Infant Bacterial Therapeutics or IBT is a Swedish pharmaceutical company based in Stockholm, Sweden. IBT solely devotes its resources to the development of new medicines for the treatment and prevention of challenging diseases of the premature infant.
IBT continuously works in close collaboration with Health Authorities in both the United States and Europe to ensure the safe use as well as the healing effects of the IBP-9414 candidate medicine in the premature infants.
The IBP-9414 candidate medicine aims at preventing necrotizing enterocolitis to occur in premature infants and to improve the feeding, growth and well being of these vulnerable infants.
Necrotizing enterocolitis (NEC) is a serious inflammatory disease of the gastrointestinal system of the premature infant in which portions of the bowel undergo tissue death (necrosis). The affected bowel segment becomes darkly discolored, stops moving and may rupture with leakage of the stools into the abdominal cavity.
NEC has an unpredictable, rapid onset that may present itself as difficulties for the baby to feed, swelling and discoloration of the abdomen, bloody stools, as well as fever, increased need of oxygen and lowered blood pressure. Today operative removal of the affected bowel segment is the only specific treatment.
NEC almost exclusively affects premature infants and the most important risk factor for its development is the degree of prematurity of the infant; the lower the birth weight and gestational age at birth are, the higher risk for NEC becomes.
The diagram below shows the proportion (%) of newborn babies in different age groups (estimated week of gestational age) developing NEC requiring supportive medical treatment only (Medical NEC) and those where abdominal operation (Surgical NEC) becomes necessary.
Not only is the risk of developing NEC higher for the smallest premature infants, but the risk of dying from NEC also is the highest for the smallest and most premature babies. More than 5,000 infants in Europe and the US die every year from the complications of NEC.
The longer-term consequences for premature infants developing NEC vary from none to short bowel syndrome, abnormal growth, and impaired neurodevelopment including cerebral palsy, intellectual impairment, visual impairment, and hearing impairment.
There is no treatment available today to prevent NEC from occurring nor are there any specific clinical signs predicting its development. Furthermore, there is no well recognized cause for the development of NEC besides the risk factors of immaturity of the premature bowel with respect to e.g. innervation, immunologic capability, movement ability and bacterial colonization. Current medical treatments are supportive and aimed at limiting ventilatory, circulatory, infectious and other complications of the bowel necrosis. Other measures include e.g. early start of oral feeding, especially with human milk, abdominal massage and attempts to limit the use of antibiotics, none of which has been shown to have a consistent effect.
The neonatal intensive care environment favors the growth of pathogenic, potentially dangerous bacteria in the developing gastrointestinal tract, which may elevate the risk of contracting not only NEC, but also potentially lethal infections. Growth of such potentially dangerous bacteria has been seen in the bowel in the days before NEC develops. This has led to clinical testing that introduction of live, beneficial (i.e. probiotic) bacteria into the preterm infant gut early in life may limit the growth of such harmful bacteria and thereby reduce the risk of developing NEC.
Despite years of research, there is still no medical drug of live bacteria that has undergone medical agency approved, rigorous pharmaceutical production and clinical risk and benefit-testing that are required for any agent that is to be used to treat or prevent any disease. IBT is alone in such a development with its medical drug candidate IBP-9414 for the prevention of NEC and the improved feeding ability of the premature infant.
Probiotic formulations today are dietary supplements that neither have been manufactured nor clinically evaluated with the rigorous demands for medical drugs, and must not, for any reason, be offered to premature infants without a Health Authority-approved clarification of the expected treatment effects.
The first weeks of nutrition are important for premature babies. Early introduction of enteral feeds (via mouth or through an oral tube) after birth and as rapid increase into full feeding volumes as possible promote the growth and maturation of the baby. At the same time nutrients and fluids must be given directly into the blood through a cannula as the immature gastrointestinal tract is not ready to accept full enteral feedings soon after birth.
While increasing daily oral feeding volumes the amount of nutrients given directly into the blood are gradually decreased. The speed by which oral feeding volumes can be increased generally is limited by signs of feeding intolerance, like vomiting or abdominal swelling. The goal of full enteral feeding usually is to reach daily volumes of at least 100-120 ml per kg body weight.
IBP-9414 is a candidate medicine that is designed to prevent the occurrence of NEC in premature babies and to enhance their ability to grow and develop through an improved oral feeding tolerance.
IBP-9414 is a frozen and dried preparation of a specific strain of the bacterium Lactobacillus reuteri that has been accepted by the Health Authorities for oral administration to premature babies during the careful monitoring of expert doctors and nurses and within the elaborate framework of an Authority-approved clinical development program.
