vesatolimod (GS-9620) / Gilead - LARVOL DELTA

Synergizing expertise: lessons learned from conducting the first HIV cure interventional trial in Africa with collaboration between academia, government, and industry (IAS-HIV 2025) - P2 | "Participants received 2 broadly neutralizing antibodies (bNAbs; VRC07-523LS and CAP256V2LS) and a Toll-like receptor 7 agonist, vesatolimod (VES), and underwent ATI for up to 55 weeks or until meeting antiretroviral therapy (ART) restart criteria. It is critical to consider context and have a concrete plan for monitoring participants who remain off ART after study conclusion. This trial was a culmination of a productive partnership between academia, government, and industry, and demonstrated the feasibility of conducting complex HIV cure trials in Africa, where the most stand to benefit from these interventions."

Human Immunodeficiency Virus • Infectious Disease • Novel Coronavirus Disease

Psychological impact of analytical treatment interruption on young women enrolled in an HIV cure-related trial in Durban, South Africa (IAS-HIV 2025) - "For the first time, this study assessed mental health among young women during an ATI-inclusive HIV cure-related trial testing a combination of two broadly neutralizing antibodies, VRC07-523-LS and CAP256V2LS, with a toll-like receptor 7 agonist (Vesatolimod) in Durban, South Africa. Twenty women (23–32 years old) participating in an ATI-inclusive trial were co-enrolled in a socio-behavioral study. ATI was well-tolerated psychologically among young women enrolled in ATI-inclusive HIV cure trial in South Africa. Sustained or improved decisional certainty, self-esteem, and resilience were observed during participation, while increased anxiety and depression were associated with prolonged-ATI (late ART restart). Findings support the inclusion of young women in ATI-inclusive trials but highlight the need for mental health assessments and directed psychosocial support, especially for trials that include prolonged ATIs."

Clinical • Late-breaking abstract • CNS Disorders • Depression • Human Immunodeficiency Virus • Infectious Disease • Mood Disorders • Psychiatry

Vesatolimod pharmacodynamic responses in a trial of vesatolimod and broadly neutralizing antibodies in early-treated South African women with clade C HIV-1 (IAS-HIV 2025) - P2 | "We investigated VES pharmacodynamic responses and associations with analytical treatment interruption (ATI) outcomes in an open-label study of VES combined with 2 broadly neutralizing antibodies (bNAbs), VRC07-523LS and CAP256V2LS, in virologically suppressed (VS) women with clade C HIV-1 (NCT05281510). This study enrolled 20 acutely treated VS Black women (age =18 years, antiretroviral therapy [ART] for =12 months) from the Females Rising through Education, Support, and Health (FRESH) cohort in South Africa. VES induced consistent upregulation of ISGs in Black female participants in this small study, suggesting a similar pharmacodynamic effect in this population, compared with previously studied populations."

Clinical • IO biomarker • PK/PD data • Human Immunodeficiency Virus • Infectious Disease • CCL19 • CCL8 • CD4 • IL1R1 • MX1

Safety and Analytical Treatment Interruption Outcomes in a Clinical Trial of 2 Broadly Neutralizing Antibodies Plus Vesatolimod in Early-Treated South African Women With Clade C HIV-1 (EACS 2025) - No abstract available

Clinical • Human Immunodeficiency Virus • Infectious Disease

Evaluation of Safety, Immunogenicity and Efficacy of a Triple Immune Regimen in Adults Initiated on ART During Acute HIV-1 (clinicaltrials.gov) - P1/2 | N=45 | Recruiting | Sponsor: National Institute of Allergy and Infectious Diseases (NIAID) | Suspended ➔ Recruiting

Enrollment open • Human Immunodeficiency Virus • Infectious Disease • CD4

Transcriptomics of proviral latency reversal in reservoirs of youth with perinatal HIV-1 (IMMUNOLOGY 2025) - "Combined GS-9620+SAHA treatment uniquely activated TNFα, interferon, and estrogen pathways. These findings reveal that HIV-1 reservoirs in perinatal infections are susceptible to reactivation through LRAs, mediated by IFNs, TGF-β, TNFα, and IL-2, providing insights into latency reversal mechanisms in AdWPH.Keywords: Animals Human; Cells T Cells; Infections AIDS; Processes Cell Activation Inflammation"

Human Immunodeficiency Virus • Infectious Disease • Inflammation • CD4 • CD69 • IFNA1 • IFNG • IL2 • IL2RA • IL6 • TGFB1 • TNFA

Biological sex and age influence GS-9620 activity ex vivo. (PubMed, JCI Insight) - "In conclusion, biological sex and age, but not sex hormones, influence GS-9620-mediated immune activation. Understanding these factors will help design and evaluate future clinical trials using GS-9620 for an HIV cure."

