Document text
&29,'9DFFLQH%173) 5HSRUWLQJ3HULRG
'HYHORSPHQW6DIHW\8SGDWH5HSRUW'6851R $SULOWKURXJ K$SULO
&21),'(17,$/
3DJH'(9(/230(17 6$)(7< 83'$7( 5(3257 1R
IRU
&29,' 9DFFLQH %17 3)
'$7( 2) 7+,6 5(3257 -XQH
3IL]HURQ EHKDOI RI %LR17HFK 6(3OHDVHQRWHWKDWWKLVUHSRUW PD\FRQWDLQ XQEOLQGHGFOLQLFDOWULDO LQIRUPDWLRQ
7KHLQIRUPDWLRQFRQWDLQHGLQWKLVGRFXPHQWLVSURSULHWDU\DQGFRQILGHQWLDO$Q\GLVFORVXUHUHSURGXFWLRQ
GLVWULEXWLRQRURWKHUGLVVHPLQDWLRQRIWKLVLQIRUPDWLRQRXWVLGHRI3IL]HULWV$IILOLDWHVLWV/LFHQVHHVRU
5HJXODWRU\$JHQFLHVLVVWULFWO\SURKLELWHG([FHSWDVPD\EHRW KHUZLVHDJUHHGWRLQZULWLQJE\DFFHSWLQJRU
UHYLHZLQJWKHVHPDWHULDOV\RXDJUHHWRKROGVXFKLQIRUPDWLRQL QFRQILGHQFHDQGQRWWRGLVFORVHLWWRRWKHUV
H[FHSWZKHUHUHTXLUHGE\DSSOLFDEOHODZQRUWRXVHLWIRUXQDXWKRUL]HGSXUSRVHV3(5,2' &29(5(' %< 7+,6 5(3257
$35,/ WR $35,/090177e19744d904\A pproved\A pproved On: 11-Jun-2021 10:28 (GMT )
FDA-CBER-2021-5683-1102865
COVID-19 Vaccine (BNT162, PF-07302048) Reporting Period
Development Safety Upd ate Report (DSUR) No. 1 22 April 2020 through 21 April 2021
CONFIDENTIAL
Page 2DATE OF THIS REPORT: 10 June 2021
SIGNATURE : ____ __________ Date : 10 June 2021
NAME AND CONTACT DETAILS OF THE QPPV:
EU Qualified Person
Barbara De Bernardi , MD
Worldwide Medical & Safety
Pfizer
Via Anna Maria Mozzoni 12
20152 Milan (Italy)telephone: +39 0248 382 343
fax number: +39 02 41498 286
email: [email protected]
EU Qualified Person Deputy
, MD
Worldwide Medical & Safety
Pfizer
Via Anna Maria Mozzoni 12
20152 Milan (Italy)telephone:
fax number
email: 090177e19744d904\A pproved\A pproved On: 11-Jun-2021 10:28 (GMT )
(b) (6)
(b) (6)
(b) (6)
(b) (6)
(b) (6)
FDA-CBER-2021-5683-1102866
&29,'9DFFLQH%173) 5HSRUWLQJ3HULRG
'HYHORSPHQW6DIHW\8SGDWH5HSRUW'6851R $SULOWKURXJ K$SULO
&21),'(17,$/
3DJH(;(&87,9(6800$5<
7KLVLVWKHILUVW'HYHORSPHQW6DIHW\8SGDWH5HSRUW'685IRU3I L]HU%LR17HFK&29,'
PHVVHQJHUULERQXFOHLFDFLGP51$YDFFLQH%173)KHUHDIWHUUHIHUUHGWR
DV&29,'YDFFLQHFRYHULQJWKHUHSRUWLQJSHULRG$SULO WKURXJK$SULO
&29,'YDFFLQHLVKLJKO\SXULILHGVLQJOHVWUDQGHG¶FDSSHG P51$SURGXFHGXVLQJD
FHOOIUHH in vitroWUDQVFULSWLRQIURPWKHFRUUHVSRQGLQJ'1$WHPSODWHVHQFRGLQJWKHYLUDO
VSLNH6SURWHLQRIVHYHUHDFXWHUHVSLUDWRU\V\QGURPHFRURQDYL UXV6$56&R97KH
51$LVIRUPXODWHGLQOLSLGQDQRSDUWLFOHV/13VZKLFKHQDEOHGH OLYHU\RIWKH51$LQWR
KRVWFHOOVWRDOORZH[SUHVVLRQRIWKH6$56&R96DQWLJHQ7KH YDFFLQHHOLFLWVERWK
QHXWUDOL]LQJDQWLERG\DQGFHOOXODULPPXQHUHVSRQVHVWRWKH6DQWLJHQZKLFKPD\FRQWULEXWHWRSURWHFWLRQDJDLQVW&29,'
&29,'YDFFLQH%17ELVDZKLWHWRRIIZKLWHIUR]HQSURGX FWS+
SURYLGHGDVFRQFHQWUDWHIRUGLVSHUVLRQIRULQMHFWLRQVWHULOHF RQFHQWUDWHDVDPXOWLGRVHYLDO
0'9WREHGLOXWHGEHIRUHXVH7KH0'9FRQWDLQVGRVHVP/ DIWHUGLOXWLRQ(DFK
GRVHFRQWDLQVJRI%17E7KHGRVLQJVFKHGXOHXQGHULQYHVW LJDWLRQLVGRVHVJLYHQ
DSSUR[LPDWHO\GD\VDSDUW3IL]HULVUHVSRQVLEOHIRUWKHSUHSDUDWLRQRIWKH'685DFFRUGLQJ WRWKHSKDUPDFRYLJLODQFH
DJUHHPHQW39$LQSODFH%LR17HFK6(LVWKHVSRQVRUIRUWKHDOO WKHFOLQLFDOWULDOV&7V
LQFOXGHGLQWKLVUHSRUW'DWDIURP%LR17HFK¶OLFHQVHSDUWQHU/36KDQJKDL)RVXQ3KDUPDFH XWLFDO,QFWKDW
FRQGXFWVWKHFOLQLFDOVWXGLHVLQ&KLQDRQ%LR17HFK6(¶VEHKDOID UHLQFOXGHGLQWKLVUHSRUWWR
IXOILOO&KLQD&HQWHUIRU'UXJ(YDOXDWLRQ&'('685UHTXLUHPHQW V
'DWDIURPUHVSHFWLYH/3VDUHSUHVHQWHGLQGLYLGXDOO\LQWKLVUHSR UW
'XULQJWKLVUHSRUWLQJSHULRGWKHUHZHUHRQJRLQJVSRQVRULQLWLDWHGFOLQLFDOWULDOV
LQYROYLQJ&29,'YDFFLQH&&&& &
&µ&¶LPSOLHVFRQGXFWHGE\3IL]HU%17%17 FRQGXFWHGE\
%LR17HFK %17DQG%1 7FRQGXFWHGE\)RVXQ
7KHUHZHUHQRFRPSOHWHGFOLQLFDOWULDOVZLWKILQDOFOLQLFDOVWXG\ UHSRUWV&65VDYDLODEOH
0RUHRYHUWKHUHZHUHRQJRLQJQRQLQWHUYHQWLRQDOSRVWDXWKRUL] DWLRQVWXGLHV3$66
&YROXQWDU\DQG&FRPPLWWHG
0DQDJHPHQW5HJXODWLRQRI'685IRUWULDOLPSOHPHQWDWLRQDSSOLF DEOHIRU'685VZLWK'/3SRVW-XO\
,QFOXGHVRQJRLQJVWXGLHVDVZHOODVVWXGLHVLQZKLFKSDWLHQWHQ UROOPHQWDQGIROORZXSKDYHEHHQ
FRPSOHWHGEXWWKHDQDO\VLVDQG&65DUHLQSURJUHVV090177e19744d904\A pproved\A pproved On: 11-Jun-2021 10:28 (GMT )
FDA-CBER-2021-5683-1102867
&29,'9DFFLQH%173) 5HSRUWLQJ3HULRG
'HYHORSPHQW6DIHW\8SGDWH5HSRUW'6851R $SULOWKURXJ K$SULO
&21),'(17,$/
3DJH&XPXODWLYHO\LWLVHVWLPDWHGWKDWVXEMHFWVKDYHSDUWLFLS DWHGLQ&29,'YDFFLQH
&FOLQLFDOWULDOV&7VZRUOGZLGH$GGLWLRQDOO\VXEMHFWV KDYHSDUWLFLSDWHGLQ%17
&7VRIZKLFKLQWKH&KLQHVH%17&7VFRQGXFWHGE\)RVXQ
$VRIWKH'DWD/RFN3RLQW'/3RIWKLV'685&29,'YDFFLQHK DVUHFHLYHGWHPSRUDU\
DXWKRUL]DWLRQIRUHPHUJHQF\XVHLQFRXQWULHVDQGFRQGLWLRQDOPDUNHWLQJDXWKRUL]DWLRQ
DSSURYDOLQFRXQWULHVJOREDOO\,QWKH8.FRQGLWLRQDOPDUNHWLQ JDXWKRUL]DWLRQDSSURYDO
ZDVJUDQWHGDIWHUWKH'/3RQ$SULOZKLOHWKHDXWKRUL]D WLRQIRUHPHUJHQF\XVHVWLOO
UHPDLQHGDFWLYHIRUDQRYHUODSSLQJWLPHIUDPH
&XPXODWLYHO\LWLVHVWLPDWHGWKDW&29,'YDFFLQH GRVHVZHUHVXSSOLHG
ZRUOGZLGHVLQFHLWVILUVWVXSSO\WRWKHFRXQWULHV$GGLWLRQDOO\ DQHVWLPDWHRI GRVHV
ZHUHGLVWULEXWHGLQ+RQJ.RQJ+.DQG0DFDXWKURXJK)RVXQ7KHUHIHUHQFHVDIHW\LQIRUPDWLRQ56,IRUWKLV'685LVWKH%17 3)
,QYHVWLJDWRU¶V%URFKXUH,%YGDWHG$SULOZKLFKZDV XSGDWHGWLPHVGXULQJ
WKHUHSRUWLQJLQWHUYDORQ-XOY$XJYDQG-DQY
56,6HFWLRQV Summary of data and guidance for the investigators DQG6HFWLRQ
Reference Safety Information for Assessment of Expectedness of Serious Adverse ReactionsZHUHXVHGSRVWYHUVLRQSUHYLRXVO\QDPHG6HFWLRQ Reference safety information LQ,%
YHUVLRQVDQG8SGDWHVZHUHPDGHWRLQFOXGHHPHUJLQJGDWD IURPWKHRQJRLQJFOLQLFDO
WULDOVLQFOXGLQJDGGLWLRQDOVDIHW\GDWD
7KHUHZHUHQRVLJQLILFDQWDFWLRQVWDNHQGXHWRVDIHW\UHDVRQVE\+HDOWK$XWKRULWLHVRUWKH
0$+V
%DVHGRQSKDUPDFRYLJLODQFHPRQLWRULQJDFWLYLWLHVVLQFHILUVWDXWKRUL]DWLRQK\SHUVHQVLWLYLW\
UHDFWLRQVRWKHUWKDQ$QDSK\OD[LV'LDUUKRHD3DLQLQH[WUHPLW \DUP9RPLWLQJ$VWKHQLD
/HWKDUJ\'HFUHDVHGDSSHWLWH+\SHUKLGURVLV1LJKWVZHDWV
DUHLGHQWLILHGULVNVQRW
LPSRUWDQWIRUWKHSXUSRVHRIULVNPDQDJHPHQWSODQQLQJDQGZHUH LQFOXGHGDUHEHLQJ
LQFOXGHGLQWKHSURGXFWODEHOLQJ9DFFLQHVWUHVVUHODWHGUHVSRQV HVLQFOXGLQJ'L]]LQHVV
3DUDHVWKHVLDDQG7DFK\FDUGLDDPRQJRWKHUVZHUHLQFOXGHGLQWKH 56,DVUHDFWLRQVWRWKH
YDFFLQDWLRQSURFHVV
7KHIROORZLQJUHDFWRJHQLFLW\HYHQWVDUHLGHQWLILHGULVNVLQWKH FOLQLFDOWULDOVQRWFRQVLGHUHG
LPSRUWDQW,QMHFWLRQVLWHSDLQ,QMHFWLRQVLWHVZHOOLQJDQG,QM HFWLRQVLWHUHGQHVV)HYHU&KLOOV
)DWLJXH+HDGDFKH0XVFOHSDLQDQG-RLQWSDLQ$VSHUWKH(8503YHUVLRQGDWHG'HFHPEHULQHIIHFW DWWKHEHJLQQLQJRIWKH
UHSRUWLQJSHULRGµ$QDSK\OD[LV¶LVDQLPSRUWDQWLGHQWLILHGULVN IRU&29,'YDFFLQHZKLOH
µ9DFFLQHDVVRFLDWHGHQKDQFHGGLVHDVH9$('LQFOXGLQJ9DFFLQHD VVRFLDWHGHQKDQFHG
UHVSLUDWRU\GLVHDVH9$(5'LVDQLPSRUWDQWSRWHQWLDOULVN7KH (8503ZDVXSGDWHGWRY
GXULQJWKHUHSRUWLQJLQWHUYDODQGUHFHLYHG&+03DSSURYDORQ $SULO$IXUWKHU
3OHDVHQRWHWKDW$VWKHQLD/HWKDUJ\'HFUHDVHGDSSHWLWH+\SHUK LGURVLV1LJKWVZHDWVZHUHLGHQWLILHGDV
ULVNVSRVWWKH'/3RQ$SULO090177e19744d904\A pproved\A pproved On: 11-Jun-2021 10:28 (GMT )
(b) (4)
FDA-CBER-2021-5683-1102868
&29,'9DFFLQH%173) 5HSRUWLQJ3HULRG
'HYHORSPHQW6DIHW\8SGDWH5HSRUW'6851R $SULOWKURXJ K$SULO
&21),'(17,$/
3DJH(8503XSGDWHY$SUWRLQFOXGHLQGLYLGXDOVDJHG \HDUVZ DVDSSURYHG
SRVWWKHGDWDORFNSRLQWRQ0D\7KHUHZHUHQRXSGDWHV WRWKHVDIHW\FRQFHUQV
PDGH
%DVHGRQWKHDYDLODEOHVDIHW\DQGHIILFDF\GDWDIRU&29,'YD FFLQHWKHEHQHILWULVN
SURILOHRIWKHYDFFLQHUHPDLQVIDYRUDEOH090177e19744d904\A pproved\A pproved On: 11-Jun-2021 10:28 (GMT )
FDA-CBER-2021-5683-1102869
&29,'9DFFLQH%173) 5HSRUWLQJ3HULRG
'HYHORSPHQW6DIHW\8SGDWH5HSRUW'6851R $SULOWKURXJ K$SULO
&21),'(17,$/
3DJH7$%/(2)&217(176
(;(&87,9(6800$5<
/,672)7$%/(6
$33(1',&(6
/,672)$%%5(9,$7,216,1752'8&7,21
:25/':,'(0$5.(7,1*$33529$/67$786
$&7,2167$.(1,17+(5(3257,1*3(5,2')256$)(7<5($6216&+$1*(6725()(5(1&(6$)(7<,1)250$7,21
,19(1725<2)&/,1,&$/75,$/621*2,1*$1'&203/(7(''85,1*
7+(5(3257,1*3(5,2'
(67,0$7('&808/$7,9((;32685(
&XPXODWLYH6XEMHFW([SRVXUHLQWKH'HYHORSPHQW3URJUDPPH
3DWLHQW([SRVXUHIURP0DUNHWLQJ([SHULHQFH
'$7$,1/,1(/,67,1*6$1'6800$5<7$%8/$7,216
5HIHUHQFH,QIRUPDWLRQ
/LQH/LVWLQJVRI6HULRXV$GYHUVH5HDFWLRQV'XULQJWKH5HSR UWLQJ3HULRG
&XPXODWLYH6XPPDU\7DEXODWLRQVRI6HULRXV$GYHUVH(YHQWV
6,*1,),&$17),1',1*6)520&/,1,&$/75,$/6'85,1*7+(
5(3257,1*3(5,2'
&RPSOHWHG&OLQLFDO7ULDOV2QJRLQJ&OLQLFDO7ULDOV/RQJWHUP)ROORZXS
2WKHU7KHUDSHXWLF8VHRI,QYHVWLJDWLRQDO'UXJ
