Randomized, Open-label,

Dose-finding, Phase 2 Study of

KRN23, a Human Monoclonal

Anti-FGF23 Antibody, in Children with

X-linked Hypophosphatemia (XLH)

Thomas Carpenter

Yale University School of Medicine,

New Haven, Connecticut

E. Imel, A. Boot, W. Högler, A. Linglart,

R. Padidela, W. van’t Hoff, M. Whyte,

CY Chen, A. Skrinar, J. San Martin, A. Portale

Disclosures

• Dr. Carpenter: grant support and travel fees from Ultragenyx

Pharmaceuticals Inc. (Ultragenyx)

• Drs. Imel, Boot, Linglart, Högler, van’t Hoff, and Portale: travel

and/or consulting fees from Ultragenyx. Dr. Padidela has

received consulting fees from Ultragenyx and Alexion

Pharmaceuticals Inc.

• Drs. Chen, Skrinar, and San Martin: employees of Ultragenyx

• Dr. Whyte: research grant support, honoraria, and travel from

Ultragenyx and Alexion Pharmaceuticals Inc.

• This study was sponsored and funded by Ultragenyx in

partnership with Kyowa Hakko Kirin Co., Ltd.

• Ting Chang, PhD, an employee of Ultragenyx, provided

medical writing support

Excess FGF23 in XLH Leads to Phosphate

Wasting and Chronic Hypophosphatemia

Serum Phosphate

Phosphate

Absorption

Defective mineralization

and delayed ossification

Razzaque MS. Nat Rev Endocrinol 2009;5:611-9. Martin A, et al. Physiol Rev 2012;92:131-55.

Phosphate

PHEX

mutation Serum

FGF23

1- hydroxylase

1,25(OH)2D

NaPi-2a

NaPi-2c

Phosphate

Excretion

Capillary

Downregulated

Phosphate

Cotransport

Renal Tubule Cell

FGFR FGF23

-KLOTHO

NaPi2a/NaPi2c

Cotransporters

Urine

KRN23 Is Designed to Inhibit FGF23 to

Improve Phosphate Homeostasis

Serum Phosphate

Phosphate

Absorption

Improved mineralization

and bone disease expected

Phosphate

PHEX

mutation

KRN23 Inhibits

Serum

FGF23

1- hydroxylase

1,25(OH)2D

NaPi-2a

NaPi-2c

Phosphate

Excretion

Capillary

Phosphate

Transport

Renal Tubule Cell

FGFR

FGF23

-KLOTHO

KRN23

NaPi2a/NaPi2c

Cotransporters

Urine

Proposed KRN23 Mechanism of Action

Pediatric Phase 2 Study Design

(UX023-CL201)

• Data available for first 36 subjects through 40 weeks

Pre-specified subgroups: 18 subjects with baseline rickets severity total

score [RSS] ≥1.5 and 18 subjects with RSS < 1.5

Key Endpoints

• Pharmacodynamics:

serum P,1,25(OH)2D,

TmP/GFR

• Rickets -- graded by two

scoring systems (RGI-C

and RSS)

• Serum alkaline

phosphatase

• Safety

Study Design

Titration

Period

16 Weeks

Treatment Period

48 Weeks

Biweekly (Q2W) Dose Group

Monthly (Q4W) Dose Group

Extension

Study

0 4 8 12 16 20 22 24 28 32 36 40 44 48 52 56 60 64

Weeks

Titration

Period

16 Weeks

Treatment Period

48 Weeks

Efficacy and

Safety Interim

Analysis

Final Efficacy

and Safety

Analysis

N = 52

Age 5-12 yrs

Tanner ≤2

Baseline Demographics and

Characteristics

KRN23

Q2W

(N = 18)

KRN23

Q4W

(N = 18)

KRN23

Overall

(N = 36)

Age, yrs 8.3 (1.6) 8.1 (2.1) 8.2 (1.8)

Male 9 (50%) 9 (50%) 18 (50%)

White 16 (89%) 16 (89%) 32 (89%)

Weight, kg 31.5 (17.6, 47.2) 24.4 (14.7, 55.2) 28.8 (14.7, 55.2)

Height Z score -1.6 (1.0) -2.2 (1.0) -1.9 (1.0)

RSS total score 1.53 (1.05) 1.33 (1.02) 1.43 (1.02)

Received Oral P / Active

Vitamin D 17 (94%) 18 (100%) 35 (97%)

Duration of Oral P / Active

Vitamin D 6.9 (1.9) 6.3 (3.1) 6.6 (2.6)

Values as mean (SD), median (min, max), or n (%) as indicated. Q2W, biweekly; Q4W, monthly; P, phosphorus; RSS,

Thacher Rickets Severity Score; SD, standard deviation

Improvement in Serum Phosphate,

TmP/GFR, and 1,25(OH)2D

• All post-baseline values

were significant (p<0.05)

compared with baseline

unless denoted as not

significant (NS)

• Mean dose (SD) at Week 40:

• Q2W:

0.8 (0.3) mg/kg

25.8 (10.8) mg total dose

• Q4W:

• 1.3 (0.4) mg/kg

• 39.2 (17.7) mg total dose

Q2W Q4W

Se

rum

Ph

osp

ho

rus

(mg

/dL

)

Tm

P/G

FR

(mg

/dL

)

1,2

5(O

H) 2

D

(pg

/mL

)

