Prevention of necrotizing enterocolitis and improvement of sustained feeding tolerance

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Necrotizing Enterocolitis

Necrotizing enterocolitis (NEC) is a leading cause of death among premature infants in neonatal intensive care units (NICU). NEC annually kills approximately 3,700 and 1,500 infants annually in Europe and the US, respectively. NEC has an unpredictable, spontaneous, and acute onset and major surgery is today the only specific treatment available. NEC is a serious inflammatory disease of the newborn bowel in which portions of the bowel undergo tissue death (necrosis).

The long-term clinical consequences for infants who survive NEC are variable and include short bowel syndrome, parenteral nutrition-associated cholestasis, abnormal growth, and adverse neurodevelopmental outcomes, including cerebral palsy, cognitive impairment, visual impairment, and hearing impairment.

Sustained Feeding Tolerance

Achieving sustained feeding tolerance (SFT) is essential to ensure the healthy development of premature infants. SFT is the ability of an infant to tolerate enteral feeds (i.e. conventional feeding via the mouth). However, evidence-based guidelines for the nutrition of VLBW infants (very low birth weight < 1500 g) recommend starting parenteral nutrition within the first hours. This is because the immature gastrointestinal tract is not mature enough to take in more than small amounts of nutrition enterally.

Establishing continuous enteral nutrition and discontinuing parenteral nutrition is an important goal, especially in VLBW and ELBW infants (extremely low birth weight <1000g). Reducing the number of days it takes to achieve SFT is clinically relevant and associated with a reduced risk of serious complications for premature infants such as intrahepatic cholestasis, increased risk of bronchopulmonary dysplasia, deterioration of pulmonary vascular resistance, IV line infections, and sepsis.  

In 2022 IBT validated its second primary endpoint in the ongoing Phase 3 study (the Connection Study). The validation demonstrates how achieving an SFT for at least 10 consecutive days is a clinically relevant correlate for several infant morbidities in their first weeks of life. The results are published in the peer reviewed journal British Journal of Gastroenterology. Thus, IBT has two independent primary endpoints evaluated in the Connection Study: the prevention of NEC and SFT.

New Biological Entity

IBP-9414, a New Biological Entity, contains the active substance Lactobacillus reuteri, which is a human bacterial strain naturally present in breast milk. Since 2012, thirteen clinical trials enrolling more than 4,000 infants have indicated proof-of-concept of the potential for Lactobacillus reuteri to prevent NEC, and nine clinical studies enrolling more than 3,000 infants have demonstrated the potential of Lactobacillus reuteri for improving SFT outcomes.

Lactobacillus reuteri is a live bacterium known to be anti-inflammatory, anti pathogenic and beneficial to gut motility and gut mucosa maturity. All of these factors aid in preventing NEC which is characterized by excess inflammation and pathogenic activity as well as inhibition of gut motility and maturation (seen below). All the while, these benefits also aid infants in achieving sustained feeding tolerance. IBP-9414 is formulated with the vulnerable target population of preterm infants in mind.

Medical Needs and Expenditures

NEC patients require medical care and in many cases also surgical interventions that increase hospital expenditures and prolong the length of stay. The economic burden of NEC amounts to 20 percent of the total cost of the initial care of all newborns in the US and represents approximately USD 5 billion spent annually on NEC. Moreover, those infants who survive NEC may face serious lifelong sequelae, which eventually decrease their quality of life and generate further costs to the patient and society. In light of this, preventive therapy for NEC and reducing the time to SFT would therefore be expected to reduce these healthcare expenses. IBT intends to demonstrate these benefits to support reimbursement for IBP-9414 in the prevention of NEC and improvement of SFT from caregivers, insurance companies and pharmaceutical authorities.

Clinical Experience

Since 2012, thirteen clinical trials enrolling more than 4,000 infants have indicated proof-of-concept of the potential for Lactobacillus reuteri to prevent NEC, and nine clinical trials enrolling more than 3,000 infants have demonstrated the potential of Lactobacillus reuteri for improving SFT outcomes.

IBT has contributed to this field of research having completed its own phase II safety and tolerability study and concluded that IBP-9414 was safe and well-tolerated in premature infants with birth weights between 500–2,000 grams. In 2019 IBT commenced its phase III pivotal trial, the Connection Study, to demonstrate the efficacy of IBP-9414 in the prevention of NEC and improving SFT in premature infants with a birth weight ≤ 1,500 grams (ClinicalTrials.gov identifier: NTC02472769).

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