selgantolimod (GS-9688) / Gilead - LARVOL DELTA

Study of Oral TLR8 Agonist Selgantolimod on HBsAg in Participants With Both Chronic Hepatitis B and HIV (clinicaltrials.gov) - P2 | N=48 | Suspended | Sponsor: National Institute of Allergy and Infectious Diseases (NIAID) | Recruiting ➔ Suspended

Trial suspension • Hepatitis B • Hepatology • Human Immunodeficiency Virus • Infectious Disease • Inflammation • CD4

IMMUNOLOGIC BIOMARKER DYNAMICS IN CHRONIC HEPATITIS B: INSIGHTS FROM A PHASE 2A OPEN-LABEL STUDY ON COMBINATION THERAPIES WITH SMALL INTERFERING RNA, SELGANTOLIMOD, AND NIVOLUMAB (AASLD 2024) - P2 | "Cohort 1 (C1; virally suppressed, received tenofovir alafenamide during study treatment, n = 42) and cohort 2A (C2A; viremic, n = 40) received VIR-2218 (200 mg SQ, every 4 weeks [Q4W]) for 24 weeks (W). A comprehensive biomarker assessment of novel HBV cure combination strategies revealed minimal immunologic changes during/after siRNA lead-in, limited increases in HBV-specific T cell responses, and expected shifts in biomarkers associated with immune modulation. These insights may guide the data-driven design of subsequent combination approaches."

Biomarker • Clinical • Combination therapy • IO biomarker • P2a data • Hepatitis B • Hepatology • Immune Modulation • Immunology • Infectious Disease • Inflammation • CD4 • CD8 • GZMB • IFNG • TLR8

A PHASE 1B, OPEN-LABEL STUDY TO EVALUATE THE SAFETY AND EFFICACY OF NOVEL HEPATITIS B VIRUS COMBINATION THERAPIES IN PATIENTS LIVING WITH CHRONIC HEPATITIS B (AASLD 2024) - "Here we present results from a Phase 1b study that evaluated the following novel agents in combination regimens in patients with CHB: nivolumab (NIVO, anti–programmed death-1 monoclonal antibody); selgantolimod (SLGN; toll-like receptor 8 agonist); and/or GS-4224 (a novel small molecule programmed death ligand-1 inhibitor). Suppression of HBsAg was previously observed in HBV/HCV coinfected patients treated with ledipasvir/sofosbuvir (LDV/SOF)... Novel treatments and combinations for HBV cure in this trial were generally safe and well tolerated; however, only a few patients achieved a ≥0.5 log10 IU/mL decline from BL in HBsAg at FU W8 and no patient experienced HBsAg loss."

Clinical • Combination therapy • P1 data • Anemia • Gastrointestinal Disorder • Hematological Disorders • Hepatitis B • Hepatitis C • Hepatology • Infectious Disease • Inflammation • TLR8

RESULTS FROM A PHASE 2A, OPEN-LABEL STUDY TO EVALUATE THE SAFETY AND EFFICACY OF NOVEL COMBINATION THERAPIES CONTAINING VIR-2218, SELGANTOLIMOD, AND NIVOLUMAB FOR THE TREATMENT OF CHRONIC HEPATITIS B (AASLD 2024) - P2 | "C1 received VIR-2218 (200 mg SQ, every 4 weeks [Q4W]) for 24 weeks (W) with tenofovir alafenamide administered during study treatment. Combinations of VIR-2218, NIVO, and SLGN for HBV cure led to low rates of HBsAg loss in this trial. The use of NIVO was associated with the emergence of irAEs in this CHB patient population."

Clinical • Combination therapy • P2a data • Hepatitis B • Hepatology • Infectious Disease • Inflammation • TLR8

Study of Oral TLR8 Agonist Selgantolimod on HBsAg in Participants With Both Chronic Hepatitis B and HIV (clinicaltrials.gov) - P2 | N=48 | Recruiting | Sponsor: National Institute of Allergy and Infectious Diseases (NIAID) | Trial completion date: Jul 2025 ➔ May 2027 | Trial primary completion date: Jan 2025 ➔ Nov 2026

Trial completion date • Trial primary completion date • Hepatitis B • Hepatology • Human Immunodeficiency Virus • Infectious Disease • Inflammation • CD4

