|---|
| Recruitment status | “Completed” |
| Study start (actual) | “2023-10-04” |
| Primary completion (actual) | “2024-05-03” |
| Study completion (actual) | “2024-05-03” |
| Results first posted | “2025-07-18” |
| Other study identifiers | “219239” |
Study design
Randomized, open-label, parallel-group design with stratification
“This was a Phase 1, open‐label, randomized, parallel‐group study (219239, NCT06058390). Participants were randomized 3:3:2:2 to receive a single dose of bepirovirsen 300 mg either administered by a HCP from a vial (Group 1), administered by a HCP using the PFS SSD (Group 2), self‐administered using the PFS SSD with training from a HCP (Group 3), or self‐administered using the PFS SSD without training from a HCP (Group 4) (Figure 1).” (opens the original PMC page at this quote in a new tab)View highlighted excerpt for this quote
“The randomization was stratified by body weight (50‐<70 kg, 70‐<80 kg, and ≥80 kg). The site of injection was randomized in a 1:1:1 ratio to the upper arm, abdomen, or thigh in Groups 1 and 2, and in a 1:1 ratio to abdomen or thigh in Groups 3 and 4.” (opens the original PMC page at this quote in a new tab)View highlighted excerpt for this quote
Eligibility criteria
Inclusion and exclusion criteria in the publication
“Healthy male and female participants, aged between 18 and 55 years, were enrolled from 2 centers in the United States. Participants were required to have body weight ≥50 kg and body mass index (BMI) within 19‐29.9 kg/m2.” (opens the original PMC page at this quote in a new tab)View highlighted excerpt for this quote
“Participants were excluded if they had: a history or presence of cardiovascular, respiratory, hepatic, renal, gastrointestinal, endocrine, hematologic, or neurological disorders capable of significantly altering the absorption, metabolism, or elimination of drugs; or any malignancy within the past 5 years; platelets <140×109/L; alanine aminotransferase (ALT) >1.5× upper limit of normal (ULN), or total bilirubin >1.5×ULN; a current or chronic history of liver disease or known hepatic or biliary abnormalities; or prior treatment with any oligonucleotide or siRNA within 12 months before dosing.” (opens the original PMC page at this quote in a new tab)View highlighted excerpt for this quote
Treatment
Single 300 mg dose given as two 150 mg injections
“All participants received a single dose of bepirovirsen 300 mg either by vial or PFS SSD, given as two 150 mg SC injections that were given as close together in time as possible (within 5 min) and spaced at least 5 cm apart.” (opens the original PMC page at this quote in a new tab)View highlighted excerpt for this quote
Prefilled syringe with safety syringe device
“The bepirovirsen PFS SSD consisted of a sterile liquid drug product in a single‐use clear glass PFS assembled into an SSD that delivered 1 mL of 150 mg/mL bepirovirsen for SC administration.” (opens the original PMC page at this quote in a new tab)View highlighted excerpt for this quote
“The formulation of bepirovirsen is identical between the vial and the PFS SSD.” (opens the original PMC page at this quote in a new tab)View highlighted excerpt for this quote
Study outcomes
Rationale for using relative bioavailability (Plasma cmax and AUC) as the primary endpoint
Primary and secondary endpoints and the bioequivalence criterion
“The primary endpoint was to estimate the relative bioavailability of a single dose of bepirovirsen delivered by SC injection by a HCP in healthy participants using a vial versus PFS SSD.” (opens the original PMC page at this quote in a new tab)View highlighted excerpt for this quote
“Bepirovirsen exposure was considered to be bioequivalent if the 90% CIs for the GMRs of both Cmax and AUC(0‐inf) fell within the standard bioequivalence reference range of 0.80 to 1.25.” (opens the original PMC page at this quote in a new tab)View highlighted excerpt for this quote
Purpose of the bioavailability comparison
Statistical analysis description
Number of participants (Planned and analyzed)
Participants screened, enrolled, and analyzed
“A total of 359 participants were screened and 160 participants enrolled in the study.” (opens the original PMC page at this quote in a new tab)View highlighted excerpt for this quote
“The latter participant was not included in the analysis, leading to a total study analysis population of 159 participants (Group 1, n = 46; Group 2, n = 49; Group 3, n = 32; Group 4, n = 32).” (opens the original PMC page at this quote in a new tab)View highlighted excerpt for this quote
