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Hepatitis B Core Protein Inhibitor, ABI-H0731, Produces Promising Results In Phase 2a Studies

ILC 2019: Interim data from two Phase 2a studies of ABI-H0731 suggest good tolerability and enhanced antiviral efficacy in combination with standard-of-care in chronic hepatitis B infection

13 April 2019, Vienna, Austria

EASL (EUROPEAN ASSOCIATION FOR THE STUDY OF THE LIVER)

An interim analysis of data from two ongoing Phase 2a studies investigating the hepatitis B core protein inhibitor (CI), ABI-H0731, reported today at The International Liver Congress™ 2019, found that, when administered in combination with nucleos(t)ide analogues (Nucs), ABI-H0731 was well tolerated and provided early and enhanced antiviral activity in both treatment-naïve and virologically-suppressed individuals.

Hepatitis B virus (HBV) infection remains a major global public health challenge and is associated with significant morbidity and mortality.1 The main goals of treatment for individuals with chronic HBV infection are to improve survival and quality of life by preventing disease progression and the development of hepatocellular carcinoma.1 Standard-of-care in chronic HBV infection is the long-term administration of Nucs,1 which suppress viremia and improve liver health, but are rarely curative.1,2

Hepatitis B core protein inhibitors are novel small molecules designed to target the HBV core protein, which is involved in multiple steps of the HBV lifecycle.3 ABI-H0731 is a potent and selective oral HBV CI that is being developed in an effort to improve functional cure rates (i.e. clearance of residual viremia and antigens1) in chronic HBV infection.4 A recently-reported Phase 1 study found that ABI-H0731 was well tolerated and associated with dose-dependent anti-HBV activity when used as monotherapy over 28 days in viremic individuals with chronic HBV infection.5

In interim analyses from the two randomized, double-blind, placebo-controlled Phase 2a studies presented today, ABI-H0731 was administered in combination with Nucs in two different study cohorts:

  • Individuals with chronic HBV infection (hepatitis B e antigen [HBeAg]-positive or negative) already suppressed on standard-of-care Nucs (n=73) who received add-on ABI-H0731 300 mg once-daily (qd) or placebo (Study ABI-H0731-201)
  • Treatment-naïve HBeAg positive individuals (n=25) who were initiated on either entecavir (ETV) + ABI-H0731 300 mg qd or ETV + placebo (Study ABI-H0731-202).

The primary efficacy endpoints of the two studies are the log10 reduction in HBsAg/HBeAg at Week 24 (Study ABI-H0731-201) and the log10 reduction in HBV DNA at Weeks 12 and 24 (Study ABI-H0731-202).

According to Dr Jacob Lalezari from Quest Clinical Research in San Francisco, USA, who presented the interim analyses, ‘ABI-H0731 has been well tolerated so far and few treatment-emergent adverse events (AEs) or laboratory abnormalities have been reported. Most AEs have been mild or moderate in intensity and none have led to treatment discontinuation.’

In Study ABI-H0731-201, the interim analysis includes 64/73 suppressed individuals that have completed the Week 12 assessment and 9 that have completed week 24 assessments. Those receiving ABI-H0731 in combination with a Nuc had significant reductions in HBV RNA levels of 2.34 log10 IU/ml compared with 0.05 log10 IU/ml in the group receiving Nuc + placebo at Week 12 (p<0.001). The reductions at Week 24 were 2.20 vs 0.15 log10 IU/ml, respectively (p=0.012). Additionally, DNA viremia was persistent at the limits of quantitation in subjects on Nuc monotherapy, while subjects on combination therapy showed a further reduction in viral DNA to below the limits of a highly sensitive PCR assay (2–5 copies).

