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TRANSCRIPT
CONFIDENTIAL - 1 -
KRN23
2 2 : CTD
2.5
KRN23 2.5
CONFIDENTIAL - 2 -
%CI % confidence interval % 1,25(OH)2D 1,25-dihydroxyvitamin D 1,25- D 25(OH)D 25-hydroxyvitamin D 25- D 6MWT Six-Minute Walk Test 6 ADHR Autosomal dominant hypophosphatemic rickets/osteomlacia
ARHR1 Autosomal recessive hypophosphatemic rickets/osteomalacia type 1
1 ARHR2 Autosomal recessive hypophosphatemic rickets/osteomalacia type 2
2 BALP Bone-specific alkaline phosphatase BPI Brief Pain Inventory BPI-Q3 Brief Pain Inventory Question 3 CSHS Cutaneous skeletal hypophosphatemia syndrome CTx Carboxy-terminal cross-linked telopeptide of type I collagen 1
C- DMP1 Dentin matrix protein 1 DXA Dual energy X-ray absorptiometry EMA European Medicines Agency Emax Maximum effect ENPP1 Ecto-nucleotide pyrophosphatase/phosphodiesterase 1 ENS Epidermal nevus syndrome ePPND Enhanced pre and post natal development study
FAM20C Family with sequence similarity 20, member C FAS Full Analysis Set FD Fibrous dysplasia FDA Food and Drug Administration FGF23 Fibroblast growth factor 23 23 FGFR Fibroblast growth factor receptor FITC-KRN23 KRN23 GNAS Guanine nucleotide binding protein, alpha stimulating gene HHD Hand held dynamometer HHRH Hereditary hypophosphatemic rickets with hypercalciuria
HRAS Harvey rat sarcoma viral oncogene homolog Hyp Hypophosphatemia Ig Immunoglobulin IV Intravenous KRAS Kirsten rat sarcoma viral oncogene homolog MAS McCune-albright syndrome McCune-Albright MHRA Medicines and Healthcare Products Regulatory Agency MLt Mineralization lag time NRAS Neuroblastoma rat sarcoma viral oncogene homolog OD Osteoglophoric dysplasia OS/BS Osteoid surface/bone surface
KRN23 2.5
CONFIDENTIAL - 3 -
OV/BV Osteoid volume/Bone volume O.Th Osteoid thickness P1NP Procollagen type 1 N-propeptide 1 N PHEX Phosphate-regulating gene with homologies to endopeptidases on the X chromosome PMDA Pharmaceuticals and Medical Devices Agency PPK Population pharmacokietics PRO Patients reported ourtcome PROMIS Patient-Reported Outcomes Measurement Information System PTH Parathyroid hormone PTHR Parathyroid hormone receptor Q2W Once every 2 weeks 2 1 Q4W Once every 4 weeks 4 1 RGI-C Radiographic Global Impression of Change RSS Rickets Severity Score STS Sit-to-stand test SC Subcutaneous TIO Tumor induced osteomalacia TmP/GFR Ratio of renal tubular maximum reabsorption rate of phosphate to glomerular filtration
rate WAL Weighted arm lift test WOMAC Western Ontario and McMaster Universities Osteoarthritis Index WT Wild type XLH X-linked hypophosphatemic rickets/osteomalacia X
ALP Alkaline phosphatase AUC0- AUC0-t t Cmin Cmax eGFR F GCP HLT MedDRA ICH MedDRA ICH PT MedDRA QOL Quality of life QTc QT SF-36 36 item short form health survey SMQ MedDRA SOC MedDRA t1/2 tmax TRP
KRN23 2.5
CONFIDENTIAL - 4 -
.................................................................................................... 2
...................................................................................................................................... 4
2.5 ................................................................................................. 9
1 ............................................................................................................ 9 1.1 .................................................................................... 9 1.1.1 ........................................................ 9 1.1.1.1 23 FGF23
............................................................................................................................................ 9 1.1.1.2 FGF23 ...................................................... 10 1.1.1.3 FGF23 ...................................................... 12 1.1.2 .................................................................................................. 13 1.2 .............................................................................................................................. 14 1.2.1 ...................................................................................................................... 14 1.2.2 .............................................................................................................. 14 1.3 GCP ............................................................................................................. 22
2 ................................................................................... 23 2.1 2.7.1-1.1 .................................................................................... 23 2.2 2.7.1-2.1 .................................................................................... 23 2.3 2.7.2-3.4 ............................................................ 23
3 ....................................................................................... 24 3.1 .............................................................................................. 24 3.1.1 XLH .................................................................... 24 3.1.1.1 KRN23-001 5.3.4.2-1 ............................................................... 24 3.1.1.1.1 .......................................................................................................................... 24 3.1.1.1.2 .............................................................................................................................. 24 3.1.1.2 UX023-CL303 5.3.5.1-2 .................................................................... 25 3.1.1.2.1 .......................................................................................................................... 25 3.1.1.2.2 .............................................................................................................................. 26 3.1.2 XLH KRN23-003 5.3.5.2-7 .............. 27 3.1.2.1 .............................................................................................................................. 27 3.1.2.2 .................................................................................................................................. 28 3.1.3 TIO ENS KRN23-002 5.3.5.2-8 ....... 29 3.1.3.1 .............................................................................................................................. 29 3.1.3.2 .................................................................................................................................. 30 3.2 ...................................................................... 31 3.2.1 XLH 2.7.2-3.2.1 ....................................................................... 31 3.2.2 XLH 2.7.2-3.2.2 ....................................................................... 31
KRN23 2.5
CONFIDENTIAL - 5 -
3.3 2.7.2-3.3.1 2.7.2-3.3.3 .................................................................... 32 3.4 2.7.2-3.3.1.2 .................................................................................. 32 3.5 XLH 2.7.2-3.3.2 ........................... 32 3.6 ...................................................................................................................................... 33 3.7 QT QTc ..................................................................................................... 33
4 ...................................................................................................... 34 4.1 .......................................................................................................................... 34 4.1.1 ...................................................................................................................... 34 4.1.1.1 XLH ................................................................................ 34 4.1.1.2 XLH ................................................................................ 35 4.1.1.3 TIO ........................................................................................... 36 4.1.2 .......................................................................................................................... 37 4.2 .............................................................................................................. 37 4.3 .................................................. 38 4.3.1 XLH ........................................................................................................................ 38 4.3.1.1 III 2.7.3-3.1.1 ....................................................................................... 38 4.3.1.1.1 .................................................................................................................. 38 4.3.1.1.2 .......................................................................... 39 4.3.2 XLH ........................................................................................................................ 39 4.3.2.1 II III 2.7.3-3.1.2 ................................................... 39 4.3.2.1.1 .................................................................................................................. 39 4.3.2.1.2 .......................................................................... 40 4.3.3 TIO 2.7.3-3.1.3 ......................................................................................................... 40 4.3.3.1 ...................................................................................................................... 40 4.3.3.2 .............................................................................. 41 4.4 .......................................................................................................................... 41 4.4.1 XLH ........................................................................................................................ 41 4.4.1.1 .......................................................................................................................... 41 4.4.1.1.1
.......................................................................................................... 41 4.4.1.1.2 .................................................................................................................. 42 4.4.1.1.3 TmP/GFR ......................................................................................................................... 43 4.4.1.1.4 1,25(OH)2D ..................................................................................................... 43 4.4.1.2 .............................................................................................................................. 44 4.4.1.2.1 OV/BV ................................................ 44 4.4.1.2.2 O.Th OS/BS MLt
.............................................................................................................. 45 4.4.1.2.3 .............................................................................................................. 45 4.4.1.2.4 ...................................................................................................... 46 4.4.1.3 PRO .............................................................................................................. 47 4.4.1.3.1 BPI ....................................................................................................................... 47
KRN23 2.5
CONFIDENTIAL - 6 -
4.4.1.3.2 WOMAC WOMAC ................................ 47 4.4.1.3.3 6MWT .............................................................................................................................. 47 4.4.2 XLH ........................................................................................................................ 48 4.4.2.1 ...................................................................................................... 48 4.4.2.1.1 RGI-C .................................................................................................................. 48 4.4.2.1.2 RSS ...................................................................................................................... 49 4.4.2.1.3 .................................................................................................................................. 50 4.4.2.2 .......................................................................................................................... 51 4.4.2.2.1 .................................................................................................................. 51 4.4.2.2.2 TmP/GFR ......................................................................................................................... 52 4.4.2.2.3 1,25(OH)2D ..................................................................................................... 53 4.4.2.3 PRO .............................................................................................................. 54 4.4.2.3.1 PROMIS ................................ 54 4.4.2.3.2 6MWT .............................................................................................................................. 55 4.4.3 TIO .................................................................................................................................. 55 4.4.3.1 .......................................................................................................................... 55 4.4.3.1.1 .................................................................................................................. 55 4.4.3.1.2 TmP/GFR ......................................................................................................................... 56 4.4.3.1.3 1,25(OH)2D ..................................................................................................... 56 4.4.3.2 .............................................................................................................................. 56 4.4.3.2.1 O.Th OS/BS OV/BV MLt ................................................... 56 4.4.3.2.2 .............................................................................................................. 56 4.4.3.2.3 99mTc .................................................................................................... 56 4.4.3.2.4 X .......................................................................................................................... 56 4.4.3.3 PRO .............................................................................................................. 57 4.4.3.3.1 BPI .................................................................................................................................... 57 4.4.3.3.2 SF-36 ............................................................................................ 57 4.4.3.3.3 6MWT .............................................................................................................................. 57 4.4.4 .............................................................................................. 57 4.4.4.1 .............................................................................................................................. 57 4.4.4.1.1 XLH ................................................................................................................ 57 4.4.4.1.2 XLH ................................................................................................................ 58 4.4.4.2 .............................................................................................................. 58 4.4.4.2.1 XLH ................................................................................................................ 58 4.4.4.2.2 .................................................................. 60 4.4.4.2.3 XLH ................................................................................................................ 61 4.4.4.2.4 .................................................................. 63 4.5 2.7.3-4 ............................................................................................... 63 4.5.1 XLH TIO ................................................................................................................. 64 4.5.1.1 XLH .................................................................................................................... 64 4.5.1.1.1 III ........................................................................................ 64 4.5.1.1.2 III ................................................................................ 64
KRN23 2.5
CONFIDENTIAL - 7 -
4.5.1.2 XLH .................................................................................................................... 65 4.5.1.3 TIO ............................................................................................................................... 67 4.5.2 XLH TIO FGF23 ................................ 68 4.5.3 13 17 XLH ............................................................................................... 69 4.6 .................................................................................. 70 4.7 2.7.3-5 ............................................................................................... 70 4.7.1 XLH ........................................................................................................................ 70 4.7.2 XLH ........................................................................................................................ 71 4.7.3 TIO .................................................................................................................................. 72
5 ...................................................................................................... 74 5.1 ...................................................................................................................... 74 5.1.1 2.7.4-1.1.1 ................................................. 74 5.1.2 .................................................................................................................. 75 5.2 2.6.2-4 2.6.6 .......... 77 5.3 .......................................................................... 79 5.3.1 ...................................................................................................................... 79 5.3.1.1 XLH .................................................................................... 79 5.3.1.2 XLH .................................................................................... 81 5.3.1.3 TIO ............................................................................................... 82 5.3.2 2.7.4-1.2.2 ..................................................................................................... 83 5.3.2.1 XLH .................................................................................... 83 5.3.2.2 XLH .................................................................................... 83 5.3.2.3 TIO ............................................................................................... 83 5.3.3 2.7.4-1.3 ............................................................ 83 5.3.3.1 XLH .................................................................................... 83 5.3.3.2 XLH .................................................................................... 84 5.3.3.3 TIO ............................................................................................... 84 5.4 ...................................................................................................................................... 85 5.4.1 2.7.4-2.1.1 ................................................. 85 5.4.1.1 XLH .................................................................................... 85 5.4.1.2 XLH .................................................................................... 86 5.4.1.3 TIO ............................................................................................... 87 5.4.2 2.7.4-2.1.2 ................................................................................. 87 5.4.3 2.7.4-2.1.3 ............................................................................. 87 5.4.3.1 XLH .................................................................................... 87 5.4.3.2 XLH .................................................................................... 88 5.4.3.3 TIO ............................................................................................... 88 5.4.4 2.7.4-2.1.4 ............................................................................. 88 5.4.4.1 XLH .................................................................................... 88 5.4.4.2 XLH .................................................................................... 88 5.4.4.3 TIO ............................................................................................... 88
KRN23 2.5
CONFIDENTIAL - 8 -
5.4.5 2.7.4-2.1.1.2.3 ....................................................................... 88 5.4.6 .............................................................................................................................. 92 5.5
...................................................................................................................................................... 95 5.5.1 XLH 2.7.4-2.1.1.2.2.1 ...................................................... 95 5.5.2 XLH 2.7.4-2.1.1.2.2.2 ...................................................... 95 5.5.3 TIO 2.7.4-2.1.1.2.2.3 ................................................................ 96 5.5.4 .............................................................................................................. 96 5.6 ...................................................................................... 96 5.7 .............................................. 96 5.7.1 2.7.4-5.5 ............................................................................................................ 96 5.7.2 2.7.4-5.6 ............................................................................................................ 96 5.7.3 2.7.4-5.7 .................................................................................... 96
6 ........................................................................ 98 6.1 .................................................................................................................................. 98 6.1.1 .......................................................................................................................... 98 6.1.2 .............................................................................................................................. 98 6.2 .............................................................................................................................. 98 6.2.1 FGF23 ..................................................... 98 6.2.2 FGF23 ..................................................... 99 6.2.3 TIO ................................................................................................................................ 100 6.2.4 ........................................................................................................ 101 6.3 ........................................................................................................................................ 101 6.4 .................................................................................................... 103
7 .................................................................................................................... 106
KRN23 2.5
CONFIDENTIAL - 9 -
2.5
1
1.1
1.1.1
1.1.1.1 23 FGF23
, 2009 FGF23FGF23
FGF23 30 pg/mL FGF23Figure 1.1.1.1-1 , 2015
FGF23Fujiwara et al, 2013 Endo et al,
2015 2009 11 2010 568 Fujiwara et al, 2013
28 135126 93%
2010 2895 FGF23Endo et al, 2015 95
2005 2009 5 311 2009 163 117 95%
95%CI : 75 , 160 Endo et al, 2015
84 41TIO 35
36 X XLH FGF23XLH TIO Endo et al, 2015
XLH 20000 1 Carpenter, 1997
KRN23 2.5
CONFIDENTIAL - 10 -
Figure 1.1.1.1-1
Source: , 2015 HHRH=
1.1.1.2 FGF23 FGF23 Klotho FGFR
FGF23 2 12a 2c1 1,25- D 1,25(OH)2D 1 -1,25(OH)2D
FGF23Razzaque and Lanske, 2007; Fukumoto, 2008; Yamazaki
et al, 2008; Shimada et al, 2004 FGF23 FGF23
FGF23 Table 1.1.1.2-1phosphate-regulating gene with
homologies to endopeptidases on the X chromosome PHEX XLH FGF23ADHR dentin matrix protein 1
DMP1 1 ARHR1ecto-nucleotide pyrophosphatase/phosphodiesterase 1 ENPP1
2 ARHR2TIO
KRN23 2.5
CONFIDENTIAL - 11 -
Table 1.1.1.2-1 FGF23
X XLH PHEX ADHR FGF23 1 2 ARHR1 2 DMP1 ENPP1 Raine FAM20C Jansen PTHR1 OD FGFR1
McCune-Albright MAS FD GNAS CSHS ENS HRAS NRAS
KRAS TIO FGF23
Source: et al, 2017, Fukumoto, 2018 PHEX=phosphate-regulating gene with homologies to endopeptidases on the X chromosome, FGF23=Fibroblast growth factor 23, DMP1=Dentin matrix protein 1, ENPP1=ecto-nucleotide pyrophosphatase/phosphodiesterase 1, FAM20C=Family with sequence similarity 20, member C, PTHR=Parathyroid hormone receptor, FGFR=Fibroblast growth factor receptor, GNAS=Guanine nucleotide binding protein, alpha stimulating gene, HRAS=Harvey rat sarcoma viral oncogene homolog, NRAS=Neuroblastoma rat sarcoma viral oncogene homolog, KRAS=Kirsten rat sarcoma viral ocogene homolog.
