A phase I study to evaluate the safety, tolerance and pharmacokinetics of anti‐Shiga toxin hyperimmune equine F (ab′)2 fragments in healthy volunteers
Yanina Hiriart, Paula Scibona, Augusto Ferraris, Waldo H. Belloso, Valeria Beruto, Facundo Garcia Bournissen, Vanesa Zylberman, Luciana Muñoz, Fernando Goldbaum, Linus Spatz, Mariana Colonna, Santiago Sanguineti, Ventura A. Simonovich- Pharmacology (medical)
- Pharmacology
Aims
Shiga toxin‐producing
Methods
A single‐centre, randomized, phase 1, single‐blind, placebo‐controlled clinical trial to evaluate INM004 safety, tolerance and pharmacokinetics (PK) in healthy adult volunteers, was conducted; in stage I, eight subjects were divided in two cohorts (n = 4) to receive a single INM004 dose of 2 or 4 mg kg−1, or placebo (INM004:placebo ratio of 3:1). In stage II, six subjects received three INM004 doses of 4 mg kg−1 repeated every 24 h, or placebo (INM004:placebo ratio of 5:1).
Results
Eight subjects (57.1%) experienced mild treatment‐emergent adverse events (TEAEs); most frequent were rhinitis, headache and flushing, resolved within 24 h without changes in treatment or additional intervention. No serious AEs were reported. Peak concentrations of INM004 occurred within 2 h after infusion, with median Cmax values of 45.1 and 77.7 μg mL−1 for 2 and 4 mg kg−1, respectively. The serum concentration of INM004 declined in a biphasic manner (t1/2 range 30.7–52.9 h). Systemic exposures increased with each subsequent dose in a dose‐proportional manner, exhibiting accumulation. Geometric median Cmax and AUC values were 149 and 10 300 μg h mL−1, respectively, in the repeated dose regimen. Additionally, samples from subjects that received INM004 at 2 mg kg−1 showed neutralizing capacity against Stx1 and Stx2 in in vitro assays.
Conclusions
The results obtained in this first‐in‐human study support progression into the phase 2 trial in children with HUS.