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本帖最后由 StephenW 于 2018-12-6 14:38 编辑
LB-13
Safety, Pharmacokinetics and Anti-Viral
Efficacy of Novel Core Protein Allosteric
Modifier GLS4 in Patients with Chronic Hepatitis
B: Interim Results from a 48 Weeks Phase 2a
Study
Hong Zhang1, Xiaoxue Zhu1, Hong Chen1, Xiaojiao Li1, Yue
Hu1, Min Wu1, Cuiyun Li1, Lin Luo2, Yingjun Zhang2, Dr. Hua
Yan Ding1, Dr. Junqi Niu3, Yan Liu2, Qingwei He2, Mr. Yunfu
Chen4, Mr. Qingyun Ren4, Baohua Gu2 and Dr. Li Jing2, (1)
Phase I Clinical Research Center, The First Hospital of Jilin
University, (2)The State Key Laboratory of Anti-Infection
Drug Development, HEC Pharma Group, (3)Department of
Hepatology, First Hospital of Jilin University, (4)The State Key
Laboratory of Anti-Infection Drug Development, HEC Pharma
Group, Dong Guan 523871, China
Background: GLS4 is a novel core protein allosteric modifier
and can interfere with the assembly of hepatitis B virus (HBV)
nuclear capsid. A previous phase 1b study revealed that
28 days GLS4/RTV treatment resulted in potent HBV DNA
inhibition. The antiviral activity, pharmacokinetics (PK), safety
was evaluated at the non-random, open and continuous
dosing 48 weeks study. Methods: 20 patients with HBV
received GLS4 120 mg BID or TID (Cohort A or B)/RTV.
This is interim analyze of 48 weeks treatment. The antiviral
activity (HBV DNA, HBsAg, HBeAg, HBV RNA and HBcr Ag),
GLS4 concentration, safety were collected. Results: GLS4
effectively inhibit HBV DNA for both HBeAg+ and HBeAgpatients.
With available data, the mean max decline in HBV
DNA were 3.28 (1.48~5.58) and 4.40 (1.51~6.09) log10 IU/mL
for cohort A and B, respectively. Three subjects had achieved
HBV DNA below the lower limit of quantification (LLOQ=20 IU/
ml). The mean max decline in HBsAg during treatment were
0.20 (0.01~0.77) and 0.44 (0.00~1.30) log10 IU/mL in cohort A
and B, respectively. HBsAg reduction was more profound in
HBeAg+ subjects, the mean max decline in HBsAg were 0.40
(0.00~1.30) and 0.14 (0.01~0.31) for HBeAg+ and HBeAgpatients
from both cohorts. For HBeAg, the mean max decline
were 0.57 (0.00~1.49) and 1.06 (0.14~2.07) log10 IU/mL for
cohort A and B, respectively. GLS4 treatment also significantly
reduced the serum level of HBcrAg and HBV RNA. GLS4/
RTV has been well tolerated in CHB patients, most of the
adverse events (AEs) were mild and there were no doselimiting
toxicities. AEs or laboratory abnormalities ≥ Grade 3
were infrequent (Cohort A: n=3/10; Cohort B: n=2/10), 45%
(9/20) experienced ≥1 AE on treatment (Cohort A: n=8/10;
Cohort B: n=1/10), there were two serious AEs occurred in
Cohort A (n=2, only one is related to study drug), all named
liver injury, which resulted in early termination. Mean ALT level
increased during the early treatment period, but then declined
gradually. At latter time points, the mean ALT, AST and bilirubin
dropped below the baseline level, indicating that GLS4 may
improve the liver functions. GLS4 in combination with RTV
have demonstrated favorable PK profiles. The mean time for
GLS4 to reach steady state is approximately 10 (Cohort A)
and 14 days (Cohort B), no significant difference in AUC were
observed between 28 and 84 days post dosing. Mean Ctrough
of GLS4 were 450 (cohort A) and 650 ng/mL (cohort B) and
is approximately 10 times of serum adjusted EC90 (55.8 ng/
ml). The mean Cmax were similar between the two cohorts, the
median Tmax were 2.4 and 3.2 hours post dosing for cohort
A and B, respectively. Conclusion: Preliminary data suggest
that long-term treatment (28 weeks, median) of GLS4/RTV is
safe, well tolerated and effective in CHB patients, especially
the potential to reduce viral antigen. Further combination
studies are ongoing to evaluate the synergistic effect between
GLS4 and nucleoside analogue. |
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发表于 2018-12-6 14:37
