Scott Moseley

Asfotase Alfa Treatment Improves Survival for Perinatal and Infantile Hypophosphatasia

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.

Asfotase alfa therapy for children with hypophosphatasia

Background. Hypophosphatasia (HPP) is caused by loss-of-function mutation(s) of the gene that encodes the tissue-nonspecific isoenzyme of alkaline phosphatase (TNSALP). Consequently, cell-surface deficiency of TNSALP phosphohydrolase activity leads to extracellular accumulation of inorganic pyrophosphate, a natural substrate of TNSALP and inhibitor of mineralization. Children with HPP can manifest rickets, skeletal pain, deformity, fracture, muscle weakness, and premature deciduous tooth loss. Asfotase alfa is a recombinant, bone-targeted, human TNSALP injected s.c. to treat HPP. In 2012, we detailed the 1-year efficacy of asfotase alfa therapy for the life-threatening perinatal and infantile forms of HPP. Methods. Here, we evaluated the efficacy and safety of asfotase alfa treatment administered to children 6-12 years of age at baseline who were substantially impaired by HPP. Two radiographic scales quantitated HPP skeletal disease, including comparisons to serial radiographs from similarly affected historical control patients. Results. Twelve children receiving treatment were studied for 5 years. The 6-month primary endpoint was met, showing significant radiographic improvement. Additional significant improvements included patient growth, strength, motor function, agility, and quality of life, which for most patients meant achieving normal values for age- and sex-matched peers that were sustained at 5 years of treatment. For most, pain and disability resolved. Mild to moderate injection-site reactions were common and were sometimes associated with lipohypertrophy. Low anti-asfotase alfa antibody titers were noted in all patients. No evidence emerged for clinically important ectopic calcification or treatment resistance. Conclusions. Asfotase alfa enzyme replacement therapy has substantial and sustained efficacy with a good safety profile for children suffering from HPP. Trial Registration. ClinicalTrials.gov NCT00952484 (https://clinicaltrials.gov/ct2/show/NCT00952484) and NCT01203826 (https://clinicaltrials.gov/ct2/show/NCT01203826). Funding. Alexion Pharmaceuticals Inc. and Shriners Hospitals for Children.

Burden of disease in adult patients with hypophosphatasia: Results from two patient-reported surveys

BACKGROUND Hypophosphatasia (HPP) is a rare metabolic bone disease caused by loss-of-function mutation(s) in the tissue-nonspecific alkaline (TNSALP) phosphatase gene, which manifests as rickets and/or osteomalacia with systemic complications and affects patients of all ages. The burden of disease is poorly characterized in adult patients. AIMS We assessed patient-reported burden of disease using two surveys reasonably specific for HPP symptomatology, the Hypophosphatasia Impact Patient Survey (HIPS) and the Hypophosphatasia Outcomes Study Telephone interview (HOST). METHODS Patients with HPP were invited to participate via patient advocacy groups or their medical provider. Survey questions captured demography, HPP-related medical history, mobility, and health-related quality of life (using Short Form 12 [version 2] Health Survey [SF-12v2]) via internet report (HIPS) or telephone interview (HOST). RESULTS One hundred twenty-five adults responded (mean [standard deviation, SD] age: 45 [14.3] years). Eighty-four patients (67%) reported pediatric-onset of their symptoms. Common clinical features in the study population included pain (95% of patients), fractures (86% of patients) muscle weakness (62%) and unusual gait (52%). Use of assistive devices for mobility (60%) was also prevalent. Twenty-six percent of patients reported more than 10 fractures. Seventy-four percent of patients had undergone orthopedic/dental surgical procedures. The health profile of patients responding on the SF-12 showed a broad and substantial impact of HPP on health-related quality of life, with domains related to physical ability showing the greatest decrement compared to normative data. CONCLUSIONS In aggregate, these data indicate that HPP can confer a high burden of illness in adulthood.

Validation of a Novel Scoring System for Changes in Skeletal Manifestations of Hypophosphatasia in Newborns, Infants, and Children: The Radiographic Global Impression of Change Scale: PEDIATRIC HPP: RADIOGRAPHIC SCORING OF SKELETAL MANIFESTATIONS

Hypophosphatasia (HPP) is the heritable metabolic disease characterized by impaired skeletal mineralization due to low activity of the tissue‐nonspecific isoenzyme of alkaline phosphatase. Although HPP during growth often manifests with distinctive radiographic skeletal features, no validated method was available to quantify them, including changes over time. We created the Radiographic Global Impression of Change (RGI‐C) scale to assess changes in the skeletal burden of pediatric HPP. Site‐specific pairs of radiographs of newborns, infants, and children with HPP from three clinical studies of asfotase alfa, an enzyme replacement therapy for HPP, were obtained at baseline and during treatment. Each pair was scored by three pediatric radiologists (“raters”), with nine raters across the three studies. Intrarater and interrater agreement was determined by weighted Kappa coefficients. Interrater reliability was assessed using intraclass correlation coefficients (ICCs) and by two‐way random effects analysis of variance (ANOVA) and a mixed‐model repeated measures ANOVA. Pearson correlation coefficients evaluated relationships of the RGI‐C to the Rickets Severity Scale (RSS), Pediatric Outcomes Data Collection Instrument Global Function Parent Normative Score, Childhood Health Assessment Questionnaire Disability Index, 6‐Minute Walk Test percent predicted, and Z‐score for height in patients aged 6 to 12 years at baseline. Eighty‐nine percent (8/9) of raters showed substantial or almost perfect intrarater agreement of sequential RGI‐C scores (weighted Kappa coefficients, 0.72 to 0.93) and moderate or substantial interrater agreement (weighted Kappa coefficients, 0.53 to 0.71) in patients aged 0 to 12 years at baseline. Moderate‐to‐good interrater reliability was observed (ICC, 0.57 to 0.65). RGI‐C scores were significantly (p ≤ 0.0065) correlated with the RSS and with measures of global function, disability, endurance, and growth in the patients aged 6 to 12 years at baseline. Thus, the RGI‐C is valid and reliable for detecting clinically important changes in skeletal manifestations of severe HPP in newborns, infants, and children, including during asfotase alfa treatment.