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

Abstract

AimsShiga 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.MethodsA 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).ResultsEight 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.ConclusionsThe results obtained in this first‐in‐human study support progression into the phase 2 trial in children with HUS.