PI-006 - PHARMACOKINETICS AND SAFETY OF SINGLE-DOSE BEPIROVERSIN IN ADULTS WITH MODERATE HEPATIC IMPAIRMENT AND HEALTHY MATCHED CONTROLS (B-ASSURED).

K. Han¹, N. Noormohamed², T. Lukic³, T. Marbury⁴, E. Lawitz⁵, H. Prescott⁶, M. Magee⁷, A. Nader⁸; ¹GlaxoSmithKline, Upper Providence, PA, USA, ²GlaxoSmithKline, Philadelphia, PA, USA, ³GlaxoSmithKline, Media City, Dubai, United Arab Emirates, ⁴Orlando Clinical Research Center, Orlando, FL, USA, ⁵Texas Liver Institute, San Antonio, TX, USA, ⁶Plus-Project Ltd., Knutsford, United Kingdom, ⁷GlaxoSmithKline, Collegeville, PA, USA, ⁸GlaxoSmithKline, King of Prussia, PA, USA.

Background: Bepirovirsen (BPV) is an anti-sense oligonucleotide (ASO) being studied for the treatment of chronic hepatitis B (CHB). Patients with CHB are at an increased risk for progressive liver disease which may lead to cirrhosis, liver failure, and hepatocellular carcinoma. This phase 1, multicenter, open-label study was conducted to assess the effect of moderate hepatic impairment (HI) on the pharmacokinetics (PK) and safety of BPV.

Methods: The study design planned for enrollment in two parts: Part 1 in participants with moderate HI (Child-Pugh B; n=12) and Part 2 in mild HI. Part 2 was planned to start enrollment if a difference in PK was observed between participants with moderate HI and matched healthy controls; defined as the geometric mean ratio (GMR) of total plasma AUC (AUC0-∞) or Cmax outside the prespecified clinical relevance range of 0.5 to 1.5. Participants were administered a single dose of 300 mg BPV subcutaneously and followed up to 50 days post-dose. PK parameters were estimated using noncompartmental analysis.

Results: The GMRs and related 90% confidence intervals of both AUC0-∞ and Cmax between participants with moderate HI and healthy controls were within the defined range (0.69 [0.59, 0.82] and 0.67 [0.52, 0.85], respectively). No clinically relevant differences were observed in geometric mean PK parameters between moderate HI and healthy participants, including AUC0-∞ (75.07 and 108.9 h*µg/mL), Cmax (6.57 and 9.83 µg/mL), t1/2 (232.2 and 204.9 h), and apparent clearance (4.00 and 2.75 L/h). There were no serious adverse events reported and there were no emerging safety concerns.

Conclusion: Results from this study show no clinically relevant effect of moderate HI on BPV PK or safety. Mild hepatic impairment was not studied based on predefined criteria.