1HZ6DIHW\'DWD5HODWHGWR&RPELQDWLRQ7KHUDSLHV
6$)(7<),1',1*6)520121,17(59(17,21$/678',(627+(5&/,1,&$/75,$/678'<6$)(7<,1)250$7,216$)(7<),1',1*6)5200$5.(7,1*(;3(5,(1&(
121&/,1,&$/'$7$/,7(5$785(
27+(5'6856/$&.2)( )),&$&<
5(*,2163(&,),&,1)250$7,21 090177e19744d904\A pproved\A pproved On: 11-Jun-2021 10:28 (GMT )
FDA-CBER-2021-5683-1102870
&29,'9DFFLQH%173) 5HSRUWLQJ3HULRG
'HYHORSPHQW6DIHW\8SGDWH5HSRUW'6851R $SULOWKURXJ K$SULO
&21),'(17,$/
3DJH/$7(%5($.,1*,1)250$7,21
29(5$//6$)(7<$66(660(17
(YDOXDWLRQRIWKH5LVNV
,PSRUWDQW,GHQWLILHG5LVNV
,PSRUWDQW3RWHQWLDO5LVNV
%HQHILW5LVN&RQVLGHUDWLRQV
6800$5<2),03257$175,6.6
&21&/86,21
/,67 2) 7$%/(6
7DEOH ,QYHQWRU\RI&29,'9DFFLQH&OLQLFDO7ULDOV'XULQJWK H'685
5HSRUWLQJ3HULRG&RQGXFWHGE\3IL]HU
7DEOH ,QYHQWRU\RI&29,'9DFFLQH&OLQLFDO7ULDOV'XULQJWK H'685
5HSRUWLQJ3HULRG&RQGXFWHGE\%LR17HFK)RVXQ
7DEOH 6HULRXV$GYHUVH5HDFWLRQV5HSRUWHG'XULQJWKH'6853HUL RG
$SUWR$SU
7DEOH 1RQ,QWHUYHQWLRQDO6WXGLHV2QJRLQJ'XULQJWKH5HSRUWLQJ3HULRG
7DEOH &OLQLFDO/LWHUDWXUH$UWLFOHVWKDW3UHVHQWHG1HZ6DIHW\ ,QIRUPDWLRQ
LQWKH5HSRUWLQJ,QWHUYDO
7DEOH 6XPPDU\RI,PSRUWDQW5LVNVIURPWKH&29,'9DFFLQH
'HYHORSPHQW3URJUDP090177e19744d904\A pproved\A pproved On: 11-Jun-2021 10:28 (GMT )
FDA-CBER-2021-5683-1102871
&29,'9DFFLQH%173) 5HSRUWLQJ3HULRG
'HYHORSPHQW6DIHW\8SGDWH5HSRUW'6851R $SULOWKURXJ K$SULO
&21),'(17,$/
3DJH$33(1',&(6
$33(1',;5()(5(1&(6$)(7<,1)250$7,21%173)
,19(67,*$725¶6%52&+85(,%$35,/
$33(1',;6$)(7<5(/$7('&+$1*(6727+(,% 12'$7$
$33(1',;%173),%-8/<
$33(1',;%173),%$8*867
$33(1',;%173),%-$18$5<
$33(1',;&808/$7,9(7$%/(2),03257$175(*8/$725<5(48(676
12'$ 7$
$33(1',;,19(1725<2)&/,1,&$/75,$/6&203/(7('&21&/8'('
:,7+),1$/&/,1,&$/678'<5(32576'85,1*7+(5(3257,1*
3(5,2' 12'$7$
$33(1',;,19(1725<2)&/,1,&$/75,$/621*2,1*67$57('25
&21&/8'(':,7+12),1$/&/,1,&$/678'<5(32576'85,1*7+(5(3257,1*3(5,2'&
$33(1',;,19(1725<2)&/,1,&$/75,$/621*2,1*67$57('2 5
&21&/8'(':,7+12),1$/&/,1,&$/678'<5(32576'85,1*7+(5(3257,1*3(5,2'%17)2681
$33(1',;68%-(&76(;32685(3(535272&2/%<75($70(17$50&
$33(1',;&808/$7,9(&/,1,&$/75,$/(;32685(:,7+'(02*5$3+,&
'$7$&
$33(1',;&808/$7,9(&/,1,&$/75,$/(;32685(:,7+'(02*5$3+, &
'$7$)52027+(5352*5$06%<7+(6321625 12'$7$
$33(1',;&808/$7,9(&/,1,&$/75,$/(;32685(:,7+'(02*5$3+, &
'$7$%17678',(6%17%17
$33(1',;&808/$7,9(&/,1,&$/75,$/(;32685(:,7+'(02*5$3+, &
'$7$%17678',(6%17%17
$33(1',;/,1(/,67,1*2)6(5,286$'9(56(5($&7,216'85,1*7+(
5(3257,1*3(5,2'&
$33(1',;/,1(/,67,1*2)6(5,286$'9(56(5($&7,216'85,1*7+ (
5(3257,1*3(5,2'%17)2681
$33(1',;&808/$7,9(6800$5<7$%8/$7,212)6(5,286$'9(56(
(9(176&
$33(1',;&808/$7,9(6800$5<7$%8/$7,212)6(5,286$'9(56(
(9(176%17)2681 090177e19744d904\A pproved\A pproved On: 11-Jun-2021 10:28 (GMT )
FDA-CBER-2021-5683-1102872
&29,'9DFFLQH%173) 5HSRUWLQJ3HULRG
'HYHORSPHQW6DIHW\8SGDWH5HSRUW'6851R $SULOWKURXJ K$SULO
&21),'(17,$/
3DJH$33(1',;6&,(17,),&$%675$&76(( 6(&7,21
$33(1',;:25/':,'(0$5.(7,1*$87+25,=$7,2167$786
$33(1',;5&808/$7,9(6800$5<7$%8/$7,212)6(5,286
$'9(56(5($&7,216)520&/,1,&$/75,$/6&
$33(1',;5&808/$7,9(6800$5<7$%8/$7,212)6(5,286
$'9(56(5($&7,216%17)2681
$33(1',;5/,1(/,67,1*2)&$6(65(3257,1*686$56'85,1* 7+(
5(3257,1*3(5,2'&
$33(1',;5/,1(/,67,1*2)&$6(65(3257,1*686$56'85,1* 7+(
5(3257,1*3(5,2'5(&(,9(')5201213),=(56321625('&/,1,&$/
75,$/6 6(($33(1',;5
$33(1',;5/,67,1*2)68%-(&76:+2',(''85,1*7+(5(3257,1 *
3(5,2'&
$33(1',;5/,67,1*2)68%-(&76:+2',(''85,1*7+(5(3257,1*
3(5,2'%17&/,1,&$/678',(6%17$1' 12'$7$
$33(1',;5/,67,1*2)68%-(&76:+2',6&217,18(''8(72
$'9(56((9(176&
$33(1',;5/,67,1*2)68%-(&76:+2',6&217,18(''8(72$'9( 56(
(9(176%17&/,1,&$/678',(6%17$1'%17
$33(1',;5/,67,1*2)68%-(&76:+2',6&217,18(''8(72$'9 (56(
(9(176%17&/,1,&$/678',(6%17$1'%17
$33(1',;56,*1,),&$173+$6(35272&2/02',),&$7,21686
12'$ 7$
$33(1',;56,*1,),&$170$18)$&785,1*&+$1*(686
$33(1',;56,*1,),&$170$18)$&785,1*&+$1*(6&+,1$
$33(1',;5'(6&5,37,212)7+(*(1(5$/,19(67,*$7,213/$1
)257+(83&20,1*<($586
$33(1',;5'(6&5,37,212)7+(*(1(5$/,19(67,*$7,213/$1
)257+(83&20,1*<($5&+,1$
$33(1',;5/2*2)28767$1',1*%86,1(66:,7+5(63(&7727+(
86,1'12'$7$090177e19744d904\A pproved\A pproved On: 11-Jun-2021 10:28 (GMT )
FDA-CBER-2021-5683-1102873
&29,'9DFFLQH%173) 5HSRUWLQJ3HULRG
'HYHORSPHQW6DIHW\8SGDWH5HSRUW'6851R $SULOWKURXJ K$SULO
&21),'(17,$/
3DJH/,672)$%%5(9,$7,216
$EEUHYLDWLRQ 7HUP
Y3Q& YDOHQWSQHXPRFRFFDOFRQMXJDWHYDFFLQH
$( $GYHUVHHYHQW
$/& >SRO\HWK\OHQHJO\FRO@ 11GLWHWUDGHF\ODFHWDPLGH
$/& K\GUR[\EXW\OD]DQHGL\OELVKH[DQHGL\OELVKH[ \OGHFDQRDWH
$0/ $FXWHP\HOREODVWLFOHXNHPLD
%17 %LR17HFK
&%(5 &HQWHUIRU%LRORJLFV(YDOXDWLRQDQG5HVHDUFK
&'( &KLQD&HQWHUIRU'UXJ(YDOXDWLRQ
&+03 &RPPLWWHHIRU0HGLFLQDO3URGXFWVIRU+XPDQ8VH
&2 &DUERQGLR[LGH
Cont’d &RQWLQXHG
&29,' FRURQDYLUXVGLVHDVH
&65 &OLQLFDOVWXG\UHSRUW
&7&$( &RPPRQ7HUPLQRORJ\&ULWHULDIRU$GYHUVH(YHQWV
'/3 'DWD/RFN3RLQW
'1$ 'HR[\ULERQXFOHLFDFLG
'63& 'LVWHDUR\OVQJO\FHUR SKRVSKRFKROLQH
'685 'HYHORSPHQW6DIHW\8SGDWH5HSRUW
(0$ (XURSHDQ0HGLFLQH$JHQF\
(8$ (PHUJHQF\XVHDXWKRUL]DWLRQ
(8503 (XURSHDQ8QLRQULVNPDQDJHPHQWSODQ
)) HPDOH
)'$ 86)RRGDQG'UXJ$GPLQLVWUDWLRQ
)6)9 )LUVWVXEMHFWILUVWYLVLW
*07 *HRPHWULFPHDQFRQFHQWUDWLRQ
,% ,QYHVWLJDWRU¶VEURFKXUH
,&' ,QIRUPHGFRQVHQWGRFXPHQW
,&+ ,QWHUQDWLRQDO&RXQFLORQ+DUPRQL]DWLRQ
,* LPPXQRJOREXOLQ
,J* LPPXQRJOREXOLQ*
,1' ,QYHVWLJDWLRQDOQHZGUXJ
,93% ,QWUDYHQRXVSLJJ\ EDFN
/13 /LSLGQDQRSDUWLFOH
/3 /LFHQVHSDUWQHU
/6/9 /DVWVXEMHFWODVWYLVLW
0 PDOH
0$+ 0DUNHWLQJ$XWKRUL]DWLRQKROGHU
0'9 0XOWLGRVHYLDO
0HG'5$ 0HGLFDO'LFWLRQDU\IRU5HJXODWRU\$FWLYLWLHV
P51$ 0HVVHQJHU51$
15 1RWUHVROYHG
23$ RSVRQRSKDJRF\WLFDFWLYLW\
36 6$56&R9IXOOOHQJWK3PXWDQWSUHIXVLRQVSLNHSURWHLQ
3$66 3RVWDXWKRUL]DWLRQVDIHW\VWXG\
3, 3URGXFWLQIRUPDWLRQ
37 0HG'5$3UHIHUUHG7HU P
39$ 3KDUPDFRYLJLODQFHDJUHHPHQW
5 UHVROYHG
5%' UHFHSWRUELQGLQJGRPDLQ
5* UHVROYLQJ
51$ ULERQXFOHLFDFLG090177e19744d904\A pproved\A pproved On: 11-Jun-2021 10:28 (GMT )
FDA-CBER-2021-5683-1102874
&29,'9DFFLQH%173) 5HSRUWLQJ3HULRG
'HYHORSPHQW6DIHW\8SGDWH5HSRUW'6851R $SULOWKURXJ K$SULO
&21),'(17,$/
3DJH$EEUHYLDWLRQ 7HUP
56, 5HIHUHQFHVDIHW\LQIRUPDWLRQ
6 VSLNHSURWHLQ
6$( 6HULRXVDGYHUVHHYHQW
6$5 6HULRXVDGYHUVHUHDFWLRQ
6$56&R9 6HYHUHDFXWHUHVSLUDWRU\V\QGURPHFRURQDYLUXV
6'9 6LQJOHGRVHYLDO
6,59$ 6KRXOGHULQMXU\UHODWHGWRYDFFLQHDGPLQLVWUDWLRQ
62& 0HG'5$6\VWHP2UJDQ&ODVV
686$5 6XVSHFWHGXQH[SHFWHGVHULRXVDGYHUVHUHDFWLRQ
8. 8QLWHG.LQJGRP
86 8QLWHG6WDWHV
9$(' 9DFFLQHDVVRFLDWHGHQKDQFHGGLVHDVH
9$(5' 9DFFLQHDVVRFLDWHGHQKDQFHGUHVSLUDWRU\GLVHDVH
9( 9DFFLQHHIILFDF\
9+$ 9HWHUDQV¶+HDOWK$GPLQLVWUDWLRQ090177e19744d904\A pproved\A pproved On: 11-Jun-2021 10:28 (GMT )
FDA-CBER-2021-5683-1102875
&29,'9DFFLQH%173) 5HSRUWLQJ3HULRG
'HYHORSPHQW6DIHW\8SGDWH5HSRUW'6851R $SULOWKURXJ K$SULO
&21),'(17,$/
3DJH ,1752'8&7,21
7KLVLVWKHILUVW'HYHORSPHQW6DIHW\8SGDWH5HSRUW'685IRU&29,'YDFFLQH
%173)FRYHULQJWKHUHSRUWLQJSHULRG$SULO WKURXJK$SULO
7KHUHSRUWIROORZVWKHJHQHUDOIRUPDWSURSRVHGE\,&+*XLGHOLQH ()1RWHIRUJXLGDQFHRQ
GHYHORSPHQWVDIHW\XSGDWHUHSRUW(0$&+03,&+>6HSWHPEHU@ ,QDFFRUGDQFHZLWKWKLVJXLGDQFHWKHUHSRUWLQJSHULRGIRUWKLV'68 5LVDOLJQHGZLWKWKHILUVW
DXWKRUL]DWLRQWRFRQGXFWDFOLQLFDOWULDOLQDQ\FRXQWU\ZRUOGZL GHXVLQJWKHGHYHORSPHQW
LQWHUQDWLRQDOELUWKGDWH 7KLV'685LVDOVREHLQJSUHSDUHGLQ VXSSRUWRI86)'$%%,1'
WRFRPSO\ZLWK&)5
3IL]HULVUHVSRQVLEOHIRUWKHSUHSDUDWLRQRIWKH'685DFFRUGLQJ WRWKH39$LQSODFHEHWZHHQ
3IL]HUDQG%LR17HFK%LR17HFK6(LVWKHVSRQVRUIRUDOO&7VLQF OXGHGLQWKLVUHSRUW
'DWDIURP%LR17HFK¶V/36KDQJKDL)RVXQ3KDUPDFHXWLFDO,QFWKDW FRQGXFWVWKHFOLQLFDO
VWXGLHVLQ&KLQDDUHLQFOXGHGLQWKLVUHSRUWWRIXOILOO&KLQD& '('685UHTXLUHPHQWV
'DWDIURPUHVSHFWLYH/3VDUHSUHVHQWHGLQGLYLGXDOO\LQWKLVUHS RUW
&29,'YDFFLQHLVDKLJKO\SXULILHGVLQJOHVWUDQGHG¶FDSSH GP51$SURGXFHGXVLQJD
FHOOIUHH in vitroWUDQVFULSWLRQIURPWKHFRUUHVSRQGLQJ'1$WHPSODWHHQFRGLQJWKH YLUDO6
SURWHLQRI6$56&R97KH51$LVIRUPXODWHGLQ/13VZKLFKHQDEOHGHOLYHU\RIWKH51$
LQWRKRVWFHOOVWRDOORZH[SUHVVLRQRIWKH6$56&R96DQWLJHQ 7KHYDFFLQHHOLFLWVERWK
QHXWUDOL]LQJDQWLERG\DQGFHOOXODULPPXQHUHVSRQVHVWRWKH6DQ WLJHQZKLFKPD\FRQWULEXWH
WRSURWHFWLRQDJDLQVW&29,'
&29,'YDFFLQH%17ELVDZKLWHWRRIIZKLWHIUR]HQSURGX FWS+
SURYLGHGDVFRQFHQWUDWHIRUGLVSHUVLRQIRULQMHFWLRQVWHULOHFRQFHQWUDWHLQDQ0'9WREH
GLOXWHGEHIRUHXVH7KH0'9F RQWDLQVGRVHVP/DIWHUGLOXW LRQ(DFKGRVHFRQWDLQV
JRI&29,'YDFFLQH7KHYDFFLQ HDOVRFRQWDLQV K\GUR[\EXW\ OD]DQHGL\OELVKH[DQH
GL\OELVKH[\OGHFDQRDWH$ /&>SRO\HWK\OHQHJO\ FRO@11
GLWHWUDGHF\ODFHWDPLGH$/&'LVWHDUR\OVQJO\FHURSKRVSKRFKROLQH'63&FKROHVWHUROSRWDVVLXPFKORULGHSRWDVVLXPGLK\GURJHQSKRVSKDWH VRGLXPFKORULGHGLVRGLXP
K\GURJHQSKRVSKDWHGLK\GUDWHVXFURVHDQGZDWHUIRULQMHFWLRQV DVH[FLSLHQWV7KHGRVLQJ
VFKHGXOHXQGHULQYHVWLJDWLRQLVGRVHVJLYHQDSSUR[LPDWHO\ GD\VDSDUW
7KHFOLQLFDOGHYHORSPHQWRI&29,'YDFFLQHVWDUWHGZLWKWKHL QYHVWLJDWLRQRIIRXU
%17YDFFLQHFDQGLGDWHV%17D%17E%17E%17F$ILIWKYDFFLQHFDQGLGDWH%17EZDVODWHUDGGHGWRWKHSURJUDP
%17EZDVVHOHFWHGIRUIXUWKHUGHYHORSPHQWDQGKDVEHHQDXWK RUL]HGIRUHPHUJHQF\XVH
RUEHHQJLYHQFRQGLWLRQDOPDUNHWLQJDXWKRUL]DWLRQLQQXPHURXVF RXQWULHVZRUOGZLGHIRU
DFWLYHLPPXQL]DWLRQWRSUHYHQW&29,'FDXVHGE\6$56&R9YL UXVLQLQGLYLGXDOV
\HDUVRIDJHDQGROGHU&RQGLWLRQDOPDUNHWLQJDXWKRUL]DWLRQZD VJUDQWHGIRU
0DQDJHPHQW5HJXODWLRQRI'685IRUWULDOLPSOHPHQWDWLRQDSSOLF DEOHIRU'685VZLWK'/3SRVW-XO\
090177e19744d904\A pproved\A pproved On: 11-Jun-2021 10:28 (GMT )
FDA-CBER-2021-5683-1102876
&29,'9DFFLQH%173) 5HSRUWLQJ3HULRG
'HYHORSPHQW6DIHW\8SGDWH5HSRUW'6851R $SULOWKURXJ K$SULO
&21),'(17,$/
3DJHDGPLQLVWUDWLRQWRDGROHVFHQWVWR\HDUVRIDJHDIWHUWKHGDWD ORFNSRLQWRIWKLVUHSRUWRQ
0D\)XUWKHUFOLQLFDOLQYHVWLJDWLRQRI%17ELVRQJR LQJWRH[SDQGWKHVWXGLHG
SRSXODWLRQV
)RU%17D%17E%17EDQG%17FDOOSODQQHGYDFFLQHDGPLQLVWUDWLRQ
WRWULDOSDUWLFLSDQWVKDVEHHQFRPSOHWHGDQGWKHGRVHGSDUWLFLS DQWVDUHFXUUHQWO\LQIROORZXS
:25/':,'( 0$5.(7,1* $33529$/ 67$786
&29,'YDFFLQH%17EUHFHLYHGILUVWWHPSRUDU\DXWKRUL]DWL RQIRUHPHUJHQF\
VXSSO\XQGHUUHJXODWLRQLQWKH8.RQ'HFHPEHUDQGLV FXUUHQWO\DXWKRUL]HGIRU
HPHUJHQF\XVHLQFRXQWULHV
&29,'YDFFLQHUHFHLYHGILUVWUHJXODWRU\FRQGLWLRQDOPDUNHWLQ JDXWKRUL]DWLRQDSSURYDOLQ
6ZLW]HUODQGRQ'HFHPEHUDQGLVFXUUHQWO\FRQGLWLRQDOO\ DSSURYHGLQFRXQWULHV
2IQRWHLQWKH8.WKHFRQGLWLRQDOPDUNHWLQJDXWKRUL]DWLRQDSS URYDOZDVJUDQWHGLQDGGLWLRQ
WRWKHDXWKRUL]DWLRQIRUHPHUJHQF\VXSSO\XQGHUUHJXODWLRQ SRVWWKH'/3RQ
$SULO7KHUHZHUHQRDXWKRUL]DWLRQZLWKGUDZDOVIRUVDIHW\UHDVRQVGXULQJWKHUHSRUWLQJLQWHUYDO'HWDLOVRILWVFXUUHQWPDUNHWLQJDXWKRUL]DWLRQVWDWXVLQFOXGLQJLQIRUPDWLRQRQFXPXODWLYH
FRXQWULHV¶DSSURYDOVDSSURYDOGDWHVDQGORFDOWUDGHQDPHVDUH SUHVHQWHGLQ $SSHQGL[
$&7,216 7$.(1 ,1 7+( 5(3257,1* 3(5,2' )25 6$)(7< 5($6216
'XULQJWKHUHSRUWLQJSHULRGQRVLJQLILFDQWDFWLRQVKDYHEHHQW DNHQZLWKUHVSHFWWR&29,'
YDFFLQHIRUVDIHW\UHDVRQVHLWKHUE\D+HDOWK$XWKRULW\RUE\ WKH0$+
7KHUHKDYHEHHQQRUHJXODWRU\DXWKRULW\UHTXHVWVWKDWKDYHSODF HGDOLPLWDWLRQRQWKHFOLQLFDO
GHYHORSPHQWRI&29,'YDFFLQH
&+$1*(6 72 5()(5(1&( 6$)(7< ,1)250$7,21
7KH56,IRUWKLV'685LVWKH%173),%DFWLYHDWWKH EHJLQQLQJRIWKH
UHSRUWLQJLQWHUYDOYGDWHG$SULOZKLFKLVORFDWHGLQ $SSHQGL[ 7KH,%ZDV
XSGDWHGWLPHVRQ-XOY$XJYDQG-DQY7KH
XSGDWHG,%VFDQEHIRXQGLQ $SSHQGL[ DQG 6HHDOVR 6HFWLRQ
8SGDWHVZHUHPDGHWRLQFOXGHGDWDHPHUJLQJIURPFOLQLFDOWULDOV LQFOXGLQJDGGLWLRQDOVDIHW\
GDWD
,19(1725<2)&/,1,&$/75,$/621*2,1*$1'&203/(7(''85,1*
7+(5(3257,1* 3(5,2'
'XULQJWKHUHSRUWLQJSHULRGWKHUHZHUHQRFRPSOHWHGFOLQLFDOWUL DOVLQYROYLQJ&29,'
YDFFLQHWKDWKDYHILQDO&65V$SSHQGL[LV1$IRUWKLVUHSRUW090177e19744d904\A pproved\A pproved On: 11-Jun-2021 10:28 (GMT )
FDA-CBER-2021-5683-1102877
&29,'9DFFLQH%173) 5HSRUWLQJ3HULRG
'HYHORSPHQW6DIHW\8SGDWH5HSRUW'6851R $SULOWKURXJ K$SULO
&21),'(17,$/
3DJH7KHUHZHUHRQJRLQJVSRQVRULQLWLDWHGLQWHUYHQWLRQDOFOLQLFDOWULDOV&&
&&&&%17%17%17DQG
%17
'HWDLOVRI3IL]HUFRQGXFWHGVWXGLHVDUHVXPPDUL]HGLQ7DEOHEHO RZ2IQRWH6WXG\
&%17KDGDQLQWHULPVWXG\UHSRUWWKDWLVDYDLODEOHX SRQUHTXHVW
7DEOH ,QYHQWRU\ RI &29,' 9DFFLQH &OLQLFDO 7ULDOV 'XULQJ WKH'685
5HSRUWLQJ3HULRG &RQGXFWHGE\3IL]HU
3URWRFRO 1R
6WXG\ $OLDV
>(XGUD&7 1R
LI DYDLODEOH@
3KDVH 1R7LWOH 6WDWXV &RXQWU\LHV
5HIHUHQFH
'RFXPHQW
6WXG\ YDFFLQH %17E %17E
&
%17>@3KDVH$3KDVH3ODFHER&RQWUROOHG5DQGRPL]HG
2EVHUYHU%OLQG'RVH)LQGLQJ6WXG\WR(YDOXDWHWKH
6DIHW\7ROHUDELOLW\,PPXQRJHQLFLW\DQG(IILFDF\
RI6$56&R951$9DFFLQH&DQGLGDWHV
$JDLQVW&29,'LQ+HDOWK\,QGLYLGXDOV2QJRLQJD$UJHQWLQD%UD]LO*HUPDQ\6RXWK$IULFD7XUNH
\86,%
6WXG\ YDFFLQH %17E
&3KDVH $3KDVH3ODFHER&RQWUROOHG5DQGRPL]HGDQG
2EVHUYHU%OLQG6WXG\WR(YDOXDWHWKH6DIHW\
7ROHUDELOLW\DQG,PPXQRJHQLFLW\RID6$56&R9
51$9DFFLQH&DQGLGDWH$JDLQVW&29,'LQ+HDOWK\
-DSDQHVH$GXOWV2QJRLQJD-DSDQ,%
&>@
3KDVH$3KDVH2SHQ/DEHO'RVH)LQGLQJ6WXG\WR(YDOXDWH
6DIHW\7ROHUDELOLW\DQG,PPXQRJHQLFLW\DQG3KDVH
3ODFHER&RQWUROOHG2EVHUYHU%OLQGHG6DIHW\
7ROHUDELOLW\DQG,PPXQRJHQLFLW\6WXG\RID
6$56&R951$9DFFLQH&DQGLGDWH$JDLQVW
&29,'LQ+HDOWK\&KLOGUHQ<HDUVRI$JH2QJRLQJD86,%
&E
>@
3KDVH$3KDVH3ODFHER&RQWUROOHG5DQGRPL]HG2EVHUYHU%OLQG6WXG\WR(YDOXDWHWKH6DIHW\7ROHUDELOLW\DQG,PPXQRJHQLFLW\RI$6$56&R9
51$9DFFLQH&DQGLGDWH%17E$JDLQVW&29,'
LQ+HDOWK\3UHJQDQW:RPHQ<HDUVRI$JHDQG2OGHU2QJRLQJ
D86,%
&3KDVH$3KDVH5DQGRPL]HG2EVHUYHU%OLQG6WXG\WR(YDOXDWHWKH6DIHW\7ROHUDELOLW\DQG,PPXQRJHQLFLW\RI0XOWLSOH3URGXFWLRQ/RWVDQG'RVH/HYHOVRIWKH
9DFFLQH&DQGLGDWH%17E$JDLQVW&29,'LQ
+HDOWK\3DUWLFLSDQWV7KURXJK<HDUVRI$JH2QJRLQJ
D86,%
&3KDVH$3KDVH5DQGRPL]HG2EVHUYHU%OLQG6WXG\WR(YDOXDWHWKH6DIHW\7ROHUDELOLW\DQG,PPXQRJHQLFLW\RID/\RSKLOL]HG)RUPXODWLRQRIWKH9DFFLQH&DQGLGDWH%17E$JDLQVW&29,'LQ+HDOWK\$GXOWV7KURXJK<HDUVRI$JH2QJRLQJ
D86,%
³2QJRLQJVWXGLHV´LQFOXGHRQJRLQJVWXGLHVDVZHOODVVWXGLHVLQ ZKLFKSDWLHQWHQUROOPHQWDQGIROORZXS
KDYHEHHQFRPSOHWHGEXWWKHDQDO\VLVDQG&65DUHLQSURJUHVV090177e19744d904\A pproved\A pproved On: 11-Jun-2021 10:28 (GMT )
FDA-CBER-2021-5683-1102878
&29,'9DFFLQH%173) 5HSRUWLQJ3HULRG
'HYHORSPHQW6DIHW\8SGDWH5HSRUW'6851R $SULOWKURXJ K$SULO
&21),'(17,$/
3DJH7DEOH ,QYHQWRU\ RI &29,' 9DFFLQH &OLQLFDO 7ULDOV 'XULQJ WKH'685
5HSRUWLQJ3HULRG &RQGXFWHGE\3IL]HU
3URWRFRO 1R
6WXG\ $OLDV
>(XGUD&7 1R
LI DYDLODEOH@
3KDVH 1R7LWOH 6WDWXV &RXQWU\LHV
5HIHUHQFH
'RFXPHQW
$EEUHYLDWLRQV '685 GHYHORSPHQWVDIHW\XSGDWHUHSRUW,% LQYHVWLJDWRUEURFKXUH3$66 SRVW
DXWKRUL]DWLRQVDIHW\6WXG\51$ ULERQXFOHLFDFLG
D ³2QJRLQJVWXGLHV´LQFOXGHRQJRLQJVWXGLHVDVZHOODVVWXGLHV LQZKLFKSDUWLFLSDQWHQUROOPHQWDQGIROORZ
XSKDYHEHHQFRPSOHWHGEXWWKHDQDO\VLVDQG&65DUHLQSURJUHV V
E 3RVWDXWKRUL]DWLRQVDIHW\VWXG\
'HWDLOVRI%LR17HFK)RVXQ&7VDUHVXPPDUL]HGLQ7DEOHEHORZ2IQ RWH%17DQG
%17KDGLQWHULPVWXG\UHSRUWVWKDWDUHDYDLODEOHXSRQUHTXHVW
7DEOH ,QYHQWRU\ RI &29,' 9DFFLQH &OLQLFDO 7ULDOV 'XULQJ WK H'685
5HSRUWLQJ 3HULRG &RQGXFWHG E\ %LR17HFK)RVXQ
3URWRFRO 1R
6WXG\ $OLDV
>(XGUD&7 1R
LI DYDLODEOH@
3KDVH 1R7LWOH 6WDWXV &RXQWU\LHV
5HIHUHQFH
'RFXPHQW
6WXG\ YDFFLQH %17D %17E %17E DQG %17F
%17>@
3KDVH$0XOWLVLWH3KDVH,,,3DUW'RVH(VFDODWLRQ7ULDO
,QYHVWLJDWLQJWKH6DIHW\DQG,PPXQRJHQLFLW\RI)RXU
3URSK\ODFWLF6$56&R951$9DFFLQHV$JDLQVW
&29,'8VLQJ'LIIHUHQW'RVLQJ5HJLPHQVLQ+HDOWK\DQG,PPXQRFRPSURPLVHG$GXOWV2QJRLQJ
DE*HUPDQ\,%
6WXG\ YDFFLQH %17E
%17F
3KDVH6DIHW\DQG,PPXQRJHQLFLW\RI6$56&R9P51$9DFFLQH%17ELQ&KLQHVH+HDOWK\6XEMHFWV$3KDVH,5DQGRPL]HG3ODFHERFRQWUROOHG2EVHUYHUEOLQG6WXG\2QJRLQJ
D&KLQD,%
6WXG\ YDFFLQH %17E
%17F
3KDVH6DIHW\DQG,PPXQRJHQLFLW\RI6$56&R9P51$
9DFFLQH%17ELQ&KLQHVH+HDOWK\3RSXODWLRQ$
3KDVH,,5DQGRPL]HG3ODFHERFRQWUROOHG2EVHUYHUEOLQG6WXG\2QJRLQJ
D&KLQD,%
6WXG\ YDFFLQH %17E
%17>@3KDVH$0XOWLVLWH3KDVH,,,3DUW'RVH(VFDODWLRQ7ULDO,QYHVWLJDWLQJWKH6DIHW\DQG,PPXQRJHQLFLW\RID3URSK\ODFWLF6$56&R951$9DFFLQH%17E2QJRLQJ
D*HUPDQ\,%
7KUHHLQWHULPUHSRUWVZHUHLVVXHGIRU6WXG\%17Y 6HSY1RYY
0DU
$QLQWHULPUHSRUWIRU6WXG\%17ZDVLVVXHGRQ)HE 090177e19744d904\A pproved\A pproved On: 11-Jun-2021 10:28 (GMT )
FDA-CBER-2021-5683-1102879
&29,'9DFFLQH%173) 5HSRUWLQJ3HULRG
'HYHORSPHQW6DIHW\8SGDWH5HSRUW'6851R $SULOWKURXJ K$SULO
&21),'(17,$/
3DJH7DEOH ,QYHQWRU\ RI &29,' 9DFFLQH &OLQLFDO 7ULDOV 'XULQJ WK H'685
5HSRUWLQJ 3HULRG &RQGXFWHG E\ %LR17HFK)RVXQ
3URWRFRO 1R
6WXG\ $OLDV
>(XGUD&7 1R
LI DYDLODEOH@
3KDVH 1R7LWOH 6WDWXV &RXQWU\LHV
5HIHUHQFH
'RFXPHQW
$JDLQVW&29,'8VLQJ'LIIHUHQW'RVLQJ5HJLPHQV
LQ+HDOWK\$GXOWV
