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. 2024 Nov;13(11):2285-2299.
doi: 10.1007/s40121-024-01034-w. Epub 2024 Sep 15.

A Pooled Analysis of Eight Clinical Studies Suggests a Link Between Influenza-Like Symptoms and Pharmacodynamics of the Toll-Like Receptor-7 Agonist Vesatolimod

Sharon A Riddler  1 , Constance A Benson  2 , Cynthia Brinson  3 , Steven G Deeks  4 , Edwin DeJesus  5 , Anthony Mills  6 , Michael F Para  7 , Moti N Ramgopal  8 , Yanhui Cai  9 , Yanan Zheng  9 , Liao Zhang  9 , Wendy Jiang  9 , Xiaopeng Liu  9 , Donovan Verrill  9 , Daina Lim  9 , Christiaan R de Vries  9 , Jeffrey J Wallin  9 , Elena Vendrame  9 , Devi SenGupta  10
Affiliations

A Pooled Analysis of Eight Clinical Studies Suggests a Link Between Influenza-Like Symptoms and Pharmacodynamics of the Toll-Like Receptor-7 Agonist Vesatolimod

Sharon A Riddler et al. Infect Dis Ther. 2024 Nov.

Abstract

Introduction: Vesatolimod is a Toll-like receptor-7 (TLR7) agonist in clinical development as part of a combination regimen for human immunodeficiency virus (HIV) cure. Influenza-like symptoms associated with TLR7-mediated immune activation have been reported in clinical trials of vesatolimod. Therefore, a broader understanding of the safety profile of vesatolimod and association with dose and mechanism of action will help inform future clinical studies.

Methods: In this analysis, data on flu-like adverse events of interest (AEIs) were pooled from eight clinical studies in which 606 participants either received single or multiple doses of vesatolimod (0.3-12 mg; n = 505) or placebo (n = 101). Vesatolimod pharmacokinetics, inflammatory responses, and pharmacodynamics were assessed.

Results: The incidence of flu-like AEIs was higher with vesatolimod versus placebo (19% [96/505] vs. 8% [8/101]) and increased with vesatolimod dose and exposure. Most flu-like AEIs with vesatolimod were grade 1 or 2 severity (55% [53 of 96] grade 1; 35% [34 of 96] grade 2) with onset primarily after the first and second dose. Occurrence of flu-like AEIs after doses 1-3 was predictive of reoccurrence after later doses. Dose-dependent elevations of pharmacodynamic biomarkers (interferon-stimulated gene 15, 2'-5'-oligoadenylate synthetase 1, myxovirus resistance-1, interferon-α, interleukin-1 receptor antagonist, interferon-γ-induced protein 10, interferon-inducible T-cell-α chemoattractant) observed in participants with flu-like AEIs suggest a link with vesatolimod mechanism of action.

Conclusions: 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.

Keywords: Influenza-like adverse events; Safety; Toll-like receptor-7 agonist; Vesatolimod.

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Conflict of interest statement

Sharon A. Riddler reports grants from Gilead and NIH/NIAID during the conduct of the study, as well as a grant from Merck outside the submitted work. Constance A. Benson reports grants from Gilead and NIH/NIAID during the conduct of the study and honoraria for educational lectures and personal fees for meeting travel from the IAS-USA, and has held leadership positions on the IAS-USA Board and the CROI Foundation Board. Cynthia Brinson is on the Speaker’s Bureau for Gilead and reports personal fees from Gilead for meeting travel. Steven G. Deeks reports grants from Gilead, consulting fees from AbbVie, GlaxoSmithKline, Hookipa, and Immunocore, and stock or stock options in BryoLogyx, Enochian BioSciences, and Trendel. Anthony Mills and Michael F. Para declare no competing interests. Edwin DeJesus reports grants and speaker and/or advisory fees from Gilead, Janssen, Abbott, Bristol Myers Squibb, Boehringer Ingelheim, GlaxoSmithKline, Merck, Sangamo, TaiMed, Theraco Technologies, Vertex and ViiV Healthcare, both during the conduct of the study and outside the submitted work. Moti N. Ramgopal reports consulting fees and/or honoraria from Gilead, AbbVie, Janssen, ViiV Healthcare, and Merck. Yanhui Cai, Yanan Zheng, Liao Zhang, Wendy Jiang, Xiaopeng Liu, Donovan Verrill, Daina Lim, Christiaan R. de Vries, Jeffrey J. Wallin, Elena Vendrame, and Devi SenGupta are employees and shareholders of Gilead.

Figures

Fig. 1
Fig. 1
Incidence of influenza-like adverse events of interest stratified by vesatolimod dose number and time of onset. A Percentages of flu-like AEI in all participants who received VES across all eight studies according to VES dose number. B Percentages of flu-like AEI according to time of onset of flu-like AEIs after first VES dose. Percentages were calculated based on the total number of flu-like AEIs (N = 53). AEI adverse events of interest, flu-like AEIs influenza-like adverse events of interest, VES vesatolimod
Fig. 2
Fig. 2
Incidence of influenza-like adverse events of interest by vesatolimod exposure. A, B Distribution of VES AUCinf and Cmax by VES dose level administered in fasted state or with empty stomach to participants with pharmacokinetic measurements across eight clinical studies. Dots represent individual data; boxes represent 25th to 75th percentiles; whiskers represent 1.5 times the interquartile range not exceeding the minimum/maximum values. Participants who experienced flu-like AEIs are highlighted in red dots. C, D Percentages of participants with flu-like AEIs are plotted by quartiles of VES AUCinf and Cmax in all participants with pharmacokinetic measurements across eight clinical studies. Error bars represent standard errors. Rates of flu-like AEIs were plotted against mean AUCinf and Cmax in each quartile. In all panels, dashed line indicates range of AUCinf or Cmax within each quartile (Q1, first quartile; Q2, second quartile; Q3, third quartile; Q4, fourth quartile). AUCinf area under the concentration–time curve to infinity after a single dose, Cmax maximal concentration, flu-like AEIs influenza-like adverse events of interest, Q quartile, VES vesatolimod
Fig. 3
Fig. 3
Changes in pharmacodynamic biomarkers 24 h after first dose administration in participants with and without influenza-like adverse events of interest. Fold changes from baseline 24 h after first dose for VES pharmacodynamic biomarkers from all eight VES studies are summarized by VES dose. Participants who presented with flu-like AEIs are highlighted in red dots. AEI adverse events of interest, flu-like AEIs influenza-like adverse events of interest, IFNα interferon-α, IL-1RA interleukin-1 receptor antagonist, IP-10 interferon-γ-induced protein 10 kDa, ISG15 interferon-stimulated gene 15, ITAC interferon-inducible T-cell-α chemoattractant, MX1 myxovirus resistance-1, OAS1 2′-5′-oligoadenylate synthetase 1, VES vesatolimod
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