A Double-blind, Placebo-controlled, Adaptive, Phase 2/3 Study to Evaluate the Pharmacokinetics, Safety, and Efficacy of INM004 in Pediatric Patients With Shiga Toxin-positive Bloody Diarrhea for Prevention of Hemolytic Uremic Syndrome

Hemolytic uremic syndrome (HUS) is a form of thrombotic microangiopathy, characterized by microangiopathic hemolytic anemia, thrombocytopenia, and acute renal impairment of varying severity, which may be preceded by an episode of diarrhea with or without blood. Karmali et al. showed the relationship between this syndrome and diarrhea caused by Shiga toxin-producing bacteria such as Escherichia coli. These cytotoxins, called Shiga-like toxins or Shiga toxins (Stx), are also called verotoxins, due to the characteristic cytopathic effect they cause on Vero cell cultures.

HUS is often classified into 3 primary types: 1) HUS due to infections associated with Shiga-toxin producing E. coli (STEC) or Shigella dysenteriae Type 1, often associated with diarrhea, with the rare exception of HUS due to a severe disseminated infection caused by Streptococcus pneumoniae, 2) HUS related to complement abnormalities or related to factor ADAMTS13 deficit, such HUS is also known as "atypical HUS" and is not associated with diarrhea, and 3) HUS of unknown etiology that usually occurs in the course of systemic diseases or physio-pathologic conditions such as pregnancy, after transplantation or after drug use.

E. coli bacteria normally live in the intestines of people and animals. Cattle and sheep are the main reservoirs of STEC, and the major transmission route is believed to be food contaminated with animal feces. Contaminated water has also been recognized as a source, and direct human-to-human and animal-to-human transmission have been reported.

E. coli consists of a diverse group of bacteria. Most of them are harmless and an important part of a healthy human intestinal tract. However, some E. coli are pathogenic, that can cause either diarrhea or illness outside of the intestinal tract. Diarrheagenic E. coli strains are categorized into 6 pathotypes: 1) Enterotoxigenic E. coli, 2) Enteropathogenic E. coli, 3) Enteroaggregative E. coli, 4) Enteroinvasive E. coli, 5) diffusely adherent E. coli, and 6) STEC. STEC may also be referred to as verocytotoxin-producing E. coli (VTEC). This last pathotype is the one most commonly associated with foodborne outbreaks.

Treatment of STEC HUS renal damage caused by Stx is available. The investigational medicinal product (IMP), INM004, proposes to neutralize the toxin in the bloodstream to prevent the interaction of the Stx with the specific receptor, by means of a polyclonal antibody to be administered upon the appearance of symptoms (bloody diarrhea) and diagnosis of infection by STEC, thereby preventing the action of the toxin in the body. Thus, the initial hypothesis for examination is for the prevention of the full expression of HUS, based upon presumptive clinical, biochemical, and other biological evidence suggesting a risk of HUS at the time of treatment application. The polyclonal antibody (F(ab')2 fragment) is obtained by processing the serum of equine animals previously immunized against engineered Stx1B and Stx2B immunogens.