D ³2QJRLQJVWXGLHV´LQFOXGHRQJRLQJVWXGLHVDVZHOODVVWXGLHVLQZKLFKSDUWLFLSDQWVHQUROOPHQWDQGIROORZXSKDYHEHHQFRPSOHWHGEXWWKHDQDO\VLVDQG&65DUHLQ SURJUHVV
E 7KLVWULDOKDVWZRSDUWV3DUW$DQG3DUW%'XHWRFKDQJHVLQWKHRYHUDOOFOLQLFDOGHYHORSPHQWSODQ3DUW%ZLOOQRORQJHUEHFRQGXFWHG7KHREMHFWLYHVRULJLQDOO\GHVFULEHGIRU3DUW%KDYHEHHQLPSOHPHQWHGLQWKH
RQJRLQJGHYHORSPHQWYLDDSLYRWDO3KDVHWULDO%17&
F 7KLVVWXG\LVFRQGXFWHGE\6KDQJKDL)RVXQ3KDUPDFHXWLFDO'HYHORSPHQW,QF
$SSHQGL[ SUHVHQWVDWDEXODULQYHQWRU\RIWULDOVFRQGXFWHGE\3IL]HUµ&¶WKDWZHUH
RQJRLQJRUFRPSOHWHGZLWKRXWDILQDOL]HG&65GXULQJWKHUHSRUWLQJSHULRG $SSHQGL[
LQFOXGHVWKHWRWDOQXPEHURIVXEMHFWVSHUWUHDWPHQWDUPIURPWKHVWDUWRIWKHVHFOLQLFDOWULDOV
$SSHQGL[ SUHVHQWVDWDEXODULQYHQWRU\RI%LR17HFK)RVXQRQJRLQJWULDOV
(67,0$7('&808/$7,9((;32685(
&XPXODWLYH6XEMHFW([SRVXUHLQWKH'HYHORSPHQW3URJUDPPH&XPXODWLYHO\LWLVHVWLPDWHGWKDWVXEMHFWVKDYHSDUWLFLSDW HGLQWKH&29,'YDFFLQH
µ&¶&7VVXEMHFWVUHFHLYHG%17EVXEMHFWVUHFHL YHG%17ERI
ZKLFKVXEMHFWVUHFHLYHG%17ESRVWXQEOLQGLQJDQGKDG UHFHLYHG3ODFHER
EHIRUHDQGVXEMHFWVUHFHLYHGDEOLQGHGERRVWZLWKHLWKHU%17 ERU%17EV
DQGKDGUHFHLYHG%17EEHIRUHUHFHLYHG%17EV
VXEMHFWVUHFHLYHG
EOLQGHGWKHUDS\DQGVXEMHFWVUHFHLYHGSODFHER
$GGLWLRQDOO\VXEMHFWVKDYHSDUWLFLSDWHGLQ%LR17HFK)RVXQ& 7VRIZKLFK
SDUWLFLSDWHGWRWKH&KLQHVHVWXGLHVFRQGXFWHGE\)RVXQ6XEMHFWGHPRJUDSKLFVGDWDHJDJHJHQGHUUDFHIRUµ&¶&7V LVSUHVHQWHGE\WUHDWPHQW
JURXSLQ$SSHQGL[ &XPXODWLYH&7H[SRVXUHVZLWKGHPRJUDSKLFGDWDIURP
%LR17HFK)RVXQ&7VLVSUHVHQWHGLQ $SSHQGLFHV DQG
3DWLHQW([SRVXUHIURP0DUNHWLQJ([SHULHQFH
,WLVQRWSRVVLEOHWRGHWHUPLQHZLWKFHUWDLQW\WKHQXPEHURILQ GLYLGXDOVZKRUHFHLYHG
&29,'YDFFLQHGXULQJWKHSHULRGRIWKLVUHYLHZ(VWLPDWHGZR UOGZLGHVKLSSHGGRVHV
PD\VHUYHDVDUHDVRQDEOHLQGLFDWRURIVXEMHFWH[SRVXUHFRQVLG HULQJWKDWDSSUR[LPDWHO\
RIWKHVKLSSHGGRVHVZHUHDGPLQLVWHUHG
%17EVLVDOVRUHIHUUHGWRDV%17E6$090177e19744d904\A pproved\A pproved On: 11-Jun-2021 10:28 (GMT )
FDA-CBER-2021-5683-1102880
&29,'9DFFLQH%173) 5HSRUWLQJ3HULRG
'HYHORSPHQW6DIHW\8SGDWH5HSRUW'6851R $SULOWKURXJ K$SULO
&21),'(17,$/
3DJH:LWKWKHVHFDYHDWVLQPLQGWKHHVWLPDWHGFXPXODWLYHZRUOGZLGH VKLSSHGGRVHVIRU&29,'
YDFFLQHIURPILUVWHPHUJHQF\XVHVXSSO\WKURXJK$SULOLVDSSUR[LPDWHO\
GRVHV
$GGLWLRQDOO\DQHVWLPDWHRI GRVHVZHUHGLVWULEXWHGLQ +RQJ.RQJDQG0DFDX
WKURXJK)RVXQ
'$7$ ,1 /,1( /,67,1*6 $1' 6800$5< 7$%8/$7,216
5HIHUHQFH,QIRUPDWLRQ7KH0HGLFDO'LFWLRQDU\IRU5HJXODWRU\$FWLYLWLHV0HG'5$YHUVL RQKDVEHHQXVHGWR
FRGHDGYHUVHHYHQWVLQOLQHOLVWLQJVDQGVXPPDU\WDEOHV 'XULQJ WKHUHSRUWLQJSHULRGWKH,%V
YHUVLRQVWR6HFWLRQ Reference Safety Information for Assessment of
Expectedness of Serious Adverse Reactions DYDLODEOHIURPYHUVLRQ
10ZHUHXVHGWR
GHWHUPLQHHYHQWH[SHFWHGQHVVDWWKHWLPHRILQGLYLGXDOFDVHSURFHVVLQJIRUH[SHGLWHG
UHSRUWLQJSXUSRVHVRI686$5V7KH56,LVSUHVHQWHGLQ 6HFWLRQChanges to Reference
Safety Information
/LQH /LVWLQJV RI6HULRXV $GYHUVH 5HDFWLRQV 'XULQJ WKH 5HSRU WLQJ 3HULRG
$SSHQGL[ DQG$SSHQGL[ SURYLGHOLQHOLVWLQJVRIVHULRXVDGYHUVHHYHQWV6$(VUHSRUWHG
LQFOLQLFDOWULDOFDVHVWKDWFRQWDLQDWOHDVWRQHVXVSHFWHGVHU LRXVDGYHUVHUHDFWLRQ6$5
UHFHLYHGE\WKHVSRQVRUIURP$SULOWKURXJK$SULO 7KHVHDSSHQGLFHVDUH
RUJDQL]HGDFFRUGLQJWR62&FRUUHVSRQGLQJWRWKHSULPDU\$(UHSRUWHGLQHDFKFDVH
'XULQJWKLV'685UHSRUWLQJSHULRGFDVHVFRQWDLQHG6$5VFRQVLGHUHGSRVVLEO\
UHODWHGWRWKHVWXG\YDFFLQHV>%173ODFHER@>%17E3ODFHE R@%17EDQGRU
WKHFOLQLFDOWULDOSURFHGXUH $OOUHSRUWHG6$5VZHUHVLQJOHRF FXUUHQFHV>37V$FXWHP\HORLG
OHXNDHPLD$QDSK\ODFWRLGUHDFWLRQ&\VWLWLV+\SHUWK\URLGLVP/\ PSKDGHQRSDWK\
0\RFDUGLDOLQIDUFWLRQ1HXULWLV3DUDHVWKHVLD3VRULDWLFDUWKUR SDWK\6KRXOGHULQMXU\UHODWHG
WRYDFFLQHDGPLQLVWUDWLRQ7K\URLGPDVV9HQWULFXODUDUUK\WKPLD HDFK@ 2IWKHVH
FDVHV6$5ZDVFRQVLGHUHGUHODWHGWREOLQGHGWKHUDS\ 1RQHRI WKHVH6$5VZHUHH[SHFWHG
DVSHU%173),%VYHUVLRQVWR56,2IWKHFDVHVQRWHGDERYHFDVHVFRQWDLQHGVXVSHFWHG686$5V ZKLFKZHUH
FRQVLGHUHGUHODWHGWRWKHVWXG\YDFFLQHV>%17E3ODFHER@>% 17E3ODFHER@RU
%71EJLYHQDVDVLQJOHDJHQWE\HLWKHUWKH,QYHVWLJDWRURU VSRQVRU2IWKHVH686$5
ZDVDOVRFRQVLGHUHGSRVVLEO\UHODWHGWRDFOLQLFDOWULDOSURFHGX UHYDFFLQHDGPLQLVWUDWLRQE\
HLWKHUWKH,QYHVWLJDWRURUWKHVSRQVRU 7KH686$5VHQFRGHGWR WKHIROORZLQJ0HG'5$37V
1RWHWKDWWKH&29,'YDFFLQHLVGLVWULEXWHGPDUNHWHGWKURXJK 6KDQJKDL)RVXQ3KDUPDFHXWLFDOLQ
WKHVHWHUULWRULHV
7KLVZDVQDPHG6HFWLRQ Reference Safety Information LQSULRU,%YHUVLRQV$SULODQG
-XO\
3OHDVHQRWHWKDWHYHQWVUHSRUWHGLQFDVH>+\SHUWK\URLGLVP7K \URLGPDVV6$5V686$5V+HSDWLF
IDLOXUH1HXWURSHQLD8ULQDU\WUDFWLQIHFWLRQ3XOPRQDU\PDVV6 $(V@GRQRWGLVSOD\LQWKH'685DSSHQGLFHV
DVWKLVZDVUHFHLYHGGD\VSRVWWKHDZDUHQHVVGD\$SU UHFHLYHGRQ$SU090177e19744d904\A pproved\A pproved On: 11-Jun-2021 10:28 (GMT )
(b) (4)
FDA-CBER-2021-5683-1102881
&29,'9DFFLQH%173) 5HSRUWLQJ3HULRG
'HYHORSPHQW6DIHW\8SGDWH5HSRUW'6851R $SULOWKURXJ K$SULO
&21),'(17,$/
3DJH$FXWHP\HORLGOHXNDHPLD$QDSK\ODFWRLGUHDFWLRQ&\VWLWLV+\SH UWK\URLGLVP
/\PSKDGHQRSDWK\0\RFDUGLDOLQIDUFWLRQ3DUDHVWKHVLD6KRXOGHU LQMXU\UHODWHGWRYDFFLQH
DGPLQLVWUDWLRQ>6,59$@7K\URLGPDVV9HQWULFXODUDUUK\WKPLD HDFK
&XPXODWLYH6XPPDU\ 7DEXODWLRQVRI6HULRXV$GYHUVH(YHQWV
$SSHQGLFHV DQGSURYLGHFXPXODWLYHVXPPDU\WDEXODWLRQVRI6$(VUHSRUWHGLQFOLQLF DO
WULDOFDVHVUHFHLYHGE\WKHVSRQVRU7KLVDSSHQGL[LVRUJDQL]HGDFFRUGLQJWR62&
6,*1,),&$17),1',1*6)520&/,1,&$/75,$/6'85,1*7+(
5(3257,1*3(5,2'
&RPSOHWHG &OLQLFDO 7ULDOV$VQRWHGDERYH 6HFWLRQQRFOLQLFDOWULDOVZHUHFRPSOHWHGGXULQJWKLVUHSRUWLQJSHULRG
2QJRLQJ &OLQLFDO 7ULDOV'XULQJWKHUHSRUWLQJSHULRGWKHUHZHUHRQJRLQJ
VSRQVRULQLWLDWHGFOLQLFDOWULDOV
&&&&&&%17%17
%17DQG%17&OLQLFDOO\LPSRUWDQWHPHUJLQJHIILF DF\DQGRUVDIHW\
ILQGLQJVZHUHLGHQWLILHGIRU6WXG\&%17DQG&D QGDUHVXPPDUL]HG
EHORZ
•6WXG\&%17
7LWOH$3KDVH3ODFHER&RQWUROOHG5DQGRPL]HG2EVHUYHU%OLQG 'RVH)LQGLQJ6WXG\
WR(YDOXDWHWKH6DIHW\7ROHUDELOLW\,PPXQRJHQLFLW\DQG(IILF DF\RI6$56&2951$
9DFFLQH&DQGLGDWHV$JDLQVW&29,'LQ+HDOWK\,QGLYLGXDOV
&RXQWULHV$UJHQWLQD%UD]LO*HUPDQ\6RXWK$IULFD7XUNH\86
6WXG\&%17LVDQRQJRLQJUDQGRPL]HGSODFHERFRQWURO OHGREVHUYHUEOLQG
GRVHILQGLQJ3KDVHUHJLVWUDWLRQVWXG\HYDOXDWLQJWKHVDIH W\WROHUDELOLW\
LPPXQRJHQLFLW\DQGHIILFDF\RI6$56&R951$YDFFLQHFDQGLGDW HVDJDLQVW&29,'
LQKHDOWK\LQGLYLGXDOV6WXG\&%17ZDVVWDUWHGD VD3KDVHVWXG\LQ
DGXOWVLQWKH86DQGZDVWKHQDPHQGHGWRH[SDQGWKHVWXG\WRD JOREDO3KDVHVWXG\WR
DFFUXHVXIILFLHQW&29,'FDVHVWRFRQGXFWDQHIILFDF\DVVHVVPHQ W7KHSURWRFRO
ZDVLQLWLDWHGLQDGXOWV\HDUVRIDJHDQGROGHUDQGVXEVHTXHQW O\DPHQGHGWRLQFOXGH
DGROHVFHQWVDV\RXQJDV\HDUVRIDJH7KHVWXG\KDVHQUROOHGDSS UR[LPDWHO\
SDUWLFLSDQWVLQFOXGLQJ\RXQJDGROHVFHQWVWR\HDUVRID JH'DWDIURPWKH3KDVH 1
SDUWRIWKHVWXG\ZDVWKHEDVLVIRUVHOHFWLRQRIWKHYDFFLQHFD QGLGDWHDQGGRVHOHYHOIRU3KDVH
7KH3KDVHSDUWRIWKHVWXG\HYDOXDWHGWKHVDIHW\LPPX QRJHQLFLW\DQGHIILFDF\RIWKH
VHOHFWHGYDFFLQHFDQGLGDWH%17EDQGLVLQWHQGHGWRVXSSRUWOLFHQVXUHJOREDOO\
7KHDYDLODEOHFOLQLFDOHYLGHQFHIRU%17ELQFOXGHVDWROHUDEOH VDIHW\SURILOHDQGKLJK9(
DJDLQVW&29,'LQLQGLYLGXDOV\HDUVRIDJH7KHSRWHQWLDOULVNVDUHEDVHGRQWKHREVHUYHGVDIHW\SURILOHWR GDWHZKLFKVKRZVPRVWO\PLOG
WRPRGHUDWHUHDFWRJHQLFLW\DQDFFHSWDEOHLQFLGHQFHRIVHYHUHRU VHULRXVHYHQWVDQGQR
FOLQLFDOO\FRQFHUQLQJVDIHW\REVHUYDWLRQV7KHYDFFLQHDSSHDUV WREHVDIHDQGZHOOWROHUDWHG090177e19744d904\A pproved\A pproved On: 11-Jun-2021 10:28 (GMT )
FDA-CBER-2021-5683-1102882
&29,'9DFFLQH%173) 5HSRUWLQJ3HULRG
'HYHORSPHQW6DIHW\8SGDWH5HSRUW'6851R $SULOWKURXJ K$SULO
&21),'(17,$/
3DJHDFURVVWKHVDIHW\SRSXODWLRQDQGZLWKLQGHPRJUDSKLFVXEJURXSVE DVHGRQDJHVH[
UDFHHWKQLFLW\FRXQWU\DQGEDVHOLQH6$56&R9VWDWXV7KHSU HSRQGHUDQFHRIVHYHUHFDVHV
RI&29,'DVGHILQHGE\WKH)'$*XLGDQFHIRU,QGXVWU\-XQH LQWKHSODFHER
JURXSUHODWLYHWRWKH%17EJURXSRIVXJJHVWVQRHYLGHQ FHRIYDFFLQHDVVRFLDWHG
HQKDQFHGGLVHDVH
9DFFLQHHIILFDF\ZDVIRUSDUWLFLSDQWVZLWKRXWSULRUHYLGHQFHRI6$56&R9
LQIHFWLRQDQG!IRUWKRVHLUUHVSHFWLYHRISULRULQIHFWLRQV2E VHUYHG9(ZDV!ZKHQ
GDWDZHUHVWUDWLILHGE\DJHVH[UDFHHWKQLFLW\DQGFRXQWU\ZL WKWKHH[FHSWLRQRIWKH³DOO
RWKHUV´UDFHJURXS9(DQG%UD]LO9(
6HYHUHFDVHVHYDOXDWHGIRUHIILFDF\ZHUHFRQILQHGSUHGRPLQDQWO\ WRWKHSODFHERJURXS
RQO\VHYHUHFDVHZDVUHSRUWHGLQWKH%17EJURXSLQWKHILQDO DQDO\VLV7KHHIILFDF\
GDWDVXJJHVWKLJKHIILFDF\DJDLQVW&29,'LQDEURDGSRSXODWLRQ RILQGLYLGXDOV
•6WXG\&