FGF23 FGF23
Huang et al, 2013; Goldsweig and Carpenter, 2015; , 2015
FGF23TmP/GFR 1,25(OH)2D
PTH Table 1.1.1.2-2
Table 1.1.1.2-3)
Table 1.1.1.2-2 FGF23
PTH
ALP
TmP/GFR 1,25(OH)2D
XLH N N, N, ADHR N N N, ARHR1 N N, N, ARHR2 N N Raine N ? N, N, OD N N N N, MAS/FD N N N, N N, N, N, ENS N N, N, N, N, N, TIO N N, N, , N , , , ? PTH Parathyroid hormone, ALP Alkaline phosphatase, TmP/GFR Ratio of renal tubular maximum reabsorption rate of phosphate to glomerular filtration rate Source: Goldsweig and Carpenter, 2015
KRN23 2.5
CONFIDENTIAL - 12 -
Table 1.1.1.2-3
TmP/GFR BAP 1,25(OH)2D 25(OH)D FGF23
FGF23
D I D II
HHRH D
, ,
BAP=Bone alkaline phosphatase, HHRH=hereditary hypophosphatemic rickets with hypercalciuria Source , 2015
FGF23
O X
Linglart et al, 2014; Carpenter et al, 2011 FGF23 TIO
FGF23TIO 35 FGF23 ,
1304.1 pg/mL 44.0, 18286.4 pg/mL FGF2341 FGF23 325.2 pg/mL 40.3, 4540.0 pg/mL
Endo et al, 2015 TIO FGF23
Dadoniene et al, 2016FGF23
QOL
1.1.1.3 FGF23 FGF23 FGF23 TIO
TIO
D and , 2016; Huang et al, 2013
FGF23
D and , 2016 D0.05 0.10 g/kg/day 1 1 0.025
KRN23 2.5
CONFIDENTIAL - 13 -
0.05 g/kg/day 1 2 3 20 40 mg/kg/day1 3 5 and , 2016
17 15 , 2008
D and , 2016 D1.0 1.5 g/day 1 1 1
250 mg/day 750 1000 mg/day 1 3 4 and , 2016
and , 2016
XLHCarpenter et al, 2011
and , 2016
1.7 1.9SD Beck-Nielsen et al, 2010; Miyamoto et al, 2000
Connor et al, 2015QOL
QOL
1.1.2 KRN23 FGF23
Ig G1 KRN23 FGF23FGF23/Klotho/FGFRFGF23 FGF23
1 -1,25(OH)2D
KRN23 FGF23 FGF23
KRN23FGF23
QOL
KRN23 2.5
CONFIDENTIAL - 14 -
1.2 KRN23 FGF23
XLHTIO XLH TIO FGF23
XLH
1.2.1 20 XLH I KRN23-US-02
I/II KRN23-INT-001 KRN23-INT-002KRN23
20 Ultragenyx Pharmaceutical Inc. UltragenyxUltragenyx
20 Food and Drug Administration FDA Medicines and Healthcare Products Regulatory Agency MHRA 5 12 XLH
II UX023-CL201 20 2 FDA Type C meeting III UX023-CL303
UX023-CL30420 XLH III
FDA End of Phase 2 meetingUX023-CL301 1 4 XLH
II UX023-CL205 KRN23-US-02KRN23-INT-001 KRN23-INT-002 KRN23
II UX023-CL203 TIO ENS20 II UX023T-CL201
KRN23 FDA European Medicines Agency EMA
2016 11 EMA 2018 219 X 1 XLH
2017 8 FDA2018 4 17 1 XLH
1.2.2 XLH I/II KRN23-INT-001
KRN23-INT-002 20XLH
KRN23 2.5
CONFIDENTIAL - 15 -
XLHKRN23-001 XLH
2015 1 PMDAII #P3470 1.13.2
XLH XLHXLH
II XLH XLHXLH XLH
III UX023-CL301 XLHXLH III UX023-CL303
UX023-CL304 XLH 20 TIO ENS II KRN23-002
20 UX023-CL301XLH III KRN23-003
III UX023-CL301 UX023-CL303 UX023-CL304XLH KRN23 KRN23-004
KRN23-002 KRN23-003 KRN23-004KRN23
XLHXLH
1.2.1TIO KRN23-002 FGF23
PMDA#P 1.13.2 XLH
XLH
KRN23-003 UX023-CL301
Table 1.2.2-1
KRN
23
2.5
CO
NFI
DE
NTI
AL
- 16
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Tabl
e 1.
2.2-
1
KR
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I
XLH
18
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2-1
KR
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02
I
XLH
18
KRN
23
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003
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0.03
0.1
0.3
mg/
kg
SC0.
10.
30.
61.
0 m
g/kg
KRN
23
IV17
SC
12
IV5
SC
4
5.3.
4.2-
2
UX
023-
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03
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XLH
18
65
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k 24
KRN
23
KRN
231.
0 m
g/kg
41
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SC
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mg/
dL
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mg/
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0 m
g/dL
24.
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g/dL
90 m
g
KRN
2368
66
24
24
I48
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20
176
8
5.
3.5.
1-1
5.3.
5.1-
2
KRN
23
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CO
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DE
NTI
AL
- 17
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Tabl
e 1.
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1 (C
ontin
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U
X02
3-C
L301
III
XLH
1
12
KRN
230.
8 m
g/kg
21
Q2W
SC
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kg
D1
KRN
2329
32
64
140
20
187
30
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3.5.
1-3
KR
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-INT-
001
I/II
X
LH
18
XLH
18
35
K
RN23
0.05
mg/
kg
0.05
0.1
0.3
0.6
mg/
kgQ
4W1
4SC
KRN
230.
05 m
g/kg
0.05
0.1
0.3
0.6
mg/
kgQ
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K
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27
KRN
231
1
110
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1
KRN
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DE
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- 18
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1 (C
ontin
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K
RN
23-IN
T-00
2I/I
I
IN
T-00
1 XLH
18
IN
T-00
1 XLH
18
35
K
RN23
0.05
0.1
0.3
0.6
1.0
mg/
kgQ
4W12
SC
K
RN23
0.05
0.1
0.3
0.6
1.0
mg/
kgQ
4W12
SC
K
RN23
-INT-
001
Day
84 3.5
mg/
dLK
RN
23-IN
T-00
111
04.
2 m
g/dL
1
K
RN23
21
KRN
231
1
11
5.
3.5.
2-2
KRN
23
2.5
CO
NFI
DE
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AL
- 19
-
Tabl
e 1.
2.2-
1 (C
ontin
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U
X02
3-C
L203
II
KR
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-INT-
001/
002
XLH
KRN
230.
30.
61.
0 m
g/kg
Q4W
SC
K
RN23
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001
KR
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2.5
mg/
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3 m
g/kg
0.6
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6 m
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1.0
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Wee
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mg/
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20
144
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818
5.
3.5.
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UX
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04
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XLH
18
65
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231.
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4.5
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24.
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90 m
g
14
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5.
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KRN
23
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CO
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DE
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- 20
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Tabl
e 1.
2.2-
1 (C
ontin
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U
X02
3-C
L201
II
XLH
5
12
KRN
23
Q2W
0.1
0.2
0.3
mg/
kg0.
12.
0 m
g/kg
Q2W
SC
Q
4W0.
20.
40.
6 m
g/kg
0.2
2.0
mg/
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4WSC
42
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0.3
mg/
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4W0.
4 m
g/kg
2.0
mg/
kgW
eek
18
15 m
g15
mg
15 m
g10
mg 90
mg
52
Q2W
26 1
5
25
3
16
Q4W
26 1
5
25
3
16
16
48
96
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1612
1
5.
3.5.
2-5
UX
023-
CL2
05
II
XLH
1
4
KRN
230.
8 m
g/kg
Q2W
SC
1.2
mg/
kg
13
64
20
174
20
5.
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2-6
KR
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-003
III
XLH
1
12
KRN
230.
8 m
g/kg
Q2W
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mg/
kg
15
40
48
20
186
25
5.
3.5.
2-7
KRN
23
2.5
CO
NFI
DE
NTI
AL
- 21
-
Tabl
e 1.
2.2-
1 (C
ontin
ued)
K
RN
23-0
02
II
TIO
ENS
18
KRN
230.
3 m
g/kg
Q4W
SC
2.0
mg/
kg
TIO
13
144
2018
53
5.
3.5.
2-8
UX
023T
-CL2
01
II
TIO
ENS
18
KRN
230.
3 m
g/kg
Q4W
SC
2.0
mg/
kg
17
TIO
14
ENS
1
XLH
2
48
168
20
181
10
5.
3.5.
2-9
UX
023-
CL0
02
X
LH
514
20
168
9
5.
3.5.
4-1
KRN23 2.5
CONFIDENTIAL - 22 -
1.3 GCP
GCP
KRN23 2.5
CONFIDENTIAL - 23 -
2
2.1 2.7.1-1.1 KRN23 2 10 20 30 mg/mL
2 mg/mLKRN23-US-02 10 mmol/L
L-histidine 252 mmol/L D-sorbitol 10 mmol/L L-methionine 0.5 mg/mL polysorbate 80 pH 6.252 10 20 30 mg/mL 10
20 30 mg/mL KRN23
2.2 2.7.1-2.1 XLH KRN23-US-02 KRN23 SC
F 0.1 0.3 mg/kg KRN23 IV SCAUC0- KRN23 SC F
90% 128%
2.3 2.7.2-3.4 10 30 mg/mL SC KRN23-INT-002 KRN23
KRN23 2KRN23
KRN23 2.5
CONFIDENTIAL - 24 -
3
3.1
3.1.1 XLH
3.1.1.1 KRN23-001 5.3.4.2-1 XLH KRN23 0.3 0.6 1.0 mg/kg SC
3.1.1.1.1 KRN23 0.3 0.6 1.0 mg/kg SC KRN23
Figure 3.1.1.1.1-1 tmax 166 167 7 KRN23 1t1/2 289 336
12 14
Figure 3.1.1.1.1-1 XLH KRN23 SC KRN23
+
Source: 5.3.4.2-1 Figure 14.2-1.1
3.1.1.1.2 KRN23 SC Figure 3.1.1.1.2-1
0.3 mg/kg Day 50.6 1.0 mg/kg Day 15
KRN23 2.5
CONFIDENTIAL - 25 -
2.57 2.86 2.66 mg/dL Day 50
Figure 3.1.1.1.2-1 XLH KRN23 SC
+
Source: 5.3.4.2-1 Figure 14.2-2.1
3.1.1.2 UX023-CL303 5.3.5.1-2 7 KRN23
III KRN23 1.0 mg/kg Q4WSC Week 24
KRN23 1.0 mg/kg Q4W SC
3.1.1.2.1 KRN23 Week 1 2 21 22
34 46 Week 4 24 36 48 Figure 3.1.1.2.1-1 KRN23/KRN23KRN23 KRN23 6
KRN23 12Week 48 5394±2882.6 ng/mL ±
KRN23 2.5
CONFIDENTIAL - 26 -
Figure 3.1.1.2.1-1 XLH KRN23 SC KRN23ng/mL
Note: All subjects received KRN23 beginning at the Week 24 visit; however, they remained blinded to their previous treatment assignment.
± Source: 5.3.5.1-2 Figure 14.2.2
3.1.1.2.2 Figure 3.1.1.2.2-1
KRN23 2.03±0.304 mg/dL 1.92±0.316 mg/dL2.5 mg/dL KRN23
Week 24KRN23 0.69±0.392 mg/dL 0.13±0.265 mg/dL
Week 24 Week 48KRN23/KRN23 N=68 0.54±0.420 mg/dL /KRN23
N=66 0.75±0.437 mg/dL
KRN23 2.5
CONFIDENTIAL - 27 -
Figure 3.1.1.2.2-1 XLH KRN23 SCmg/dL
Placebo subjects cross over to KRN23 treatment at week 24 and all subjects receive open-label KRN23 after week 24.
± Source: 5.3.5.1-2 Figure 14.2.3.1.1.1.99.2
3.1.2 XLH KRN23-003 5.3.5.2-7 1 12 XLH KRN23
III KRN23 SCKRN23 0.8 mg/kg Q2W
1.2 mg/kg
3.1.2.1 KRN23 Figure 3.1.2.1-1 KRN23 Week 1 tmax
KRN23 Week 24KRN23 Week 40 11650±4610 ng/mL
KRN23 2.5
CONFIDENTIAL - 28 -
Figure 3.1.2.1-1 XLH KRN23 SC KRN23
Source: 5.3.5.2-7 Figure 14.2.2-1
3.1.2.2 KRN23 SC Figure 3.1.2.2-1
2.61±0.32 mg/dLWeek 4 3.73±0.54 mg/dL
1.12±0.41 mg/dL Week 403.51±0.45 mg/dL
KRN23 2.5
CONFIDENTIAL - 29 -
Figure 3.1.2.2-1 XLH KRN23 SC
+
Source: 5.3.5.2-7 Figure 14.2.1-1.1.1
3.1.3 TIO ENS KRN23-002 5.3.5.2-8 TIO ENS II
KRN23 SC0.3 mg/kg Q4W 2.0 mg/kg
KRN23-002 KRN23 13 TIO
3.1.3.1 KRN23 Figure 3.1.3.1-1 KRN23
Week 24 Week 0 Week 20tmax 167 178
Cmax AUC0-t Week 0 1.49±0.43 g/mL730±234 g·h/mL Week 20 7.81±4.31 g/mL 3620±1860 g·h/mLWeek 20 Week 44 0.71 0.89 mg/kg
KRN23 2.5
CONFIDENTIAL - 30 -
Figure 3.1.3.1-1 TIO KRN23 SC KRN23
Source: 5.3.5.2-8 Figure 14.2.2-1
3.1.3.2 KRN23 SC Figure 3.1.3.2-1
1.62±0.49 mg/dL 2.5 mg/dL 2 2.28±0.95 mg/dL
Week 24 Week 48 Week 72 Week 882.65±0.62 mg/dL 2.70±0.44 mg/dL 2.73±0.39 mg/dL 2.72±0.43 mg/dL
KRN23 2.5
CONFIDENTIAL - 31 -
Figure 3.1.3.2-1 TIO KRN23 SC
Reference line: Lower limit of normal serum phosphorus concentration (2.5 mg/dL).