Study to Evaluate the Safety and Efficacy of Selgantolimod (SLGN)-Containing Combination Therapies for the Treatment of Chronic Hepatitis B (CHB) (clinicaltrials.gov) - P2 | N=103 | Completed | Sponsor: Gilead Sciences | Active, not recruiting ➔ Completed

Combination therapy • Trial completion • Hepatitis B • Hepatology • Infectious Disease • Inflammation

Immunomodulation and entry inhibition: selgantolimod's double punch against hepatitis B virus. (PubMed, Gut) - No abstract available

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

Precision-cut liver slices as a pre-clinical model for the evaluation of host-targeting agents against hepatitis B virus and hepatitis delta virus infection (EASL-ILC 2024) - "The impact of HTAs targeting hepatocytes (i.e. Bulevirtide – 1 µM), non-parenchymal immune cells (i.e. Selgantolimod – 1 µM) or multiple populations (i.e. Lonafarnib – 2 µM) was evaluated by the quantification of viral parameters and the production of inflammatory cytokines. Our results represent the first characterization of PCLS as a relevant ex vivo study model of HBV/HDV co-infection. Moreover, the evaluation of HTAs directed against parenchymal and non- parenchymal hepatic cell populations highlights the potential relevance of this system for the pre-clinical study of novel molecules aimed to achieve HBV/HDV cure."

Preclinical • Hepatitis B • Hepatology • Infectious Disease • Inflammation • IL6

TLR8 agonist selgantolimod regulates Kupffer cell differentiation status and impairs HBV entry into hepatocytes via an IL-6-dependent mechanism. (PubMed, Gut) - "Our transcriptomic characterisation of SLGN sheds light into the programmes regulating KC activation. Furthermore, in addition to its previously described effect on established HBV infection and adaptive immunity, we show that SLGN impairs HBV entry. Altogether, SLGN may contribute through KCs to remodelling the intrahepatic immune microenvironment and may thus represent an important component of future combinations to cure HBV infection."

IO biomarker • Journal • Hepatitis B • Hepatology • Infectious Disease • Inflammation • IL6 • S100A12 • TLR8

Crosstalk Between TLR-8 and RLR Enhanced Antiviral Immunity Against Acute HIV-1 and PWH (CROI 2024) - "Immune responses; cytokine levels, type I IFN responses, and co-stimulatory molecules, were assessed.TLR8 agonist GS9688 induced pro-inflammatory cytokines IL6 and IL12...Crosstalk between TLR8 and RLR is disrupted following chronic infection with HIV-1, initiation of ART in the acute phase of infection preserves this crosstalk to a large extent. Our data suggest that HIV-related monocyte dysfunction might underlie this lack of crosstalk, as monocytes respond to this form of TLR8 and RLR stimulation. Differences between treated acute and chronic infection suggest that this phenomenon is more pronounced during chronically treated infection."

Human Immunodeficiency Virus • Infectious Disease • CD4 • CD8 • IL12A • IL6 • TLR8

Safety, pharmacodynamics, and antiviral activity of selgantolimod in viremic patients with chronic hepatitis B virus infection. (PubMed, JHEP Rep) - P2 | "This phase II study (NCT03615066) evaluated the safety, pharmacodynamics, and antiviral activity of selgantolimod (a Toll-like receptor 8 agonist [TLR8]) with tenofovir alafenamide (TAF). These findings suggest a potential differential response to selgantolimod based on patients' baseline HBV-specific immune response, which should be considered in future investigations characterizing the underlying mechanisms of selgantolimod treatment and in HBV cure studies using similar immunomodulatory pathways. NCT03615066 be found at https://www.gileadclinicaltrials.com/transparency-policy/."

Journal • PK/PD data • Fatigue • Hepatitis B • Hepatology • Infectious Disease • Inflammation • Pain • TLR8

Safety and efficacy of the oral TLR8 agonist selgantolimod in individuals with chronic hepatitis B under viral suppression. (PubMed, J Hepatol) - P2 | "Oral selgantolimod up to 3 mg once weekly for 24 weeks was generally safe and well tolerated and led to serologic changes associated with progression to durable cure in two individuals by week 48."