7LWOH$3KDVH3ODFHER&RQWUROOHG5DQGRPL]HGDQG2EVHUYHU%OL QG6WXG\WR(YDOXDWH
WKH6DIHW\7ROHUDELOLW\DQG, PPXQRJHQLFLW \RID6$56 &R951$ 9DFFLQH&DQGLGDWH
$JDLQVW&RYLG,Q+HDOWK\-DSDQHVH$GXOWV
&RXQWU\-DSDQ
6WXG\&LVD3KDVHUDQGRPL]HGSODFHERFRQWUROOHGDQ GREVHUYHUEOLQGVWXG\
LQKHDOWK\-DSDQHVHDGXOWV7KHVWXG\ZLOOHYDOXDWHWKHVDIHW\ WROHUDELOLW\DQG
LPPXQRJHQLFLW\RIWKH6$56&R9P51$YDFFLQHFDQGLGDWH%17EDJDLQVW
&29,'DGPLQLVWHUHGDVWZRJGRVHVGD\VDSDUWLQ-DSD QHVHDGXOWVWR\HDUV
RIDJH
&OLQLFDOODERUDWRU\WHVWVZHUHSHUIRUPHGIRUWKHILUVWSDUWL FLSDQWVSDUWLFLSDQWV
WR yHDUVRIDJHDQGSDUWLFLSDQWVWR\HDUVRIDJHFOLQLFDOODERUDWRU\VXEVHW
/RFDOUHDFWLRQVUHGQHVVVZHOOLQJDQGSDLQDWWKHLQMHFWLRQV LWHV\VWHPLFHYHQWVIHYHU
YRPLWLQJGLDUUKHDKHDGDFKHIDWLJXHFKLOOVQHZRUZRUVHQHG PXVFOHSDLQDQGQHZRU
ZRUVHQHGMRLQWSDLQDQGXVHRIDQWLS\UHWLFPHGLFDWLRQZHUHFR OOHFWHGE\DOOSDUWLFLSDQWVLQ
DQHGLDU\IURP'D\WKURXJK'D\DIWHUHDFKDGPLQLVWUDWLRQRIVWXG\LQWHUYHQWLRQ$(V
ZHUHFROOHFWHGIURPWKHWLPHWKHSDUWLFLSDQWSURYLGHGLQIRUPHG FRQVHQWWKURXJK
PRQWKDIWHU'RVH6$(VZLOOEHFROOHFWHGIURPWKHVLJQLQJRIWKH ,&'WRDSSUR[LPDWHO\
PRQWKVDIWHU'RVH
,QWKLVVWXG\-DSDQHVHSDUWLFLSDQWVLQFOXGLQJSDUWLFLS DQWVWR\HDUVRIDJH
>\RXQJHUDJHJURXS@DQGSDUWLFLSDQWVWR\HDUVRIDJH>ROGHUDJHJURXS@ZHUH
UDQGRPL]HGLQDQDSSUR[LPDWHUDWLRRI%17EWRSODFHER,QW HULPGDWDVKRZ
%17EZDVZHOOWROHUDWHGZLWKORFDOUHDFWLRQVDQGV\VWHPLFH YHQWVPRVWO\PLOGRU
PRGHUDWHLQVHYHULW\DQGQRLPPHGLDWH$(VZLWKLQPLQXWHVUH SRUWHG$QDFFHSWDEOH
VDIHW\SURILOHZDVREVHUYHGLQERWK\RXQJHUDQGROGHU-DSDQHVH DGXOWVZLWKQR6$(VUHSRUWHG
'HYHORSPHQWDQG/LFHQVXUHRI9DFFLQHVWR3UHYHQW&29,'*XLGD QFHIRU,QGXVWU\-XQH090177e19744d904\A pproved\A pproved On: 11-Jun-2021 10:28 (GMT )
FDA-CBER-2021-5683-1102883
&29,'9DFFLQH%173) 5HSRUWLQJ3HULRG
'HYHORSPHQW6DIHW\8SGDWH5HSRUW'6851R $SULOWKURXJ K$SULO
&21),'(17,$/
3DJHWKURXJKPRQWKDIWHU'RVH,PPXQHUHVSRQVHVHOLFLWHGE\%17EZHUHUREXVW month
DIWHU'RVHFRQVLVWHQWZLWKGDWDIURPWKHJOREDOSURJUDP7KHVH HQFRXUDJLQJUHVXOWVOHGWR
WKHPDUNHWLQJDXWKRUL]DWLRQRI%17ELQ-DSDQ7KLVVWXG\KDVV LQFHEHHQFRQYHUWHGWRD
SRVWPDUNHWLQJVWXG\
%DVHGXSRQWKHDYDLODEOHFOLQLFDOGDWDUHYLHZHGGXULQJWKHUHSRU WLQJSHULRGQRFOLQLFDOO\
VLJQLILFDQWVDIHW\DQGRUHIILFDF\LQIRUPDWLRQKDVHPHUJHGIURP %LR17HFK)RVXQ¶VRQJRLQJ
FOLQLFDOWULDOV6WXG\%171%17%17DQG%17
'XULQJWKHUHSRUWLQJSHULRGFDVHVIURPRQJRLQJVWXGLHV>& %17
RU%17@UHSRUWHG6$5VLHDGYHUVHHYHQWWKDWZHUHFRQVLGH UHGWREHUHODWHGWRWKH
VWXG\YDFFLQHV>%17E3ODFHER@>%17E3ODFHER@%17E DQGRUWKHFOLQLFDO
WULDOSURFHGXUHE\WKH,QYHVWLJDWRUDQGRUWKHVSRQVRURQHFDVH
$QDSK\ODFWRLGUHDFWLRQZDVGHWHUPLQHGWREHUHOHYDQWWRWKHVDI HW\FRQFHUQVOLVWHGLQ
6HFWLRQ QRQHUHSUHVHQWHGDVLJQDO7KHRYHUDOOFDVHVDUHSUHVHQWHGE\3 URWRFROLQ
7DEOH686$5VGHQRWHGLQEROG
7DEOH 6HULRXV $GYHUVH 5HDFWLRQV 5HSRUWHG 'XULQJ WKH '685 3HULRG $SU
WR $SU
$(5 &RXQWU\$JH
\HDUV *HQGHU37 686$5V GHQRWHG LQ
EROG 2XWFRPH&RPPHQW
6WXG\ &
86D
)6KRXOGHU LQMXU\ UHODWHG
WR YDFFLQHDGPLQLVWUDWLRQ >6,59$@
>5@7KHVXEMHFWKDGDKLVWRU\RIDOOHUJLHVDQGUHFHLYHGGRVHVRIWKHVWXG\YDFFLQHRQ$XJDQGRQ6HS6,59$RFFXUUHGRQWKHVDPHGD\RIWKHVHFRQGGRVH
DGPLQLVWUDWLRQ7KHHYHQWLPSURYHGXSRQSK\VLFDOWKHUDS\
DQGWKHVXEMHFWFRPSOHWHO\UHFRYHUHGRQ)HE7KHLQYHVWLJDWRUFRQVLGHUHGWKHUHZDVDUHDVRQDEOHSRVVLELOLW\WKDWWKHHYHQWZDVUHODWHGWRWKHFOLQLFDOSURFHGXUHYDFFLQHDGPLQLVWUDWLRQDQGWKHVWXG\YDFFLQH%17E
3ODFHER7KH&RPSDQ\DJUHHVZLWKWKH,QYHVWLJDWRU
DVVHVVPHQW
86D
)/\PSKDGHQRSDWK\ >5@ 7KHVXEMHFWKDGDKLVWRU\RIVHDVRQDODOOHUJLHVVLQXVKHDGDFKHEHQLJQSDUR[\VPDOYHUWLJRRVWHRDUWKULWLVDQGHF]HPDVKHDOVRKDGXWHULQHILEURLGVPHQRUUKDJLDIURPWR6KHUHFHLYHGDVLQJOHGRVHRIYDFFLQHRQ6HSWKHVHFRQGGRVHGXHRQ6HSZDVQRW
DGPLQLVWHUHG7KHVXEMHFWH[SHULHQFHGULJKWD[LOODU\
O\PSKDGHQRSDWK\RQ6HSDQGZDVWUHDWHGZLWKNHWRURODF%LRSV\FRPSOHWHGRQ2FWVKRZHGQRPDUNHUVIRUO\PSKRPDRURWKHUFDQFHU6KHFRPSOHWHO\UHFRYHUHGRQ1RY7KH,QYHVWLJDWRUFRQVLGHUHGWKHHYHQWDVSRVVLEO\UHODWHGWRWKHVWXG\YDFFLQH%17E
3ODFHER7KHFRPSDQ\GLGQRWFRQFXUZLWKWKH
,QYHVWLJDWRU¶VDVVHVVPHQWWKHYDFFLQHZDVDGPLQLVWHUHGRQWKHOHIWGHOWRLGPXVFOHZKHUHDVO\PSKDGHQRSDWK\RFFXUUHGLQWKHULJKWD[LOOD
86D
)9HQWULFXODU DUUK\WKPLD>5@7KHVXEMHFWKDGDUHOHYDQWFDUGLDFKLVWRU\RIFRPSOHWHDWULRYHQWULFXODUEORFNIRUZKLFKDFDUGLDFSDFHPDNHUZDVLQVHUWHGVLQRDWULDOQRGHG\VIXQFWLRQSDUR[\VPDODWULDO
ILEULOODWLRQDQGSDUR[\VPDOVXSUDYHQWULFXODUWDFK\FDUGLD090177e19744d904\A pproved\A pproved On: 11-Jun-2021 10:28 (GMT )
(b) (6)
(b) (6)
(b) (6)
(b) (6)
FDA-CBER-2021-5683-1102884
&29,'9DFFLQH%173) 5HSRUWLQJ3HULRG
'HYHORSPHQW6DIHW\8SGDWH5HSRUW'6851R $SULOWKURXJ K$SULO
&21),'(17,$/
3DJH7DEOH 6HULRXV $GYHUVH 5HDFWLRQV 5HSRUWHG 'XULQJ WKH '685 3HULRG $SU
WR $SU
$(5 &RXQWU\$JH
\HDUV *HQGHU37 686$5V GHQRWHG LQ
EROG 2XWFRPH&RPPHQW
6KHUHFHLYHGGRVHVRIWKHYDFFLQHRQ6HSDQGRQ
2FW6LQFHWKHGD\RIWKHVHFRQGGRVHVKHH[SHULHQFHGHSLVRGHVRIYHQWULFXODUWDFK\FDUGLDRQHDFKRI
WKHIROORZLQJGD\VDVVRFLDWHGZLWKIDWLJXHDQGPDODLVH
7KHSDWLHQWXQGHUZHQWHOHFWURSK\VLRORJ\VWXG\QRFDUGLRYHUWHUGHILEULOODWRUSODFHPHQW7KHVXEMHFWUHFRYHUHGRQ2FW7KHLQYHVWLJDWRUFRQVLGHUHGWKHUHZDVDUHDVRQDEOHSRVVLELOLW\WKDWWKHHYHQW
SDUR[\VPDOYHQWULFXODUDUUK\WKPLDV
ZDVUHODWHGWRWKHEOLQGHGYDFFLQH
%17E3ODFHEREDVHGRQWKHWHPSRUDOUHODWLRQVKLS
7KHFRPSDQ\FRQVLGHUHGWKHVXEMHFW¶VXQGHUO\LQJFRQGLWLRQDPRUHSODXVLEOHFDXVH
86D
)3DUDHVWKHVLD >5*@ 7KHVXEMHFWKDGDKLVWRU\RIFKURQLFPLJUDLQHVQHFNSDLQYLWDPLQ'GHILFLHQF\DQG9LWDPLQ%GHILFLHQF\6KHUHFHLYHGGRVHVRIWKHYDFFLQHRQ$XJDQGRQ6HS2Q2FWWKHVXEMHFWVWDUWHGH[SHULHQFLQJ
ULJKWOHJSDUDHVWKHVLDFORVHUWRZHHNVDIWHUYDFFLQDWLRQ
7KH,QYHVWLJDWRUFRQVLGHUHGWKHHYHQWSRVVLEO\UHODWHGWRWKHVWXG\YDFFLQH%17E3ODFHEREDVHGRQDWHPSRUDOUHODWLRQVKLSDQGQRDOWHUQDWLYHFDXVHVWKHFRPSDQ\FRQVLGHUHGWKHVXEMHFW
VXQGHUO\LQJNQRZQQHXURORJLFDOFRQGLWLRQVDPRUHSODXVLEOHFDXVH
86
)1HXULWLV>5 @ 7KHVXEMHFWKDGDKLVWRU\RIGHYLDWHGVHSWXP6KHUH FHLYHG
GRVHVRIWKHYDFFLQHRQ-XQDQGRQ-XO2Q-XOWKHVXEMHFWH[SHULHQFHGQHXULWLVZKLFKKDGEHHQRFFXUULQJLQWHUPLWWHQWO\VLQFHDEORRGGUDZGRQHLQWKHULJKWDQWHFXELWDOIRVVDRQYLVLW6KHUHFRYHUHGRQ0DU7KHLQYHVWLJDWRUFRQVLGHUHGWKHUHZDVDUHDVRQDEOHSRVVLELOLW\WKDWWKHHYHQWQHXULWLVZDVUHODWHGWR
FOLQLFDOWULDOSURFHGXUHXQUHODWHGWREOLQGHGVWXG\YDFFLQH
DQGFRQFRPLWDQWPHGLFDWLRQ7KHFRPSDQ\FRQFXUUHGZLWKWKH,QYHVWLJDWRU¶VDVVHVVPHQW
86
03VRULDWLFDUWKURSDWK\>15@ 7KHVXEMHFWKDGDKLVWRU\RIVHDVRQDO DOOHUJ\DQGPLJUDLQHV
+HUHFHLYHGGRVHVRIWKHYDFFLQHRQ-XODQGRQ$XJ0RUHWKDQRQHPRQWKIROORZLQJWKHVHFRQGGRVHRIWKHEOLQGHGVWXG\YDFFLQHKHGHYHORSHGSVRULDWLF
DUWKULWLVZKLFKGLGQRWUHFRYHUDWWKHWLPHRIWKHUHSRUW7KH
LQYHVWLJDWRUFRQVLGHUHGWKHUHZDVDUHDVRQDEOHSRVVLELOLW\WKDWWKHHYHQWSVRULDWLFDUWKULWLVZDVUHODWHGWRWKHEOLQGHGVWXG\YDFFLQHDQGWRWKHFOLQLFDOWULDOSURFHGXUH7KHFRPSDQ\FRQVLGHUHGWKHHYHQWDQLQFLGHQWDOPHGLFDOFRQGLWLRQDQGGLGQRWFRQVLGHULWUHODWHG
7XUNH\
00\RFDUGLDO LQIDUFWLRQ
>5@7KHVXEMHFWZLWKQRSULRUPHGLFDOKLVWRU\UHSRUWHGUHFHLYHGGRVHVRIWKHVWXG\YDFFLQHRQ1RYDQG
1RY
2Q)HEWKHVXEMHFWH[SHULHQFHGD
SUREDEOHKHDUWDWWDFN7KHLQYHVWLJDWRUFRQVLGHUHGWKDWWKHUH
ZDVDUHDVRQDEOHSRVVLELOLW\WKDWWKHHYHQWZDVUHODWHGWREOLQGHGVWXG\YDFFLQH%17%3ODFHERDVWKHVXEMHFW
GHVFULEHGKLPVHOIDVKHDOWK\KDYLQJQRFDUGLDFGLVHDVHQR
FDUGLDFFRPSODLQWQRFRURQDU\REVWUXFWLRQEHIRUH090177e19744d904\A pproved\A pproved On: 11-Jun-2021 10:28 (GMT )
(b) (6)
(b) (6)
(b) (6)
(b) (6)
FDA-CBER-2021-5683-1102885
&29,'9DFFLQH%173) 5HSRUWLQJ3HULRG
'HYHORSPHQW6DIHW\8SGDWH5HSRUW'6851R $SULOWKURXJ K$SULO
&21),'(17,$/
3DJH7DEOH 6HULRXV $GYHUVH 5HDFWLRQV 5HSRUWHG 'XULQJ WKH '685 3HULRG $SU
WR $SU
$(5 &RXQWU\$JH
\HDUV *HQGHU37 686$5V GHQRWHG LQ
EROG 2XWFRPH&RPPHQW
YDFFLQDWLRQDQGQRIDPLO\KLVWRU\RIKHDUWGLVHDVH7KH
FRPSDQ\GLGQRWFRQFXUZLWKWKH,QYHVWLJDWRUDVVHVVPHQWEDVHGRQWKHILQGLQJRIVORZIORZDQGSODTXHLQWKHOHIW
GHVFHQGLQJFRURQDU\DUWHU\RQWKHSDWKRSK\VLRORJ\RIWKH
HYHQWDQGWKHWHPSRUDOUHODWLRQVKLSPRQWKVGD\VODWHQF\
6WXG\ & ±2SHQ ODEHO
86
)$QDSK\ODFWRLG UHDFWLRQ>5@7KHVXEMHFWZDV
LQWKHRSHQODEHOSKDVHRIWKHVWXG\ZKHQ
WKHHYHQWRFFXUUHGVKHKDGDKLVWRU\RIPXOWLSOHDOOHUJLHVIRRGDQGPHGLFDWLRQZLWKDQDSK\OD[LV6KHUHFHLYHGSULRUGRVHVRISODFHERRQ1RYDQG'HF
DQGUHFHLYHGWKHILUVWGRVHRI%17ERQ-DQ
7ZRGD\VODWHUVKHH[SHULHQFHGOHIWDUPKLYHVVKRUWQHVVRIEUHDWKDQGDGLDJQRVLVRIDQDSK\ODFWRLGUHDFWLRQ7KHVXEMHFWVHOIDGPLQLVWHUHGKHUHSLSHQWRWUHDWV\PSWRPVZKLFKUHVROYHG7KHVHFRQGGRVHRI%17EZDVQRWDGPLQLVWHUHGZLWKLQVWXG\FRQGXFW6KHUHFHLYHGDVHFRQG