+ Source: 5.3.5.2-8 Figure 14.2.1-1
3.2
3.2.1 XLH 2.7.2-3.2.1 I KRN23-001 KRN23-US-02 KRN23 0.3
0.6 1.0 mg/kg SC1,25(OH)2D TmP/GFR
KRN23 SC KRN23
III UX023-CL303 KRN23 SCKRN23 1.0 mg/kg Q4W SC
KRN23
3.2.2 XLH 2.7.2-3.2.2 III KRN23-003 UX023-CL301 KRN23
SCKRN23 0.8 mg/kg Q2W KRN23 SCWeek 40 KRN23
KRN23 2.5
CONFIDENTIAL - 32 -
3.3 2.7.2-3.3.1 2.7.2-3.3.3 XLH XLH
KRN23 Nonlinear mixed-effect modeling PPK 5.3.3.5-1
KRN23 PK XLH TIOXLH PPK
5.3.3.5-2 PPKPPK 1- KRN23
V/F CL/FKRN23
FGF23
PHEXKRN23
XLH TIO
3.4 2.7.2-3.3.1.2 PPK
KRN23 Emax
Emax
Emax
PPK XLHUX023-CL201 KRN23
Cmax Cmin
Emax 77% 72% KRN23Q2W KRN23
XLHUX023-CL303 Cmax Cmin
Emax 64% 48%KRN23 Q4W
3.5 XLH 2.7.2-3.3.2 XLH KRN23-003 1
12 UX023-CL301 1 12 UX023-CL201 5 12 UX023-CL205 1 4XLH 18 XLH
13 17 PPK
XLH 18XLH 1 12 XLH
KRN23 2.5
CONFIDENTIAL - 33 -
XLH XLH 0.8 mg/kgQ2W SC 1.0 mg/kg Q4W SC XLH
0.8 mg/kg Q2W SC 1.0 mg/kg Q4WSC 3.34
3.30 mg/dL 3.2 mg/dL3.18 2.93 mg/dL
0.8 mg/kg Q2W SC 1.0 mg/kg Q4W SC5.0 mg/dL
2.9% 3.3%
3.6 UX023-CL002 KRN23
KRN23 2.7.1-1.3.2 2.7.1-1.3.32.7.4-4.2 KRN23-INT-001 KRN23-INT-002 KRN23-003 UX023-CL301
KRN23-002 2.7.6-1.3.4 KRN23-001 2.7.6-2.3.3 KRN23-US-02 2.7.6-3.3.3UX023-CL303 2.7.6-7.3.6 UX023-CL203 2.7.6-8.3.3 UX023-CL304
2.7.6-9.3.4 UX023-CL201 2.7.6-10.3.4 UX023-CL205 2.7.6-13.3.3 UX023T-CL201
3.7 QT QTc QT/QTc
21 10 23 1023 1QT/QTc KRN23 FGF23 IgG1
QTTIO ENS II
KRN23-002 QTcF KRN23UX023-CL303 UX023-CL304 UX023-CL301
KRN23-0032.7.4-4.1.2 KRN23 QT
KRN23 2.5
CONFIDENTIAL - 34 -
4 XLH KRN23 I/II KRN23-INT-001
KRN23-INT-002 KRN23 IIIUX023-CL303 UX023-CL304 KRN23
XLH KRN23 IIUX023-CL201 II UX023-CL205III UX023-CL301 III KRN23-003
KRN23 TIOII KRN23-002
4.1
4.1.1
4.1.1.1 XLH XLH I/II KRN23-INT-001
KRN23-INT-002 III UX023-CL303 UX023-CL304Table 4.1.1.1-1
KRN23-INT-001 KRN23-INT-002 2.5 mg/dL2.5 mg/dL 3.5 mg/dL 3.5 mg/dL 4.5 mg/dL 4.5 mg/dL
UX023-CL303 Week 24Week 2 6 10 14 18 22
2.5 mg/dL 0.81 mmol/L Brief Pain Inventory BPI question 3 BPI-Q3 Western Ontario and McMaster Universities Osteoarthritis Index WOMAC WOMAC
Week 24 UX023-CL304Week 48 OV/BV
Week 24 Week 2 6 1422
BPI 2
PRO BPI-Q3 24 010 WOMAC
48 04 5
KRN23 2.5
CONFIDENTIAL - 35 -
Table 4.1.1.1-1 XLH I/II III
KRN23-INT-001KRN23-INT-002 UX023-CL303 UX023-CL304
1,25(OH)2D
TmP/GFR
P1NP CTx BALP OV/BV
O.Th
OS/BS
MLt
PRO
BPI-Q3 BPIa WOMACb 6MWT
TmP/GFR=ratio of renal tubular maximum reabsorption rate of phosphate to glomerular filtration rate, P1NP=procollagen type 1 N-propeptide, CTx=carboxy-terminal cross-linked telopeptide of type I collagen, BALP=bone-specific alkaline phosphatase, OV/BV=Osteoid volume/Bone volume, O.Th=osteoid thickness, OS/BS=osteoid surface/bone surface, MLt=Mineralization lag time, PRO=patient-reported outcome, BPI=Brief Pain Inventory, WOMAC=Western Ontario and McMaster Universities Osteoarthritis Index, 6MWT=Six-Minute Walk Test a: BPI BPI b: WOMAC KRN23-INT-001 KRN23-INT-002 WOMAC WOMAC
4.1.1.2 XLH XLH II UX023-CL201 UX023-CL205
III UX023-CL301 III KRN23-003Table 4.1.1.2-1
UX023-CL201 Rickets Severity Score RSSUX023-CL205
UX023-CL301Radiographic Global Impression of Change RGI-C
Week 40 KRN23RSS RGI-C Z
KRN23 KRN23-003
RSSX
RGI-C 3+3
KRN23 2.5
CONFIDENTIAL - 36 -
7 XRGI-C X
Table 4.1.1.2-1 XLH
UX023-CL201
UX023-CL205
UX023-CL301
KRN23-003b
1,25(OH)2D
TmP/GFR
RSS RSS
RGI-C
RGI-C
RGI-C
Z a
PRO
6MWT POSNA-PODCI PROMIS
TmP/GFR=ratio of renal tubular maximum reabsorption rate of phosphate to glomerular filtration rate, RSS=Rickets Severity Score, RGI-C=Radiographic Global Impression of Change, PRO=patient-reported outcome, 6MWT=Six-Minute Walk Test, POSNA-PODCI=Pediatric Orthopedic Society of North America-Pediatric Outcomes Data Collection Instrument, PROMIS=Patient-Reported Outcomes Measurement Information System a: UX023-CL201 b: KRN23-003
4.1.1.3 TIO TIO II KRN23-002
•
•
– Week 24 Week 2 6 10 14 222.5 mg/dL 0.81 mmol/L
– Week 48 42.5 mg/dL 0.81 mmol/L
– Week 2 6 10 14 22
KRN23 2.5
CONFIDENTIAL - 37 -
– Week 48 Week 48
– • O.Th OS/BS OV/BV MLt Week 48 • FGF23 ALP 1,25(OH)2D TRP TmP/GFR
• CTx P1NP BALP • HHD STS WAL 6MWT
• PRO BPI BFI SF-36
• 99mTc • Dual energy X-ray absorptiometry DXA • X
4.1.2 XLH XLH TIO
2.7.3-1.3.1.1 2.7.3-1.3.1.2 2.7.3-1.3.1.3
4.2 KRN23 XLH XLH TIO
ICH E510 8 11 672
I KRN23-001 I KRN23-US-02III UX023-CL303 UX023-CL301 III
KRN23-003KRN23
2.7.3-3 1 2 XLH III UX023-CL303
KRN23 XLHIII UX023-CL304BPI-Q3
XLH III UX023-CL301
KRN23KRN23
KRN23 2.5
CONFIDENTIAL - 38 -
2.7.4-2.3.9.1, 2.7.4-2.3.9.2TIO II
KRN23-002
XLH KRN23-INT-001 KRN23-INT-002XLH UX023-CL201 2.7.3-3 3
KRN23-INT-001 KRN23-INT-002
28 254 60 74% 1.0 mg/kg
XLH1.0 mg/kg Q4W III UX023-CL303
UX023-CL304 UX023-CL2015 12 XLH KRN23 Q4W
Q2W RGI-CRSS Z Q4W Q2W
KRN23 Q2WWeek 24 0.8 mg/kg Week 40 64 1.0 mg/kg
XLHKRN23 0.8 mg/kg Q2W 1
4 XLH II UX023-CL205III UX023-CL301
4.3
4.3.1 XLH
4.3.1.1 III 2.7.3-3.1.1
4.3.1.1.1 UX023-CL303 163 134
66 KRN23 68 1 1 134
KRN23 1 24134 133 1 KRN23
126 94.0%1 0.7% 6 4.5%
15 126
1
KRN23 2.5
CONFIDENTIAL - 39 -
UX023-CL304 25 14 17.1% Week 48 13 92.9% 48
4.3.1.1.2 UX023-CL303 ± 39.99±12.20 KRN23
41.29±11.58 38.65±12.76 87 64.9%KRN23 44 64.7% 43 65.2%70.65±18.89 kg KRN23 70.06±19.00 kg 71.27±18.89 kg
152.42±10.67 cm KRN23 152.15±9.49 cm 152.69±11.84 cm1.98±0.31 mg/dL KRN23
2.03±0.30 mg/dL 1.92±0.32 mg/dL 1.25(OH)2D33.0±14.28 pg/mL KRN23 32.4±12.96 pg/mL 33.5±15.61 pg/mL TmP/GFR
1.64±0.39 mg/dL KRN23 1.68±0.40 mg/dL 1.60±0.37 mg/dLPHEX KRN23 62 91.2%65 98.5% KRN23 PHEX
2 FAM20C2 ENPP1
UX023-CL304 40.13±8.73 6 42.9% 857.1% 70.26±22.00 kg 150.42±8.98 cm
2.24±0.40 mg/dL 1,25(OH)2D37.25±11.69 pg/mL TmP/GFR 1.87±0.31 mg/dL PHEX
9 64.3% 535.7%
4.3.2 XLH
4.3.2.1 II III 2.7.3-3.1.2
4.3.2.1.1 UX023-CL205 13 2017 4 20
Week 40 UX023-CL301 122 61
KRN23 29 32 1 161 RSS 2 55
3.0 mg/mL 0.97 nmol/L 13 661 Full Analysis Set FAS KRN23 15
20 35 FAS 5 2018 7 30Week 64
7 KRN23 2 5 Week 643 KRN23 2 1
KRN23 2.5
CONFIDENTIAL - 40 -
Week 64 KRN23 25 26
KRN23-003 1 1515 Week 40
4.3.2.1.2 UX023-CL205 2.94±1.15 9 69.2%
4 30.8% 89.15±7.60 cm12.92±1.82 kg Z 1.38±1.19
RSS 2.92±1.37 1.27±0.70 1.65±0.8012 1.1 40.3
1.4 53.9 2.51±0.28 mg/dL1,25(OH)2D 44.83±17.62 pg/mL PHEX
11 84.6% 1 7.7%
UX023-CL301 6.10±3.31 5 26 KRN2314 12 27 44.3% 34 55.7%
104.67±19.81 cm 20.62±8.93 kgZ 2.17±1.02 5.0 0.1
0.0 11.3 3.84±3.090.5 12.2 RSS 3.18±1.06 1.47±0.74
1.71±0.55 2.0 KRN23 RSS2.36±0.26 mg/dL
TmP/GFR 2.09±0.36 mg/dL 1,25(OH)2D 42.99±17.66 pg/mL PHEX55 90.2%
3 4.9% KRN23-003 6.7±3.2 2 13.3% 13 86.7%
113.79±20.16 cm 20.91±6.96 kgZ 1.65±0.87 RSS
1.29±1.17 0.37±0.52 0.93±0.68 2.61±0.32 mg/dL1,25(OH)2D 24.65±12.70 pg/mL TmP/GFR 2.44±0.49 mg/dL PHEX
13 86.7%
4.3.3 TIO 2.7.3-3.1.3
4.3.3.1 KRN23-002 14 4
14 113 KRN23 1
2018 5 3 12 Week 88
KRN23 2.5
CONFIDENTIAL - 41 -
4.3.3.2 KRN23-002 KRN23 13 TIO 60.5±10.8
6 46.2% 7 53.8%151.45±10.43 cm 61.38±13.02 kg
1.62±0.49 mg/dL 1,25(OH)2D 22.58±11.87 pg/dL TmP/GFR 1.15±0.43 mg/dL
4.4
4.4.1 XLH XLH KRN23 III UX023-CL303
5.3.5.1-1, 5.3.5.1-2 UX023-CL304 5.3.5.2-4
4.4.1.1
4.4.1.1.1
Week 242.5 mg/dL 0.81 mmol/L
UX023-CL303 UX023-CL304
1 UX023-CL303 Week 24 Week 2 6 10 14 18 22
2.7.3 Table 3.2.1.1.1-1Week 24
95%CI KRN23 68 64 94.1% 85.8, 97.7% 66 5 7.6% 3.3, 16.5% KRN23
p<0.0001 Week 24Week 4 8 12 16 20 24
95%CI 6.1% 2.4, 14.6% KRN2367.6% 55.8, 77.6%
2 UX023-CL304 Week 24 Week 2 6 14 22
2.7.3 Table 3.2.1.1.1-2Week 24
95%CI 92.9% 68.5, 98.7%Week 24
95%CI 78.6% 52.4, 92.4%
KRN23 2.5
CONFIDENTIAL - 42 -
4.4.1.1.2
1 UX023-CL303 Week 48
2.7.3 Figure 3.2.1.1.1-12.7.3 Figure 3.2.1.1.1-2
Week 24± KRN23 1.21±0.51 mg/dL
0.16±0.27 mg/dL Week 24Week 48KRN23/KRN23 KRN23 KRN23 680.99±0.47 mg/dL /KRN23 KRN23
66 1.32±0.51 mg/dL /KRN23 59 89.4% Week 24Week 48
Week 24
KRN23 0.69±0.39 mg/dL 0.13±0.27 mg/dLWeek 24 Week 48
/KRN23 0.75±0.44 mg/dL Week 24
2.07±0.34 mg/dL KRN23 2.53±0.45 mg/dL Week 24± 95%CI KRN23
0.40±0.06 mg/dL 0.28, 0.51 Week 24± 95%CI KRN23
20.79±3.12% 14.68, 26.91 Week 48 KRN23/KRN23
2.47±0.46 mg/dL /KRN23 2.47±0.49 mg/dL KRN23/KRN23 Week 1
/KRN23 Week 24KRN23 Week 24 Week 26 Week 48
KRN23
2 UX023-CL304 Week 48
2.7.3 Figure 3.2.1.1.1-32.7.3 Figure 3.2.1.1.1-4
Week 241.07±0.30 mg/dL 50.39±19.94%
Week 240.46±0.30 mg/dL 23.32±19.84% Week 24 Week 48
2.60±0.33 mg/dL 2.43±0.30 mg/dL
KRN23 2.5
CONFIDENTIAL - 43 -
4.4.1.1.3 TmP/GFR
1 UX023-CL303 TmP/GFR 2.7.3 Figure 3.2.1.1.1-5 TmP/GFR KRN23
KRN23Week 24 TmP/GFR TmP/GFR KRN23 1.68±0.40 0.95 3.41 mg/dL
1.60±0.37 0.71 2.62 mg/dL Week 24 TmP/GFR KRN232.22±0.49 mg/dL 1.73±0.42 mg/dL
± KRN23 0.56±0.10 mg/dL 0.13±0.08 mg/dL± KRN23 35.94±5.81%
7.08±4.81% ± KRN230.43±0.07 mg/dL ± KRN23
28.87±4.34% Week 48TmP/GFR KRN23/KRN23 2.20±0.52 mg/dL /KRN23 2.21±0.59 mg/dL