Journal • Preclinical • Human Immunodeficiency Virus • Infectious Disease • CD4 • CD8 • IFNG • IL12A

Evaluation of Safety, Immunogenicity and Efficacy of a Triple Immune Regimen in Adults Initiated on ART During Acute HIV-1 (clinicaltrials.gov) - P1/2 | N=45 | Suspended | Sponsor: National Institute of Allergy and Infectious Diseases (NIAID) | Recruiting ➔ Suspended

Trial suspension • Human Immunodeficiency Virus • Infectious Disease • CD4

Transcriptomics of Proviral Latency Reversal in Reservoirs of Youth With Perinatal HIV-1 (CROI 2025) - "High GS-9620+SAHA responders had upregulated TNFα, interferon and estrogen responses (Table 1). Conclusions HIV-1 reservoirs in perinatal infections are susceptible to reactivation with TLR7 agonists and HDAC inhibitors through upregulation of pro-inflammatory pathways mediated by IFNs, TGF- β, TNFα and IL-2, offering insights into proviral reactivation and control for AdLWPH."

Human Immunodeficiency Virus • Infectious Disease • CD4 • CD69 • IFNA1 • IFNG • IL2 • IL2RA • TGFB1 • TNFA

Evaluation of 2 bNAbs Plus Vesatolimod in Early-Treated South African Women With HIV-1 During ATI (CROI 2025) - P2 | "Background Antiretroviral therapy (ART) can reduce morbidity and mortality but does not eradicate HIV. VES, VRC07-523LS, and CAP256V2LS were safe and well tolerated in acutely treated South African women. Potential mechanisms for the variable patterns of virologic control observed in this novel study are under investigation."

Clinical • Human Immunodeficiency Virus • Infectious Disease • Inflammation • CD4

Safety, immunogenicity and effect on viral rebound of HTI vaccines combined with a TLR7 agonist in early-treated HIV-1 infection: a randomized, placebo-controlled phase 2a trial. (PubMed, Nat Commun) - P2a | "Building on results from the AELIX-002 trial with HIVACAT T-cell immunogen (HTI)-based vaccines, the AELIX-003 (NCT04364035) trial tested the safety of the combination of ChAdOx1.HTI (C) and MVA.HTI (M), with the TLR7 agonist vesatolimod (VES), in a double-blind, placebo-controlled, randomized clinical trial in 50 virally suppressed early-treated men with HIV-1 infection. Post hoc analysis confirmed a correlation between levels of HTI-specific T cells and prolonged time off antiretroviral therapy. The combination of HTI vaccines and VES was safe and elicited robust T-cell responses."

Clinical • Journal • P2a data • Fatigue • Human Immunodeficiency Virus • Infectious Disease • Influenza • Pain • Respiratory Diseases

Evaluation of Safety, Immunogenicity and Efficacy of a Triple Immune Regimen in Adults Initiated on ART During Acute HIV-1 (clinicaltrials.gov) - P1/2 | N=45 | Recruiting | Sponsor: National Institute of Allergy and Infectious Diseases (NIAID) | Trial completion date: Apr 2026 ➔ Aug 2029 | Trial primary completion date: Apr 2026 ➔ Apr 2028

Trial completion date • Trial primary completion date • Human Immunodeficiency Virus • Infectious Disease • CD4

Study of VRC07-523LS, CAP256V2LS, and Vesatolimod, in Early Antiretroviral-treated HIV-1 Clade C-infected Women (clinicaltrials.gov) - P2 | N=20 | Completed | Sponsor: Gilead Sciences | Active, not recruiting ➔ Completed

Trial completion • Human Immunodeficiency Virus • Infectious Disease

SHIV remission in macaques with early treatment initiation and ultra long-lasting antiviral activity. (PubMed, Nat Commun) - "Here we treat macaques infected with RT-SHIV with oral emtricitabine/tenofovir alafenamide and long-acting cabotegravir/rilpivirine without (n = 4) or with (n = 4) the immune activator vesatolimod after the initial onset of viremia. We show efficient multidrug penetration in virus reservoirs and persisting rilpivirine in plasma for 2 years after the last dose. Our results document a type of virus remission that is achieved through early treatment initiation and provision of ultra long-lasting antiviral activity that persists after treatment cessation."

Journal • Human Immunodeficiency Virus • Infectious Disease • CD8

Unveiling shared therapeutic targets and pathological pathways between coronary artery disease and major depressive disorder through bioinformatics analysis. (PubMed, Sci Rep) - "The drug candidate GS-9620 was identified as a potential protective agent against both disorders. In conclusion, CDC42, NDUFB3, and TXN held potential as molecular biomarkers and therapeutic targets for the simultaneous treatment of CAD and MDD."

Journal • Cardiovascular • CNS Disorders • Coronary Artery Disease • Depression • Herpes Simplex • Infectious Disease • Major Depressive Disorder • Mood Disorders • Psychiatry • CDC42

The combination of the toll-like receptor agonist vesatolimod together with the HDAC inhibitor romidepsin as a new option in colorectal cancer (DGHO 2024) - "Combinational treatment of HDACi and TLR7/8a has demonstrated significant activity in preclinical studies, which warrants further clinical phase 1 testing."

