vesatolimod (GS-9620) / Gilead - LARVOL DELTA

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=36 | Suspended | Sponsor: National Institute of Allergy and Infectious Diseases (NIAID) | Recruiting ➔ Suspended

Trial suspension • Human Immunodeficiency Virus • Infectious Disease • CD4

GS-9620 alleviates psoriasis-like inflammation by regulating autophagy in keratinocytes. (PubMed, Animal Model Exp Med) - "GS-9620 alleviates psoriasis by enhancing autophagy and dampening NLRP3-mediated inflammation, offering a promising therapeutic avenue."

Journal • Dermatology • Immunology • Inflammation • Psoriasis • CD4 • HMGB1 • IL17A • IL18 • IL1B • IL6 • NLRP3 • TNFA

Development of a novel TLR-7 agonist SA-5 as a therapeutic option for chronic hepatitis B: a multimodal biomarker scoring for safety and efficacy in the first-in-human study (EASL 2026) - "SA-5 had comparable immunostimulatory activity to GS9620 but with reduced adverse biomarker shifts. SA-5 is a safer, next-generation TLR-7 agonist for chronic HBV infection, highlighting the importance of integrated biomarker profiling in preclinical immunomodulatory anti-HBV drug development."

Biomarker • Clinical • First-in-human • P1 data • Hepatitis B • Hepatitis C • Hepatology • Infectious Disease • Inflammation • CD8

Persistent immune dysfunction during suppressive antiretroviral therapy: implications for analytical treatment interruption trials for chronic HIV infections in sub-Saharan Africa. (PubMed, Front Immunol) - "Similarly, adjunct therapies with TLR7 agonists, such as vesatolimod, could potentially increase cytotoxic capabilities of dendritic and natural killer cells to improve HIV latency reversal and viral clearance during ART. Innovative combination immunotherapies to avert persistent immune dysfunction, such as therapeutic vaccines, combination bNabs, enhancer of zeste homolog 2 (EZH2) inhibitors to boost CD8+ T-cell function and augment post-ART viral control, and latency reversal agents to increase cytotoxicity potential of dendritic cell and natural killer cells, among others, could potentially optimize HIV-specific CD8 T-cell cytotoxicity and viral clearance, and delay viral rebound during ATI trials in SSA."

Journal • Review • Human Immunodeficiency Virus • Infectious Disease • Inflammation • CD4 • CD8

Rational Design and Identification of Highly Selective TLR8 Agonists as Potent HIV-1 Latency Reversal Agents. (PubMed, J Med Chem) - P2 | "Notably, compound 23a exhibits potent reactivation of latent HIV-1 reservoirs in both infected cell lines and primary PBMCs from HAART-treated patients, demonstrating superior efficacy compared to the TLR7 agonist GS-9620 (NCT05281510). Additionally, 23a (SV-128) effectively activated innate cytolytic effectors, including natural killer (NK) cells, which targeted HIV-infected CD4+ T cells. These findings demonstrate the promising therapeutic potential of TLR8 agonists for HIV-1 eradication, combining both "shock" (latency reversal) and "kill" (immune-mediated clearance) mechanisms."

Journal • Human Immunodeficiency Virus • Infectious Disease • CD4 • TLR8

Predictors of virological outcomes after analytical interruption of antiretroviral therapy and HTI vaccination in early treated people with HIV-1._. (PubMed, Commun Med (Lond)) - "These findings confirm that HTI-specific T-cell magnitude at ATI initiation is the strongest predictor of ATI outcomes observed in AELIX002/003 studies and that a threshold of vaccine-induced HTI-specific T-cell responses can be used as futility criteria before ATI and/or guide participant selection in future HTI-based HIV cure trials aimed at achieving therapy-free remission."

Clinical • Journal • Human Immunodeficiency Virus • Infectious Disease

Preclinical assessment of oral TLR7 agonist SA-5 in a non-human primate model. (PubMed, JCI Insight) - "SA-5 had comparable immunostimulatory activity to GS-9620 but with reduced adverse biomarker shifts. In aged macaques, efficacy was maintained with modestly increased safety responses. These findings support SA-5 as a safer next-generation TLR7 agonist effective across age groups, highlighting integrated biomarker profiling in preclinical immunomodulatory drug development."

