Long-Term Extension Study of KRN23 in Adult Subjects With X-Linked Hypophosphatemia (XLH)

• ClinicalTrials.gov Identifier: NCT02312687
• Recruitment Status: Completed
• First Posted: December 9, 2014
• Results First Posted: December 16, 2019
• Last Update Posted: December 16, 2019
• Sponsor: Ultragenyx Pharmaceutical Inc
• Collaborator: Kyowa Kirin Co., Ltd.
• Information provided by (Responsible Party): Ultragenyx Pharmaceutical Inc

• Study Type: Interventional
• Study Design: Allocation: N/A; Intervention Model: Single Group Assignment; Masking: None (Open Label); Primary Purpose: Treatment
• Condition: X-Linked Hypophosphatemia
• Intervention: Biological: KRN23
• Enrollment: 20

Participant Flow

Recruitment Details
Pre-assignment Details

Arm/Group Title	KRN23
Arm/Group Description	KRN23 subcutaneous (SC) injections every 4 weeks
Period Title: Overall Study
Started	20
Completed	19
Not Completed	1
Reason Not Completed
Other, Not Specified	1

Baseline Characteristics

Arm/Group Title		KRN23
Arm/Group Description		KRN23 SC injections every 4 weeks
Overall Number of Baseline Participants		20
Baseline Analysis Population Description		[Not Specified]
Age, Continuous; Mean (Standard Deviation); Unit of measure: Years
	Number Analyzed	20 participants
		49.8 (12.87)
Sex: Female, Male; Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	20 participants
	Female	14 70.0%
	Male	6 30.0%
Ethnicity (NIH/OMB); Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	20 participants
	Hispanic or Latino	1 5.0%
	Not Hispanic or Latino	19 95.0%
	Unknown or Not Reported	0 0.0%
Race (NIH/OMB); Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	20 participants
	American Indian or Alaska Native	0 0.0%
	Asian	0 0.0%
	Native Hawaiian or Other Pacific Islander	0 0.0%
	Black or African American	1 5.0%
	White	19 95.0%
	More than one race	0 0.0%
	Unknown or Not Reported	0 0.0%
Serum Phosphorus; Mean (Standard Deviation); Unit of measure: mg/dL
	Number Analyzed	20 participants
		1.89 (0.301)
Serum Intact Parathyroid Hormone (iPTH); Mean (Standard Deviation); Unit of measure: pg/mL
	Number Analyzed	20 participants
		110.8 (43.70)
Serum Total Fibroblast Growth Factor 23 (FGF23); Mean (Standard Deviation); Unit of measure: pg/mL
	Number Analyzed	20 participants
		262.9 (227.02)
Serum Free FGF23; Mean (Standard Deviation); Unit of measure: pg/mL
	Number Analyzed	20 participants
		81.9 (42.33)
Serum 1,25-dihydroxy vitamin D [1,25(OH)2D]; Mean (Standard Deviation); Unit of measure: pg/mL
	Number Analyzed	20 participants
		31.7 (12.61)
2-hour Urine TmP/GFR [1]; Mean (Standard Deviation); Unit of measure: mg/dL
	Number Analyzed	20 participants
		1.583 (0.2566)
		[1] Measure Description: TmP/GFR: ratio of renal tubular maximum phosphate reabsorption rate to glomerular filtration rate
2-hour Urine Tubular Reabsorption of Phosphate (TRP); Mean (Standard Deviation); Unit of measure: Fraction of phosphorus reabsorbed
	Number Analyzed	20 participants
		0.783 (0.0792)
Fractional Excretion of Phosphorus (FEP); Mean (Standard Deviation); Unit of measure: Fraction of phosphorus excreted
	Number Analyzed	20 participants
		0.217 (0.0792)
24-hour Urine Phosphorus; Mean (Standard Deviation); Unit of measure: G/24hr
	Number Analyzed	20 participants
		0.74 (0.322)
24-Hour Urine Calcium [1]; Mean (Standard Deviation); Unit of measure: Mg/24hr
	Number Analyzed	17 participants
		96.118 (75.9530)
		[1] Measure Analysis Population Description: participants with an assessment
24-Hour Urine Creatinine; Mean (Standard Deviation); Unit of measure: Mg/24hr
	Number Analyzed	20 participants
		1058.150 (444.3073)
24-Hour Urine Calcium/Creatinine Ratio [1]; Mean (Standard Deviation); Unit of measure: Mg/mg
	Number Analyzed	17 participants
		0.0881 (0.05034)
		[1] Measure Analysis Population Description: participants with an assessment
Total Alkaline Phosphatase (ALP); Mean (Standard Deviation); Unit of measure: U/L
	Number Analyzed	20 participants
		131.1 (50.50)
Bone-Specific Alkaline Phosphatase (BALP); Mean (Standard Deviation); Unit of measure: mcg/L
	Number Analyzed	20 participants
		31.26 (18.528)
Carboxy Terminal Cross-Linked Telopeptide of Type I Collagen (CTx); Mean (Standard Deviation); Unit of measure: pg/mL
	Number Analyzed	20 participants
		732.4 (404.01)
Procollagen Type N-Propeptide (P1NP); Mean (Standard Deviation); Unit of measure: ng/mL
	Number Analyzed	20 participants
		76.5 (41.58)

Outcome Measures

1. Primary Outcome

Title	Number of Participants With Adverse Events (AEs), Treatment Emergent AEs (TEAEs), Serious AEs (SAEs), and AEs Leading to Discontinuation or Death
Description	An AE is defined as any untoward medical occurrence, whether or not considered drug related. An SAE or serious suspected adverse reaction is an AE or suspected adverse reaction that at any dose, in the view of either the investigator or sponsor, results in any of the following outcomes: death; a life-threatening AE; inpatient hospitalization or prolongation of existing hospitalization; persistent or significant incapacity or substantial disruption of the ability to conduct normal life functions; a congenital anomaly/birth defect; an important medical event. A TEAE is an AE that occurred on or after the first burosumab dose. AEs were graded as 1 (mild), 2 (moderate), 3 (severe), 4 (life-threatening), 5 (death). AEs were classified by the Investigator as possibly related, probably related, or definitely related.
Time Frame	Screening through the end of study plus 4-8 weeks. The mean duration of burosumab exposure was 165.6 weeks (range: 68-184 weeks).

Outcome Measure Data

Analysis Population Description

Safety Analysis Set

Arm/Group Title	KRN23
Arm/Group Description:	KRN23 SC injections every 4 weeks
Overall Number of Participants Analyzed	20
Measure Type: Count of Participants; Unit of Measure: Participants
All AEs	20 100.0%
TEAEs	20 100.0%
Related AEs	12 60.0%
SAEs	9 45.0%
Related SAEs	1 5.0%
Grade 3 and 4 AEs	10 50.0%
AEs Leading to Discontinuation	0 0.0%
AEs Leading to Death	0 0.0%

2. Primary Outcome

Title	Number of Participants With Clinically Significant Changes From Baseline in Vital Signs
Description	Clinically significant changes from baseline reported as adverse events are presented.
Time Frame	Through Week 184

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	KRN23
Arm/Group Description:	KRN23 SC injections every 4 weeks
Overall Number of Participants Analyzed	20
Measure Type: Count of Participants; Unit of Measure: Participants
Hypertension	2 10.0%
Decreased blood pressure	1 5.0%

3. Primary Outcome

Title	Number of Participants With Clinically Significant Changes From Baseline in Laboratory Values, by Category
Description	Clinically significant changes from baseline reported as adverse events are presented.
Time Frame	Through Week 184

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	KRN23
Arm/Group Description:	KRN23 SC injections every 4 weeks
Overall Number of Participants Analyzed	20
Measure Type: Count of Participants; Unit of Measure: Participants
Elevated eosinophils	1 5.0%
Hypercholesterolemia	1 5.0%
Hyperkalemia	1 5.0%
Hyperglycemia	1 5.0%
Elevated alanine aminotransferase	1 5.0%
Elevated aspartate aminotransferase	1 5.0%
Elevated gamma-glutamyl transferase	2 10.0%
Proteinuria	2 10.0%
Elevated amylase	2 10.0%
Elevated alkaline phosphatase	1 5.0%
Elevated lipase	1 5.0%
Hypercalciuria	1 5.0%
Worsening hypercholesterolemia	2 10.0%
Decreased hemoglobin	2 10.0%
Hypocalcemia (intermittent)	1 5.0%
Hypovitaminosis D	1 5.0%
Elevated cholesterol	1 5.0%
Hyperparathyroidism	1 5.0%
Urine electrophoresis abnormal	1 5.0%

4. Primary Outcome

Title	Number of Participants With Clinically Significant Changes From Baseline in Physical Exams, by Category
Description	Clinically significant changes from baseline reported as adverse events are presented.
Time Frame	Through Week 184

