Efficacy and safety of asfotase alfa in infants and young children with hypophosphatasia: a phase 2 open-label study

Christine E Hofmann; Paul Harmatz; Jerry Vockley; Wolfgang Högler; Hideki Nakayama; Nick Bishop; Gabriel Á Martos-moreno; Scott Moseley; Kenji P Fujita; Johannes Liese; Cheryl Rockman-greenberg

doi:10.1210/jc.2018-02335

Efficacy and safety of asfotase alfa in infants and young children with hypophosphatasia: a phase 2 open-label study

Christine E Hofmann, Paul Harmatz, Jerry Vockley, Wolfgang Högler, Hideki Nakayama, Nick Bishop, Gabriel Á Martos-moreno, Scott Moseley, Kenji P Fujita, Johannes Liese, Cheryl Rockman-greenberg

Metabolism and Systems Science

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Abstract

CONTEXT: Long-term data on enzyme replacement treatment of hypophosphatasia (HPP) are limited.

OBJECTIVE: To evaluate efficacy and safety of asfotase alfa in patients aged ≤5 years with HPP followed for up to 6 years.

DESIGN: Phase 2 open-label study (July 2010 to September 2016).

SETTING: Twenty-two sites; 12 countries.

PARTICIPANTS: Sixty-nine patients [median (range) age: 16.0 (0.02 to 72) months] with severe HPP and sign/symptom onset before age 6 months.

INTERVENTION: Asfotase alfa 2 mg/kg three times/week or 1 mg/kg six times/week subcutaneously.

MAIN OUTCOME MEASURES: Primary efficacy measure: Radiographic Global Impression of Change (RGI-C) score [-3 (severe worsening) to +3 (complete/near-complete healing)]. Additional outcome measures: respiratory status, growth, and safety. Post hoc analysis: characteristics of radiographic responders vs nonresponders at Year 1 (RGI-C: ≥+2 vs <+2).

RESULTS: During median (minimum, maximum) 2.3 (0.02, 5.8) years of treatment, RGI-C scores improved significantly at Month 6 [+2.0 (-1.7, +3.0)], Year 1 [+2.0 (-2.3, +3.0)], and Last Assessment [+2.3 (-2.7, +3.0); P < 0.0001 all]. Of 24 patients requiring respiratory support at Baseline, 11 (46%) no longer needed support. Height/weight z scores generally increased. Nine patients died (13%). All patients experienced at least one adverse event; pyrexia was most common. Compared with responders [n = 50 (72%)], nonresponders [n = 19 (28%)] had more severe disease at Baseline and a higher rate of neutralizing antibodies (NAbs) at Last Assessment.

CONCLUSIONS: Most infants/young children given asfotase alfa showed early radiographic and clinical improvement sustained up to 6 years; radiographic nonresponders had more severe disease and more frequent NAbs at Last Assessment.

Original language	English
Pages (from-to)	2735-2747
Number of pages	13
Journal	Journal of Clinical Endocrinology and Metabolism
Volume	104
Issue number	7
Early online date	27 Feb 2019
DOIs	https://doi.org/10.1210/jc.2018-02335
Publication status	Published - 1 Jul 2019

Bibliographical note

ASJC Scopus subject areas

Endocrinology, Diabetes and Metabolism
Biochemistry
Endocrinology
Clinical Biochemistry
Biochemistry, medical

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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Christine_E_Hofmann_et_al_Efficacy_and_safety_of_asfotase_alfa_in_infants_and_young_children_with_hypophosphatasia_Journal_of_Clinical_Endocrinology_and_Metabolism_2019
Checked for eligibility: 20/03/2019 This is a pre-copyedited, author-produced version of an article accepted for publication in The Journal of Clinical Endocrinology & Metabolism following peer review. The version of record Christine E Hofmann, Paul Harmatz, Jerry Vockley, Wolfgang Högler, Hideki Nakayama, Nick Bishop, Gabriel Á Martos-Moreno, Scott Moseley, Kenji P Fujita, Johannes Liese, Cheryl Rockman-Greenberg; Efficacy and Safety of Asfotase Alfa in Infants and Young Children With Hypophosphatasia: a Phase 2 Open-Label Study, The Journal of Clinical Endocrinology & Metabolism, is available online at: https://doi.org/10.1210/jc.2018-02335.
Accepted author manuscript, 587 KBLicence: None: All rights reserved

https://academic.oup.com/jcem/advance-article/doi/10.1210/jc.2018-02335/5364747Licence: None: All rights reserved

