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Asfotase alfa safe, effective for long-term hypophosphatasia treatment in children
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Infants and young children with perinatal or infantile hypophosphatasia treated with asfotase alfa before age 3 years experienced “substantial early improvements” in skeletal mineralization and respiratory function, as well as increases in weight, gross motor and cognitive functioning that was sustained over 7 years, according to an analysis of long-term follow-up data published in The Lancet Diabetes & Endocrinology.
“Although mortality historically has been high in patients with perinatal and infantile hypophosphatasia, most of the 11 individuals in our study who began therapy as infants or young children showed rapid and substantial improvements in skeletal mineralization and then respiratory, motor and cognitive function documented at 1 year of treatment with asfotase alfa,” Michael P. Whyte, MD, medical-scientific director of the Center for Metabolic Bone Disease and Molecular Research at Shriners Hospitals for Children in St. Louis, and colleagues wrote. “These improvements persisted over 7 years of therapy.”
Whyte and colleagues analyzed 7-year follow-up data from a single-arm, open-label, phase 2 trial that included 11 children aged 3 years or younger with perinatal hypophosphatasia, recruited from 10 hospitals between October 2008 and December 200 9 (median age at enrollment, 30 weeks; seven girls) . P atients received 1 mg asfotase alfa (Strensiq, Alexion Pharmaceuticals) three times per week, adjusted to 3 mg three times per week if required, for up to 7 years, or until the product became commercially available. Researchers assessed the drug’s long-term tolerability, defined as the number of patients with one or more treatment-related adverse events, as well as skeletal manifestations associated with hypophosphatasia, evaluated using the Radiographic Global Impression of Change (RGI-C) scale (–3 indicating severe worsening; 3 indicating complete or near-complete healing).
Within the cohort, 10 children completed a 6-month treatment period and entered the extension phase of the trial. Of those, nine children received asfotase alfa for at least 6 years and completed the study, with four children treated for more than 7 years. Median duration of treatment was 6.6 years.
The researchers found that RGI-C scores demonstrated improvements in skeletal parameters as early as month 3 of treatment , with changes sustained over 7 years. All patients had an RGI-C score of at least 2 at year 6 (median score, 2) and at year 7 (median score, 2.3). Four patients in the cohort had an RGI-C score of 3, with three children obtaining this score by the end of year 1. All four children maintained scores of at least 2 at all of the time points thereafter, according to researchers.
They also found that weight z scores improved to within the normal range from year 3 to the end of the study, whereas length or height z scores improved, but remained below normal for the duration of the study. Researchers also observed improvements in age-equivalent scores on gross motor, fine motor and cognitive subscales of the Bayley Scales of Infant and Toddler Development.
All patients in the cohort experienced at least one treatment-related adverse event. The most common adverse events were pyrexia (eight patients), upper respiratory tract infection (eight patients), craniosynostosis (seven patients) and pneumonia (seven patients). One patient died from sepsis at age 8 months after 7.5 months of therapy.
In commentary accompanying the study, Raja Padidela, MD, DNB, MRCPCH, a consultant in pediatric endocrinology at Royal Manchester Children’s Hospital in Manchester, United Kingdom, called the data “reassuring” that asfotase alfa was safe and effective.
“More specifically, skeletal improvements were remarkable, with all patients showing substantial or complete healing of rickets, which probably contributed to continuing improvement in the participants’ respiratory status, so that none required respiratory support beyond 4 years of treatment,” Padidela wrote. “Although their quality of life was not systemically measured, sustained improvement in growth and motor and cognitive skills was recorded.”
Padidela noted that failure to thrive is an important feature of hypophosphatasia and that children in the cohort will probably remain short statured.
“The question remains whether they will have a satisfactory pubertal growth spurt, which is often blunted in children with skeletal dysplasia,” he wrote. – by Regina Schaffer
Disclosures: Alexion Pharmaceuticals funded this study. Whyte reports he received honoraria, travel support and research grants from Alexion Pharmaceuticals. Please see the study for the other authors’ relevant financial disclosures. Padidela reports he has received personal fees from Alexion Pharmaceuticals, Kyowa Kirin Ltd. and Ultragenyx.
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