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	KRN23
Arm/Group Description:	KRN23 SC injections every 4 weeks
Overall Number of Participants Analyzed	20
Measure Type: Count of Participants; Unit of Measure: Participants
Bone pain	1 5.0%
Conjunctival haemorrhage	1 5.0%
Hypoacusis	1 5.0%
Dermal cyst	1 5.0%
Osteoarthritis	1 5.0%
Gravitational oedema	1 5.0%
Hypoaesthesia	1 5.0%
Neuropathy peripheral	2 10.0%
Arthralgia	1 5.0%
Peroneal nerve palsy	1 5.0%
Spinal pain	1 5.0%
Bone lesion	1 5.0%
Femur fracture	1 5.0%
Scrotal oedema	1 5.0%
Synovial cyst	1 5.0%
Testicular swelling	1 5.0%
Thermal burn	1 5.0%
Weight decreased	1 5.0%

5. Primary Outcome

Title	Number of Participants With Clinically Significant Changes From Baseline in Echocardiogram (ECHO) Tests
Description	Clinically significant changes from baseline reported as adverse events are presented.
Time Frame	Through Week 184

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	KRN23
Arm/Group Description:	KRN23 SC injections every 4 weeks
Overall Number of Participants Analyzed	20
Measure Type: Count of Participants; Unit of Measure: Participants
	0 0.0%

6. Primary Outcome

Title	Number of Participants With Clinically Significant Changes From Baseline in ECGs
Description	Clinically significant changes from baseline reported as adverse events are presented.
Time Frame	Through Week 184

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	KRN23
Arm/Group Description:	KRN23 SC injections every 4 weeks
Overall Number of Participants Analyzed	20
Measure Type: Count of Participants; Unit of Measure: Participants
	0 0.0%

7. Primary Outcome

Title	Number of Participants With Clinically Significant Changes From Baseline in Renal Ultrasound, by Category
Description	Clinically significant changes from baseline reported as adverse events are presented.
Time Frame	Through Week 184

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	KRN23
Arm/Group Description:	KRN23 SC injections every 4 weeks
Overall Number of Participants Analyzed	20
Measure Type: Count of Participants; Unit of Measure: Participants
Kidney stone(s)	1 5.0%
Nephrocalcinosis	1 5.0%
Right renal mass	1 5.0%
Nephrolithiasis	2 10.0%

8. Primary Outcome

Title	Number of Participants Positive for Anti-KRN23 Antibodies and Neutralizing Antibodies at Baseline and Anytime Post-Baseline
Description	[Not Specified]
Time Frame	Through Week 184

Outcome Measure Data

Analysis Population Description

Participants tested for neutralizing antibodies (n=4) are those who were positive for anti-KRN23 antibodies at any time during the study.

Arm/Group Title		KRN23
Arm/Group Description:		KRN23 SC injections every 4 weeks
Overall Number of Participants Analyzed		20
Measure Type: Count of Participants; Unit of Measure: Participants
Baseline: Anti-KRN23 Antibodies	Number Analyzed	20 participants
		2 10.0%
Post Baseline:Anti-KRN23 Antibodies	Number Analyzed	20 participants
		4 20.0%
Baseline: Neutralizing Antibodies	Number Analyzed	2 participants
		0 0.0%
Postbaseline: Neutralizing Antibodies	Number Analyzed	4 participants
		0 0.0%

9. Primary Outcome

Title	Percentage of Participants Reaching Serum Phosphorus Normal Range at Baseline and Any Time After Dosing
Description	[Not Specified]
Time Frame	Through Week 184

Outcome Measure Data

Analysis Population Description

Pharmacodynamic (PD) Analysis Set: all participants who received at least 1 dose of burosumab and had evaluable serum/urinary data.

Arm/Group Title	KRN23
Arm/Group Description:	KRN23 SC injections every 4 weeks
Overall Number of Participants Analyzed	20
Measure Type: Number; Number (95% Confidence Interval); Unit of Measure: percentage of participants
	100; (83.9 to 100.0)

10. Primary Outcome

Title	Change From Baseline Over Time in Serum Phosphorus
Description	[Not Specified]
Time Frame	Baseline, Weeks 24, 48, 72, 96, 120, 144

Outcome Measure Data

Analysis Population Description

PD Analysis Set (all participants who received at least 1 dose of burosumab and had evaluable serum/urinary data) with an assessment at given time point.

Arm/Group Title		KRN23
Arm/Group Description:		KRN23 SC injections every 4 weeks
Overall Number of Participants Analyzed		20
Least Squares Mean (Standard Error); Unit of Measure: mg/dL
Change at Week 24	Number Analyzed	16 participants
		0.68 (0.103)
Change at Week 48	Number Analyzed	19 participants
		0.68 (0.055)
Change at Week 72	Number Analyzed	20 participants
		0.59 (0.077)
Change at Week 96	Number Analyzed	19 participants
		0.47 (0.081)
Change at Week 120	Number Analyzed	18 participants
		0.57 (0.082)
Change at Week 144	Number Analyzed	18 participants
		0.59 (0.084)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	KRN23
	Comments	Change at Week 24
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	< 0.0001
	Comments	The generalized estimation equation (GEE) model includes the change from baseline as the dependent variable, time as the categorical variable and adjusted for baseline measurement, with compound symmetry covariance structure.
	Method	generalized estimation equation (GEE)
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Least Squares (LS) Mean
	Estimated Value	0.68
	Confidence Interval	(2-Sided) 95%; 0.48 to 0.88
	Estimation Comments	[Not Specified]

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	KRN23
	Comments	Change at Week 48
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	< 0.0001
	Comments	The GEE model includes the change from baseline as the dependent variable, time as the categorical variable and adjusted for baseline measurement, with compound symmetry covariance structure.
	Method	GEE
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	LS Mean
	Estimated Value	0.68
	Confidence Interval	(2-Sided) 95%; 0.57 to 0.79
	Estimation Comments	[Not Specified]

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	KRN23
	Comments	Change at Week 72
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	< 0.0001
	Comments	The GEE model includes the change from baseline as the dependent variable, time as the categorical variable and adjusted for baseline measurement, with compound symmetry covariance structure.
	Method	GEE
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	LS Mean
	Estimated Value	0.59
	Confidence Interval	(2-Sided) 95%; 0.44 to 0.75
	Estimation Comments	[Not Specified]

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	KRN23
	Comments	Change at Week 96
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	< 0.0001
	Comments	The GEE model includes the change from baseline as the dependent variable, time as the categorical variable and adjusted for baseline measurement, with compound symmetry covariance structure.
	Method	GEE
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	LS Mean
	Estimated Value	0.47
	Confidence Interval	(2-Sided) 95%; 0.31 to 0.63
	Estimation Comments	[Not Specified]

Statistical Analysis 5

Statistical Analysis Overview	Comparison Group Selection	KRN23
	Comments	Change at Week 120
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	< 0.0001
	Comments	The GEE model includes the change from baseline as the dependent variable, time as the categorical variable and adjusted for baseline measurement, with compound symmetry covariance structure.
	Method	GEE
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	LS Mean
	Estimated Value	0.57
	Confidence Interval	(2-Sided) 95%; 0.41 to 0.73
	Estimation Comments	[Not Specified]

Statistical Analysis 6

Statistical Analysis Overview	Comparison Group Selection	KRN23
	Comments	Change at Week 144
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	< 0.0001
	Comments	The GEE model includes the change from baseline as the dependent variable, time as the categorical variable and adjusted for baseline measurement, with compound symmetry covariance structure.
	Method	GEE
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	LS Mean
	Estimated Value	0.59
	Confidence Interval	(2-Sided) 95%; 0.43 to 0.76
	Estimation Comments	[Not Specified]

11. Primary Outcome

Title	Change From Baseline Over Time in Serum iPTH
Description	[Not Specified]
Time Frame	Baseline, Weeks 24, 48, 72, 96, 120, 144

Outcome Measure Data

Analysis Population Description

PD Analysis Set (all participants who received at least 1 dose of burosumab and had evaluable serum/urinary data) with an assessment at given time point.