± KRN23/KRN230.52±0.10 mg/dL /KRN23 0.61±0.10 mg/dL
± KRN23/KRN23 33.63±5.88% /KRN23 38.92±5.82%
2 UX023-CL304 TmP/GFR 2.7.3 Figure 3.2.1.1.1-6 TmP/GFR
1.87±0.31 mg/dL Week 24 Week 48 2.31±0.42 mg/dL 2.09±0.36 mg/dLWeek 24 Week 48 ±
26.18±5.30% 13.12±4.29%
4.4.1.1.4 1,25(OH)2D
1 UX023-CL303 1,25(OH)2D 2.7.3 Figure 3.2.1.1.1-7
KRN23 1,25(OH)2DWeek 24
1,25(OH)2D KRN23 32.4±12.96 pg/mL33.5±15.61 pg/mL Week 22 1,25(OH)2D
KRN23 57.0±18.02 pg/mL ±25.85±3.38 pg/mL ±
102.36±16.75% Week 22 1,25(OH)2D34.9±14.52 pg/mL ± 3.12±2.64 pg/mL
± 20.33±13.80%± KRN23 22.73±2.37 pg/mL
Week 20 KRN23 1,25(OH)2D 38.1±11.58 pg/mL
± 7.77±2.92 pg/mL± 40.8±14.83% Week 20
KRN23 2.5
CONFIDENTIAL - 44 -
1,25(OH)2D 34.4±13.47 pg/mL ±2.12±2.71 pg/mL ±
19.5±14.49% ± KRN235.66±1.85 pg/mL ± KRN23
21.2±9.43% KRN23 Week 46
1,25(OH)2D KRN23/KRN23 53.7±20.66 pg/mL /KRN23 56.7±17.59 pg/mL± KRN23/KRN23
96.94±18.89% /KRN23 129.55±25.02% Week 481,25(OH)2D KRN23/KRN23 38.0±13.62 pg/mL /KRN23 41.9±13.42 pg/mL
± KRN23/KRN2334.91±14.68% /KRN23 69.35±19.60%
2 UX023-CL304 1,25(OH)2D 2.7.3 Figure 3.2.1.1.1-8 1,25(OH)2D KRN23 1,25(OH)2D
KRN23 1 2 4
1,25(OH)2D 37.25±11.69 pg/mL Week 2248.46±9.05 pg/mL Week 24 Week 48 37.33±10.34 pg/mL33.92±8.98 pg/mL Week 22 ±
11.50±4.06 pg/mL ±40.10±8.08% Week 24 Week 48
± 3.04±4.89 pg/mL 1.72±4.19 pg/mL Week 24Week 48 ±
0.98±15.58% 2.39±7.39%
4.4.1.2
4.4.1.2.1 OV/BV OV/BV UX023-CL304 5.3.5.2-4 1
UX023-CL304 Week 48 OV/BV 2.7.3 Figure 3.2.1.1.2-111
11 5 45.5% 5.3.5.2-4 Table 14.2.1.1.85 4 KRN23 48
OV/BV 26.12±12.36% Week 48 OV/BV11.85±6.60% 5.3.5.2-4 Table 14.2.1.1.1 2 10
OV/BV 14.94±10.97%54.18±20.21% KRN23 48 11 OV/BV
Week 48 31.2 83.6%
KRN23 2.5
CONFIDENTIAL - 45 -
4.4.1.2.2 O.Th OS/BS MLt
O.Th OS/BS MLtUX023-CL304 5.3.5.2-4 1
O.Th 17.21±4.11 m Week 48 11.55±3.11 m 32.21±11.97%5.3.5.2-4 Table 14.2.1.1.2 OS/BS 91.73±3.44% Week 48
67.82±13.67% 26.00±15.01% 5.3.5.2-4 Table 14.2.1.1.3 MLt1539.81±1587.09 Week 48 195.50±77.71 52.24±58.49%
5.3.5.2-4 Table 14.2.1.1.4 MLt5 Week 48 1 MLt
MLt 593.55±675.23 Week 48 195.50±77.71 26.96±64.99%5.3.5.2-4 Table 14.2.1.1.4.99.1
4.4.1.2.3
1 UX023-CL303 P1NP CTx Week 24 KRN23
BALP KRN23 Week 24KRN23 /KRN23 P1NP CTx BALP
KRN23/KRN23 P1NP CTx BALPWeek 48
P1NP KRN23 85.2±50.72 ng/mL 87.8±53.28 ng/mLWeek 24 P1NP KRN23 155.5±97.30 ng/mL 94.8±57.74 ng/mL
Week 24 KRN23 80.82±53.26%16.07±40.20% ± KRN23
61.98±7.64 ng/mL ± KRN2365.39±8.06% Week 48 P1NP KRN23/KRN23
130.1±68.82 ng/mL /KRN23 174.1±132.46 ng/mLKRN23/KRN23 56.14±10.53% /KRN23 95.72±11.99% 5.3.5.1-2
Table 14.2.3.6 CTx KRN23 702.4±395.54 pg/mL 720.5±417.91 pg/mL
Week 24 CTx KRN23 930.1±494.79 pg/mL 739.5±440.14 pg/mLWeek 24 KRN23 38.21±46.60%
10.87±44.75% ± KRN23192.62±41.90 pg/mL ±
KRN23 27.83±7.31% Week 48 CTx KRN23/KRN23876.5±423.62 pg/mL /KRN23 1051.0±654.99 pg/mL
KRN23/KRN23 28.91±5.75% /KRN23 49.16±7.00%5.3.5.1-2 Table 14.2.3.7
BALP KRN23 24.0±19.68 g/L 24.7±17.25 g/L5.3.5.1-2 Table 14.2.3.5 Week 24 BALP KRN23 30.2±26.26 g/L
26.0±17.33 g/L Week 24 KRN2342.84±84.28% 32.99±82.30%
KRN23 2.5
CONFIDENTIAL - 46 -
± KRN23 4.06±2.45 g/L± KRN23 9.73±13.51% Week 48 BALP
KRN23/KRN23 26.4±19.42 g/L /KRN23 31.2±19.36 g/LKRN23/KRN23 23.65±10.52% /KRN23 50.21±11.79%
2 UX023-CL304 BALP 20.43±9.29 g/L Week 12 32.38±20.48 g/L Week 48
22.77±14.97 g/L 5.3.5.2-4 Table 14.2.3.5 P1NP77.00±33.27 ng/mL Week 48 127.31±57.88 ng/mL 5.3.5.2-4 Table 14.2.3.6 CTx
646.93±401.64 pg/mL Week 48 828.69±420.48 pg/mL 5.3.5.2-4 Table 14.2.3.7 CTx P1NP KRN23
4.4.1.2.4
1 UX023-CL303 X 59.0%
34.3% 11.9%47.0% 5.3.5.1-1 Table 14.2.1.7.2 KRN23
65 915.3.5.1-1 Table 14.2.1.7.4
KRN23 Week 12 Week 2420.0% 43.1% Week 12 Week 24 7.7%KRN23/KRN23 Week 36 Week 48 50.8% 63.1% /KRN23
Week 36 Week 48 23.1% 35.2% 5.3.5.1-2 Table 14.2.1.7.4 KRN23KRN23
14 5113 78 Week 24 KRN23 7
50.0% Week 48 KRN23/KRN23 8 57.1% Week 240 0.0% Week 48 /KRN23 6 46.2%
Week 24 KRN23 21 41.2% Week 48KRN23/KRN23 33 64.7% Week 24
7 9.0% Week 48 /KRN23 26 33.3%5.3.5.1-2 Table 14.2.1.7.4
2 UX023-CL304 4 5.3.5.2-4 Table 14.2.1.4.2
Week 12 2 2 KRN23 48X 3
KRN23
KRN23 2.5
CONFIDENTIAL - 47 -
4.4.1.3 PRO
4.4.1.3.1 BPI
1 UX023-CL303 BPI-Q3 KRN23 6.81±1.31 Week 24 5.82±1.92
6.54±1.43 Week 24 6.09±2.01Week 24 BPI-Q3 ± KRN23
0.46±0.28 p=0.0919 0.05 KRN235.3.5.1-1 Table
14.2.1.1.1.1
2 UX023-CL304 KRN23 48 BPI 5.3.5.2-4
Table 14.2.1.2.1 BPI-Q3 6.64±1.99 Week 48 4.92±2.60± 1.86±0.67
5.3.5.2-4 Table 14.2.1.2.1 7 53.8% BPI-Q330% 5.3.5.2-4 Table 14.2.1.2.3
BPI 5.09±1.80 Week 48 3.42±2.24± 1.77±0.55 BPI
5.22±2.26 Week 48 3.96±2.68± 1.47±0.53 5.3.5.2-4 Table 14.2.1.2.2
4.4.1.3.2 WOMAC WOMAC WOMAC WOMAC UX023-CL303 5.3.5.1-21
WOMAC KRN23 50.79±19.66 Week 2443.43±19.51 43.89±19.94 Week 24 42.65±22.76
Week 24 WOMAC± KRN23 4.90±2.48 p=0.0478 0.025
KRN235.3.5.1-2 Table 14.2.1.2.2.1.1
WOMAC KRN23 64.71±20.25 Week 2453.73±20.76 61.36±20.77 Week 24 60.38±21.83
Week 24 WOMAC± KRN23 8.31±3.25 p=0.0106 0.0167
KRN23 5.3.5.1-2 Table 14.2.1.2.1.1.1
4.4.1.3.3 6MWT 6MWT UX023-CL303 5.3.5.1-1, 5.3.5.1-2 1
KRN23 2.5
CONFIDENTIAL - 48 -
6MWT KRN23Week 24 KRN23
KRN23 356.78±109.46 m 55.0 643.0 m367.42±103.41 m 160.0 615.0 m 362.02±106.25 m
Week 24 KRN23 381.45±108.46 m 369.44±103.39 m± KRN23
17.12±7.46 m 2.81±7.57 m ±KRN23 19.93±7.94 m Week 48 KRN23/KRN23 392.49±107.15 m /KRN23
390.86±106.51 m ±KRN23/KRN23 30.50±6.93 m /KRN23 20.19±8.76 m 5.3.5.1-1 Table
14.2.1.4.1
4.4.2 XLH XLH KRN23 II UX023-CL205
5.3.5.2-6 III UX023-CL301 5.3.5.1-3 IIIKRN23-003 5.3.5.2-7
4.4.2.1
4.4.2.1.1 RGI-C
1 UX023-CL205
1 RGI-C Week 40 RGI-C 2.7.3 Table 3.2.2.1.1-1 Week 40 RGI-C +2± +2.33±0.08 +2.26±0.11
+2.21±0.15 p<0.0001
2 RGI-C Week 40 RGI-C RGI-C
Week 40 ± +1.26±0.14 p<0.0001 5.3.5.2-6 Table 14.2.1.2.1 13 10 +1 2 +2 5.3.5.2-6 Listing 16.2.6.1
2 UX023-CL301
1 RGI-C Week 40 Week 64 RGI-C 2.7.3 Table 3.2.2.1.1-2
2.7.3 Table 3.2.2.1.1-3 Week 40 KRN23
Week 40 RGI-C ±KRN23 +1.92±0.11 +0.77±0.11 KRN23
1.14 95%CI: 0.83, 1.45 p<0.0001 RGI-C KRN23
KRN23 2.5
CONFIDENTIAL - 49 -
RGI-C± KRN23 1.83±0.10 2.07±0.15 0.71±0.10 0.76±0.15
KRN23 1.12 95%CI: 0.84, 1.41 p<0.0001 1.31 95%CI: 0.89, 1.74 p<0.0001
Week 64 Week 40 KRN23Week 64 RGI-C ± KRN23
2.06±0.07 1.03±0.14 KRN23 1.02 95%CI: 0.72, 1.33 p<0.0001 RGI-C KRN23
RGI-C ±KRN23 2.03±0.06 2.14±0.12 1.03±0.14 0.99±0.14
KRN23 1.01 95%CI: 0.71, 1.30 p < 0.0001 1.15 95%CI: 0.78, 1.51 p<0.0001
2 RGI-C Week 40 Week 64 RGI-C 2.7.3 Table 3.2.2.1.1-4
2.7.3 Table 3.2.2.1.1-5 Week 40 RGI-C ± KRN23 +0.62±0.15
+0.22±0.08 KRN23 0.40 95%CI: 0.07, 0.72 p=0.0162
Week 40 KRN23 29 14 48.3% RGI-C 1.032 4 12.5% 1.0
KRN23 3 10.3% Week 40 RGI-C 07 21.9% 0 5.3.5.1-3 Table 14.2.1.1.15.1
Week 64 RGI-C ± KRN23 +1.25±0.17+0.29±0.12 KRN23 0.97 95%CI: 0.57, 1.37 p<0.0001
Week 64 KRN23 29 20 69.0% RGI-C 1.032 7 21.9% 1.0
Week 64 RGI-C 0 KRN231 3.4% 4 12.5% 5.3.5.1-3 Table 14.2.1.1.15.1
3 KRN23-003 Week 40 RGI-C 2.7.3 Table 3.2.2.1.1-6 Week 40 RGI-C 1.51±0.80
1.61±0.91 1.40±0.92 Week 40 RGI-C 0.73±0.85
4.4.2.1.2 RSS
1 UX023-CL205 Week 40 RSS 2.7.3 Table 3.2.2.1.2-1
Week 40 RSS RSS2.92±1.37 Week 40 1.19±0.52 5.3.5.2-6 Table
KRN23 2.5
CONFIDENTIAL - 50 -
14.2.1.1.1 RSS ± 1.73±0.13p<0.0001 RSS Week 40
2 UX023-CL301 Week 40 RSS 2.7.3 Table 3.2.2.1.2-2
Week 64 RSS 2.7.3 Table 3.2.2.1.2-3 Week 40 KRN23 1 RSS Week 40
ANCOVA KRN23 28 32 Week 64GEE
KRN23 RSS Week 40 ANCOVA 283.16±0.99 Week 64 GEE 29 3.17±0.98 RSS3.19±1.14 KRN23 5.3.5.1-3 Table 14.2.1.2.1.1 KRN23 Week 40
RSS 1.13±0.72 ±2.04±0.15 Week 40 RSS 2.47±1.09
± 0.71±0.14 KRN23Week 40 2 KRN23 1.34
95%CI: 1.74, 0.94 p<0.0001 Week 64 KRN23 RSS 0.95±0.72
± 2.23±0.12 RSS 2.17±0.95± 1.01±0.15
Week 64 KRN23 1.21 95%CI: 1.59, 0.83 p<0.0001 KRN23 RSS Week 40 Week 64
Week 40 RSSKRN23 0.69 95%CI: 0.91, 0.46 p<0.0001
0.69 95%CI: 0.97, 0.41 p<0.0001 Week 64 0.58 95%CI: 0.80, 0.36 p<0.0001 0.65 95%CI: 0.90, 0.39 p<0.0001
3 KRN23-003 Week 40 RSS 2.7.3 Table 3.2.2.1.2-4 RSS
1.29±1.17 Week 40 0.62±0.58 0.77±0.995.3.5.2-7 Table 14.2.1-1.3
RSS 0.93±0.68 0.37±0.52Week 40 0.54±0.52 0.07±0.18
RSS 0.46±0.59 0.30±0.53
4.4.2.1.3
1 UX023-CL205
13 7 24
KRN23 2.5
CONFIDENTIAL - 51 -
89.15±7.60 cm Week 4093.44±7.05 cm 5.3.5.2-6 Table 14.2.1.3.1Z 1.38±1.19 Week 40 1.65±1.12 5.3.5.2-6 Table 14.2.1.3.1 Z ±
0.20±0.13 p=0.1396 5.3.5.2-6 Table 14.2.1.3.2 KRN23
2 UX023-CL301 Week 40 Week 64 Z 2.7.3 Table
3.2.2.1.3-1 Z KRN23 2.32±1.17 Week 40
2.12±1.22 Week 64 2.11±1.11 2.05±0.87 Week 402.02±0.85 Week 64 2.03±0.83 Week 64 Z
KRN23 Week 40 Week 64 2.7.3 Table
3.2.2.1.3-2 KRN23Z 1.37±1.33 0.96±1.36 Week 40 Week 64
Z KRN23 0.53±1.80 0.34±1.460.37±1.32 0.75±0.88 Week 40 Week 64
Z ±KRN23 1.76±0.34 1.53±0.26 0.73±0.34 0.41±0.27
Week 40 Week 64 ZKRN23 1.02 95%CI: 0.06, 1.99 p=0.0386 1.12 95%CI: 0.37, 1.88 p=0.0047
KRN23 Week 40 Week 64
6.52±4.04 cm/year 7.03±2.05 cm/year 6.65±1.46 cm/year Week 40 Week 64+0.51±2.75 cm/year +0.13±3.23 cm/year
Week 40 Week 64 6.40±2.39 cm/year6.27±1.31 cm/year 5.94±1.12 cm/year Week 40 Week 64
0.12±2.09 cm/year 0.46±1.99 cm/year 5.3.5.1-3 Table 14.2.1.3.99.1
3 KRN23-003 Z 2.7.3 Table 3.2.2.1.3-3
Z 1.65±0.87 Week 24 1.71±0.81 Week 401.69±0.76 Week 24 Week 40 0.06±0.15
0.04±0.23
4.4.2.2
4.4.2.2.1
1 UX023-CL205 2.7.3 Figure 3.2.2.2.1-1
KRN23 2.5
CONFIDENTIAL - 52 -
KRN232.51±0.28 mg/dL 3.2 6.1 mg/dL 5.3.5.2-6
Table 14.2.3.1.1p<0.0001 5.3.5.2-6 Table 14.2.3.1.1 Week 40 3.47±0.49 mg/dL
0.96±0.44 mg/dL
2 UX023-CL301 2.7.3 Figure 3.2.2.2.1-2
7 D3.0 mg/dL
KRN23 2.42±0.24 mg/dL 2.30±0.26 mg/dL3.2 mg/dL 5.3.5.1-3 Table 14.2.3.1.1.1.1.40 KRN23
3.2 mg/dL KRN23 2.42±0.24 mg/dLWeek 40 3.30±0.43 mg/dL Week 64 3.29±0.42 mg/dL
Week 40 Week 64 ± 0.92±0.08 mg/dL0.91±0.08 mg/dL
2.30±0.26 mg/dLWeek 40 2.53±0.34 mg/dL Week 64 2.54±0.39 mg/dL Week 40
Week 64 ± 0.20±0.06 mg/dL0.21±0.06 mg/dL Week 40 Week 64
KRN23 0.71 95%CI: 0.52, 0.91 p<0.0001 0.69 95%CI: 0.49, 0.90 p<0.0001 5.3.5.1-3 Table 14.2.3.1.1.1.1.40, Table 14.2.3.1.1.1.1
3 KRN23-003 2.7.3 Figure 3.2.2.2.1-3
KRN23 2.61±0.32 mg/dL Week 43.73±0.54 mg/dL Week 40 3.51±0.45 mg/dL
5.3.5.2-7 Table 14.2.1-1.1
4.4.2.2.2 TmP/GFR TmP/GFR UX023-CL205 UX023-CL301 KRN23-003 2
1 UX023-CL301 TmP/GFR 2.7.3 Figure 3.2.2.2.2-1 TmP/GFR KRN23
KRN23 TmP/GFR 2.19±0.37 mg/dL Week 40 3.35±0.67 mg/dLWeek 64 3.28±0.65 mg/dL Week 40 Week 64
± 1.19±0.11 mg/dL 1.16±0.13 mg/dLTmP/GFR
TmP/GFR 2.01±0.33 mg/dL Week 40 1.82±0.35 mg/dL Week 641.89±0.49 mg/dL Week 40 Week 64
KRN23 2.5
CONFIDENTIAL - 53 -
± 0.16±0.05 mg/dL 0.09±0.07 mg/dLWeek 40 Week 64 KRN23
1.35 95%CI: 1.10, 1.61 p<0.0001 1.25 95%CI: 0.96, 1.54 p < 0.0001 5.3.5.1-3 Table 14.2.3.3.1.1.1.40, Table 14.2.3.3.1.1.1
2 KRN23-003 TmP/GFR 2.7.3 Figure 3.2.2.2.2-2 TmP/GFR 2.44±0.49 mg/dL Week 8
4.02±0.80 mg/dL 1.58±0.67 mg/dLWeek 40 3.61±0.61 mg/dL 5.3.5.2-7 Table 14.2.1-1.1
4.4.2.2.3 1,25(OH)2D
1 UX023-CL205 1,25(OH)2D 2.7.3 Figure 3.2.2.2.3-1 1,25(OH)2D 44.83±17.62 pg/mL Week 1 2
94.09±28.95 pg/mL Week 40 56.75±10.34 pg/mL 5.3.5.2-6 Table 14.2.3.2.11,25(OH)2D Week 40
p<0.01 5.3.5.2-6 Table 14.2.3.2.1
2 UX023-CL301 1,25(OH)2D 2.7.3 Figure 3.2.2.2.3-2 1,25(OH)2D KRN23
KRN23 46.00±20.06 pg/mL Week 4072.60±21.36 pg/mL Week 64 54.1±13.0 pg/mL Week 40
Week 64 ± 29.53±3.78 pg/mL9.89±2.24 pg/mL 40.18±14.89 pgm/L Week 4059.28±19.49 pg/mL Week 64 44.08±13.67 pg/mLWeek 40 Week 64 ± 18.58±3.70 pg/mL
1.19±2.79 pg/mL Week 40 Week 64 KRN23
10.95 pg/mL 95%CI: 0.46, 21.44 pg/mL p=0.0408 8.70 pg/mL 95%CI:1.72, 15.68 pg/mL p=0.0145 5.3.5.1-3 Table 14.2.3.2.1.1.1.40, Table 14.2.3.2.1.1.1
Week 1 4 8 16 24 40 64 KRN231,25(OH)2D Week 40 Week 64
KRN23 96.06±91.27% 38.12±69.08% 78.63±96.47%30.00±71.96%
3 KRN23-003 1,25(OH)2D 2.7.3 Figure 3.2.2.2.3-3 1,25(OH)2D 24.65±12.70 pg/mL
Week 1 70.81±21.49 pg/mL 46.16±15.55 pg/mL
KRN23 2.5
CONFIDENTIAL - 54 -
Week 40 62.19±12.50 pg/mL 5.3.5.2-7 Table 14.2.1-1.1
4.4.2.3 PRO
4.4.2.3.1 PROMIS PROMIS
UX023-CL301 5.3.5.1-3 1 UX023-CL301 5
T 50 10
KRN23 T 53.1±10.95
49.9±12.05 Week 40 KRN23 T47.6±9.84 50.4±9.51 T Week 40
± KRN23 5.31±1.71 0.29±1.54KRN23 5.02 95%CI: 9.29, 0.75 p=0.0212 5.3.5.1-3 Table
14.2.1.4.1.1.40 Week 64 KRN23 T 49.3±8.07
49.4±9.52 T Week 64± KRN23 3.55±1.87 1.29±1.27 KRN23
2.26 95%CI: 6.61, 2.09 p=0.3091 5.3.5.1-3 Table 14.2.1.4.1.1 KRN23 T 45.2±9.05
45.5±9.86 Week 40 KRN23 T47.9±8.32 45.5±9.71 T
Week 40 ± KRN23 2.78±1.34 0.10±0.97KRN23 2.68 95%CI: 0.52, 5.89 p=0.1009 5.3.5.1-3
Table 14.2.1.4.1.1.40 Week 64 KRN23 T 47.9±9.2446.3±9.63 T Week 64
± KRN23 2.82±1.65 0.92±0.96 KRN231.90 95%CI: 1.80, 5.59 p=0.3145 5.3.5.1-3 Table 14.2.1.4.1.1
KRN23 T 48.8±9.6047.0±13.70 Week 40 KRN23 T 44.7±10.49
46.6±10.73 T Week 40± KRN23 4.29±1.71 1.05±1.75 KRN23
3.25 95%CI: 7.86, 1.37 p=0.1676 5.3.5.1-3 Table 14.2.1.4.1.1 Week 64 KRN23 T 45.2±10.69 45.0±11.17
T Week 64 ±KRN23 3.65±2.12 2.57±1.55 KRN23 1.08
95%CI: 6.21, 4.06 p=0.6810 5.3.5.1-3 Table 14.2.1.4.1.1
KRN23 2.5
CONFIDENTIAL - 55 -
4.4.2.3.2 6MWT 6MWT UX023-CL205 UX023-CL301 5.3.5.1-3
KRN23-003 5.3.5.2-7 2
1 UX023-CL301 6MWT 2.7.3 Figure 3.2.2.3.2-15 6MWT
6MWT KRN23 365.93±118.08 mWeek 40 434.73±79.34 m Week 64 463.80±81.99 m Week 40 Week 64
± +52.08±16.21 m +78.95±11.41 m5.3.5.1-3 Table 14.2.1.6.1.1.40, Table 14.2.1.6.1.1
450.50±106.43 m Week 40 457.40±95.57 m Week 64 481.30±113.06 m Week 40 Week 64 ± +10.56±14.11 m +35.75±16.71 m
KRN23 Week 40 6MWT+41.52 m 95%CI: 0.60, +83.64 m p=0.0534 Week 64
+43.20 m 95%CI: +2.33, +84.07 p=0.0383
2 KRN-003 6MWT 2.7.3 Table 3.2.2.3.2-1 6MWT
425.0±81.3 m Week 24 461.1±58.2 m Week 40 437.6±77.3 mWeek 24 Week 40 24.1±60.7 m
12.6±75.5 m
4.4.3 TIO TIO III II
KRN23-002 KRN230.3 mg/kg Q4W
PRO
4.4.3.1
4.4.3.1.1 2.7.3 Figure 3.2.3.1.1-1
KRN23 Q4W1.62±0.49 mg/dL Week 1 2 4 2.20±0.89 mg/dL
2.28±0.95 mg/dL 1.94±0.87 mg/dL Week 2Week 20 Week 21 Week 22 Week 24 2.51±0.58 mg/dL 2.90±0.69 mg/dL
3.04±0.72 mg/dL 2.65±0.62 mg/dL 5.3.5.2-8 Table 14.2.1-1 Week 200.71 mg/kg 5.3.5.2-8 Table 14.1-6 Week 48 Week 72 Week 88
2.70±0.44 mg/dL 2.73±0.39 mg/dL 2.72±0.43 mg/dL Week 24 Week 48
KRN23 2.5
CONFIDENTIAL - 56 -
Week 72 Week 88 0.97±0.68 mg/dL0.99±0.48 mg/dL 1.05±0.48 mg/dL 1.03±0.51 mg/dL
4.4.3.1.2 TmP/GFR TmP/GFR 2.7.3 Figure 3.2.3.1.2-1 TmP/GFR 1.15±0.43 mg/dL Week 24 Week 48 Week 72
2.30±0.71 mg/dL 2.30±0.48 mg/dL 2.29±0.50 mg/dL 5.3.5.2-8 Table 14.2.1-8Week 24
4.4.3.1.3 1,25(OH)2D 1,25(OH)2D 2.7.3 Figure 3.2.3.1.3-1 1,25(OH)2D 22.58±11.87 pg/mL Week 24 Week 48 Week 72
45.29±12.83 pg/mL 49.29±10.89 pg/mL 41.34±8.53 pg/mL 5.3.5.2-8 Table 14.2.1-8
4.4.3.2
4.4.3.2.1 O.Th OS/BS OV/BV MLt 3
5.3.5.2-8 Listing 16.2.6-3.3 2 Week 48 Week 48MLt
4.4.3.2.2 CTx P1NP BALP KRN23
5.3.5.2-8 Table 14.2.1-9 CTx0.61±0.57 ng/mL Week 24 0.89±0.80 ng/mL Week 72 0.69±0.43 ng/mL
P1NP 72.34±72.87 ng/mL Week 24 112.89±105.43 ng/mLWeek 72 83.63±40.22 ng/mL BALP 36.21±21.66 g/L
Week 16 43.97±31.68 g/L Week 72 30.38±19.50 g/L27.81±28.85 ng/mL Week 24 37.48±37.88 ng/mL
Week 72 32.67±31.81 ng/mL
4.4.3.2.3 99mTc 99mTc
164Week 48 24
285.3.5.2-8 Table 14.2.1-12
4.4.3.2.4 X 4 Week 12 2
Week 48 3 12 5.3.5.2-8 Table 14.2.1-14
KRN23 2.5
CONFIDENTIAL - 57 -
4.4.3.3 PRO
4.4.3.3.1 BPI BPI-Q3 Week 24 Week 48 Week 72 4.4±2.6 3.0±2.7
2.9±2.9 2.9±2.7 5.3.5.2-8 Table 14.2.1-11
4.4.3.3.2 SF-36 SF-36 T Week 24 Week 48 Week 72 35.89±7.71
45.22±10.72 41.38±11.83 43.30±11.17 T Week 24Week 48 Week 72 32.30±11.43 43.40±14.68 43.38±13.59 42.30±14.86
5.3.5.2-8 Table 14.2.1-11 SF-36
4.4.3.3.3 6MWT 6MWT 295.8±96.0 m Week 24 Week 48
329.2±115.0 m 353.7±115.8 m Week 24 Week 4833.0 m 57.5 m 5.3.5.2-8 Table 14.2.1-10
4.4.4
4.4.4.1
4.4.4.1.1 XLH III UX023-CL303 5.3.5.1-1
Week 242.5 mg/dL 0.81 mmol/L
2.7.3-3.3.1.1
Week 24
• BPI-Q3 6.0 >6.0 • BPI-Q5 6.0 >6.0 • • •
KRN23 Week 24
BPI-Q3 WOMAC WOMAC
Week 24 • BPI-Q3 >6.0 6.0 • BPI-Q5 >6.0 6.0 • •
KRN23 2.5
CONFIDENTIAL - 58 -
• •
• WOMAC 47.8 >47.8 • WOMAC 62.5 >62.5 •
KRN23 ±
KRN23
4.4.4.1.2 XLH III UX023-CL301 5.3.5.1-3 FASRGI-C Z KRN23
• RSS 2.5 >2.5 • <5 5 • • • PHEX
KRN23 RGI-CKRN23
Z 2.7.3-3.3.1.2
4.4.4.2
4.4.4.2.1 XLH XLH UX023-CL303 UX023-CL304
1
UX023-CL303 UX023-CL3042.7.3 Table 3.3.2.1.1-1
UX023-CL303 KRN23 6 5 11KRN23 42.6±14.6 32.0±14.9 KRN23
3 50.0% 2 40.0% 3 60.0%KRN23 148.85±5.75 cm 149.00±10.06 cm
KRN23 51.62±10.49 kg 50.78±16.73 kgKRN23 2.03±0.31 mg/dL 1.90±0.16 mg/dL
UX023-CL304 4 KRN23 45.6±6.1
2 50.0% 143.95±10.89 cm 58.98±13.16 kg1.95±0.53 mg/dL
KRN23 2.5
CONFIDENTIAL - 59 -
UX023-CL303 UX023-CL304
2
UX023-CL303 UX023-CL303 KRN23 6Week 24
5.3.5.1-1 Table 14.2.3.1.5
3 BPI-Q3 WOMAC WOMAC BPI-Q3 UX023-CL303 5.3.5.1-1, 5.3.5.1-2
UX023-CL304 5.3.5.2-4 2 WOMAC WOMACUX023-CL303 5.3.5.1-1, 5.3.5.1-2 1
UX023-CL303 UX023-CL303 BPI-Q3 WOMAC
WOMAC Week 24BPI-Q3 WOMAC WOMAC
2.7.3 Figure 3.3.2.1.3-1 BPI-Q3 KRN23 Week 24
6.45±2.13 5.54±2.32 5.55±1.44 4.03±2.07 5.3.5.1-2 Table 14.2.1.1.1.6 Week 24 ±
KRN23 0.86±0.79 WOMAC KRN23 Week 24
38.73±24.03 34.56±21.22 18.82±15.1218.82±14.54 5.3.5.1-2 Table 14.2.1.2.2.6 Week 24
± KRN23 1.99±5.26 WOMAC KRN23 Week 24
66.67±25.82 45.83±29.23 37.50±23.3935.00±18.54 5.3.5.1-2 Table 14.2.1.2.1.6 Week 24
± KRN23 1.25+13.96
WOMAC KRN23WOMAC BPI-Q3
KRN23
UX023-CL304 4 2 KRN23 BPI-Q3
25.3.5.2-4 Listing 16.2.6.2.1
4 UX023-CL303 1,25(OH)2D TmP/GFR UX023-CL303
5.3.5.1-1 1
KRN23 2.5
CONFIDENTIAL - 60 -
UX023-CL303 1,25(OH)2DTmP/GFR 2.7.3 Figure 3.3.2.1.4-1 2.7.3 Figure 3.3.2.1.5-1 2.7.3 Figure 3.3.2.1.6-1
KRN23 2.03±0.31 mg/dL
1.90±0.16 mg/dL Week 24KRN23 2.63±0.54 mg/dL 2.16±0.25 mg/dL Week 48
KRN23 2.48±0.27 mg/dL 2.38±0.18 mg/dL5.3.5.3-1 Table 535313-2.1 KRN23 Week 24 KRN23
