A Pooled Analysis of Eight Clinical Studies Suggests a Link Between Influenza-Like Symptoms and Pharmacodynamics of the Toll-Like Receptor-7 Agonist Vesatolimod.
Influenza-like adverse events
Safety
Toll-like receptor-7 agonist
Vesatolimod
Journal
Infectious diseases and therapy
ISSN: 2193-8229
Titre abrégé: Infect Dis Ther
Pays: New Zealand
ID NLM: 101634499
Informations de publication
Date de publication:
15 Sep 2024
15 Sep 2024
Historique:
received:
12
07
2024
accepted:
15
08
2024
medline:
16
9
2024
pubmed:
16
9
2024
entrez:
15
9
2024
Statut:
aheadofprint
Résumé
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. 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. 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. 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.
Identifiants
pubmed: 39278975
doi: 10.1007/s40121-024-01034-w
pii: 10.1007/s40121-024-01034-w
doi:
Types de publication
Journal Article
Langues
eng
Informations de copyright
© 2024. The Author(s).
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