Arm/Group Title		KRN23
Arm/Group Description:		KRN23 SC injections every 4 weeks
Overall Number of Participants Analyzed		20
Least Squares Mean (Standard Error); Unit of Measure: pg/mL
Change at Week 24	Number Analyzed	18 participants
		-9.75 (6.551)
Change at Week 48	Number Analyzed	20 participants
		-11.17 (7.444)
Change at Week 72	Number Analyzed	20 participants
		-18.12 (4.567)
Change at Week 96	Number Analyzed	19 participants
		-25.28 (5.577)
Change at Week 120	Number Analyzed	19 participants
		-22.39 (4.655)
Change at Week 144	Number Analyzed	19 participants
		-28.33 (6.007)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	KRN23
	Comments	Change at Week 24
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.1366
	Comments	The GEE model includes the change from baseline as the dependent variable, time as the categorical variable and adjusted for baseline measurement, with compound symmetry covariance structure.
	Method	GEE estimate
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	LS Mean
	Estimated Value	-9.75
	Confidence Interval	(2-Sided) 95%; -22.59 to 3.09
	Estimation Comments	[Not Specified]

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	KRN23
	Comments	Change at Week 48
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.1334
	Comments	The GEE model includes the change from baseline as the dependent variable, time as the categorical variable and adjusted for baseline measurement, with compound symmetry covariance structure.
	Method	GEE estimate
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	LS Mean
	Estimated Value	-11.17
	Confidence Interval	(2-Sided) 95%; -25.76 to 3.42
	Estimation Comments	[Not Specified]

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	KRN23
	Comments	Change at Week 72
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	< 0.0001
	Comments	The GEE model includes the change from baseline as the dependent variable, time as the categorical variable and adjusted for baseline measurement, with compound symmetry covariance structure.
	Method	GEE estimate
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	LS Mean
	Estimated Value	-18.12
	Confidence Interval	(2-Sided) 95%; -27.07 to -9.17
	Estimation Comments	[Not Specified]

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	KRN23
	Comments	Change at Week 96
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	< 0.0001
	Comments	The GEE model includes the change from baseline as the dependent variable, time as the categorical variable and adjusted for baseline measurement, with compound symmetry covariance structure.
	Method	GEE estimate
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	LS Mean
	Estimated Value	-25.28
	Confidence Interval	(2-Sided) 95%; -36.21 to -14.35
	Estimation Comments	[Not Specified]

Statistical Analysis 5

Statistical Analysis Overview	Comparison Group Selection	KRN23
	Comments	Change at Week 120
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	< 0.0001
	Comments	The GEE model includes the change from baseline as the dependent variable, time as the categorical variable and adjusted for baseline measurement, with compound symmetry covariance structure.
	Method	GEE estimate
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	LS Mean
	Estimated Value	-22.39
	Confidence Interval	(2-Sided) 95%; -31.51 to -13.26
	Estimation Comments	[Not Specified]

Statistical Analysis 6

Statistical Analysis Overview	Comparison Group Selection	KRN23
	Comments	Change at Week 144
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	< 0.0001
	Comments	The GEE model includes the change from baseline as the dependent variable, time as the categorical variable and adjusted for baseline measurement, with compound symmetry covariance structure.
	Method	GEE estimate
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	LS Mean
	Estimated Value	-28.33
	Confidence Interval	(2-Sided) 95%; -40.11 to -16.56
	Estimation Comments	[Not Specified]

12. Primary Outcome

Title	Change From Baseline Over Time in Serum Total FGF23
Description	[Not Specified]
Time Frame	Baseline, Weeks 24, 48, 72, 96, 120, 144

Outcome Measure Data

Analysis Population Description

PD Analysis Set (all participants who received at least 1 dose of burosumab and had evaluable serum/urinary data) with an assessment at given time point.

Arm/Group Title		KRN23
Arm/Group Description:		KRN23 SC injections every 4 weeks
Overall Number of Participants Analyzed		20
Mean (Standard Error); Unit of Measure: pg/mL
Change at Week 24	Number Analyzed	20 participants
		215493.38 (10634.172)
Change at Week 48	Number Analyzed	20 participants
		202525.38 (17429.124)
Change at Week 72	Number Analyzed	20 participants
		221481.03 (21353.941)
Change at Week 96	Number Analyzed	19 participants
		221674.07 (20592.592)
Change at Week 120	Number Analyzed	19 participants
		208270.02 (20945.303)
Change at Week 144	Number Analyzed	17 participants
		235953.55 (35634.821)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	KRN23
	Comments	Change at Week 24
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	< 0.0001
	Comments	The GEE model includes the change from baseline as the dependent variable, time as the categorical variable and adjusted for baseline measurement, with compound symmetry covariance structure.
	Method	GEE
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	LS Mean
	Estimated Value	215493.38
	Confidence Interval	(2-Sided) 95%; 194650.78 to 236335.97
	Estimation Comments	[Not Specified]

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	KRN23
	Comments	Change at Week 48
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	< 0.0001
	Comments	The GEE model includes the change from baseline as the dependent variable, time as the categorical variable and adjusted for baseline measurement, with compound symmetry covariance structure.
	Method	GEE
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	LS Mean
	Estimated Value	202525.38
	Confidence Interval	(2-Sided) 95%; 168364.92 to 236685.83
	Estimation Comments	[Not Specified]

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	KRN23
	Comments	Change at Week 72
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	< 0.0001
	Comments	The GEE model includes the change from baseline as the dependent variable, time as the categorical variable and adjusted for baseline measurement, with compound symmetry covariance structure.
	Method	GEE
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	LS Mean
	Estimated Value	221481.03
	Confidence Interval	(2-Sided) 95%; 179628.07 to 263333.98
	Estimation Comments	[Not Specified]

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	KRN23
	Comments	Change at Week 96
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	< 0.0001
	Comments	The GEE model includes the change from baseline as the dependent variable, time as the categorical variable and adjusted for baseline measurement, with compound symmetry covariance structure.
	Method	GEE
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	LS Mean
	Estimated Value	221674.07
	Confidence Interval	(2-Sided) 95%; 181313.34 to 262034.81
	Estimation Comments	[Not Specified]

Statistical Analysis 5

Statistical Analysis Overview	Comparison Group Selection	KRN23
	Comments	Change at Week 120
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	< 0.0001
	Comments	The GEE model includes the change from baseline as the dependent variable, time as the categorical variable and adjusted for baseline measurement, with compound symmetry covariance structure.
	Method	GEE
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	LS Mean
	Estimated Value	208270.02
	Confidence Interval	(2-Sided) 95%; 167217.98 to 249322.06
	Estimation Comments	[Not Specified]

Statistical Analysis 6

Statistical Analysis Overview	Comparison Group Selection	KRN23
	Comments	Change at Week 144
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	< 0.0001
	Comments	The GEE model includes the change from baseline as the dependent variable, time as the categorical variable and adjusted for baseline measurement, with compound symmetry covariance structure.
	Method	GEE
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	LS Mean
	Estimated Value	235953.55
	Confidence Interval	(2-Sided) 95%; 166110.59 to 305796.52
	Estimation Comments	[Not Specified]

13. Primary Outcome

Title	Change From Baseline Over Time in Serum Free FGF23
Description	[Not Specified]
Time Frame	Baseline, Weeks 24, 48, 72, 96, 120, 144

Outcome Measure Data

Analysis Population Description

PD Analysis Set (all participants who received at least 1 dose of burosumab and had evaluable serum/urinary data) with an assessment at given time point.

Arm/Group Title		KRN23
Arm/Group Description:		KRN23 SC injections every 4 weeks
Overall Number of Participants Analyzed		20
Least Squares Mean (Standard Error); Unit of Measure: pg/mL
Change at Week 24	Number Analyzed	20 participants
		1277.84 (38.521)
Change at Week 48	Number Analyzed	20 participants
		1244.99 (40.250)
Change at Week 72	Number Analyzed	20 participants
		1298.49 (33.129)
Change at Week 96	Number Analyzed	19 participants
		1311.05 (37.119)
Change at Week 120	Number Analyzed	19 participants
		1368.68 (21.063)
Change at Week 144	Number Analyzed	17 participants
		1298.41 (45.972)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	KRN23
	Comments	Change at Week 24
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	< 0.0001
	Comments	The GEE model includes the change from baseline as the dependent variable, time as the categorical variable and adjusted for baseline measurement, with compound symmetry covariance structure.
	Method	GEE
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	LS Mean
	Estimated Value	1277.84
	Confidence Interval	(2-Sided) 95%; 1202.34 to 1353.34
	Estimation Comments	[Not Specified]

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	KRN23
	Comments	Change at Week 48
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	< 0.0001
	Comments	The GEE model includes the change from baseline as the dependent variable, time as the categorical variable and adjusted for baseline measurement, with compound symmetry covariance structure.
	Method	GEE
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	LS Mean
	Estimated Value	1244.99
	Confidence Interval	(2-Sided) 95%; 1166.10 to 1323.88
	Estimation Comments	[Not Specified]

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	KRN23
	Comments	Change at Week 72
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	< 0.0001
	Comments	The GEE model includes the change from baseline as the dependent variable, time as the categorical variable and adjusted for baseline measurement, with compound symmetry covariance structure.
	Method	GEE
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	LS Mean
	Estimated Value	1298.49
	Confidence Interval	(2-Sided) 95%; 1233.56 to 1363.43
	Estimation Comments	[Not Specified]

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	KRN23
	Comments	Change at Week 96
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	< 0.0001
	Comments	The GEE model includes the change from baseline as the dependent variable, time as the categorical variable and adjusted for baseline measurement, with compound symmetry covariance structure.
	Method	GEE
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	LS Mean
	Estimated Value	1311.05
	Confidence Interval	(2-Sided) 95%; 1238.30 to 1383.80
	Estimation Comments	[Not Specified]

Statistical Analysis 5

Statistical Analysis Overview	Comparison Group Selection	KRN23
	Comments	Change at Week 120
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	< 0.0001
	Comments	The GEE model includes the change from baseline as the dependent variable, time as the categorical variable and adjusted for baseline measurement, with compound symmetry covariance structure.
	Method	GEE
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	LS Mean
	Estimated Value	1368.68
	Confidence Interval	(2-Sided) 95%; 1327.40 to 1409.96
	Estimation Comments	[Not Specified]

Statistical Analysis 6

Statistical Analysis Overview	Comparison Group Selection	KRN23
	Comments	Change at Week 144
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	< 0.0001
	Comments	The GEE model includes the change from baseline as the dependent variable, time as the categorical variable and adjusted for baseline measurement, with compound symmetry covariance structure.
	Method	GEE
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	LS Mean
	Estimated Value	1298.41
	Confidence Interval	(2-Sided) 95%; 1208.31 to 1388.51
	Estimation Comments	[Not Specified]

14. Primary Outcome

Title	Change From Baseline Over Time in Serum 1,25(OH)2D
Description	[Not Specified]
Time Frame	Baseline, Weeks 24, 48, 72, 96, 120, 144

Outcome Measure Data

Analysis Population Description

PD Analysis Set (all participants who received at least 1 dose of burosumab and had evaluable serum/urinary data) with an assessment at given time point.

