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Asfotase Alfa Treatment Improves Survival for Perinatal and Infantile Hypophosphatasia
Michael P Whyte1, Cheryl Rockman-Greenberg1, Keiichi Ozono1
1Shriners Hospital for Children (M.P.W.) and Division of Bone and Mineral Diseases at Washington University School of Medicine (M.P.W.), St Louis, Missouri 63110; University of Manitoba and Children's Hospital Research Institute of Manitoba (C.R.-G.), Winnipeg, MB R3T 2N2 Canada; Graduate School of Medicine (K.O.), Osaka University, Osaka, 565-0871 Japan; Alexion Pharmaceuticals, Inc. (R.R., S.M., A.M., D.D.T.), Cheshire, Connecticut 06410; Department of Human Metabolism (N.B.), University of Sheffield, Sheffield, S10 2TN United Kingdom; Sheffield Children's Hospital (N.B.), Sheffield, S10 2TH United Kingdom; University Children's Hospital (C.H.), University of Würzburg, Würzburg, D-97080 Germany.
Insights
Asfotase alfa significantly improves survival rates in infants with severe Hypophosphatasia (HPP). This enzyme replacement therapy enhances respiratory function and skeletal health, offering a lifeline for patients with this rare metabolic disorder.
Area of Science:
- Biochemistry and Metabolism
- Genetics and Rare Diseases
- Pediatric Medicine
Background:
- Hypophosphatasia (HPP) is a severe inherited metabolic disorder with high mortality in perinatal and infantile forms, often due to respiratory failure.
- Current treatment options for severe HPP are limited, highlighting the need for effective therapies.
Purpose of the Study:
- To evaluate the impact of asfotase alfa, a novel enzyme replacement therapy, on survival in neonates and infants with severe Hypophosphatasia.
- To assess the effects of asfotase alfa on skeletal mineralization and respiratory function in this patient population.
Main Methods:
- A comparative study involving 37 treated patients receiving asfotase alfa and 48 historical controls with severe HPP.
- Data collected from ongoing phase 2 clinical trials and a retrospective natural history study.
- Key outcome measures included survival rates, radiographic skeletal health, and ventilatory status.
Main Results:
- Asfotase alfa treatment demonstrated a significant increase in survival rates: 95% at age 1 year and 84% at age 5 years, compared to 42% and 27% in historical controls, respectively.
- Survival among ventilated patients treated with asfotase alfa was 76%, with 75% successfully weaned off support.
- Radiographic evidence showed improved skeletal mineralization and health in treated patients.
Conclusions:
- Asfotase alfa effectively mineralizes the skeleton, including the ribs, in patients with severe HPP.
- The therapy significantly improves respiratory function and survival outcomes in life-threatening perinatal and infantile Hypophosphatasia.
- Asfotase alfa represents a promising therapeutic option for severe HPP, addressing critical unmet needs.
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.
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