Study of KRN23 in Adults With X-linked Hypophosphatemia (XLH)

Overview

The primary efficacy objective of this study is to establish the effect of burosumab treatment compared with placebo on increasing serum phosphorus levels in adults with XLH.

Full Title of Study: “A Randomized, Double-Blind, Placebo-Controlled, Phase 3 Study With Open-Label Extension to Assess the Efficacy and Safety of KRN23 in Adults With X-linked Hypophosphatemia (XLH)”

Study Type

  • Study Type: Interventional
  • Study Design
    • Allocation: Randomized
    • Intervention Model: Crossover Assignment
    • Primary Purpose: Treatment
    • Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
  • Study Primary Completion Date: December 22, 2016

Interventions

  • Biological: burosumab
    • solution for SC injection
  • Other: Placebo
    • saline solution for SC injection

Arms, Groups and Cohorts

  • Experimental: Burosumab 1 mg/kg
    • Burosumab 1 mg/kg administered subcutaneously (SC) every 4 weeks, for the duration of the study.
  • Placebo Comparator: Placebo
    • Placebo administered SC every 4 weeks through Week 24, followed by burosumab 1 mg/kg, for the duration of the study.

Clinical Trial Outcome Measures

Primary Measures

  • Percentage of Participants Achieving Mean Serum Phosphorus Levels Above the LLN (2.5 mg/dL [0.81 mmol/L]) at the Mid-Point of the Dose Interval, as Averaged Across Dose Cycles Between Baseline and Week 24
    • Time Frame: Baseline through Week 24

