morphothiadine mesilate (GLS4) / HEC Pharm - LARVOL DELTA

Design, Synthesis, and Biological Evaluation of Highly Potent Boronic Acid (Boronate Ester)-Bearing Heteroaryldihydropyrimidine Derivatives as HBV Capsid Assembly Modulators. (PubMed, J Med Chem) - "Preliminary drug-likeness evaluation indicated that CAB7-3 displayed improved water solubility, superior microsomal metabolic stability in liver (T1/2 = 169.0 min) and lower hERG cardiotoxicity (IC50 = 6.5375 μM) compared to GLS4. All data demonstrated that CAB7-3 may be used as a potential candidate for further drug development."

Journal • Cardiovascular • Hepatitis B • Infectious Disease • Inflammation

GLS4 INHIBITS HEPATITIS B VIRUS INFECTION BY ACTIVATING THE INTERFERON SIGNALING PATHWAY (AASLD 2025) - "This study suggests that GLS4 inhibits HBV replication by not only disrupting the correct assembly of the nucleocapsid, but also activating the interferon signaling pathway."

Hepatitis B • Hepatocellular Cancer • Hepatology • Infectious Disease • Inflammation • Liver Cancer • Solid Tumor • IFNAR2

HBV capsid assembly modulators differentially modulate the assembly of wild-type and drug-resistant core protein chimeric nucleocapsids and empty capsids. (PubMed, PLoS Pathog) - "However, 50% Cp with T33N substitution conferred complete resistance to the assembly of chimeric empty capsids induced by AB-506 but remained sensitive to GLS4, as determined in an in vitro capsid assembly assay and in transfected hepatoma cells. Our results thus suggest that although disruption of nucleocapsid assembly requires only small numbers of CAM binding pockets at Cp dimer-dimer interfaces to be engaged, induction of mature nucleocapsid disassembly requires much larger numbers of CAM binding pockets to be occupied. The strong WT Cp dominance in CAM suppression of nucleocapsid assembly may slow down the emergence of CAM-resistant HBV variants under CAM therapy."

Journal • Hepatitis B • Hepatocellular Cancer • Infectious Disease • Inflammation • Liver Cancer • Solid Tumor

Design, synthesis and evaluation of new dihydropyrimidine derivatives as HBV capsid protein inhibitors. (PubMed, Bioorg Med Chem) - "Furthermore, predictions regarding the properties of I-3e suggested it aligns well with Lipinski's five rules and is anticipated to possess pharmacokinetic characteristics similar to those of GLS4. This research lays a foundation for discovering effective HBV capsid protein assembly inhibitors."

Journal • Hepatitis B • Infectious Disease • Inflammation

Discovery and mechanism verification of first-in-class hydrophobic tagging-based degraders of HBV core protein. (PubMed, Acta Pharm Sin B) - "Remarkably, HyT-S7 effectively degraded 11 drug-resistant mutants, including highly resistant strains P25G and T33N, to Phase III drug GLS4. Furthermore, cellular thermal shift assay, surface plasmon resonance assay, and molecular dynamics simulations revealed the precise mode of HyT-S7 binding to HBC with the adamantyl group potentially mimicking protein misfolding to facilitate HBC degradation. This first proof-of-concept study highlights the potential of HyT-mediated TPD in HBC as a promising avenue for discovering novel HBV and other antiviral agents with favorable drug resistance profiles."

Journal • Hepatitis B • Infectious Disease • Inflammation • Targeted Protein Degradation

Residual Viral Expression in siRNA-Treated HBV-Replicating Cell and Mouse Models. (PubMed, Antiviral Res) - "Furthermore, the combination of siRNA and the HBV core inhibitor GLS4 further reduced intracellular viral DNA in primary human hepatocytes. These findings obtained from experimental models incorporating in situ detection techniques reveal the expression patterns of residual HBV antigens and nucleic acids under siRNA treatment, deepening the understanding of its antiviral effects, while clinical complexities require further investigation."

