NCT02304367

Study of Burosumab (KRN23) in Adults With Tumor-Induced Osteomalacia (TIO) or Epidermal Nevus Syndrome (ENS)

Completed Phase 2 Results posted Last updated 6 May 2024

What this trial tests

Phase 2 trial testing Burosumab in Tumor Induced Osteomalacia (TIO) in 17 participants. Completed in 21 January 2021.

Timeline

24 March 2015

Primary endpoint
27 July 2017

21 January 2021

Quick facts

Lead sponsor	Kyowa Kirin, Inc.
Phase	Phase 2
Status	Completed
Study type	INTERVENTIONAL
Allocation	na
Design	single group
Masking	none
Primary purpose	treatment
Enrollment	17
Start date	24 March 2015
Primary completion	27 July 2017
Estimated completion	21 January 2021
Sites	7 locations across United States

Drugs / interventions tested

• Burosumab (BUROSUMAB) — full drug profile →

Conditions studied

• Tumor Induced Osteomalacia (TIO) — all drugs for Tumor Induced Osteomalacia (TIO) →
• Epidermal Nevus Syndrome (ENS) — all drugs for Epidermal Nevus Syndrome (ENS) →

Sponsor

Kyowa Kirin, Inc. — full company profile →

Who can join

18 and older, any sex, with Tumor Induced Osteomalacia (TIO) or Epidermal Nevus Syndrome (ENS). Patients with the condition only — healthy volunteers not accepted.

Results — posted to ClinicalTrials.gov

Per-arm endpoint measurements with 95% confidence intervals where reported. Source: trial results section.

Percentage of Participants Achieving Mean Serum Phosphorus Levels Above 2.5 mg/dL at the Mid-Point of the Dose Intervals Between Baseline and Week 24 Primary · Mid-point of each dose interval from Baseline to Week 24 (Weeks 2, 6, 10, 14 and 22 [there was no study visit at Week 18])

The percentage of participants achieving mean serum phosphorus levels above the lower limit of normal (LLN; 2.5 mg/dL \[0.81 mmol/L\]) at the mid-point of the dose interval (2 weeks after dosing), as averaged across dose cycles between Baseline and Week 24 (i.e. the average of serum phosphorus levels at Weeks 2, 6, 10, 14 and 22).

Group	Value	95% CI
Burosumab	50.0	26.80 – 73.20

Change From Baseline to Week 48 in Osteoid Thickness Primary · Baseline, Week 48

Histomorphometry of trans-iliac crest bone biopsies was assessed by a blinded, central reader. Osteoid thickness is the mean thickness of osteoid seams.

Group	Value	95% CI
Burosumab	-5.12	-10.04 – -0.20

Change From Baseline to Week 48 in Osteoid Surface/Bone Surface (OS/BS) Primary · Baseline, Week 48

Histomorphometry of trans-iliac crest bone biopsies was assessed by a blinded, central reader. Osteoid surface/bone surface is expressed as the percentage of bone surface covered in osteoid.

Group	Value	95% CI
Burosumab	-0.18	-13.86 – 13.50

Change From Baseline to Week 48 in Osteoid Volume/Bone Volume (OV/BV) Primary · Baseline, Week 48

Histomorphometry of trans-iliac crest bone biopsies was assessed by a blinded, central reader. Osteoid volume/bone volume is expressed as the percentage of a given volume of bone tissue that consists of unmineralized bone (osteoid).

Group	Value	95% CI
Burosumab	-5.47	-11.87 – 0.93

Change From Baseline to Week 48 in Mineralization Lag Time (MLt) Primary · Baseline, Week 48

Mineralization lag time is a dynamic modeling parameter representing the mean time interval between the formation of osteoid and its subsequent mineralization which can be measured using histomorphometry with double tetracycline labeling. Mlt was calculated by dividing the osteoid width by the mineralizing apposition rate (MAR; the average rate at which new bone mineral is being added on any actively forming surface). If Mlt could not be calculated directly due to low tetracycline uptake, Mlt was imputed according to the following: Mlt = O.Th/(MAR\*MS/OS), where O.Th = osteoid thickness, MA

