Asfotase Alfa Treatment Improves Survival for Perinatal and Infantile Hypophosphatasia

Abstract

Context: Hypophosphatasia (HPP) is an inborn error of metabolism that, in its most severe perinatal and infantile forms, results in 50-100% mortality, typically from respiratory complications.

Objectives: Our objective was to better understand the effect of treatment with asfotase alfa, a first-in-class enzyme replacement therapy, on mortality in neonates and infants with severe HPP.

Design/setting: Data from patients with the perinatal and infantile forms of HPP in two ongoing, multicenter, multinational, open-label, phase 2 interventional studies of asfotase alfa treatment were compared with data from similar patients from a retrospective natural history study.

Patients: Thirty-seven treated patients (median treatment duration, 2.7 years) and 48 historical controls of similar chronological age and HPP characteristics.

Interventions: Treated patients received asfotase alfa as sc injections either 1 mg/kg six times per week or 2 mg/kg thrice weekly.

Main outcome measures: Survival, skeletal health quantified radiographically on treatment, and ventilatory status were the main outcome measures for this study.

Results: Asfotase alfa was associated with improved survival in treated patients vs historical controls: 95% vs 42% at age 1 year and 84% vs 27% at age 5 years, respectively (P < .0001, Kaplan-Meier log-rank test). Whereas 5% (1/20) of the historical controls who required ventilatory assistance survived, 76% (16/21) of the ventilated and treated patients survived, among whom 75% (12/16) were weaned from ventilatory support. This better respiratory outcome accompanied radiographic improvements in skeletal mineralization and health.

Conclusions: Asfotase alfa mineralizes the HPP skeleton, including the ribs, and improves respiratory function and survival in life-threatening perinatal and infantile HPP.

Trial registration: ClinicalTrials.gov NCT00744042 NCT01176266 NCT01205152 NCT01419028.

Figures

Figure 1.

Kaplan-Meier analysis of survival of patients with perinatal and infantile hypophosphatasia. Asfotase alfa–treated patients (studies ENB-002-08/ENB-003-08 and ENB-010-10) had a significantly better survival rate, calculated using the Kaplan-Meier product-limit estimate, compared with historical controls (study ENB-011-10; P < .0001, Kaplan-Meier log-rank test).

Figure 2.

Ventilatory support and patient outcomes in asfotase alfa–treated and historical control patients. (A) Ventilatory status and patient outcome for the 20 historical control patients (study ENB-011-10) who required ventilatory support in the first 5 years of life. (B) Ventilatory support status improved with bone mineralization for asfotase alfa–treated patients who required ventilatory support at baseline (n = 14) or (C) did not require ventilatory support at baseline but required support later in the study (n = 7). Initiation and discontinuation of ventilatory support are shown as colored bars. Death is indicated by black diamonds. Patient number, age at enrollment in studies ENB-002-08/ENB-003-08 (patients numbered according to Whyte et al (1)) and ENB-010-10, and baseline Rickets Severity Score (RSS); 0 = no rickets, 10 = severe rickets (21)) are shown on the left. Numbers within the colored bars represent the Radiographic Global Impression of Change (RGI-C) scale score. NR, not recorded.

Figure 3.

Patient outcomes according to ventilatory status at baseline. Ventilation includes both noninvasive and invasive (see Materials and Methods).

Figure 4.

Radiographic changes with asfotase alfa treatment (Patient 10–3). Better rib mineralization, chest structure, and thoracic volume with improved ventilatory status in an infant with hypophosphatasia (5.1 weeks of age at treatment baseline). RGI-C, Radiographic Global Impression of Change scale.