Vesatolimod, a Toll-like Receptor 7 Agonist, Induces Immune Activation in Virally Suppressed Adults Living With Human Immunodeficiency Virus–1

Abstract

Background Treatment with vesatolimod, an investigational oral toll-like receptor 7 (TLR7) agonist, leads to sustained viral remission in some non-human primates when combined with anti-envelope antibodies or therapeutic vaccines. We report results of a phase 1 study evaluating safety, pharmacokinetics, and pharmacodynamics of vesatolimod in adults living with HIV-1. Methods In this double-blind, multicentre, placebo-controlled trial (ClinicalTrials.gov NCT02858401), participants on antiretroviral therapy with screening plasma HIV-1 RNA levels <50 copies/mL were randomized (6:2) to receive 6-10 doses of vesatolimod (1-12 mg) or matching placebo orally every other week in sequential dose escalation cohorts. Primary study objectives included safety and virologic effects of vesatolimod (change from baseline in plasma HIV-1 RNA). Pharmacokinetics and pharmacodynamic/immunologic activity were assessed as secondary objectives. Findings A total of 48 individuals were randomly assigned to vesatolimod (n=36) or placebo (n=12). Vesatolimod was generally well tolerated with no study drug-related serious adverse events or adverse events leading to study discontinuation. There were no statistically significant changes from baseline in plasma HIV-1 RNA in the vesatolimod groups compared to placebo. Vesatolimod plasma exposures increased dose-proportionally; consistent responses in cytokines, interferon-stimulated gene expression, and lymphocyte activation were observed with increasing dose levels above 4 mg. Peak elevations 24 hours post 6 mg dose were >3·9-fold for IP-10, IL-1Ra, and ITAC when compared to baseline values. Interpretation Vesatolimod was well tolerated at doses ranging from 1 to 12 mg. Immune stimulation observed at doses above 4 mg, providing rationale for future combination trials in people with HIV.

Multiply spliced HIV RNA is a predictive measure of virus production ex vivo and in vivo following reversal of HIV latency

“…In a non-human primate model using simian immunodeficiency virus (SIV) or SIV containing an HIV envelope (SHIV), significant increases in plasma SIV RNA were observed following the repeated administration of the TLR-7 agonists GS-986 or GS-9620 in some but not all studies [31À33]. In PLWH on ART, a dose-escalation, placebo-controlled study of the TLR7 agonist Vesatolimod (GS-9620) had no effect on the cell-associated HIV DNA, RNA, or plasma viral load [34]. It is currently unclear what biomarker can predict effective latency reversal in vivo, and which LRAs are able to induce production of HIV proteins and virions from latently infected cells.…”

Activation of the Anti-Oxidative Stress Response Reactivates Latent HIV-1 Through the Mitochondrial Antiviral Signaling Protein Isoform MiniMAVS

“…TLR agonists reactivate latent HIV, increase immune activation and promote antiviral responses [for a review see (8)]. Several TLR agonists, including the TLR3-agonist Poly-ICLC, the TLR7-agonist vesatolimod and the TLR9-agonist MGN1703, have already reached clinical trials for HIV eradication (9)(10)(11)(12). Whether RLR agonists can reactivate latent HIV-1 has not been fully explored.…”

Knowledge From London and Berlin: Finding Threads to a Functional HIV Cure

“…Treatment with MGN1703 increased the activation of plasmacytoid dendritic cells, enhanced activation of cytotoxic NK cells and CD8+ T cells, upregulated cytokine levels, and induced plasma HIV RNA (106). In a multicenter, placebo-controlled, double-blind trial (ClinicalTrials.gov Identifier: NCT02858401), vesatolimod was shown to be well tolerated with no adverse events at doses ranging from 1 to 12 mg; immune stimulation was observed at doses above 4 mg, providing a rationale for future trials in people with HIV (102).…”