Cite this

Hofmann, C. E., Harmatz, P., Vockley, J., Högler, W., Nakayama, H., Bishop, N., Martos-moreno, G. Á., Moseley, S., Fujita, K. P., Liese, J., & Rockman-greenberg, C. (2019). Efficacy and safety of asfotase alfa in infants and young children with hypophosphatasia: a phase 2 open-label study. Journal of Clinical Endocrinology and Metabolism, 104(7), 2735-2747. https://doi.org/10.1210/jc.2018-02335

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title = "Efficacy and safety of asfotase alfa in infants and young children with hypophosphatasia: a phase 2 open-label study",

abstract = "CONTEXT: Long-term data on enzyme replacement treatment of hypophosphatasia (HPP) are limited.OBJECTIVE: To evaluate efficacy and safety of asfotase alfa in patients aged ≤5 years with HPP followed for up to 6 years.DESIGN: Phase 2 open-label study (July 2010 to September 2016).SETTING: Twenty-two sites; 12 countries.PARTICIPANTS: Sixty-nine patients [median (range) age: 16.0 (0.02 to 72) months] with severe HPP and sign/symptom onset before age 6 months.INTERVENTION: Asfotase alfa 2 mg/kg three times/week or 1 mg/kg six times/week subcutaneously.MAIN OUTCOME MEASURES: Primary efficacy measure: Radiographic Global Impression of Change (RGI-C) score [-3 (severe worsening) to +3 (complete/near-complete healing)]. Additional outcome measures: respiratory status, growth, and safety. Post hoc analysis: characteristics of radiographic responders vs nonresponders at Year 1 (RGI-C: ≥+2 vs <+2).RESULTS: During median (minimum, maximum) 2.3 (0.02, 5.8) years of treatment, RGI-C scores improved significantly at Month 6 [+2.0 (-1.7, +3.0)], Year 1 [+2.0 (-2.3, +3.0)], and Last Assessment [+2.3 (-2.7, +3.0); P < 0.0001 all]. Of 24 patients requiring respiratory support at Baseline, 11 (46%) no longer needed support. Height/weight z scores generally increased. Nine patients died (13%). All patients experienced at least one adverse event; pyrexia was most common. Compared with responders [n = 50 (72%)], nonresponders [n = 19 (28%)] had more severe disease at Baseline and a higher rate of neutralizing antibodies (NAbs) at Last Assessment.CONCLUSIONS: Most infants/young children given asfotase alfa showed early radiographic and clinical improvement sustained up to 6 years; radiographic nonresponders had more severe disease and more frequent NAbs at Last Assessment.",

author = "Hofmann, {Christine E} and Paul Harmatz and Jerry Vockley and Wolfgang H{\"o}gler and Hideki Nakayama and Nick Bishop and Martos-moreno, {Gabriel {\'A}} and Scott Moseley and Fujita, {Kenji P} and Johannes Liese and Cheryl Rockman-greenberg",

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Hofmann, CE, Harmatz, P, Vockley, J, Högler, W, Nakayama, H, Bishop, N, Martos-moreno, GÁ, Moseley, S, Fujita, KP, Liese, J & Rockman-greenberg, C 2019, 'Efficacy and safety of asfotase alfa in infants and young children with hypophosphatasia: a phase 2 open-label study', Journal of Clinical Endocrinology and Metabolism, vol. 104, no. 7, pp. 2735-2747. https://doi.org/10.1210/jc.2018-02335

TY - JOUR

T1 - Efficacy and safety of asfotase alfa in infants and young children with hypophosphatasia