Journal • Preclinical • Hepatitis B • Infectious Disease • Inflammation

Efficacy and safety of GLS4 with entecavir vs entecavir alone in chronic hepatitis B patients: a multicenter clinical trial (APASL 2025) - P2 | "This study evaluated the antiviral activity and safety of GLS4/ritonavir (RTV) combined with entecavir (ETV) versus ETV alone in hepatitis B e antigen (HBeAg)-positive patients with chronic HBV infection (CHB). The primary analysis at week 48 showed that the antiviral efficacy of GLS4/RTV with ETV was clearly superior to that of ETV monotherapy. GLS4/RTV with ETV was well tolerated; further studies evaluating its safety and efficacy are ongoing. (clinical trial identifier: NCT04147208)."

Clinical • Dyslipidemia • Hepatitis B • Hepatology • Hypertriglyceridemia • Infectious Disease • Inflammation

Efficacy and safety of GLS4 with entecavir vs entecavir alone in chronic hepatitis B patients: a multicenter clinical trial. (PubMed, J Infect) - P2 | "The primary analysis at week 48 showed that the antiviral efficacy of GLS4/RTV with ETV was clearly superior to that of ETV monotherapy. GLS4/RTV with ETV was well tolerated; further studies evaluating its safety and efficacy are ongoing. (clinical trial identifier: NCT04147208)."

Journal • Dyslipidemia • Hepatitis B • Hepatology • Hypertriglyceridemia • Infectious Disease • Inflammation

Identification of peptide-based hepatitis B virus capsid inhibitors based on the viral core protein. (PubMed, Bioorg Med Chem Lett) - "Molecular dynamics simulations revealed that despite their overlapping sequence, 19Ac and 20Ac bonded to different regions of the core protein, thereby inhibiting capsid assembly through distinct mechanisms. These peptides could serve as valuable seed compounds for the further development of HBV capsid inhibitors, including GLS4-resistant strains."

Journal • Hepatitis B • Hepatology • Infectious Disease • Inflammation

Improved Preclinical Drug Metabolism and Pharmacokinetics of Pibothiadine (HEC121210), a Novel Hepatitis B Virus Capsid Assembly Modulator. (PubMed, Xenobiotica) - "Pibothiadine (PBD; HEC121120) is a novel hepatitis B virus capsid assembly modulator based on GLS4 (morphothiadine) and has inhibitory activities against resistant strains.To assess the overall preclinical drug metabolism and pharmacokinetics (DMPK) properties of PBD, in vivo pharmacokinetics studies in rats and dogs have been performed along with a series of in vitro metabolism assays.The oral bioavailability of PBD in rats and dogs might be related to its medium permeability in Caco-2 cells and largely be impacted by the pH-dependent solubility. In addition, the enhanced liver/plasma exposure ratio could further increase the local exposure around the target. These improved DMPK properties might indicate better development of PBD in the clinical phase."

Journal • PK/PD data • Preclinical • Hepatitis B • Hepatology • Infectious Disease • Inflammation

Physiologically-based pharmacokinetic modeling predicts the drug interaction potential of GLS4 in co-administered with ritonavir. (PubMed, CPT Pharmacometrics Syst Pharmacol) - "Additionally, with the severity of HI increased, there was a corresponding increase in the exposure to GLS4 when co-administered with ritonavir. The GLS4/ritonavir PBPK model can potentially be used as an alternative to clinical studies or guide the design of clinical trial protocols."

Journal • PK/PD data • Hepatitis B • Hepatology • Infectious Disease • Inflammation • CYP3A4

Evaluate the Safety, Tolerability, and Antiviral Activity of GLS4 With Ritonavir in Patients With Chronic HBV Infection (clinicaltrials.gov) - P2 | N=250 | Completed | Sponsor: Sunshine Lake Pharma Co., Ltd. | Recruiting ➔ Completed | Trial completion date: May 2023 ➔ Sep 2023

Combination therapy • Trial completion • Trial completion date • Hepatitis B • Infectious Disease

Discovery of carboxyl-containing heteroaryldihydropyrimidine derivatives as novel HBV capsid assembly modulators with significantly improved metabolic stability. (PubMed, RSC Med Chem) - "The results from biological evaluation demonstrated that compound 6a-25 (EC = 0.020 μM) exhibited greater potency than the positive drug lamivudine (EC = 0.09 μM), and was comparable to the lead compound GLS4 (EC = 0.007 μM)...Preliminary assessment of drug-likeness revealed that 6a-25 exhibited superior water solubility (pH 2.0: 374.81 μg mL; pH 7.0: 6.85 μg mL; pH 7.4: 25.48 μg mL), liver microsomal metabolic stability (t = 108.2 min), and lower hERG toxicity (10 μM inhibition rate was 72.66%) compared to the lead compound GLS4. Overall, compound 6a-25 holds promise for further investigation."