“A total of 153 of the 159 study analysis participants were included in the PK summaries and statistical comparisons of the PK data for the primary and secondary endpoint analyses.” (opens the original PMC page at this quote in a new tab)View highlighted excerpt for this quote
Description of analysis sets
Analysis sets in the registry results
Statistical model for relative bioavailability
“For each of the primary and secondary endpoints, data were analyzed using separate linear fixed effects models with randomized group (i.e. Group 1 versus Group 2 for the primary analysis; Group 2 versus Group 3, and Group 2 versus Group 4 for the secondary analyses) and injection site (arm, abdomen, or thigh for Groups 1 and 2, and abdomen or thigh for Groups 3 and 4) included as categorical covariates, and natural logarithm transformed baseline weight as a continuous covariate.” (opens the original PMC page at this quote in a new tab)View highlighted excerpt for this quote
Results
Participant disposition
Withdrawals and incomplete doses
“In total, 5 participants across Groups 3 and 4 withdrew from the study, of whom 1 participant (Group 4) was withdrawn due to physician decision (based on failure to cooperate and complete outpatient visits), 3 participants (2 in Group 3 and 1 in Group 4) were lost to follow‐up, and 1 participant (Group 4) did not remove the cap from the PFS SSD during dosing and did not receive any study intervention.” (opens the original PMC page at this quote in a new tab)View highlighted excerpt for this quote
“There were 6 participants (3 in Group 3 and 3 in Group 4) who each received an incomplete dose (of either the first or second dose or both) of study intervention due to incorrect use of the PFS and were excluded from the PK analyses (Table S3).” (opens the original PMC page at this quote in a new tab)View highlighted excerpt for this quote
Baseline characteristics
Demographics of the analysis population
“In the overall study population, 52% of participants were female, the mean (SD) age was 36.5 (9.35) years, and the mean (SD) BMI was 25.68 (2.746) kg/m2. The majority of participants were of White (48%) or Black/African American (35%) race and were not of Hispanic/Latino ethnicity (67%). Most of the participants were in the 50 to <70 kg (39%) and 70 to <80 kg (36%) weight categories, with similar distribution between weight categories across all 4 treatment groups.” (opens the original PMC page at this quote in a new tab)View highlighted excerpt for this quote
Efficacy results
Primary endpoint: vial versus PFS SSD given by a healthcare professional
“Analysis of the primary endpoint demonstrated the bioequivalence of bepirovirsen exposure from a vial versus PFS SSD when HCP‐administered, as the GMR (90% CI) was 1.02 (0.91, 1.14) for Cmax and 1.05 (0.96, 1.15) for AUC(0‐inf) (Table 3).” (opens the original PMC page at this quote in a new tab)View highlighted excerpt for this quote
Secondary endpoints: self-administration with and without training
“The GMR (90% CI) with participant training (Group 2 versus Group 3) was 1.02 (0.88, 1.18) for Cmax and 0.98 (0.88, 1.09) for AUC(0‐inf), and without participant training (Group 2 versus Group 4) was 0.99 (0.87, 1.13) for Cmax and 0.97 (0.87, 1.08) for AUC(0‐inf).” (opens the original PMC page at this quote in a new tab)View highlighted excerpt for this quote
Plasma PK parameters by group (geometric mean, % CV)
| Parameter | Vial by HCP (N = 46) | PFS SSD by HCP (N = 49) | PFS SSD self-administered with training (N = 29) | PFS SSD self-administered without training (N = 29) |
|---|---|---|---|---|
| Cmax (ng/mL) | “9873.38 (40.96)”View highlighted excerpt for this quote | “10,242.48 (39.54)”View highlighted excerpt for this quote | “10,391.83 (42.70)”View highlighted excerpt for this quote | “9516.35 (47.41)”View highlighted excerpt for this quote |
| AUC(0‐inf) (ng·h/mL) | “111,843.70 (32.93)”View highlighted excerpt for this quote | “119,271.61 (29.70)”View highlighted excerpt for this quote | “119,080.46 (26.28)”View highlighted excerpt for this quote | “112,338.58 (35.01)”View highlighted excerpt for this quote |
Effect of body weight and injection site
“Between the 50‐<70kg and ≥80kg groups, there was a decrease of 24%‐47% in geometric mean Cmax and a decrease of 19%‐43% in geometric mean AUC(0‐inf).” (opens the original PMC page at this quote in a new tab)View highlighted excerpt for this quote
“Across all treatment groups the geometric mean Cmax of bepirovirsen tended to be lower when administered in the thigh compared with the other injection sites.” (opens the original PMC page at this quote in a new tab)View highlighted excerpt for this quote
Registry results: 90% confidence intervals for the primary comparison
Health-related quality of life and patient-reported outcomes
Not applicable.
Safety results
Overall adverse events
“A total of 94% (150/159) of participants reported AEs, with similar proportions of participants reporting AEs across all treatment groups (88‐100%; Table 5 and Table S4). Most AEs were considered related to study drug by the investigator (148/159 participants [93%]; Table S5). There were no serious or fatal AEs. Most AEs were Grade 1/2 in severity; <10% of participants reported Grade 3 AEs, and no Grade 4, Grade 5, or unknown Grade AEs were reported.” (opens the original PMC page at this quote in a new tab)View highlighted excerpt for this quote
Adverse events reported in at least 3% of participants overall
Adverse events of special interest: injection site reactions, thrombocytopenia, and ALT increases
“The proportion of participants experiencing injection site reactions was higher when PFS SSD was self‐administered (Group 3: 32/32 [100%], Group 4: 30/32 [94%]) compared with HCP administration (Group 2: 43/49 [88%]).” (opens the original PMC page at this quote in a new tab)View highlighted excerpt for this quote
“AESIs related to thrombocytopenia were reported by 18% (29/159) of participants with no clear difference between treatment groups” (opens the original PMC page at this quote in a new tab)View highlighted excerpt for this quote
“Both ALT increases were <5× ULN. One participant in the self‐administered PFS SSD without training group reported a Grade 3 platelet decline to <100×109/L. This occurred 65 days after study‐dose administration, the participant was asymptomatic and had no clinical bleeding.” (opens the original PMC page at this quote in a new tab)View highlighted excerpt for this quote
Deaths, serious adverse events, and thrombocytopenia in the registry results
| Event | Vial by HCP | PFS SSD by HCP | PFS SSD self-administered after training | PFS SSD self-administered without training |
|---|---|---|---|---|
| All-cause mortality | “0/46 (0.00%)” | “0/49 (0.00%)” | “0/32 (0.00%)” | “0/32 (0.00%)” |
| Serious adverse events | “0/46 (0.00%)” | “0/49 (0.00%)” | “0/32 (0.00%)” | “0/32 (0.00%)” |
| Thrombocytopenia | “1/46 (2.17%)” | “0/49 (0.00%)” | “0/32 (0.00%)” | “2/32 (6.25%)” |
Study limitations
Summary: study limitations
Study 219239 compared a single 300 mg dose in 159 healthy participants aged 18 to 55 years, so it provides no information on repeated dosing over the 24-week course or on device use by patients with chronic hepatitis B. Six participants in the self-administration groups (3 in Group 3 and 3 in Group 4, each of 32 participants) received an incomplete dose because of incorrect use of the prefilled syringe and were excluded from the PK analyses, and injection site reactions occurred in 100% and 94% of the self-administration groups compared with 88% with healthcare professional administration. Exposure was lower in the thigh and decreased with increasing body weight, and the authors state that it is unclear whether the injection-site difference is real or due to variability.
Limitations stated by the investigators
“However, the use of healthy participants may also be considered a limitation because this is not the intended population for bepirovirsen; this is a common approach for relative bioavailability studies, owing to the difficulty of enrolling patients in a single‐dose study.” (opens the original PMC page at this quote in a new tab)View highlighted excerpt for this quote
“It is unclear from the data whether the difference in exposure by injection site is real or due to variability.” (opens the original PMC page at this quote in a new tab)View highlighted excerpt for this quote
“While 6 participants received an incomplete dose of bepirovirsen, owing to incorrect use of the PFS (4 of them injected approximately 75% to 95% of the dose), device usability was evaluated in separate formative and summative human factors studies, and the device and instructions for use were successfully validated for self‐administration (unpublished data).” (opens the original PMC page at this quote in a new tab)View highlighted excerpt for this quote