558 - The Outcomes of Anakinra Pilot - A First-in-Population Clinical Trial Assessing Safety, Feasibility and Pharmacokinetics of IL-1 Receptor Antagonist in Preterm Infants

Publication Number: 558.6829

Marcel F.. Nold, Monash University, Monash Children's Hospital, Hudson Institute, Melbourne, Victoria, Australia; Elys Green, Monash University, Melbourne, Victoria, Australia; Robert Galinsky, Hudson Institute of Medical Research, Melbourne, Victoria, Australia; David Metz, Monash University, Melbourne, Victoria, Australia; Gergely Toldi, University of Auckland, Auckland, Auckland, New Zealand; Carl M. Kirkpatrick, Monash University, Melbourne, Victoria, Australia; Claudia Nold-Petry, Hudson Institute of Medical Research, Clayton, Victoria, Australia; Rod W. hunt, Monash University, CLAYTON, Victoria, Australia

Background: Survival of extremely premature infants has improved over the last decades. However, this improvement has come at the price of an increased incidence of early life diseases affecting lung, heart, gut and brain, and causing substantial morbidity and mortality in these young patients. There is extensive evidence that inflammation is a central pathophysiological driver of these illnesses – and that the pro-inflammatory cytokine IL-1 is a key culprit in initiating and perpetuating this inflammation. Blockade of IL-1 with its endogenous antagonist IL-1Ra (medication name anakinra) has an excellent safety record, established in 200,000+ adults and children.

Objective: Hence, aided by parents with lived experience, we designed and conducted the first-in-population clinical trial Anakinra Pilot (NCT05280340), in which we aimed to establish safety, feasibility and population-pharmacokinetics (PK) of anakinra therapy in preterm infants.

Design/Methods: Anakinra Pilot was an investigator-initiated dose-escalation trial in infants born 24+0 to 27+6 weeks of gestational age. We recruited 25 infants at Monash Children’s Hospital, Melbourne, Australia and Starship Hospital, Auckland, New Zealand from 2022 to 2024. Anakinra was administered intravenously from d1 to d21 of life. Initial dosing was determined through population-PK simulation; second stage dosing was based on interim analyses that largely confirmed the initial PK predictions. Besides standard monitoring, we conducted extensive immunophenotyping, microbiomics and plasma proteomics. Safety was defined as the frequency of adverse outcomes/events not exceeding that expected in infants born 24+0-27+6 weeks at the participating centres.

Results: After a short overview of the scientific journey that led to Anakinra Pilot, we will present the main outcomes, i.e. that it is safe and feasible to administer anakinra to preterm infants according to our protocol. We will also give an overview of the PK of anakinra in this population – an insight of unprecedented precision and depth.

Conclusion(s): Anakinra Pilot has achieved its goal, namely taking a pivotal step towards widespread application of the first pathophysiology-directed anti-inflammatory therapy for preterm infants. Out trial has paved the way for a large randomised, placebo-controlled trial to determine anakinra’s efficacy at ameliorating early-life inflammation. Through this future trial, we plan to deliver the great potential of anakinra to preterm infants worldwide, alleviating multiple complications of prematurity and thus substantially brightening the outlook for these young patients and their families.