GRVHGD\VDIWHUWKHILUVWRQHWKURXJKKHUSULPDU\FDUH
ZLWKRXW$(V7KH,QYHVWLJDWRUFRQVLGHUHGWKHHYHQWWREHSRVVLEO\UHODWHGWRWKHILUVW%17EGRVH7KHFRPSDQ\FRQFXUUHGZLWKWKH,QYHVWLJDWRUDVVHVVPHQW
86
0$FXWH P\HORLG OHXNDHPLD
>15@7KHVXEMHFWZDVLQWKHRSHQODEHOSKDVHRIWKHVWXG\ZKHQWKHHYHQWRFFXUUHGKHUHFHLYHGGRVHVRI3ODFHERRQ$XJDQG6HSDQGZDVDGPLQLVWHUHGILUVW
DQGVHFRQGGRVHVRI%17ERQ-DQDQG)HE
UHVSHFWLYHO\7KHVXEMHFWZDVGLDJQRVHGZLWKDFXWHP\HOREODVWLFOHXNHPLD$0/RQ0DU+HKDGPXOWLSOHPHGLFDOKLVWRULHVLQFOXGLQJGLDEHWHVPHOOLWXVW\SHK\SHUFKROHVWHUROHPLDREHVLW\K\SHUWHQVLRQVOHHSDSQHDNQHHV¶RVWHRDUWKULWLVJDVWURHVRSKDJHDOUHIOX[GLVHDVH
$GGLWLRQDOO\PHGLFDOFRQGLWLRQVUHSRUWHGSRVW%17E
YDFFLQDWLRQLQFOXGHGFRURQDU\DUWHU\GLVHDVHSURGXFWLYHFRXJKK\SRNDOHPLDSRWHQWLDOO\GHFRPSHQVDWHGHDUO\DQJLQDSQHXPRQLDHOHYDWHGWURSRQLQOHYHOQRQ67HOHYDWLRQP\RFDUGLDOLQIDUFWLRQ$(5 ZLWK
FRURQDU\VSDVP$(5 FRURQDU\EORRGVWDVLV
$(5 DQGZRUVHQLQJRIHOHYDWHGWURSRQLQ
OHYHOUHSRUWHGFRQFRPLWDQWO\WRWKH$0/GLDJQRVLV7KHVXEMHFWZDVDGPLWWHGWRWKHKRVSLWDOIRULQGXFWLRQFKHPRWKHUDS\RQSURWRFRORQ$SUZLWKSODQQHGWUHDWPHQWGDWHVWKURXJK$XJZLWKD]DF\WLGLQH
PJLQWUDYHQRXVSLJJ\EDFN,93%YHQHWRFOD[PJ
RUDO[GD\DQGLYRVLGHQLE&RQFRPLWDQWPHGLFDWLRQVLQFOXGHGULYDUR[DEDQLVRVRUELGHDWRUYDVWDWLQPHWRSUROROLSUDWURSLXPEURPLGHLSUDWURSLXPEURPLGHDOEXWHUROYDODF\FORYLUVLWDJOLSWLQPHWIRUPLQLQVXOLQOLVSURFDVSRIXQJLQFHIWD]LGLPHOLQH]ROLG
OHYRFHWLUL]LQH$GGLWLRQDOPHGLFDWLRQVLQFOXGHSDUDFHWDPRO090177e19744d904\A pproved\A pproved On: 11-Jun-2021 10:28 (GMT )
(b) (6)
(b) (6)
(b) (6)
(b) (6)
(b) (6)
FDA-CBER-2021-5683-1102886
&29,'9DFFLQH%173) 5HSRUWLQJ3HULRG
'HYHORSPHQW6DIHW\8SGDWH5HSRUW'6851R $SULOWKURXJ K$SULO
&21),'(17,$/
3DJH7DEOH 6HULRXV $GYHUVH 5HDFWLRQV 5HSRUWHG 'XULQJ WKH '685 3HULRG $SU
WR $SU
$(5 &RXQWU\$JH
\HDUV *HQGHU37 686$5V GHQRWHG LQ
EROG 2XWFRPH&RPPHQW
K\GUR[\XUHDDOORSXULQRO7KHRXWFRPHRIWKHHYHQWZDVQRW
UHFRYHUHG
7KHLQYHVWLJDWRUFRQVLGHUHGWKHUHZDVDUHDVRQDEOH
SRVVLELOLW\WKDW$0/ZDVUHODWHGWR%17EZKLOHXQUHODWHGWREOLQGHGVWXG\YDFFLQHFRQFRPLWDQWGUXJVRUFOLQLFDOWULDOSURFHGXUH7KHLQYHVWLJDWRUKDGFRQVLGHUHGWKHWLPHIUDPHRIWKHHYHQWDVLWRFFXUUHGZLWKLQPRQWKVRIWKHVXEMHFW
VYDFFLQDWLRQDQGWKHODFNRIDOWHUQDWLYHH[SODQDWLRQ
7KHFRPSDQ\GLGQRWFRQFXUZLWKWKHLQYHVWLJDWRU¶V
DVVHVVPHQWEDVHGRQWKHDEVHQFHRIDSODXVLEOHSDWKRSK\VLRORJLFDOPHFKDQLVPE\ZKLFKWKHYDFFLQHZRXOGEHH[SHFWHGWRFDXVHWKHHYHQW
6WXG\ %17 2SHQ ODEHO
*HUPDQ\
)&\VWLWLV>5@ 7KHVXEMHFWUHFHLYHGGRVHVRI% 17ERQ'HF
DQG'HFUHVSHFWLYHO\7ZRGD\VSRVWWKHVHFRQGGRVHVKHH[SHULHQFHGDEGRPLQDOSDLQDQGDGLDJQRVLVRIF\VWLWLV&7&$(JUDGHZDVPDGHDWWKHKRVSLWDO7KH
VXEMHFWZDVWUHDWHGZLWKSDUDFHWDPROPJ)RVIRP\FLQ
JVLQJOHGRVHVDQG,9PHWDPL]ROHJGD\IRUGD\V6KHZDVGLVFKDUJHGIURPWKHKRVSLWDORQ-DQ$EGRPLQDOSDLQ16UHFXUUHGRQ-DQDQGUHFRYHUHGXSRQWUHDWPHQWZLWKRUDOFHIR]LGLPHPJWKULFHGDLO\IRUGD\V6\PSWRPVZHUHUHSRUWHGDV
UHVROYHGDVRI-DQ7KH,QYHVWLJDWRUGLGQRW
FRQVLGHUWKHHYHQWWREHUHODWHGWR%17EKRZHYHUWKH0$+GLGQRWH[FOXGHDFDXVDOUHODWLRQVKLSEDVHGRQWKHWHPSRUDOUHODWLRQVKLS
%17
&KLQD
)+\SHUWK\URLGLVP>5*@
7K\URLG PDVV>15@E7KHVXEMHFWUHFHLYHGGRVHVRIWKHVWXG\YDFFLQH
>%17ESODFHER@RQ-XODQGRQ$XJUHVSHFWLYHO\2Q-DQDEQRUPDOWK\URLGIXQFWLRQZDVGHWHFWHG7KHSDWLHQWZDVKRVSLWDOL]HGRQ0DU
'LDJQRVLVRQGLVFKDUJHRQ$SUZDV
K\SHUWK\URLGLVPKHSDWLFLQVXIILFLHQF\QHXWURSHQLDIDWW\OLYHUWK\URLGQRGXOHVROLWDU\SXOPRQDU\QRGXOHXULQDU\WUDFWLQIHFWLRQ 7KH,QYHVWLJDWRUFRQVLGHUHGWKDWWKHHYHQWVRI+\SHUWK\URLGLVPDQG7K\URLGQRGXOHZHUHSRVVLEO\UHODWHGWRWKHVWXG\YDFFLQH7KH0$+FRQVLGHUHGWKH
HYHQWVDVXQUHODWHGWKHUHSRUWHG686$5VµWK\URLGQRGXOH¶
µK\SHUWK\URLGLVP¶DQG6$(PLOGIDWW\OLYHUZHUHVXEMHFW¶VSUHH[LVWLQJFRQGLWLRQV
&OLQLFDO2XWFRPHV15 1RWUHVROYHG5 UHVROYHG5* UHVROY LQJ
D 3RODFN)37KRPDV6-.LWFKLQ1HWDO6DIHW\DQG(IILFDF\RI WKH%17EP51$&RYLG9DFFLQH
1(-0'2,1(-0RD
E 7KHIROORZLQJXQUHODWHGHYHQWVZHUHDOVRUHSRUWHGIRUWKLVVX EMHFW+HSDWLFIDLOXUH1HXWURSHQLD8ULQDU\
WUDFWLQIHFWLRQ3XOPRQDU\PDVV090177e19744d904\A pproved\A pproved On: 11-Jun-2021 10:28 (GMT )
(b) (6)
(b) (6)
FDA-CBER-2021-5683-1102887
&29,'9DFFLQH%173) 5HSRUWLQJ3HULRG
'HYHORSPHQW6DIHW\8SGDWH5HSRUW'6851R $SULOWKURXJ K$SULO
&21),'(17,$/
3DJH$VQRWHGLQ 7DEOHEROGHG6$5VWKHUHZHUHFDVHVUHSRUWLQJHYHQWVFRQVLGHUHG
686$5VIRUVWXG\YDFFLQHV>%17E3ODFHER@>%17E3ODFHER @RU%17E
'XULQJWKHUHSRUWLQJSHULRGWKHUHZHUHQRFDVHVZLWKDIDWDORXWF RPHWKDWZHUHFRQVLGHUHG
SRVVLEO\UHODWHGWRWKH&29,'YDFFLQH
/RQJWHUP )ROORZXS
7KHUHLVQRLQIRUPDWLRQZLWKUHJDUGVWRORQJWHUPIROORZXSRIFO LQLFDOWULDOSDUWLFLSDQWVIRU
WKLVUHSRUWLQJSHULRG 2WKHU 7KHUDSHXWLF 8VH RI ,QYHVWLJDWLRQDO 'UXJ
7KHUHLVQRUHOHYDQWLQIRUPDWLRQSHUWDLQLQJWRRWKHUWKHUDSHXWLFX VHVRI&29,'IRUWKLV
UHSRUWLQJSHULRG 1HZ 6DIHW\ 'DWD 5HODWHG WR &RPELQDWLRQ 7KHUDSLHV
&29,'YDFFLQHLVQRWXVHGLQIL[HGRUPXOWLGUXJFRPE LQDWLRQZLWKRWKHUFRPSRXQGV
6$)(7< ),1',1*6 )520 121,17(59(17,21$/ 678',(6'XULQJWKLVUHSRUWLQJSHULRGWKHUHZHUHRQJRLQJQRQLQWHUYHQW LRQDOVWXGLHV&
&DQG&ZKLFKDUHSUHVHQWHGLQ7DEOHEHORZ
7DEOH 1RQ,QWHUYHQWLRQDO 6WXGLHV 2QJRLQJ 'XULQJ WKH 5HSRUWLQJ 3HULRG
6WXG\ 1R 6WXG\ 7LWOH DQG &RXQWU\
& 6WXG\ 7LWOH *HQHUDO,QYHVWLJDWLRQRI&20,51$7<,QWUDPXVFXODU,QMHFWLRQ)ROORZXS
VWXG\IRU6XEMHFWV>+HDOWKFDUH3URIHVVLRQDOV@:KRDUH9DFFLQDWHGDWDQ(DUO\SRVW
$SSURYDO6WDJH
&RXQWU\-DSDQ
6WXG\ REMHFWLYH 7KHKHDOWKFDUHSURIHVVLRQDOVZKRDUHYDFFLQDWHGZLWKWKLVSURGXFWHDUO\
DIWHUWKHPDUNHWLQJDSSURYDORIWKLVSURGXFWSDUWLFLSDQWVLQW KH,QYHVWLJDWLRQRI+HDOWK
6WDWXVRI5HFLSLHQWV9DFFLQDWHG)LUVWFRQGXFWHGE\WKH6FLHQFH5HVHDUFK*URXSRIWKH
0LQLVWU\RI+HDOWK/DERXUDQG:HOIDUHZLOOEHIROORZHGIRU PRQWKVIURPWKHGD\
IROORZLQJGD\VDIWHUWKHILQDOYDFFLQDWLRQRIWKLVSURGXFW HQGGDWHRIREVHUYDWLRQ
SHULRGLQ,QYHVWLJDWLRQRI+HDOWK6WDWXVRI5HFLSLHQWV9DFFLQDW HG)LUVWWRPRQWKV
DIWHUWKHILQDOYDFFLQDWLRQRIWKLVSURGXFWLQIRUPDWLRQRQVHU LRXVDGYHUVHHYHQWVDQG
&29,'REVHUYHGGXULQJWKHIROORZXSSHULRGZLOOEHFROOHFWHG DQGWKHORQJWHUP
VDIHW\RIWKLVSURGXFWZLOOEHDVVHVVHGWREHFRQGXFWHGDV PRQWKIROORZXS
LQYHVWLJDWLRQDIWHUFRPSOHWLRQRI,QYHVWLJDWLRQRI+HDOWK6WDWXVRI5HFLSLHQWV9DFFLQDWHG
)LUVW
&D
3$666WXG\ 7LWOH +(527RJHWKHU$SRVW(PHUJHQF\8VH$XWKRUL]DWLRQREVHUYDWLRQDO
FRKRUWVWXG\WRHYDOXDWHWKHVDIHW\RIWKH3IL]HU%LR17HFK&29, 'YDFFLQHLQ86
KHDOWKFDUHZRUNHUV&RXQWU\8QLWHG6WDWHV
3ULPDU\ VWXG\ REMHFWLYHV
•(VWLPDWHWKHUHDOZRUOGLQFLGHQFHRIVDIHW\HYHQWVRILQWHUHVW DQGRWKHUFOLQLFDOO\
VLJQLILFDQWHYHQWVDPRQJ86KHDOWKFDUHZRUNHUVYDFFLQDWHGZLWK WKH3IL]HU
%LR17HFK&29,'YDFFLQHIROORZLQJ(PHUJHQF\8VH$XWKRUL]DWLRQ 090177e19744d904\A pproved\A pproved On: 11-Jun-2021 10:28 (GMT )
FDA-CBER-2021-5683-1102888
&29,'9DFFLQH%173) 5HSRUWLQJ3HULRG
'HYHORSPHQW6DIHW\8SGDWH5HSRUW'6851R $SULOWKURXJ K$SULO
&21),'(17,$/
3DJH7DEOH 1RQ,QWHUYHQWLRQDO 6WXGLHV 2QJRLQJ 'XULQJ WKH 5HSRUWL QJ 3HULRG
6WXG\ 1R 6WXG\ 7LWOH DQG &RXQWU\
6HFRQGDU\ REMHFWLYHV
•(YDOXDWHZKHWKHUWKHYDFFLQHUHFLSLHQWVH[SHULHQFHLQFUHDVHGULVNRIVDIHW\
HYHQWVRILQWHUHVWDQGRWKHUFOLQLFDOO\VLJQLILFDQWHYHQWVSRVWYDFFLQDWLRQ
•(VWLPDWHWKHLQFLGHQFHUDWHVRIVDIHW\HYHQWVRILQWHUHVWDQGR WKHUFOLQLFDOO\
VLJQLILFDQWHYHQWVDPRQJVXEFRKRUWVRILQWHUHVWVXFKDVLQGLYLGXDOVZKRDUHSUHJQDQWLQGLYLGXDOVZKRDUHLPPXQRFRPSURPLVHGDQGVWUDWLILHGE\DJH
&E
3$666WXG\ 7LWOH 3RVW(PHUJHQF\8VH$XWKRUL]DWLRQ$FWLYH6DIHW\6XUYHLOODQFH6WXG\
DPRQJ,QGLYLGXDOVLQWKH9HWHUDQ¶V$IIDLUV+HDOWK6\VWHP5HFHLY LQJ3IL]HU%LR17HFK
&RURQDYLUXV'LVHDVH&29,'9DFFLQH&RXQWU\8QLWHG6WDWHV
3ULPDU\ VWXG\ REMHFWLYHV
•7RDVVHVVZKHWKHULQGLYLGXDOVLQWKH9+$V\VWHPH[SHULHQFHLQFUHDVHGULVNRIVDIHW\HYHQWVRILQWHUHVWIROORZLQJUHFHLSWRIWKH3IL]HU%LR17 HFK&29,'
YDFFLQH
•7RDVVHVVZKHWKHUVXEFRKRUWVRILQWHUHVWLHLPPXQRFRPSURPL VHGHOGHUO\
LQGLYLGXDOVZLWKVSHFLILFFRPRUELGLWLHVLQGLYLGXDOVUHFHLYLQJRQO\RQHGRVHRIWKH3IL]HU%LR17HFK&29,'YDFFLQHDQGLQGLYLGXDOVZLWKSULR U6$56
&R9LQIHFWLRQLQWKH9+$V\VWHPH[SHULHQFHLQFUHDVHGULVNRIVDIHW\HYHQWVRILQWHUHVWIROORZLQJUHFHLSWRIWKH3IL]HU%LR17HFK&29,'YDFFLQH
6HFRQGDU\ VWXG\ REMHFWLYH
•7RFKDUDFWHUL]HXWLOL]DWLRQSDWWHUQVRIWKH3IL]HU%LR17HFK&29 ,'YDFFLQH
DPRQJLQGLYLGXDOVZLWKLQWKH9+$LQFOXGLQJHVWLPDWLQJWKHSURSRUWLRQRILQGLYLGXDOVUHFHLYLQJYDFFLQHGRVHYDFFLQHFRPSOHWLRQUDWHDQGGLVWULEXWLRQRIWLPHJDSVEHWZHHQWKHILUVWDQGVHFRQGGRVHGHPRJUDSKLFVDQGKHDOWKKLVWRULHVRIUHFLSLHQWVRYHUDOODQGDPRQJWKHVXEFRKRUWVRIL QWHUHVW