Week 24KRN23 Week 24 Week 26 Week 48
1,25(OH)2D KRN23 33.25±10.28 pg/mL
33.25±10.87 pg/mL 5.3.5.3-1 Table 535313-2.2Week 22 1,25(OH)2D KRN23 56.33±22.62 pg/mL
36.20±10.89 pg/mL Week 20 KRN2340.67±8.24 pg/mL 34.40±9.81 pg/mL KRN23
Week 46 KRN23 61.17±22.36 pg/mL64.80±16.90 pg/mL 1,25(OH)2D
Week 48 1,25(OH)2D KRN23 39.00±9.61 pg/mL49.00±22.75 pg/mL
TmP/GFR KRN23Week 24 TmP/GFR KRN231.66±0.21 mg/dL 1.61±0.14 mg/dL 5.3.5.3-1 Table 535313-2.3 Week 24
TmP/GFR KRN23 2.37±0.65 mg/dL1.71±0.27 mg/dL Week 48 TmP/GFR KRN232.17±0.35 mg/dL 2.44±0.51 mg/dL
1,25(OH)2DTmP/GFR
4.4.4.2.2 UX023-CL303 UX023-CL304
UX023-CL303
WOMAC 1,25(OH)2D TmP/GFRKRN23 UX023-CL304
42 BPI-Q3
KRN23 2.5
CONFIDENTIAL - 61 -
XLH KRN23
4.4.4.2.3 XLH XLH UX023-CL301
1
UX023-CL301 2.7.3 Table 3.3.2.2.1-1
KRN23 2 3 5KRN23 6.20±6.22 9.87±2.25 KRN23 2
2 66.7% 1 33.3% KRN23100.95±33.87 cm 123.53±9.98 cm KRN23 16.35±9.27 kg
30.07±8.61 kg KRN232.20±0.28 mg/dL 2.30±0.27 mg/dL KRN23
2 RGI-C
RGI-C 2.7.3 Table 3.3.2.2.2-1 KRN23 Week 40 RGI-C
+1.00±0.00 +0.78±0.69 RGI-CKRN23 +0.83±0.24 +1.00±0.00 +0.78±0.69 0.22±0.39 RGI-C
KRN23 0.17±0.24 0.22±0.39 Week 64 RGI-CKRN23 1.17±0.24 1.11±0.19 RGI-C
KRN23 1.33±0.00 1.17±0.24 1.11±0.19 0.67±0.33RGI-C KRN23 0.50±0.71 0.22±0.39
KRN23 KRN23
3 RSS RSS 2.7.3 Table 3.3.2.2.3-1 KRN23
RSS 4.25±3.18 Week 40 2.75±1.77 Week 642.25±1.77 Week 40 Week 64
1.50±1.41 2.00±1.41 RSS 2.50±0.50Week 40 2.33±1.61 Week 64 1.67±1.04 Week 40 Week 64
0.17±1.16 0.83±0.58 RSS KRN23 Week 40 Week 64 2.25±1.06
1.25±0.35 0.75±0.35 Week 40 Week 641.00±0.71 1.50±0.71 Week 40 Week 64
1.33±0.29 1.00±0.50 0.67±0.29 Week 40 Week 640.33±0.76 0.67±0.58
KRN23 2.5
CONFIDENTIAL - 62 -
RSS KRN23 Week 40 Week 64 2.00±2.121.50±1.41 1.50±1.41 Week 40 Week 64
0.50±0.71 0.50±0.71 Week 40 Week 641.17±0.76 1.33±1.16 1.00±0.87 Week 40 Week 64
0.17±0.76 0.17±0.58 RSS Week 64 KRN23
RSS
4 Z
5.3.5.1-3 Table 14.2.1.3.10.1 5.3.5.1-3 Table 14.2.1.3.4.1 Z KRN23 2.68±0.13 Week 40
2.88±0.54 Week 64 2.97±0.70 2.33±0.13 Week 402.17±0.07 Week 64 2.03±0.06 Week 40 Week 64
KRN23 0.21±0.41 0.29±0.56 0.16±0.12 0.29±0.08
Z KRN23 1 0.92Week 40 0.30 Week 64 0.46 1.08±0.40 Week 40 0.11±0.82 Week 64
0.42±0.48 Week 40 Week 64 KRN230.62 0.46 0.97±1.22 1.50±0.88
5
1,25(OH)2D TmP/GFR5.3.5.1-3 Table 14.2.3.1.1.4.1 5.3.5.1-3 Table 14.2.3.2.1.4.1 5.3.5.1-3 Table 14.2.3.3.1.4.1
KRN23 2.20±0.28 mg/dL2.30±0.27 mg/dL Week 40 KRN23 2.60±0.57 mg/dL
2.60±0.20 mg/dL Week 40 KRN230.40±0.28 mg/dL 0.30±0.10 mg/dL Week 40
Week 64 KRN23 2.65±0.21 mg/dL2.50±0.52 mg/dL Week 64 KRN23
0.45±0.07 mg/dL 0.20±0.27 mg/dL Week 64
1,25(OH)2D KRN2339.45±28.07 pg/mL 30.13±14.85 pg/mL Week 40 1,25(OH)2DKRN23 59.10±11.46 pg/mL 59.70±30.45 pg/mL Week 40
KRN23 19.65±39.53 pg/mL 29.57±30.35 pg/mLWeek 40 1,25(OH)2D Week 64
1,25(OH)2D KRN23 53.55±8.42 pg/mL 38.43±8.76 pg/mL Week 64KRN23 14.10±19.66 pg/mL 8.30±15.35 pg/mL
Week 64 1,25(OH)2D TmP/GFR KRN23 1.92 mg/dL
2.15±0.31 mg/dL Week 40 TmP/GFR KRN23 2.21±0.48 mg/dL
KRN23 2.5
CONFIDENTIAL - 63 -
2.21±0.52 mg/dL Week 40 KRN23 0.63 mg/dL0.06±0.21 mg/dL Week 64 TmP/GFR KRN23 2.50 mg/dL
2.02±0.53 mg/dL Week 64 KRN23 0.58 mg/dL0.13±0.37 mg/dL KRN23 Week 64 TmP/GFR
KRN23 TmP/GFR Week 64 1
4.4.4.2.4 UX023-CL301
KRN23 RGI-C
KRN23 RSSKRN23 KRN23
1,25(OH)2D TmP/GFR KRN23
XLH KRN23
4.5 2.7.3-4 4.2 XLH KRN23
XLH I/II KRN23-INT-001KRN23-INT-002 III UX023-CL303 UX023-CL304
XLH IIUX023-CL201 UX023-CL205 III UX023-CL301
III KRN23-003 FGF23 XLH
FGF23 TIO FGF23TIO FGF23
TIOXLH II
KRN23-002 KRN23 FGF23 XLH TIO
FGF23XLH
TIO KRN234.5.2
KRN23 2.5
CONFIDENTIAL - 64 -
4.5.1 XLH TIO
4.5.1.1 XLH
4.5.1.1.1 III KRN23-INT-001 0.05 mg/kg Q4W SC
0.05 0.1 0.3 0.6 mg/kg Q4W 4 KRN23-INT-002KRN23-INT-001 KRN23-INT-001 Day 84
SC 0.05 0.1 0.30.6 1.0 mg/kg Q4W 12 KRN23-INT-0021.0 mg/kg
KRN23-INT-001 KRN23-INT-002KRN23-INT-002 KRN23 ±
0.54±0.20 mg/kg 2 3 0.77±0.27 mg/kg0.73±0.28 mg/kg 4 12 0.81 0.88 mg/kg 4
12 60 74% 1.0 mg/kg
5.3.5.2-1 Section 12.4.2.1, 5.3.5.2-2 Section 12.4.2.1
KRN23-INT-001 KRN23-INT-002 UX023-CL2035.3.5.2-3 KRN23-INT-001 KRN23-INT-0020.3 0.6 1.0 mg/kg SC0.3 0.6 1.0 mg/kg Q4W
5.3.5.2-3 KRN23-INT-001 KRN23-INT-002 UX023-CL203
UX023-CL203 1 Week 24.9 mg/dL Week 4 KRN23
KRN23-INT-001 KNR23-INT-002
28 254 60 74% 1.0 mg/kg
XLH1.0 mg/kg Q4W
4.5.1.1.2 III 4.5.1.1.1 XLH 1.0 mg/kg
Q4W III UX023-CL303 UX023-CL3041.0 mg/kg Q4W 1.0 mg/kg KRN23
10 mg 90 mg
KRN23 2.5
CONFIDENTIAL - 65 -
5.0 mg/dL 4.5 mg/dL5.0 mg/dL 2 4.5 mg/dL
UX023-CL303 Week 24
KRN23 4.4.1.1.1 1,25(OH)2D TmP/GFRKRN23 KRN23
KRN234.4.1.2 PRO
KRN23 4.4.1.3KRN23 9 13.2% 5
5 4 10.2 mg/kg 5.3.5.1-1
Table 12.7.2.1.1 UX023-CL304 OV/BV
KRN234.4.1.2 14 13 92.9%
Week 244.4.1.1.1 1,25(OH)2D TmP/GFR
KRN23
4.4.1.2 PRO BPI4.4.1.3 KRN23
2.7.4-3.2.1.1
XLH KRN23 1.0 mg/kg 10 mg 90 mg Q4WKRN23
4.5.1.2 XLH UX023-CL201 XLH
Q4W Q2W Q4W 0.2 0.4 0.6 mg/kgQ2W 0.1 0.2 0.3 mg/kg 4
2 Q2W 0.3 mg/kg Q4W 0.4 mg/kg2.0 mg/kg Week 18 15 mg
15 mg 15 mg 10 mg 90 mg KRN23 Q4W Q2W
2.7.3-3 3 RGI-C RSSQ4W Q2W
2.7.4-2.1.1.2 KRN23 Q2WWeek 24 0.8 mg/kg
Week 40 64 1.0 mg/kg 2.7.3 Figure 4.1.2-1 Q2W
KRN23 2.5
CONFIDENTIAL - 66 -
Q4W 2.0 mg/kg 13.2 6.1 mg/dL 5.2 mg/dL
5.3.5.2-5 Section 12.5.3
XLH KRN23 0.8 mg/kg 10 mg
Q2W III UX023-CL3010.8 mg/kg Q2W
1.2 mg/kg 90 mg
RGI-C Week 40 KRN23
4.4.2.1.1 RSSWeek 40 Week 64 KRN23
4.4.2.1.2 KRN23Week 64
3.2 mg/dL 4.4.2.2.1 ZWeek 40 KRN23
KRN23Week 64 KRN23
4.4.2.1.3 6MWT KRN234.4.2.3.2
III KRN23-003 UX023-CL301 0.8 mg/kg Q2W1.2 mg/kg
0.2 mg/kg0.2 mg/kg
Week 4
4.4.2.2.1 RGI-CRSS Week 40 4.4.2.1.1
4.4.2.1.2 6MWT KRN234.4.2.3.2 Z4.4.2.1.3
UX023-CL301 KRN23-003 KRN232.7.4-3.2.2.1
XLH KRN23 0.8 mg/kg 10 mg Q2W
KRN23
KRN23 2.5
CONFIDENTIAL - 67 -
4.5.1.3 TIO KRN23-002 0.3 mg/kg Q4W 2
2.0 mg/kg • 2.5 mg/dL 0.2 mg/kg • 2.5 mg/dL 4.0 mg/dL • 4.0 mg/dL 4.5 mg/dL 0.2 mg/kg • 4.5 mg/dL 0.3 mg/kg 0.6 mg/kg
KRN23 Week 2448 72 88 4.4.3.1.1
4.4.3.2 PRO 4.4.3.3UX023T-CL201 5.3.5.2-9
1 Week 6 4.5 mg/dL
4.6 mg/dL Week 8 Week 12KRN23 0.1 mg/kg 5.3.5.2-8 Section 12.3.2.3
2.7.4-3.2.32.7 mg/dL 2.5 mg/dL
Week 36
Week 64 1.0 mg/kg XLHXLH 0.1 2.0 mg/kg
TIO 0.3 mg/kg
0.3 mg/kg
TIO
TIOKRN23-002
1.0 mg/kgTIO
XLHKRN23-002 XLH
I/II KRN23-INT-002 III UX023-CL303 UX023-CL304TIO KRN23-002
0.3 mg/kg KRN23-INT-0020.6 mg/kg Week 48 19 6
1.0 mg/kg 1.0 mg/kgUX023-CL303 UX023-CL304
UX023-CL303 134 11 8.2% 9
KRN23 2.5
CONFIDENTIAL - 68 -
2 UX023-CL3040.3 mg/kg 0.5 mg/kg
0.6 mg/kg 30.6 mg/kg TIO/ENS
UX023T-CL201 0.4 mg/kgTIO 0.5 mg/kg
TIO KRN23 0.5 mg/kg Q4W
KRN23-002 2.0 mg/kg 0.5 mg/kgTIO 2.0 mg/kg
4.5.2 XLH TIO FGF23 FGF23 XLH TIO
FGF23 , 2015; Huang et al, 2013; Goldsweig and Carpenter, 2015 XLH TIO FGF23
KRN23XLH TIO FGF23
XLH D TIOFGF23
FGF23TIO XLH
XLH TIOXLH XLH PHEX
UX023-CL303 FAM20C ENPP1XLH
KRN23 KRN23 XLH TIO XLH TIO
XLH XLH UX023-CL303 KRN23 9 24
KRN232.7.4-3.2.1.1 XLH
4.5.1.2, 5.3.5.2-6 Section 12.5.3, 2.7.4-3.2.2.1KRN23
XLH TIO FGF23XLH
KRN23 2.5
CONFIDENTIAL - 69 -
4.5.3 13 17 XLH XLH KRN23 1 12 XLH 18
XLH 13 17 XLH1 12 XLH 18 XLH
KRN23
1317 1 12 XLH
18 XLH1 12 XLH 18 XLH
XLH XLH 0.8 mg/kg Q2W SC 1.0 mg/kg Q4W SC XLH
0.8 mg/kg Q2W SC 1.0 mg/kg Q4W SC3.34 3.30 mg/dL
3.2 mg/dL3.18 2.93 mg/dL 0.8 mg/kg Q2W
SC 1.0 mg/kg Q4W SC5.0 mg/dL 2.9% 3.3% 3.5
XLH 0.8 mg/kg Q2W SC 1.0 mg/kg Q4W SC
XLH 0.8 mg/kg Q2W SC 1.0 mg/kg Q4W SC
XLH KRN23 136 II UX023-CL201
3 III UX023-CL301 2 III KRN23-0031 6 12 13
5.3.5.2-5 Listing 16.2.6.11, 5.3.5.1-3 Listing 16.2.6.9, 5.3.5.2-7 Listing 14.3.4-1 6 12
13 2.7.4-5.1.1 XLH
17 15 1.1.1.3KRN23 13 17
KRN23
KRN23 2.5
CONFIDENTIAL - 70 -
FGF23
4 1 1 mg/kg1 1 mg/kg 90 mg
2 1 0.8 mg/kg
1 2 mg/kg 90 mg17 15
4
1 0.5 mg/kg1 2 mg/kg
4.6 TIO KRN23
TIO KRN23-002 0.3 mg/kg Q4W2.0 mg/kg
KRN231
2.7.3-4.1.3 TIO KRN23-002 KRN23 0.3 mg/kg Q4W
2.0 mg/kg KRN23
FGF23 4 1 1 mg/kg
1 90 mg 2 1 0.8 mg/kg
1 2 mg/kg 190 mg
4 1 0.3 mg/kg1 2 mg/kg
4.7 2.7.3-5
4.7.1 XLH XLH KRN23 KRN23-INT-001 KRN23-INT-002
UX023-CL203
KRN23 2.5
CONFIDENTIAL - 71 -
KRN23-INT-001 KRN23 27 0.05 mg/kgQ4W 4 0.05 0.1 0.3 0.6 mg/kg 1 KRN23-INT-001
KRN23-INT-002 22KRN23-INT-001 Day 84 0.05 0.1 0.30.6 1.0 mg/kg Q4W 12
2.7.3-3 3 • KRN23-INT-001 KRN23 Q4W 4 SC
TmP/GFR 1,25(OH)2D • KRN23-INT-002 2.5
4.5 mg/dL 1,25(OH)2D TmP/GFR KRN23
UX023-CL203 KRN23-INT-001 KRN23-INT-002 1KRN23 20 KRN23-INT-001
KRN23-INT-002 0.3 0.6 1.0 mg/kgQ4W 2016 8 18
2.7.3-2.1.3.3 • Week 2 Week 48 Week 36
2.46 mg/dL • BPI-SF WOMAC SF-36v2
Week 48 • 6MWT Week 48
XLH KRN23 PRO
4.7.2 XLH XLH KRN23 UX023-CL201 UX023-CL301
UX023-CL201 Q2W Q4W 26 52 KRN23
Q4W 0.2 0.4 0.6 mg/kg Q2W 0.1 0.2 0.3 mg/kgQ2W 0.3 mg/kg Q4W 0.4 mg/kg
2.0 mg/kg 90 mg Week 642016 12 1
2.7.3-3 3 • Q2W Week 24
3.2 mg/dL Q4W
• Q2W Q4W TmP/GFR Q2WWeek 4 2.6 mg/dL Q4W
KRN23 2.5
CONFIDENTIAL - 72 -