T2 - a phase 2 open-label study

AU - Hofmann, Christine E

AU - Harmatz, Paul

AU - Vockley, Jerry

AU - Högler, Wolfgang

AU - Nakayama, Hideki

AU - Bishop, Nick

AU - Martos-moreno, Gabriel Á

AU - Moseley, Scott

AU - Fujita, Kenji P

AU - Liese, Johannes

AU - Rockman-greenberg, Cheryl

PY - 2019/7/1

Y1 - 2019/7/1

N2 - CONTEXT: Long-term data on enzyme replacement treatment of hypophosphatasia (HPP) are limited.OBJECTIVE: To evaluate efficacy and safety of asfotase alfa in patients aged ≤5 years with HPP followed for up to 6 years.DESIGN: Phase 2 open-label study (July 2010 to September 2016).SETTING: Twenty-two sites; 12 countries.PARTICIPANTS: Sixty-nine patients [median (range) age: 16.0 (0.02 to 72) months] with severe HPP and sign/symptom onset before age 6 months.INTERVENTION: Asfotase alfa 2 mg/kg three times/week or 1 mg/kg six times/week subcutaneously.MAIN OUTCOME MEASURES: Primary efficacy measure: Radiographic Global Impression of Change (RGI-C) score [-3 (severe worsening) to +3 (complete/near-complete healing)]. Additional outcome measures: respiratory status, growth, and safety. Post hoc analysis: characteristics of radiographic responders vs nonresponders at Year 1 (RGI-C: ≥+2 vs <+2).RESULTS: During median (minimum, maximum) 2.3 (0.02, 5.8) years of treatment, RGI-C scores improved significantly at Month 6 [+2.0 (-1.7, +3.0)], Year 1 [+2.0 (-2.3, +3.0)], and Last Assessment [+2.3 (-2.7, +3.0); P < 0.0001 all]. Of 24 patients requiring respiratory support at Baseline, 11 (46%) no longer needed support. Height/weight z scores generally increased. Nine patients died (13%). All patients experienced at least one adverse event; pyrexia was most common. Compared with responders [n = 50 (72%)], nonresponders [n = 19 (28%)] had more severe disease at Baseline and a higher rate of neutralizing antibodies (NAbs) at Last Assessment.CONCLUSIONS: Most infants/young children given asfotase alfa showed early radiographic and clinical improvement sustained up to 6 years; radiographic nonresponders had more severe disease and more frequent NAbs at Last Assessment.

AB - CONTEXT: Long-term data on enzyme replacement treatment of hypophosphatasia (HPP) are limited.OBJECTIVE: To evaluate efficacy and safety of asfotase alfa in patients aged ≤5 years with HPP followed for up to 6 years.DESIGN: Phase 2 open-label study (July 2010 to September 2016).SETTING: Twenty-two sites; 12 countries.PARTICIPANTS: Sixty-nine patients [median (range) age: 16.0 (0.02 to 72) months] with severe HPP and sign/symptom onset before age 6 months.INTERVENTION: Asfotase alfa 2 mg/kg three times/week or 1 mg/kg six times/week subcutaneously.MAIN OUTCOME MEASURES: Primary efficacy measure: Radiographic Global Impression of Change (RGI-C) score [-3 (severe worsening) to +3 (complete/near-complete healing)]. Additional outcome measures: respiratory status, growth, and safety. Post hoc analysis: characteristics of radiographic responders vs nonresponders at Year 1 (RGI-C: ≥+2 vs <+2).RESULTS: During median (minimum, maximum) 2.3 (0.02, 5.8) years of treatment, RGI-C scores improved significantly at Month 6 [+2.0 (-1.7, +3.0)], Year 1 [+2.0 (-2.3, +3.0)], and Last Assessment [+2.3 (-2.7, +3.0); P < 0.0001 all]. Of 24 patients requiring respiratory support at Baseline, 11 (46%) no longer needed support. Height/weight z scores generally increased. Nine patients died (13%). All patients experienced at least one adverse event; pyrexia was most common. Compared with responders [n = 50 (72%)], nonresponders [n = 19 (28%)] had more severe disease at Baseline and a higher rate of neutralizing antibodies (NAbs) at Last Assessment.CONCLUSIONS: Most infants/young children given asfotase alfa showed early radiographic and clinical improvement sustained up to 6 years; radiographic nonresponders had more severe disease and more frequent NAbs at Last Assessment.

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Efficacy and safety of asfotase alfa in infants and young children with hypophosphatasia: a phase 2 open-label study

Abstract

Bibliographical note

ASJC Scopus subject areas

UN SDGs

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