Introduction
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The 2022 European Association for the Study of the Liver (EASL 2022) will be held in London, UK from June 22 to 26. This meeting announced the latest research data of a number of new chronic hepatitis B (CHB) drugs. This article will focus on the research and development progress of EDP-514, GST-HG141 and ALG-020572, as described below.
EDP-514: A 28-Day Phase 1b Study in Virologically Suppressed CHB Patients Data Release
(Abstract No.: SAT390)
Research background
EDP-514 is a novel type II hepatitis B virus (HBV ) core inhibitor, reduced viral load by >4-log in a mouse model of HBV. Phase 1b study evaluating the safety, pharmacokinetics (PK) and antiviral efficacy of multiple ascending doses (MAD) of EDP-514 in virologically suppressed CHB patients treated with nucleoside analog (NUC) active.
Research Methods
This Phase 1a/b, randomized, double-blind, placebo-controlled study was conducted in two parts. In Part 1, healthy adult subjects received single or multiple ascending doses of EDP-514 or placebo. In Part 2, non-cirrhotic, hepatitis B e antigen (HBeAg) positive or negative subjects who achieved virological suppression on NUC treatment received EDP-514 or placebo in a 3:1 ratio (24 received Subjects were divided into 3 cohorts: 200 mg, 400 mg, and 800 mg) for 28 days.
Findings
24 subjects enrolled were predominantly male (63%), Asian (67%), HBeAg-negative (88%), receiving tenofovir (92%), mean age 45 years, mean weight The index (BMI) was 27 kg/m2.
Except for 1 case of moderate abdominal pain (200 mg group) leading to discontinuation and 1 case of severe allergic reaction to aloe vera cream (800 mg group) Except for the mg group), all treatment-emergent adverse events (TEAEs) (n=20) were mild. There were no other grade 3 TEAEs or any serious adverse events (SAEs). No clinically significant laboratory abnormalities, elevated liver function tests, or clinically relevant changes in electrocardiogram (ECG) or vital signs were observed.
The PK of EDP-514 supports once-daily (QD) dosing with a trough concentration of approximately paEC50< 21 times the size of /span>. During the 28-day treatment period, HBV DNA remained undetectable, and no virological failures or breakthroughs were reported. On day 28, the largest reductions in HBV RNA were observed in HBeAg-negative and HBeAg-positive patients of 2.3 log and 2.8 log, respectively, in the EDP-514 group, compared with 1.2 log in the placebo group. There were no significant changes in HBeAg, hepatitis B core-associated antigen (HBcrAg) and hepatitis B surface antigen (HBsAg).
Study Conclusions
28-day treatment with EDP-514 was safe and well-tolerated in patients with CHB who were virologically suppressed by NUC, showing a time-linear PK supporting QD dosing at a concentration of paEC50 and resulted in a higher log reduction in HBV RNA, with a maximum reduction of 2.8 log observed in HBeAg-positive patients receiving EDP-514.
Evaluation of safety, PK and antiviral activity of GST-HG141 in CHB subjects
(Abstract number: SAT423)
Research background
GST-HG141 is a novel HBV capsid protein assembly regulator, which is Safety, tolerability and PK in subjects have been previously reported. This study aimed to evaluate the safety, PK and antiviral activity of multiple doses of GST-HG141 in CHB patients.
Research Methods
This is a multicenter, randomized, double-blind, placebo-controlled, multi-dose escalating Phase Ib study. No interferon or NUC therapy (>12 or >6 months, respectively), HBeAg positive or negative (serum HBV DNA ≥2×10, respectively5 or ≥2× 104 IU/mL) CHB patients received GST-HG141 (25, 50 and 100 mg orally, BID dosing) for 28 days. Ten patients in each cohort were randomized to receive drug or placebo (4:1).
Quantitative determination of GST-HG141 in plasma using a validated LC-MS/MS method. PK parameters were calculated using WinNonlin 8.3 software. Serum HBV DNA and HBV pgRNA were determined using quantitative real-time PCR, and serum HBV antigens were determined by ELISA.
