Recombinant alkaline phosphatase for use in treating sepsis-associated acute kidney injury
Inventors
PICKKERS, Roelof Peter • Mehta, Ravindra Lall • Murray, Patrick Thomas • Joannidis, Michael • Van Den Berg, Erik Jan • Arend, Jacques Salomon Robert
Assignees
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Publication Number
US-12178857-B2
Publication Date
2024-12-31
Expiration Date
Abstract
The present disclosure relates to the use of alkaline phosphatases, and in particular improved alkaline phosphatases such as RecAP, for the prevention, treatment, cure, or amelioration of the symptoms of acute kidney injury caused, e.g., by sepsis. The application relates to methods of preserving renal function renal function, shortening the duration of renal replacement therapy, increasing the creatinine clearance, decreasing the risk of death in subjects with sepsis-associate acute kidney injury (SA-AKI) or at risk of SA-AKI.
Core Innovation
The disclosure describes recombinant chimeric alkaline phosphatase (RecAP; SEQ ID NO:1) for treating sepsis-associated acute kidney injury (SA-AKI). The approach treats a subject in need thereof by administering an effective amount of alkaline phosphatase (AP) such that renal function increases.
A subject is selected based on baseline kidney impairment defined by ECC (endogenous creatinine clearance) or eGFR (estimated glomerular filtration rate), and the AP is administered as a chimeric AP having 100% sequence identity to the amino acid sequence of SEQ ID NO:1. The disclosure links subject stratification by ECC/eGFR threshold ranges to differential efficacy.
The disclosure requires AP dosing within 500 U/kg to 2,000 U/kg and specifies that administration results in an increase in renal function compared with no-treatment, including increased ECC versus no-treatment and increased eGFR versus no-treatment. The disclosure reports clinical-trial outcomes from the STOP-AKI study evaluating RecAP in SA-AKI, including renal endpoints and safety/clinical outcomes.
Claims Coverage
The partial content includes one independent claim, which defines a method of treating SA-AKI using a chimeric AP with 100% sequence identity to SEQ ID NO:1. The claim includes three core inventive elements: subject baseline kidney impairment thresholds, a defined chimeric AP sequence identity, and AP dosing that increases renal function.
Chimeric AP sequence identity to SEQ ID NO: 1
The AP is a chimeric AP having 100% sequence identity to the amino acid sequence of SEQ ID NO: 1.
Baseline kidney impairment selection by ECC or eGFR
The subject has an ECC rate 15-60 mL/min prior to treatment with AP or an eGFR 15-60 mL/min prior to treatment with AP.
Dose range that increases renal function
AP is administered in at least one dose of 500 U/kg to 2,000 U/kg, and administration results in an increase in renal function.
Across the single independent claim, the method is defined by chimeric AP with 100% sequence identity to SEQ ID NO:1, a subject selection based on ECC or eGFR ranges of 15-60 mL/min, and AP dosing within 500 U/kg to 2,000 U/kg that results in increased renal function.
Stated Advantages
Increased renal function after administration compared with no-treatment (e.g., increased ECC and/or increased eGFR).
Later improvements in ECC and reduced major adverse kidney events and mortality in the STOP-AKI study (including lower 28-day mortality vs placebo).
Improved long-term renal recovery and survival.
Documented Applications
Treatment of sepsis-associated acute kidney injury (SA-AKI) in a subject in need thereof.
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