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.

Physical therapy management of infants and children with hypophosphatasia.

Hypophosphatasia (HPP) is a rare inborn error of metabolism resulting in undermineralization of bone and subsequent skeletal abnormalities. The natural history of HPP is characterized by rickets and osteomalacia, increased propensity for bone fracture, early loss of teeth in childhood, and muscle weakness. There is a wide heterogeneity in disease presentation, and the functional impact of the disease can vary from perinatal death to gait abnormalities. Recent clinical trials of enzyme replacement therapy have begun to offer an opportunity for improvement in survival and function. The role of physical therapy in the treatment of the underlying musculoskeletal dysfunction in HPP is underrecognized. It is important for physical therapists to understand the disease characteristics of the natural history of a rare disease like HPP and how the impairment and activity limitations may change in response to medical interventions. An understanding of when and how to intervene is also important in order to optimally impact body function, lessen structural impairment, and facilitate increased functional independence in mobility and activities of daily living. Individualizing treatment to the child's needs, medical fragility, and setting (home/school/hospital), while educating parents, caregivers, and school staff regarding approved activities and therapy frequency, may improve function and development in children with HPP.