medwireNews: Researchers report sustained improvements in skeletal mineralisation, along with other benefits including improved growth and respiratory function, in children with life-threatening perinatal or infantile hypophosphatasia during 7 years of treatment with asfotase alfa.
The current findings, reported by Michael Whyte (Shriners Hospital for Children, St Louis, Missouri, USA) and co-researchers cover nine patients – of the original 11 patients – who received treatment for at least 6 years. The children were all 3 years old or younger at the start of treatment and had severe hypophosphatasia that manifested before the age of 6 months.
After 1 year of treatment, eight of the nine patients were classed as responders on the Radiographic Global Impression of Change (RGI-C) scale, with a score of at least +2, and all seven patients assessed at 7 years achieved this score. Four patients achieved “the highest possible” score of +3 at some point during follow-up, and all of these patients had scores of at least +2 thereafter.
In addition, the median score on the Rickets Severity Scale fell from 8.3 at baseline to just 0.5 at year 4, which was sustained at year 7.
In a commentary that accompanies the publication in The Lancet Diabetes & Endocrinology, Raja Padidela (Royal Manchester Children’s Hospital, UK) describes the skeletal improvements as “remarkable” and suggests that this contributed to improvements in their respiratory function.
Five patients required respiratory support at baseline, ranging from supplemental oxygen to mechanical ventilation, and all were free of this need from 4.5 years of treatment. The children also showed motor improvements over time, with several achieving scores within the normal range at their last assessment.
Treatment had a moderate positive effect on the children’s height, with the median height/length standard deviation score (SDS) improving from –3.72 at baseline to –3.02 at year 7, but only four patients had height SDS values within the normal range at the most recent assessment.
Padidela observes that “[t]hese children will probably remain short, and the question remains whether they will have a satisfactory pubertal growth spurt, which is often blunted in children with skeletal dysplasia.”
He also highlights the “progressive discrepancy of weight and height over time”. Weight SDS rose from –3.84 to –0.99, with potential consequences for cardiovascular risk.
Adverse events considered to be related to asfotase alfa were infrequent, with the most common being injection-site erythema. There were three serious adverse events thought to be related to treatment: severe chronic hepatitis associated with use of the asthma/allergy medication montelukast; moderate immediate post-injection reaction; and severe craniosynostosis with severe conductive deafness. Another six patients had craniosynostosis events that were not thought to be related to treatment.
Padidela notes that a “fine balance” is needed with the asfotase alfa dose, to achieve skeletal healing and improved respiratory function and motor development without “excessive suppression of inorganic pyrophosphate, which might in turn cause vascular calcification, as seen in generalised arterial calcification in infancy”.
He concludes: “Therefore, a reliable biomarker for monitoring treatment in this heterogeneous disorder with varying severity is needed.”
By Eleanor McDermid
Lancet Diabetes Endocrinol 2018; doi: 10.1016/S2213-8587(18)30307-3
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