Teprasiran, a Small Interfering RNA, for the Prevention of Acute Kidney Injury in High-Risk Patients Undergoing Cardiac Surgery: A Randomized Clinical Study

Abstract

Background: Acute kidney injury (AKI) affects up to 30% of patients undergoing cardiac surgery, leading to increased in-hospital and long-term morbidity and mortality. Teprasiran is a novel small interfering RNA that temporarily inhibits p53-mediated cell death that underlies AKI.

Methods: This prospective, multicenter, double-blind, randomized, controlled phase 2 trial evaluated the efficacy and safety of a single 10 mg/kg dose of teprasiran versus placebo (1:1), in reducing the incidence, severity, and duration of AKI after cardiac surgery in high-risk patients. The primary end point was the proportion of patients who developed AKI determined by serum creatinine by postoperative day 5. Other end points included AKI severity and duration using various prespecified criteria. To inform future clinical development, a composite end point of major adverse kidney events at day 90, including death, renal replacement therapy, and ≥25% reduction of estimated glomerular filtration rate was assessed. Both serum creatinine and serum cystatin-C were used for estimated glomerular filtration rate assessments.

Results: A total of 360 patients were randomly assigned in 41 centers; 341 dosed patients were 73±7.5 years of age (mean±SD), 72% were men, and median European System for Cardiac Operative Risk Evaluation score was 2.6%. Demographics and surgical parameters were similar between groups. AKI incidence was 37% for teprasiran- versus 50% for placebo-treated patients, a 12.8% absolute risk reduction, P=0.02; odds ratio, 0.58 (95% CI, 0.37-0.92). AKI severity and duration were also improved with teprasiran: 2.5% of teprasiran- versus 6.7% of placebo-treated patients had grade 3 AKI; 7% teprasiran- versus 13% placebo-treated patients had AKI lasting for 5 days. No significant difference was observed for the major adverse kidney events at day 90 composite in the overall population. No safety issues were identified with teprasiran treatment.

Conclusions: The incidence, severity, and duration of early AKI in high-risk patients undergoing cardiac surgery were significantly reduced after teprasiran administration. A phase 3 study with a major adverse kidney event at day 90 primary outcome that has recently completed enrollment was designed on the basis of these findings (NCT03510897). Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT02610283.

Keywords: RNA, small interfering; acute kidney injury; thoracic surgery.

Figures

Figure 1.

Patient disposition. Patients were assigned in a 1:1 ratio to the teprasiran or placebo groups. Of the 360 patients randomly assigned, 19 patients (6 assigned to placebo and 13 assigned to teprasiran) were discontinued before dosing because of events arising during or after the surgery (eg, death, physician decision, withdrawal by subject, or hemodynamic instability). Of those dosed, 93.2% of the placebo group and 92.7% of the teprasiran group completed the day 90 visit. *Two subjects (1 subject in each treatment group) died after study day 90. Both subjects experienced SAEs with fatal outcomes that began before study day 90.

Figure 2.

Subgroup analysis of the primary end point (modified intention-to-treat–baseline serum creatinine required analysis set). The forest plot presents, for each subgroup, acute kidney injury odds ratio (OR) between treatments by a dot and its 95% CI by a horizontal line. The size of the dot varies proportionally with the total (Nteprasiran+Nplacebo) sample size of each subgroup. On the left side of the figure, the subgroup sample size by treatment is presented with the corresponding acute kidney injury rate. The column on the right lists the odds ratio and its 95% CI; the x-axis of the plot is in log scale. P values for odds ratio interaction between subgroups are as follows: age=0.17, CPB time=0.98, diabetes=0.34, eGFR=0.71, procedure=0.43. CPB indicates cardiopulmonary bypass; and eGFR, estimated glomerular filtration rate. *Diabetes requiring insulin treatment.

Figure 3.

Serum creatinine and serum cystatin C dynamics over time. Serum cystatin C values over time per cohort are presented as absolute (A) and change from baseline (BL; B). After a decrease in values on day 0 (day of surgery), an increase in serum cystatin C is observed in the acute postoperative period starting on day 1 in both treatment cohorts. The observed increase is maintained through day 90. Serum creatinine (sCr) values over time per cohort as absolute (C) and change from baseline (D). A rapid increase is observed on day 0 (day of surgery), reaching peak values on days 2 to 3 and decreasing to near presurgery values by day 5. sCr values at day 90 closely resemble baseline sCr values.