Asfotase alfa for infants and young children with hypophosphatasia: 7 year outcomes of a single-arm, open-label, phase 2 extension trial

Abstract

Background: Our Phase 2, open-label study of 11 infants and young children with lifethreatening perinatal or infantile hypophosphatasia (HPP) demonstrated 1-year safety and efficacy of asfotase alfa, an enzyme replacement therapy. We report outcomes over ~7 years. Methods: Patients received asfotase alfa (1 mg/kg thrice weekly subcutaneously; adjusted to 3 mg/kg thrice weekly if required). HPP skeletal manifestations were evaluated on the Radiographic Global Impression of Change (RGI-C) scale (−3=severe worsening; +3=complete/near complete healing). Respiratory support, growth, and cognitive and motor function were also evaluated. Findings: Ten patients completed a 6-month treatment period and entered an extension; nine received asfotase alfa for ≥6 years and completed the study, with four treated >7 years. Skeletal healing was sustained over 7 years of treatment; all evaluable patients had RGI-C scores ≥+2 at Years 6 and 7. No patient who completed the study required respiratory support after Year 4. Weight Z-scores improved to within normal range from Year 3 to study end; length/height Z-scores improved but remained below normal. Age-equivalent scores on Gross Motor, Fine Motor, and Cognitive subscales of the Bayley Scales of Infant and Toddler Development also improved. Treatment was generally well tolerated; adverse events were similar to those previously published. Interpretation: Patients with perinatal or infantile HPP treated with asfotase alfa for up to 7 years showed early, sustained improvements in skeletal mineralization. Respiratory function, growth, and cognitive and motor function also improved. Asfotase alfa is safe and effective in perinatal/infantile HPP.

Natural History of Perinatal and Infantile Hypophosphatasia: A Retrospective Study

“…Delays in diagnosis for some patients that occurred despite the presence of the most severe characteristics of hypophosphatasia underscore the need for better appreciation of the signs, symptoms, and biochemical and radiographic hallmarks of hypophosphatasia, especially now that an effective treatment is available for patients with hypophosphatasia, including for severely affected newborns and infants. 14,18 The 13 surviving patients in our study nevertheless suffered significant morbidity during their first 5 years of life. Those with available data had failure to thrive and chest deformity, but reportedly none had vitamin B6-dependent seizures, which in hypophosphatasia is considered a sign of impending death.…”

“…Patients selected for this study were required to have a history of rachitic chest deformity, respiratory compromise, or vitamin B6-dependent seizures to represent the extreme end of the hypophosphatasia disease spectrum and, therefore, to reflect the perinatal and infantile hypophosphatasia patient population involved in a clinical study of asfotase alfa treatment. 12,14 Patients with benign prenatal hypophosphatasia 9 were excluded, as shown by the severe clinical course of the study subjects. Our data from 48 patients manifesting complications of hypophosphatasia before 6 months of life, and frequently within the first month of life, showed that skeletal disease in utero was suspected based on prenatal ultrasound scan in only one-third.…”

“…12 A portion of the data from that study regarding overall survival and ventilatory support requirements was published in 2016, 13 and the findings after an average of 7 years of treatment were published in 2019. 14 Now we report unpublished data concerning clinical characteristics including signs, symptoms, and complications; medical history (including respiratory support, medications, and hospitalizations); and routine clinical laboratory values and ALPL mutations in this natural history cohort of patients with perinatal or infantile hypophosphatasia.…”

Clinical application experience of asfotase alfa for a young patient with childhood hypophosphatasia

“…По мере накопления результатов клинических исследований было показано значительное улучшение минерализации, гистологической структуры костной ткани, увеличение общей выживаемости пациентов на фоне лечения асфотазой альфа [19,20]. В настоящее время имеются данные, свидетельствующие об эффективности фермент-заместительной терапии TNSALP у подростков и взрослых пациентов с гипофосфатазией [10,21]. Результаты пятилетних наблюдений в рамках многоцентрового рандомизированного открытого исследования II фазы (NCT01163149) 19 больных, средний возраст которых составил 55 лет (13-66 лет), указывают на значительную положительную динамику в отношении показателей минерализации кости, снижения внеклеточных субстратов TNSALP, улучшения двигательной активности и качества жизни пациентов, уменьшения болевого синдрома при применении препарата в дозах 0,3 мг/кг/сут или 0,5 мг/кг/сут с последующим увеличение до 1 мг/кг/сут подкожно 6 раз в неделю.…”

Hypophosphatasie – eine klinisch und genetisch variable Erkrankung

“…Die Auswertung der 9 Patienten, die die Studie abgeschlossen haben, zeigte, dass es zu einer deutlichen Verbesserung der Knochenmineralisation, der Muskelkraft und der Atemfunktion gekommen war [31]. Die Analyse der 7-Jahres-Ergebnisse der oben genannten Studie bestätigt eine prolongierte Verbesserung der skelettalen Mineralisation, der respiratorischen Funktion, des Wachstums und der motorischen Entwicklung bei insgesamt guter Verträglichkeit [33]. der Knochenqualität unter Enzymersatztherapie wurde in einer Fallbeobachtung darüber hinaus histologisch eine Verbesserung der Knochenmineralisation sowie anderer Knochenqualitätsparameter beobachtet [34].…”