Title: Asfotase alfa for treating paediatric-onset hypophosphatasia (review of HST6) [ID3927]
Funder: Department of Health and Social Care

Abstract: Hypophosphatasia is a genetic disorder caused by mutations in the TNSALP gene which reduce the activity of the enzyme tissue nonspecific alkaline phosphatase. Over 375 different mutations of this gene leading to hypophosphatasia have been identified. The reduction of this enzyme’s activity disrupts mineralisation, a process in which calcium and phosphorous are deposited in developing bones and teeth. This leads to ricket-like symptoms, softening and weakening of the bones (osteomalacia), bone deformity and a greater incidence of fractures. Fractures are particularly common in adults but less common in children. Hypophosphatasia can also lead to generalised seizures because of vitamin B6 deficiency, as well as renal and respiratory complications._x000D_ _x000D_ The signs and symptoms of hypophosphatasia vary widely and can appear anytime from before birth to adulthood. Six clinical forms are currently recognised: perinatal (lethal), perinatal (benign [non-lethal]), infantile (where symptoms start within 6 months after birth), childhood, adult, and odontohypophosphatasia (which only affects the teeth). The most severe hypophosphatasia tends to present before birth and in early infancy. Infants with hypophosphatasia are born with short limbs, craniosynostosis and soft skull bones, vitamin B6-responsive seizures, and an abnormally shaped chest which can lead to further complications. Additional complications in infancy include poor feeding and a failure to gain weight, respiratory problems, and high levels of calcium in the blood (hypercalcaemia), which can lead to recurrent vomiting and kidney problems. These complications can be lifethreatening. Infants who present with hypophosphatasia in the first 6 months of life have a high mortality rate, around half of infants dying within the first year of life primarily due to respiratory failure. Hypophosphatasia that manifests later in childhood or in adults is typically less severe than hypophosphatasia manifesting in infancy. Children may have short stature with bowed legs or knock knees, enlarged wrist and ankle joints, and an abnormal skull shape causing musculoskeletal pain, fatigue, exhaustion, and decreased mobility. Adult forms of hypophosphatasia are characterised by a softening of the bones, premature loss of secondary (adult) teeth and increased risk of fractures in the foot and thigh bones, bone pain, joint pain, decreased mobility, fatigue, exhaustion, and inflammation. Physical symptoms can severely impact quality of life._x000D_ _x000D_ The prevalence of severe forms of hypophosphatasia, (that is, those which present at birth or in early childhood), is unknown in England. However, in Europe, the rate of perinatal/infantile hypophosphatasia is estimated as 1 per 300,000 live births. Milder forms, in which signs and symptoms have a later onset, are more common and are estimated to be present in 1 per 6,370 of the population. It is estimated that between 1 and 7 people are diagnosed with perinatal- and infantile-onset hypophosphatasia each year in England. _x000D_ _x000D_ Diagnosis is made on the basis of physical and radiographic findings consistent with hypophosphatasia and low or abnormal serum alkaline phosphatase. There is no standardised diagnostic algorithm. There is currently no treatment for hypophosphatasia. Medical management is aimed at monitoring and alleviating symptoms and decreasing morbidity. Vitamin B6 may also be given to reduce seizures. _x000D_ _x000D_ This is a re-evaluation of NICE highly specialised technologies guidance on asfotase alfa for treating paediatric-onset hypophosphatasia (HST6), in line with the completion of the managed access agreement.

Lay abstract: To evaluate the benefits and costs of asfotase alfa within its marketing authorisation for treating paediatric-onset hypophosphatasia for national commissioning by NHS England.

Research activity codes: 6.1 PHARMACEUTICALS
Health categories: CONGENITAL DISORDERS