Faculty Bibliography

Background and aims: ABI-H0731 (731) is a first-generation HBV core inhibitor in development for the treatment of chronic hepatitis B infection (CHB). In the Phase 2a studies 202 and 201, treatment naive (TN) and virally suppressed (VS) HBeAg-positive patients (pts) with CHB were randomized 1:1 to 731 or placebo (Pbo) with NrtI in a blinded manner for 24 weeks. The combination of 731+NrtI was well tolerated and demonstrated faster and greater reductions in HBV DNA and pgRNA than NrtI alone. Following study completion, eligible pts entering an open-label extension study 211 received 731+NrtI for up to an additional 76 weeks. Here we report the updated data from study 211 through the current last reported observation.
Method(s): For TN pts, HBV DNA was measured by COBAS TaqMan 2.0 (LLOQ = 20 IU/mL) and pgRNA by an in-house quantitative PCR assay (LLOQ = 135 U/mL). For VS pts, HBV DNA was measured by an in-house semi-quantitative PCR assay (LLOD = 5 IU/mL) and pgRNA by an in-house semi-quantitative RT-PCR assay (LLOD = 5 IU/mL). For all pts, quantitative HBeAg and HBsAg were measured by Abbott Architect (LLOQ = 0.11 IU/mL and 0.05 IU/mL, respectively) and HBcrAg by Lumipulse G (LLOD = 1 kU/mL). Safety was assessed by adverse events (AEs) and laboratory parameters.
Result(s): Of the 23 TN pts from study 202, median (range) treatment duration 57 (36-83) weeks, 21 pts have DNA declines to <100 IU/mL and 6 pts have pgRNA declines to <500 U/mL. Declines of >=1 log or at 5% was upper respiratory tract infection (4 pts, 6%). Most laboratory abnormalities were Grade 1 or 2. Transient or intermittent Grade 3 elevations in ALT were observed in 2 pts (3%), both of whom continue on study drug.
Conclusion(s): Results from the ongoing Phase 2a extension study demonstrate continued declines in HBV DNA, pgRNA and viral antigens in pts treated with 731+NrtI. 731 continues to exhibit a favorable safety and tolerability profile in pts treated for over 1 year. The data support the continued development of 731.
Copyright

Background and aims: Machine learning (ML) may facilitate interpretation of histologic changes associated with treatment of chronic hepatitis B virus (HBV) infection. We developed ML models that identify and quantify histologic features in a clinical study of HBV patients receiving antiviral therapy.
Method(s): ML models were developed using H&E histology images from 330 patients enrolled in registrational studies for tenofovir disoproxil fumarate for HBV (GS-US-174-0102, GS-US-174-0103). Histological improvement and regression of cirrhosis were assessed by a central pathologist at baseline (BL) and weeks 48 and 240 according to the Ishak/Knodell necroinflammatory scoring and Ishak fibrosis staging systems. Images were split into training (N = 1090) and testing sets (N = 1061). Models were trained using the PathAI research platform (Boston, MA) to identify inflamed regions and immune cells (lymphocytes and plasma cells) using annotations from 40 board-certified pathologists. Additional annotations of steatosis and ballooning from previous models were included in training. Slide-level, quantitative ML features were computed and correlated with pathologist scores to assess accuracy. Regression analysis was performed to determine associations of ML features at BL and changes from BL with cirrhosis regression at week 240. Results were generated using the testing image set.
Result(s): ML % area of portal inflammation correlated strongly with Ishak portal inflammation scores (rho = 0.643; p < 0.001) and ML % area of interface inflammation correlated strongly with Ishak periportal necrosis scores (rho = 0.716; p < 0.001). Of the 48 patients in the testing set with cirrhosis at BL, 36 patients (75%) no longer had cirrhosis at week 240. Lower ML % area of steatosis (Figure) and greater ML % area of lobular inflammation at BL were predictive of cirrhosis regression (p = 0.006, p = 0.047, respectively), indicating the presence of underlying fatty liver in those who do not resolve cirrhosis. Change from baseline in ML % area of portal and lobular inflammation as well as change in lymphocyte density correlated with regression of cirrhosis at week 240 (p = 0.010, p = 0.026, p = 0.031 respectively). [Figure presented]
Conclusion(s): An ML approach accurately classified histopathologic features in H&E images from HBV clinical trial biopsies. ML features at BL and changes in ML features with treatment were significant associated with cirrhosis regression. An ML approach for evaluating liver histology in patients with HBV can provide mechanistic insight into both HBV disease pathogenesis and cirrhosis regression.
Copyright

