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Review
. 2025 Sep;42(9):4270-4299.
doi: 10.1007/s12325-025-03309-1. Epub 2025 Jul 25.

Key Learnings from Clinical Research and Real-World Evidence on Asfotase Alfa Effectiveness in Hypophosphatasia: 10 Years Post-Approval

Aliya A Khan  1 , Eric T Rush  2   3 , Craig Wakeford  4 , Daniel Staub  5 , Maria Luisa Brandi  6
Affiliations
Review

Key Learnings from Clinical Research and Real-World Evidence on Asfotase Alfa Effectiveness in Hypophosphatasia: 10 Years Post-Approval

Aliya A Khan et al. Adv Ther. 2025 Sep.

Abstract

First reported in 1948, hypophosphatasia (HPP) is a rare systemic disease caused by deficient activity of tissue-nonspecific alkaline phosphatase (ALP) enzyme. Patients with HPP experience skeletal and dental manifestations such as rickets/osteomalacia, fractures, pseudofractures, and premature tooth loss, as well as nonskeletal symptoms such as pain and muscle weakness, which result in impaired mobility and poor quality of life. For decades, no specific treatment was available for HPP and the disease was often fatal in infants. Asfotase alfa is a tissue-nonspecific ALP enzyme replacement therapy (ERT) that received first regulatory approval in 2015 in Japan, the European Union, and the United States for the treatment of HPP. This review draws from clinical trial findings, real-world evidence, and relevant case study data demonstrating the safety and effectiveness of asfotase alfa in improving a broad range of skeletal and nonskeletal manifestations in both pediatric and adult patients. Asfotase alfa has been shown to be well tolerated, with manageable side effects. Further, asfotase alfa treatment has improved survival and respiratory outcomes, skeletal outcomes, physical and motor function, pain, disability, and quality of life in patients with HPP. This evidence-based review aims to generate a foundation for improving the understanding of disease pathophysiology, hence enhancing the effectiveness of ERT in patients with HPP.

Keywords: Asfotase alfa; Bone; Effectiveness; Hypophosphatasia; Quality of life; Treatment.

Plain language summary

We conducted this research to understand the efficacy in clinical trials, effectiveness in real-world studies, and overall safety of asfotase alfa. Asfotase alfa is a treatment for hypophosphatasia, a rare disease identified in 1948. This review marks 10 years since asfotase alfa’s first approval in 2015. Hypophosphatasia leads to a variety of health issues, including bone problems like rickets and fractures, premature tooth loss, and muscle weakness, pain, and poor quality of life. Before asfotase alfa, there was no specific treatment, and the disease could be deadly in infants. We gathered and analyzed data from clinical trials, real-world patient experiences, and case studies. This comprehensive review focused on various outcomes in both children and adults with hypophosphatasia. We looked at survival rates, the need for respiratory support, improvements in bone and dental health, physical abilities, pain, disability, and overall quality of life. We also reviewed the safety of asfotase alfa. The findings from the past decade show that asfotase alfa is effective in managing the wide range of symptoms associated with hypophosphatasia, from bone-related issues to muscle weakness. It has significantly improved survival in infants showing symptoms before six months of age. Asfotase alfa has also enhanced patients’ quality of life. These results provide a solid base for healthcare providers to assess and treat hypophosphatasia and guide future research directions to further benefit patients.

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Conflict of interest statement

Declarations. Conflict of Interest: Aliya A. Khan has received honoraria from Amgen and Alexion and support from Ascendis, Calcilytix, Amolyt, and Alexion, AstraZeneca Rare Disease. Eric T. Rush has received consulting fees, support for attending meetings, and honoraria from Alexion, AstraZeneca Rare Disease. He is also on the Alexion advisory board and his institution has received grants from Alexion, AstraZeneca Rare Disease. Craig Wakeford and Daniel Staub are employees of and may own stock/options in Alexion, AstraZeneca Rare Disease. Maria Luisa Brandi has received consulting fees, support for attending meetings, and honoraria from Alexion, AstraZeneca Rare Disease. She is also on the Alexion advisory board and her institution has received grants from Alexion, AstraZeneca Rare Disease. Ethical Approval: This review article did not require institutional review board or institutional animal care and use committee approval, as it is based on previously conducted studies and does not contain any new studies with human participants or animals performed by any of the authors.

Figures

Fig. 1
Fig. 1
Asfotase alfa treatment improves survival and decreases need for respiratory support in infants and young children with life-threatening HPP. (A) Survival in historical controls and treated patients with life-threatening HPP, reproduced from Whyte et al. 2016, with permission [5]. (B) Respiratory support requirement; studies included children with HPP who first displayed signs and symptoms of HPP at age < 6 months [5, 6, 65, 69]. Follow-up time varies as indicated: Whyte et al. 2012—48 weeks; Whyte et al. 2016—up to 5.5 years; Kitaoka et al. 2017—up to 1.8 years; Hofmann et al. 2019—up to 6 years. a84% observed survival; 31 of 37 treated patients survived to 5 years of age
Fig. 2
Fig. 2
Asfotase alfa treatment improves measures of rickets in children. Median improvements in (A) RGI-C score and (B) RSS score. For RGI-C, patients were classified as treatment responders if their score improved by ≥ 2 points, indicating substantial healing [6, 64, 65, 67, 69]. Follow-up times varied as indicated: Whyte et al. 2012—48 weeks; Whyte et al. 2016—5 years; Kitaoka et al. 2017—24 weeks; Hofmann et al. 2019—up to 6 years; Whyte et al. 2019—7 years. RGI-C Radiographic Global Impression of Change, RSS Rickets Severity Scale
Fig. 3
Fig. 3
Asfotase alfa improves performance on the 6-Minute Walk Test. Studies shown assess 6-Minute Walk Test in children [64, 68, 76] and adults [48, 68, 71, 73, 85]. Data are presented as distance walked (darker colors) and/or percent predicted distance walked (lighter colors) depending on data availability. Follow-up times varied as indicated: Whyte et al. 2016—5 years; Padidela et al. 2025—3 months; Kishnani et al. 2019—5 years; Kishnani et al. 2024—1 year; Genest et al. 2020—1 year; Seefried et al. 2023—1 year; Moss et al. in preparation—3 years. aKishnani, et al. 2019 reports data from 6 adolescents aged 13 to < 18 years and 13 adults aged ≥ 18 years
Fig. 4
Fig. 4
Asfotase alfa treatment improves SF-36v2 scores. Studies show improvements in Mental and Physical Component Summary scores in patients in the observational EmPATHY study after up to 2 years of follow-up [71, 73]
See this image and copyright information in PMC

References

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