The Exploratory Study Of GLS4 In Chronic HBV Infection Patients With A Continuous Administration For 24 Weeks

ObjectiveGLS4 is a new antiviral drug of dihydro-pyrimidine,a kind of nucleocapsid inhibitor similar to Bay4109 which acts on the assembly process of hepatitis B virus（HBV）core particles.Because GLS4 has an obvious first pass elimination and short elimination half-life(t_1/2),ritonavir[RTV]-the liver drug enzyme inhibitor is needed to increase the exposure in plasma.In this paper,we evaluated the safety and efficacy of GLS4 combined with RTV tablets in patients with chronic hepatitis B（CHB）by an exploratory study with non-random,open,multiple and continuous administrated design to provide a basis for subsequent clinical trial design.Method20 hepatitis B surface antigen（HBsAg）positive CHB patients aged18-65 years old were enrolled,and according to the enrollment order,they were divided into two groups.The first 10 subjects entered GSL4/RTV（120mg/100mg）administered twice a day group（Cohort A）,assess the safety of the subjects for 2 weeks,then enrolled another10subjects to the GLS4/RTV（120 mg/100 mg）administered three times a day group（Cohort B）,both group dosing a total of 20 weeks.In the end,evaluated the safety and efficiency of GLS4 by monitoring laboratory indicators,vital signs,physical examination,electrocardiogram,adverse events（AEs）,HBV DNA,HBsAg,HBeAg,etc.during the test.Result58 HBsAg-positive CHB patients were screened and 20 of them were enrolled.Considered for safety,the first 3 subjects dosing for 4weeks,the fourth patient dosing for 12 weeks,and the others extended dosing time until 24 weeks.The ratio of male and female in Cohort A and Cohort B were 8:2 and 9:1,the ratio of HBeAg positive and negative were 5:5 and 9:1.The baseline dates of Cohort A and Cohort B respectively are:age 40.5（31-52）and 39.4（28-49）years,body mass index（BMI）23.8±3.2 Kg/m² and 26.2±3.3 Kg/m²,liver FibroScan score7.0±2.8kPa and 7.6±4.2kPa,alanineaminotransferase（ALT）95.34±37.80 U/L and 106.36±36.20 U/L,HBV DNA 6.89±1.29log₁₀IU/mL and 7.77±1.52 log₁₀IU/mL,HBsAg 3.68±0.79 log₁₀IU/mL and 4.30±1.20 log₁₀IU/mL,HBeAg 2.45±.23 log₁₀IU/mL and 2.92±0.38log₁₀IU/mL.There is no significant difference in baseline dates between the two groups（P>0.05）except the ratio of positive HBeAg.GLS4 combined with RTV were well tolerated in CHB patients with most of the AEs were grade 1-2.The common AEs in the study were ALT elevated,aspartate aminotransferase（AST）elevated,gamma glutamyl transferase（GGT）elevated,hypertriglyceridemia,leukopenia,rash,etc.,most of which recovered automatically with only one serious AEs of aminotransferase elevation in Cohort A resulted in early termination at 18 weeks treatment.There were no drug-related abnormal of vital signs and ECG.The effective indicators max decreased after 24 weeks treatment of Cohort A and Cohort B respectively are:HBV DNA 3.26（1.48-5.77）and4.50（1.51-6.09）log₁₀IU/mL,HBsAg 0.27（0.01-1.20）and 0.53（0.15-1.30）log₁₀IU/mL,HBeAg 0.57（0.01-1.49）and 1.01（0.14-2.01）log₁₀IU/mL.Compared with baseline,the declines of HBV DNA are statistically significant（P<0.05）.ConclusionGLS4 120 mg combined with RTV 100 mg was well tolerated in CHB patients after 24 weeks multiple and continuous administrated.GLS4 120 mg combined with RTV 100 mg could significantly inhibited HBV DNA replication and decreased HBsAg,pgRNA and HBcrAg,indicating that GLS4 has the potential to inhibit cccDNA.