IO biomarker • Colorectal Cancer • Gastrointestinal Cancer • Oncology • Solid Tumor

A Pooled Analysis of Eight Clinical Studies Suggests a Link Between Influenza-Like Symptoms and Pharmacodynamics of the Toll-Like Receptor-7 Agonist Vesatolimod. (PubMed, Infect Dis Ther) - "Flu-like AEIs associated with vesatolimod administration were typically mild but increased with exposure, which may be predicted by the response to initial doses. The data suggest that adaptive clinical monitoring could help maximize pharmacodynamic responses and balance adverse events in future clinical trials of vesatolimod."

IO biomarker • Journal • PK/PD data • Retrospective data • Human Immunodeficiency Virus • Infectious Disease • Inflammation • Influenza • Respiratory Diseases • IFNG • OAS1

Circulating immune and plasma biomarkers of time to HIV rebound in HIV controllers treated with vesatolimod. (PubMed, Front Immunol) - "Notable differences were observed between HIV controllers vs. non-controllers in some specific markers. For the first time, exploratory biomarkers of ATI viral outcomes in HIV-controllers were investigated but require further validation."

Biomarker • Clinical • Journal • Human Immunodeficiency Virus • Infectious Disease • Inflammation • CD69 • CD8

HIV rebound in HIV controllers is associated with a specific fecal microbiome profile. (PubMed, Eur J Immunol) - P1b | "Specific types of fecal microbiome abundance (e.g. Alistipes putredinis) positively correlated with HIV rebound. In conclusion, variability in the composition of the fecal microbiome is associated with markers of immune activation following vesatolimod treatment and ART interruption."

Journal • Human Immunodeficiency Virus • Infectious Disease

Pharmacological activation of TLR7 exerts inhibition on the replication of EV-D68 in respiratory cells. (PubMed, J Virol) - "Subsequently, we investigated the impact of Vesatolimod (GS-9620), a Toll-like receptor 7 agonist, on EV-D68 replication...Notably, our findings demonstrate that pharmacological activation of TLR7 effectively suppresses EV-D68 replication in respiratory tract cells through a TLR7/MyD88-dependent mechanism. This study not only presents a promising drug candidate and target against EV-D68 dissemination but also highlights the potential to exploit unique alterations in cellular innate immune responses induced by viral infections, selectively inducing a defensive state in infected cells while safeguarding uninfected normal cells from potential adverse effects associated with therapeutic interventions."

IO biomarker • Journal • CNS Disorders • Infectious Disease • Respiratory Diseases • MYD88 • TLR7

Quantitative and Qualitative Distinctions between HIV-1 and SIV Reservoirs: Implications for HIV-1 Cure-Related Studies. (PubMed, Viruses) - "Because these are experimental variables dictated by the investigator, we offer guidance on study design for cure-related studies performed in the NHP model. Finally, we highlight the case of GS-9620 (Vesatolimod), an antiviral TLR7 agonist tested in multiple independent pre-clinical studies in which virological outcomes may have been influenced by study-related variables."

Journal • Review • Human Immunodeficiency Virus • Infectious Disease

Differential susceptibility of cells infected with defective and intact HIV proviruses to killing by obatoclax and other small molecules. (PubMed, AIDS) - "Obatoclax and other Bcl-2 inhibitors deserve further study in combination therapies aimed at reducing the intact HIV reservoir in order to achieve a functional cure and/or reduce HIV-associated immune activation."

Journal • Human Immunodeficiency Virus • Infectious Disease • IFNG

Evaluation of Safety, Immunogenicity and Efficacy of a Triple Immune Regimen in Adults Initiated on ART During Acute HIV-1 (clinicaltrials.gov) - P1/2 | N=45 | Recruiting | Sponsor: National Institute of Allergy and Infectious Diseases (NIAID) | Not yet recruiting ➔ Recruiting

Enrollment open • Human Immunodeficiency Virus • Infectious Disease • CD4

Type I IFN Signaling and Regulation in Vesatolimod-Treated Virally Suppressed Adults With HIV-1 (CROI 2024) - P1b | "Whole blood transcriptome analysis identified pronounced differences in gene expression based on VES dose and administration order. The results suggest that a cumulative effect of multiple VES doses could modulate VES pharmacodynamic response, which should be taken into account in future combination studies with VES."

Clinical • IO biomarker • Human Immunodeficiency Virus • Infectious Disease

Latency Reversal Effects of TLR7 Agonist and HDACi in Long-Standing Perinatal HIV-1 Infection (CROI 2024) - "These findings suggest that pediatric reservoirs can be reactivated with innate immune enhancers, such as TLR7 agonist and HDACi, with implications for use as therapeutics to purge HIV-1 reservoirs."

Human Immunodeficiency Virus • Infectious Disease • Pediatrics • CD4 • CD69 • IL2RA • IL6