Journal • Hepatitis B • Hepatology • Infectious Disease • Inflammation

Design, Synthesis, and Biological Evaluation of Novel Thioureidobenzamide (TBA) Derivatives as HBV Capsid Assembly Modulators. (PubMed, J Med Chem) - "Moreover, 17i displayed a better inhibitory effect on the assembly of HBV capsid protein compared with NVR 3-778 and a inhibitory effect similar to the clinical drug GLS4. In addition, 17i showed moderate metabolic stability in human microsomes, had excellent oral bioavailability in Sprague-Dawley (SD) rats, and inhibited HBV replication in the HBV carrier mice model, which could be considered as a promising candidate drug for further development."

Journal • Hepatitis B • Hepatology • Infectious Disease • Inflammation

Evaluate the Safety, Tolerability, and Antiviral Activity of GLS4 With Ritonavir in Patients With Chronic HBV Infection (clinicaltrials.gov) - P2 | N=250 | Recruiting | Sponsor: Sunshine Lake Pharma Co., Ltd. | Trial completion date: Oct 2022 ➔ May 2023 | Trial primary completion date: Feb 2022 ➔ May 2023

Combination therapy • Trial completion date • Trial primary completion date • Hepatitis B • Infectious Disease

Development and Clinical Outcome Evaluation of Cascaded AI algorithm for Cancer Detection and Grading in Prostate Cancer (USCAP 2023) - "Of test patients with available RFS information from Center3 (Table 1), quantitative burden of AI-predicted Gleason 4 and Gleason 5 resulted in significant association to RFS (AI-Gls4 HR=1.5[1.1-2.0];p=0.004, AI-Gls5 HR=1.5[1.1-2.1];p=0.021). AI can accurately detect and grade prostate cancer, providing quantitative heterogeneity estimations of grade distribution that may improve prognostication of patients after surgery."

Clinical • Clinical data • Genito-urinary Cancer • Oncology • Prostate Cancer • Solid Tumor

[VIRTUAL] Efficacy and safety of GLS4/ritonavir combined with entecavir in HBeAg-positive patients with chronic hepatitis B: interim results from phase 2b, multi-center study (EASL-ILC-I 2020) - P2 | "Interim results showed that the antiviral efficacy of combination therapy of GLS4/RTV with ETV is remarkably superior to ETV monotherapy, further studies are ongoing to evaluate the safety and efficacy of the combination therapy."

Clinical • P2b data • Dyslipidemia • Hepatitis B • Hepatology • Hypertriglyceridemia • Infectious Disease

[VIRTUAL] Efficacy and safety of GLS4/ritonavir combined with entecavir in HBeAg-positive patients with chronic hepatitis B: interim results from phase 2b, multicentre study (EASL-ILC-I 2020) - P2 | "Interim results showed that the antiviral efficacy of combination therapy of GLS4/RTV with ETV is remarkably superior to ETV monotherapy, further studies are ongoing to evaluate the safety and efficacy of the combination therapy."

Clinical • P2b data • Dyslipidemia • Hepatitis B • Hepatology • Hypertriglyceridemia • Infectious Disease

Computational prediction of susceptibility and resistance for HBV capsid assembly effectors (ACS-Fall 2022) - "The results also suggest that GLP-26 will possess broad anti-HBV activity, more so than GLS4. This study demonstrates the utility of computational resistance prediction in the context of drug discovery, which can be applied to many viral protiens."

