Asfotase alfa therapy for children with hypophosphatasia

Whyte, Michael P.; Madson, Katherine L.; Phillips, Dawn; Reeves, Amy; McAlister, William H.; Yakimoski, Amy; Mack, Karen; Hamilton, Kim; Kagan, K G; Fujita, Kenji; Thompson, David D.; Moseley, Scott; Odrljin, Tatjana; Rockman‐Greenberg, Cheryl

doi:10.1172/jci.insight.85971

Cited by 129 publications

(126 citation statements)

References 21 publications

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“…HPP is classified into six forms, and each is characterized by age of onset and severity of symptoms, ranging from severe perinatal (lethal), where respiratory distress from a hypoplastic chest is the main cause of death, to milder odontohypophosphatasia, where only dental manifestations are seen . Patients present perinatally or in childhood and >30% may have hypercalcemia . The hypercalcemia is seen in the infantile form of HPP, and may resolve spontaneously within the first year of life, or following targeted asfotase alfa enzyme replacement therapy .…”

Section: Pth‐independent Hypercalcemiamentioning

confidence: 99%

Hypercalcemic Disorders in Children

Stokes

Nielsen

Hannan

et al. 2017

Journal of Bone and Mineral Research

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Hypercalcemia is defined as a serum calcium concentration that is greater than two standard deviations above the normal mean, which in children may vary with age and sex, reflecting changes in the normal physiology at each developmental stage. Hypercalcemic disorders in children may present with hypotonia, poor feeding, vomiting, constipation, abdominal pain, lethargy, polyuria, dehydration, failure to thrive, and seizures. In severe cases renal failure, pancreatitis and reduced consciousness may also occur and older children and adolescents may present with psychiatric symptoms. The causes of hypercalcemia in children can be classified as parathyroid hormone (PTH)‐dependent or PTH‐independent, and may be congenital or acquired. PTH‐independent hypercalcemia, ie, hypercalcemia associated with a suppressed PTH, is commoner in children than PTH‐dependent hypercalcemia. Acquired causes of PTH‐independent hypercalcemia in children include hypervitaminosis; granulomatous disorders, and endocrinopathies. Congenital syndromes associated with PTH‐independent hypercalcemia include idiopathic infantile hypercalcemia (IIH), William's syndrome, and inborn errors of metabolism. PTH‐dependent hypercalcemia is usually caused by parathyroid tumors, which may give rise to primary hyperparathyroidism (PHPT) or tertiary hyperparathyroidism, which usually arises in association with chronic renal failure and in the treatment of hypophosphatemic rickets. Acquired causes of PTH‐dependent hypercalcemia in neonates include maternal hypocalcemia and extracorporeal membrane oxygenation. PHPT usually occurs as an isolated nonsyndromic and nonhereditary endocrinopathy, but may also occur as a hereditary hypercalcemic disorder such as familial hypocalciuric hypercalcemia, neonatal severe primary hyperparathyroidism, and familial isolated primary hyperparathyroidism, and less commonly, as part of inherited complex syndromic disorders such as multiple endocrine neoplasia (MEN). Advances in identifying the genetic causes have resulted in increased understanding of the underlying biological pathways and improvements in diagnosis. The management of symptomatic hypercalcemia includes interventions such as fluids, antiresorptive medications, and parathyroid surgery. This article presents a clinical, biochemical, and genetic approach to investigating the causes of pediatric hypercalcemia. © 2017 The Authors. Journal of Bone and Mineral Research Published by Wiley Periodicals Inc.

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Section: Pth‐independent Hypercalcemiamentioning

confidence: 99%

Hypercalcemic Disorders in Children

Stokes

Nielsen

Hannan

et al. 2017

Journal of Bone and Mineral Research

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“…This recombinant glycoprotein contains the catalytic domain of TNSALP, human immunoglobulin G 1 Fc domain, and a deca‐aspartate peptide, which attaches to bone. Clinical studies of asfotase alfa have focused on a pediatric‐age population with fewer data in adults . Asfotase alfa‐treated infants and children with HPP show improvements in bone mineralization and respiratory and motor function .…”

Section: Introductionmentioning

confidence: 99%

Fracture Healing in Two Adult Patients With Hypophosphatasia After Asfotase Alfa Therapy

