Pharmacodynamics of asfotase alfa in adults with pediatric-onset hypophosphatasia

• Published in: Bone (New York, N.Y.) N.Y.), 2021-01, Vol.142, p.115664-115664, Article 115664
• Main Authors: Seefried, Lothar, Kishnani, Priya S., Moseley, Scott, Denker, Andrew E., Watsky, Eric, Whyte, Michael P., Dahir, Kathryn M.
• Format: Article
• Language: English
• Subjects: Adolescent; Adult; Aged; Alkaline Phosphatase; Child; Clinical trials; Diseases and disorders of/related to bone Disorders of calcium/phosphate metabolism; Female; Humans; Hypophosphatasia - drug therapy; Immunoglobulin G; Inborn-error-of-metabolism; Inorganic pyrophosphate; Middle Aged; Osteomalacia; Pyridoxal 5'-phosphate; Recombinant Fusion Proteins; Rickets; Therapeutics; Vitamin B6
• ISSN: 8756-3282; 1873-2763
• DOI: 10.1016/j.bone.2020.115664

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. 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). 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