Elsevier

Bone

Volume 142, January 2021, 115664
Bone

Pharmacodynamics of asfotase alfa in adults with pediatric-onset hypophosphatasia

https://doi.org/10.1016/j.bone.2020.115664Get rights and content
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Highlights

  • HPP is the rare, inherited, metabolic bone disease caused by low TNSALP activity.

  • PD/safety were evaluated for different asfotase alfa doses in adults with HPP.

  • PPi/PLP reductions were significantly larger with 6.0 and 9.0 vs 1.5 mg/kg/wk.

  • Injection site reactions were the most common treatment-emergent AEs.

Abstract

Background

Hypophosphatasia (HPP) is the rare, inherited, metabolic bone disease characterized by low activity of the tissue-nonspecific isoenzyme of alkaline phosphatase (TNSALP) leading to excess extracellular inorganic pyrophosphate (PPi) and pyridoxal 5'-phosphate (PLP). Asfotase alfa is the human recombinant enzyme-replacement therapy that replaces deficient TNSALP. However, there is limited information concerning the appropriate dose of asfotase alfa for adult patients with pediatric-onset HPP. Thus, we evaluated the pharmacodynamics and safety/tolerability of different doses of asfotase alfa in such patients.

Methods

This 13-week, Phase 2a, open-label study enrolled adults (aged ≥18 years) with pediatric-onset HPP. They were randomized 1:1:1 to receive a single subcutaneous dose of asfotase alfa (0.5, 2.0, or 3.0 mg/kg) at Week 1, then 3 times per week (ie, 1.5, 6.0, or 9.0 mg/kg/wk) starting at Week 3 for 7 weeks. Key outcome measures included change from Baseline to before the third dose during Week 9 (trough) in plasma PPi (primary outcome measure) and PLP (secondary outcome measure).

Results

Twenty-seven adults received asfotase alfa 0.5 (n = 8), 2.0 (n = 10), and 3.0 (n = 9) mg/kg; all completed the study. Median (range) age was 45 (18–77) years; most patients were white (96%) and female (59%). Median plasma PPi and PLP concentrations decreased from Baseline to Week 9 in all 3 cohorts. Differences in least squares mean (LSM) changes in PPi were significant with 2.0 mg/kg (p = 0.0008) and 3.0 mg/kg (p < 0.0001) vs. 0.5 mg/kg. Differences in LSM changes in PLP were also significant for 2.0 mg/kg (p = 0.0239) and 3.0 mg/kg (p = 0.0128) vs. 0.5 mg/kg. Injection site reactions were the most frequent treatment-emergent adverse event (78%), showing increasing frequency with increasing dose.

Conclusions

Adults with pediatric-onset HPP receiving asfotase alfa at 6.0 mg/kg/wk (the recommended dose) or 9.0 mg/kg/wk had greater reductions in circulating PPi and PLP concentrations compared with a lower dose of 1.5 mg/kg/wk.

Trial registration: Clinicaltrials.gov identifier NCT02797821.

Keywords

Alkaline phosphatase
Clinical trials
Diseases and disorders of/related to bone Disorders of calcium/phosphate metabolism
Inborn-error-of-metabolism
Inorganic pyrophosphate
Osteomalacia
Pyridoxal 5'-phosphate
Rickets
Therapeutics
Vitamin B6

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