Selgantolimod (GS-9688) is an orally selective small molecule TLR8 agonist with antiviral potential being developed by Gilead Sciences, which has been shown to be safe and well tolerated in patients with chronic hepatitis B with viral suppression and viremia, and is currently in Phase 2 clinical trials in patients with chronic hepatitis B.
The researchers published the results of the safety, pharmacodynamics and antiviral activity of the drug in patients with viral suppression and viremia chronic hepatitis B in a period of nearly a year.
A Clinical Study in Patients With Viraemic Chronic Hepatitis B (NCT03615066).
The study aims to evaluate the safety, pharmacodynamics, and antiviral activity of 24-week selgantolimod in combination with tenofovir alafenamide (TAF) in patients with viraemic chronic hepatitis B, and to evaluate the safety and persistence of antiviral activity at 48 weeks after discontinuation.
The study is a randomized, double-blind, placebo-controlled, multicenter phase II clinical study. Patients with HBEAG-positive and HBE-negative chronic hepatitis B were included as subjects and were divided into two cohorts (positive for Cohort 1 and negative for Cohort 2) based on their HBEAG status (positive or negative). Patients in each cohort were randomized in a 2:2:1 ratio to receive selgantolimod 3 mg (orally once weekly), selgantolimod 15 mg (orally once weekly) or placebo**. After receiving 24 weeks of selgantolimod + tenofovir (TAF) or placebo + tenofovir (TAF)**, TAF monotherapy** was continued until week 48, after which a 48-week follow-up period followed.
The primary endpoints of the study: Proportion of patients with adverse effects (TEAEs) at Week 24 with abnormal laboratory test results and a decrease of 1 log10 IU ML or more compared to baseline hepatitis B surface antigen (HBSAG). Secondary endpoints include the proportion of patients with undetectable HBV DNA and negative conversion of HBSAG and HBeag after 48 weeks of treatment. Exploratory endpoints include change from baseline in markers such as HBEAG, HBCRAG, HBV RNA, IL-12P40, etc.
Findings:
The baseline of enrolled patients is shown in the table below.
The safety results are shown in the table below.
Pharmacodynamic results (omitted).
Antiviral activity results.
No patients met the primary endpoint of HBSAG-reduction of 1 log10 IU mL or greater at 24 weeks.
At week 24, selgantolimod 3 mg, selgantolimod 1The mean change in HBSAG in the 5mg and placebo groups was -0., respectively08、-0.11 and -003 log10 iu/ml；At week 48, the change was -012、-0.16 and -012 log10 iu/ml。
At week 24, selgantolimod 3mg group, selgantolimod 12 out of 24 patients in the 5mg group and 0 in the placebo group** had a decrease in HBSAG, 1 in 2 (4%), and 0 in the placebo group, respectively5 log10 IU ML or above. At week 48, 2 of 24 patients (7%) and 0 patients had a decrease in HBSAG5 log10 IU ML or above. Overall, HBSAG declined slightly at week 48 and then returned to near baseline during the follow-up period.
Patients were stratified according to HBV genotype (B and C) or baseline HBsAg levels (<1,000 IU mL vs. > 1,000 IU mL), and no difference in HBSag levels at 48 weeks was noted. Viremia levels (stratified in patients with baseline HBV DNA > 20,000 IU ML) did not affect HBSAG levels at 48 weeks.
At week 24, selgantolimod 3mg group, selgantolimod 1HBV DNA was below the limit of detection in 9 24 (38%), 9 28 (32%), and 4 12 (33%) patients in the 5mg and placebo groups, respectively. At week 48, selgantolimod 3mg group, selgantolimod 112 24 (50%), 12 27 (44%), and 5 11 (46%) patients in the 5mg and placebo groups had HBV DNA below the limit of detection.
The remaining results (omitted) are discussed in the study (omitted).
Clinical Study in Patients With Viral Suppression of Chronic Hepatitis B (NCT03491553).
The study was conducted in patients with chronic hepatitis B who were virally suppressed, and the study objectives, drug regimens, and primary endpoints were similar to those in patients with viremia.
Since the experimental data is not very attractive, I am too lazy to view the full text, and here is a summary of the research results in the abstract part of the article to everyone.
One patient in the study met the primary endpoint, who was HBEAG negative and received selgantolimod 15 mg**。Only patients with selgantolimod ** (n = 39) had a decrease in HBSAG of more than 01 log10 IU ml, HBSAG negative (5%, 2 39 to 48 weeks) or HBEAG negative (16%, 3 19 to 48 weeks). The most common adverse reactions in the selgantolimod ** group were nausea (46%), upper respiratory tract infection (23%), and vomiting (23%). Gastrointestinal disorders are mostly mild and transient. Selgantolimod induces transient dose-dependent elevations in serum cytokines, including IL-12P40, IFN-, and IL-1RA, as well as rapid redistribution of some circulating immune cell subsets.
The drug did not meet the primary endpoint in two phase 2 clinical studies (in fact, some clinical results published a long time ago showed that the drug had little effect on HBSAG), but the drug is still in Gilead Sciences' latest chronic hepatitis B pipeline and has not been delisted. For more information, please refer to the original English articleStay tuned for more information on new drug research for liver diseases".Liver time"WeChat***
Original English text: 1safety and efficacy of the oral tlr8 agonist selgantolimod in individuals with chronic hepatitis b under viral suppression
2.safety, pharmacodynamics, and antiviral activity of selgantolimod in viremic patients with chronic hepatitis b virus infection
**: Heparspace