D 9ROXQWDU\3$66E &RPPLWWHG3$66&DWHJRU\6WXG\LQWKH(8
'XULQJWKLVUHSRUWLQJSHULRGWKHUHZDVQRQHZVDIHW\LQIRUPDWL RQUHSRUWHGUHJDUGLQJWKHVH
RQJRLQJQRQLQWHUYHQWLRQDOVWXGLHV
7KHUHZHUHQR1,6VFRPSOHWHGGXULQJWKLVUHSRUWLQJSHULRG 27+(5&/,1,&$/75,$/678'<6$)(7<,1)250$7,21
'XULQJWKLVUHSRUWLQJSHULRGWKHUHZDVQRQHZVDIHW\LQIRUPDWL RQUHSRUWHGIURPRWKHU
FOLQLFDOWULDOV
6$)(7<),1',1*6)5200$5.(7,1*(;3(5,(1&(
$VVWDWHGLQ 6HFWLRQDVRIWKH'/3RIWKLVUHSRUW&29,'YDFFLQHKDVEHHQDXWKRU L]HG
IRUHPHUJHQF\XVHRUEHHQJLYHQFRQGLWLRQDOPDUNHWLQJDXWKRUL]D WLRQLQRYHUDOOFRXQWULHV
ZRUOGZLGHZLWKPRUHWKDQPLOOLRQGRVHVGLVWULEXWHG0RVWFRPPRQO\UHSRUWHG$(VLQ
WKHSRVWDXWKRUL]DWLRQUHYLHZZKLFKLQFOXGHVJOREDOUHSRUWLQJ UHIOHFWWKHVDPHSURILOH
REVHUYHGLQWKHEOLQGHGSODFHERFRQWUROOHGIROORZXSSHULRGRI WKHSLYRWDOFOLQLFDOVWXG\
SULPDULO\UHIOHFWLQJVKRUWOLYHGDQGUHVROYLQJUHDFWRJHQLFLW\H YHQWV$(VRIFOLQLFDOLQWHUHVW
FRQWLQXHWREHHYDOXDWHGLQWKHSRVWDXWKRUL]DWLRQVHWWLQJ090177e19744d904\A pproved\A pproved On: 11-Jun-2021 10:28 (GMT )
FDA-CBER-2021-5683-1102889
&29,'9DFFLQH%173) 5HSRUWLQJ3HULRG
'HYHORSPHQW6DIHW\8SGDWH5HSRUW'6851R $SULOWKURXJ K$SULO
&21),'(17,$/
3DJH%DVHGRQSKDUPDFRYLJLODQFHPRQLWRULQJDFWLYLWLHVVLQFHILUVWD XWKRUL]DWLRQDQDSK\OD[LVKDV
EHHQUHFRJQL]HGDVDQLPSRUWDQWLGHQWLILHGULVN+\SHUVHQVLWLYLW\UHDFWLRQVRWKHUWKDQ
$QDSK\OD[LV'LDUUKRHD3DLQLQH[WUHPLW\DUPDQG9RPLWLQJZ HUHDOVRDVVHVVHGDV
LGHQWLILHGULVNVQRWLPSRUWDQWIRUWKHSXUSRVHRIULVNPDQDJHP HQWSODQQLQJDQGDGGHGDV
DGYHUVHUHDFWLRQVWRWKHODEHOLQJ$VWKHQLD/HWKDUJ\'HFUHDVH GDSSHWLWH+\SHUKLGURVLV
1LJKWVZHDWVZHUHHYDOXDWHGWREHLGHQWLILHGULVNVQRWLPSRUWD QWIRUWKHSXUSRVHRIULVN
PDQDJHPHQWSODQQLQJDQGWKH\ZLOOEHDGGHGWRWKH56,9DFFLQH VWUHVVUHODWHGUHVSRQVHV
LQFOXGLQJ'L]]LQHVV3DUDHVWKHVLDDQG7DFK\FDUGLDDPRQJRWKHU ZHUHLQFOXGHGLQWKH56,DV
UHDFWLRQVWRWKHYDFFLQDWLRQSURFHVV
9DFFLQHDVVRFLDWHGHQKDQFHGGLVHDVH9$('LQFOXGLQJ9DFFLQHDVVRFLDWHGHQKDQFHG
UHVSLUDWRU\GLVHDVH9$(5'LVDQLPSRUWDQWSRWHQWLDOULVNIRU &29,'YDFFLQH
%DVHGRQVDIHW\DQGHIILFDF\GDWDDYDLODEOHWRGDWHIRU%17E WKHEHQHILWULVNSURILOHRI
&29,'YDFFLQHUHPDLQVIDYRUDEOH
121&/,1,&$/'$7$
'XULQJWKHUHSRUWLQJSHULRGQRQHZQRQFOLQLFDOVDIHW\ILQGLQJV ZHUHLGHQWLILHG
/,7(5$785(1RQ&OLQLFDO3XEOLVKHG
$VHDUFKRIWKH0HGOLQHDQG(PEDVHGDWDEDVHVGLGQRWLGHQWLI\Q RQFOLQLFDOVWXGLHVWKDW
SUHVHQWHGLPSRUWDQWQHZVDIHW\ILQGLQJVIRU&29,'YDFFLQH
&OLQLFDO3XEOLVKHG
$VHDUFKRIWKH0HGOLQHDQG(PEDVHGDWDEDVHVLGHQWLILHGFOLQLF DOWULDOVWKDWSUHVHQWHG
LPSRUWDQWQHZVDIHW\HIILFDF\ILQGLQJVIRU&RYLGYDFFLQHZKHQ DGPLQLVWHUHGLQDWULVN
SDWLHQWVLHSDWLHQWVRQKHPRGLDO\VLVRUVSHFLDOSRSXODWLRQL QFOXGLQJHOGHUO\DQG
SUHJQDQWODFWDWLQJZRPHQ 7KHDEVWUDFWVDUHSUHVHQWHGLQ7DEOH EHORZ)XOOSXEOLFDWLRQV
DUHDYDLODEOHXSRQUHTXHVW
7DEOH &OLQLFDO /LWHUDWXUH $UWLFOHV WKDW 3UHVHQWHG 1HZ 6DIHW\ ,QIRUPDWLRQ LQ WKH
5HSRUWLQJ,QWHUYDO
1R &LWDWLRQ$EVWUDFW
$W 5LVN 3DWLHQWV
*UXSSHU$6KDURQ1)LQQ7HWDO+XPRUDO5HVSRQVHWRWKH3IL]HU%17E9DFFLQHLQ3DWLHQWV
8QGHUJRLQJ0DLQWHQDQFH+HPRGLDO\VLV&OLQ-$P6RF1HSKUROGRL&-1090177e19744d904\A pproved\A pproved On: 11-Jun-2021 10:28 (GMT )
FDA-CBER-2021-5683-1102890
&29,'9DFFLQH%173) 5HSRUWLQJ3HULRG
'HYHORSPHQW6DIHW\8SGDWH5HSRUW'6851R $SULOWKURXJ K$SULO
&21),'(17,$/
3DJH7DEOH &OLQLFDO /LWHUDWXUH $UWLFOHV WKDW 3UHVHQWHG 1HZ 6DIHW\ ,QIRUPDWLRQ LQ WKH
5HSRUWLQJ,QWHUYDO
1R &LWDWLRQ$EVWUDFW
%DFNJURXQG DQG REMHFWLYHV &RURQDYLUXVGLVHDVH&29,'LVDVVRFLDWHGZLWKKLJKHU
PRUELGLW\DQGPRUWDOLW\LQSDWLHQWVRQPDLQWHQDQFHKHPRGLDO\VLV3DWLHQWVRQGLDO\VLVWHQGWRKDYHD
UHGXFHGLPPXQHUHVSRQVHWRLQIHFWLRQRUYDFFLQDWLRQ:HDLPHGW RDVVHVVIRUWKHILUVWWLPHWRWKHEHVW
RIRXUNQRZOHGJHWKHKXPRUDOUHVSRQVHIROORZLQJYDFFLQDWLRQZL WKWKH%17EYDFFLQHLQSDWLHQWV
RQPDLQWHQDQFHKHPRGLDO\VLVDQGWKHIDFWRUVDVVRFLDWHGZLWKLW
'HVLJQ VHWWLQJ SDUWLFLSDQWV PHDVXUHPHQWV 7KHVWXG\LQFOXGHGSDWLHQWVRQPDLQWHQDQFH
KHPRGLDO\VLVGLDO\VLVJURXSDQGDFRQWUROJURXSFRPSRVHGRI KHDOWKFDUHZRUNHUV$OOSDUWLFLSDQWV
KDGUHFHLYHGWZRGRVHVRIWKH%17E3IL]HU%LR17HFKYDFFLQ H7KHVHURORJ\WHVWLQJZDVGRQH
XVLQJ4XDQW,,,J*DQWL6SLNHVHYHUHDFXWHUHVSLUDWRU\V\QGURPH FRURQDYLUXV6$56&R9DVVD\
E\$EERWWDPHGLDQRIGD\VDIWHUUHFHLSWRIWKHVHFRQGGRVHRIWKHYDFFLQH5HVXOWV$OOVXEMHFWVLQWKHFRQWUROJURXSGHYHORSHGDQDQWLERG\UHVSRQV HFRPSDUHGZLWKRI
SRVLWLYHUHVSRQGHUVLQWKHGLDO\VLVJURXS7KH,J*OHYHOVL QWKHGLDO\VLVJURXSPHGLDQ
LQWHUTXDUWLOHUDQJH±ZHUHVLJQLILFDQWO\ORZHUWKDQLQWKHFRQWUROJURXSPHGLDQ
LQWHUTXDUWLOHUDQJH±$0DQQ±:KLWQH\8WHVWLQGLFDWHGWKDWWKLVGLIIHUHQFHZDV
VWDWLVWLFDOO\VLJQLILFDQW8 37KHUHZDVDVLJQLI LFDQWLQYHUVHFRUUHODWLRQRIDJHDQG,J*
OHYHOVLQERWKJURXSV7KHRGGVRIEHLQJLQWKHORZHUTXDUWLOH ZHUHVLJQLILFDQWO\KLJKHUIRUROGHU
LQGLYLGXDOVRGGVUDWLRSHU\HDURIDJHFRQILGHQFHL QWHUYDOWR3 DQGIRU
WKHGLDO\VLVJURXSFRPSDUHGZLWKWKHFRQWUROJURXSRGGVUDWLRFRQILGHQFHLQWHUYDOWR
3 :LWKLQWKHGLDO\VLVJURXSROGHUDJHDQGORZHUO \PSKRF\WHFRXQWZHUHDVVRFLDWHGZLWK
DQWLERG\UHVSRQVHLQWKHORZHUTXDUWLOHRGGVUDWLRSHU\HDUROGHUFRQILGHQFHLQWHUYDO
WR3 DQGRGGVUDWLRSHUHOKLJKHUO \PSKRF\WHFRXQWFRQILGHQFH
LQWHUYDOWR3
&RQFOXVLRQV $OWKRXJKPRVWSDWLHQWVRQPDLQWHQDQFHKHPRGLDO\VLVGHYHORSHGD VXEVWDQWLDOKXPRUDO
UHVSRQVHIROORZLQJWKH%17EYDFFLQHLWZDVVLJQLILFDQWO\O RZHUWKDQFRQWUROV$JHZDVDQ
LPSRUWDQWIDFWRULQWKHKXPRUDOUHVSRQVHUHJDUGOHVVRIFKURQLFPHGLFDOFRQGLWLRQV
6SHFLDO 3DWLHQW 3RSXODWLRQV
$EX-DEDO.%HQ$PUDP+%HLUXWL.HWDO,PSDFWRIDJHHW KQLFLW\VH[DQGSULRULQIHFWLRQVWDWXVRQ
LPPXQRJHQLFLW\IROORZLQJDVLQJOHGRVHRIWKH%17EP51$&29,'YDFFLQH5HDOZRUOG
HYLGHQFHIURPKHDOWKFDUHZRUNHUV,VUDHO'HFHPEHUWR-DQX DU\(XUR6XUYHLOO
GRL(6
7KH%17EP51$&29,'YDFFLQHVKRZHGKLJKHIILFDF\LQFOLQ LFDOWULDOVEXWREVHUYDWLRQDO
GDWDIURPSRSXODWLRQVQRWLQFOXGHGLQWULDOVDUHQHHGHG:HGHVFULEHLPPXQRJHQLFLW\GD\VSRVWGRVHDPRQJ,VUDHOLKHDOWKFDUHZRUNHUVE\DJHHWKQLFLW\ VH[DQGSULRU&29,'LQIHFWLRQ
,PPXQRJHQLFLW\ZDVVLPLODUE\HWKQLFLW\DQGVH[EXWGHFUHDVHGZ LWKDJH7KRVHZLWKSULRULQIHFWLRQ
KDGDQWLERG\WLWUHVRQHPDJQLWXGHRUGHUKLJKHUWKDQQDwYHLQGLYLGXDOVUHJDUGOHVVRIWKHSUHVHQFHRIGHWHFWDEOH,J*DQWLERGLHVSUHYDFFLQDWLRQ
5RWWHQVWUHLFK$=DUELY*2LNQLQH'MLDQ(HWDO(IILFLHQWPDWHUQRIHWDOWUDQVSODFHQWDOWUDQVIHURIDQWL
6$56&R9VSLNHDQWLERGLHVDIWHUDQWHQDWDO6$56&R9%17E P51$YDFFLQDWLRQ&OLQ
,QIHFW'LVFLDEGRLFLGFLDE$FFHSWHGPDQXVFULSW
0DWHUQDODQGFRUGEORRGVHUDZHUHFROOHFWHGIURPSDUWXULHQWV ZKRUHFHLYHGWKH%17EYDFFLQH
$OOZRPHQDQGLQIDQWVZHUHSRVLWLYHIRUDQWL6DQGDQWL5%'VSH FLILF,J*&RUGEORRGDQWLERG\
FRQFHQWUDWLRQVZHUHFRUUHODWHGWRPDWHUQDOOHYHOVDQGWRWLPHV LQFHYDFFLQDWLRQ$QWHQDWDO6$56&R9
YDFFLQDWLRQPD\SURYLGHPDWHUQDODQGQHRQDWDOSURWHFWLRQ
.HOO\-&&DUWHU(%5DJKXUDPDQ1HWDO$QWL6$56&R9DQWLERGLHVLQGXFHGLQEUHDVWPLONDIWHU
3IL]HU%LR17HFK%17EYDFFLQDWLRQ6$56&R9DQWLERGLHVLQ EUHDVWPLONDIWHUYDFFLQDWLRQ
$P-2EVWHW*\QHFRO6GRL MDMRJ090177e19744d904\A pproved\A pproved On: 11-Jun-2021 10:28 (GMT )
FDA-CBER-2021-5683-1102891
&29,'9DFFLQH%173) 5HSRUWLQJ3HULRG
'HYHORSPHQW6DIHW\8SGDWH5HSRUW'6851R $SULOWKURXJ K$SULO
&21),'(17,$/
3DJH7DEOH &OLQLFDO /LWHUDWXUH $UWLFOHV WKDW 3UHVHQWHG 1HZ 6DIHW\ ,QIRUPDWLRQ LQ WKH
5HSRUWLQJ,QWHUYDO
1R &LWDWLRQ$EVWUDFW
2EMHFWLYH ,Q'HFHPEHUOLSLGQDQRSDUWLFOHIRUPXODWHGQXFOHRVLGHP RGLILHGPHVVHQJHU51$±
EDVHGYDFFLQHVUHFHLYHGHPHUJHQF\XVHDXWKRUL]DWLRQE\WKH86) RRGDQG'UXJ$GPLQLVWUDWLRQDIWHU
WKHLUWULDOVGHPRQVWUDWHGWRHIILFDF\LQSUHYHQWLQJFRU RQDYLUXVGLVHDVH&29,'
$OWKRXJKQRODFWDWLQJSHRSOHZHUHLQFOXGHGLQWKHYDFFLQHWULDOVQDWLRQDORUJDQL]DWLRQVVXSSRUW
YDFFLQDWLRQRIWKLVSRSXODWLRQVXJJHVWLQJSRWHQWLDOLQIDQWSURWHFWLRQE\SDVVLYHWUD QVIHURIPDWHUQDO
DQWLERGLHV7KHDXWKRUV VRXJKWWRFKDUDFWHUL]HEUHDVWPLONOHYHOVRIDQWL±VHYHUHDFXWHUHVSLUDWRU\V\QGURPHFRURQDYLUXV6$56&R9DQWLERGLHVLQODFWDWLQJSHR SOHXQGHUJRLQJ&29,'
YDFFLQDWLRQ
6WXG\ 'HVLJQ 3DUWLFLSDQWVZHUHSURVSHFWLYHO\UHFUXLWHGGXULQJSKDVH,$UROOR XWRIWKH&29,'
YDFFLQHDWDWHUWLDU\FDUHFHQWHUDIWHULQVWLWXWLRQDOUHYLHZE RDUGDSSURYDO,QFOXVLRQFULWHULDLQFOXGHG
ODFWDWLRQDQGSODQQHGYDFFLQDWLRQZLWKWKH3IL]HU%LR17HFK%17 EYDFFLQH$IWHUREWDLQLQJ
LQIRUPHGFRQVHQWSDUWLFLSDQWVSURYLGHGIUR]HQEUHDVWPLONVDPSOHVDWWKHIROORZLQJWLPHSRLQWVRI
