Lothar Seefried1, Priya S Kishnani2, Scott Moseley3, Andrew E Denker3, Eric Watsky3, Michael P Whyte4, Kathryn M Dahir5. 1. Orthopedic Department, University of Würzburg, Würzburg, Bavaria, Germany. Electronic address: l-seefried.klh@uni-wuerzburg.de. 2. Department of Pediatrics, Duke University Medical Center, Durham, NC, USA. 3. Alexion Pharmaceuticals, Inc., Boston, MA, USA. 4. Center for Metabolic Bone Disease and Molecular Research, Shriners Hospitals for Children-St. Louis, St. Louis, MO, USA; Division of Bone and Mineral Diseases, Department of Internal Medicine, Washington University School of Medicine at Barnes-Jewish Hospital, St Louis, MO, USA. 5. Program for Metabolic Bone Disorders at Vanderbilt, Division of Diabetes and Endocrinology, Vanderbilt University Medical Center, Nashville, TN, USA.
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.
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.