TY - JOUR
T1 - Pharmacodynamics of asfotase alfa in adults with pediatric-onset hypophosphatasia
AU - Seefried, Lothar
AU - Kishnani, Priya S.
AU - Moseley, Scott
AU - Denker, Andrew E.
AU - Watsky, Eric
AU - Whyte, Michael P.
AU - Dahir, Kathryn M.
N1 - Funding Information:
This study was sponsored by Alexion Pharmaceuticals , Inc., Boston, MA, USA. Editorial and writing support was provided by Lela Creutz, PhD, and Bina J. Patel, PharmD, CMPP, of Peloton Advantage, LLC, Parsippany, NJ, an OPEN Health company, and was funded by Alexion Pharmaceuticals , Inc.
Funding Information:
We thank the patients and their families for their participation in this study and the healthcare professionals and investigators who treated these patients and made this study possible. We acknowledge the contributions of Shriners Hospitals for Children and staff members Gary S. Gottesman, MD, Amy Reeves, MS, CCRP, and Vinieth Bijanki, MS, CCRP, along with Katherine L. Madson, MD, PhD, Upasana Nanda, MPH, and Karen E. Mack, LPN, who were employees at Shriners Hospitals for Children at the time of the study, and the many professionals at the study sites. We acknowledge the contributions of Margaret Burks, MD, MMHC, and Margo Black, MSN, RN, CCRP, at Vanderbilt University Medical Center; Thomas J. Weber, MD, Seung-Hye Jung, PhD, Stephanie DeArmey, PA-C, and the Duke Early Phase Research Unit staff at Duke University; and Franca Genest, MD, Ursula Hellwich, Jasmin Baumann, and Silke Achtziger, RN, at W?rzburg University. This study was sponsored by Alexion Pharmaceuticals, Inc. Boston, MA, USA. Editorial and writing support was provided by Lela Creutz, PhD, and Bina J. Patel, PharmD, CMPP, of Peloton Advantage, LLC, Parsippany, NJ, an OPEN Health company, and was funded by Alexion Pharmaceuticals, Inc. Alexion will consider requests for disclosure of clinical study participant-level data provided that participant privacy is assured through methods like data de-identification, pseudonymization, or anonymization (as required by applicable law), and if such disclosure was included in the relevant study informed consent form or similar documentation. Qualified academic investigators may request participant-level clinical data and supporting documents (statistical analysis plan and protocol) pertaining to Alexion-sponsored studies. Further details regarding data availability and instructions for requesting information are available in the Alexion Clinical Trials Disclosure and Transparency Policy at http://alexion.com/research-development. Link to Data Request Form: https://alexion.com/contact-alexion/medical-information. Study design: AED, SM, and LS. Study lead investigator: LS. Enrolled and studied patients: LS, PSK, KMD, and MPW. Collection and assembly of data: LS, MPW, KD, and study site investigators. Data analysis: AED and SM. Data interpretation: All authors. Manuscript preparation: All authors. Manuscript content review and revisions: All authors. Final approval of manuscript: All authors. All authors take responsibility for the integrity of the data analysis.
Publisher Copyright:
© 2020 The Authors
PY - 2021/1
Y1 - 2021/1
N2 - 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.
AB - 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.
KW - Alkaline phosphatase
KW - Clinical trials
KW - Diseases and disorders of/related to bone Disorders of calcium/phosphate metabolism
KW - Inborn-error-of-metabolism
KW - Inorganic pyrophosphate
KW - Osteomalacia
KW - Pyridoxal 5'-phosphate
KW - Rickets
KW - Therapeutics
KW - Vitamin B6
UR - http://www.scopus.com/inward/record.url?scp=85092089004&partnerID=8YFLogxK
U2 - 10.1016/j.bone.2020.115664
DO - 10.1016/j.bone.2020.115664
M3 - Article
C2 - 32987199
AN - SCOPUS:85092089004
VL - 142
JO - Bone
JF - Bone
SN - 8756-3282
M1 - 115664
ER -