Group	Value	95% CI
Burosumab	-565.20	-2037.42 – 907.02

Percentage of Participants Achieving Mean Serum Phosphorus Levels Above 2.5 mg/dL at the End of the Dose Intervals Between Baseline and Week 24 Secondary · End of each dose interval from Baseline to Week 24 (Weeks 4, 8, 12, 16, 20, and 24)

The percentage of participants achieving mean serum phosphorus levels above the lower limit of normal (2.5 mg/dL \[0.81 mmol/L\]) at the end of the dose interval (4 weeks post-dose, prior to the next dose), as averaged across dose cycles between Baseline and Week 24 (i.e. the average of serum phosphorus levels at Weeks 4, 8, 12, 16, 20, and 24).

Group	Value	95% CI
Burosumab	21.4	7.57 – 47.59

Mean Change From Baseline in Serum Phosphorus Levels at the Mid-Point of the Dose Interval, as Averaged Across Dose Cycles Between Baseline and Week 24 Secondary · Baseline and the mid-point of each dose interval from Baseline to Week 24 (Weeks 2, 6, 10, 14 and 22)

Mean change from Baseline to the mid-point of the dose interval (2 weeks after dosing) averaged across dose cycles between Baseline and Week 24 (i.e. the average of serum phosphorus levels at Weeks 2, 6, 10, 14 and 22).

Group	Value	95% CI
Burosumab	1.039	± 0.5622

Percent Change From Baseline in Serum Phosphorus Levels at the Mid-Point of the Dose Interval, as Averaged Across Dose Cycles Between Baseline and Week 24 Secondary · Baseline and the mid-point of each dose interval from Baseline to Week 24 (Weeks 2, 6, 10, 14 and 22)

Mean percent change from Baseline to the mid-point of the dose interval (2 weeks after dosing) averaged across dose cycles between Baseline and Week 24 (i.e. the average of serum phosphorus levels at Weeks 2, 6, 10, 14 and 22).

Group	Value	95% CI
Burosumab	69.77	± 43.743

Mean Change From Baseline in Serum Phosphorus Levels at the End of the Dosing Cycle, as Averaged Across Dose Cycles Between Baseline and Week 24 Secondary · Baseline and Weeks 4, 8, 12, 16, 20, and 24

Mean change from Baseline at the end of the dose interval (4 weeks post-dose, prior to the next dose) averaged across dose cycles between Baseline and Week 24 (i.e. the average of serum phosphorus levels at Weeks 4, 8, 12, 16, 20, and 24).

Group	Value	95% CI
Burosumab	0.550	± 0.4260

Percent Mean Change From Baseline in Serum Phosphorus Levels at the End of the Dosing Cycle, as Averaged Across Dose Cycles Between Baseline and Week 24 Secondary · Baseline and Weeks 4, 8, 12, 16, 20, and 24

Mean percent change from Baseline at the end of the dose interval (4 weeks post-dose, prior to the next dose) averaged across dose cycles between Baseline and Week 24 (i.e. the average of serum phosphorus levels at Weeks 4, 8, 12, 16, 20, and 24).

Group	Value	95% CI
Burosumab	38.56	± 33.027

Time-Adjusted Area Under the Curve (AUC) of Serum Phosphorus Levels Between Baseline and Week 24 Secondary · Pre-dose on Day 1 and at Weeks 1, 2, 4, 6, 8, 10, 12, 14, 16, 20, 21, 22, and 24

Serum phosphorus level versus time AUC was calculated using the trapezoidal rule. Time-adjusted AUC was calculated by dividing the AUC by duration of time included in AUC calculation.

Group	Value	95% CI
Burosumab	2.36	± 0.632

Change From Baseline Over Time in Serum 1,25-dihydroxyvitamin D (1,25(OH)2D) Concentration Secondary · Baseline and Weeks 24, 48, 96, 144, 168, 192, 216, and 240

Least squares (LS) means and standard errors (SE) were estimated from a generalized estimation equation (GEE) model which includes the change from Baseline as the dependent variable, time as the categorical variable and adjusted for Baseline 1,25(OH)2D, with compound symmetry covariance structure.

