A phase I study to evaluate the safety, tolerance and pharmacokinetics of anti-Shiga toxin hyperimmune equine F (ab)₂ fragments in healthy volunteers

Aims: Shiga toxin-producing Escherichia coli-haemolytic uraemic syndrome (STEC-HUS) is considered a toxaemic disorder in which early intervention with neutralizing antibodies may have therapeutic benefits. INM004, composed of F (ab')(2) fragments from equine immunoglobulins, neutralizes Stx1/Stx2, potentially preventing the onset of HUS. 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 C-max values of 45.1 and 77.7 mu g mL(-1) for 2 and 4 mg kg(-1) , respectively. The serum concentration of INM004 declined in a biphasic manner (t(1/2) range 30.7-52.9 h). Systemic exposures increased with each subsequent dose in a dose-proportional manner, exhibiting accumulation. Geometric median C-max and AUC values were 149 and 10 300 mu g 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.