Fibrosis • Hepatitis B • Hepatology • Immunology • Infectious Disease • Inflammation • Oncology

HEC121120, a novel allosteric modulator of HBV core protein demonstrates potent antiviral activities in vitro and in vivo (EASL-ILC 2022) - "In PHH isolated from chronically infected humanized liver mouse, 14 days of GLS4 (5 μM) and HEC121120 (2 μM) treatment resulted in suppression of HBV DNA, HBsAg and HBeAg while entecavir (ETV) had no effect on either viral antigen. HEC121120 is a novel class I CAM, which demonstrated improved antiviral properties both in vitro and in vivo, further clinical study will be conducted to evaluate the antiviral potency in CHB patients."

Preclinical • Hepatitis B • Hepatology • Infectious Disease • Inflammation

GST-HG141 inhibits de novo HBV cccDNA formation in cultured primary human hepatocytes (EASL-ILC 2022) - "Treatment with GST-HG141, GLS4, or Entecavir (ETV) started concurrently with infection, or 5 days postinfection. These data demonstrate that GST-HG141 prevents de novo synthesis of cccDNA, but has no effect on the established cccDNA pools in cultured PHH. It acts on different steps of the HBV life cycle, suggesting dual/multiple mechanisms of antiviral action. Further development of GST-HG141 for chronic HBV infections is warranted."

Hepatitis B • Infectious Disease

An automated microfluidic platform for the screening and characterization of novel hepatitis B virus capsid assembly modulators. (PubMed, Anal Methods) - "CAM-A compounds like BAY 41-4109 and GLS4 showed rapid kinetics, with assembly rates above 80% of the core protein after only a 7 second exposure to the compound, whereas CAM-N compounds like ABI-H0731 and JNJ-56136379 showed significantly slower kinetics. With this proof-of-concept study, we believe that this microfluidic system is a robust primary screening tool for HBV CAM drug discovery, especially for the hit finding and hit-to-lead optimization phases. In addition to EC values, this system gives valuable first information about the mode of action of novel CAM screening compounds."

Journal • Hepatitis B • Hepatology • Infectious Disease • Inflammation

Design, synthesis and evaluation of heteroaryldihydropyrimidine analogues bearing spiro ring as hepatitis B virus capsid protein inhibitors. (PubMed, Eur J Med Chem) - "Potent in vitroanti-HBV activity and low cytotoxicity were observed for compound 4r (EC = 0.20 ± 0.00 μM, CC > 87.03 μM), which was more potent than the positive control lamivudine (EC = 0.37 ± 0.04 μM, CC > 100.00 μM) in this assay and was about a quarter as effective as GLS4 (EC = 0.045 ± 0.01 μM, CC > 99.20 μM)...In terms of the physicochemical properties, 4r was predicted to be consistent with the rule-of-five, which means 4r may have favourable absorption and permeation. Finally, ADMET and PK characteristics of 4r and GLS4 were predicted to be comparable in most aspects, implying that the two compounds may have similar profiles in vivo."

Journal • Hepatitis B • Hepatology • Infectious Disease • Inflammation

Design, Synthesis and Evaluation of Novel Heteroaryldihydropyrimidines Derivatives as Non-nucleoside Hepatitis B Virus Inhibitors by Exploring the Solvent-exposed Region. (PubMed, Chem Biol Drug Des) - "Herein, the morpholine ring of GLS4 was replaced with substituted sulfonamides and triazoles to generate novel non-nucleoside HBV inhibitors with desirable potency. In in vitro biological evaluation, several derivatives showed good anti-HBV DNA replication activity compared to lamivudine. In particular, compound II-1 displayed the most potent activity against HBV DNA replication (IC = 0.35 ± 0.04 ?M). The preliminary structure-activity relationships (SARs) of the new compounds were summarized, which may help in discovering more potent anti-HBV agents via rational drug design."

Journal • Hepatitis B • Hepatology • Immunology • Infectious Disease • Inflammation

GLS4/RTV and TAF Drug-drug Interaction (clinicaltrials.gov) - P1; N=28; Completed; Sponsor: Sunshine Lake Pharma Co., Ltd.; Not yet recruiting ➔ Completed

Clinical • Trial completion • Hepatitis B • Hepatology • Infectious Disease • Inflammation