Vesatolimod, a Toll-like Receptor 7 Agonist, Induces Immune Activation in Virally Suppressed Adults Living With Human Immunodeficiency Virus-1.
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 Ib study evaluating safety, pharmacokinetics, and pharmacodynamics of vesatolimod in adults living with human immunodeficiency virus (HIV)-1.


METHODS
In this double-blind, multicenter, placebo-controlled trial, 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. The primary study objectives included establishing the safety and virologic effects of vesatolimod (change from baseline in plasma HIV-1 RNA). Pharmacokinetics and pharmacodynamic/immunologic activity were assessed as secondary objectives.


RESULTS
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 drug 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 after receipt of a 6 mg dose were >3.9-fold higher for interferon gamma-induced protein 10 (IP-10), interleukin-1 receptor antagonist (IL-1RA), interferon-inducible T-cell alpha chemoattractant (ITAC) when compared to baseline values.


CONCLUSIONS
Vesatolimod was well tolerated at doses ranging from 1 to 12 mg. Immune stimulation was observed at doses above 4 mg, providing rationale for future combination trials in people living with HIV.


CLINICAL TRIALS REGISTRATION
NCT02858401.
['Riddler|Sharon A|SA|', 'Para|Michael|M|', 'Benson|Constance A|CA|', 'Mills|Anthony|A|', 'Ramgopal|Moti|M|', 'DeJesus|Edwin|E|', 'Brinson|Cynthia|C|', 'Cyktor|Joshua|J|', 'Jacobs|Jana|J|', 'Koontz|Dianna|D|', 'Mellors|John W|JW|', 'Laird|Gregory M|GM|', 'Wrin|Terri|T|', 'Patel|Heena|H|', 'Guo|Susan|S|', 'Wallin|Jeffrey|J|', 'Boice|Jillian|J|', 'Zhang|Liao|L|', 'Humeniuk|Rita|R|', 'Begley|Rebecca|R|', 'German|Polina|P|', 'Graham|Hiba|H|', 'Geleziunas|Romas|R|', 'Brainard|Diana M|DM|', 'SenGupta|Devi|D|']
D000998:Antiviral Agents D004311:Double-Blind Method D015658:HIV Infections D015497:HIV-1 D006801:Humans D011621:Pteridines D051199:Toll-Like Receptor 7
vesatolimod HIV-1 TLR7 agonist immune modulator