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 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 such as severe pain. 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 pediatric-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 to severe disease often remain untreated and can be left with reduced quality of life and severely debilitating pain, muscle weakness, and mobility issues. There is a clear unmet need for individuals whose hypophosphatasia is diagnosed in adulthood.
Ilofotase alfa in HPP
Ilofotase alfa is able to cleave pyrophosphate to release inorganic phosphate which can be incorporated into hydroxyapatite crystals that mineralize bones, 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 pain and muscle weakness associated with elevated levels of other substrates such as pyridoxal 5’-phosphate (PLP). Recent preclinical studies support ilofotase alfa’s potential to extend the effects beyond bone health, with potential benefits for other body systems, such as muscle, affected by HPP[1].
Further preclinical proof-of-concept was demonstrated 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[3].
The Phase 1b clinical proof of concept study with ilofotase alfa in adult HPP patients showed increased alkaline phosphatase activity levels, a dose-dependent, pharmacological relevant effect on all primary disease-specific biomarkers (PPi, PLP, PEA), and a positive safety profile[2].
The pre-clinical data indicate potential efficacy for ilofotase alfa in HPP and are supported by clinical data in healthy volunteers; additionally clinical safety data in healthy volunteers and patients with other disease indications, indicate a very favorable safety profile.
Our Phase 1B study in adult HPP patients
The Phase 1b study with ilofotase alfa in adult HPP patients showed a positive safety profie and a dose-dependent effect on key disease biomarkersIlofotase alfa is Phase 2-ready, with an agreed development plan built around a single pivotal study.
Background information on HPP
- Berkseth KE, Tebben PJ, Drake MT, Hefferan TE, Jewison DE, Wermers RA. Clinical spectrum of hypophosphatasia diagnosed in adults. Bone. 2013;54:21–27. doi:10.1016/j.bone.2013.01.024.
- 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. doi:10.3389/fendo.2023.1138599.
- 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. doi:10.1186/s13023-022-02420-3.
- DeMambro V, et al. Improved VO₂max, muscle function and endurance in adult HPP “PAKO” mice treated with ilofotase alfa. In: Proceedings of the American Society for Bone and Mineral Research (ASBMR) Annual Meeting; 2025. Abstract 1020.
- Gasque KC, Foster BL, Kuss P, et al. Improvement of the skeletal and dental hypophosphatasia phenotype in Alpl⁻/⁻ mice by administration of soluble (non-targeted) chimeric alkaline phosphatase. Bone. 2015;72:137–147. doi:10.1016/j.bone.2014.11.017.
- Millán JL. Hypophosphatasia – pathophysiological understanding, preclinical data looking beyond the skeleton, and upcoming treatments. J Bone Miner Res. 2025 Oct 7:zjaf141. doi:10.1093/jbmr/zjaf141. Epub ahead of print. PMID:41055578.
- Mornet E. Hypophosphatasia. Metabolism. 2018;82:142–155. doi:10.1016/j.metabol.2017.08.013.
- Mornet E, Yvard A, Taillandier A, Fauvert D, Simon-Bouy B. A molecular-based estimation of the prevalence of hypophosphatasia in the European population. Ann Hum Genet. 2011;75:439–445. doi:10.1111/j.1469-1809.2011.00644.x.
- Salles JP. Hypophosphatasia: biological and clinical aspects, avenues for therapy. Clin Biochem Rev. 2020;41(1):13–27. doi:10.33176/AACB-19-00031.
- Schmidt T, Mussawy H, Rolvien T, et al. Clinical, radiographic and biochemical characteristics of adult hypophosphatasia. Osteoporos Int. 2017;28(9):2653–2662. doi:10.1007/s00198-017-4091-y.
- 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. doi:10.1002/jbmr.4130.
- Seefried L, Kishnani PS, Moseley S, et al. Pharmacodynamics of asfotase alfa in adults with pediatric-onset hypophosphatasia. Bone. 2021;142:115664. doi:10.1016/j.bone.2020.115664.
- Seefried L, Rak D, Petryk A, Genest F. Bone turnover and mineral metabolism in adult patients with hypophosphatasia treated with asfotase alfa. Osteoporos Int. 2021;32:2505–2513. doi:10.1007/s00198-020-05760-y.
- Seefried L, et al. A randomized phase 1b trial evaluating the pharmacodynamics of ilofotase alfa in adults with hypophosphatasia. J Bone Miner Res. 2025;zjaf185. doi:10.1093/jbmr/zjaf185.
- Weber TJ, Sawyer EK, Moseley S, Odrljin T, Kishnani PS. Burden of disease in adult patients with hypophosphatasia: results from two patient-reported surveys. Metabolism. 2016;65(10):1522–1530. doi:10.1016/j.metabol.2016.07.006.
- Whyte MP. Hypophosphatasia: aetiology, nosology, pathogenesis, diagnosis and treatment. Nat Rev Endocrinol. 2016;12:233–246. doi:10.1038/nrendo.2016.14.
- 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. doi:10.1172/JCI117874.
[1] DeMambro V, et al. Improved VO₂max, muscle function and endurance in adult HPP “PAKO” mice treated with ilofotase alfa. In: Proceedings of the American Society for Bone and Mineral Research (ASBMR) Annual Meeting; 2025. Abstract 1020. Accessed via: https://asbmr.confex.com/asbmr/2025/meetingapp.cgi/Paper/5008
[2] Seefried L, Bernholz J, Kraan M, Nitschke Y, Rutsch F, Mallek M, Kleinert S, Genest F. A randomized Phase 1b trial evaluating the pharmacodynamics of ilofotase alfa in adults with hypophosphatasia. J Bone Miner Res. 2025 Dec 11:zjaf185. doi: 10.1093/jbmr/zjaf185. Epub ahead of print.https://doi.org/10.1093/jbmr/zjaf023
[3] Gasque, Kellen CS, et al. Improvement of the skeletal and dental hypophosphatasia phenotype in Alpl−/− mice by administration of soluble (non-targeted) chimeric alkaline phosphatase, Bone 72 (2015): 137-147.