Arm/Group Title		KRN23
Arm/Group Description:		KRN23 SC injections every 4 weeks
Overall Number of Participants Analyzed		20
Least Squares Mean (Standard Error); Unit of Measure: pg/mL
Change at Week 24	Number Analyzed	20 participants
		7.87 (2.403)
Change at Week 48	Number Analyzed	19 participants
		2.70 (2.653)
Change at Week 72	Number Analyzed	20 participants
		2.62 (2.505)
Change at Week 96	Number Analyzed	19 participants
		0.31 (2.052)
Change at Week 120	Number Analyzed	19 participants
		-0.48 (2.365)
Change at Week 144	Number Analyzed	19 participants
		-3.43 (2.844)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	KRN23
	Comments	Change at Week 24
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.0011
	Comments	The GEE model includes the change from baseline as the dependent variable, time as the categorical variable and adjusted for baseline measurement, with compound symmetry covariance structure.
	Method	GEE
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	LS Mean
	Estimated Value	7.87
	Confidence Interval	(2-Sided) 95%; 3.16 to 12.58
	Estimation Comments	[Not Specified]

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	KRN23
	Comments	Change at Week 48
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.3092
	Comments	The GEE model includes the change from baseline as the dependent variable, time as the categorical variable and adjusted for baseline measurement, with compound symmetry covariance structure.
	Method	GEE
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	LS Mean
	Estimated Value	2.70
	Confidence Interval	(2-Sided) 95%; -2.50 to 7.90
	Estimation Comments	[Not Specified]

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	KRN23
	Comments	Change at Week 72
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.2958
	Comments	The GEE model includes the change from baseline as the dependent variable, time as the categorical variable and adjusted for baseline measurement, with compound symmetry covariance structure.
	Method	GEE
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	LS Mean
	Estimated Value	2.62
	Confidence Interval	(2-Sided) 95%; -2.29 to 7.53
	Estimation Comments	[Not Specified]

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	KRN23
	Comments	Change at Week 96
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.8796
	Comments	The GEE model includes the change from baseline as the dependent variable, time as the categorical variable and adjusted for baseline measurement, with compound symmetry covariance structure.
	Method	GEE
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	LS Mean
	Estimated Value	0.31
	Confidence Interval	(2-Sided) 95%; -3.71 to 4.33
	Estimation Comments	[Not Specified]

Statistical Analysis 5

Statistical Analysis Overview	Comparison Group Selection	KRN23
	Comments	Change at Week 120
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.8396
	Comments	The GEE model includes the change from baseline as the dependent variable, time as the categorical variable and adjusted for baseline measurement, with compound symmetry covariance structure.
	Method	GEE
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	LS Mean
	Estimated Value	-0.48
	Confidence Interval	(2-Sided) 95%; -5.11 to 4.16
	Estimation Comments	[Not Specified]

Statistical Analysis 6

Statistical Analysis Overview	Comparison Group Selection	KRN23
	Comments	Change at Week 144
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.2284
	Comments	The GEE model includes the change from baseline as the dependent variable, time as the categorical variable and adjusted for baseline measurement, with compound symmetry covariance structure.
	Method	GEE
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	LS Mean
	Estimated Value	-3.43
	Confidence Interval	(2-Sided) 95%; -9.00 to 2.15
	Estimation Comments	[Not Specified]

15. Primary Outcome

Title	Change From Baseline Ovr Time in 2-hour Urine TmP/GFR
Description	[Not Specified]
Time Frame	Baseline, Weeks 24, 48, 72, 96, 120, 144

Outcome Measure Data

Analysis Population Description

PD Analysis Set (all participants who received at least 1 dose of burosumab and had evaluable serum/urinary data) with an assessment at given time point.

Arm/Group Title		KRN23
Arm/Group Description:		KRN23 SC injections every 4 weeks
Overall Number of Participants Analyzed		20
Least Squares Mean (Standard Error); Unit of Measure: mg/dL
Change at Week 24	Number Analyzed	16 participants
		0.57 (0.128)
Change at Week 48	Number Analyzed	19 participants
		0.47 (0.047)
Change at Week 72	Number Analyzed	20 participants
		0.42 (0.072)
Change at Week 96	Number Analyzed	19 participants
		0.44 (0.084)
Change at Week 120	Number Analyzed	18 participants
		0.36 (0.066)
Change at Week 144	Number Analyzed	18 participants
		0.47 (0.078)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	KRN23
	Comments	Change at Week 24
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	LS Mean
	Estimated Value	0.57
	Confidence Interval	(2-Sided) 95%; 0.32 to 0.83
	Estimation Comments	[Not Specified]

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	KRN23
	Comments	Change at Week 48
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	LS Mean
	Estimated Value	0.47
	Confidence Interval	(2-Sided) 95%; 0.37 to 0.56
	Estimation Comments	[Not Specified]

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	KRN23
	Comments	Change at Week 72
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	LS Mean
	Estimated Value	0.42
	Confidence Interval	(2-Sided) 95%; 0.28 to 0.56
	Estimation Comments	[Not Specified]

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	KRN23
	Comments	Change at Week 96
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	LS Mean
	Estimated Value	0.44
	Confidence Interval	(2-Sided) 95%; 0.27 to 0.60
	Estimation Comments	[Not Specified]

Statistical Analysis 5

Statistical Analysis Overview	Comparison Group Selection	KRN23
	Comments	Change at Week 120
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	LS Mean
	Estimated Value	0.36
	Confidence Interval	(2-Sided) 95%; 0.23 to 0.48
	Estimation Comments	[Not Specified]

Statistical Analysis 6

Statistical Analysis Overview	Comparison Group Selection	KRN23
	Comments	Change at Week 144
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	LS Mean
	Estimated Value	0.47
	Confidence Interval	(2-Sided) 95%; 0.32 to 0.62
	Estimation Comments	[Not Specified]

16. Primary Outcome

Title	Change From Baseline Over Time in in 2-hour Urine TRP
Description	[Not Specified]
Time Frame	Baseline, Weeks 24, 48, 72, 96, 120, 144

Outcome Measure Data

Analysis Population Description

PD Analysis Set (all participants who received at least 1 dose of burosumab and had evaluable serum/urinary data) with an assessment at given time point.

Arm/Group Title		KRN23
Arm/Group Description:		KRN23 SC injections every 4 weeks
Overall Number of Participants Analyzed		20
Least Squares Mean (Standard Error); Unit of Measure: fraction of phosphorus reabsorbed
Change at Week 24	Number Analyzed	18 participants
		0.04 (0.015)
Change at Week 48	Number Analyzed	19 participants
		0.01 (0.011)
Change at Week 72	Number Analyzed	20 participants
		0.01 (0.011)
Change at Week 96	Number Analyzed	19 participants
		0.05 (0.012)
Change at Week 120	Number Analyzed	18 participants
		0.01 (0.012)
Change at Week 144	Number Analyzed	18 participants
		0.02 (0.017)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	KRN23
	Comments	Change at Week 24
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	LS Mean
	Estimated Value	0.04
	Confidence Interval	(2-Sided) 95%; 0.01 to 0.07
	Estimation Comments	[Not Specified]

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	KRN23
	Comments	Change at Week 48
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	LS Mean
	Estimated Value	0.01
	Confidence Interval	(2-Sided) 95%; -0.01 to 0.03
	Estimation Comments	[Not Specified]

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	KRN23
	Comments	Change at Week 72
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	LS Mean
	Estimated Value	0.01
	Confidence Interval	(2-Sided) 95%; -0.01 to 0.04
	Estimation Comments	[Not Specified]

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	KRN23
	Comments	Change at Week 96
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	LS Mean
	Estimated Value	0.05
	Confidence Interval	(2-Sided) 95%; 0.02 to 0.07
	Estimation Comments	[Not Specified]

Statistical Analysis 5

Statistical Analysis Overview	Comparison Group Selection	KRN23
	Comments	Change at Week 120
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	LS Mean
	Estimated Value	0.01
	Confidence Interval	(2-Sided) 95%; -0.02 to 0.03
	Estimation Comments	[Not Specified]

Statistical Analysis 6

Statistical Analysis Overview	Comparison Group Selection	KRN23
	Comments	Change at Week 144
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	LS Mean
	Estimated Value	0.02
	Confidence Interval	(2-Sided) 95%; -0.01 to 0.05
	Estimation Comments	[Not Specified]

17. Primary Outcome

Title	Change From Baseline Over Time in FEP
Description	[Not Specified]
Time Frame	Baseline, Weeks 24, 48, 72, 96, 120, 144

Outcome Measure Data

Analysis Population Description

PD Analysis Set (all participants who received at least 1 dose of burosumab and had evaluable serum/urinary data) with an assessment at given time point.