3.4

3.8

3.0

2.6

2.2

1.8

4.2

3.6

3.0

2.4

1.8

100

80

60

40

20

NS

0 2 14 16 28 40 38 Week

Two Rickets Scoring Systems Utilized

Thacher Rickets Severity Score (RSS)

• Total 0-10: wrist (0-4) plus knee (0-6)

• Read centrally by an expert blinded to

dose and patient

Radiographic Global Impression of

Change (RGI-C)

• 7-point scale describing changes at

wrist, knee, and leg during treatment

• X-rays read by 3 independent experts

blinded to dose

-3 -2 -1 0 +1 +2 +3

Severe

Worsening

Moderate

Worsening

Minimal

Worsening

No

Change

Minimal

Healing

Substantial

Healing

Complete

or Near

Complete

Healing

Knee X-Ray

Score 1.0 Score 2.0

Mean Change from Baseline to Week 40

in RSS

1.53 1.33 1.43

0.86

1.14 1.00

0

0.5

1

1.5

2

2.5

Q2W (N=18) Q4W (N=18) All (N=36)

Me

an

RS

S T

ota

l S

co

re ±

SE

at

We

ek

40

Baseline Week 40

2.44 2.17 2.31

1.00

1.44

1.22

0.0

0.5

1.0

1.5

2.0

2.5

Q2W (N=9) Q4W (N=9) All (N=18)

Baseline Week 40

All Patients (N=36)

p value based on paired t test

Baseline RSS Total Score ≥1.5 (N = 18)

30%

p=0.008 p=0.013 p=0.3

44% 14%

p<0.0001

47%

p<0.0001 p=0.008

59% 33%

Mean RGI-C Global Score at Week 40

P value is based on one sample t test

RGI-C Scores: +1.0 = minimal healing; +2.0 = substantial healing; +3.0 = complete or near complete healing

1.56

1.20 1.38

0.0

0.5

1.0

1.5

2.0

2.5

Q2W (N=18) Q4W (N=18) All (N=36)

Me

an

RG

I-C

Sc

ore

± S

E a

t W

ee

k 4

0 2.00

1.70 1.85

0.0

0.5

1.0

1.5

2.0

2.5

Q2W (N=9) Q4W (N=9) All (N=18)

All Patients (N=36)

p<0.0001 p<0.0001 p<0.0001

Baseline RSS Total Score ≥1.5 (N = 18)

p<0.0001 p<0.0001 p<0.0001 +

+

+

+

+

+

+

+

+

+

Proportion of Subjects with Substantial

Healing (RGI-C Global Score ≥2.0) at Week 40

0

10

20

30

40

50

60

70

80

90

100

Perc

en

t o

f S

ub

jects

89% (8/9)

44% (4/9)

67% (12/18)

56% (10/18)

28% (5/18)

42% (15/36)

All Patients (N=36) Baseline RSS Total Score ≥1.5 (N = 18)

Q2W Q4W All Q2W Q4W All

Radiographic Appearance of Rickets at

Baseline and Follow-up

Knee X-rays in 12 yr-old girl before (left) and after 40 wks (center) and

64 wks (right) of KRN23 therapy for XLH. Noted the improved rachtic

findings at the growth plate.

Change in Serum Alkaline Phosphatase

* p=0.01; p value calculated from paired t test based on baseline and Week 40 value

*

520

500

480

460

440

420

400

380

360

Mean

± S

E A

lkali

ne P

ho

sp

hata

se (

U/L

)

Week 0 4 8 16 24 40

Q2W Q4W

Summary of Safety Measures

Subject Incidence

(%)

KRN23

Q2W

(N = 18)

KRN23

Q4W

(N = 18)

KRN23

Overall

(N = 36)

Any Adverse Events (AEs) 18 (100%) 18 (100%) 36 (100%)

Drug-related AEs* 13 (72%) 13 (72%) 26 (72%)

Injection Site Reaction 7 (39%) 7 (39%) 14 (39%)

Erythema 4 (22%) 3 (17%) 7 (19%)

Swelling 3 (17 %) 1 (6 %) 4 (11%)

Rash 1 (6%) 2 (11%) 3 (8%)

Pain in Extremity 2 (11%) 2 (11%) 4 (11%)

Arthralgia 2 (11%) 1 (6%) 3 (8%)

Serious AEs 0 1 (6%) 1 (3%)

AEs leading to discontinuation 0 0 0

AEs leading to death 0 0 0

* Assessed by the investigator as possibly or probably related to investigational product; the most common

(≥ 3 subjects) drug-related AEs are listed by preferred terms

PTH and Urine Calcium

• No meaningful increases in

serum PTH levels

• No increases in serum or

urinary calcium levels were

observed

30

40

50

60

70

80

90

100

24

H U

rin

e C

alc

ium

Ex

c.

Rate

(m

g/d

ay)

0 8 40 20 28

30

40

50

60

70

35

45

55

65

Week

iPT

H (

pg

/mL

)

16

Q2W Q4W

Summary

• KRN23, an investigational product, improved P

homeostasis and rickets in children with XLH previously

treated for a mean of 6.6 years

• Greater improvement in rickets scores occurred with Q2W

dosing and in subjects with more severe baseline rickets

(RSS total score ≥1.5)

• KRN23 was well-tolerated and no subject became

hyperphosphatemic

• No clinically meaningful changes in serum PTH, serum or

urine calcium, or renal ultrasound were observed

• Inhibition of FGF23 has the potential to improve clinical

outcomes in children with XLH