Examining the Effect of Burosumab on Muscle Function
Condition: X-linked Hypophosphatemia
MeSH terms: Familial Hypophosphatemic Rickets; Hypophosphatemia
Study type: Interventional
Phase: Phase 4

Summary: 
      Patients with X-linked hypophosphatemia (XLH) often report symptoms of fatigue and weakness
      particularly after exertion, in addition to their skeletal complaints. In previous trials
      using KRN23 (same drug as burosumab/Crysvita®), patients report these symptoms improve. The
      investigators wish to test this hypothesis directly by measuring muscle energy when patients
      begin treatment with Crysvita® for the first time.
    

Detailed description: 
      X-linked hypophosphatemia is a skeletal dysplasia. The mineralized tissue complications of
      XLH have been the focus of investigative studies seeking to understand its pathogenesis, as
      well as studies directed at new therapies. However, in addition to their skeletal complaints,
      patients with XLH have among their most frequent symptoms, fatigue and weakness, which
      manifest as both a generalized sense of a lack of energy as well as a more specific feeling
      that their muscular function is impaired. Objectively, patients complain of fatigue after
      exertion, when otherwise they do not think they should expect to feel so spent. These
      symptoms occur in individuals who otherwise have good cardiovascular and respiratory health,
      so co-morbidities are unlikely to explain these pervasive complaints. Anecdotally, the
      investigators open-label trial data using KRN23 suggest that these symptoms are dramatically
      ameliorated by treatment with the drug. In a recent study¹, the investigators found that when
      stressed by a low-phosphate diet, rates of insulin-stimulated myocyte Adenosine triphosphate
      (ATP) flux were reduced by 50% in an experimental model of systemic hypophosphatemia (the
      NaPi2a knockout mouse). Moreover, ATP synthetic flux correlated directly with cellular and
      mitochondrial phosphate uptake in two rodent myocyte cell lines, as well as in freshly
      isolated myocyte mitochondria. As direct evidence that these preclinical findings are
      relevant to human hypophosphatemic genetic syndromes we studied a patient with Heredity
      Hypophosphatemic Rickets with Hypercalciuria (HHRH) who was not being treated at the time of
      our experiment. In this patient who had a 50% reduction in serum phosphate, muscle ATP
      content was also significantly reduced ¹. Both of these parameters normalized completely with
      oral phosphate repletion ¹. These data strongly support the hypothesis that reduced muscle
      ATP flux may underlie the myopathy seen in patients with XLH. The investigators propose to
      directly test this hypothesis, in patients about to begin treatment with Crysvita® for the
      first time.

      Muscle tissue phosphorus concentration and ATP flux rates will be assessed in the right
      gastrocnemius of the lower leg using 31P-NMR (nuclear magnetic resonance) spectroscopy over
      the course of the 3 month study. The study consists of 5 visits total over 3 months. At
      visits 1,4 and 5, patients will undergo magnetic resonance (MR) spectroscopy assessments and
      functional testing along with blood and urine analysis. At visits 1,2 and 3 patients will
      receive Burosumab/Crysvita® by subcutaneous injection.
    

Intervention name(s): Burosumab Injection [Crysvita]
Intervention type(s): Drug
Intervention description(s): Burosumab/Crysvita SC injection monthly
Other intervention name(s): Crysvita
Intervention MeSH terms: Antibodies, Monoclonal
Intervention model: Single Group Assignment
Masking: None (Open Label)
Primary purpose: Other
Keywords: Crysvita; Burosumab