Secondary Measures

  • Change From Baseline to Week 24 in Brief Pain Inventory (BPI) Question 3 (Q3; Worst Pain in Past 24 Hours) Score
    • Time Frame: Baseline, 24 weeks
    • The BPI evaluates the condition of all pain over the previous 24 hours. Two dimensions are measured: pain severity (worst, least, average, and now) and the impact of pain on functioning (pain interference with general activity, walking, work, mood, enjoyment of life, relations with others, and sleep). Question 3 of the short-form BPI (BPI-Q3) asks subjects to rate their pain at its worst in the last 24 hours on a scale of 0 (no pain) to 10 (pain as bad as you can imagine). From the generalized estimating equation (GEE) model, which includes the change from Baseline for the endpoint of interest as the dependent variable; region, visit, treatment, actual randomization stratification (not included for analysis of BPI Worst Pain), and visit by treatment as fixed factors; and Baseline value for the endpoint of interest as a covariate, with compound symmetry covariance structure.
  • Change From Baseline to Week 24 in the Western Ontario and McMaster University Osteoarthritis Index (WOMAC) Stiffness Score
    • Time Frame: Baseline, 24 weeks
    • The WOMAC is a 24-item participant-reported questionnaire with two domains, Stiffness (2 questions) and Physical Function (17 questions) over the previous 48 hours. The WOMAC is administered in a 5-point Likert-scale format using descriptors of none, mild, moderate, severe, and extreme corresponding to an ordinal scale of 0-4. Higher scores on the WOMAC indicate worse stiffness and functional limitations. Scores are normalized to a 0-100 metric where 0 was the best health state and 100 the worst. The GEE estimates are from the GEE model which includes the change from baseline for WOMAC Stiffness as the dependent variable, region, visit, treatment, actual randomization stratification and visit by treatment as fixed factors, and baseline of WOMAC Stiffness as a covariate, with compound symmetry covariance structure.
  • Change From Baseline to Week 24 in the WOMAC Physical Function Score
    • Time Frame: Baseline, 24 weeks
    • The WOMAC is a 24-item participant-reported questionnaire with two domains, Stiffness (2 questions) and Physical Function (17 questions) over the previous 48 hours. The WOMAC is administered in a 5-point Likert-scale format using descriptors of none, mild, moderate, severe, and extreme corresponding to an ordinal scale of 0-4. Higher scores on the WOMAC indicate worse stiffness and functional limitations. Scores are normalized to a 0-100 metric where 0 was the best health state and 100 the worst. The GEE Estimates are from the GEE model which includes the change from baseline for WOMAC Physical Function as the dependent variable, region, visit, treatment, actual randomization stratification and visit by treatment as fixed factors, and baseline of WOMAC Physical Function as a covariate, with compound symmetry covariance structure.
  • Change From Baseline Over Time in BPI Worst Pain Score
    • Time Frame: Baseline, Weeks 12, 24, 36, 48, 72, 96
    • Change from baseline to post-baseline visits in BPI-Q3 (Worst Pain) score as averaged from daily diary scores recorded over 1 week and the study visit score. The BPI evaluates the condition of all pain over the previous 24 hours. Two dimensions are measured: pain severity (worst, least, average, and now) and the impact of pain on functioning (pain interference with general activity, walking, work, mood, enjoyment of life, relations with others, and sleep). Question 3 of the short-form BPI (BPI-Q3) asks subjects to rate their pain at its worst in the last 24 hours on a scale of 0 (no pain) to 10 (pain as bad as you can imagine). The GEE Estimates are from the GEE model which includes the change from baseline for BPI worst pain as the dependent variable, region, visit, treatment and visit by treatment as fixed factors, and baseline of BPI Worst Pain as a covariate, with compound symmetry covariance structure.
  • Change From Baseline Over Time in BPI Pain Severity Score
    • Time Frame: Baseline, Weeks 12, 24, 36, 48, 72, 96
    • Change from baseline to post-baseline visits in BPI pain severity score as averaged from daily diary scores recorded over 1 week and the study visit score. The BPI evaluates the condition of all pain over the previous 24 hours. Two dimensions are measured: pain severity (worst, least, average, and now) and the impact of pain on functioning (pain interference with general activity, walking, work, mood, enjoyment of life, relations with others, and sleep). The severity of pain in the last 24 hours is rated on a scale of 0 (no pain) to 10 (pain as bad as you can imagine). The GEE Estimates are from the GEE model which includes the change from baseline for each BPI endpoint as the dependent variable, region, visit, treatment, and visit by treatment as fixed factors, and baseline of each BPI endpoint as a covariate, with compound symmetry covariance structure.
  • Change From Baseline Over Time in BPI Pain Interference Score
    • Time Frame: Baseline, Weeks 12, 24, 36, 48, 72, 96
    • Change from baseline to post-baseline visits in BPI pain interference score as recorded on the day of the study visit. The BPI evaluates the condition of all pain over the previous 24 hours. Two dimensions are measured: pain severity (worst, least, average, and now) and the impact of pain on functioning (pain interference with general activity, walking, work, mood, enjoyment of life, relations with others, and sleep). Pain interference in the last 24 hours is rated on a scale of 0 (does not interfere) to 10 (completely interferes). The GEE Estimates are from the GEE model which includes the change from baseline for each BPI endpoint as the dependent variable, region, visit, treatment, and visit by treatment as fixed factors, and baseline of each BPI endpoint as a covariate, with compound symmetry covariance structure.
  • Change From Baseline Over Time in WOMAC Stiffness Score
    • Time Frame: Baseline, Weeks 12, 24, 36, 48, 72, 96, 120, 144
