Efficacy and safety of therapeutic alpha-1-microglobulin RMC-035 in reducing kidney injury after cardiac surgery: a multicentre, randomised, double-blind, parallel group, phase 2a trial.

Background

Cardiac surgery invariably triggers acute kidney stress causing adverse renal outcomes. The AKITA study evaluated the efficacy and safety of RMC-035, a novel analogue of alpha-1-microglobulin, for reducing cardiac surgery-associated kidney injury.

Methods

In this randomised double-blind placebo-controlled phase 2a study, we randomly assigned (1:1) adult hospitalised patients undergoing open-chest cardiac surgery at high risk for acute kidney injury (AKI) at 21 sites in North America and Europe to receive either RMC-035 (1.3 or 0.65 mg/kg) or placebo (1:1) for 2 days (5 intravenous infusions), stratified by region and renal function. Eligible patients had at least one pre-defined AKI risk factor. Patients with severe renal impairment (estimated glomerular filtration rate [eGFR] <30 mL/min/1.73 m

Findings

Patient enrolment was stopped at interim analysis due to futility. Between March 31, 2022 and July 12, 2023, 177 patients (RMC-035: 89, placebo: 88) were randomised and treated. AKI rate for RMC-035 vs placebo was 50.6% (n = 45) and 39.8% (n = 35) (relative risk [RR]: 1.30, 90% confidence interval [90% CI]: 0.99, 1.71; p = 0.12). A short-lived creatinine increase was observed with the higher RMC-035 dose. Treatment with RMC-035 was associated with improved secondary renal outcomes at Day 90: placebo-adjusted eGFR change from baseline 4.3 mL/min/1.73 m

Interpretation

In this proof-of-concept study, RMC-035 did not reduce AKI 72 h after cardiac surgery. Evaluations may have been confounded by a drug-induced transient creatinine increase in a subgroup of patients. RMC-035 was associated with improved secondary renal outcomes. These results merit further investigation and should be interpreted with caution, as the study was not powered for these outcomes.

Funding

Guard Therapeutics.

Informations de copyright

© 2024 The Author(s).

Déclaration de conflit d'intérêts

AZ received consulting and lecture fees and grants from German Research Foundation, BioMerieux, Baxter, Fresenius, Paion, Viatris, Bayer, Novartis, AM Pharma, and Alexion, received meeting and travel support from Sphingotec and held leadership and fiduciary roles at the German Interdisciplinary Association for Intensive and Emergency Medicine, the International Anesthesia Research Society and the journal “Der Anästhesist”. JLK received consulting fees from Biomerieux, Baxter, Alexion, SeaStar, Novartis, Guard Therapeutics and research funding from the NIH, Fresenius Medical and Biomerieux. TEL is a shareholder and employee of Guard Therapeutics. MR holds stock options and is a paid consultant to Guard Therapeutics. CDM received consulting fees from Alexion. AB was past-president of the German society for heart, thorax and vascular surgery, served on the DSMB for the INCREASE study and received consulting, lecture and advisory board fees from Guard Therapeutics, Marizyme, Abbott, and Abiomed, Data Monitoring Committee payments from Amopharma and patient fees from Guard Therapeutics. JoB received travel costs payments from Guard Therapeutics for an investigator meeting. DE is president of the ERAS Cardiac Society and was a member of Data Safety Monitoring Boards/Advisory Boards for Arthrex, Edwards Lifescience, Medella, Atricure, Pharmacosmos, Renibus, Alexion, and Genentech. AM, BdV, JaB, KM, ML, MT and NN declare no competing interests.