Arm/Group Title		KRN23
Arm/Group Description:		KRN23 SC injections every 4 weeks
Overall Number of Participants Analyzed		20
Least Squares Mean (Standard Error); Unit of Measure: fraction of phosphorus excreted
Change at Week 24	Number Analyzed	18 participants
		-0.04 (0.015)
Change at Week 48	Number Analyzed	19 participants
		-0.01 (0.011)
Change at Week 72	Number Analyzed	20 participants
		-0.01 (0.011)
Change at Week 96	Number Analyzed	19 participants
		-0.05 (0.012)
Change at Week 120	Number Analyzed	18 participants
		-0.01 (0.012)
Change at Week 144	Number Analyzed	18 participants
		-0.02 (0.017)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	KRN23
	Comments	Change at Week 24
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	LS Mean
	Estimated Value	-0.04
	Confidence Interval	(2-Sided) 95%; -0.07 to -0.01
	Estimation Comments	[Not Specified]

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	KRN23
	Comments	Change at Week 48
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	LS Mean
	Estimated Value	-0.01
	Confidence Interval	(2-Sided) 95%; -0.03 to 0.01
	Estimation Comments	[Not Specified]

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	KRN23
	Comments	Change at Week 72
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	LS Mean
	Estimated Value	-0.01
	Confidence Interval	(2-Sided) 95%; -0.04 to 0.01
	Estimation Comments	[Not Specified]

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	KRN23
	Comments	Change at Week 96
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	LS Mean
	Estimated Value	-0.05
	Confidence Interval	(2-Sided) 95%; -0.07 to -0.02
	Estimation Comments	[Not Specified]

Statistical Analysis 5

Statistical Analysis Overview	Comparison Group Selection	KRN23
	Comments	Change at Week 120
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	LS Mean
	Estimated Value	-0.01
	Confidence Interval	(2-Sided) 95%; -0.03 to 0.02
	Estimation Comments	[Not Specified]

Statistical Analysis 6

Statistical Analysis Overview	Comparison Group Selection	KRN23
	Comments	Change at Week 144
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	LS Mean
	Estimated Value	-0.02
	Confidence Interval	(2-Sided) 95%; -0.05 to 0.01
	Estimation Comments	[Not Specified]

18. Primary Outcome

Title	Change From Baseline Over Time in 24-hour Urine Phosphorus
Description	[Not Specified]
Time Frame	Baseline, Weeks 24, 48, 72, 96, 120, 144

Outcome Measure Data

Analysis Population Description

PD Analysis Set (all participants who received at least 1 dose of burosumab and had evaluable serum/urinary data) with an assessment at given time point.

Arm/Group Title		KRN23
Arm/Group Description:		KRN23 SC injections every 4 weeks
Overall Number of Participants Analyzed		20
Least Squares Mean (Standard Error); Unit of Measure: g/24hr
Change at Week 24	Number Analyzed	18 participants
		-0.01 (0.045)
Change at Week 48	Number Analyzed	20 participants
		0.02 (0.044)
Change at Week 72	Number Analyzed	19 participants
		0.08 (0.044)
Change at Week 96	Number Analyzed	19 participants
		-0.01 (0.040)
Change at Week 120	Number Analyzed	19 participants
		-0.01 (0.058)
Change at Week 144	Number Analyzed	16 participants
		-0.05 (0.054)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	KRN23
	Comments	Change at Week 24
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	LS Mean
	Estimated Value	-0.01
	Confidence Interval	(2-Sided) 95%; -0.10 to 0.08
	Estimation Comments	[Not Specified]

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	KRN23
	Comments	Change at Week 48
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	LS Mean
	Estimated Value	0.02
	Confidence Interval	(2-Sided) 95%; -0.07 to 0.10
	Estimation Comments	[Not Specified]

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	KRN23
	Comments	Change at Week 72
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	LS Mean
	Estimated Value	0.08
	Confidence Interval	(2-Sided) 95%; -0.01 to 0.16
	Estimation Comments	[Not Specified]

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	KRN23
	Comments	Change at Week 96
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	LS Mean
	Estimated Value	-0.01
	Confidence Interval	(2-Sided) 95%; -0.09 to 0.06
	Estimation Comments	[Not Specified]

Statistical Analysis 5

Statistical Analysis Overview	Comparison Group Selection	KRN23
	Comments	Change at Week 120
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	LS Mean
	Estimated Value	-0.01
	Confidence Interval	(2-Sided) 95%; -0.12 to 0.10
	Estimation Comments	[Not Specified]

Statistical Analysis 6

Statistical Analysis Overview	Comparison Group Selection	KRN23
	Comments	Change at Week 144
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	LS Mean
	Estimated Value	-0.05
	Confidence Interval	(2-Sided) 95%; -0.16 to 0.06
	Estimation Comments	[Not Specified]

19. Primary Outcome

Title	Change From Baseline Over Time in 24-Hour Urine Calcium
Description	[Not Specified]
Time Frame	Baseline, Weeks 24, 48, 72, 96, 120, 144

Outcome Measure Data

Analysis Population Description

PD Analysis Set (all participants who received at least 1 dose of burosumab and had evaluable serum/urinary data) with an assessment at given time point.

Arm/Group Title		KRN23
Arm/Group Description:		KRN23 SC injections every 4 weeks
Overall Number of Participants Analyzed		20
Least Squares Mean (Standard Error); Unit of Measure: mg/24hr
Change at Week 24	Number Analyzed	13 participants
		22.89 (12.605)
Change at Week 48	Number Analyzed	15 participants
		15.15 (8.914)
Change at Week 72	Number Analyzed	14 participants
		11.10 (12.975)
Change at Week 96	Number Analyzed	12 participants
		-16.65 (10.637)
Change at Week 120	Number Analyzed	13 participants
		3.48 (18.375)
Change at Week 144	Number Analyzed	14 participants
		28.55 (20.239)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	KRN23
	Comments	Change at Week 24
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	LS Mean
	Estimated Value	22.89
	Confidence Interval	(2-Sided) 95%; -1.81 to 47.60
	Estimation Comments	[Not Specified]

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	KRN23
	Comments	Change at Week 48
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	LS Mean
	Estimated Value	15.15
	Confidence Interval	(2-Sided) 95%; -2.32 to 32.62
	Estimation Comments	[Not Specified]

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	KRN23
	Comments	Change at Week 72
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	LS Mean
	Estimated Value	11.10
	Confidence Interval	(2-Sided) 95%; -14.33 to 36.53
	Estimation Comments	[Not Specified]

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	KRN23
	Comments	Change at Week 96
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	LS Mean
	Estimated Value	-16.65
	Confidence Interval	(2-Sided) 95%; -37.50 to 4.20
	Estimation Comments	[Not Specified]

Statistical Analysis 5

Statistical Analysis Overview	Comparison Group Selection	KRN23
	Comments	Change at Week 120
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	LS Mean
	Estimated Value	3.48
	Confidence Interval	(2-Sided) 95%; -32.53 to 39.49
	Estimation Comments	[Not Specified]

Statistical Analysis 6

Statistical Analysis Overview	Comparison Group Selection	KRN23
	Comments	Change at Week 144
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	LS Mean
	Estimated Value	28.55
	Confidence Interval	(2-Sided) 95%; -11.12 to 68.22
	Estimation Comments	[Not Specified]

20. Primary Outcome

Title	Change From Baseline Over Time in 24-Hour Urine Creatinine
Description	[Not Specified]
Time Frame	Baseline, Weeks 24, 48, 72, 96, 120, 144

Outcome Measure Data

Analysis Population Description

PD Analysis Set (all participants who received at least 1 dose of burosumab and had evaluable serum/urinary data) with an assessment at given time point.