Week 24

Group	Value	95% CI
Burosumab	9.90	± 4.10

Week 48

Group	Value	95% CI
Burosumab	10.49	± 4.82

Week 96

Group	Value	95% CI
Burosumab	4.28	± 3.80

Week 144

Group	Value	95% CI
Burosumab	3.15	± 3.34

Week 168

Group	Value	95% CI
Burosumab	4.91	± 3.94

Week 192

Group	Value	95% CI
Burosumab	0.67	± 4.19

Week 216

Group	Value	95% CI
Burosumab	9.78	± 3.04

Week 240

Group	Value	95% CI
Burosumab	6.56	± 3.19

Adverse events — posted to ClinicalTrials.gov

Time frame: From first dose of study drug up to database lock date (July 07, 2021); median duration of treatment in the TIO analysis set was 1594.0 (range: 168-2106) days.. Reporting threshold: 5%. Adverse-event reports describe events observed during the trial — not all are caused by the drug.

KRN23 TIO

Serious: 8/14 (57%)

Deaths: 2/14

KRN23 XLH and ENS

Serious: 0/3 (0%)

Deaths: 0/3

Serious adverse events (20 terms)

Reaction	System	KRN23 TIO	KRN23 XLH and ENS
Neoplasm Progression	Neoplasms benign, malignant and unspecified (incl cysts and polyps)	—	—
Cardiac Arrest	Cardiac disorders	—	—
Acute Respiratory Failure	Respiratory, thoracic and mediastinal disorders	—	—
Pulseless Electrical Activity	Cardiac disorders	—	—
Ascites	Gastrointestinal disorders	—	—
Pancreatitis	Gastrointestinal disorders	—	—
Multi-Organ Failure	General disorders	—	—
Cholangitis	Hepatobiliary disorders	—	—
Septic Shock	Infections and infestations	—	—
Sialoadenitis	Infections and infestations	—	—
Tooth Abscess	Infections and infestations	—	—
Hypophosphataemia	Metabolism and nutrition disorders	—	—
Rheumatoid Arthritis	Musculoskeletal and connective tissue disorders	—	—
Metastases To Lung	Neoplasms benign, malignant and unspecified (incl cysts and polyps)	—	—
Ovarian Cancer	Neoplasms benign, malignant and unspecified (incl cysts and polyps)	—	—
Tumour Compression	Neoplasms benign, malignant and unspecified (incl cysts and polyps)	—	—
Acute Kidney Injury	Renal and urinary disorders	—	—
Pickwickian Syndrome	Respiratory, thoracic and mediastinal disorders	—	—
Pleural Effusion	Respiratory, thoracic and mediastinal disorders	—	—
Pulmonary Embolism	Respiratory, thoracic and mediastinal disorders	—	—

Other adverse events (244 terms — click to expand)