Lactobacillus reuteri occurs naturally in breast milk and in the gastrointestinal tract of babies. It belongs to a group of helpful ‘probiotic’ bacteria and has been shown to improve the movement, food uptake and maturation of the vulnerable bowel of premature babies. In addition Lactobacillus reuteri can fight the potentially harmful bacteria that can cause serious diseases of the premature infant.
Many neonatologists have performed clinical studies to test if Lactobacillus reuteri can affect the development of NEC, and also whether giving the bacteria to the premature infant can improve their ability to take food by mouth. These studies involving thousands of babies indicate the favorable effect of Lactobacillus reuteri on NEC and on the oral feeding of the babies but cannot form the basis for a Medical Health Agency-approval of a medicine.
Before starting clinical studies for a candidate medicine, IBT discussed several aspects of the IBP-9414 development program with the Medical Health Authorities. These agreements included careful evaluation of the production and packaging of the product, its purity and content of the live bacteria as well as the design, continuous monitoring and results evaluation of the planned clinical studies.
This process vastly differentiates the IBP-9414 candidate medicine from so-called probiotics that currently are marketed as ‘food supplements’ and IBT is alone in developing a probiotic live bacterial therapy for the treatment or prevention of disease.
Evaluation of the effects of IBP-9414 in premature babies started with a completed so-called phase 2 study in which the focus was on the safety of the candidate medicine and the appropriate dose for the prevention of NEC. In agreement with the Health Authorities in both the United States and Europe, the medicine candidate was considered safe and progression into the large-scale ‘Connection study’ involving more than 2000 premature babies was agreed.
This large scale clinical study has been initiated and offers premature babies weighing from 500 to 1500 grams daily treatment with one dose of IBP-9414 in sterile water or sterile water alone (placebo) for the prevention of NEC and the improvement of enteral (oral) feeding.
Placebo (non-active drug) is used for comparison (to IBP-9414) in this and other high quality clinical studies to ensure that differences in study outcomes are related as little as possible to variable patient characteristics at study entry. The placebo group is intended also to mirror what happens to babies undergoing current routine treatment practices. In order to obtain this, randomization of who gets which treatment is important and that all personnel involved in the study have no knowledge of which group each baby belongs to during the entire study period. Should serious complications arise during the study, records on who got what can always be clarified.
Below are some key features of The Connection Study. Additional info can be found at Clinical Trials.org .
A randomized, double blind, parallel-group, placebo-controlled study to evaluate the efficacy and safety of IBP-9414 in premature infants 500-1500g birth weight in the prevention of necrotizing enterocolitis.
Subjects must fulfill all of the following criteria for inclusion into the study
– Gestational age at birth of 23 weeks + 0 days -32 weeks + 0 days
– Birth weight of 500-1500g
– Written informed consent from the subject ́s legally authorized representative
The first dose of study medication must occur within 48 hours after birth and should continue once a day until the baby reaches 34 weeks + 6 days post-menstrual age, or earlier if treatment is permanently discontinued. A follow-up assessment is made at 40 weeks ± 7 days postmenstrual age.
Participation in the study is voluntary and may be terminated at any time.
The primary objectives are to evaluate if IBP-9414 can prevent necrotizing enterocolitis, improve the oral feeding of the baby, and the safety characteristics of IBP- 9414. Other (so-called secondary) objectives include the effect of IBP-9414 on different severities of NEC, mortality, length of the hospital stay, growth of the baby and signs of feeding intolerance.
Assessments during the study:
The study is designed to interfere as little as possible with the routine care in the Neonatal Intensive Care Unit. Within the study framework the following will be measured: Body weight and oral nutrient volume, study drug administration, abdominal X-rays (gathered for clinical signs of NEC), other medications and any medical or surgical complication occurring during the study.
It should be recognized that clinical trials are performed with the purpose of clarifying the safety (and treatment effect) of candidate medicines, whereby the risk of receiving the study medication yet remains to be fully clarified. For this reason the number of exposed babies was increased gradually when progression from the concluded phase 2 trial into the Connection Study was approved for IBP-9414.
The important standard precautions of any Health Authority- approved clinical trial will be applied. Besides continuous recording of any treatment complication (related or unrelated to the study conduct), an independent safety monitoring board (DMC) will monitor the incidence of necrotizing enterocolitis throughout the study and evaluate the safety of IBP-9414 (compared to placebo) when 300, 600 and 1400 babies have concluded the study. Should treating neonatologist believe complications arising in any baby depend on IBP-9414 (or placebo) particular attention, including potential evaluation by the DMC will occur.