• Q2W Q4W 1,25(OH)2D Q2WWeek 4 Q4W
• Q2W Q4W Week 40 RSS RGI-C
Week 64 • Q2W Q4W Z
Week 64 • Q2W Q4W 6MWT Week 64
UX023-CL301 KRN23 29 KRN23 Q2W 0.8 mg/kg
1.2 mg/kg 90 mgWeek 64 Week 64 2018
7 30 • Week 64
3.2 mg/dL • TmP/GFR Week 64
• 1,25(OH)2D Week 64
• Week 40 RGI-C
Week 64 RSS Week 40Week 64
• Z Week 64 • 6MWT Week 40 Week 64
XLH KRN23 Q2W Q4W
4.7.3 TIO TIO KRN23 KRN23-002 KRN23-002 13 0.3 mg/kg 0.1 2.0 mg/kg
Q4W 144 Week 882018 5 3
4.4.3 • Week 2 2.28±0.95 mg/dL
Week 20 0.71 mg/kg Week 881,25(OH)2D TmP/GFR
Week 24 Week 72
•
KRN23 2.5
CONFIDENTIAL - 73 -
• 99mTc X • 6MWT Week 24 Week 48 • BPI SF-36 Week 24 48 72
TIO KRN23 Q4WPRO
KRN23 2.5
CONFIDENTIAL - 74 -
5
5.1
5.1.1 2.7.4-1.1.1 KRN23 Ultragenyx XLH 3XLH 31 Kyowa Hakko Kirin Pharma XLH 2
XLH 11
XLH Kyowa Hakko Kirin Pharma I/II KRN23-INT-001KRN23-INT-001 KRN23-INT-002 Ultragenyx
III UX023-CL303 XLHKRN23 III UX023-CL304
4 Ultragenyx IIUX023-CL203 5 XLH
KRN23 XLH Ultragenyx
5 12 XLH IIUX023-CL201 1 4 XLH II UX023-CL205
1 12 XLH IIIUX023-CL301 1 12XLH III KRN23-003 44 XLH KRN23
TIOTIO ENS II
KRN23-002 Ultragenyx TIO ENSKRN23 II UX023T-CL201
2 TIO KRN23
UX023-CL303 UX023-CL304 XLHUX023-CL301 KRN23-003
KRN23 XLH KRN23-002KRN23 TIO XLH
UX023-CL303 UX023-CL304 KRN23XLH UX023-CL301
KRN23 KRN23-003KRN23 FGF23
KRN23 KRN23-INT-001KRN23-INT-002 9
KRN23 2.5
CONFIDENTIAL - 75 -
5.1.2 2.7.4-1.1.2
1 1
2
12KRN23 UX023-CL303 UX023-CL304 UX023-CL201
KRN23-003 KRN23-002
UX023-CL301
UX023-CL301
KRN23-003
KRN23-002
3 XLH XLH TIO
4 UX023-CL303 UX023-CL304 INT-001/002
• >50 50 •
KRN23 2.5
CONFIDENTIAL - 76 -
UX023-CL201 UX023-CL205 UX023-CL301
• UX023-CL303 UX023-CL304 UX023-CL301
• KRN23-002 KRN23-003
•
KRN23-INT-001 KRN23-INT-001KRN23-INT-002
5 KRN23
KRN23 KRN23
UX023-CL303 UX023-CL304 UX023-CL301 KRN23-003 KRN23-002
HLTPT SMQ PT
PTTable 5.1-1
PT PTPT
HLT PT PT
Table 5.1-1 PT
MedDRA PT
KRN23 2.5
CONFIDENTIAL - 77 -
Table 5.1-1 PT (Continued)
MedDRA PT
5.2 2.6.2-4 2.6.6 KRN23 Table 5.2-1
Table 5.2-1
14
1 2
14 1 2
6
40 1 2
13
40
In vitro
14 2 Hypa b a Hypophosphatemia b KRN23 FGF23
14 1 40 2 0.03 30 mg/kg
144.2.3.2-3 KRN23
KRN23 2.5
CONFIDENTIAL - 78 -
KRN2340 4.2.3.2-4
30 mg/kg 13 30 mg/kg1 39 ST 30 mg/kg
30 mg/kg>8 mg/dL
KRN2340
4.2.3.2-5 KRN23 2 1 0.03 0.3 3 mg/kg3 mg/kg KRN23
KRN23 3 mg/kg
1 3 mg/kgKRN23
1,25(OH)2D 3 mg/kg 8 mg/dL
Eckermann-Ross, 2008 KRN23
14 1 141 40 1 4
1,25(OH)2D14
3 mg/kg 140 30 mg/kg 1
13 15 mg/dL KRN23
KRN23 DNA
KRN23FGF23
KRN23 2.5
CONFIDENTIAL - 79 -
4040 KRN23
KRN23
ePPND KRN23
KRN23 NOAEL 0.3 mg/kg 3 30 mg/kgKRN23 KRN23
KRN23
40
KRN23 FITC-KRN23FITC-KRN23 0.5 2.5 g/mL
KRN23 XLH Hyp
KRN23 FGF23WT C57BL/6J Hyp
B6.Cg-PhexHyp/J FGF23 KRN23 1 22 Hyp IP FGF23
WT Hyp
FGF23 WT Hyp FGF23
5.3
5.3.1
5.3.1.1 XLH UX023-CL303 UX023-CL304 Table 5.3.1.1-1
UX023-CL304 8XLH
Table 5.3.1.1-2
KRN23 2.5
CONFIDENTIAL - 80 -
Table 5.3.1.1-1 UX023-CL303 UX023-CL304
UX023-CL303 UX023-CL304 18 65 XLH
XLH XLH1
X PHEXiFGF23 30 pg/mL
8 XLH 2.5 mg/dL 0.81 mmol/L
TmP/GFR 2.5 mg/dL BPI-Q3 4 XLH
eGFR 60 mL/min eGFR
45 mL/min 60 mL/min 21
60 mg/ - 8
Table 5.3.1.1-2 UX023-CL303 UX023-CL304
UX023-CL303 UX023-CL304 14 D
2 D
14
2
7
2 6 2
2 11 10.8 mg/dL 2.7 mmol/L
iPTH 2.5 60 PTH
- PT/PTT
-
24
-
6 -
90 KRN23 KRN23
-
KRN23 2.5
CONFIDENTIAL - 81 -
5.3.1.2 XLH UX023-CL301 KRN23-003 Table 5.3.1.2-1 Table
5.3.1.2-2
12UX023-CL301 Tanner 4UX023-CL301
RSS 2.0
KRN23
5
Table 5.3.1.2-1 UX023-CL301 KRN23-003
UX023-CL301 KRN23-003 1 12 XLH
-
- KRN23
RSS 2.0 X
-
PHEX X
- FGF23 30 pg/mL
-
X
X O
4 3.0 mg/dL 0.97 mmol/L
4
4 25- D25(OH)D 16 ng/mL
7D 12
3 6 3
-
KRN23 2.5
CONFIDENTIAL - 82 -
Table 5.3.1.2-2 UX023-CL301 KRN23-003
UX023-CL301 KRN23-003
Tanner 4 -
50 7 Maalox® Mylanta®
Lupron® Viadur® Eligard® TRELSTAR® Zoladex®
12
Grade 4 40
8
8
iPTH 2.5
iPTH 163 pg/mL
2 PTH
60 PTH
90
5.3.1.3 TIO KRN23-002 TIO ENS
• 18 • FGF23 TIO ENS
• 2.5 mg/dL • FGF23 100 pg/mL • TmP/GFR 2.5 mg/dL • eGFR 60 mL/min/1.73 m2
eGFR 30 mL/min/1.73 m2 60 mL/min/1.73 m2
• Ca 10.8 mg/dL
• 14 D TIO/ENS
• 60 PTH
• 90 KRN23
KRN23 2.5
CONFIDENTIAL - 83 -
5.3.2 2.7.4-1.2.2
5.3.2.1 XLH UX023-CL303 KRN23 ±
KRN23 Total KRN23 44.20±15.07KRN23 24.10±0.59 2.7.4 Table 1.2.2.1.1-1 Total
KRN23 KRN23 24 48 44.8% 4847.0% KRN23 80.9%
KRN23 24 4 Total KRN231.06±0.14 mg/kg KRN23 0.97±0.09 mg/kg Total KRN23 11.49±3.75 mg/kg KRN23 5.87±0.52 mg/kg
UX023-CL304 KRN23 59.21±9.2692.9% 48 KRN23 4
1.06±0.03 mg/kg 15.57±1.95 mg/kg
5.3.2.2 XLH UX023-CL301 KRN23 2
0.80 mg/kg Week 64 0.80 0.88 mg/kg 5.3.5.1-3 Table 14.1.3.2.1
KRN23-003 KRN23 40.16±0.264 1.76±0.17 mg/kg 17.63±1.75 mg/kg
5.3.5.2-7 Table 14.3.7-1
5.3.2.3 TIO KRN23-002 KRN23 81.90±21.06
4 0.86±0.47 mg/kg 17.45±11.27 mg/kg5.3.5.2-8 Table 14.3.7-1
5.3.3 2.7.4-1.3
5.3.3.1 XLH UX023-CL303 Total KRN23 134 87 64.9% 40.0±12.2
152.42±10.67 cm 1.98±0.31 mg/dLKRN23 64.7% 65.2% KRN23 41.3±11.6
38.6±12.8 KRN23 152.15±9.49 cm 152.69±11.84 cmKRN23 2.03±0.30 mg/dL 1.92±0.32 mg/dL
2.7.4 Table 1.3.1.1-1 UX023-CL303 108 80.6%
21 15.7% 3 2.2% 21.5% 5.3.5.1-2 Table 14.1.2.1
UX023-CL303 PHEX 134 12794.8% 95 70.9%
15 11.2% 17 12.7% PHEX
KRN23 2.5
CONFIDENTIAL - 84 -
KRN23 62 91.2% 65 98.5%KRN23
KRN23 66.2% 75.8% KRN23 11.8%10.6% KRN23 13.2% 12.1%
5.3.5.1-2 Table 14.1.2.2.5.1 UX023-CL304 14 8 57.1% 40.1±8.7 150.42±8.98 cm
2.24±0.40 mg/dL 9 64.3%4 28.6% 1 7.1% 5.3.5.2-4 Table
14.1.2.1 PHEX9 64.3% 5 35.7% 5.3.5.2-4 Table 14.1.2.1
5.3.3.2 XLH UX023-CL301 61 34 55.7% 2.7.4 Table 1.3.2.1-1
6.10±3.314 5 26 KRN23 14 125.3.5.1-3 Table 14.1.2.1.3.1 104.67±19.806 cm
5.80±9.645 Z2.17±1.018 Z 2.18
Z 2 2.36±0.256 mg/dL
KRN23 55.2% 56.3% KRN23 5.83±3.4266.34±3.244 KRN23 5.87±9.976
5.74±9.505 Z KRN23 2.32±1.167 2.05±0.868 KRN232.42±0.244 mg/dL 2.30±0.257 mg/dL
UX023-CL301 50 82.0%8 13.1% 3 4.9% 5.3.5.1-3 Table 14.1.2.1.1.1
PHEX KRN23 27 100% 3196.9% KRN23 93.1% 87.5%
KRN23 6.9% 3.1% KRN230% 6.3%
KRN23-003 15 13 86.7% 2.7.4 Table 1.3.2.2-16.7±3.2 5 4 26.7% 113.79±20.16 cm
KRN23-003 13 86.7% PHEX
5.3.3.3 TIO KRN23-002 13 TIO 2.7.4 Table 1.3.3.1-1
7 53.8% 6 46.2% 9 69.2%4 30.8% TIO 12
92.3% D 13 100% 60.5±10.8151.45±10.43 cm 1.62±0.49 mg/dL
KRN23 2.5
CONFIDENTIAL - 85 -
5.4 XLH
UX023-CL303 KRN23KRN23 Total KRN23 UX023-CL304
KRN23 INT-001/002 KRN23 KRN23Overall KRN23 6 UX023-CL303 KRN23
Total KRN23KRN23
XLH UX023-CL301KRN23-003
UX023-CL201 Q4W Q2W KRN23Total KRN23 UX023-CL205 KRN23 Q2W
UX023-CL201 UX023-CL205 Q2W Overall KRN23 Q2WKRN23 Overall KRN23 6 UX023-CL301
KRN23 D2
TIO KRN23-002KRN23 1
XLH10% XLH
20%
5.4.1 2.7.4-2.1.1
5.4.1.1 XLH
1 UX023-CL303 KRN23 68 64 94.1%
66 61 92.4% 2.7.4 Table 2.1.1.1.1.1-1 Total KRN23 134 131 97.8%
KRN23 10 14.7%9 13.2%
8 11.8% 7 10.3%16 24.2% 10 15.2%
KRN23
KRN23 10%KRN23 8.8% 24.2% KRN23
10% Total KRN23 32 23.9%
30 22.4% 27 20.1% 22
KRN23 2.5
CONFIDENTIAL - 86 -
16.4% 18 13.4%15 11.2%
UX023-CL304 KRN23 14 14 100%7 50.0%
5 35.7% 4 28.6%3 21.4%
2 UX023-CL303 KRN23 68 30 44.1%
66 26 39.4% 2.7.4 Table 2.1.1.1.1.1-2 Total KRN23 134 74 55.2%
KRN238 11.8% 3 4.4%
2 2.9% 1 1.5%4 6.1%
2 3.0%1 1.5%
KRN23KRN23 10%
Total KRN23 14 10.4%11 8.2% 8 6.0%
6 4.5% 4 3.0%2 1.5%
UX023-CL304 KRN23 14 10 71.4%2 14.3%
17.1%
5.4.1.2 XLH
1 UX023-CL301 Week 0 64 KRN23 29
32 27 84.4% 2.7.4 Table 2.1.1.1.2.1-1 KRN2316 55.2% 15 51.7%
13 44.8% 12 41.4%11 37.9% 10 34.5% 9 31.0%
8 27.6% 7 24.1%D 6 20.7% 14 43.8%
10 31.3% 8 25.0%
KRN23 2.5
CONFIDENTIAL - 87 -
KRN23-003 15 14 93.3% 2.7.4 Table 2.1.1.1.2.2-13 20.0%
2 13.3%
2 UX023-CL301 Week 0 64 KRN23 29 1758.6% 32 7 21.9% 2.7.4 Table 2.1.1.1.2.1-2
KRN23 8 27.6%7 24.1% 6 20.7%
4 13.8% 3 10.3%4 12.5%
1 3.1% KRN23-003 15 2 13.3%
25- 1 6.7%Grade 1 3
25- Day 113Grade 1
5.3.5.2-7 Listing 16.2.7-1.2
5.4.1.3 TIO KRN23-002 KRN23 13 12 92.3%
KRN23 8 61.5%3 23.1%
KRN23 5 38.5%
5.4.2 2.7.4-2.1.2 XLH XLH
TIO UX023T-CL201 1 5.9%
58 TIO Day 3575.3.5.2-9 Listing 16.2.7.3
5.4.3 2.7.4-2.1.3
5.4.3.1 XLH UX023-CL303 KRN23 68 2
2.9% 66 2 3.0%2.7.4 Table 2.1.3.1.1-1 Total KRN23
15 11.2% KRN23 1 1.5%
1 1.5%
KRN23 2.5
CONFIDENTIAL - 88 -
Total KRN23
1 0.7%5.3.5.3-1 Table 535314-2.10.2
UX023-CL304 KRN23 2 14.3%1 7.1%
5.4.3.2 XLH UX023-CL301 Week 0 64 KRN23
29 3 10.3% 32 3 9.4% KRN231 3.4%
1 3.1%5.3.5.3-1 Table 535314-1.29.2, Table 535314-1.30.2
KRN23 KRN23 15.3.5.1-3 Table 14.3.1.6.1
KRN23-003 1 6.7%5.3.5.2-7 Table 14.3.2-2.2 Day 109 Grade 3
Day 142 5.3.5.2-7 Listing 16.2.7-1.25.3.5.2-7 Table 14.3.2-2.2
5.4.3.3 TIO KRN23-002 13 3 23.1%
2 15.4% 1 7.7%5.3.5.2-8 Table 14.3.2-2.2
5.4.4 2.7.4-2.1.4
5.4.4.1 XLH UX023-CL303 UX023-CL304
5.4.4.2 XLH UX023-CL301
KRN23-003
5.4.4.3 TIO KRN23-002
5.4.5 2.7.4-2.1.1.2.3
1 UX023-CL303 19 66 UX023-CL304
25 52 UX023-CL303 UX023-CL304
KRN23 2.5
CONFIDENTIAL - 89 -
50 50 UX023-CL303 50106 50 28 UX023-CL304 50 12
50 2 UX023-CL301 0.8 12.8KRN23-003 1 12