Background and Aims: Nucleos(t)ide reverse transcriptase inhibitors (NrtI) are the standard of care for the treatment of chronic HBV (CHB) infection. While these agents achieve viral suppression in most patients (pts), sustained response is rarely achieved following cessation of treatment. The HBV core inhibitor ABI-H0731 (731) in combination with a NrtI is currently being evaluated in Phase 2 clinical studies.
Method(s): ABI-H0731-201 is a double-blind, placebo (Pbo)-controlled study in NrtI-suppressed pts with CHB. Patients were randomized 3:2 to receive 731 (300 mg QD) +NrtI or Pbo+NrtI for 24 wks. Eligible pts had HBV DNA <=LLOQ for >= 6 mos, HBsAg >1000 IU/mL, ALT <=5x ULN and Metavir F0-F2. HBV DNA was measured by COBAS TaqMan 2.0 (LLOQ = 20 IU/mL) and an in-house (ASMB) semi-quantitative PCR assay (LLOQ = 5 IU/mL). HBV pgRNA was measured by an ASMB RT-qPCR assay (LLOQ = 35 IU/mL). Safety was assessed through reporting of adverse events (AE) and laboratory abnormalities. This report summarizes the antiviral activity and safety for the HBeAg-negative pts only.
Result(s): Of the 26 HBeAg-negative pts enrolled in the study, 16 received 731+NrtI and 10 received Pbo+NrtI. Overall, the mean (range) age was 48 (34-64) years, 16 (62%) were male, 21 (81%) were Asian. Results are shown in the table. Treatment with 731+NrtI resulted in a higher proportion of pts achieving TND by the ASMB HBV DNA assay compared with Pbo+NrtI. At baseline and throughout the study, the pgRNA and HBcrAg levels were low and the HBsAg levels did not change. The safety profile of 731+NrtI was similar to Pbo +NrtI. Both treatments were well-tolerated, with no serious adverse events or discontinuations due to AEs. All AEs and lab abnormalities were mild or moderate in severity. Only one pt receiving 731+NrtI reported a Grade 1 rash that resolved on study without treatment interruption. No Grade 3 ALT elevations were observed. [Table presented]
Conclusion(s): In 24weeks of treatment, a higher proportion of HBeAg-negative pts receiving 731+NrtI achieved HBV DNA TND by highly sensitive PCR methodology compared to Pbo+NrtI. 731 has a favorable safety and tolerability profile. These data suggest the contribution of 731 to the standard of care in achieving deeper viral suppression and support continued treatment with 731+NrtI in the open-label Phase 2 study ABI-H0731-211.
Copyright

Background and Aims: Noninvasive tests of fibrosis (NITs) are an alternative to liver biopsy for fibrosis staging and monitoring; however, associations between NITs and disease progression are poorly understood. Our aim was to evaluate the risk of liver-related complications according to baseline at enrolment (BL) and changes in the Enhanced Liver Fibrosis (ELF) test and liver stiffness by transient elastography (LS by TE) following sustained virologic response (SVR) in patients with HCV cirrhosis.
Method(s): Patients with pre-treatment HCV cirrhosis who achieved SVR with sofosbuvir (SOF)-based regimens were enrolled in an ongoing, prospective registry (NCT02292706). Patients underwent routine clinical and laboratory assessments, including semi-annual ELF testing and annual LS by TE. At BL, fibrosis stage was defined based on ELF (F0-F2, <9.8; F3, 9.8-11.3; F4, >11.3) and LS by TE (F0-F2, <9.6 kPa; F3, 9.6-12.5 kPa; F4,?>12.5 kPa). Changes at 48 weeks (improved, no change, worse) were defined based on ELF response (>=0.5 unit change from BL) and LS by TE response (>=25% change from BL). Associations between NITs and all-cause mortality, hepatocellular carcinoma (HCC), and total liver-related events (hepatic decompensation, transplantation, HCC, and liver-related death) were evaluated using Cox regression.
Result(s): We included 1,370 subjects with HCV Child-Pugh A cirrhosis (median 60 years of age, 32% female). At BL, median ELF was 9.8 (IQR 9.1, 10.7); 530 (39%) and 158 (12%) patients had ELF scores consistent with F3 and F4 fibrosis, respectively. Median LS by TE was 13.9 kPa (IQR 9.1, 21.3); 210 (15%) and 640 (47%) patients had LS by TE consistent with F3 and F4 fibrosis, respectively. After a median follow-up from BL of 144 weeks (IQR 119, 172), BL ELF and LS by TE class were associated with risks of all-cause mortality, HCC, and liver-related events (Table). Relative to BL F0-F2, significantly increased risks for all outcomes were observed for both F3 and F4 fibrosis defined by ELF, and F4 fibrosis defined by LS by TE. Worsening of ELF at 48 weeks was significantly associated with increased risk of all-cause mortality, while risks of HCC and total liver-related events were numerically, but non-significantly, higher for this group. In contrast, worsening of LS by TE at 48 weeks was not significantly associated with increased risks of the studied outcomes. Improvements in either measure were not associated with the risk of complications.
Conclusion(s): Following successful HCV therapy in patients with HCV-related cirrhosis, BL NITs are prognostic. Changes in NITs over 48 weeks may also be predictive of disease progression; however, further study is necessary following the accrual of additional follow-up time and events. This study is among the first to show an association between changes in liver fibrosis and changes in liver-associated morbidity and mortality in patients with compensated cirrhosis. [Figure presented]
Copyright

PT150 is a clinical-stage molecule, taken orally, with a strong safety profile having completed Phase 1 and Phase 2 clinical trials for its original use as an antidepressant. It has an active IND for COVID-19. Antiviral activities have been found for PT150 and other members of its class in a variety of virus families; thus, it was now tested against SARS-CoV-2 in human bronchial epithelial lining cells and showed effective 90% inhibitory antiviral concentration (EC90) of 5.55 µM. PT150 is a member of an extended platform of novel glucocorticoid receptor (GR) and androgen receptor (AR) modulating molecules. In vivo, their predominant net effect is one of systemic glucocorticoid antagonism, but they also show direct downregulation of AR and minor GR agonism at the cellular level. We hypothesize that anti-SARS-CoV-2 activity depends in part on this AR downregulation through diminished TMPRSS2 expression and modulation of ACE2 activity. Given that hypercortisolemia is now suggested to be a significant co-factor for COVID-19 progression, we also postulate an additive role for its potent immunomodulatory effects through systemic antagonism of cortisol.