    • The WOMAC is a 24-item participant-reported questionnaire with two domains, Stiffness (2 questions) and Physical Function (17 questions) over the previous 48 hours. The WOMAC is administered in a 5-point Likert-scale format using descriptors of none, mild, moderate, severe, and extreme corresponding to an ordinal scale of 0-4. Higher scores on the WOMAC indicate worse stiffness and functional limitations. Scores are normalized to a 0-100 metric where 0 was the best health state and 100 the worst. The GEE Estimates are from the GEE model which includes the change from baseline for WOMAC Stiffness as the dependent variable, region, visit, treatment, actual randomization stratification and visit by treatment as fixed factors, and baseline of WOMAC Stiffness as a covariate, with compound symmetry covariance structure.
  • Change From Baseline Over Time in WOMAC Physical Function Score
    • Time Frame: Baseline, Weeks 12, 24, 36, 48, 72, 96, 120, 144
    • The WOMAC is a 24-item participant-reported questionnaire with two domains, Stiffness (2 questions) and Physical Function (17 questions) over the previous 48 hours. The WOMAC is administered in a 5-point Likert-scale format using descriptors of none, mild, moderate, severe, and extreme corresponding to an ordinal scale of 0-4. Higher scores on the WOMAC indicate worse stiffness and functional limitations. Scores are normalized to a 0-100 metric where 0 was the best health state and 100 the worst. The GEE Estimates are from the GEE model which includes the change from baseline for WOMAC Stiffness as the dependent variable, region, visit, treatment, actual randomization stratification and visit by treatment as fixed factors, and baseline of WOMAC Stiffness as a covariate, with compound symmetry covariance structure.
  • Change From Baseline Over Time in BFI Worst Fatigue Score
    • Time Frame: Baseline, Weeks 12, 24, 36, 48, 72, 96
    • Change from baseline to post-baseline visits in Brief Fatigue Inventory Question 3 (Worst Fatigue in Past 24 Hours; BFI-Q3) as averaged from daily diary scores recorded over 1 week and the study visit score. The BFI is a self-reported questionnaire consisting of 9 items related to fatigue rated on a 0 to 10 numerical scale with a recall period of 24 hours. Two dimensions are measured: fatigue severity and the interference of fatigue on daily life (activity, mood, walking ability, work, relations with others, and enjoyment of life). Participants are asked to rate their worst fatigue over the past 24 hours from 0 (no fatigue) to 10 (as bad a you can imagine). The GEE Estimates are from the GEE model which includes the change from baseline for each BFI endpoint as the dependent variable, region, visit, treatment, actual randomization stratification and visit by treatment as fixed factors, and baseline of each BFI endpoint as a covariate, with compound symmetry covariance structure.
  • Change From Baseline Over Time in BFI Global Fatigue Score
    • Time Frame: Baseline, Weeks 12, 24, 36, 48, 72, 96
    • Change from baseline to post-baseline visits in BFI global fatigue score, calculated by averaging all 9 BFI items as recorded on the day of the study visit. The BFI is a self-reported questionnaire consisting of 9 items related to fatigue that are rated on a numerical scale with a recall period of 24 hours. Two dimensions are measured: fatigue severity and the interference of fatigue on daily life (activity, mood, walking ability, work, relations with others, and enjoyment of life). BFI Global Fatigue score was calculated by averaging all 9 items on the BFI. Global scores range from 0 to 10, with higher score indicating worse fatigue severity and interference. The GEE Estimates are from the GEE model which includes the change from baseline for each BFI endpoint as the dependent variable, region, visit, treatment, actual randomization stratification and visit by treatment as fixed factors, and baseline of each BFI endpoint as a covariate, with compound symmetry covariance structure.
  • Change From Baseline Over Time in Biochemical Marker of Bone Remodeling Procollagen Type 1 N-Propeptide (P1NP)
    • Time Frame: Baseline, Weeks 12, 24, 36, 48, 72, 96
  • Percent Change From Baseline Over Time in Biochemical Marker of Bone Remodeling P1NP
    • Time Frame: Baseline, Weeks 12, 24, 36, 48, 72, 96
  • Change From Baseline Over Time in Biochemical Marker of Bone Remodeling Carboxy-Terminal Cross-Linked Telopeptide of Type I Collagen (CTx)
    • Time Frame: Baseline, Weeks 12, 24, 36, 48, 72, 96
    • The GEE Estimates are from the GEE model which includes the change from baseline for CTx as the dependent variable, region, visit, treatment, actual randomization stratification and visit by treatment as fixed factors, and baseline of CTx as a covariate, with compound symmetry covariance structure.
  • Percent Change From Baseline Over Time in Biochemical Marker of Bone Remodeling CTx
    • Time Frame: Baseline, Weeks 12, 24, 36, 48, 72, 96
    • The GEE Estimates are from the GEE model which includes the percent change from baseline for CTx as the dependent variable, region, visit, treatment, actual randomization stratification and visit by treatment as fixed factors, and baseline of CTx as a covariate, with compound symmetry covariance structure.
  • Change From Baseline Over Time in Biochemical Marker of Bone Remodeling Bone-Specific Alkaline Phosphatase (BALP)
    • Time Frame: Baseline, Weeks 12, 24, 36, 48, 72, 96
    • The GEE Estimates are from the GEE model which includes the change from baseline for BALP as the dependent variable, region, visit, treatment, actual randomization stratification and visit by treatment as fixed factors, and baseline of BALP as a covariate, with compound symmetry covariance structure.
  • Percent Change From Baseline Over Time in Biochemical Marker of Bone Remodeling BALP
    • Time Frame: Baseline, Weeks 12, 24, 36, 48, 72, 96
    • The GEE Estimates are from the GEE model which includes the percent change from baseline for BALP as the dependent variable, region, visit, treatment, actual randomization stratification and visit by treatment as fixed factors, and baseline of Bone ALP as a covariate, with compound symmetry covariance structure.
