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A Phase I study to evaluate the safety, tolerance and pharmacokinetics of anti-Shiga toxin hyperimmune equine F(ab’)2 fragments in healthy volunteers
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  • yanina Hiriart,
  • Paula Scibona,
  • Augusto Ferraris,
  • Waldo Belloso,
  • Valeria Beruto,
  • Facundo Garcia-Bournissen,
  • Vanesa Zylberman,
  • Luciana Muñoz,
  • Fernando Goldbaum,
  • Linus Spatz,
  • Mariana Colonna,
  • Santiago Sanguineti,
  • Ventura Simonovich
yanina Hiriart
CONICET
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Paula Scibona
Hospital Italiano de Buenos Aires
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Augusto Ferraris
Hospital Italiano de Buenos Aires
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Waldo Belloso
Hospital Italiano de Buenos Aires
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Valeria Beruto
Hospital Italiano de Buenos Aires
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Facundo Garcia-Bournissen
London Health Sciences Centre
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Vanesa Zylberman
CONICET
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Luciana Muñoz
Inmunova
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Fernando Goldbaum
CONICET
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Linus Spatz
Inmunova
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Mariana Colonna
Inmunova
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Santiago Sanguineti
Inmunova
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Ventura Simonovich
Hospital Italiano de Buenos Aires

Corresponding Author:ventura.simonovich@hospitalitaliano.org.ar

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Abstract

Shiga toxin-producing Escherichia coli-associated hemolytic uremic syndrome (STEC-HUS) is considered a toxemic 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. A single-center, 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 rate 3:1). In Stage II six subjects received either three INM004 doses of 4 mg.kg-1 repeated every 24 h, or placebo (INM004:placebo rate of 5:1). Hospital discharged was 24 hours after the last infusion. INM004 was quantified by ELISA in serum samples obtained at predefined times. Safety and tolerability were assessed in both Stages by monitoring adverse events (AEs), laboratory test values, and vital signs. Eight subjects (57.1%) experienced treatment-emergent AEs (TEAEs), that resolved within 24 hours without requiring changes in treatment or additional intervention. No serious AEs were reported. Most TEAEs were of mild or moderate intensity, and four were possibly drug-related. Peak concentrations (Cmax) of INM004 were 45.1 µg.mL-1 and 77.7 µg.mL-1 for different doses, within two hours after infusion. The serum concentration declined in a biphasic manner (t1/2 range 30.7-52.9 hours). Systemic exposures showed accumulation in the repeated dose regimen (Cmax Day1 85.7 vs.149 µg.mL-1 Day3). These results supporting progression into the phase 2 trial in children with HUS
12 Jul 2023Submitted to British Journal of Clinical Pharmacology
13 Jul 2023Submission Checks Completed
13 Jul 2023Assigned to Editor
13 Jul 2023Review(s) Completed, Editorial Evaluation Pending
30 Jul 2023Reviewer(s) Assigned
06 Aug 2023Editorial Decision: Revise Major
30 Oct 20231st Revision Received
30 Oct 2023Submission Checks Completed
30 Oct 2023Assigned to Editor
30 Oct 2023Review(s) Completed, Editorial Evaluation Pending
13 Nov 2023Editorial Decision: Revise Major