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:
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- 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.