IBP-9414 for the prevention of necrotizing enterocolitis (NEC) contains the active substance Lactobacillus reuteri, which is a co-evolved human bacterial strain naturally present in breast milk. Lactobacillus reuteri is a live bacteria known to be anti-inflammatory, anti-pathogenic and beneficial to gut motility.
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 in Europe and in the US, respectively. NEC has an unpredictable, spontaneous, and acute onset and major surgery is today the only available treatment. NEC is a serious inflammatory disease of the newborn bowel in which portions of the bowel undergo tissue death (necrosis).
Necrosis of the intestinal tissue (photos from Centers for Disease Control and Prevention, National Center on Birth Defects and Developmental Disabilities)
NEC primarily affects premature infants and the single most significant risk factor for the development of NEC is the degree of prematurity of the infant, with lower birth weight and lower gestational age increasing the risk for the disease. Occurrence of NEC by estimated gestational age is as set forth in Figure 1.
Figure 1. Occurrence of NEC by gestational age (Clark et al, 2012)
The disease has a higher rate of mortality in the younger and less mature infants. Mortality in infants who had a diagnosis of NEC by estimated gestational age is as set forth in Figure 2.
The number listed outside parentheses in the table above is estimated gestational age in weeks. The number listed within parentheses represents the number of patients with NEC within each gestational age group.
Figure 2. Mortality in infants who had a diagnosis of NEC by estimated gestational age (Clark et al, 2012)
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.
IBT is currently developing its lead drug candidate IBP-9414 to prevent NEC in premature infants.
IBP-9414 contains the active substance Lactobacillus reuteri, which is a co-evolved human bacterial strain naturally present in breast milk. Lactobacillus reuteri is a live bacteria known to be anti-inflammatory, anti-pathogenic and beneficial to gut motility. IBP-9414 is formulated with close considerations of age-appropriateness of the vulnerable target population of preterm infants.
IBT was granted Orphan Drug Designation by the FDA for Lactobacillus reuteri for the prevention of NEC in premature infants in 2013 and by the European Commission for IBP-9414 including Lactobacillus reuteri for the prevention of NEC in premature infants in 2015. IBT also received Rare Pediatric Disease Designation from FDA for IBP-9414 in 2016, meaning that IBT may be awarded a priority review voucher following market approval.
In June 2016, IBT commenced the Safety and Tolerability study. In late 2017, the results demonstrated a similar safety and tolerability profile in the active group as in the placebo group.
The pivotal Phase III study, the Connection study, is planned to commence in 2018.
Lactobacillus reuteri has strain-specific attributes which affect the NEC pathogenesis.
The development plan for IBP-9414 consists of two clinical trials: the completed safety and tolerability study followed by the planned pivotal phase III study. The Safety and Tolerability study, has been completed on time in Q4 2017. The subsequent Pivotal Phase III study is expected to be initiated in 2018.
The first study was a randomized, double blind, parallel-group, dose escalation placebo-controlled multicentre study to investigate the safety and tolerability of IBP-9414 administered in premature infants (ClinicalTrials.gov identifier: NTC02472769). The study included 120 premature infants, defined as a gestational age ≤ 32 weeks and birth-weight ranging from 500 to 2,000 grams, recruited and randomized to receive either IBP-9414 or placebo. The first dose of study drug was administered within 48 hours of birth and continued daily for a period of 14 days. Follow-up assessments were occasionally made up to six months after the last dose of the study drug. The primary outcome in this trial was safety and tolerability. This Safety and Tolerability study has been completed on time in Q4 2017. The study demonstrated that treatment with IBP-9414 leads to presence of Lactobacillus reuteri in the feces on the day of the last dose and that 30 days after the last dose, the bacteria have been washed out. The safety and tolerability study concluded that IBP-9414 was safe and well-tolerated in premature infants with birth weights between 500–2,000 grams, with high compliance to treatment with the study drug and that there was no evidence of cross-contamination with IBP-9414 in placebo treated infants. With these results in hand, the IBP-9414 clinical development program is now moving forward into the planned pivotal phase III study.
The subsequent pivotal phase III study is designed to demonstrate and document efficacy of IBP-9414 over placebo in the prevention of NEC in premature infants with a birth weight ≤ 1,500 grams. This study will also include safety evaluation.
Given the urgency to provide an effective preventative therapy to this unmet medical need, IBT plans to utilize the available FDA and EMA expedited programs to reach the market as soon as possible. Submission for market approval for IBP-9414 is targeted to be in 2020.
There has been little or no progress in recent years in improving outcomes for infants that are affected by NEC once the disease is underway. Nor is there definitive treatment that modifies the underlying risk factors for the disease. Approximately 20 to 40 percent of patients with NEC will require surgery. Thus, NEC prevention strategies are vital and urgently needed but to date none have been successful or generally adopted as the standard of care. Subsequently, a preventive treatment against NEC remains an unmet medical need.
NEC patients require medical care and in many cases also surgical interventions that increase hospital expenditures and prolong length of stay. The economic burden of NEC has been evaluated to be almost 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 the light of this, a preventive therapy for NEC such as IBP-9414 would therefore be expected to indirectly reduce these healthcare expenses. IBT intends to demonstrate these benefits to support reimbursement for IBP-9414 in the prevention of NEC from caregivers, insurance companies and pharmaceutical authorities.
Since 2012, ten published clinical trials that enrolled more than 2,800 infants has indicated proof-of-concept of the clinical potential of Lactobacillus reuteri to prevent NEC. The table below shows a summary of studies using Lactobacillus reuteri showing clear clinical signal for the reduction in NEC incidence.