Pharmacodynamics of asfotase alfa in adults with pediatric-onset hypophosphatasia

Seefried, Lothar; Kishnani, Priya S.; Moseley, Scott; Denker, Andrew E.; Watsky, Eric; Whyte, Michael P.; Dahir, Kathryn M.

Affiliations

¹Orthopedic Department, University of Würzburg, Würzburg, Bavaria, Germany

²Department of Pediatrics, Duke University Medical Center, Durham, NC, USA

³Alexion Pharmaceuticals, Inc., Boston, MA, USA

⁴Center for Metabolic Bone Disease and Molecular Research, Shriners Hospitals for Children-St. Louis, St. Louis, MO, USA

⁵Division of Bone and Mineral Diseases, Department of Internal Medicine, Washington University School of Medicine at Barnes-Jewish Hospital, St Louis, MO, USA

⁶Program for Metabolic Bone Disorders at Vanderbilt, Division of Diabetes and Endocrinology, Vanderbilt University Medical Center, Nashville, TN, USA

Abstract and keywords

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

Links

DOI: 10.1016/j.bone.2020.115664

PubMed: 32987199

WoS: 000601337400007

History

Received: 2020-06-22

Revised: 2020-09-23

Accepted: 2020-09-23

Online: 2020-09-26

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Cited By (1)

Year	Entry
2021	Whyte MP, May JD, McAlister WH, Burgener K, Cortez SR, Kreienkamp R, Castro O, Verzola R, Zavala AS, McPherson CC, Gottesman GS, Ericson KL, Coburn SP, Arbelaez AM. Vitamin B₆ deficiency with normal plasma levels of pyridoxal 5′-phosphate in perinatal hypophosphatasia. Bone. September 2021;150:116007.