Arm/Group Title		KRN23
Arm/Group Description:		KRN23 SC injections every 4 weeks
Overall Number of Participants Analyzed		20
Least Squares Mean (Standard Error); Unit of Measure: mg/24hr
Change at Week 24	Number Analyzed	18 participants
		-14.77 (37.170)
Change at Week 48	Number Analyzed	20 participants
		-70.79 (46.186)
Change at Week 72	Number Analyzed	19 participants
		-16.11 (48.389)
Change at Week 96	Number Analyzed	19 participants
		-41.74 (55.546)
Change at Week 120	Number Analyzed	19 participants
		-76.11 (82.239)
Change at Week 144	Number Analyzed	17 participants
		-96.06 (56.389)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	KRN23
	Comments	Change at Week 24
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	LS Mean
	Estimated Value	-14.77
	Confidence Interval	(2-Sided) 95%; -87.62 to 58.08
	Estimation Comments	[Not Specified]

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	KRN23
	Comments	Change at Week 48
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	LS Mean
	Estimated Value	-70.79
	Confidence Interval	(2-Sided) 95%; -161.31 to 19.74
	Estimation Comments	[Not Specified]

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	KRN23
	Comments	Change at Week 72
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	LS Mean
	Estimated Value	-16.11
	Confidence Interval	(2-Sided) 95%; -110.96 to 78.73
	Estimation Comments	[Not Specified]

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	KRN23
	Comments	Change at Week 96
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	LS Mean
	Estimated Value	-41.74
	Confidence Interval	(2-Sided) 95%; -150.61 to 67.13
	Estimation Comments	[Not Specified]

Statistical Analysis 5

Statistical Analysis Overview	Comparison Group Selection	KRN23
	Comments	Change at Week 120
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	LS Mean
	Estimated Value	-76.11
	Confidence Interval	(2-Sided) 95%; -237.29 to 85.08
	Estimation Comments	[Not Specified]

Statistical Analysis 6

Statistical Analysis Overview	Comparison Group Selection	KRN23
	Comments	Change at Week 144
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	LS Mean
	Estimated Value	-96.06
	Confidence Interval	(2-Sided) 95%; -206.59 to 14.46
	Estimation Comments	[Not Specified]

21. Primary Outcome

Title	Change From Baseline Over Time in 24-Hour Urine Calcium/Creatinine Ratio
Description	[Not Specified]
Time Frame	Baseline, Weeks 24, 48, 72, 96, 120, 144

Outcome Measure Data

Analysis Population Description

PD Analysis Set (all participants who received at least 1 dose of burosumab and had evaluable serum/urinary data) with an assessment at given time point.

Arm/Group Title		KRN23
Arm/Group Description:		KRN23 SC injections every 4 weeks
Overall Number of Participants Analyzed		20
Least Squares Mean (Standard Error); Unit of Measure: mg/mg
Change at Week 24	Number Analyzed	13 participants
		0.01 (0.010)
Change at Week 48	Number Analyzed	15 participants
		0.01 (0.011)
Change at Week 72	Number Analyzed	14 participants
		0.00 (0.011)
Change at Week 96	Number Analyzed	12 participants
		-0.01 (0.013)
Change at Week 120	Number Analyzed	13 participants
		0.00 (0.013)
Change at Week 144	Number Analyzed	14 participants
		0.03 (0.023)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	KRN23
	Comments	Change at Week 24
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	LS Mean
	Estimated Value	0.01
	Confidence Interval	(2-Sided) 95%; -0.01 to 0.03
	Estimation Comments	[Not Specified]

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	KRN23
	Comments	Change at Week 48
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	LS Mean
	Estimated Value	0.01
	Confidence Interval	(2-Sided) 95%; -0.01 to 0.04
	Estimation Comments	[Not Specified]

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	KRN23
	Comments	Change at Week 72
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	LS Mean
	Estimated Value	0.00
	Confidence Interval	(2-Sided) 95%; -0.02 to 0.02
	Estimation Comments	[Not Specified]

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	KRN23
	Comments	Change at Week 96
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	LS Mean
	Estimated Value	-0.01
	Confidence Interval	(2-Sided) 95%; -0.04 to 0.02
	Estimation Comments	[Not Specified]

Statistical Analysis 5

Statistical Analysis Overview	Comparison Group Selection	KRN23
	Comments	Change at Week 120
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	LS Mean
	Estimated Value	0.00
	Confidence Interval	(2-Sided) 95%; -0.02 to 0.03
	Estimation Comments	[Not Specified]

Statistical Analysis 6

Statistical Analysis Overview	Comparison Group Selection	KRN23
	Comments	Change at Week 144
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	LS Mean
	Estimated Value	0.03
	Confidence Interval	(2-Sided) 95%; -0.01 to 0.08
	Estimation Comments	[Not Specified]

22. Primary Outcome

Title	Change From Baseline Over Time in Total ALP
Description	[Not Specified]
Time Frame	Baseline, Weeks 24, 48, 72, 96, 120, 144

Outcome Measure Data

Analysis Population Description

PD Analysis Set (all participants who received at least 1 dose of burosumab and had evaluable serum/urinary data) with an assessment at given time point.

Arm/Group Title		KRN23
Arm/Group Description:		KRN23 SC injections every 4 weeks
Overall Number of Participants Analyzed		20
Least Squares Mean (Standard Error); Unit of Measure: U/L
Change at Week 24	Number Analyzed	20 participants
		14.92 (6.935)
Change at Week 48	Number Analyzed	20 participants
		-1.73 (5.752)
Change at Week 72	Number Analyzed	20 participants
		-22.28 (4.044)
Change at Week 96	Number Analyzed	19 participants
		-20.93 (3.567)
Change at Week 120	Number Analyzed	19 participants
		-18.77 (7.228)
Change at Week 144	Number Analyzed	19 participants
		-25.72 (5.701)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	KRN23
	Comments	Change at Week 24
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.0314
	Comments	The GEE model includes the change from baseline as the dependent variable, time as the categorical variable and adjusted for baseline measurement, with compound symmetry covariance structure.
	Method	GEE
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	LS Mean
	Estimated Value	14.92
	Confidence Interval	(2-Sided) 95%; 1.33 to 28.52
	Estimation Comments	[Not Specified]

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	KRN23
	Comments	Change at Week 48
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.7640
	Comments	The GEE model includes the change from baseline as the dependent variable, time as the categorical variable and adjusted for baseline measurement, with compound symmetry covariance structure.
	Method	GEE
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	LS Mean
	Estimated Value	-1.73
	Confidence Interval	(2-Sided) 95%; -13.00 to 9.55
	Estimation Comments	[Not Specified]

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	KRN23
	Comments	Change at Week 72
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	< 0.0001
	Comments	The GEE model includes the change from baseline as the dependent variable, time as the categorical variable and adjusted for baseline measurement, with compound symmetry covariance structure.
	Method	GEE
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	LS Mean
	Estimated Value	-22.28
	Confidence Interval	(2-Sided) 95%; -30.20 to -14.35
	Estimation Comments	[Not Specified]

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	KRN23
	Comments	Change at Week 96
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	< 0.0001
	Comments	The GEE model includes the change from baseline as the dependent variable, time as the categorical variable and adjusted for baseline measurement, with compound symmetry covariance structure.
	Method	GEE
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	LS Mean
	Estimated Value	-20.93
	Confidence Interval	(2-Sided) 95%; -27.92 to -13.94
	Estimation Comments	[Not Specified]

Statistical Analysis 5

Statistical Analysis Overview	Comparison Group Selection	KRN23
	Comments	Change at Week 120
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.0094
	Comments	The GEE model includes the change from baseline as the dependent variable, time as the categorical variable and adjusted for baseline measurement, with compound symmetry covariance structure.
	Method	GEE
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	LS Mean
	Estimated Value	-18.77
	Confidence Interval	(2-Sided) 95%; -32.93 to -4.60
	Estimation Comments	[Not Specified]

Statistical Analysis 6

Statistical Analysis Overview	Comparison Group Selection	KRN23
	Comments	Change at Week 144
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	< 0.0001
	Comments	The GEE model includes the change from baseline as the dependent variable, time as the categorical variable and adjusted for baseline measurement, with compound symmetry covariance structure.
	Method	GEE
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	LS Mean
	Estimated Value	-25.72
	Confidence Interval	(2-Sided) 95%; -36.89 to -14.54
	Estimation Comments	[Not Specified]

23. Primary Outcome

Title	Change From Baseline Over Time in BALP
Description	[Not Specified]
Time Frame	Baseline, Weeks 24, 48, 72, 96, 120, 144

Outcome Measure Data

Analysis Population Description

PD Analysis Set (all participants who received at least 1 dose of burosumab and had evaluable serum/urinary data) with an assessment at given time point.