Klidaras

Severt

Aggers³

et al. 2018

JBMR Plus

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Infants and children with hypophosphatasia (HPP) treated with asfotase alfa show improvement in bone mineralization and motor function, but it is unclear whether the medication can affect fracture healing in adult HPP patients. We present the course of fracture healing in two adults with HPP on enzyme replacement. Case 1 is a 41‐year‐old female with infantile‐onset HPP who was wheelchair‐bound due to a nonhealing tibial fragility fracture sustained 3 years before and also had nonhealing femoral pseudofracture sustained 17 years before starting asfotase alfa therapy in December 2015. One month after medication initiation, she underwent elective osteotomy of tibia and fibula with intramedullary nail fixation. After 3 months of enzyme replacement, she was full weight‐bearing and radiographs demonstrated callus formation at osteotomy sites, and at 11 months of therapy, radiographs showed union of the osteotomies. By 11 months of asfotase alfa therapy, there was near resolution of the femoral pseudofracture without interval surgery at this site. Case 2 is a 61‐year‐old male who showed nonunion of a fragility fracture of the right femur 8 years prior, intramedullary nail fixation 6 years prior, and stress fracture of the left femoral diaphysis sustained 1 year before starting asfotase alfa in October 2015. A trial of teriparatide was unsuccessful in healing of these fractures. On asfotase alfa, radiographs revealed interval healing of the left femur fracture after 12 months and complete healing of the right femur fracture and near resolution of the left femur fracture after 16 months of medical therapy. These two adult patients with HPP showed significant clinical and radiographic improvements in a total of four recalcitrant fractures on enzyme replacement therapy with asfotase alfa. © 2018 The Authors. JBMR Plus published by Wiley Periodicals, Inc. on behalf of American Society for Bone and Mineral Research.

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“…Data from two clinical studies of asfotase alfa (Strensiq®; Alexion Pharmaceuticals, Inc., Boston, MA, USA), a TNSALP enzyme replacement therapy for the treatment of HPP, were used for these analyses. Study 1 was a Phase 2, open‐label, 6‐month study of asfotase alfa and its 6‐year extension in children aged 6 to 12 years at enrollment (NCT00952484 and NCT01203826) . Study 2 was a Phase 2, open‐label, 6‐month study of asfotase alfa and its 6‐year extension in adolescents and adults aged 13 to 65 years at enrollment (NCT01163149).…”

Section: Methodsmentioning

confidence: 99%

Reliability and Validity of the 6‐Minute Walk Test in Hypophosphatasia

et al. 2019

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This investigation evaluated the reliability and validity of the 6‐Minute Walk Test (6MWT) in patients with pediatric hypophosphatasia (HPP). Children (aged 6 to 12 years; n = 11), adolescents (13 to 17 years; n = 4), and adults (18 to 65 years; n = 9) completed the 6MWT at screening and baseline in two clinical studies of asfotase alfa. Test‐retest reliability of the 6MWT, evaluated with Pearson's correlation coefficients ( r ) for screening versus baseline, was high for children ( r = 0.95; p < 0.0001), adolescents ( r = 0.81; p = 0.125), and adults ( r = 0.94; p = 0.0001). The most conservative minimal clinically important differences, estimated using distribution‐based methods, were 31 m (children and adults) and 43 m (adolescents). In children, the 6MWT correlated significantly with scores on measures of skeletal disease, which included the Radiographic Global Impression of Change scale ( r = 0.50; p < 0.0001) and the Rickets Severity Scale ( r = −0.78; p < 0.0001), such that distance walked increased as the severity of skeletal disease decreased. Significant ( p < 0.0001) correlations with the 6MWT distance walked were also observed for children with scores on parent‐reported measures of disability ( r = −0.67), ability to function in activities of daily living ( r = 0.71 to 0.77), and parent‐reported measures of pain ( r = −0.39). In adolescents and adults, 6MWT distance walked correlated significantly ( p < 0.05) with measures of lower extremity function ( r = 0.83 and 0.60, respectively), total pain severity ( r = −0.41 and −0.36, respectively), and total pain interference ( r = −0.41 and −0.49, respectively). Collectively, these data indicate that the 6MWT is a reliable, valid measure of physical functioning in patients with pediatric HPP. © 2018 The Authors. JBMR Plus Published by Wiley Periodicals, Inc. on behalf of the American Society for Bone and Mineral Research.

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Asfotase alfa therapy for children with hypophosphatasia

Cited by 129 publications

References 21 publications

Hypercalcemic Disorders in Children

Hypercalcemic Disorders in Children

Fracture Healing in Two Adult Patients With Hypophosphatasia After Asfotase Alfa Therapy

Reliability and Validity of the 6‐Minute Walk Test in Hypophosphatasia

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