Orthopedic Department, University of Würzburg, Würzburg, Bavaria, Germany.
Department of Pediatrics, Duke University Medical Center, Durham, NC, USA.
Bone. 2021 Jan;142:115664. doi: 10.1016/j.bone.2020.115664. Epub 2020 Sep 26.
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 < 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.
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.
Clinicaltrials.gov identifier NCT02797821.
低磷酸酯酶症（HPP）是一种罕见的遗传性代谢性骨病，其特征是组织非特异性碱性磷酸酶（TNSALP）活性降低，导致细胞外无机焦磷酸盐（PPi）和吡哆醛 5'-磷酸（PLP）过多。阿法特酶是一种人重组酶替代疗法，可替代缺乏的 TNSALP。然而，对于儿科起病的 HPP 成年患者，阿法特酶的适当剂量信息有限。因此，我们评估了不同剂量的阿法特酶在这些患者中的药效学和安全性/耐受性。
这是一项为期 13 周的 2a 期、开放标签研究，纳入了儿科起病的 HPP 成年患者（年龄≥18 岁）。他们按 1:1:1 的比例随机接受单次皮下注射阿法特酶（0.5、2.0 或 3.0mg/kg），第 1 周，然后从第 3 周开始每周 3 次（即 1.5、6.0 或 9.0mg/kg/周），持续 7 周。主要终点是第 9 周（谷值）时与基线相比血浆 PPi（主要终点）和 PLP（次要终点）的变化。
27 名成年患者接受了阿法特酶 0.5（n=8）、2.0（n=10）和 3.0（n=9）mg/kg；所有人均完成了研究。中位（范围）年龄为 45（18-77）岁；大多数患者为白人（96%）和女性（59%）。所有 3 个队列的血浆 PPi 和 PLP 浓度均从基线下降至第 9 周。2.0mg/kg（p=0.0008）和 3.0mg/kg（p<0.0001）与 0.5mg/kg 相比，PPi 的最小二乘均数（LSM）变化差异有统计学意义。2.0mg/kg（p=0.0239）和 3.0mg/kg（p=0.0128）与 0.5mg/kg 相比，PLP 的 LSM 变化差异也有统计学意义。注射部位反应是最常见的治疗后出现的不良事件（78%），随着剂量的增加而出现频率增加。
接受阿法特酶 6.0mg/kg/周（推荐剂量）或 9.0mg/kg/周治疗的儿科起病 HPP 成年患者，与 1.5mg/kg/周的较低剂量相比，循环 PPi 和 PLP 浓度降低幅度更大。
Clinicaltrials.gov 标识符 NCT02797821。