Journal • Gastroenterology • Gastrointestinal Disorder • Hepatitis B • Hepatology • Infectious Disease • Inflammation • Respiratory Diseases • IFNG • IL1R1 • TLR8

Study to Evaluate the Safety and Efficacy of Selgantolimod (SLGN)-Containing Combination Therapies for the Treatment of Chronic Hepatitis B (CHB) (clinicaltrials.gov) - P2 | N=103 | Active, not recruiting | Sponsor: Gilead Sciences | Phase classification: P2a ➔ P2

Phase classification • Hepatitis B • Hepatology • Infectious Disease • Inflammation

PERIPHERAL SINGLE CELL GENE EXPRESSION CHANGES IN RESPONSE TO TOLL-LIKE RECEPTOR 8 AGONIST TREATMENT IN CHRONIC HEPATITIS B PATIENTS (AASLD 2023) - "Background: Selgantolimod (SLGN) is an oral selective small molecule TLR8 agonist with antiviral potential that has been shown to be safe and well-tolerated in individual's with chronic hepatitis B (CHB)... Single cell PBMC analysis from SLGN-treated CHB viremic patients identified substantive changes in gene expression in multiple cell types. These findings provide greater insight into the cellular changes following SLGN treatment, and may inform complementary mechanisms for a HBV cure combination strategy."

Clinical • IO biomarker • Hepatitis B • Hepatology • Infectious Disease • Inflammation • FKBP5 • IL1R1 • MX1 • STAT1 • TLR8

Study of Oral TLR8 Agonist Selgantolimod on HBsAg in Participants With Both Chronic Hepatitis B and HIV (clinicaltrials.gov) - P2 | N=48 | Recruiting | Sponsor: National Institute of Allergy and Infectious Diseases (NIAID) | Trial completion date: Nov 2024 ➔ Jul 2025 | Trial primary completion date: Mar 2024 ➔ Jan 2025

Trial completion date • Trial primary completion date • Hepatitis B • Hepatology • Human Immunodeficiency Virus • Infectious Disease • Inflammation • CD4

The TLR8 agonist Selgantolimod modulates Kupffer cell differentiation status and indirectly impairs HBV entry into hepatocytes via an IL-6-dependent mechanism (EASL-ILC 2023) - "Our results suggest that in addition to its previously described therapeutic antiviral activity in HBV-infected hepatocytes, SLGN also has a prophylactic effect via an IL-6-dependent mechanism. Moreover, our characterization of SLGN sheds light into the general transcriptional programs regulating KC activation and underscores the importance of considering cell states when annotating hepatic cell populations based on scRNA-seq data."

Fibrosis • Gastrointestinal Cancer • Hepatitis B • Hepatocellular Cancer • Hepatology • Immune Modulation • Immunology • Infectious Disease • Oncology • Solid Tumor • EREG • IL6 • S100A12 • TLR8

Preliminary results of a Phase 1b, open-label, multicenter study of selgantolimod (GS-9688) in special populations of patients with chronic hepatitis B (EASL-ILC 2023) - "In these unique populations of CHB, selgantolimod was safe with only 1 severe treatment- related AE. There was a small but consistent HBsAg decline in all cohorts with a trend in HDV RNA decline in the HDV/HBV Cohort. All ALT elevations were <Grade 3, and 1 met AASLD flare criteria."

Clinical • IO biomarker • P1 data • Fibrosis • Gastrointestinal Cancer • Hepatitis B • Hepatocellular Cancer • Hepatology • Infectious Disease • Inflammation • Oncology • Solid Tumor • IL1R1 • TLR8

Transcriptional analysis of HBV infected liver after treatment with selgantolimod reveals longitudinal changes in both inflammation-related pathways and B cell receptor repertoire (EASL-ILC 2023) - "Our data indicate that selgantolimod treatment in CHB patients could drive upregulation of inflammation-associated genes within the liver microenvironment, promoting activation of pro-inflammatory myeloid, B and T lymphocytes. Additionally, subsequent weekly treatment with selgantolimod may drive changes to the B cell compartment to both increase diversity of the immunoglobulin repertoire and enrich specific antibody families that may be specific to HBV."

IO biomarker • Hepatitis B • Hepatology • Inflammation • CD69 • CSF1 • IL6 • LYN • MYD88 • STAT1 • TAP1 • TLR7 • TLR8 • TNFAIP3

The TLR8 agonist Selgantolimod modulates Kupffer cell differentiation status and indirectly impairs HBV entry into hepatocytes via an IL-6-dependent mechanism (EASL-ILC 2023) - "Our results suggest that in addition to its previously described therapeutic antiviral activity in HBV-infected hepatocytes, SLGN also has a prophylactic effect via an IL-6-dependent mechanism. Moreover, our characterization of SLGN sheds light into the general transcriptional programs regulating KC activation and underscores the importance of considering cell states when annotating hepatic cell populations based on scRNA-seq data."

