Acute Kidney Injury (AKI) involves an inflammatory process in the kidney which can lead to complete loss of renal function. Hospital-acquired AKI affects annually around 2 million patients. It occurs in as many as 4% of hospital admissions and 40% of critical care admissions. Depending on the severity and cause of renal injury, mortality ranges from 10% to as high as 70%. Annually, the deaths of around 700,000 patients in Europe, US and Japan are related to AKI. In the US alone, around USD10 billion is spent each year on managing this big medical problem. The most important causes of AKI are sepsis, cardiovascular surgery, exposure to nephrotoxic drugs and trauma. AKI patients that need dialysis have the worst prognosis. Currently the only treatment option is dialysis and supportive care. No drugs are approved to treat this condition. Typically these patients are treated in Intensive Care, often with support of nephrologists. The incidence is increasing because of an aging population, an increasing exposure to nephrotoxic drugs in hospitals, increasing number of surgical interventions and an increasing incidence of hospital infections. An effective drug to treat AKI could be commercially very important. Because of the large number of patients suffering from AKI, the high medical need and the lack of competitors, worldwide annual sales of over USD2 billion could be achieved with an effective drug treatment.
Clinical trials
Intravenous administration of bovine AP was proven to be safe in healthy volunteers in two phase I clinical studies.
Two Phase II clinical trials with Bovine AP were conducted in patients. Safety was confirmed in these trials.
The first study (AP SEP) was a double-blind, randomized, placebo-controlled multicenter trial with 24 hour treatment in 36 patients sepsis. Retrospectively a subgroup of sixteen patients (11 active, 5 placebo) with Acute Kidney Injury did particularly well with regard to kidney function. In this studythe dialysis requirement (RRT) in the subgroup of renal failure patients that received placebo treatment was (80%) and 36% in the group that received AP (see Figure 1).
Figure 1: Dialysis need (RRT) in the subgroup of sepsis patients with AKI.
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Alkaline Phosphatase for treatment of sepsis and acute kidney injury (201 KB) |
The second phase II (AP REN) study was designed to prospectively confirm the findings of the first study. The APREN study was a double-blind, randomized, placebo-controlled multicenter trial with 24 hour treatment in 36 patients with Acute Kidney Injury and confirmed sepsis. Acute Kidney Injury was diagnosed according to Acute Kidney Injury Guidelines at baseline. Preservation and improvement of the primary efficacy parameter, kidney function, was confirmed by improvement of the filtration function (measured by creatinine clearance rate) and a reduced requirement for both initiation as well as duration of dialysis. Positive results were also observed in secondary parameters as length of ICU and hospital stay, need for mechanical ventilation, and a range of surrogate markers for kidney injury (KIM-1, IL-18, GSTA1-1) and general inflammation (CRP, LBP).
The results of this successful trial in sepsis associated acute kidney injury patients have been presented at several international conferences (a/o ISICEM 2010, Renal Week 2010) and have been submitted for publication.
