AM-Pharma’s purpose is to save and improve the lives of patients confronted with severe medical conditions. Our initial focus is sepsis-associated acute kidney injury, the cause of death for hundreds of thousands of people hospitalized each year. Our proprietary compound, ilofotase alfa, has the potential to become the first treatment for sepsis-associated acute kidney injury and is now in a global pivotal Phase III clinical trial. We are a dedicated team driven to bring treatment options to severely ill patients, their families and acute care professionals.
Our Product and its Mode of Action
RECOMBINANT ALKALINE PHOSPHATASE
We have developed a proprietary recombinant alkaline phosphatase (ilofotase alfa), constructed from two human isoforms of alkaline phosphatase, that has demonstrated in multiple clinical trials to be stable and highly active.
Mechanism of Action
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. 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).
The anti-inflammatory properties of alkaline phosphatase 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 alkaline phosphatase in AKI. Read more in our publication section.
Acute Kidney Injury (AKI)
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.1,2,3,4,5
With no drugs currently approved to treat the condition, recombinant alkaline phosphatase could become the first pharmacological treatment for critically ill AKI patients.
OUR AKI PIPELINE
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 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.
Sepsis-Associated AKI
The majority of patients develop AKI at the background of sepsis. Indeed, AKI is a common complication in hospitalized and critically ill patients. The kidney is the most commonly affected organ, resulting in SA-AKI and significantly increasing the risk for mortality and morbidity in sepsis. No singular effective therapy to alter the progression of these devastating conditions has been approved. AM-Pharma initiated in 2020 its Phase III pivotal study REVIVAL which will be conducted on 3 continents involving 13 countries and 100+ hospitals.
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
COVID-19 and AKI
The outbreak of coronavirus disease 2019 (COVID-19) has rapidly evolved into a global pandemic. Most patients with COVID-19 have mild symptoms, but about 5% develop severe symptoms which can include acute respiratory distress syndrome, septic shock, and multiple organ failure and can lead to death in 20-50% of the severe cases.
Kidney involvement in COVID-19 is frequent, with clinical presentation ranging from mild proteinuria to progressive acute kidney injury (AKI) necessitating renal replacement therapy including dialysis, as the illness develops and afterwards as patient recovers from COVID-19. An expanding literature base shows that kidney disease plays a central role in the cycle of multi-organ failure in advanced disease stages, ultimately leading to death. The incidence of AKI in severe COVID-19 ranges between publications from 30-80%. AKI is considered a marker of disease severity and negative prognostic factor for survival.
Despite the fact that a handful of drugs have received conditional approval in some countries or show promising clinical results, mortality remains high and more specific treatment options for the critically ill COVID-19 patients are required. Ilofotase alfa 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.
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 recently.6
Further information about this study can be found at NCT04411472 (REVIVAL).
Moderate to severe Chronic Kidney Disease and AKI
Chronic Kidney Disease (CKD) is a condition characterized by a gradual loss of kidney function over time. If kidney disease gets worse, wastes can build to high levels in the blood and make patients feel sick. Additional complications may include high blood pressure, anemia (low blood count), weak bones, poor nutritional health and nerve damage. Also, kidney disease increases the risk of having heart and blood vessel disease. These problems may happen slowly over a long period of time. CKD may be caused by diabetes, high blood pressure and other disorders. When kidney disease progresses, it may eventually lead to kidney failure, which requires dialysis or a kidney transplant to maintain life.
Patients with CKD also experience episodes of AKI with increased risk of death or worsening of CKD. Furthermore, patients who were administrated ilofotase alfa shown a decreased risk for CKD and next AKI episode.7
We have therefore included an additional exploratory cohort to REVIVAL, up to 100 patients with moderate to severe CKD will be enrolled. Treatment with ilofotase alfa may also protect renal function as well as reduce mortality in this patient population.
Cardiovascular Surgery and Acute Kidney Injury
Based upon the mechanism of action of ilofotase alfa together with data generated in animal models of ischemia reperfusion injury (IRI) relevant for cardiac surgery associated acute kidney injury (CSA-AKI), it is considered that treatment with ilofotase alfa will reduce the protect renal function, inflammation and improve recovery in patients undergoing elective cardiac surgery (e.g. coronary artery bypass grafts (CABG) and/or valve surgery).
CSA-AKI occurs in 8-17% of patients with CABG and/or valve replacement. AKI after CSA increases the total index hospital costs with ~US$40,000, totaling to US$1bln annually in the US.8
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
6 Hirsch, J.S. et al. Kidney International, 2020; DOI: 10.1016/j.kint.2020.05.006
7 Simon Sawhney, Simon Fraser, PMCID: PMC5648688 DOI: 10.1053/j.ackd.2017.05.001
8 Husain N. Alshaikh, Nevin M. Katz, et al. PMID: 29275828.DOI: 10.1016/j.athoracsur.2017.10.053