Fibrosis • Gastrointestinal Cancer • Hepatitis B • Hepatocellular Cancer • Hepatology • Immune Modulation • Immunology • Infectious Disease • Oncology • Solid Tumor • EREG • IL6 • S100A12 • TLR8

Study of Oral TLR8 Agonist Selgantolimod on HBsAg in Participants With Both Chronic Hepatitis B and HIV (clinicaltrials.gov) - P2 | N=48 | Recruiting | Sponsor: National Institute of Allergy and Infectious Diseases (NIAID) | Initiation date: Dec 2022 ➔ Mar 2023

Trial initiation date • Hepatitis B • Hepatology • Human Immunodeficiency Virus • Infectious Disease • Inflammation • CD4

Study of Oral TLR8 Agonist Selgantolimod on HBsAg in Participants With Both Chronic Hepatitis B and HIV (clinicaltrials.gov) - P2 | N=48 | Recruiting | Sponsor: National Institute of Allergy and Infectious Diseases (NIAID) | Not yet recruiting ➔ Recruiting

Enrollment open • Hepatitis B • Hepatology • Human Immunodeficiency Virus • Infectious Disease • Inflammation • CD4

Study to Evaluate the Safety and Efficacy of Selgantolimod (SLGN)-Containing Combination Therapies for the Treatment of Chronic Hepatitis B (CHB) (clinicaltrials.gov) - P2a | N=103 | Active, not recruiting | Sponsor: Gilead Sciences | Recruiting ➔ Active, not recruiting | Trial completion date: Apr 2024 ➔ Jul 2024 | Trial primary completion date: Oct 2023 ➔ Jan 2024

Combination therapy • Enrollment closed • Trial completion date • Trial primary completion date • Hepatitis B • Hepatology • Infectious Disease • Inflammation

Safety and Efficacy of Oral TLR8 Agonist, Selgantolimod, in Viremic Adult Patients With Chronic Hepatitis B (ACG 2022) - " In this multicenter, double-blind, phase 2 study, viremic CHB patients were randomized (2:2:1) to SLGN 3 mg, 1.5 mg, and placebo (PBO) once a week for 24 weeks in combination with tenofovir alafenamide. 67 patients (39 HBeAg-positive) were randomized. Baseline characteristics were similar across groups: majority were Asian (98.5%), male (58%) with a median (IQR) age of 47 (35–54) years, HBsAg level of 4.1 (3.5–4.7) log10IU/ml, and HBV DNA level of 7.5 (5.4–8.3) log10IU/ml. No patients achieved the primary end point of ≥1 log10IU/ml decline in HBsAg levels at week 24; however, 3 (6%) patients in the SLGN-treated achieved HBsAg decline ≥0.5 log10IU/ml compared to none in the placebo group."

Clinical • IO biomarker • Fatigue • Hepatitis B • Hepatology • Immune Modulation • Infectious Disease • Inflammation • Pain • IL1R1 • TLR8

Study of Oral TLR8 Agonist Selgantolimod on HBsAg in Participants With Both Chronic Hepatitis B and HIV (clinicaltrials.gov) - P2 | N=48 | Not yet recruiting | Sponsor: National Institute of Allergy and Infectious Diseases (NIAID)

New P2 trial • Hepatitis B • Hepatology • Human Immunodeficiency Virus • Infectious Disease • Inflammation • CD4

Toward a cure for chronic hepatitis B: The development of Selgantolimod (GS-9688) (ACS-Sp 2022) - "Selgantolimod (GS 9688) is a small molecule API in development at Gilead Sciences for the treatment and cure of chronic hepatitis B. Selgantolimod is a selective, potent and orally active small molecule toll like receptor 8 (TLR8) agonist that has been shown to inhibit hepatitis B virus in primary human hepatocytes and to activate antiviral functions of human immune cells. This talk will focus on the development of phase appropriate routes to Selgantolimod, with an emphasis on how the potent compound categorization of Selgantolimod (OEL of 30 ng/m3 to 500 ng/m3) necessitated synthetic innovation and inspired strategic bond disconnections for early and late stage enabling deliveries."

Hepatitis B • Hepatology • Infectious Disease • Inflammation • TLR8