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Asfotase Alfa for Infants and Young Children with Hypophosphatasia: 7 Year Outcomes of a Single-Arm, Open-Label, Phase 2 Extension Trial

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Asfotase Alfa for Infants and Young Children with Hypophosphatasia: 7 Year Outcomes of a Single-Arm, Open-Label, Phase 2 Extension Trial Articles Asfotase alfa for infants and young children with hypophosphatasia: 7 year outcomes of a single-arm, open-label, phase 2 extension trial Michael P Whyte, Jill H Simmons, Scott Moseley, Kenji P Fujita, Nicholas Bishop, Nada J Salman, John Taylor, Dawn Phillips, Mairead McGinn, William H McAlister Summary Background Our previous phase 2, open-label study of 11 infants and young children with life-threatening perinatal or Lancet Diabetes Endocrinol infantile hypophosphatasia showed 1 year safety and efficacy of asfotase alfa, an enzyme replacement therapy. We 2019; 7: 93–105 aimed to report the long-term outcomes over approximately 7 years of treatment. Published Online December 14, 2018 http://dx.doi.org/10.1016/ Methods We did a prespecified, end of study, 7 year follow-up of our single-arm, open-label, phase 2 trial in which S2213-8587(18)30307-3 children aged 3 years or younger with life-threatening perinatal or infantile hypophosphatasia were recruited from This online publication has been ten hospitals (six in the USA, two in the UK, one in Canada, and one in the United Arab Emirates). Patients received corrected. The corrected version asfotase alfa (1 mg/kg three times per week subcutaneously, adjusted to 3 mg/kg three times per week if required) for first appeared at thelancet. up to 7 years (primary treatment period plus extension phase) or until the product became commercially available; com/diabetes-endocrinology on January 22, 2019 dosage adjustments were made at each visit according to changes in the patient’s weight. The primary objectives of See Comment page 76 this extension study were to assess the long-term tolerability of asfotase alfa, defined as the number of patients with Center for Metabolic Bone one or more treatment-emergent adverse events, and skeletal manifestations associated with hypophosphatasia, Disease and Molecular evaluated using the Radiographic Global Impression of Change (RGI-C) scale (−3 indicating severe worsening, and Research, Shriners Hospital for +3 complete or near-complete healing). Respiratory support, growth, and cognitive and motor functions were also Children, St Louis, MO, USA evaluated. All efficacy and safety analyses were done in all patients who received any asfotase alfa (full-analysis (Prof M P Whyte MD); Division of Bone and Mineral Diseases, population). This study and extension phase are registered with ClinicalTrials.gov, number NCT01205152, and Department of Internal EudraCT, number 2009-009369-32. Medicine, Washington University School of Medicine at Barnes-Jewish Hospital, Findings 11 participants were recruited between Oct 6, 2008, and Dec 4, 2009. Ten patients completed a 6 month St Louis, MO, USA treatment period and entered the extension phase; nine received asfotase alfa for at least 6 years and completed the (Prof M P Whyte); Vanderbilt study, with four being treated for more than 7 years. Skeletal healing was sustained over 7 years of treatment; all University Medical Center, evaluable patients had RGI-C scores of at least +2 at year 6 (n=9; median score +2·0 [range 2·0–3·0]) and year 7 (n=7; Department of Pediatrics, median score +2·3 [2·0–3·0]). No patient who completed the study required respiratory support after year 4. Weight Vanderbilt University, Nashville, TN, USA Z scores improved to within normal range from year 3 to study end; length or height Z scores improved but remained (J H Simmons MD); Alexion below normal. Age-equivalent scores on gross motor, fine motor, and cognitive subscales of the Bayley Scales of Pharmaceuticals, Boston, MA, Infant and Toddler Development also improved. All 11 patients had at least one treatment-emergent adverse event. USA (S Moseley MS, The most common adverse events were pyrexia (eight [73%] of 11 patients), upper respiratory tract infection K P Fujita MD); Sheffield Children’s Hospital, Sheffield, (eight [73%]), craniosynostosis (seven [64%]), and pneumonia (seven [64%]). Serious adverse events related to asfotase UK (Prof N Bishop MD); alfa occurred in three (27%) patients (severe chronic hepatitis; moderate immediate post-injection reaction; and Tawam Hospital, Al Ain, United severe craniosynostosis with severe conductive deafness). Arab Emirates (N J Salman MD); Prevea Health Clinic, Hospital Sisters Health System Interpretation Patients with perinatal or infantile hypophosphatasia treated with asfotase alfa for up to 7 years showed St Vincent Hospital, Green Bay, early, sustained improvements in skeletal mineralisation. Respiratory function, growth, and cognitive and motor WI, USA (J Taylor DO); Division function also improved, and