ECE2020 Oral Communications Bone and Calcium (7 abstracts)
Real-life clinical study: 1-year of treatment with burosumab of children and adolescents affected with X-linked hypophosphatemia
Volha Zhukouskaya 1,2 , Ines Mannes 3 , Catherine Chaussain 4,5 , Christelle Audrain 1 , Anne-Sophie Lambert 1,6 , Catherine Adamsbaum 1,3,7 , Peter Kamenicky 1,7,8 , Jerome Nevoux 1,7,9 , Philippe Wicart 1,5,10 , Karine Briot 1,5,11 , Federico Di Rocco 1,12,13 , Séverine Trabado 7,14 , Dominique Prié 5,15 , Carolina Di Somma 2 , Annamaria Colao 2 , Anya Rothenbuhler 1,6 & Agnès Linglart 1,6,7
1AP-HP, Reference Center for Rare Disorders of the Calcium and Phosphate Metabolism, Filière OSCAR and Platform of expertise for rare diseases Paris-Saclay, Bicêtre Paris-Saclay Hospital, Le Kremlin-Bicetre, France; 2University of Naples Federico II, Department of Clinical Medicine and Surgery, Division of Endocrinology, Naples, Italy; 3Bicetre Hospital AP-HP, Department Pediatric Radiology, Le Kremlin-Bicêtre, France; 4Hôpital Bretonneau, Department of Odontology-Maladies Rares, Paris, France; 5Universite Paris Descartes, Paris, France; 6Bicetre Hospital AP-HP, Department of Endocrinology and Diabetology for children and Department of Adolescent Medicine, Le Kremlin-Bicêtre, France; 7Paris Sud - Paris Saclay University, Faculté de Médecine, Le Kremlin-Bicetre, France; 8Bicetre Hospital AP-HP, Department of Endocrinology and Reproductive Diseases, Le Kremlin-Bicêtre, France; 9Bicetre Hospital AP-HP, Department of ORL, Le Kremlin-Bicêtre, France; 10Hôpital Necker, Department of Pediatric orthopaedic surgery, Paris, France; 11Hospital Cochin, Department of Rheumatology , Paris, France; 12Hospital Femme Mere Enfant, Hospices Civiles de Lyon and University Claude Bernard Lyon, Pediatric Neurosurgery, Lyon, France; 13Reference Center for Craniosynostosis, INSERM 1033, Lyon, France; 14Bicetre Hospital AP-HP, Department of Molecular Genetics, Pharmacogenetics and Hormonology, Le Kremlin-Bicêtre, France; 15Hôpital Necker, INSERM U1151, Paris, France
Background/Aim: X-linked hypophosphatemia (XLH) is a rare disease caused by PHEX mutation, leading to elevated FGF23, renal phosphate wasting, hypophosphatemia, insufficient 1,25(OH)2D synthesis. Clinically, it manifests with rickets including leg deformities, poor growth, dental abscesses, craniosynostosis, and hearing loss. Beyond conventional treatment (phosphate supplements + active vitamin D), burosumab is pathogenetic anti-FGF23 therapeutic approach, whose efficacy was demonstrated in clinical trials on 1–12 years-old children affected with XLH. Here, we prospectively assessed the efficacy and safety of burosumab on a large cohort of children in clinical practice, including adolescents ≥ 13 years of age at moment of treatment.
Patients/methods: 57 XLH-children (36 girls/21 boys; 9.1 ± 8.9 years; including 10 adolescents ≥ 13 year-old, 14.5 ± 1.2 years) were switched from conventional therapy to burosumab.
Objectives: The primary end-point was the change from baseline (M0) to 12 months (M12) in the rachitic lesions evaluated through knee MRI by measuring of the maximum width of physis and the transverse extent of widening. The secondary end-points were the changes in biochemical (serum phosphate (sP), TmP/eGFR, ALP, 1,25(OH)2D, PTH), clinical parameters (height-SDS, function evaluated through 6-minutes walking test [6MWT]), incidence of dental-hearing-neurological manifestations and safety (incidence of any adverse events, nephrocalcinosis, hyperparathyroidism). In France, the target sP was > 1.2 mmol/l ( > 3.7 mg/dl).
Results: 1-year treatment with burosumab significantly reduced the disease activity, as shown by reduction of the transverse extent of widening and the maximum width of medial physis by 50% and 44% (M0→M12: 62 ± 34 → 31 ± 20%; 5.5 ± 2.1 → 3.2 ± 1.4 mm, P = 0.00 for all, respectively). This was associated with significant reduction in ALP (M0 → M12: 418 ± 150 → 299 ± 146U/l, P = 0.006) and improvement in physical ability expressed as age-adjusted 6MWT-SDS (M0 → M12: −3.3 ± 1.3 → −2.8 ± 1.3, P = 0.03). As expected, we found a rescue of phosphate wasting (M0→M12:sP 0.73 ± 0.12 → 1.19 ± 0.15 mmol/l, TmP/eGFR 0.62 ± 0.12 → 1.07 ± 0.17) and 1,25(OH)2D synthesis (M0 → M12: 25 ± 15 → 79 ± 22 pg/ml); P = 0.00 for all. There were no significant changes in height-SDS and incidence of complications after 1 year. The most common side effects were bone-muscular-abdominal pain, headache, reactions at sites of injection. Adolescents showed higher baseline PTH levels, however, upon burosumab, PTH reduced overtime (M0 → M6 → M12: PTH 85 ± 43 → 57 ± 27 → 66 ± 39 ng/l, P = 0.7). Secondary hyperparathyroidism in adolescents was associated to a slower restoration of phosphate metabolism.
Conclusion: Our findings on efficacy and safety of burosumab confirm those of clinical trials. Restoration of phosphatemia and endogenous calcitriol synthesis by burosumab leads to healing of rickets, reduction of disease activity and improvement of physical function. XLH-adolescents show slower restoration of phosphate wasting under burosumab likely due to secondary hyperparathyroidism; noteworthy, the use of burosumab seems to control PTH in adolescents.
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