A Retrospective, Multi-National, Non-Interventional, Natural History Study of the Childhood Form of Hypophosphatasia
Presentation Number: LB-OR01-4
Date of Presentation: March 5th, 2015
Michael P. Whyte*1, Katherine L Madson2, Craig Frank Munns3, Amy L Reeves2, Kenji Fujita4, Hui Zhang5 and Nick James Bishop6
1Shriners Hosp for Children, Saint Louis, MO, 2Shriners Hospital for Children, St. Louis, MO, 3The Children's Hospital at Westmead, Sydney, Australia, 4Alexion Pharmaceuticals, Inc., Cheshire, CT, 5Alexion Pharmaceuticals, Cheshire, CT, 6Univ of Sheffield, Sheffield, United Kingdom
Hypophosphatasia (HPP) is the rare disease caused by loss-of-function mutation(s) in the tissue-nonspecific alkaline phosphatase (ALP) gene. Resultant low ALP activity can cause a wide spectrum of sequelae in children including premature loss of primary teeth, rickets, poor growth, muscle weakness, fractures, and pain (1 ,2). The clinical course of these manifestations is not well characterized.
This is a retrospective, multi-national, non-interventional chart review of patients (pts) with childhood HPP (symptom onset ≥6 months [mo] to <18 years [y]). Data were collected from 5 to 15 years of age or until Tanner stage >2, whichever occurred first. Study inclusion required HPP-related skeletal abnormalities, ≥1 set of paired radiographs 6 mo–5 y apart, and 2 height measurements ≥3 y apart. Children who previously received experimental or other treatments impacting bone or growth were excluded. Co-primary outcome measures were change in bone health (evaluated by the 7-point Radiographic Global Impression of Change (RGI-C) scale (-3 = severe worsening; +3 = complete healing) and change in height Z-score (Centers for Disease Control and Prevention [CDC] growth charts). Data are reported as median (min, max).
32 pts (69% boys, 97% white, 78% North American) were enrolled at 9 clinical sites, including 22 children from a large natural history database maintained at one site (2). Age at HPP symptom onset was 1.3 y (0.6, 3.4); age at diagnosis was 3.3 y (1.0, 13.1). Common HPP-related disease characteristics in this cohort included gait disturbance (59%), arthralgia (53%), bone pain (50%), muscle weakness (47%), muscle pain (38%), and fracture (34%). 28% of pts reported HPP-related hospitalizations, primarily for surgical correction of HPP-related deformity. 94% required non-pharmacological interventions such as physiotherapy (34%), orthotics (31%), and mobility aids (13%). 63% received medications for HPP-related complaints, most frequently for relief of pain and discomfort. No significant change between first and last assessment (LA) (time elapsed: 4.25 y [0.66, 7.95]) in radiographic assessment of bone health was observed (RGI-C was +0.33 [-2.33, +2.33; p=0.08]). Height and weight z-scores at first assessment varied considerably within the cohort (-0.86 [‑4.9, +2.6]; -0.86 [-5.0, +2.1], respectively) and all subsequent assessments, with no significant change to LA (p>0.05); at LA, height was -0.92 (-4.9, +1.8) and weight -0.98 (-5.7, +2.1).
As demonstrated by this retrospective chart review study, these children with childhood HPP had morbidity and no significant change in rickets or height z-score during childhood and early adolescence.
Disclosure: MPW: Principal Investigator, Alexion. KLM: Coinvestigator, Alexion. CFM: Advisory Group Member, Alexion. KF: Employee, Alexion. HZ: Employee, Alexion. NJB: Study Investigator, Alexion. Nothing to Disclose: ALR