Arm/Group Title		KRN23
Arm/Group Description:		KRN23 SC injections every 4 weeks
Overall Number of Participants Analyzed		20
Least Squares Mean (Standard Error); Unit of Measure: mcg/L
Change at Week 24	Number Analyzed	18 participants
		4.68 (3.389)
Change at Week 48	Number Analyzed	20 participants
		-2.68 (2.247)
Change at Week 72	Number Analyzed	19 participants
		-7.45 (1.067)
Change at Week 96	Number Analyzed	19 participants
		-8.08 (0.910)
Change at Week 120	Number Analyzed	19 participants
		-10.01 (1.561)
Change at Week 144	Number Analyzed	16 participants
		-10.89 (1.979)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	KRN23
	Comments	Change at Week 24
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.1673
	Comments	The GEE model includes the change from baseline as the dependent variable, time as the categorical variable and adjusted for baseline measurement, with compound symmetry covariance structure.
	Method	GEE
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	LS Mean
	Estimated Value	4.68
	Confidence Interval	(2-Sided) 95%; -1.96 to 11.32
	Estimation Comments	[Not Specified]

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	KRN23
	Comments	Change at Week 48
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.2330
	Comments	The GEE model includes the change from baseline as the dependent variable, time as the categorical variable and adjusted for baseline measurement, with compound symmetry covariance structure.
	Method	GEE
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	LS Mean
	Estimated Value	-2.68
	Confidence Interval	(2-Sided) 95%; -7.09 to 1.72
	Estimation Comments	[Not Specified]

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	KRN23
	Comments	Change at Week 72
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	< 0.0001
	Comments	The GEE model includes the change from baseline as the dependent variable, time as the categorical variable and adjusted for baseline measurement, with compound symmetry covariance structure.
	Method	GEE
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	LS Mean
	Estimated Value	-7.45
	Confidence Interval	(2-Sided) 95%; -9.54 to -5.36
	Estimation Comments	[Not Specified]

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	KRN23
	Comments	Change at Week 96
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	< 0.0001
	Comments	The GEE model includes the change from baseline as the dependent variable, time as the categorical variable and adjusted for baseline measurement, with compound symmetry covariance structure.
	Method	GEE
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	LS Mean
	Estimated Value	-8.08
	Confidence Interval	(2-Sided) 95%; -9.86 to -6.29
	Estimation Comments	[Not Specified]

Statistical Analysis 5

Statistical Analysis Overview	Comparison Group Selection	KRN23
	Comments	Change at Week 120
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	< 0.0001
	Comments	The GEE model includes the change from baseline as the dependent variable, time as the categorical variable and adjusted for baseline measurement, with compound symmetry covariance structure.
	Method	GEE
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	LS Mean
	Estimated Value	-10.01
	Confidence Interval	(2-Sided) 95%; -13.07 to -6.95
	Estimation Comments	[Not Specified]

Statistical Analysis 6

Statistical Analysis Overview	Comparison Group Selection	KRN23
	Comments	Change at Week 144
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	< 0.0001
	Comments	The GEE model includes the change from baseline as the dependent variable, time as the categorical variable and adjusted for baseline measurement, with compound symmetry covariance structure.
	Method	GEE
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	LS Mean
	Estimated Value	-10.89
	Confidence Interval	(2-Sided) 95%; -14.77 to -7.02
	Estimation Comments	[Not Specified]

24. Primary Outcome

Title	Change From Baseline Over Time in CTx
Description	[Not Specified]
Time Frame	Baseline, Weeks 24, 48, 72, 96, 120, 144

Outcome Measure Data

Analysis Population Description

PD Analysis Set (all participants who received at least 1 dose of burosumab and had evaluable serum/urinary data) with an assessment at given time point.

Arm/Group Title		KRN23
Arm/Group Description:		KRN23 SC injections every 4 weeks
Overall Number of Participants Analyzed		20
Least Squares Mean (Standard Error); Unit of Measure: pg/mL
Change at Week 24	Number Analyzed	18 participants
		343.38 (135.575)
Change at Week 48	Number Analyzed	20 participants
		41.45 (61.062)
Change at Week 72	Number Analyzed	19 participants
		-61.96 (63.458)
Change at Week 96	Number Analyzed	19 participants
		-68.62 (63.152)
Change at Week 120	Number Analyzed	19 participants
		-53.41 (50.545)
Change at Week 144	Number Analyzed	19 participants
		-97.46 (55.670)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	KRN23
	Comments	Change at Week 24
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.0113
	Comments	The GEE model includes the change from baseline as the dependent variable, time as the categorical variable and adjusted for baseline measurement, with compound symmetry covariance structure.
	Method	GEE
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	LS Mean
	Estimated Value	343.38
	Confidence Interval	(2-Sided) 95%; 77.66 to 609.11
	Estimation Comments	[Not Specified]

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	KRN23
	Comments	Change at Week 48
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.4972
	Comments	The GEE model includes the change from baseline as the dependent variable, time as the categorical variable and adjusted for baseline measurement, with compound symmetry covariance structure.
	Method	GEE
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	LS Mean
	Estimated Value	41.45
	Confidence Interval	(2-Sided) 95%; -78.23 to 161.13
	Estimation Comments	[Not Specified]

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	KRN23
	Comments	Change at Week 72
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.3288
	Comments	The GEE model includes the change from baseline as the dependent variable, time as the categorical variable and adjusted for baseline measurement, with compound symmetry covariance structure.
	Method	GEE
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	LS Mean
	Estimated Value	-61.96
	Confidence Interval	(2-Sided) 95%; -186.34 to 62.41
	Estimation Comments	[Not Specified]

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	KRN23
	Comments	Change at Week 96
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.2772
	Comments	The GEE model includes the change from baseline as the dependent variable, time as the categorical variable and adjusted for baseline measurement, with compound symmetry covariance structure.
	Method	GEE
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	LS Mean
	Estimated Value	-68.62
	Confidence Interval	(2-Sided) 95%; -192.39 to 55.16
	Estimation Comments	[Not Specified]

Statistical Analysis 5

Statistical Analysis Overview	Comparison Group Selection	KRN23
	Comments	Change at Week 120
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.2907
	Comments	The GEE model includes the change from baseline as the dependent variable, time as the categorical variable and adjusted for baseline measurement, with compound symmetry covariance structure.
	Method	GEE
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	LS Mean
	Estimated Value	-53.41
	Confidence Interval	(2-Sided) 95%; -152.47 to 45.66
	Estimation Comments	[Not Specified]

Statistical Analysis 6

Statistical Analysis Overview	Comparison Group Selection	KRN23
	Comments	Change at Week 144
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.0800
	Comments	The GEE model includes the change from baseline as the dependent variable, time as the categorical variable and adjusted for baseline measurement, with compound symmetry covariance structure.
	Method	GEE
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	LS Mean
	Estimated Value	-97.46
	Confidence Interval	(2-Sided) 95%; -206.57 to 11.65
	Estimation Comments	[Not Specified]

25. Primary Outcome

Title	Change From Baseline Over Time in P1NP
Description	[Not Specified]
Time Frame	Baseline, Weeks 24, 48, 72, 96, 120, 144

Outcome Measure Data

Analysis Population Description

PD Analysis Set (all participants who received at least 1 dose of burosumab and had evaluable serum/urinary data) with an assessment at given time point.

Arm/Group Title		KRN23
Arm/Group Description:		KRN23 SC injections every 4 weeks
Overall Number of Participants Analyzed		20
Least Squares Mean (Standard Error); Unit of Measure: ng/mL
Change at Week 24	Number Analyzed	20 participants
		72.45 (16.962)
Change at Week 48	Number Analyzed	20 participants
		44.40 (7.175)
Change at Week 72	Number Analyzed	20 participants
		28.30 (7.684)
Change at Week 96	Number Analyzed	19 participants
		27.02 (6.739)
Change at Week 120	Number Analyzed	19 participants
		13.02 (8.359)
Change at Week 144	Number Analyzed	19 participants
		43.12 (33.717)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	KRN23
	Comments	Change at Week 24
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	< 0.0001
	Comments	The GEE model includes the change from baseline as the dependent variable, time as the categorical variable and adjusted for baseline measurement, with compound symmetry covariance structure.
	Method	GEE
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	LS Mean
	Estimated Value	72.45
	Confidence Interval	(2-Sided) 95%; 39.21 to 105.70
	Estimation Comments	[Not Specified]

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	KRN23
	Comments	Change at Week 48
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	< 0.0001
	Comments	The GEE model includes the change from baseline as the dependent variable, time as the categorical variable and adjusted for baseline measurement, with compound symmetry covariance structure.
	Method	GEE
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	LS Mean
	Estimated Value	44.40
	Confidence Interval	(2-Sided) 95%; 30.34 to 58.47
	Estimation Comments	[Not Specified]

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	KRN23
	Comments	Change at Week 72
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.0002
	Comments	The GEE model includes the change from baseline as the dependent variable, time as the categorical variable and adjusted for baseline measurement, with compound symmetry covariance structure.
	Method	GEE
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	LS Mean
	Estimated Value	28.30
	Confidence Interval	(2-Sided) 95%; 13.24 to 43.37
	Estimation Comments	[Not Specified]

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	KRN23
	Comments	Change at Week 96
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	< 0.0001
	Comments	The GEE model includes the change from baseline as the dependent variable, time as the categorical variable and adjusted for baseline measurement, with compound symmetry covariance structure.
	Method	GEE
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	LS Mean
	Estimated Value	27.02
	Confidence Interval	(2-Sided) 95%; 13.81 to 40.22
	Estimation Comments	[Not Specified]

