Burosumab: Neue Horizonte in der Behandlung der X-chromosomalen hypophosphatämischen Rachitis (XLH)

Zusammenfassung

Die X-chromosmale hypophosphatämische Rachitis (XLH) ist eine seltene, durch chronische Mineralisationsstörung, skelettale Deformitäten und Minderwuchs gekennzeichnete Erkrankung mit Erstmanifestation in Kleinkindesalter. Durch genetische Veränderungen im PHEX Gen kommt es zur übermäßigen Synthese des Phosphatregulators Fibroblast Growth Factor 23 (FGF23) und somit zu einem krankheitsverursachenden chronischen Phosphatverlust. Die konventionelle Behandlung von Patienten mit XLH mit Phosphatsalzen und aktiven Vitamin D-Derivaten stellt einen klinischen Drahtseilakt zwischen Hypomineralisation und Nephrokalzinose, Knochenschmerz und Hyperparathyreoidismus dar. Mit der Zulassung von Burosumab, einem monoklonalen Antikörper gegen humanes FGF23, steht nun erstmals ein direkt in den Pathomechanismus eingreifende Therapie zur Verfügung. Im Rahmen dieses Übersichtsartikels werden Hintergrund und rezente Studiendaten erläutert, sowie auf offene Diskussionspunkte hinsichtlich der neuen Antikörpertherapie hingewiesen.

Abstract

X-linked hypophosphatemic rickets (XLH) is a rare genetic disorder characterized by skeletal hypomineralization, deformities and short stature. Alterations in PHEX lead to increased levels of the phosphate-regulating hormone fibroblast growth factor 23 (FGF23) causing chronic phosphate depletion, the major disease mechanism in XLH. While clinical phenotypes can be variable, skeletal symptoms usually manifest in the first years of life. Managing patients with XLH can be a challenging task: conventional therapy with phosphate supplements and active vitamin D derivates not only ameliorate skeletal symptoms, but can induce complications such as nephrocalcinosis and hyperparthyreodismus. Burosumab, a monoclonal antibody inhibiting FGF23 represents the first targeted therapy for patients with XLH. Pediatric phase II and adult phase III trials have shown a normalization of phosphate excretion and substantial improvement in functional- and pain scores under therapy. By 2018, Burosumab was conditionally approved by the EMA for children with XLH from 1 year of age until the cessation of linear growth. This review aims to discuss background, clinical study data and remaining open questions regarding this novel treatment option.

Schlüsselwörter

Phosphatdiabetes - XLH - Antikörper - Orphan disease

Key words

XLH - antibody - orphan disease - phosphate

• Literatur

• 1 Kuro-O M, Moe OW. FGF23-αKlotho as a paradigm for a kidney-bone network. Bone 07/2017; 100: 4-118
• 2 Bastepe M, Jüppner H. Inherited hypophosphatemic disorders in children and the evolving mechanisms of phosphate regulation. Rev Endocr Metab Disord 26.03.2008; 9 (02) 171-180
• 3 Chesher D, Oddy M, Darbar U. et al. Outcome of adult patients with X-linked hypophosphatemia caused by PHEX gene mutations. J Inherit Metab Dis 01.09.2018; 41 (05) 865-876
• 4 Carpenter TO, Imel EA, Holm IA. et al. A CLINICIAN’S GUIDE TO X-LINKED HYPOPHOSPHATEMIA. J Bone Miner Res Off J Am Soc Bone Miner Res 07/2011; 26 (07) 1381-1388
• 5 Linglart A, Biosse-Duplan M, Briot K. et al. Therapeutic management of hypophosphatemic rickets from infancy to adulthood. Endocr Connect 2014; 3 (01) R13-R30
• 6 Mäkitie O, Doria A, Kooh SW. et al. Early Treatment Improves Growth and Biochemical and Radiographic Outcome in X-Linked Hypophosphatemic Rickets. J Clin Endocrinol Metab 08/2003; 88 (08) 3591-3597
• 7 Taylor A, Sherman NH, Norman ME. Nephrocalcinosis in X-linked hypophosphatemia: effect of treatment versus disease. Pediatr Nephrol Berl Ger 04/1995; 9 (02) 173-175
• 8 Carpenter TO, Whyte MP, Imel EA. et al. Burosumab Therapy in Children with X-Linked Hypophosphatemia. N Engl J Med 24..2018; 378 (21) 1987-9198
• 9 Imel E, Carpenter T, Gottesman GS. et al. KRN23 effects on phosphate and vitamin D dysregulation in children <5 years old with X-Linked Hypophosphatemia (XLH). In BioScientifica. 2017 [zitiert 5. November 2018]. Verfügbar unter: http://www.bone-abstracts.org/ba/0006/ba0006oc24
• 10 Insogna KL, Briot K, Imel EA. et al. A Randomized, Double-Blind, Placebo-Controlled, Phase 3 Trial Evaluating the Efficacy of Burosumab, an Anti-FGF23 Antibody, in Adults With X-Linked Hypophosphatemia: Week 24 Primary Analysis. J Bone Miner Res 01.08.2018; 33 (08) 1383-1393
• 11 Efficacy and Safety of KRN23 Versus Oral Phosphate and Active Vitamin D Treatment in Pediatric Patients With X Linked Hypophosphatemia (XLH) – Full Text View – ClinicalTrials.gov [Internet]. [zitiert 5. November 2018]. Verfügbar unter: https://clinicaltrials.gov/ct2/show/NCT02915705