AM-Pharma’s purpose is to save and improve the lives of patients confronted with severe medical conditions. Our focus is acute on chronic kidney injury, impacting hundreds of thousands of people hospitalized each year. Our proprietary compound, ilofotase alfa, has the potential to become the first treatment for acute kidney injury and its safety and a potential reno-protective effect has been demonstrated in global clinical trials involving approximately 1,000 subjects. In addition, based upon preclinical data showing improved overall survival and restored phenotypes associated with hypophosphatasia (HPP) as well as a biomarker dose response in adult patients with HPP treated with ilofotase alfa, we are developing ilofotase alfa as a potential enzyme replacement therapy in HPP. We are a dedicated team driven to bring treatment options to severely ill patients, their families and health 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
About ilofotase alfa
Ilofotase alfa is a proprietary recombinant alkaline phosphatase, constructed from two human isoforms of alkaline phosphatase, that has been shown to be well tolerated, stable and highly active in multiple clinical trials in acute kidney injury and hypophosphatasia.
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 and microvascular ischemia found in acute kidney injury. 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.
In hypophosphatasia, ilofotase alfa addresses elevated levels of pyridoxal-5′-phosphate (PLP), inorganic pyrophosphates (PPi), two disease related biomarkers that are related to, for example, bone mineralization and pain sensation.
Read more in our publication section.
OUR PIPELINE: AKI AND HPP
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. Especially patients with a Chronic Kidney Disease background are particularly vulnerable to experiencing an AKI event. 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 is developing a novel recombinant human alkaline phosphatase, ilofotase alfa, as a medicinal product to be used via intravenous injection for the prevention of AKI in patients with CKD undergoing cardiovascular surgery and treatment of patients with CKD and sepsis-associated acute kidney injury (SA-AKI). 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.1,2,3,4,5
With no drugs currently approved to treat these conditions, ilofotase alfa has the potential to become the first pharmacological treatment for acute on chronic kidney injury patients.
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.
In REVIVAL, around 50% of patients with moderate to severe CKD were 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 experience episodes of AKI with increased risk of death or worsening of CKD. Furthermore, patients who were administered ilofotase alfa have shown a decreased risk of CKD and subsequent AKI episode.7
PHASE III STUDY REVIVAL UPDATE
We have completed 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 (https://bmjopen.bmj.com/content/13/4/e065613). 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 consistent with results from the Phase II STOP-AKI study (JAMA: https://jamanetwork.com/journals/jama/fullarticle/2710776)
Further data on REVIVAL have been presented at scientific conferences (https://www.isicem.org/19/Abstract.asp, P179; www.crrtonline.com/conference/support/AKI&CRRT2023_Syllabus.pdf) and will be published in a peer-reviewed journal.
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 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, and is advancing ilofotase alfa into a Phase II study.
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
Hypophosphatasia (HPP)
Hypophosphatasia is an inherited disease associated with low serum alkaline phosphatase activity.
Adult hypophosphatasia disease characteristics
In adults reduced serum alkaline phosphatase activity generally results in functional limitations with quality of life that is compromised by muscle weakness, mobility constraints, pain and fatigue. Disease often occurs in middle-aged adults and has a progressive but varied presentation.
Patients can develop a range of other complications including: chondrocalcinosis, joint inflammation, osteoarthropathy, vertebral fracture, musculoskeletal discomfort, muscle fatigue, hypercalcemia, nephrocalcinosis, kidney failure, chronic inflammation, and neurological symptoms (fatigue, headache, sleep disturbance, gait changes, vertigo, depression, neuropathy, anxiety disorder, and hearing loss.Data from patients in the Global Hypophosphatasia Registry show that considerable disability and compromised quality of life occur even in patients without overt skeletal manifestations.
Hypophosphatasia disease management
For adults with paediatric-onset hypophosphatasia there is currently one treatment option, an alkaline phosphatase enzyme replacement therapy (asfotase alfa) administered via subcutaneous injection, to treat bone manifestations. Asfotase alfa is not indicated for hypophosphatasia identified in adults.