Statistical Analysis 5

Statistical Analysis Overview	Comparison Group Selection	KRN23
	Comments	Change at Week 120
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.1195
	Comments	The GEE model includes the change from baseline as the dependent variable, time as the categorical variable and adjusted for baseline measurement, with compound symmetry covariance structure.
	Method	GEE
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	LS Mean
	Estimated Value	13.02
	Confidence Interval	(2-Sided) 95%; -3.37 to 29.40
	Estimation Comments	[Not Specified]

Statistical Analysis 6

Statistical Analysis Overview	Comparison Group Selection	KRN23
	Comments	Change at Week 144
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.2009
	Comments	The GEE model includes the change from baseline as the dependent variable, time as the categorical variable and adjusted for baseline measurement, with compound symmetry covariance structure.
	Method	GEE
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	LS Mean
	Estimated Value	43.12
	Confidence Interval	(2-Sided) 95%; -22.96 to 109.20
	Estimation Comments	[Not Specified]

Adverse Events

Time Frame	Screening through the end of study plus 4-8 weeks. The mean duration of burosumab exposure was 165.6 weeks (range: 68-184 weeks).
Adverse Event Reporting Description	[Not Specified]
Arm/Group Title	KRN23
Arm/Group Description	KRN23 SC injections every 4 weeks
All-Cause Mortality
	KRN23
	Affected / at Risk (%)
Total	0/20 (0.00%)
Serious Adverse Events
	KRN23
	Affected / at Risk (%)
Total	9/20 (45.00%)
Congenital, familial and genetic disorders
Hereditary Non-Polyposis Colorectal Cancer Syndrome † 1	1/20 (5.00%)
Gastrointestinal disorders
Small Intestinal Obstruction † 1	1/20 (5.00%)
Hepatobiliary disorders
Cholecystitis Acute † 1	1/20 (5.00%)
Infections and infestations
Medical Device Site Joint Infection † 1	1/20 (5.00%)
Musculoskeletal and connective tissue disorders
Musculoskeletal Chest Pain † 1	1/20 (5.00%)
Osteoarthritis † 1	1/20 (5.00%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Adenocarcinoma Of Colon † 1	1/20 (5.00%)
Chordoma † 1	1/20 (5.00%)
Lung Adenocarcinoma † 1	1/20 (5.00%)
Nervous system disorders
Hemianaesthesia † 1	1/20 (5.00%)
Hemiparesis † 1	1/20 (5.00%)
Skin and subcutaneous tissue disorders
Angioedema † 1	1/20 (5.00%)
1 Term from vocabulary, MedDRA 18.1; † Indicates events were collected by systematic assessment
Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events	5%
	KRN23
	Affected / at Risk (%)
Total	20/20 (100.00%)
Cardiac disorders
Atrial Fibrillation † 1	1/20 (5.00%)
Palpitations † 1	1/20 (5.00%)
Ear and labyrinth disorders
Hypoacusis † 1	2/20 (10.00%)
Tinnitus † 1	1/20 (5.00%)
Vertigo † 1	3/20 (15.00%)
Vertigo Positional † 1	1/20 (5.00%)
Endocrine disorders
Hyperparathyroidism † 1	1/20 (5.00%)
Eye disorders
Cataract † 1	2/20 (10.00%)
Conjunctival Haemorrhage † 1	1/20 (5.00%)
Diplopia † 1	1/20 (5.00%)
Dry Eye † 1	1/20 (5.00%)
Vision Blurred † 1	1/20 (5.00%)
Visual Impairment † 1	1/20 (5.00%)
Vitreous Floaters † 1	1/20 (5.00%)
Gastrointestinal disorders
Abdominal Distension † 1	1/20 (5.00%)
Abdominal Pain † 1	1/20 (5.00%)
Abdominal Pain Lower † 1	2/20 (10.00%)
Constipation † 1	2/20 (10.00%)
Diarrhoea † 1	3/20 (15.00%)
Dyspepsia † 1	2/20 (10.00%)
Faecal Incontinence † 1	1/20 (5.00%)
Gastritis † 1	1/20 (5.00%)
Gastrooesophageal Reflux Disease † 1	2/20 (10.00%)
Ileus † 1	1/20 (5.00%)
Intestinal Dilatation † 1	1/20 (5.00%)
Irritable Bowel Syndrome † 1	1/20 (5.00%)
Large Intestinal Stenosis † 1	1/20 (5.00%)
Nausea † 1	6/20 (30.00%)
Pancreatic Calcification † 1	1/20 (5.00%)
Pancreatic Duct Dilatation † 1	1/20 (5.00%)
Vomiting † 1	5/20 (25.00%)
General disorders
Asthenia † 1	1/20 (5.00%)
Cyst † 1	1/20 (5.00%)
Fatigue † 1	4/20 (20.00%)
Gravitational Oedema † 1	1/20 (5.00%)
Injection Site Erythema † 1	3/20 (15.00%)
Injection Site Pain † 1	1/20 (5.00%)
Injection Site Reaction † 1	4/20 (20.00%)
Medical Device Site Pain † 1	1/20 (5.00%)
Pain † 1	2/20 (10.00%)
Pyrexia † 1	1/20 (5.00%)
Tenderness † 1	1/20 (5.00%)
Hepatobiliary disorders
Ampulla Of Vater Stenosis † 1	1/20 (5.00%)
Biliary Dilatation † 1	1/20 (5.00%)
Hepatic Steatosis † 1	2/20 (10.00%)
Immune system disorders
Seasonal Allergy † 1	2/20 (10.00%)
Infections and infestations
Arthritis Infective † 1	1/20 (5.00%)
Breast Abscess † 1	1/20 (5.00%)
Bronchitis † 1	4/20 (20.00%)
Cystitis † 1	1/20 (5.00%)
Ear Infection † 1	3/20 (15.00%)
Gingivitis † 1	1/20 (5.00%)
Herpes Zoster † 1	1/20 (5.00%)
Hordeolum † 1	1/20 (5.00%)
Incision Site Infection † 1	1/20 (5.00%)
Infected Bite † 1	1/20 (5.00%)
Influenza † 1	1/20 (5.00%)
Localised Infection † 1	1/20 (5.00%)
Lyme Disease † 1	1/20 (5.00%)
Nasopharyngitis † 1	7/20 (35.00%)
Otitis Externa † 1	1/20 (5.00%)
Pharyngitis Streptococcal † 1	1/20 (5.00%)
Pneumonia † 1	1/20 (5.00%)
Respiratory Tract Infection † 1	1/20 (5.00%)
Sepsis † 1	1/20 (5.00%)
Sinusitis † 1	3/20 (15.00%)
Sinusitis Bacterial † 1	1/20 (5.00%)
Tooth Abscess † 1	2/20 (10.00%)
Tooth Infection † 1	2/20 (10.00%)
Upper Respiratory Tract Infection † 1	5/20 (25.00%)
Urinary Tract Infection † 1	2/20 (10.00%)
Urinary Tract Infection Enterococcal † 1	1/20 (5.00%)
Injury, poisoning and procedural complications
Arthropod Bite † 1	1/20 (5.00%)
Contusion † 1	2/20 (10.00%)
Fall † 1	6/20 (30.00%)
Femur Fracture † 1	1/20 (5.00%)
Hand Fracture † 1	2/20 (10.00%)
Ligament Sprain † 1	1/20 (5.00%)
Meniscus Injury † 1	2/20 (10.00%)
Procedural Hypertension † 1	1/20 (5.00%)
Procedural Nausea † 1	1/20 (5.00%)
Procedural Pain † 1	2/20 (10.00%)
Seroma † 1	1/20 (5.00%)
Sunburn † 1	1/20 (5.00%)
Thermal Burn † 1	1/20 (5.00%)
Tooth Fracture † 1	3/20 (15.00%)
Tooth Injury † 1	1/20 (5.00%)
Investigations
Alanine Aminotransferase Increased † 1	1/20 (5.00%)
Amylase Increased † 1	2/20 (10.00%)
Aspartate Aminotransferase Increased † 1	1/20 (5.00%)
Blood Alkaline Phosphatase Increased † 1	1/20 (5.00%)
Blood Cholesterol Increased † 1	1/20 (5.00%)
Blood Iron Decreased † 1	1/20 (5.00%)
Blood Pressure Decreased † 1	1/20 (5.00%)
Eosinophil Count Increased † 1	1/20 (5.00%)
Gamma-Glutamyltransferase Increased † 1	2/20 (10.00%)
Haemoglobin Decreased † 1	1/20 (5.00%)
Lipase Increased † 1	1/20 (5.00%)
Oxygen Saturation Decreased † 1	1/20 (5.00%)
Smear Cervix Abnormal † 1	1/20 (5.00%)
Urine Electrophoresis Abnormal † 1	1/20 (5.00%)
Weight Decreased † 1	1/20 (5.00%)