AM-Pharma’s purpose is to save and improve the lives of patients confronted with severe medical conditions. Our focus is on cardiac surgery-associated renal damage (CSA-RD), which occurrs in 40% of all cardiac surgeries. Our proprietary compound, ilofotase alfa, has a demonstrated safety profile and showed reno-protective effects in global clinical trials involving over 1,000 subjects. In addition, based on 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 Compound and its Mode of Action
RECOMBINANT ALKALINE PHOSPHATASE
We have developed ilofotase alfa, our proprietary recombinant alkaline phosphatase, 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: CSA-RD AND HPP
CARDIAC SURGERY-ASSOCIATED RENAL DAMAGE (CSA-RD)
Around the world, over 2 million cardiac surgeries are conducted on an annual basis. Acute Kidney Injury (AKI) is a serious complication after cardiac surgery and the incidence is as high as 40%.1 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. 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. 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. The company has demonstrated 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, there are no drugs approved to treat AKI.1,2,3,4,5
Chronic Kidney Disease and AKI
Chronic Kidney Disease (CKD) is a condition characterized by a gradual loss of kidney function over time. When kidney disease progresses, it may eventually lead to kidney failure, which requires dialysis or a kidney transplant to maintain life.
In our completed Phase III REVIVAL pivotal study, we included an additional exploratory cohort, around 50% of patients with moderate to severe CKD were enrolled (reference eGFR < 75ml/min). Patients who were administrated ilofotase alfa have shown a decreased risk of CKD and subsequent AKI episode.7 Treatment with ilofotase alfa may also protect renal function as well as reduce mortality in this patient population, supporting our decision to include patients with pre-operative impaired kidney function in our Phase II CSA-RD study.
Cardiovascular Surgery and Acute Kidney Injury
Based on 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), treatment with ilofotase alfa could 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).
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
AM-Pharma obtained regulatory advice from both the US FDA and EMA for its proposed clinical trial and is advancing ilofotase alfa into a Phase II study.
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 is published https://doi.org/10.1007/s00134-023-07271-w.
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)
HPP is an inherited disease associated with low serum alkaline phosphatase activity.
Adult HPP 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. 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.
HPP disease management
For adults with paediatric-onset HPP 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. There is a clear unmet need for individuals whose hypophosphatasia is diagnosed in adulthood.
Ilofotase alfa’s potential in HPP
Ilofotase alfa is able to cleave pyrophosphate to release inorganic phosphate which can be incorporated into hydroxyapatite crystals that mineralize bone, with the potential to restore skeletal integrity in HPP 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 HPP was shown in mice with a knockout mutation in the TNAP gene. Ilofotase alfa alleviated multiple HPP manifestations in these animals: improving bone and dental mineralization and cartilage development; reducing the development of craniosynostosis, kidney inflammation/calcification, and seizures; and normalizing body weight and lifespan. These early pre-clinical data indicate potential efficacy for ilofotase alfa in HPP and are supported by extensive pre-clinical and clinical safety data in healthy volunteers and patients with other disease indications, indicating a very favorable safety profile.
Our phase 1B study in adult HPP patients
We are currently conducting a single-center, open-label, pilot study to assess the effects of intravenous ilofotase alfa administration on HPP biomarker levels in adults with the disease. As ilofotase alfa will be required as a life-long treatment in HPP, we are developing a subcutaneous dose formulation that can be readily administered by the patient at home.
Background information on HPP:
- Mornet E. Hypophosphatasia. Metab. 2018;82:142-15
- 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.
