A phase I study to evaluate the safety, tolerance and pharmacokinetics of anti-Shiga toxin hyperimmune equine F (ab')2 fragments in healthy volunteers
- PMID: 38288879
- DOI: 10.1111/bcp.15999
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
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.
Trial registration: ClinicalTrials.gov 03388216.
Keywords: F (ab′)2 fragments; HUS treatment; INM004; anti‐Shiga toxins; pharmacokinetics.
© 2024 British Pharmacological Society.
Conflict of interest statement
This study was sponsored by Inmunova SA. Yanina Hiriart, Linus Spatz, Mariana Colonna and Santiago Sanguineti are employees of Inmunova SA. Fernando Goldbaum is the scientific director of Inmunova SA.
References
REFERENCES
-
- Glanantonio CA, Vltacco M, Mendilaharzu F, Gallo GE, Sojo ET. The hemolytic‐uremic syndrome. Nephron. 1973;11(2–4):174‐192. doi:10.1159/000180229
-
- Karmali MA, Petric M, Lim C, Fleming PC, Steele BT. Escherichia coli cytotoxin, haemolytic‐uraemic syndrome, and haemorrhagic colitis. Lancet. 1983;2(8362):1299‐1300. doi:10.1016/s0140‐6736(83)91167‐4
-
- Alconcher LF, Lucarelli LI, Bronfen S. Long‐term kidney outcomes in non‐dialyzed children with Shiga‐toxin Escherichia coli associated hemolytic uremic syndrome. Pediatr Nephrol. 2023;38(7):2131‐2136. doi:10.1007/s00467‐022‐05851‐4
-
- Freedman SB, van de Kar NCAJ, Tarr PI. Shiga toxin–producing Escherichia coli and the hemolytic–uremic syndrome. N Engl J Med. 2023;389(15):1402‐1414. doi:10.1056/NEJMra2108739
-
- López EL, Contrini MM, Glatstein E, et al. Safety and pharmacokinetics of urtoxazumab, a humanized monoclonal antibody, against Shiga‐like toxin 2 in healthy adults and in pediatric patients infected with Shiga‐like toxin‐producing Escherichia coli. Antimicrob Agents Chemother. 2010;54(1):239‐243. doi:10.1128/AAC.00343‐09
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