Guard Therapeutics International AB (publ) announced top-line results from its Phase 2 clinical study AKITA, evaluating RMC-035 for the prevention of kidney injury in open-heart surgery. In line with previous communication patient recruitment was prematurely stopped, and as expected the primary (short-term) endpoint, incidence of acute kidney injury (AKI) within 72 hours after surgery, was not reached. Importantly though, pre-defined secondary endpoints demonstrated the intended long-term benefit of RMC-035 with improved kidney function compared to placebo.

These results clearly support advancement in the clinical development program and highlight the potential of RMC-035 as a novel short-term treatment for kidney protection. The AKITA study is a randomized, double-blind, placebo-controlled Phase 2 study of RMC-035 in patients undergoing open-heart surgery and at increased risk to develop kidney injuries. A total of 177 patients were randomized and dosed in the study (89 in the RMC-035 group, 88 in the placebo group).

Patients were followed for 90 days after surgery. AKI rate was 50.6% for RMC-035 versus 39.8% for placebo (relative risk [RR]=1.30, p=0.12). AKI rate in the pre-defined subgroup of patients having a better kidney function at the time of surgery (estimated glomerular filtration rate [eGFR] 60 mL/min/1.73m2) and who received the higher start dose of 1.3 mg/kg (n=112; 63%): 56.4% for RMC-035 versus 35.1% for placebo (RR=1.66, p=0.01), AKI rate in the pre-defined subgroup with worse kidney function at the time of surgery (eGFR <60 mL/min/1.73m2) and who received the lower start dose of 0.65 mg/kg (n=65;37%): 41.2% for RMC-035 versus 48.4% for placebo (RR=0.85, p=0.57).

Based on the primary endpoint analysis, a key learning going forward concerns identification of the most appropriate RMC-035 dose. Notably, the overall higher AKI rate for subjects on RMC-035 treatment was driven by the higher RMC-035 start dose in the subgroup of eGFR 60 mL/min/1. 73m2, which caused an acute (within 12 hours) drug-induced increase in serum creatinine. This directly explains the higher AKI rate (and potentially failure to meet the primary endpoint) since an acute increase in creatinine, although reversible, triggers AKI per definition.

Hence, the conclusion, and the basis for the Data Monitoring Committee (DMC) recommendation to discontinue further patient enrolment, are linked to a too high dose of RMC-035. Secondary endpoints (to assess long-term kidney function): eGFR change from baseline (before surgery): In the total study population, the difference in eGFR change from baseline on Day 90 for RMC-035 versus placebo was 4.3 mL/min/1.73m2 (p=0.06), in favor of RMC-035 This effect was greater in the subgroup of patients with eGFR <60 mL/min/1.73m2 who had received the lower RMC-035 dose: 7.9 mL/min/1.73m2 (p=0.05), The effect was weaker in the subgroup of patients with eGFR 60 mL/min/1.73m2 who received the higher start dose: 2.3 mL/min/1.73m2 (p=0.41), The number of MAKE events on Day 90 was significantly reduced with RMC-035 treatment: 6.7% for RMC-035 vs 15.9% for placebo (relative risk 0.41 (p=0.047)). This effect was consistent across the two eGFR subgroups and in a sensitivity analysis using a combination of creatinine and cystatin C for eGFR assessment.

The company considers the overall improved long-term kidney function (eGFR) with RMC-035 treatment as clinically relevant and predictive of the efficacy in a registrational Phase 3 clinical study required to support a future marketing authorization application/new drug application. In particular, the more pronounced effect in patients with lower kidney function (eGFR <60 mL/min/1. 73m2) is remarkable given that generally these patients have a diagnosis of chronic kidney disease (CKD). Since the stronger treatment effect in this subgroup is likely to be attributed to the lower start dose (i.e. not causing an acute creatinine increase and higher AKI rate), the observed eGFR effect in the full AKITA study population may be underestimated in relation to the potentially achievable effect with an optimized dose of RMC-035.

Importantly, the MAKE endpoint on Day 90, which was successfully met with statistical significance in this study, is the expected primary endpoint in a pivotal Phase 3 study as required by the U.S. Food and Drug Administration (FDA). This composite endpoint captures an irreversible loss of kidney function (i.e., a disease-modifying effect) and includes any of the following components: death, post-surgery dialysis treatment, or 25% reduction in eGFR compared to baseline. The MAKE reduction is consistent with the observed improvement of eGFR, providing clear support for the kidney-protective effect of RMC-035.