  • Change From Baseline Over Time in Serum Phosphorus
    • Time Frame: Baseline, Weeks 1, 2, 4, 6, 10, 12, 14, 18, 20, 21, 22, 24, 26, 28, 34, 36, 46, 48, 60, 70, 72, 84, 94, 96, 108, 120, 132, 144
    • The GEE Estimates are from the GEE model which includes the change from baseline for serum phosphorus as the dependent variable, region, visit, treatment, actual randomization stratification and visit by treatment as fixed factors, and baseline of serum phosphorus as a covariate, with compound symmetry covariance structure.
  • Percent Change From Baseline Over Time in Serum Phosphorus
    • Time Frame: Baseline, Weeks 1, 2, 4, 6, 10, 12, 14, 18, 20, 21, 22, 24, 26, 28, 34, 36, 46, 48, 60, 70, 72, 84, 94, 96, 108, 120, 132, 144
    • The GEE Estimates are from the GEE model which includes the percent change from baseline for serum phosphorus as the dependent variable, region, visit, treatment, actual randomization stratification and visit by treatment as fixed factors, and baseline of serum phosphorus as a covariate, with compound symmetry covariance structure.
  • Change From Baseline Over Time in Serum 1,25(OH)2D
    • Time Frame: Baseline, Weeks 1, 2, 4, 20, 21, 22, 46, 48, 60, 70, 72, 84, 94, 96, 108, 120, 132, 144
    • The GEE Estimates are from the GEE model which includes the change from baseline for 1,25(OH)2D as the dependent variable, region, visit, treatment, actual randomization stratification and visit by treatment as fixed factors, and baseline of 1, 25 (OH)2 D as a covariate, with compound symmetry covariance structure.
  • Percent Change From Baseline Over Time in Serum 1,25(OH)2D
    • Time Frame: Baseline, Weeks 1, 2, 4, 20, 21, 22, 46, 48, 60, 70, 72, 84, 94, 96, 108, 120, 132, 144
    • The GEE Estimates are from the GEE model which includes the percent change from baseline for 1,25(OH)2D as the dependent variable, region, visit, treatment, actual randomization stratification and visit by treatment as fixed factors, and baseline of 1, 25 (OH)2 D as a covariate, with compound symmetry covariance structure.
  • Change From Baseline Over Time in 24-Hour Urinary Phosphorus
    • Time Frame: Baseline, Week 12, 24, 36, 48, 72, 96
    • The GEE Estimates are from the GEE model which includes the change from baseline for 24-Hour urinary phosphorus as the dependent variable, region, visit, treatment, actual randomization stratification and visit by treatment as fixed factors, and baseline of urinary phosphorus as a covariate, with compound symmetry covariance structure.
  • Percent Change From Baseline Over Time in 24-Hour Urinary Phosphorus
    • Time Frame: Baseline, Week 12, 24, 36, 48, 72, 96
    • The GEE Estimates are from the GEE model which includes the percent change from baseline for 24-hour urinary phosphorus as the dependent variable, region, visit, treatment, actual randomization stratification and visit by treatment as fixed factors, and baseline of urinary phosphorus as a covariate, with compound symmetry covariance structure.
  • Change From Baseline Over Time in Ratio of Renal Tubular Maximum Reabsorption Rate of Phosphate to Glomerular Filtration Rate (TmP/GFR)
    • Time Frame: Baseline, Weeks 2, 4, 12, 22, 24, 48, 60, 72, 84, 96
    • The GEE Estimates are from the GEE model which includes the change from baseline for TmP/GFR as the dependent variable, region, visit, treatment, actual randomization stratification and visit by treatment as fixed factors, and baseline of TmP/GFR as a covariate, with compound symmetry covariance structure.
  • Percent Change From Baseline Over Time in TmP/GFR
    • Time Frame: Baseline, Weeks 2, 4, 12, 22, 24, 48, 60, 72, 84, 96
    • The GEE Estimates are from the GEE model which includes the percent change from baseline for TmP/GFR as the dependent variable, region, visit, treatment, actual randomization stratification and visit by treatment as fixed factors, and baseline of TmP/GFR as a covariate, with compound symmetry covariance structure.
  • Change From Baseline Over Time in Tubular Reabsorption of Phosphate (TRP)
    • Time Frame: Baseline, Weeks 2, 4, 12, 22, 24, 48, 60, 72, 84, 96
    • The GEE Estimates are from the GEE model which includes the change from baseline for TRP as the dependent variable, region, visit, treatment, actual randomization stratification and visit by treatment as fixed factors, and baseline of TRP as a covariate, with compound symmetry covariance structure.
  • Percent Change From Baseline Over Time in TRP
    • Time Frame: Baseline, Weeks 2, 4, 12, 22, 24, 48, 60, 72, 84, 96
    • The GEE Estimates are from the GEE model which includes the percent change from baseline for TRP as the dependent variable, region, visit, treatment, actual randomization stratification and visit by treatment as fixed factors, and baseline of TRP as a covariate, with compound symmetry covariance structure.
  • Percentage of Participants Achieving Mean Serum Phosphorus Levels Above the LLN (2.5 mg/dL [0.81 mmol/L]) at the End of the Dosing Cycle, as Averaged Across Dose Cycles Between Baseline and Week 24
    • Time Frame: Baseline through Week 24
  • Change From Baseline in Serum Phosphorus at Each Mid-Point of Dosing Cycle, as Averaged Across Dose Cycles Between Baseline and Week 24
    • Time Frame: Baseline through Week 24
  • Percent Change From Baseline in Serum Phosphorus at Each Mid-Point of Dosing Cycle, as Averaged Across Dose Cycles Between Baseline and Week 24
    • Time Frame: Baseline through Week 24
  • Change From Baseline in Serum Phosphorus at Each End of Dosing Cycle, as Averaged Across Dose Cycles Between Baseline and Week 24
    • Time Frame: Baseline through Week 24
  • Percent Change From Baseline in Serum Phosphorus at Each End of Dosing Cycle, as Averaged Across Dose Cycles Between Baseline and Week 24
    • Time Frame: Baseline through Week 24
  • Time-Adjusted Area Under the Curve (AUC) of Serum Phosphorus Between Baseline and Week 24
    • Time Frame: Baseline through Week 24