However, moderately-affected patients are less likely to be diagnosed when young and, as a result, are ineligible for asfotase alfa treatment, and they therefore do not receive disease-specific treatment as symptoms develop in later life . As a result, older patients with moderate-severity disease often remain untreated and can be left with reduced quality of life, pain, muscle weakness, and mobility issues. Hence there is a clear unmet treatment need for individuals whose hypophosphatasia is diagnosed in adulthood.
Ilofotase alfa is able to cleave pyrophosphate to release inorganic phosphate which can be incorporated into hydroxyapatite crystals that mineralise bone, with the potential to restore skeletal integrity in hypophosphatasia patients. Ilofotase alfa does not contain a bone-targeting sequence, which raises the possibility that it could also manage non-bone consequences such as the muscle weakness associated with elevated levels of other substrates such as pyridoxal 5’-phosphate (PLP). Initial proof-of-concept for the potential applicability of ilofotase alfa in hypophosphatasia was shown when it was administered to mice with a knockout mutation in the TNAP gene. Ilofotase alfa alleviated multiple hypophosphatasia manifestations in these animals: improving bone and dental mineralisation and cartilage development; reducing the development of craniosynostosis, kidney inflammation/calcification, and seizures; and normalizing body weight and lifespan. These early nonclinical data indicating potential efficacy for ilofotase alfa in the hypophosphatasia setting are supported by extensive nonclinical and clinical safety data in healthy volunteers and patients with other disease indications, which indicate a very favourable safety profile.
We are currently conducting a single-center, open-label, pilot study to assess the effects of intravenous (i.v.) ilofotase alfa administration on hypophosphatasia biomarker levels in adults with the disease. As ilofotase alfa will be required as a life-long treatment in the hypophosphatasia indication, we are developing a s.c. flat-dose formulation that can be readily administered by the patient at home.
Background information on HPP:
Mornet E. Hypophosphatasia. Metab. 2018;82:142-155
Whyte MP, Landt M, Ryan LM, et al. Alkaline phosphatase: placental and tissue-nonspecific isoenzymes hydrolyze phosphoethanolamine, inorganic pyrophosphate, and pyridoxal 5’-phosphate. J Clin Invest. 1995;95(4):1440-1445.
Whyte MP. Hypophosphatasia – aetiology, nosology, pathogenesis, diagnosis and treatment. Endocrinology. 2016;12:233-246.
Dahir KM, Seefried L, Kishnani PS, et al. Clinical profiles of treated and untreated adults with hypophosphatasia in the Global HPP Registry. Orphanet J Rare Dis. 2022;17(1):277.
Dahir KM, Kishnani PS, Martos-Moreno GA, et al. Impact of muscular symptoms and/or pain on disease characteristics, disability, and quality of life in adult patients with hypophosphatasia: A cross-sectional analysis from the Global HPP Registry. Front Endocrinol. 2023;14:1138599.
Salles JP. Hypophosphatasia: Biological and clinical aspects, avenues for therapy. Clin Biochem Rev. 2020;41(1):13-27.
Seefried L, Dahir K, Petryk A, et al. Burden of illness in adults with hypophosphatasia: data from the global hypophosphatasia patient registry. J Bone Miner Res. 2020;35(11):2171-2178.
Seefried L, Kishnani PS, Moseley S, et al. Pharmacodynamics of asfotase alfa in adults with pediatric-onset hypophosphatasia. Bone. 2021a;142:115664.
Seefried L, Rak D, Petryk A, Genest F. Bone turnover and mineral metabolism in adult patients with hypophosphatasia treated with asfotase alfa. Osteoporos Int. 2021b;32:2505-2513.
Schmidt T, Mussawy H, Rolvien T, et al. Clinical, radiographic and biochemical characteristics of adult hypophosphatasia. Osteoporos Int. 2017;28(9):2653-2662.
Weber TJ, Sawyer EK, Moseley S, et al. Burden of disease in adult patients with hypophosphatasia: Results from two patient-reported surveys. Metabolism. 2016;65(10):1522-1530.
Berkseth KE, Tebben PJ, Drake MT, et al. Clinical spectrum of hypophosphatasia diagnosed in adults. Bone. 2013;54:21-27.
