Abstracts

American Journal of Respiratory and Critical Care Medicine, 2023;207:A5688  https://doi.org/10.1164/ajrccm-conference.2023.207.1_MeetingAbstracts.A5688 

Abstract

RATIONALE: Neutrophils play an important role in several lung diseases such as acute lung injury, adult respiratory distress syndrome (ARDS), pneumonia, severe asthma, and chronic obstructive pulmonary disease (COPD). RLS-0071 is a small peptide dual-targeting inhibitor of complement and neutrophil effectors and has been demonstrated to inhibit neutrophil inflammation in preclinical models. Protocol RLS-0071-103 (NCT05351671) was a proof-of-mechanism (POM) study intended to establish RLS-0071 translatability from animal disease models to humans by inhibiting neutrophil-mediated inflammation at the tissue level.

METHODS: Healthy participants (n=30) inhaled LPS to induce a temporary neutrophil-mediated lung inflammation. Thirty minutes, 8 hours, and 16 hours after LPS challenge they received RLS-0071 or placebo by IV infusion. Participants were randomized 1:1:1 into one of three treatment arms, placebo (saline), low-dose RLS-0071 at 10 mg/kg IV Q8hr or high-dose RLS-0071 at 120 mg/kg IV followed by Q8hr 40 mg/kg dosing. Sputum samples were obtained at a baseline visit and 6 hours after LPS inhalation at Ctrough to ensure results evaluated tissue level effects and not effects driven by maximum plasma level. Sputum plugs were processed to yield absolute neutrophil counts per gram sputum and sputum supernatants were assayed for cytokines and various mediators.

RESULTS: Log-transformed neutrophil counts in sputum were lower after low-dose (p=0.035) and high-dose (p=0.11) RLS treatment and led to a 50% decrease in median absolute sputum neutrophil counts at 6 hours for combined treatment groups compared to placebo. In addition to quantitative data analysis, responders were defined as subjects meeting a > 40% decrease from placebo at 6 hours. A responder rate of 8 of 10 (P = 0.001) was seen in the low-dose arm with a similar responder rate of 7 of 10 (P = 0.035) in the high-dose-arm. Lower sputum neutrophil counts for the treatment groups versus placebo were maintained through the last sample timepoint of 24 hours demonstrating a sustained effect. The concentration of IL-8, MPO and neutrophil elastase in sputum supernatant were lower after treatment with RLS-0071 compared with placebo.

CONCLUSION: Overall, these results demonstrate that RLS-0071 met proof of mechanism in humans and can decrease neutrophil-mediated inflammation in the lungs by greater than 40% with a responder rate of 80% for a 10 mg/kg/dose regimen. These findings warrant further efficacy evaluation of RLS-0071 for the treatment of neutrophil-dominated lung diseases.

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