Participating in This Clinical Trial

Inclusion Criteria

1. Male or female, aged 18 – 65 years, inclusive 2. Diagnosis of XLH supported by classic clinical features of adult XLH (such as short stature or bowed legs) and at least ONE of the following at Screening:

  • Documented phosphate-regulating gene with homologies to endopeptidases on the X chromosome (PHEX) mutation in the patient or a directly related family member with appropriate X-linked inheritance – Serum intact FGF23 (iFGF23) level > 30 pg/mL by Kainos assay 3. Biochemical findings consistent with XLH at Screening Visit 2 following overnight fasting (min. 8 hours): – Serum phosphorus < 2.5 mg/dL – TmP/GFR of < 2.5 mg/dL 4. Presence of skeletal pain attributed to XLH/osteomalacia, as defined by a score of ≥ 4 on Brief Pain Inventory (BPI) Questions 3 (Worst Pain) at Screening Visit 1. (Skeletal pain that, in the opinion of the investigator, is attributed solely to causes other than XLH/osteomalacia-for example, back or joint pain in the presence of severe osteoarthritis by radiograph in that anatomical location-in the absence of any skeletal pain likely attributed to XLH/osteomalacia should not be considered for eligibility) 5. Estimated glomerular filtration rate (eGFR) ≥ 60 mL/min (using the Chronic Kidney Disease Epidemiology Collaboration [CKD-EPI] equation) or eGFR of 45 60 mL/min at Screening Visit 2 with confirmation that the renal insufficiency is not due to nephrocalcinosis 6. If taking chronic pain medications (including narcotic pain medications/opioids), must be on a stable regimen for at least 21 days prior to Screening Visit 1, and be willing to maintain medications at the same stable dose(s) and schedule throughout the Placebo-controlled Treatment Period of the study. The dose must not exceed 60 mg oral morphine equivalents/day 7. Provide written informed consent or if a minor, provide written consent and have a legally authorized representative willing and able to provide written informed consent, after the nature of the study has been explained, and prior to any research-related procedures 8. Willing to provide access to prior medical records for the collection of biochemical and radiographic data and disease history 9. Females of child-bearing potential must have a negative urine pregnancy test at Screening and be willing to have additional pregnancy tests during the study. Females considered not to be of childbearing potential include those who have been in menopause for at least two years prior to Screening, or have had tubal ligation at least one year prior to Screening, or have had a total hysterectomy or bilateral salpingo-oophorectomy 10. Participants of child-bearing potential or with partners of child-bearing potential who have not undergone a bilateral salpingo-oophorectomy and are sexually active must consent to use an effective method of contraception as determined by the site investigator (i.e. oral hormonal contraceptives, patch hormonal contraceptives, vaginal ring, intrauterine device, physical double-barrier methods, surgical hysterectomy, vasectomy, tubal ligation, or true abstinence) from the period following the signing of the informed consent through 12 weeks after last dose of study drug 11. Must, in the opinion of the investigator, be willing and able to complete all aspects of the study, adhere to the study visit schedule and comply with the assessments 12. Must have completed at least 4 of 7 days of the patient diaries before the Baseline visit. Exclusion Criteria:

1. Use of a pharmacologic vitamin D metabolite or analog (calcitriol, doxercalciferol, and paricalcitol) within 14 days prior to Screening Visit 2 2. Use of oral phosphate within 14 days prior to Screening Visit 2 3. Use of aluminum hydroxide antacids, acetazolamides, and thiazides within 7 days prior to Screening Visit 2 4. Chronic use of systemic corticosteroids defined as more than 10 days in the previous 2 months 5. Corrected serum calcium level ≥ 10.8 mg/dL (2.7 mmol/L) at Screening Visit 2 6. Serum intact parathyroid hormone (iPTH) ≥ 2.5 upper limit of normal (ULN) at Screening Visit 1 7. Use of medication to suppress parathyroid hormone (PTH) (cinacalcet for example) within 60 days prior to Screening Visit 1 8. Use of oral bisphosphonates for 6 months or more in the 2 years prior to Screening Visit 1 9. Use of denosumab in the 6 months prior to Screening Visit 1 10. Use of teriparatide in the 2 months prior to Screening Visit 1 11. Planned or recommended orthopedic surgery within the first 24 weeks of the clinical trial period 12. History of traumatic fracture or orthopedic surgery within 6 months prior to Screening Visit 1 13. Use of KRN23, or any other therapeutic monoclonal antibody within 90 days prior to Screening Visit 1 14. Use of any investigational product or investigational medical device within 30 days prior to Screening Visit 1, or requirement for any investigational agent prior to completion of all scheduled study assessments. OR, in Japan, use of any investigational product or investigational medical device within 4 months prior to Screening, or requirement for any investigational agent prior to completion of all scheduled study assessments. 15. Pregnant or breastfeeding at Screening /Baseline or planning to become pregnant (self or partner) at any time during the study 16. Unable or unwilling to withhold prohibited medications throughout the study 17. Presence or history of any hypersensitivity, allergic or anaphylactic reactions to any monoclonal antibody or KRN23 excipients that, in the judgment of the investigator, places the subject at increased risk for adverse effects. 18. Prior history of positive test for human immunodeficiency virus antibody, hepatitis B surface antigen, and/or hepatitis C antibody 19. History of recurrent infection or predisposition to infection, or of known immunodeficiency 20. Presence of malignant neoplasm (except basal cell carcinoma) 21. Presence of a concurrent disease or condition that would interfere with study participation or affect safety 22. Presence or history of any condition that, in the view of the investigator, places the subject at high risk of poor treatment compliance or of not completing the study

Gender Eligibility: All

Minimum Age: 18 Years

Maximum Age: 65 Years

Are Healthy Volunteers Accepted: No

Investigator Details

  • Lead Sponsor
    • Kyowa Kirin, Inc.
  • Collaborator
    • Kyowa Kirin Co., Ltd.
  • Provider of Information About this Clinical Study
    • Sponsor
  • Overall Official(s)
    • Medical Director, Study Director, Ultragenyx Pharmaceutical Inc

Citations Reporting on Results

Insogna KL, Briot K, Imel EA, Kamenicky P, Ruppe MD, Portale AA, Weber T, Pitukcheewanont P, Cheong HI, Jan de Beur S, Imanishi Y, Ito N, Lachmann RH, Tanaka H, Perwad F, Zhang L, Chen CY, Theodore-Oklota C, Mealiffe M, San Martin J, Carpenter TO; AXLES 1 Investigators. 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. 2018 Aug;33(8):1383-1393. doi: 10.1002/jbmr.3475. Epub 2018 Jun 26.

Portale AA, Carpenter TO, Brandi ML, Briot K, Cheong HI, Cohen-Solal M, Crowley R, Jan De Beur S, Eastell R, Imanishi Y, Imel EA, Ing S, Ito N, Javaid M, Kamenicky P, Keen R, Kubota T, Lachmann R, Perwad F, Pitukcheewanont P, Ralston SH, Takeuchi Y, Tanaka H, Weber TJ, Yoo HW, Zhang L, Theodore-Oklota C, Mealiffe M, San Martin J, Insogna K. Continued Beneficial Effects of Burosumab in Adults with X-Linked Hypophosphatemia: Results from a 24-Week Treatment Continuation Period After a 24-Week Double-Blind Placebo-Controlled Period. Calcif Tissue Int. 2019 Sep;105(3):271-284. doi: 10.1007/s00223-019-00568-3. Epub 2019 Jun 4.

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