Polimorfismos de un solo nucleótido en el sitio de unión de bepirovirsen tienen un impacto limitado en la respuesta...

Single nucleotide polymorphisms (SNPs) in the hepatitis B virus (HBV) genome may impact efficacy of novel drugs for chronic HBV infection. This analysis of the B-Clear study (NCT04449029) evaluated the frequency of baseline and treatment-emergent SNPs in the bepirovirsen binding site and association with virological response.

HBV sequencing was attempted on all baseline samples collected from B-Clear participants and select post-baseline samples from participants meeting pre-defined resistance monitoring criteria. Participants were categorized according to nucleos(t)ide analog (NA) treatment status and HBsAg response. SNPs were identified using next-generation sequencing and reported if the allelic frequency was ≥5%. Binding site SNPs effect on viral fitness and susceptibility to bepirovirsen was assessed in vitro.

Baseline sequences were obtained for 40% (90/226) and 96% (219/229) of On-NA and Not-on-NA participants, respectively. Baseline SNPs were identified in 7% (22/309) of participants. These participants showed numerically smaller HBsAg reductions than those without SNPs, but 18% (4/22) achieved transient HBsAg loss. Post-baseline sequences were obtained for 22% (49/226) and 62% (143/229) of On-NA and Not-on-NA participants, respectively. Of 16 post-baseline SNPs, 8 were treatment-emergent. SNPs were detected at 12 of the 20 binding site positions, however only two SNPs had an allelic frequency >50% (C1589A [max 99%] and C1600T [max 99%]). Six SNPs showed sufficient viral fitness to be evaluated for susceptibility to bepirovirsen in vitro. C1589A demonstrated the largest reduction in susceptibility (4.1-fold) to bepirovirsen.

The majority of participants achieved >1 log HBsAg reductions, including transient HBsAg loss in some, though numerically smaller HBsAg reductions in participants with baseline SNPs require further investigation to better understand resistance mechanisms to bepirovirsen.

HBV sequence polymorphisms can lead to antiviral resistance for the treatment of chronic HBV infection. Therefore, it is important for HCPs to understand the prevalence and development of bepirovirsen binding site SNPs and how their presence in patients with chronic HBV infection may impact the virological response to bepirovirsen treatment. The Phase 2b clinical study findings reported here show that the large majority (92%) of non-responders, partial responders or relapsers did not have bepirovirsen binding site SNPs. Those with bepirovirsen binding site SNPs (7% of participants) still achieved HBsAg reductions, indicating that there is no need at this stage to test for specific HBV variants when administering bepirovirsen, and that treatment resistance via a change in sequence complementarity may be minimal and likely multifactorial. Additional data from ongoing Phase 3 studies of bepirovirsen will provide additional context for assessing this need, and for understanding potential mechanisms of resistance to bepirovirsen.