Progress of new hepatitis B drugs The first human study results of APG-1387 in the treatment of chronic hepatitis B were announced

Targeting apoptotic protein inhibitory factor (IAP) may be a novel immunotherapy strategy
to achieve a functional cure for chronic hepatitis B (CHB).
The new drug under investigation, APG-1387, is a new generation of IAP antagonist, which can enhance hepatitis B virus (HBV)-specific T cell response and induce HBV antigen-expressing apoptosis
of hepatocytes.
At the 2022 American Association for the Study of Liver Diseases Annual Meeting (AASLD 2022), Professor Hou Jinlin's team from Southern Hospital of Southern Medical University announced the first human study results
of APG-1387 in the treatment of CHB.

The first human results of APG-1387 treatment of CHB are published

(Summary number: 32)

Research methods

This study evaluates the safety, tolerability, pharmacokinetics (PK) and pharmacodynamics (PD)
of APG-1387 in Chinese CHB patients for the first time.
Patients treated with CHB were enrolled in weekly doses of APG-1387 (7 mg, 12 mg, 20 mg, and 30 mg) intravenously for 4 weeks, followed by observation
for 12 weeks.
Nucleoside (acid) analogue (NA) therapy
is started during follow-up according to clinical guidelines.

The concentration
of APG-1387 in plasma was determined using the validated LC-MS/MS method.
Biomarker studies include quantification of viral load and detection of immune parameters in peripheral blood, including lymphocyte subsets and cytokines
.

Study results

A total of 49 patients with a median age of 31 years were included, of whom 33 were male and 29 were positive
for hepatitis B e antigen (HBeAg).
PK analysis showed that plasma exposure increased in proportion to dose in the dose range of 7-30 mg, with no accumulation
after multiple doses.

Adverse events (AEs) considered relevant to study treatment occurred in 30 patients, most commonly transient alanine aminotransferase (ALT)/aspartate aminotransferase (AST) elevation [9/49 (18.
4%)] and reversible Bell's palsy [7/49 (14.
3%)].

On day 28 after the end of APG-1387 administration, HBV DNA, hepatitis B surface antigen (HBsAg) levels, and HBeAg levels were significantly reduced
in the 12 mg and 30 mg dose groups.
During the observation period, 14 patients received NA treatment, and the median (nadir point) reduction of HBV DNA, HBsAg, and HBeAg was 4.
69 (6.
46) log 10 IU/ml, 0.
25 (2.
44) log 10 IU/ml, and 1.
73 (2.
49) log_{10 on day 112}, respectively S/CO (0.
05 for all index P compared to monotherapy group) <) (Figure 1).

Fig.
1 Changes in HBsAg and HBeAg levels in each dose group during APG-1387 treatment (days 1-28) and observation (days 28-112).

In four patients, HBeAg levels were positive
when the lower limit of quantification was approached.
One patient achieved HBeAg clearance
.
IL-12 was dose-dependently increased, and IFN-γ, IL-10 and TNF-α levels were also elevated 24 h after the first dose of APG-1387, suggesting that APG-1387 has immunomodulatory function
.

Conclusion of the study

APG-1387 has significant anti-HBV effects at doses of 12 and 30 mg, and has a synergistic effect
with NA sequential therapy.
These preliminary safety and efficacy data support the continued development of APG-1387 in combination with other drugs for the functional cure
of chronic HBV infection.

References: Zhang X, Xu X, Guan Y, et al.
First-in-human study of APG1387, targeting inhibitor of apoptosis proteins, for the treatment of patients with chronic hepatitis B.
AASLD 2022.
Abrasts 32.