By Arnaldo Lopez-Ruiz, MD
Attending Physician, Division of Critical Care, AdventHealth Medical Group, AdventHealth Orlando, FL
SYNOPSIS: This Phase III, international, multicenter, double-blind, randomized controlled trial did not show a reduction in 28-day all-cause mortality with ilofotase alfa (recombinant human alkaline phosphatase). However, the study showed evidence to suggest that ilofotase alfa reduced major adverse kidney events at 90 days, mainly driven by lowering the incidence of renal replacement therapy through day 90 in these patients.
SOURCE: Pickkers P, Angus DC, Bass K, et al; REVIVAL Investigators. Phase-3 trial of recombinant alkaline phosphatase for patients with sepsis-associated acute kidney injury (REVIVAL). Intensive Care Med 2024;50:68-78.
Sepsis-associated acute kidney injury (SA-AKI) is a strong contributor to poor intensive care unit (ICU) outcomes.1 Currently there are no specific pharmacological therapies approved for the treatment of SA-AKI, and the management mainly consists of supportive care, sepsis treatment, and prevention of additional renal insults.1 Ilofotase alfa is a human recombinant alkaline phosphatase with reno-protective effects that previously showed improved survival and reduced major adverse kidney events by 90 days (MAKE90) in SA-AKI patients in Phase II studies.2 The REVIVAL study was a Phase III trial conducted to confirm the drug’s efficacy and safety.
In this international, double-blinded, randomized controlled trial, the cohort of patients was pre-categorized into three groups: patients with SA-AKI with a pre-acute kidney injury (AKI) estimated glomerular filtration rate (eGFR) ≥ 45 mL/min/1.73 m2 and no proven or suspected COVID-19 at the time of randomization (“main trial population”); patients with SA-AKI with a pre-AKI eGFR ≥ 25 and < 45 mL/min/1.73 m2 with no COVID-19 (“moderate-to-severe CKD population or mCKD”); and patients with COVID-19-induced sepsis and AKI at the time of randomization (“COVID-19 population”).3 Patients received the study medication within 24 hours if sepsis was present prior to the development of AKI and within 48 hours if AKI was diagnosed at the time of sepsis. Ilofotase alfa was administered at 1.6 mg/kg per day for three consecutive days, with a maximal dose of 192 mg for those patients weighing more than 120 kg.
The study’s primary endpoint was 28-day all-cause mortality. The main secondary endpoint was MAKE90, which included two definitions: MAKE90A and MAKE90B. MAKE90A was defined as death, > 25% decline of eGFR, renal replacement therapy (RRT) status at day 90, any RRT needs through day 28, and rehospitalization. MAKE90B included death through day 90, > 25% decline of eGFR at day 28 and day 90, or RRT at day 90. Additional secondary endpoints included days alive and without the need for organ support through day 28, days alive and free from the ICU through day 28, and time to death through day 90.
Overall, 649 patients were treated and analyzed (330 in the ilofotase alfa group and 319 in the placebo group). The observed mortality rates were 27.9% in the ilofotase alfa group and 27.9% in the placebo group at 28 days, and 33.9% in the ilofotase alfa group vs. 34.8% in the placebo group at 90 days. The researchers stopped the trial for futility on the primary endpoint. The observed proportion of patients with MAKE90A and MAKE90B events was 56.7% and 37.4%, respectively, in the ilofotase alfa group compared to 64.6% and 42.8%, respectively, in the placebo group. The median days alive and without the need for organ support were 17 days (interquartile range [IQR], 0-24 days) vs. 14 days (IQR, 0-24 days). The number of days alive and out of the ICU through day 28 were 15 days (IQR, 0-22 days) in the ilofotase alfa group vs. 10 days (IQR, 0-22 days) in the placebo group. Adverse events were reported in 67.9% of patients in the ilofotase group and in 75% patients in the placebo group. In summary, among critically ill patients with SA-AKI, ilofotase alfa did not improve day 28 survival. However, ilofotase alfa contributed to significantly reduced MAKE90 events, mainly by reducing the rate of RRT at 90 days. No safety concerns were identified.