Findings
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28 days of GST-HG141 BID dosing at 25, 50 or 100 mg was well tolerated. No SAEs were reported or the number of adverse events (AEs) was dose-relatedIncrease. There were no TEAEs leading to treatment discontinuation.
A rapid and robust decrease in serum HBV DNA was observed (median 2.9, 3.3 and 3.5 for the 25, 50 and 100 mg dose groups, respectively log10 IU/ml). On day 29 of treatment, the median reduction in serum HBV pgRNA levels was 2.2 log10 U/ml across all dose groups, with the largest median reduction in the 100 mg dose group is 2.40 log10 U/ml.
No virological breakthroughs were observed. No statistically significant decrease in serum HBsAg, HBeAg or HBcrAg was observed. However, the serum HBeAg and HBcrAg in patients receiving drug treatment showed a downward trend. Plasma GST-HG141 exposure increased dose proportionally. Moderate accumulation was observed after 28 days of dosing (mean 1.67-2.38).
Study Conclusions
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Oral administration of 25, 50 or 100 mg of GST-HG141 BID for 28 days was safe and well tolerated. It resulted in a rapid, robust and dose-dependent decrease in serum HBV DNA and a significant decrease in serum HBV pgRNA levels. Plasma GST-HG141 exposure was almost dose proportional. Therefore, further clinical development of GST-HG141 in the treatment of CHB is necessary.
Evaluation of safety, tolerability and PK of ALG-020572 in healthy subjects with single escalating doses< /strong>
(abstract number: SAT343)
Background
ALG-020572 is an anti-HBsAg-lowering drug The purpose of this study is to evaluate the safety, tolerability, PK and antiviral activity of ALG-020572 in CHB subjects.
Research Methods
This is a double-blind, randomized, placebo-controlled, single-dose and multiple ascending-dose study conducted in two parts. Part 1 enrolled 8 healthy subjects (including at least 4 Asian patients) who were randomized 3:1 to receive single escalating subcutaneous (SC) administration of ALG-020572 or placebo. Part 2 plans to enroll 8 CHB subjects randomized in a 3:1 ratio to receive multiple escalating SC dosing of ALG-020572 or placebo. Safety assessments, viral markers (Part 2), and plasma/urine PK samples were collected throughout the study.
Findings
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In Part 1, healthy subjects from the first 2 cohorts received a single 50 or 150 mg SC dose of ALG-020572 or placebo. The mean age of the subjects was 28 years, 94% were male, and 50% were Asian.
ALG-020572 was well tolerated. No SAEs or dose-limiting toxicities occurred, and all TEAEs were mild in severity with the exception of one patient who experienced injection site tenderness (grade 2). All laboratory abnormalities occurring during treatment were ≤ grade 2. No clinically significant physical examination, vital signs, or ECG abnormalities were reported.
Plasma ALG-020572 exposure increased in a slightly above dose-proportional manner between 50-150 mg, with low to moderate variability . ALG-020572 exhibits rapid absorption, high volume of distribution, high plasma clearance, and low urinary excretion. No differences in safety or PK were observed between Asian and non-Asian subjects. Based on observed exposure and nonclinical studies, ALG-020572 is expected to have antiviral activity in CHB subjects at doses ≥150 mg.
Study Conclusions
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ALG-020572 was safe and well-tolerated with a predictable PK profile in healthy subjects up to a single SC administration of up to 150 mg.
References:
< p>1. Feld J, Lawitz E, Nguyen TT, et al. EDP-514, a novel pangenotypic class II hepatitis B virus core inhibitor: final results of a 28-day phase 1b study in nuc-suppressed chronic hepatitis B patients. EASL 2022. Abrasts SAT390.
2. Mai J, Zhang H, Wu M, et al. Safety, pharmacokinetics and antiviral activity of GST-HG141, a hepatitis B virus capsid assembly modulator, in subjects with chronic hepatitis B. EASL 2022. Abrasts SAT423.
3.Gane EJ, Yuen MF, Schwabe C, et al. Safety, tolerability and pharmacokinetics of single ascending doses of ALG-020572, a GalNAc-conjugated antisense oligonucleotide, in healthy subjects. EASL 2022. Abrasts SAT343.< /p>