In Study ABI-H0731-202, 24 treatment-naive individuals have completed Week 12 assessments, and 12 have completed Week 24. At Week 12, HBV DNA declines in the combination arm were 4.54 log10 IU/ml, compared with 3.29 log10 IU/ml for the group receiving ETV + placebo (p<0.011). HBV RNA declines in the combination arm were 2.27 log10 IU/ml, compared with 0.44 log10 IU/ml for the group receiving ETV + placebo (p<0.005).

At week 24, HBV DNA declines in the combination arm were 5.94 log10 IU/ml, compared with 3.99 log10 IU/ml in the group receiving ETV + placebo (p<0.005). HBV RNA declines were 2.54 log10 IU/ml in the combination arm compared with 0.61 log10 copies/ml in the group receiving ETV + placebo (p<0.005).

‘This interim analysis of two studies supports that ABI-H0731 in combination with Nucs appears to provide rapid, enhanced anti-HBV activity,’ said Dr Lalezari. ‘Although decreases in HBeAg and HBsAg in some individuals have been observed in both studies, it is too early to draw meaningful conclusions about this endpoint. The accelerated decline and significant loss of baseline RNA and DNA viremia suggest that combination therapy with a core inhibitor + Nuc may enhance loss of cccDNA and viral antigen once residual viremia has been fully cleared.’

‘It is great to see that new HBV treatments are being developed,’ said Professor Markus Cornberg from Hannover Medical School in Germany, a member of EASL’s governing board. ‘This Hepatitis B core protein inhibitor shows an effect on HBV RNA levels and thus an additional antiviral efficacy. However, it too early to conclude if this treatment could lead to HBV cure.’

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About The International Liver Congress™

This annual congress is the biggest event in the EASL calendar, attracting scientific and medical experts from around the world to learn about the latest in liver research. Attending specialists present, share, debate and conclude on the latest science and research in hepatology, working to enhance the treatment and management of liver disease in clinical practice. This year, the congress is expected to attract approximately 10,000 delegates from all corners of the globe. The International Liver Congress™ 2019 will take place from 10­–14 April 2019 at the Reed Messe Wien Congress and Exhibition Center, Vienna, Austria.

About The European Association for the Study of the Liver (EASL)

Since its foundation in 1966, this not-for-profit organization has grown to over 4,000 members from all over the world, including many of the leading hepatologists in Europe and beyond. EASL is the leading liver association in Europe, having evolved into a major European association with international influence, and with an impressive track record in promoting research in liver disease, supporting wider education and promoting changes in European liver policy.

Contact

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Onsite location reference

Session title: ‘Late breaker’

Time, date and location of session: 17:15–17:30, 13 April 2019, Main plenary

Presenter: Jacob Lalezari, USA

Abstract:  Interim safety and efficacy results of the ABI-H0731 Phase 2a program exploring the combination of ABI-H0731 with NUC therapy in treatment-naive and treatment-suppressed chronic hepatitis B patients (LB-06)

 

Author disclosures

Dr Jacob Lalezari currently serves as a consultant to Assembly Biosciences

References

  1. European Association for the Study of the Liver. EASL 2017 Clinical Practice Guidelines on the management of hepatitis B virus infection. J Hepatol. 2017;67(2):370–89.
  2. Yuen MF, et al. Hepatitis B virus Nat Rev Dis Primers. 2018;4:18035.
  3. Schlicksup CJ, et al. Hepatitis B virus core protein allosteric modulators can distort and disrupt intact capsids. Elife. 2018 Jan 29;7. pii: e31473.
  4. Yuen M-F, et al. Interim safety, tolerability, pharmacokinetics, and antiviral activity of ABI-H0731, a novel core protein allosteric modulator, in healthy volunteers and non-cirrhotic viremic subjects with chronic hepatitis B. J Hepatol. 2018;68(1):S111; Abstract LBP-02.
  5. Yuen M-F, et al. Final results of a Phase 1b 28-day study of ABI-H0731, a novel core inhibitor, in non-cirrhotic viremic subjects with chronic hepatitis B. 2018;68(S1):47A; Abstract 73.