Sepsis-Associated Acute Kidney Injury

Our goal is to develop and commercialize our proprietary recombinant human alkaline phosphatase therapeutic to transform the treatment prospects for patients with Sepsis-Associated Acute Kidney Injury (SA-AKI) – a devastating disease with high mortality rates and no approved pharmacological treatments, affecting millions of patients worldwide.

URGENT MEDICAL NEED

Acute kidney injury (AKI) is an acute inflammation of the kidney, which impairs the kidney function. It involves inflammatory processes in the kidney which may result in the need for dialysis. If the patient survives, the damage may not always be reversible and can even lead to complete loss of renal function, requiring kidney replacement. 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.
Patients with AKI have reduced alkaline phosphatase levels and activity in the kidneys. Alkaline phosphatase is a common endogenous enzyme present in many cells and organs (e.g. intestines, placenta, liver, bone, kidney and granulocytes). AM-Pharma has developed a novel recombinant human alkaline phosphatase as a medicinal product to be used via intravenous injection for the treatment of sepsis-associated acute kidney injury (SA-AKI). The recombinant alkaline phosphatase is an optimized recombinant human alkaline phosphatase with high stability and high activity.
AM-Pharma has shown that a short-term treatment with recombinant alkaline phosphatase helps protect kidney function in AKI, which can be classified as a disease modifying anti-inflammatory effect. Currently the only treatment option is dialysis and supportive care and no drugs are approved to treat AKI. Typically, these patients are treated in Intensive Care Units, often with support of nephrologists.^1,2,3,4

With no drugs currently approved to treat the condition, recombinant alkaline phosphatase could become the first pharmacological treatment for critically ill AKI patients.

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}

CLINICAL STUDIES

PHASE III STUDY UPDATE

We are conducting our Phase III REVIVAL pivotal study, a randomized, double-blind, placebo-controlled, two-arm, parallel-group, multi-center trial to evaluate the efficacy and safety of our proprietary human recombinant alkaline phosphatase for the treatment of patients with SA-AKI. The study will enroll approximately 1400 patients with SA-AKI in the main study population. In two exploratory cohorts, up to 100 patients with moderate Chronic Kidney Disease (CDK) and up to 100 patients with COVID-19 will be enrolled. 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 www.clinicaltrials.gov, NCT04411472 (REVIVAL).

Recombinant Alkaline Phosphatase in COVID-19

Systemic administration of recombinant alkaline phosphatase demonstrated potent inhibition of acute inflammation in kidney, lungs, liver, gut and other organs. The recombinant enzyme displays exquisite activity towards dephosphorylating and detoxifying damage-associated molecular patterns (DAMPs) and pathogen-associated molecular patterns (PAMPs) such as lipopolysaccharide (LPS), ATP, ADP and other extracellular substrates that drive acute inflammation, coagulation and microvascular ischemia found in kidney, lung and liver following sepsis or ischemia-induced damage. These potent inhibition processes of acute inflammation and coagulation by dephosphorylating extracellular ATP/ADP are considered to be highly relevant to the respiratory failure and other organ failures described for COVID-19 patients admitted to the ICU.

AM-Pharma included an exploratory cohort to its Phase III REVIVAL pivotal study, to test recombinant alkaline phosphatase in up to 100 COVID-19 patients admitted to the ICU with respiratory issues and AKI to prevent worsening of the disease and to enhance the chance for patients to recover with adequate organ function by including a COVID-19 cohort in its Phase III clinical trial.
Severe COVD-19 patients often present acute inflammation, organ failure with variable rates of Acute Kidney Injury (AKI) and thrombosis; up to 90% of the patients that received mechanical ventilation also suffered from AKI, as reported in the US recently1.

Potentially over 100 sites across Europe, the United Kingdom and North America will enroll patients in the study. Topline safety and futility analyses on the first patients is expected by the end of 2021. Target enrollment of up to 1,600 patients and data on the primary endpoint of 28-day all-cause mortality is expected in 2023.

Further information about this study can be found at www.clinicaltrials.gov, NCT04411472 (REVIVAL).

PHASE I AND II STUDY SUMMARY

AM-Pharma has completed an adaptive Phase II study for the use of recombinant alkaline phosphatase in patients with AKI. This was the largest interventional clinical study in AKI to date, involving 301 patients.
The STOP-AKI (Sepsis Trial Of alkaline Phosphatase in Acute Kidney Injury) trial was a safety, tolerability, efficacy and Quality of Life study of human recombinant alkaline phosphatase for the treatment of SA-AKI patients.

This international, randomized, double-blind, placebo-controlled clinical study involved 301 sepsis patients and 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 recombinant alkaline phosphatase 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, recombinant alkaline phosphatase was shown to well tolerated and did not raise any safety concerns.

In 2014, AM-Pharma successfully completed a Phase I clinical trial with recombinant human alkaline phosphatase in healthy volunteers and no safety issues were observed in any of the dosing groups.

Further details about the study protocol can be found here.

The full report on the study data can be found in JAMA.

The US FDA has granted Fast Track designation to recombinant alkaline phosphatase for the treatment of sepsis-associated AKI.