Pharmacokinetics

“Pharmacokinetic parameters are presented as arithmetic mean (SD), derived from population PK model simulations at steady state following subcutaneous administration of HIBSAGO 300 mg weekly in participants with chronic HBV infection (CHB).” (opens the prescribing information at this quote)CopyFlag

“Pharmacokinetic parameters are presented as geometric mean (CV%) from post-hoc individual estimates from Phase 3 population PK model.” (opens the prescribing information at this quote)CopyFlag

“Based on population pharmacokinetic analyses, following subcutaneous administration, there were no clinically meaningful changes in the pharmacokinetics of bepirovirsen by race (Asian, Black, White, Other), ethnicity,” (opens the prescribing information at this quote)CopyFlag

“age (18-87 years old), sex, body weight (39 kg to 148 kg), injection site location (thigh, upper arm, abdomen) and anti-drug antibodies (ADA) status.” (opens the prescribing information at this quote)CopyFlag

“In the Phase 3 B-Well trials, 43% (517/1,203) of participants treated with HIBSAGO tested positive for ADAs. The presence of ADAs resulted in a 26.6% lower systemic clearance of bepirovirsen. The development of these antibodies did not appear to be associated with a reduced treatment response or differences in the safety profile.” (opens the prescribing information at this quote)CopyFlag

“Following a single SC injection in all cohorts at all dose levels, the concentration‐time profile of bepirovirsen featured a rapid absorption phase, followed by an initial rapid distribution phase and a slower elimination phase (Figure 2). Median bepirovirsen tmax ranged from 3 to 8 hours after dosing across all cohorts and study days (Table 1).” (opens the original PMC page at this quote in a new tab)View highlighted excerpt for this quoteCopyFlag

“Following a single SC injection of bepirovirsen, Cmax and total exposure, expressed as the AUC, increased with increasing dose (Table 1) and appeared to be dose proportional between 150 mg and 450 mg but were lower than dose proportional between 75 mg and 150 mg (Table 1).” (opens the original PMC page at this quote in a new tab)View highlighted excerpt for this quoteCopyFlag

“Following the final dose on study day 22, the mean terminal plasma elimination half‐life was 22.4 to 24.2 days across cohorts.” (opens the original PMC page at this quote in a new tab)View highlighted excerpt for this quoteCopyFlag

“Within the first 24 hours after dosing, urinary excretion of intact full‐length bepirovirsen accounted for <2% of the administered dose across all dose levels evaluated.” (opens the original PMC page at this quote in a new tab)View highlighted excerpt for this quoteCopyFlag

“Bepirovirsen PK data were well-described by a linear, three-compartment model with first-order absorption and absorption delay. Chronic HBV infection status, body weight, and Asian versus non-Asian race were key covariates included in the final model.” (opens the original PMC page at this quote in a new tab)View highlighted excerpt for this quoteCopyFlag

“In simulations, bepirovirsen systemic exposure was dosed proportionally and predicted to be almost completely washed out by 12 weeks following the final 300-mg dose. Differences in body weight, Asian race, or disease status did not result in clinically relevant differences in exposure.” (opens the original PMC page at this quote in a new tab)View highlighted excerpt for this quoteCopyFlag

“The lack of clinically relevant differences seen in exposure indicate that dose adjustments are not recommended for bepirovirsen based on demographics or clinical characteristics.” (opens the original PMC page at this quote in a new tab)View highlighted excerpt for this quoteCopyFlag

“When body weight increased from 40 to 100 kg, the median (90% CI) for AUCtau decreased from 131.0 (78.4, 209.0) to 83.2 µg·h/ml (49.8, 133.0), Cmax reduced from 12.5 (6.3, 23.2) to 6.6 µg/ml (3.4, 11.9), and Ctrough from 0.0383 (0.0217, 0.0686) to 0.0160 µg/ml (0.0090, 0.0289). However, the ranges were not considered clinically relevant.” (opens the original PMC page at this quote in a new tab)View highlighted excerpt for this quoteCopyFlag

“In participants who received bepirovirsen 300 mg weekly for 24 weeks, the median (95% CI) predicted concentration at week 36 was 93% lower than at the end of treatment (week 24: 0.0224 [0.0113, 0.0461] µg/ml versus week 36: 0.0017 [0.000048, 0.0102] µg/ml).” (opens the original PMC page at this quote in a new tab)View highlighted excerpt for this quoteCopyFlag

“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 quoteCopyFlag

“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 quoteCopyFlag

“The geometric mean bepirovirsen Cmax and AUC(0‐inf) decreased with increasing body weight. 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 quoteCopyFlag

“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 quoteCopyFlag

“Based on extrapolations from concentration measurements in preclinical species, the total liver concentration of bepirovirsen at steady state was estimated to be 34.8 µM, which seems, on first appearance, to be higher than the plasma. However, when the distribution between the hepatocytes and nonparenchymal cells is factored in, only 15% (5 µM) of the liver concentration is associated with the hepatocytes. Furthermore, multiple sources estimate that greater than 98% of the concentration of the drug in the hepatocytes is sequestered in the endo‐lysosomal system,” (opens the original PMC page at this quote in a new tab)View highlighted excerpt for this quoteCopyFlag

“Bepirovirsen was localized primarily in nonparenchymal liver cells and proximal renal tubules.” (opens the original PMC page at this quote in a new tab)View highlighted excerpt for this quoteCopyFlag

“Positive liver signal was quantified using HALO AI, with 12.9% of the ASO localized to the hepatocytes and 87.1% in nonparenchymal cells.” (opens the original PMC page at this quote in a new tab)View highlighted excerpt for this quoteCopyFlag

“Liver and kidney partition coefficients were calculated to be 2147 and 2822, respectively.” (opens the original PubMed page at this quote in a new tab)View highlighted excerpt for this quoteCopyFlag

“Predicted vs. observed clearance (L/h), AUC0-inf (µg.h/mL) and Cmax (µg/mL) for the 300 mg single dose in healthy volunteers were 2.94, 114.43, and 10.56 vs. 2.25, 136.6, and 6.5, respectively.” (opens the original PubMed page at this quote in a new tab)View highlighted excerpt for this quoteCopyFlag

“The PBPK model predicted the liver and kidney tissue Cmax values to be 172 and 132 µg/mL, respectively.” (opens the original PubMed page at this quote in a new tab)View highlighted excerpt for this quoteCopyFlag

“Renal Impairment: Bepirovirsen pharmacokinetics were similar between patients with CHB with an eGFR 60 to 89 mL/min/1.73m2 compared to patients with an eGFR ≥90 mL/min/1.73 m2. Insufficient data are available in patients with moderate or severe renal impairment.” (opens the prescribing information at this quote)CopyFlag

“Hepatic Impairment: The pharmacokinetics of bepirovirsen have not been evaluated in CHB patients with hepatic impairment (Child-Pugh Class A, B, or C) [see Contraindications (4)].” (opens the prescribing information at this quote)CopyFlag

“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)CopyFlag

“AUC0-∞ and Cmax were lower in participants with moderate HI (GMR 0.69 and 0.67, respectively) than in HPs, while apparent clearance (CL/F) and apparent terminal phase volume of distribution (Vz/F) were higher (GMR 1.44 and 1.64, respectively), but fell within the predefined thresholds of difference for this study.” (opens the source at this quote in a new tab)CopyFlag