tetano
Editor, Senior Moderator
Infect Dis Ther
. 2024 Sep 15.
doi: 10.1007/s40121-024-01034-w. Online ahead of print. 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[SUP] 1 [/SUP], Constance A Benson[SUP] 2 [/SUP], Cynthia Brinson[SUP] 3 [/SUP], Steven G Deeks[SUP] 4 [/SUP], Edwin DeJesus[SUP] 5 [/SUP], Anthony Mills[SUP] 6 [/SUP], Michael F Para[SUP] 7 [/SUP], Moti N Ramgopal[SUP] 8 [/SUP], Yanhui Cai[SUP] 9 [/SUP], Yanan Zheng[SUP] 9 [/SUP], Liao Zhang[SUP] 9 [/SUP], Wendy Jiang[SUP] 9 [/SUP], Xiaopeng Liu[SUP] 9 [/SUP], Donovan Verrill[SUP] 9 [/SUP], Daina Lim[SUP] 9 [/SUP], Christiaan R de Vries[SUP] 9 [/SUP], Jeffrey J Wallin[SUP] 9 [/SUP], Elena Vendrame[SUP] 9 [/SUP], Devi SenGupta[SUP] 10 [/SUP]
Affiliations
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.
. 2024 Sep 15.
doi: 10.1007/s40121-024-01034-w. Online ahead of print. 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[SUP] 1 [/SUP], Constance A Benson[SUP] 2 [/SUP], Cynthia Brinson[SUP] 3 [/SUP], Steven G Deeks[SUP] 4 [/SUP], Edwin DeJesus[SUP] 5 [/SUP], Anthony Mills[SUP] 6 [/SUP], Michael F Para[SUP] 7 [/SUP], Moti N Ramgopal[SUP] 8 [/SUP], Yanhui Cai[SUP] 9 [/SUP], Yanan Zheng[SUP] 9 [/SUP], Liao Zhang[SUP] 9 [/SUP], Wendy Jiang[SUP] 9 [/SUP], Xiaopeng Liu[SUP] 9 [/SUP], Donovan Verrill[SUP] 9 [/SUP], Daina Lim[SUP] 9 [/SUP], Christiaan R de Vries[SUP] 9 [/SUP], Jeffrey J Wallin[SUP] 9 [/SUP], Elena Vendrame[SUP] 9 [/SUP], Devi SenGupta[SUP] 10 [/SUP]
Affiliations
- PMID: 39278975
- DOI: 10.1007/s40121-024-01034-w
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.