Examining the Effect of Burosumab on Muscle Function

Examining the Effect of Burosumab on Muscle Function Using MR Spectroscopy

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.

Study Overview

• Status: Completed
• Conditions: X-linked Hypophosphatemia
• Intervention / Treatment: Drug: Burosumab Injection [Crysvita]

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.

• Study Type: Interventional
• Enrollment (Actual): 10
• Phase: Phase 4

Contacts and Locations

Study Locations

• United States
  • Connecticut
    • New Haven, Connecticut, United States, 06520
      • Yale University School of Medicine

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 65 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

1. 18-65 years of age
2. Diagnosis of XLH
3. eGFR ≥ 50 (estimated glomerular filtration rate)
4. Normal serum calcium
5. Phosphate ≤ 2.5 mg/dl
6. Deemed clinically appropriate for starting therapy with Burosumab/Crysvita® (based on the treating physician's evaluation)
7. Deemed appropriate for MR Spectroscopy

Exclusion Criteria:

1. Patients with fixed skeletal abnormalities which would prevent them from successfully completing study-related functional assessments
2. Patients unwilling to stop therapy with supplemental phosphate and calcitriol 2 weeks prior to enrollment.
3. Patients who have undergone an orthopaedic procedure within the previous 6 months involving implantation of metal hardware

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Other
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Patients with XLH; Patients will receive Burosumab monthly at visits 1,2 and 3 subcutaneously at a dose of 1.0 mg/kg. Dose may be adjusted as needed.	Drug: Burosumab Injection [Crysvita]; Burosumab/Crysvita SC injection monthly; Other Names: Crysvita

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Skeletal Muscle Adenosine Triphosphate (ATP) Synthesis Rate	Rates of mitochondrial phosphorylation activity were assessed in the soleus/gastrocnemius muscle complex of the right calf by 31P magnetic resonance spectroscopy saturation transfer technique (micro-mol/g/min)	2.5 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Serum Phosphate	measured in mg/dl	2.5 months
Intracellular Phosphate Concentration in Umol/g Muscle	Intracellular phosphorus concentration in skeletal muscle (umol/g muscle)	2.5 months

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Six-minute Walk Test	functional testing outcome measured in meters	2.5 months
Sit to Stand	functional testing outcome measured in the number completed in 30 seconds	2.5 months
Timed up and go Test	functional testing outcome measured in seconds	2.5 months

Collaborators and Investigators

• Sponsor: Yale University
• Investigators: Principal Investigator: Karl L Insogna, M.D., Yale University

Publications and helpful links

General Publications

• Pesta DH, Tsirigotis DN, Befroy DE, Caballero D, Jurczak MJ, Rahimi Y, Cline GW, Dufour S, Birkenfeld AL, Rothman DL, Carpenter TO, Insogna K, Petersen KF, Bergwitz C, Shulman GI. Hypophosphatemia promotes lower rates of muscle ATP synthesis. FASEB J. 2016 Oct;30(10):3378-3387. doi: 10.1096/fj.201600473R. Epub 2016 Jun 23.

Study record dates

Study Major Dates

• Study Start (Actual): November 13, 2019
• Primary Completion (Actual): August 25, 2022
• Study Completion (Actual): August 25, 2022

Study Registration Dates

• First Submitted: October 29, 2019
• First Submitted That Met QC Criteria: October 29, 2019
• First Posted (Actual): October 31, 2019

Study Record Updates

• Last Update Posted (Actual): August 24, 2023
• Last Update Submitted That Met QC Criteria: August 22, 2023
• Last Verified: August 1, 2023

More Information

Terms related to this study

• Keywords: Crysvita; Burosumab
• Additional Relevant MeSH Terms: Metabolic Diseases; Kidney Diseases; Urologic Diseases; Nutrition Disorders; Genetic Diseases, Inborn; Musculoskeletal Diseases; Avitaminosis; Deficiency Diseases; Malnutrition; Bone Diseases; Metabolism, Inborn Errors; Bone Diseases, Metabolic; Renal Tubular Transport, Inborn Errors; Calcium Metabolism Disorders; Metal Metabolism, Inborn Errors; Phosphorus Metabolism Disorders; Rickets; Vitamin D Deficiency; Rickets, Hypophosphatemic; Hypophosphatemia, Familial; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Male Urogenital Diseases; Familial Hypophosphatemic Rickets; Hypophosphatemia; Physiological Effects of Drugs; Immunologic Factors; Antibodies, Monoclonal
• Other Study ID Numbers: 2000026400

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No