IO biomarker • Journal • Preclinical • Hematological Disorders • Hepatology • Infectious Disease • Oncology • IFNA1

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) - P2 | "Method : Twenty women living with HIV who initiated antiretroviral therapy (ART) during the hyperacute infection phase (suppressed viremia <50 copies/mL and CD4 + T-cell counts ≥500 cells/μL at enrollment) were treated with a biweekly regimen of VES (up to 10 doses) and 2 bNAbs, CAP256V2LS and VRC07-523LS, infused 1 week after the first VES dose. Conclusions : Overall, the combination of bNAbs and VES was generally safe, and safety was comparable across 3 viral control groups, suggesting the potential of an HIV cure regimen with a favorable benefit-risk profile. However, conclusions are limited given the low participant numbers and lack of placebo arm."

Clinical • Human Immunodeficiency Virus • Infectious Disease • CD4

Neuroprotective Effects of Vesatolimod in EAE: Modulating Immune Balance and Microglial Polarization. (PubMed, Int J Mol Sci) - "Proteomic profiling further revealed the downregulation of inflammation-related proteins, specifically those associated with TNF, IL-17, and NOD-like receptor signaling pathways. Collectively, these findings demonstrate that VES alleviates neuroinflammation in EAE through multimodal mechanisms-including peripheral and central immune regulation, BBB protection, and activation of endogenous antioxidant defenses-supporting its further development as a promising therapeutic candidate for MS."

IO biomarker • Journal • CNS Disorders • Immunology • Inflammation • Multiple Sclerosis • Solid Tumor • IL17A

Investigation of synergistic effects of β-defensin, vesatolimod and resiquimod in increasing the potency of a therapeutic HIV-1 vaccine candidate. (PubMed, J Pharm Sci) - "It was interesting that no significant differences in TNF-α and Granzyme B secretion were observed between groups receiving β-defensin-Nefmut-Tat protein + GS-9620 and β-defensin-Nefmut-Tat protein + R848; although group receiving β-defensin-Nefmut-Tat protein + R848 could significantly induce IFN-γ secretion in uninfected and infected splenocytes compared to group receiving β-defensin-Nefmut-Tat protein + GS-9620. These findings demonstrated that the simultaneous use of TLR 4, 7 and 8 agonists could improve and maintain cellular immunity against SCR HIV-1 infection suggesting an effective approach for eradication of latent HIV reservoir."

Journal • Human Immunodeficiency Virus • Infectious Disease • GZMB • IFNG • TLR4 • TNFA

The TLR7 agonist vesatolimod does not measurably induce SIV expression in macaques receiving combination antiretroviral therapy initiated during chronic infection. (PubMed, Antimicrob Agents Chemother) - "Although VES treatment induced expected transient increases in interferon-stimulated gene expression and immune cell phenotypic changes, it did not lead to measurable PVL increases in peripheral or hepatic portal vein blood using a highly sensitive PVL assay or increases in cell-associated vRNA:vDNA ratios, nor to measurable reductions in vDNA in blood or tissues. These results align with recent clinical data and confirm that TLR7 agonist treatment does not reliably induce significant virus expression in vivo."

Journal • Human Immunodeficiency Virus • Infectious Disease • IGFBP7

The Effects of Cobicistat and Voriconazole on the Safety, Pharmacokinetics, and Pharmacodynamics of the TLR7 Agonist Vesatolimod in People with HIV. (PubMed, Infect Dis Ther) - P1 | "VES was well tolerated when administered alone or in combination with COBI or VOR in PWH. Coadministration of COBI, but not VOR, increased plasma VES concentrations, suggesting that inhibition of transporters (P-gp and/or BCRP) may have a greater impact on VES PK than inhibition of the drug-metabolizing enzyme (CYP3A)."

IO biomarker • Journal • PK/PD data • Breast Cancer • Human Immunodeficiency Virus • Infectious Disease • Oncology • Solid Tumor

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

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

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