COMMENTARY
Sepsis is the leading cause of AKI in critically ill patients secondary to inflammatory, direct nephrotoxic, and ischemic processes.4 Development SA-AKI is independently associated with increased morbidity and mortality.1 Previous preclinical, observational, and Phase II studies have shown that ilofotase alfa exerts a potent reno-protective action by inducing dephosphorylation of extracellular pro-inflammatory molecules such as endotoxin or adenosine triphosphate (ATP).5,6
The REVIVAL trial evaluated the safety and efficacy of this new potent anti-inflammatory drug. The reno-protective role of ilofotase alfa for the REVIVAL trial was supported by the previous results of the STOP-AKI Phase II trial in which 300 critically ill patients with sepsis but without evidence of AKI were randomized to ilofotase alfa.2 Although recombinant alkaline phosphatase did not result in improvement of renal function at 28 days, there was a trend in fewer major adverse kidney events (MAKE) at 60 and 90 days, driven primarily by differences in mortality between the groups.2 This difference in mortality was 14% in the ilofotase alfa group vs. 27% in the placebo group.2
Of note, in the REVIVAL study, the patients had a baseline mean eGFR of 71 mL/min/1.73 m2 before the AKI event, and most of the enrolled patients had mild (43%) to moderate (28%) AKI, which usually are the patients with higher chances of renal recovery. Also notable was that the observed 28-day mortality rates in the ilofotase alfa and control groups (27.9% and 27.9%, respectively) both were well below the expected 35% event rate in the control group, a finding that can negatively affect the overall power of the planned study, which also incorporated a somewhat unrealistic proposed effect size of an 8% absolute mortality difference.
Similar to the STOP-AKI trial, the REVIVAL trial also showed that ilofotase alfa markedly reduced MAKE90A events (57% vs. 65% in the placebo arm), mainly driven by a lower incidence of RRT through day 90.2 Ilofotase alfa showed a benefit over placebo in the probability of a MAKE90A event for patients with lower baseline (pre-AKI) eGFRs. A post hoc analysis showed evidence of an interaction between renal function before the SA-AKI episode (pre-AKI eGFR) and the incidence of a MAKE90A event, which suggests that the therapeutic efficacy of ilofotase alfa was more pronounced in patients with a lower pre-AKI eGFR (i.e., more severe preexisting chronic kidney disease) (P = 0.024).
Although the REVIVAL trial was stopped early due to futility, ilofotase alfa still may hold some promise as a treatment for SA-AKI as it was associated with fewer MAKE90 events with no serious major safety concerns. It will be interesting to evaluate these patients at 180 days, which has not been reported yet. Further studies should focus on: 1) determining if early mild-moderate stages of AKI (stage 1 and 2) are more likely to respond to the drug; 2) evaluating a phenotype that may predict which patients will respond to this medication; 3) evaluating the impact of ilofotase alfa on lung injury associated with sepsis; and 4) using a standardized criteria for MAKE90.
REFERENCES
- Zarbock A, Nadim MK, Pickkers P, et al. Sepsis-associated acute kidney injury: Consensus report of the 28th Acute Disease Quality Initiative Workgroup. Nat Rev Nephrol 2023;19:401-417.
- Pickkers P, Mehta RL, Murray PT, et al; STOP-AKI Investigators. Effect of human recombinant alkaline phosphatase on 7-day creatinine clearance in patients with sepsis-associated acute kidney injury: A randomized clinical trial. JAMA 2018;320:1998-2009.
- Pickkers P, Angus DC, Arend J, et al. Study protocol of a randomised, double-blind, placebo-controlled, two-arm parallel-group, multi-centre phase 3 pivotal trial to investigate the efficacy and safety of recombinant human alkaline phosphatase for treatment of patients with sepsis-associated acute kidney injury. BMJ Open 2023;13:E065613.
- Wen X, Peng Z, Kellum JA. Pathogenesis of acute kidney injury: Effects of remote tissue damage on the kidney. Contrib Nephrol 2011;174:129-137.
- Peters E, Geraci S, Heemskerk S, et al. Alkaline phosphatase protects against renal inflammation through dephosphorylation of lipopolysaccharide and adenosine triphosphate. Br J Pharmacol 2015;172:4932-4945.
- Heemskerk S, Masereeuw R, Moesker O, et al; APSEP Study Group. Alkaline phosphatase treatment improves renal function in severe sepsis or septic shock patients. Crit Care Med 2009;37:417-423, e1.
