IBP-9414 improves GI outcomes, cuts death rates in VLBW infants

IBP-9414, a live biotherapeutic product (LBP), delivers gastrointestinal (GI) and mortality benefits in very low birth weight (VLBW) infants (BW 500–1,500g) born between 23 and 32 weeks gestational age in the phase III Connection study presented at PAS 2025.

“We measured the effects of IBP-9414 on necrotizing enterocolitis (NEC), time to full enteral feeding, and mortality in VLBW infants,” said the researchers.

“Treatment with IBP-9414 did not reach statistical significance for the primary endpoints of confirmed NEC and sustained feeding tolerance (SFT). However, IBP-9414 significantly reduced all-cause mortality among treated infants,” they said.

In the modified intention-to-treat population (mITT), the IBP-9414 and placebo arms had similar incidences of NEC (8.7 percent vs 10.2 percent; relative risk [RR], 0.86; p=0.248) and SFT (21 vs 23 days; hazard ratio [HR], 1.095; p=0.076). [PAS 2025, abstract 2100.6]

SFT incidences also did not differ significantly between the experimental and comparator arms in the 750–999 g (19 vs 21 days; HR, 1.03; p=0.680) and 1,001–1,500 g (10 vs 11 days; HR, 1.20; p=0.200) BW subgroups.

Deaths were significantly fewer with IBP-9414 than placebo, both in the mITT cohort (6.2 percent vs 8.5 percent; RR, 0.73; p=0.036) and beyond 14 days (2.2 percent vs 4.2 percent; RR, 0.52; p=0.007).

Moreover, NEC incidence beyond 14 days was lower with the investigational agent than placebo (5.7 percent vs 7.7 percent; RR, 0.74; p=0.067), as was NEC incidence beyond 14 days by surgery/autopsy (0.3 percent vs 1 percent; RR, 0.29; p=0.046).

“The pharmacodynamic effect of IBP-9414 on mortality and NEC was seen after 14 days of treatment,” said the researchers. The reduced all-cause mortality events after the initial 14-day treatment period underpin a significant protective effect of IBP-9414 on long-term survival.

Safety-wise, they noted no differences in the treatment and placebo arms in terms of sepsis, patent ductus arteriosus, abdominal distention, respiratory failure, intraventricular haemorrhage, osteopenia, metabolic imbalances, and hyper- or hypoglycaemia.

Favourable benefit-risk profile

There is considerable controversy regarding the use of live bacteria (probiotics) for NEC in VLBW infants and currently, preterm infants are exposed to probiotics without FDA approval, the researchers noted.

Studies have looked into the efficacy of lactobacillus reuteri (L. reuteri), a commensal bacterium present in human milk that prevents intestinal injury through improved mucosal defences, GI motility, and local and systemic anti-inflammatory actions.

A total of 2,153 VLBW infants (median BW 850 g, 50 percent female) were randomized 1:1 to IBP-9414 (L. reuteri) or placebo. IBP-9414 was given orally within 48 hours of birth, then one daily dose (10⁹ CFU) at postmenstrual age of 34 weeks plus 6 days, with follow-up at week 40. A majority (64 percent) of participants weighed between 750 and 1,000 g, and over three-quarters (77 percent) were delivered via Caesarean section.

According to the investigators, this is the largest study ever conducted on the effect of LBP in premature infants. “[The study shows that] IBP-9414 led to a significant reduction in the risk of death from any cause, as well as numerical reduction in NEC incidence and improvement in enteral feeding.”

The findings align with previous evidence on L. reuteri, showing improved intestinal maturity and function and reduced GI-related mortality in VLBW infants. Moreover, there were no safety concerns, and L. reuteri was never found in blood cultures taken for clinical suspicion of sepsis.

“The study shows the positive benefit-risk profile of IBP-9414 in premature VLBW infants,” they concluded. Breakthrough therapy designation for reduction in GI mortality in VLBW infants has been granted by the FDA in 2025.