A phase I study to evaluate the safety, tolerance and pharmacokinetics of anti-Shiga toxin hyperimmune equine F (ab')2 fragments in healthy volunteers
© 2024 British Pharmacological Society..
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 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.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2024 |
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| Erschienen: |
2024 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:90 |
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| Enthalten in: |
British journal of clinical pharmacology - 90(2024), 4 vom: 01. März, Seite 1142-1151 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Hiriart, Yanina [VerfasserIn] |
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| Links: |
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| Themen: |
Anti‐Shiga toxins |
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| Anmerkungen: |
Date Completed 29.03.2024 Date Revised 29.03.2024 published: Print-Electronic Citation Status MEDLINE |
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| doi: |
10.1111/bcp.15999 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| PPN (Katalog-ID): |
NLM367792230 |
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| 245 | 1 | 2 | |a A phase I study to evaluate the safety, tolerance and pharmacokinetics of anti-Shiga toxin hyperimmune equine F (ab')2 fragments in healthy volunteers |
| 264 | 1 | |c 2024 | |
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| 500 | |a Date Revised 29.03.2024 | ||
| 500 | |a published: Print-Electronic | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a © 2024 British Pharmacological Society. | ||
| 520 | |a 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 | ||
| 520 | |a 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) | ||
| 520 | |a 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 | ||
| 520 | |a CONCLUSIONS: The results obtained in this first-in-human study support progression into the phase 2 trial in children with HUS | ||
| 650 | 4 | |a Randomized Controlled Trial | |
| 650 | 4 | |a Clinical Trial, Phase I | |
| 650 | 4 | |a Journal Article | |
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| 650 | 4 | |a HUS treatment | |
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| 650 | 4 | |a anti‐Shiga toxins | |
| 650 | 4 | |a pharmacokinetics | |
| 650 | 7 | |a Shiga Toxin 2 |2 NLM | |
| 650 | 7 | |a Shiga Toxin 1 |2 NLM | |
| 700 | 1 | |a Scibona, Paula |e verfasserin |4 aut | |
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| 700 | 1 | |a Beruto, Valeria |e verfasserin |4 aut | |
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| 700 | 1 | |a Muñoz, Luciana |e verfasserin |4 aut | |
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| 700 | 1 | |a Colonna, Mariana |e verfasserin |4 aut | |
| 700 | 1 | |a Sanguineti, Santiago |e verfasserin |4 aut | |
| 700 | 1 | |a Simonovich, Ventura A |e verfasserin |4 aut | |
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