AM-Pharma strives to develop medicines for patients confronted with severe medical conditions. Our proprietary asset, ilofotase alfa, is initially being developed for the treatment of patients with acute kidney injury and has been granted FDA fast-track status. With approximately 1000 patients evaluated to date in clinical trials, ilofotase alfa has a proven safety profile and a demonstrated kidney benefit. 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 ilofotase alfa 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 around 3 million patients annually 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, ilofotase alfa, as a medicinal product to be used via intravenous injection for the treatment of sepsis-associated acute kidney injury (SA-AKI). Ilofotase alfa is an optimized recombinant human alkaline phosphatase with high stability and high activity.
AM-Pharma has shown that a short-term treatment with ilofotase alfa 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, ilofotase alfa has the potential to become the first pharmacological treatment for critically ill AKI patients.
OUR AKI PIPELINE
PHASE III STUDY REVIVAL UPDATE
We are finalizing 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, ilofotase alfa, for the treatment of patients with SA-AKI. The study stopped per recommendation of the data monitoring committee after per-protocol pre-specified interim futility analysis on the study’s primary endpoint, 28-day mortality, without any safety concern. After review of the unblinded data for all 649 patients in the study at the time of termination, the data showed a nominally significant reduction in Major Adverse Kidney Events by day 90. The Company intends to progress its research and development of ilofotase alfa in acute kidney injury. Further information on this study can be found at NCT04411472 (REVIVAL).
Further data will be published in a peer-reviewed journal and at scientific conferences in the first half of 2023.
Sepsis-Associated AKI
The majority of patients develop AKI at the background of sepsis. 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 dialysis need, mortality and morbidity. No singular effective therapy to alter the progression of these devastating conditions has been approved.
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 nominal significant relative reduction in major adverse kidney events at day 90 and a 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 was 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) 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.
AM-Pharma included an exploratory cohort to its Phase III REVIVAL pivotal study, to study ilofotase alfa in up to 33 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.
In the COVID-19 cohort of the REVIVAL study, patients treated with ilofotase alfa experienced a nominal reduction in 28-day all-cause mortality compared to those treated with placebo (nominal p <0.05).
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’s potent inhibition processes of acute inflammation and coagulation by dephosphorylating extracellular ATP/ADP are considered highly relevant to the respiratory failure and other organ failures described for COVID-19 patients admitted to the ICU.
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).
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 occur 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.
We have therefore included an additional exploratory cohort to REVIVAL, around 50% of patients with moderate to severe CKD were be enrolled (reference eGFR < 75ml/min). Treatment with ilofotase alfa may also protect renal function as well as reduce mortality in this patient population.
Patients with CKD also experience episodes of AKI with increased risk of death or worsening of CKD. Furthermore, patients who were administrated ilofotase alfa have shown a decreased risk of CKD and subsequent AKI episode.7
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 protect renal function, reduce inflammation and improve recovery in patients undergoing elective cardiac surgery (e.g. coronary artery bypass grafts (CABG) and/or valve surgery).
AM-Pharma obtained regulatory advice from both FDA and EMA for its proposed clinical trial.
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 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