Reaction	System	KRN23 TIO	KRN23 XLH and ENS
Arthralgia	Musculoskeletal and connective tissue disorders	—	—
Pain In Extremity	Musculoskeletal and connective tissue disorders	—	—
Upper Respiratory Tract Infection	Infections and infestations	—	—
Cough	Respiratory, thoracic and mediastinal disorders	—	—
Diarrhoea	Gastrointestinal disorders	—	—
Nausea	Gastrointestinal disorders	—	—
Vomiting	Gastrointestinal disorders	—	—
Nasopharyngitis	Infections and infestations	—	—
Back Pain	Musculoskeletal and connective tissue disorders	—	—
Muscle Spasms	Musculoskeletal and connective tissue disorders	—	—
Constipation	Gastrointestinal disorders	—	—
Pain	General disorders	—	—
Urinary Tract Infection	Infections and infestations	—	—
Fall	Injury, poisoning and procedural complications	—	—
Amylase Increased	Investigations	—	—
Musculoskeletal Pain	Musculoskeletal and connective tissue disorders	—	—
Myalgia	Musculoskeletal and connective tissue disorders	—	—
Insomnia	Psychiatric disorders	—	—
Hypertension	Vascular disorders	—	—
Abdominal Pain	Gastrointestinal disorders	—	—
Fatigue	General disorders	—	—
Oedema Peripheral	General disorders	—	—
Bronchitis	Infections and infestations	—	—
Influenza	Infections and infestations	—	—
Contusion	Injury, poisoning and procedural complications	—	—
Ligament Sprain	Injury, poisoning and procedural complications	—	—
Procedural Pain	Injury, poisoning and procedural complications	—	—
Hypomagnesaemia	Metabolism and nutrition disorders	—	—
Vitamin D Deficiency	Metabolism and nutrition disorders	—	—
Joint Range Of Motion Decreased	Musculoskeletal and connective tissue disorders	—	—
Musculoskeletal Chest Pain	Musculoskeletal and connective tissue disorders	—	—
Neoplasm Progression	Neoplasms benign, malignant and unspecified (incl cysts and polyps)	—	—
Restless Legs Syndrome	Nervous system disorders	—	—
Nasal Congestion	Respiratory, thoracic and mediastinal disorders	—	—
Oropharyngeal Pain	Respiratory, thoracic and mediastinal disorders	—	—
Pulmonary Mass	Respiratory, thoracic and mediastinal disorders	—	—
Respiratory Tract Congestion	Respiratory, thoracic and mediastinal disorders	—	—
Rash	Skin and subcutaneous tissue disorders	—	—
Anaemia	Blood and lymphatic system disorders	—	—
Tinnitus	Ear and labyrinth disorders	—	—

Most-reported serious reactions: Neoplasm Progression, Cardiac Arrest, Acute Respiratory Failure, Pulseless Electrical Activity, Ascites, Pancreatitis, Multi-Organ Failure, Cholangitis.

Data from ClinicalTrials.gov NCT02304367 adverse events section.

Sponsor's own description

The primary objectives of this study are to evaluate the effect of burosumab treatment on:

* Increasing serum phosphorus levels in adults with TIO or ENS-associated osteomalacia
* Improvement in TIO/ENS-associated osteomalacia as determined by osteoid thickness (O.Th), osteoid surface/bone surface (OS/BS), osteoid volume/bone volume (OV/BV) and mineralization lag time (MLt).

Publications & conference data

8 peer-reviewed publications reference this trial (live from Europe PMC):

1. Burosumab for the Treatment of Tumor-Induced Osteomalacia.
   Jan de Beur SM, Miller PD, Weber TJ, Peacock M, et al · · 2021 · cited 125× · PMID 33338281 · DOI 10.1002/jbmr.4233
2. Interim Analysis of a Phase 2 Open-Label Trial Assessing Burosumab Efficacy and Safety in Patients With Tumor-Induced Osteomalacia.
   Imanishi Y, Ito N, Rhee Y, Takeuchi Y, et al · · 2021 · cited 66× · PMID 32967046 · DOI 10.1002/jbmr.4184
3. Pharmacological management of X-linked hypophosphataemia.
   Imel EA, White KE. · · 2019 · cited 20× · PMID 30207609 · DOI 10.1111/bcp.13763
4. Burosumab treatment in a child with cutaneous skeletal hypophosphatemia syndrome: A case report.
   Khadora M, Mughal MZ. · · 2021 · cited 16× · PMID 34660853 · DOI 10.1016/j.bonr.2021.101138
5. A literature review to understand the burden of disease in people living with tumour-induced osteomalacia.
   Minisola S, Barlassina A, Vincent SA, Wood S, et al · · 2022 · cited 15× · PMID 35643939 · DOI 10.1007/s00198-022-06432-9
6. Burosumab Improves Patient-Reported Outcomes in Adults With Tumor-Induced Osteomalacia: Mixed-Methods Analysis.
   Jan de Beur SM, Cimms T, Nixon A, Theodore-Oklota C, et al · · 2023 · cited 12× · PMID 37578099 · DOI 10.1002/jbmr.4900
7. Pathology and Therapeutic Significance of Fibroblast Growth Factors.
   Edirisinghe O, Ternier G, Kumar TKS. · · 2025 · cited 1× · PMID 41743400 · DOI 10.3390/targets3010005
8. Real-world efficacy and safety of burosumab in tumor-induced osteomalacia: case series from an early access program
   · 2025