Physical Function and Health‐Related Quality of Life in Adults Treated With Asfotase Alfa for Pediatric‐Onset Hypophosphatasia

Abstract

Hypophosphatasia (HPP) is a rare, inherited, metabolic disease characterized by tissue‐nonspecific alkaline phosphatase deficiency resulting in musculoskeletal and systemic clinical manifestations. This observational study evaluated the effectiveness of enzyme replacement therapy with asfotase alfa on physical function and health‐related quality of life (HRQoL) among adults with pediatric‐onset HPP who received asfotase alfa for 12 months at a single center (http://ClinicalTrial.gov no.: NCT03418389). Primary outcomes evaluated physical function with the 6‐minute walk test (6MWT), timed up‐and‐go (TUG) test, Short Physical Performance Battery (SPPB), and handheld dynamometry (HHD). Secondary outcome measures included the Lower Extremity Functional Scale (LEFS), pain prevalence/intensity, and pain medication use; HRQoL was evaluated using the 36‐Item Short‐Form Health Survey version 2 (SF‐36v2). Safety data were collected throughout the study. All 14 patients (11 women) had compound heterozygous ALPL gene mutations and ≥1 HPP bone manifestation, including history of ≥1 fracture. Mean (min, max) age was 51 (19 to 78) years. From baseline to 12 months of treatment, median 6MWT distance increased from 267 m to 320 m (n = 13; p = 0.023); median TUG test time improved from 14.4 s to 11.3 s (n = 9; p = 0.008). Specific components of the SPPB also improved significantly: median 4‐m gait speed increased from 0.8 m/s to 1.1 m/s (n = 10; p = 0.007) and median repeated chair‐rise time improved from 22 s to 13 s (n = 9; p = 0.008). LEFS score improved from 24 points to 53 points (n = 10; p = 0.002). Improvements in HHD were not clinically significant. SF‐36v2 Physical Component Score (PCS) improved after 12 months of treatment (n = 9; p = 0.010). Pain level did not change significantly from baseline to 12 months of treatment. There were significant improvements on chair‐rise time and SF‐36v2 PCS by 3 months, and on TUG test time after 6 months. No new safety signals were identified. These results show the real‐world effectiveness of asfotase alfa in improving physical functioning and HRQoL in adults with pediatric‐onset HPP. © 2020 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research.

Hypophosphatasia: A Unique Disorder of Bone Mineralization

“…Recent studies have shown the effectiveness of asfotase alfa treatment in adults and adolescents with pediatric-onset HPP, showing an improvement of osseous consolidation of non-unions [ 119 ], a normalization of circulating TNSALP substrate levels, and improved functional abilities and health-related quality of life [ 119 , 120 , 121 ], without severe adverse events.…”

Tissue-Nonspecific Alkaline Phosphatase in Central Nervous System Health and Disease: A Focus on Brain Microvascular Endothelial Cells

“…Further screening for additional candidates with higher selectivity and potency identified a second inhibitor, SBI-425, which is more appropriate for in vivo applications [ 101 ]. SBI-425 has been used in several studies related to vascular calcification [ 94 , 97 , 102 ] and by our own lab to identify its applicability for studying TNAP’s role in the brain. In collaboration with the developers of TNAPi and SBI-425, we demonstrated that the SBI-425 inhibitor is unable to cross the BBB in healthy mice [ 35 ].…”

“…This drug works through the cleavage of inorganic pyrophosphate (PPi) to phosphate (Pi) so that Pi may bind with calcium to form hydroxyapatite crystals needed for healthy bones [ 48 , 105 , 106 ]. Overall, this treatment has shown to help improve physical function and health-related quality of life in adults with pediatric-onset HPP [ 102 ]. Recombinant human TNAP (rhTNAP) purified from rabbit transgenic milk samples and administered to LPS-infected mice resulted in increased survival [ 107 ].…”

“…A significant number of studies have demonstrated a role for peripheral endothelial TNAP in disease [ 92 , 97 , 102 , 123 ]; however, there is a paucity of data on the function of brain microvascular TNAP activity in disease states. In this section, we examine emerging data for the role of brain microvascular TNAP in aging and disease.…”

Therapie der Hypophosphatasie

“…Alltagsmobilität, wie etwa dem Chair-Rise Test und dem 6-Minute Walk Test[20]. Interessant wird sein, im Verlauf zu verstehen, inwiefern dies wesentlich mit einer verbesserten Belastbarkeit des Knochens assoziiert ist oder aber auch indirekte Effekte auf die Muskulatur und andere Stoffwechselprozesse eine ursächliche Rolle spielen, etwa durch Veränderungen der Konzentration von Substraten oder durch zirkulierendes Enzym.…”