Hypophosphatasia is the rare, inherited, metabolic bone disease caused by loss-of-function mutations of the alkaline phosphatase biomineralisation-associated gene (ALPL) that encodes the tissue non-specific isoenzyme of alkaline phosphatase (TNSALP).1, 2 Low TNSALP activity on cell surfaces results in extracellular accumulation of its substrates, including inorganic pyrophosphate (PPi) and pyridoxal 5′-phosphate (PLP).1, 3, 4, 5 PPi potently inhibits mineralisation by blocking hydroxyapatite crystal formation.6, 7 Thus, the superabundance of PPi in hypophosphatasia often leads to rickets during growth.6, 7 TNSALP dephosphorylates PLP (the principal circulating form of vitamin B6) to pyridoxal, which allows the compound to cross cell plasma membranes and be rephosphorylated intracellularly to PLP. Therefore, vitamin B6-dependent seizures occur in some infants who are severely affected by hypophosphatasia.4, 7, 8, 9 Life-threatening complications in the severe perinatal and infantile forms of hypophosphatasia can include respiratory failure from rachitic chest deformity and rib fractures, elevated intracranial pressure due to craniosynostosis, and hypercalcaemia leading to nephrocalcinosis and renal compromise.7, 10, 11, 12 Other potential complications of paediatric hypophosphatasia include long-bone deformity and muscle weakness.7, 10 Historically, perinatal hypophosphatasia has been considered lethal, and infantile hypophosphatasia has around 50% mortality during the first year of life.13, 14, 15
Research in context
Evidence before this study
In 2012, we reported the 1 year findings from the first open-label, phase 2, multinational study that evaluated the safety and efficacy of asfotase alfa, an enzyme replacement therapy, in infants and young children with the life-threatening perinatal or infantile forms of hypophosphatasia, a heritable metabolic bone disease. Clinically significant healing of the skeleton was accompanied by improved respiratory function and developmental milestones, and this drug was generally well tolerated. At that time, no treatment was approved for hypophosphatasia, and management of the disease involved supportive care. Asfotase alfa was approved multinationally in 2015, based in part on the findings from this pivotal open-label study. In a 2016 publication, these same patients had improved survival and respiratory outcomes compared with historical controls. In another 2016 study, older children with symptomatic hypophosphatasia showed sustained improvement in skeletal mineralisation, with most achieving normal values for age-matched and sex-matched peers in growth, strength, and motor function during 5 years of treatment with asfotase alfa.
Added value of this study
This Article reports long-term follow-up data since the initial 2012 publication. The impact of asfotase alfa treatment is presented for infants and young children with life-threatening hypophosphatasia who were given a median of 6·6 years of therapy, representing the longest follow-up to date in patients with hypophosphatasia receiving treatment with asfotase alfa. The early improvements were sustained for up to 7 years of treatment. Typically, the improved skeletal mineralisation during the first 6 months of treatment was followed by withdrawal of respiratory support, and was then associated with improved motor and cognitive function that persisted until study end. Although most patients had required prolonged pulmonary support, all nine who completed the study no longer needed it after year 4. For most patients, improvements in length or height and weight Z scores indicated catch-up growth. Improvements from baseline in gross motor, fine motor, and cognitive function reached levels that could match those of healthy peers. Asfotase alfa was generally well tolerated, with the most common treatment-emergent adverse events consistent with sequelae of hypophosphatasia. No evidence of resistance to the therapy emerged.
Implications of all the available evidence
This now completed study documents long-term safety and efficacy of asfotase alfa treatment for infants and young children with life-threatening hypophosphatasia. The findings complement observations from the 5 year study of the treatment of older children with hypophosphatasia. For life-threatening paediatric-onset hypophosphatasia, prompt diagnosis and commencement of asfotase alfa treatment can rescue such patients and give them enjoyable health.
Asfotase alfa (Strensiq, Alexion Pharmaceuticals, Boston, MA, USA) is a human, recombinant, TNSALP replacement therapy that was approved multinationally in 2015, typically for the treatment of paediatric-onset hypophosphatasia.16, 17 The safety and efficacy of asfotase alfa were first evaluated during our phase 2, open-label study in paediatric patients aged 3 years or younger with life-threatening perinatal or infantile hypophosphatasia.18 This study enrolled 11 patients with hypophosphatasia (five with perinatal hypophosphatasia and six with infantile hypophosphatasia) ranging in age from 2 weeks to 3 years for the 6 month initial trial.18 Patients manifested complications of hypophosphatasia before age 6 months, including skeletal abnormalities, such as shortened or bowed limbs, rachitic chest deformity, fractures, osteopenia, craniosynostosis, or other rachitic findings. All but one patient had failure to thrive, most patients (nine [82%] of 11) required respiratory support, and all had gross motor delay. A single 2 mg/kg intravenous infusion of asfotase alfa preceded subcutaneous injections, starting at 1 mg/kg three times per week. Results from this study published in 2012 showed outcomes after 12 months or longer (range 12–26) of treatment with asfotase alfa.18 One patient had consent withdrawn on day 1 because of infusion-associated reactions, and one patient died of pneumonia and sepsis after 7·5 months of treatment.18, 19 The study met its primary efficacy measure of change in hypophosphatasia skeletal disease severity from baseline to month 6 on the basis of assessment of skeletal radiographs using the validated 7 point Radiographic Global Impression of Change (RGI-C) scale (median +2·0, minimum 0, maximum +2·3; p=0·004). Skeletal healing was accompanied by improvements in secondary outcome measures of respiratory and motor function over 1 year of treatment. Asfotase alfa was generally well tolerated.18
In this Article, we report the long-term efficacy (skeletal manifestations, respiratory support, growth, and motor and cognitive function), pharmacodynamics, and safety after approximately 7 years of treatment with asfotase alfa.