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ANALYSIS OF FACTORS INFLUENCING THE EFFICACY AND
SAFETY OF GLS4 TREATMENT IN PATIENTS WITH CHRONIC
HEPATITIS B
Hong Zhang1, Junqi Niu2, Hua Yan Ding3, Yingjun Zhang4,
Lin Luo4, Cuiyun Li5, Min Wu5, Yue Hu5, Xiaojiao Li3, Hong
Chen3, Xiaoxue Zhu3, Yan Liu6, Qingwei He6, Yunfu Chen Jr.6,
Qingyun Ren7, Baohua Gu6 and Li Jing6, (1)Phase I Clinical
Research Center, the First Hospital of Jilin University, The
First Hospital of Jilin University, (2)Department of Hepatology,
The First Hospital of Jilin University, (3)Phase I Clinical
Research Center, The First Hospital of Jilin University, (4)The
State Key Laboratory of Anti-Infection Drug Development,
HEC Pharma Group, (5)Phase I Clinical Research Center,
the First Hospital of Jilin University, (6)HEC R&D Center,
Sunshine Lake Pharma Co., Ltd, (7)The State Key Laboratory
of Anti-Infection Drug Development, HEC Pharma Group,
Dong Guan 523871, China
Background: GLS4 can interfere with the assembly and
disassembly of hepatitis B virus (HBV) nucleocapsid. The
antiviral activity of GLS4 is confirmed in chronic HBV patients.
However, the influencing factors for its antiviral efficacy and
safety remains to be elucidated Methods: We conducted
an analysis of data from 20 patients in a phase IIa clinical
trial (GLS4 120 mg twice or three times a day (Cohort A
or B) for 24 weeks treatment), including antiviral efficacy,
pharmacokinetics, adverse reaction, and changes in immune
function, to screen out the key factors affecting the anti-HBV
outcome of nucleocapsid inhibitor Results: After 24 weeks of
treatment, the mean maximal decline in HBV DNA were 3.13
and 4 37 log10 IU/mL, and those of HBsAg were 0 18 and 0 42
log10 IU/mL, and those of HBeAg were 0 56 and 1 01 log10
IU/mL, and those of pgRNA were 2 82 and 2 47 log10 IU/mL,
and those of HBcrAg were 1 42 and 1 53 log10 kU/mL at cohort
A and cohort B, respectively The higher steady state trough
concentration was associated with higher anti-virus activities
Mean Ctrough of GLS4 was 519 (Cohort A: BID dosing) and
719 ng/mL (Cohort B: TID dosing) which is approximately 9 and
13 times the serum adjusted EC90 (55 8 ng/ml) GLS4 could
effectively inhibit HBV DNA regardless of their baseline levels.
Notably, reduction of HBsAg and HBeAg were observed in
subjects with or without ALT flare. In addition, cytokines, such
as IFN-γ, TNF-α, MIP, had a transient increase that seem to
be associated with immune activation and enhanced antiviral
efficacy. Patient incompliance and resistance mutation is the
major reason for virus breakthrough (DNA＞1 log increased
from nidir) Decreased trough concentration of GLS4 was
observed before virus breakthrough, the mean lowest trough
concentrations were 380 and 599 ng/mL for the breakthrough
group and no breakthrough group, respectively Furthermore,
four patients had T109I mutation in the core protein that
have confirmed reduced suscetibility to GLS4. Although
the patient with resistance did not have significantly lower
trough concentration of GLS4, but they had declined trough
concentration before resistance occurred, thus reduced trough
concentration might account for the emergence of resistance
mutation For safety analysis, patient with higher baseline ALT
level have greater chance of developing ALT flare on treatment
and thus better antiviral efficacy, however, these flare were
well tolerated and did altered the liver function (No signifianct
change in albumin, PT or bilirubin) Conclusion: GLS4 has
multiple antiviral effects in CHB patients and various factors
are associated with antiviral activity Trough concentration,
baseline ALT, HBeAg positive and immune status seem to be
key for optimizing antiviral efficacy and safety. Further study
with larger study cohorts is needed to identify patients benefit
most from this novel therapy. |
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发表于 2019-11-1 18:54