UX023-CL303 KRN23 68 64 94.1%Total KRN23 134 131 97.8%
KRN23 2 2.9% Total KRN2315 11.2% KRN23 30 44.1%
Total KRN23 74 55.2%
KRN23KRN23 10%
Total KRN23
UX023-CL303 Total KRN23 50 50100% 50 52.8%
50 64.3% 50 UX023-CL303Total KRN23 50 50 10%
50 50 10%50 16.0% 50 46.4% 50
7.5% 50 25.0% 50 8.5% 50 21.4%50 3.8% 50 25.0%
1 Grade 1 Grade 2UX023-CL303 Total KRN23 50 50 10%
50 5010% 50 3.8% 50 25.0%
50 7.5% 50 21.4%Grade 1 Grade 2 5050
UX023-CL304 14 14 100% 10 71.4%2 14.3%
UX023-CL301 Week 0 64 KRN23 29
KRN23 17 58.6% KRN233 10.3%
KRN231 Grade
3Grade 1 Grade 2 1 Grade 3
Grade 3 KRN2322 13 59.1%
KRN23 2.5
CONFIDENTIAL - 90 -
KRN23 22 KRN231 3.4%
KRN23 KRN23-003 15 14 93.3% 1
6.7%2 13.3%
1 Grade 3Grade 1 Grade 2 Grade 3
UX023-CL301 KRN23-003
XLH 12 KRN23
UX023-CL301 2 KRN23-003 1 UX023-CL2013
12 KRN23UX023-CL301 1 Grade 3
UX023-CL301 1 Grade 31
KRN23
2 UX023-CL303 UX023-CL304 UX023-CL301
UX023-CL303 47 87 UX023-CL304 68 UX023-CL301 13 16
UX023-CL303 Total KRN23100%
10%10% 14.9% 28.7%
Grade 1 2 5.3.5.1-2 Listing 16.2.7.1.1 50%
10%UX023-CL304
100% 70%
UX023-CL301
20%61.5% 25.0% 46.2% 12.5%
KRN23 2.5
CONFIDENTIAL - 91 -
38.5% 12.5%20% 30.8% 56.3%
60%20%
KRN23
3 UX023-CL303
UX023-CL304 UX023-CL301 KRN23-002 11 4 59 KRN23-003 15 UX023-CL303
UX023-CL304 UX023-CL301
UX023-CL303 Total KRN23 UX023-CL304 KRN23 UX023-CL301KRN23
KRN23-003
KRN23-002
KRN23
4 KRN23-003 Week 16
KRN23-002 Week 48
4 21,25(OH)2D total FGF23
TmP/GFR 5.3.5.2-8 Figure 14.2.1-6intact PTH 25(OH)D
5.3.5.2-8 Figure 14.2.1-63 1
5.3.5.2-8 Listing 16.2.7-3 KRN23
KRN23 2.5
CONFIDENTIAL - 92 -
5.4.6
1 KRN23 UX023-CL303 Total KRN23 UX023-CL304 KRN23
20.1% 35.7% 19.4% 35.7%UX023-CL301 Week 0 64 KRN23-003 KRN23
51.7% 6.7% 44.8% 6.7%KRN23-002 KRN23
15.4% 7.7% 2.7.4-2.1.5.2.1
UX023-CL303 KRN23 811.8% 8 12.1% KRN23 7 10.3%
6 9.1%Grade 1
Grade 2KRN23
2 UX023-CL303 Total KRN23 UX023-CL304 KRN23
11.2% 57.1% 3.7% 35.7% UX023-CL301Week 0 64 KRN23-003 KRN23
37.9% 13.3% 17.2% 0% KRN23-00223.1% 15.4% 2.7.4-2.1.5.2.2
UX023-CL303 KRN23 4 5.9%4 6.1%
Grade 1 Grade 2 KRN23
IgGNelson et al, 2010 KRN23
3 KRN23
UX023-CL303 Total KRN23 6.0%UX023-CL304 UX023-CL301 Week 0 64 KRN23-003
KRN23-002 KRN23
KRN23 2.5
CONFIDENTIAL - 93 -
2.7.4-2.1.5.2.3 UX023-CL303 Grade 1Grade 2
UX023-CL303 UX023-CL3044.5 mg/dL 1.45 mmol/L 6.5 mg/dL
2.1 mmol/L KRN232.7.4-3.2.1.1 UX023-CL301 KRN23 2 4.5 mg/dL1.45 mmol/L 6.5 mg/dL
2.7.4-3.2.2.1 KRN23-003 6.5 mg/dL3 4.5 mg/dL 1.45 mmol/L KRN23
KRN23-002 14.5 mg/dL 1.45 mmol/L
6.5 mg/dL 2.1 mmol/L KRN232.7.4-3.2.3
4 8 mg/dL 2.5 mmol/L
D 1Goodyer et al, 1987; Verge CF et al, 1991;
Kooh et al, 1994; Makitie et al, 2003; Carpenter et al, 2011 UX023-CL303 Total KRN23 6.7% 5.2%
UX023-CL304 UX023-CL301 Week 0 64 KRN23-003KRN23-002 KRN23
2.7.4-2.1.5.2.4 KRN23-INT-002 1
UX023-CL303 UX023-CL304 UX023-CL301
UX023-CL303 88.8% 05.3.5.1-2 Table 14.3.6.4.2 79.1%
Week 24 Week 48 0 Week 48 Overall KRN23 6 4.5%1 0 Week 48 Overall
KRN23 4 3.0% 0 1 Week 24 Week 482
UX023-CL304 0Week 24 Week 48 0 5.3.5.2-4 Table
14.3.6.4.25.3.5.2-4 Table 14.3.6.4.1
UX023-CL304 1 Week 4877.1% Week 24 77.4% Week 48 65.7%
KRN23 2.5
CONFIDENTIAL - 94 -
UX023-CL301
11
5 UX023-CL303 UX023-CL30411.2% 7.1% 10.4% 7.1% UX023-CL301
Week 0 64 KRN23-003 KRN23-002 KRN232.7.4-2.1.5.2.5
KRN23-INT-002 1 Grade 3KRN23 5
6 XLH
UX023-CL303 KRN23 11.8% 6.1%KRN23
UX023-CL303 UX023-CL304Grade 1 Grade 2
KRN23
6 KRN23 UX023-CL303 Total KRN23 5.2%
2.2% UX023-CL304 UX023-CL301 KRN23-003 KRN23-002KRN23
2.7.4-2.1.5.2.6 UX023-CL303 KRN23
5.9% 1.5%Grade 1
intact PTH XLH XLHTIO
KRN23 2.5
CONFIDENTIAL - 95 -
KRN23 intact PTH
KRN23
5.5
UX023-CL303 UX023-CL304UX023-CL301 KRN23-003 KRN23-002
5.5.1 XLH 2.7.4-2.1.1.2.2.1 UX023-CL303 KRN23 Week 011 54 Week 12 23 10 Week 24 0
Week 0 11 53 Week 12 23 8 Week 24 0Total KRN23 Week 0 11
105 Week 12 23 15 Week 24 35 9 Week 36 2KRN23 Total KRN23 Week 0 11
UX023-CL304 KRN23 Week 0 11 12 Week 1223 0 Week 24 35 2 Week 36 0 UX023-CL304
Week 0 11 UX023-CL303 KRN23 Week 0 1125 Week 12 23 3 Week 24 2 Week 0
11 16 Week 12 23 7 Week 24 3Total KRN23 Week 0 11 45
Week 12 23 11 Week 24 35 9 Week 36 9KRN23 Total KRN23 Week 0 11
UX023-CL304 KRN23 Week 0 11 4 Week 1223 1 Week 24 35 3 Week 36 2
5.5.2 XLH 2.7.4-2.1.1.2.2.2 UX023-CL301 Week 0 64 KRN23
Week 0 11 27 Week 12 23 1 Week 24 35 0 Week 36 1Week 0 11 16 Week 12 23 6 Week 24 35 1 Week 36 4
UX023-CL301 Week 0 11 UX023-CL301 KRN23 Week 0 11 12
Week 12 23 4 Week 24 35 1 Week 36 0 Week 0 11 1Week 12 23 3 Week 24 35 0 Week 36 3 UX023-CL301KRN23 Week 0 11
KRN23 2.5
CONFIDENTIAL - 96 -
KRN23-003 Week 0 11 8 Week 12 23 5Week 24 35 1 Week 36 0 KRN23-003
Week 0 11 Week 0 11 1 Week 12 23 1 Week 24 35 0
Week 36 0
5.5.3 TIO 2.7.4-2.1.1.2.2.3 KRN23-002 Week 0 11 8 Week 12 23 1
Week 24 35 2 Week 36 1 KRN23-002 Week 011 KRN23-002 Week 0 11 3 Week 12 23 0
Week 24 35 1 Week 36 1
5.5.4 KRN23 ±
XLH UX023-CL303UX023-CL304 44.20±15.07 72.14 59.21±9.26
83.86 2.7.4 Table 1.2.2.1.1-1 XLH UX023-CL301KRN23 64 2.7.4-1.2.2.1 TIO
KRN23-002 81.90±21.06 88.3 5.3.5.2-8 Table 14.3.7-1 KRN23
Week 0 11
5.6 5.1.2 5 KRN23
XLH
5.7
5.7.1 2.7.4-5.5 KRN23
5.7.2 2.7.4-5.6
5.7.3 2.7.4-5.7 KRN23-INT-001 KRN23-INT-002 UX023-CL203
KRN23-INT-002 KRN23KRN23-INT-002 UX023-CL203 1.5 3.5
KRN23 2.5
CONFIDENTIAL - 97 -
KRN23
KRN23 2.5
CONFIDENTIAL - 98 -
6
6.1
6.1.1 FGF23 FGF23
FGF232005 2009 5
311 Endo et al, 2015 FGF23FGF23
et al, 2017 FGF23 TmP/GFR1,25(OH)2D
Huang et al, 2013; Goldsweig and Carpenter, 2015; , 2015
6.1.2 FGF23 FGF23 TIO
TIO
D and , 2016D
QOL
6.2 TIO FGF23
FGF23 Huang et al, 2013; Goldsweig and Carpenter, 2015; , 2015; and , 2016
XLH FGF23FGF23 TIO
TIOFGF23 TIO
6.2.1 FGF23
1 UX023-CL303 Week 24 Week 2
6 10 14 18 22 2.5 mg/dLKRN23 94.1% 95%CI: 85.8, 97.7% 7.6% 95%CI: 3.3, 16.5%
KRN23 2.5
CONFIDENTIAL - 99 -
p<0.0001 Week 48 12 16 20 24 2.5 mg/dL
KRN23 67.6% 95%CI: 55.8, 77.6% 6.1% 95%CI: 2.4, 14.6%Week 24
TmP/GFR 1,25(OH)2DKRN23
TmP/GFR 1,25(OH)2DFGF23
KRN23 TmP/GFR1,25(OH)2D XLH
KRN23
2 UX023-CL304 XLH OV/BV O.Th
OS/BS MLt KRN23 48UX023-CL304 5
48 KRN23 4CTx P1NP
XLH UX023-CL303 X24 KRN23
43.1% 7.7%
3 QOL UX023-CL303 WOMAC KRN23
KRN23: 8.31 p=0.0106 0.0167 WOMAC BPI-Q3
6MWTKRN23
KRN23 ± 19.93±7.94 m KRN23 QOL
6.2.2 FGF23
1 UX023-CL301 KRN23
3.2 mg/dLD
TmP/GFR
KRN23 2.5
CONFIDENTIAL - 100 -
1,25(OH)2D KRN23KRN23 KRN23
TmP/GFR 1,25(OH)2D XLH
KRN23
2 UX023-CL301 KRN23 RGI-C
Week 40KRN23 1.14 95%CI 0.83, 1.45 p<0.0001
RSSKRN23 RSS KRN23
1.34 95%CI 1.74, 0.94 KRN23Week 64 KRN23
RGI-C RSSXLH
UX023-CL301 KRN23 ZZ KRN23
KRN23
3 QOL UX023-CL301 PROMIS
Week 64 KRN23 2.2695%CI 6.61, 2.09 KRN23 1.90 95%CI 1.80,
5.59 KRN23 1.08 95%CI 6.21, 4.06
UX023-CL301 6MWT KRN23 +43.20 m 95%CI+2.33, +84.07 m KRN23
KRN23QOL
6.2.3 TIO
1 KRN23-002 KRN23
Week 20 Week 88 Week 20 2448 72 88 2.5 mg/dL TmP/GFR 1,25(OH)2D
KRN23
KRN23 2.5
CONFIDENTIAL - 101 -
2 KRN23-002 99mTc 164
KRN23 14.6% 24P1NP CTx 72
32
1 KRN23
3 QOL KRN23-002 BPI-Q3 ± KRN23
4.4±2.6 72 2.9±2.7 SF36T KRN23 T
35.89±7.71 72 43.30±11.17 T32.30±11.43 72 42.30±14.86
6MWT 295.8±96.0 m 48 353.7±115.8 m
KRN23 TIO QOL
6.2.4 FGF23
QOLKRN23
TIO FGF23
QOLFGF23
QOL
48 88 4.7
6.3 XLH TIO KRN23
KRN23 KRN23
KRN23 2.5
CONFIDENTIAL - 102 -
XLHTIO FGF23
Huang et al, 2013; Goldsweig and Carpenter, 2015; , 2015; and , 2016
•
XLH UX023-CL303 KRN2320.1% 134 27 Grade 1 2 Grade 3
KRN2312.1% 66 8 11.8% 68 8 XLH
UX023-CL301 Week 0 64 KRN2351.7% 29 15 Grade 1 2 Grade 3
TIO KRN23-002 15.4% 13 2Grade 1 2 Grade 3
KRN23KRN23-INT-001 1
•
XLH UX023-CL303 KRN2311.2% 134 15 Grade 1 2 Grade 3
KRN236.1% 66 4 5.9% 68 4 XLH
UX023-CL301 Week 0 64 KRN23 37.9%29 11 18.8% 32 6 Grade 12 Grade 3 TIO KRN23-002
23.1% 13 3 Grade 1 2 Grade 3XLH UX023-CL203 1
KRN23-INT-001 1
KRN23
• XLH UX023-CL303
KRN23 6.0% 134 8 Grade 1 Grade 2
KRN23 2.5
CONFIDENTIAL - 103 -
Grade 3KRN23 5.9% 68 4
UX023-CL303 4.5 mg/dL6.5 mg/dL
KRN23
• XLH UX023-CL303
KRN23 6.7% 134 9 Grade 1Grade 2 Grade 3
XLH UX023-CL301KRN23
KRN231
KRN23
intact PTH
6.4 XLH XLH
D TIOFGF23 KRN23
QOLKRN23 FGF23
KRN23
KRN23
intact PTH
TIO FGF23
TIO
KRN23 2.5
CONFIDENTIAL - 104 -
XLH TIOKRN23
KRN23 XLH TIO FGF23KRN23
FGF23 XLH TIOFGF23 Huang
et al, 2013; Goldsweig and Carpenter, 2015; , 2015; and , 2016XLH TIO FGF23
TIO FGF23
XLH D TIOFGF23
FGF23TIO XLH XLH
FGF23 XLHKRN23
KRN23 1 12 XLH 18 XLH TIO13 17 FGF23
and , 2016XLH
KRN2317 15
, 2008KRN23
KRN23 6.3 XLH TIOFGF23 13 17
KRN23
FGF23
4 1 1 mg/kg
1 1 mg/kg 90 mg
KRN23 2.5
CONFIDENTIAL - 105 -
2 1 0.8 mg/kg1 2 mg/kg 90 mg
17 15
41 0.5 mg/kg
1 2 mg/kg
TIO KRN23KRN23
FGF23 4 1 1 mg/kg
1 90 mg 2 1 0.8 mg/kg
1 2 mg/kg 190 mg
4 1 0.3 mg/kg1 2 mg/kg
KRN23 2.5
CONFIDENTIAL - 106 -
7
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