Acute Kidney Injury (AKI)
Our goal is to develop and commercialize our recombinant human Alkaline Phosphatase therapeutic (ilofotase alfa) to transform the treatment prospects for patients with Acute Kidney Injury (AKI) – a devastating disease with high mortality rate and no approved pharmacological treatments, affecting millions of patients worldwide.
Urgent medical need
Acute Kidney Injury (AKI) involves inflammatory processes in the kidney which can lead to complete loss of renal function. Hospital‐acquired AKI affects annually around 3 million patients in Europe, the US and Japan, and is associated with mortality in roughly 700,000 patients. It occurs in 40-60% of critical care admissions. Depending on the severity and cause of renal injury, mortality ranges from 10% to as high as 60%. In the US alone, hospitals spend around $10 billion each year on managing this major medical problem. The most important causes of AKI are sepsis, cardiovascular surgery, exposure to nephrotoxic drugs and trauma. 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 Units, often with support of nephrologists.1,2,3,4
AM-Pharma has designed and developed an innovative recombinant human Alkaline Phosphatase (AP) therapeutic (ilofotase alfa) for the treatment of AKI, from scientific research to promising Phase II clinical trials. With no drugs currently approved to treat the condition, ilofotase alfa could become the first pharmacological treatment for critically ill AKI patients.5
Background information on AKI’s medical need:
1 U.S. Food and Drug Administration
2 Murugan R. and Kellum J.A., (2011) Nat Rev Nephrol. Vol 7: 209-217
3 Heung M. and Chawla L., (2014) Nephron Clin Pract. Vol 127: 30-34
4 Chertow et al., (2005) J Am Soc Nephrol. Vol 16: 3365-3370 Soc Nephrol. Vol 16: 3365-3370
5 Knotnerus DDW 2014 Developing the first treatment for AKI
AM-Pharma has completed an adaptive Phase II study for ilofotase alfa in patients with AKI. This was the largest interventional clinical study in AKI to date, involving 301 patients.
AM-Pharma started the REVIVAL Phase III pivotal study in H1 2020.
Phase III Study REVIVAL
The REVIVAL trial is a Phase III pivotal, randomized, double-blind, placebo-controlled, two-arm, parallel-group, multi-center study evaluating the efficacy and safety of AM-Pharma’s proprietary recombinant alkaline phosphatase, ilofotase alfa, for the treatment of patients with SA-AKI. The primary endpoint of the study is all-cause mortality 28 days post-treatment start with ilofotase alfa at a dose of 1.6 mg/kg. In the Phase II study of ilofotase alfa, the patient group treated with this dose experienced a statistically significant 46% relative reduction in mortality compared to the group treated with placebo (p= 0.022). REVIVAL was initiated in November 2020 and is enrolling up to 1,400 patients with SA-AKI in the main study population in North America, Europe and Japan. As per the study protocol, four interim analyses for futility and/or efficacy will be conducted when enrollment hits certain levels and the first futility analysis will occur when 400 patients have been treated.
The primary aim of the study is to confirm the improvement on the primary endpoint of 28-day all-cause mortality, as observed in the Phase II STOP-AKI study. Secondary endpoints include the treatment effect on long-term Major Adverse Kidney Events (MAKE), on the use of organ support, length of stay in the ICU and on 90-day all-cause mortality. Further information on this study can be found at at NCT04411472 (REVIVAL).
Target enrolment of up to 1,400 patients and data on the primary endpoint of 28-day all-cause mortality are expected in 2023.
In addition to the REVIVAL study, the PMDA has approved enrollment into a Phase I pharmacokinetics (PK), safety and tolerability study in healthy Japanese subjects, which is being conducted in parallel to REVIVAL in Japan.
Phase II study summary
The STOP-AKI (Sepsis Trial Of alkaline Phosphatase in Acute Kidney Injury) trial was a safety, tolerability, efficacy and QoL study of human recAP in the treatment of patients.
This international, randomized, double-blind, placebo-controlled clinical study involved 301 sepsis patients. It was conducted at 53 intensive care unit sites, across 11 countries in Western Europe and North America.
The study demonstrated a significant relative reduction in mortality of more than 40% in the treatment group compared to the placebo group. While the addition of ilofotase alfa to the standard of care did not affect kidney function in the first week of the study (the primary endpoint), it did show a significant, progressive and sustained improvement in renal function over the 28-day study period. Throughout the study, ilofotase alfa well tolerated and did not raise any safety concern.
The full report on the study data can be found in JAMA: https://jamanetwork.com/journals/jama/fullarticle/2710776
Further details about the study protocol can be found at: https://bmjopen.bmj.com/content/6/9/e012371
Background information on the STOP-AKI adaptive trial design:
AM-Pharma starts adaptive phase II trial of recAP in AKI
Robust STOP-AKI clinical data with strong positive read-through to pivotal trial
To support regulatory approval from the US Food and Drug Administration (FDA) and European Medicines Agency (EMA), AM-Pharma has initiated its large multinational Phase III REVIVAL pivotal study.
The US FDA has granted Fast Track designation to recAP for the treatment of sepsis-associated AKI.
ilofotase alfa (formerly reCAP)
ilofotase alfa is a proprietary protein constructed from two naturally occurring human isoforms of AP, optimized to achieve high stability and activity. ilofotase alfa is manufactured according to cGMP for clinical trial supply, and then formulated for intravenous use. The process has been scaled-up for phase-III clinical and commercial supply.
Molecular model of recombinant Alkaline Phosphatase (AP), recAP, a homodimer consisting of the activity domains from human intestinal AP (displayed in white) and the stability or crown domains from placental AP (red). (courtesy of Prof J.L. Millan, Sanford Burnham Institute Medical Research, UCSD, La Jolla, CA)
Mechanism of action
Acute Kidney Injury (AKI) is a severe inflammation and damage of the kidney resulting in a sudden drop in kidney function, which can sometimes result in complete kidney failure. AM-Pharma has discovered that one key function of the enzyme Alkaline Phosphatase (AP) is to protect organs against inflammation and tissue damage.
AP acts as a detoxifying agent by removing phosphate from extracellular substrates. The dephosphorylation of pro-inflammatory substances like lipopolysaccharides (LPS) and extracellular ATP plays an important anti-inflammatory role. Research has shown that ATP dephosphorylation has a double effect in protecting against kidney injury. When the pro-inflammatory ATP is dephosphorylated the resulting adenosine further reduces inflammation through the activation of the immunosuppressive adenosine A2a receptor pathway (A2aR).
Our proprietary recombinant human AP (recAP) has a dual mechanism of action via dephosphorylation of lipopolysaccharides (LPS) and extracellular ATP. We have shown that treatment of patients with exogenous AP not only reduces local and systemic inflammation but also protects the kidney against further damage.
The anti-inflammatory properties of AP were first published by professor Poelstra and team at Groningen University, the Netherlands. Our scientists and affiliated researchers have since published extensively on the role of AP in AKI. Read more in our publication section.
For further information on the mode of action of AP in AKI patients please see: