Recombinant alpha-1 microglobulin to improve outcomes in survivors of AKI

Acute kidney injury (AKI) is a serious and common complication among patients undergoing major surgery. The underlying pathophysiologic mechanism includes ischemia-reperfusion injury, complement activation, oxidative stress, and heme toxicity. Among potential preventive measures, recombinant alpha-1 microglobulin (A1M) emerged as a promising therapeutic candidate to mitigate kidney injury in high-risk clinical settings. Preclinical studies have shown its protective effect in different in vitro models such as cellular damage induced by radiation, proteases, and oxidative stress. In animal models, pretreatment with A1M significantly attenuated glomerular permeability changes induced by free fetal hemoglobin, reduced markers of oxidative injury in radiation-induced kidney damage, and conferred protection in ischemia-reperfusion injury by stabilizing mitochondrial function. These promising results led to the use of A1M in human patients. In Phase 1 clinical trials, RMC-035 demonstrated a safety profile with predictable, dose-linear pharmacokinetics. Moreover, in a Phase 1 study involving cardiac surgery patients, RMC-035 showed early signals of renal protection as indicated by reductions of renal tubular stress and injury biomarkers. Although a Phase 2 trial in cardiac surgery patients did not meet its primary endpoint of reducing the rate of AKI within 72 hours after surgery, a significant decline in major adverse kidney events at 90 days was observed that was mainly driven by a reduced rate of persistent renal dysfunction. An ongoing Phase 2b study aims to refine dosing strategies and better delineate its long-term renoprotective efficacy. Collectively, these studies seek to answer whether RMC-035 may improve kidney outcomes in settings characterized by oxidative and ischemia-reperfusion injury.