asfotase alfa was generally well tolerated. of Physical Therapy, University of North Carolina, Chapel Hill, NC, USA (D Phillips PhD); Funding Alexion Pharmaceuticals, Inc. Royal Belfast Hospital for Sick Children, Belfast, UK Copyright © 2018 Elsevier Ltd. All rights reserved. (M McGinn MD); and Mallinckrodt Institute of Radiology, Washington Introduction pyrophosphate (PPi) and pyridoxal 5’-phosphate University School of Medicine, Hypophosphatasia is the rare, inherited, metabolic (PLP).1,3–5 PPi potently inhibits mineralisation by St Louis, MO, USA bone disease caused by loss-of-function mutations of blocking hydro xyapatite crystal form ation.6,7 Thus, the (Prof W H McAlister MD) the alkaline phosphatase biomineralisation-associated super abundance of PPi in hypophosphatasia often gene (ALPL) that encodes the tissue non-specific leads to rickets during growth.6,7 TNSALP dephos- isoenzyme of alkaline phosphatase (TNSALP).1,2 Low phorylates PLP (the principal circulating form of TNSALP activity on cell surfaces results in extracellular vitamin B6) to pyridoxal, which allows the compound to accumulation of its substrates, including inorganic cross cell plasma membranes and be rephosphorylated www.thelancet.com/diabetes-endocrinology Vol 7 February 2019 93 Downloaded for Anonymous User (n/a) at President and Fellows of Harvard College on behalf of Harvard University from ClinicalKey.com by Elsevier on February 19, 2019. For personal use only. No other uses without permission. Copyright ©2019. Elsevier Inc. All rights reserved. Articles Correspondence to: Prof Michael P Whyte, Center for Research in context Metabolic Bone Disease and Molecular Research, Shriners Evidence before this study with hypophosphatasia receiving treatment with asfotase alfa. Hospital for Children, St Louis, In 2012, we reported the 1 year findings from the first open-label, The early improvements were sustained for up to 7 years of MO 63110, USA phase 2, multinational study that evaluated the safety and efficacy treatment. Typically, the improved skeletal mineralisation [email protected] of asfotase alfa, an enzyme replacement therapy, in infants and during the first 6 months of treatment was followed by young children with the life-threatening perinatal or infantile withdrawal of respiratory support, and was then associated forms of hypophosphatasia, a heritable metabolic bone disease. with improved motor and cognitive function that persisted Clinically significant healing of the skeleton was accompanied by until study end. Although most patients had required improved respiratory function and developmental milestones, prolonged pulmonary support, all nine who completed the and this drug was generally well tolerated. At that time, study no longer needed it after year 4. For most patients, no treatment was approved for hypophosphatasia, and improvements in length or height and weight Z scores management of the disease involved supportive care. Asfotase indicated catch-up growth. Improvements from baseline in alfa was approved multinationally in 2015, based in part on the gross motor, fine motor, and cognitive function reached levels findings from this pivotal open-label study. In a 2016 publication, that could match those of healthy peers. Asfotase alfa was these same patients had improved survival and respiratory generally well tolerated, with the most common outcomes compared with historical controls. In another 2016 treatment-emergent adverse events consistent with sequelae study, older children with symptomatic hypophosphatasia of hypophosphatasia. No evidence of resistance to the therapy showed sustained improvement in skeletal mineralisation, with emerged. most achieving normal values for age-matched and sex-matched Implications of all the available evidence peers in growth, strength, and motor function during 5 years of This now completed study documents long-term safety and treatment with asfotase alfa. efficacy of asfotase alfa treatment for infants and young Added value of this study children with life-threatening hypophosphatasia. The findings This Article reports long-term follow-up data since the initial complement observations from the 5 year study of the 2012 publication. The impact of asfotase alfa treatment is treatment of older children with hypophosphatasia. For presented for infants and young children with life-threatening life-threatening paediatric-onset hypophosphatasia, prompt hypophosphatasia who were given a median of 6·6 years of diagnosis and commencement of asfotase alfa treatment can therapy, representing the longest follow-up to date in patients rescue such patients and give them enjoyable health. intra cellularly to PLP. Therefore, vitamin B6-dependent manifested complications of hypophosphatasia before seizures occur in some infants who are severely affected age 6 months, including skeletal abnormalities, such as by hypophosphatasia.4,7–9 Life-threatening complications
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