YDFFLQDWLRQEHIRUHZLWKLQWKHILUVWKRXUVDQGWKHIROORZL QJZHHN6DPSOHVZHUHDVVHVVHGIRU
6$56&R951$E\TXDQWLWDWLYHUHDOWLPHSRO\PHUDVHFKDLQUHDFW LRQDQGDQWLVSLNHLPPXQRJOREXOLQ
,J*DQG,J$E\DQHQ]\PHOLQNHGLPPXQRVRUEHQWDVVD\
5HVXOWV$WRWDORIVXEMHFWVDQGKXPDQPLONVDPSOHVZHUHLQFOXGHGLQWKHDQDO\VLV$OO
SUHYDFFLQHPLONVDPSOHVWHVWHGQHJDWLYHIRU6$56&R951$DV GHILQHGE\WKHF\FOHWKUHVKROG
YDOXHRI!IRUWKH1WDUJHW$QWLVSLNH,J*DQG,J$OHYHOVZHUHVLJQLILFDQWO\HOHYDWHGUHODWLYHWRWKH
SUHYDFFLQHEDVHOLQHDWDOOWLPHSRLQWV$QWLVSLNHSURWHLQ,J*UHPDLQHGVXVWDLQHGDWDVLJQLILFDQW
HOHYDWLRQEHJLQQLQJDWGD\VDIWHUWKHILUVWGRVHFRPSDUHGZLWKWKHSUHYDFFLQHEDVHOLQH3 WKURXJKWKHILQDOPLONVDPSOHGD\±3 !GD\V3 /HYHOVRIDQWLVSLNHSURWHLQ,J$ZHUHVLJQLILFDQWO\HOHYDWHGIURPEDVHOLQHVWDUWLQJZHHNVDIW HUWKHILUVWGRVH3 WKURXJKWRWKH
ILQDOVDPSOHGD\±3 GD\±3 !GD\V3 KRZHYHULQGLYLGXDOOHYHO
GDWDVXJJHVWDSRVVLEOHJUDGXDOGHFOLQHLQDQWLVSLNH,J$LQKXPDQPLONRYHUWLPHDIWHUWKHVHFRQGGRVH
8QSXEOLVKHGPDQXVFULSWVDEVWUDFWVVFLHQWLILFPHHWLQJILQGLQJV
'XULQJWKHUHSRUWLQJSHULRGQRQHZVDIHW\ILQGLQJVZHUHLGHQWLILHG
27+(5 '6856
'XULQJWKHUHSRUWLQJSHULRGWKHVSRQVRU3IL]HUDQG)RVXQGLGQRWVXEPLWDQRWKHU'685IRU
&29,'YDFFLQH
/$&.2)()),&$&<
'XULQJWKHUHSRUWLQJSHULRGQRUHOHYDQWODFNRIHIILFDF\LQIRUPDWLRQZDVLGHQWLILHGWKDW
FRXOGFRQVWLWXWHDVLJQLILFDQWULVNWRFOLQLFDOWULDOVXEMHFWV
5(*,2163(&,),&,1)250$7,21
$SSHQGLFHV5 DQG5SURYLGHFXPXODWLYHVXPPDU\WDEXODWLRQVRI6$5VUHFHLYHG
E\WKHVSRQVRUDQGLGHQWLILHVXQH[SHFWHGDGYHUVHUHDFWLRQWHUPV LQFOXGLQJ686$5V 7KLV
DSSHQGL[LVRUJDQL]HGDFFRUGLQJWR62&090177e19744d904\A pproved\A pproved On: 11-Jun-2021 10:28 (GMT )
FDA-CBER-2021-5683-1102892
&29,'9DFFLQH%173) 5HSRUWLQJ3HULRG
'HYHORSPHQW6DIHW\8SGDWH5HSRUW'6851R $SULOWKURXJ K$SULO
&21),'(17,$/
3DJH$SSHQGL[5 SURYLGHVDOLQHOLVWLQJRIFDVHVUHSRUWLQJ686$5VGXULQJWKHUH SRUWLQJ
SHULRG3OHDVHQRWHWKDWGXHWRDWHFKQLFDOLVVXHWKH686$5FDV HVUHFHLYHGIURP
%17RSHQODEHODQG%17&7VDUHQRWVKRZQLQWKLV$SSHQGL[
$SSHQGL[5 SURYLGHVDOLQHOLVWLQJRIVXEMHFWVZKRGLHGGXULQJUHSRUWLQJS HULRG
UHJDUGOHVVRIUHODWHGQHVVDOOIURP6WXG\& 'XULQJWKH UHSRUWLQJSHULRGQRVXEMHFW
GHDWKVZHUHUHSRUWHGIURP6WXGLHV%17DQG
$SSHQGLFHV5 5DQG5 SURYLGHOLQHOLVWLQJVRIVXEMHFWVZKRGURSSHGRXWRI
FOLQLFDOWULDOV3IL]HU¶V%LR17HFKDQG)RVXQ&7VUHVSHFWLYHO\ GXULQJWKHUHSRUWLQJSHULRG
GXHWRDQDVVRFLDWHG$('XULQJWKHUHSRUWLQJSHULRGWKHUHZHUHQRVLJQLILFDQWSKDVHSURWRFROPRGLILFDWLRQVPDGH
WKDWZHUHQRWSUHYLRXVO\UHSRUWHGWRWKH,1'LQDSURWRFRODPHQ GPHQW$SSHQGL[5LV
1$
$SSHQGL[5 DQG$SSHQGL[5 GHVFULEHVLJQLILFDQWPDQXIDFWXULQJFKDQJHVWKDW
RFFXUUHGGXULQJWKHFXUUHQWUHSRUWLQJSHULRGLQWKH86DQG&KLQ DUHVSHFWLYHO\
$SSHQGL[5 SURYLGHVDGHVFULSWLRQRIWKHJHQHUDOLQYHVWLJDWLRQDOSODQIRUWKHXSFRPLQJ
\HDUZLWKUHVSHFWWRD86,1'ZKHUHDV $SSHQGL[5 SURYLGHVDGHVFULSWLRQRIWKH
JHQHUDOLQYHVWLJDWLRQDOSODQVSHFLILFWR&KLQDRIQRWHZLWKW KHH[FHSWLRQRIWKHFXUUHQWO\
RQJRLQJ6WXGLHV%17DQG%17GHVFULEHGWKHUHDUHQR SODQQHG
LQYHVWLJDWLRQVIRUWKHXSFRPLQJ\HDUVSHFLILFWR&KLQD /$7(%5($.,1*,1)250$7,21
$IWHUWKHGDWDORFNSRLQWRIWKLV'685WKH(8503YGDWHG $SULOKDVEHHQ
DSSURYHGH[SDQGLQJWKHFRQGLWLRQDOPDUNHWLQJDXWKRUL]DWLRQWRL QFOXGHDGPLQLVWUDWLRQLQ
DGROHVFHQWVWR\HDUVROG
29(5$// 6$)(7< $66(660(17
(YDOXDWLRQ RI WKH 5LVNV1RWDOOSRWHQWLDORULGHQWLILHGULVNVIRUWKHYDFFLQHDUHFRQVLGHUHGWRPHHWWKHOHYHORI
LPSRUWDQFHQHFHVVLWDWLQJLQFOXVLRQLQWKHOLVWRIVDIHW\FRQFHU QVIRUWKHSXUSRVHRIULVN
PDQDJHPHQWSODQQLQJ
The following reactogenicity events are identified risks not considered as Important:
Injection site pain, Injection site swelling and Injection site redness, Fever, Chills, Fatigue, Headache, Muscle pain, and Joint pain.
9HU\UDUHSRWHQWLDOULVNVIRUDQ\PHGLFLQDOWUHDWPHQWLQFOXGLQ JYDFFLQHVZKLFKDUHZHOO
NQRZQWRKHDOWKFDUHSURIHVVLRQDOVDUHQRWLQFOXGHGLQWKHOLVW RIVDIHW\FRQFHUQV
7KHUHDFWRJHQLFLW\SURILOHRI&29,'YDFFLQHLVGLVFXVVHGEHORZZLWKUHVSHFWWRREVHUYHG
GLIIHUHQFHVLQVROLFLWHGUHDFWRJHQLFLW\V\VWHPLFHYHQWVEHWZHHQ 'RVHDQG'RVH7KH
REVHUYHGGLIIHUHQFHVGRQRWLPSDFWWKHVDIHW\SURILOHRIWKHYD FFLQHDQGDUHQRWSURSRVHGWR090177e19744d904\A pproved\A pproved On: 11-Jun-2021 10:28 (GMT )
FDA-CBER-2021-5683-1102893
&29,'9DFFLQH%173) 5HSRUWLQJ3HULRG
'HYHORSPHQW6DIHW\8SGDWH5HSRUW'6851R $SULOWKURXJ K$SULO
&21),'(17,$/
3DJHEHLQFOXGHGLQWKHOLVWRIVDIHW\FRQFHUQVUDWKHUWKH\DUHGLV FXVVHGIRUFRPSOHWHQHVVLQWKH
SUHVHQWDWLRQRIWKHVDIHW\SURILOH
%DVHGRQWKHUHFHQF\RIDSSURYDORIWKHFRQGLWLRQDODXWKRUL]DWLR QLQDGROHVFHQWVWR
\HDUVRIDJHUHDFWRJHQLFLW\GDWDLVSUHVHQWHGVHSDUDWHO\ZLW KUHVSHFWWRWKDWRILQGLYLGXDOV
\HDUVLQFOXGHGLQWKHLQLWLDOPDUNHWLQJDXWKRUL]DWLRQDSSOL FDWLRQ
6DIHW\3RSXODWLRQ± $GXOWV<HDUVRI$JH
7KHVDIHW\SRSXODWLRQDJHJURXSRIDGXOWV\HDUVRIDJH LQFOXGHGSDUWLFLSDQWV
LQWKH%17EJURXSDQGSDUWLFLSDQWVLQWKHSODFHERJU RXS
5HDFWRJHQLFLW\±$GXOWV<HDUVRI$JH
5HDFWRJHQLFLW\ORFDOUHDFWLRQVDQGV\VWHPLFHYHQWVZDVDVVHVVHGYLDHGLDU\LQDVXEVHWRI
SDUWLFLSDQWVLQXSWRGD\VDIWHUHDFKGRVH
•/RFDO5HDFWLRQV
$PRQJDGXOWV \HDUVRIDJH LQWKH%17EJURXSSDLQDW WKHLQMHFWLRQVLWHZDVWKH
PRVWIUHTXHQWO\UHSRUWHGORFDOUHDFWLRQZLWKVLPLODUIUHTXHQF\ DIWHU'RVHFRPSDUHGZLWK
'RVHRI%17E
,QWKH%17EJURXSIUHTXHQFLHVRIUHGQHVVYVDQG VZHOOLQJYV
ZHUHVLPLODUDIWHU'RVHDQG ,QWKHSODFHERJURXSUHGQHVVD QGVZHOOLQJZHUHUHSRUWHG
LQIUHTXHQWO\DIWHU'RVHVDQG3DLQDWLQMHFWLRQVLWH ZDVUHSRUWHGZLWKDKLJKHU
IUHTXHQF\LQWKH%17EJURXSDIWHU'RVHDQG'RVHWKDQLQ WKHSODFHERJURXS'RVH
YV'RVHYV2YHUDOOSDLQDWWKHLQMHFWLRQVLWHGLGQRWLQFUHDVHDIWHU'RVH DQGUHGQHVVDQGVZHOOLQJZHUH
JHQHUDOO\VLPLODULQIUHTXHQF\DIWHU'RVHDQG'RVH$IWHUH LWKHUGRVHPRVWORFDO
UHDFWLRQVZHUHPLOGRUPRGHUDWHLQVHYHULW\6HYHUHORFDOUHDFW LRQVZHUHUHSRUWHG
LQIUHTXHQWO\LQWKH%17EJURXSDIWHUHLWKHUGRVH1 R*UDGHORFDOUHDFWLRQV
ZHUHUHSRUWHG/RFDOUHDFWLRQVIRUWKHDGXOWDJHJURXSDIWHUHLWKHUGRVHKDGD PHGLDQRQVHWGD\RQ'D\
'D\ZDVWKHGD\RIYDFFLQDWLRQDQGUHVROYHGZLWKDPHGLDQG XUDWLRQRIGD\V
•6\VWHPLF(YHQWV
6\VWHPLFHYHQWVLQWKHDGXOWJURXS \HDUVRID JHZHUHJHQHUDOO\LQFUHDVHGLQ
IUHTXHQF\DQGVHYHULW\ZLWKQXPEHURIGRVHVZLWKWKHH[FHSWLRQ VRIYRPLWLQJDQGGLDUUKHD
ZKLFKZHUHUHSRUWHGXQIUHTXHQWO\DQGDWVLPLODULQFLGHQFHVDIWHUHD FKGRVH
6\VWHPLFHYHQWVLQGHFUHDVLQJRUGHURIIUHTXHQF\E\GRVH'RVH YV'RVHZHUH
•)DWLJXH%17EYVFRPSDUHGWRSODFHERY V
•KHDGDFKH%17EYVFRPSDUHGWRSODFHER YV090177e19744d904\A pproved\A pproved On: 11-Jun-2021 10:28 (GMT )
FDA-CBER-2021-5683-1102894
&29,'9DFFLQH%173) 5HSRUWLQJ3HULRG
'HYHORSPHQW6DIHW\8SGDWH5HSRUW'6851R $SULOWKURXJ K$SULO
&21),'(17,$/
3DJH•PXVFOHSDLQ%17EYVFRPSDUHGWRSODFHER YV
•FKLOOV%17EYVFRPSDUHGWRSODFHERYV
•MRLQWSDLQ%17EYVFRPSDUHGWRSODFHERY V
•IHYHU%17EYVFRPSDUHGWRSODFHERYV
•YRPLWLQJUHSRUWHGLQIUHTXHQWO\DQGVLPLODUDIWHUHLWKHUGRVH
•GLDUUKHDUHSRUWHGLQIUHTXHQWO\DQGVLPLODUDIWHUHDFKGRVH
6\VWHPLFHYHQWVZHUHJHQHUDOO\UHSRUWHGOHVVIUHTXHQWO\LQWKH SODFHERJURXSWKDQLQ
WKH%17EJURXSZLWKVRPHH[FHSWLRQV9RPLWLQJDQGGLDUUKHD DIWHU'RVHDQG'RVH
ZHUHUHSRUWHGDWVLPLODUIUHTXHQFLHVLQWKHSODFHERJURXSDQ GWKH%17EJURXS
,QWKH%17EXVHRIDQWLS\UHWLFSDLQPHGLFDWLRQZDVY VDIWHU'RVHDQG
'RVHUHVSHFWLYHO\8VHRIDQWLS\UHWLFSDLQPHGLFDWLRQZDVOHVVIUHTXHQWLQWKHSODFHER
JURXSDIWHU'RVHDQG'RVHDQGWKDQLQWKH%17 EJURXS
$IWHUWKHILUVWDQGVHFRQGGRVHWKHPDMRULW\RIV\VWHPLFHYHQWV ZHUHPLOGRUPRGHUDWHLQ
VHYHULW\6HYHUHIHYHU!&WR&ZDVUHSRUWHGLQWK H%17EJURXSDIWHU'RVH
IRUDQGDIWHU'RVHIRURISDUWLFLSDQWVDQGLQWKHSODFHERJURXSDIWHU'RVHIRUDQGDIWHU'RVHIRURISDUWLFLSDQWV*UDGHIHYHU!&ZDVUHSRUWHGIRUSDUWLFLSDQWLQWKH%17EJURXSDQGQRSDUWLFLSDQWVLQWKHSO DFHERJURXS
6\VWHPLFHYHQWVIRUWKHDGXOW\HDUVRIDJHJURXSDIWHUHL WKHUGRVHKDGDPHGLDQRQVHW
GD\RI'D\'D\ZDVWKHGD\RIYDFFLQDWLRQDQGUHVROYHGZL WKDPHGLDQGXUDWLRQRI
GD\V1RFOLQLFDOO\PHDQLQJIXOGLIIHUHQFHVLQV\VWHPLFHYHQWVZH UHREVHUYHGE\DJHDQGRU
EDVHOLQH6$56&R9VWDWXVVXEJURXSV
6DIHW\3RSXODWLRQ± $GROHVFHQWV<HDUVRI$JH7KHVDIHW\SRSXODWLRQVLQFOXGLQJVXEVHWVDQGH[FOXVLRQVIRUD GROHVFHQWV\HDUVRI
DJHDQG\RXQJDGXOWV\HDUVRIDJHZHUHVLPLODULQWKH FRUUHVSRQGLQJ%17EDQG
SODFHERJURXSV6DIHW\DQDO\VLVUHVXOWVDUHSUHVHQWHGIRUDGROH VFHQWDQG\RXQJDGXOWVDIHW\
SRSXODWLRQLQFOXGLQJWKHUHDFWRJHQLFLW\VXEVHWXSWRPRQWK DIWHU'RVHDQGIRUDOO
DYDLODEOHGDWDXSWRWKH0DUFK5HDFWRJHQLFLW\±$GROHVFHQWV<HDUVRI$JH
5HDFWRJHQLFLW\ORFDOUHDFWLRQVDQGV\VWHPLFHYHQWVZDVDVVHVV HGYLDHGLDU\LQDOO
DGROHVFHQWVDQGDVXEVHWRI\RXQJDGXOWSDUWLFLSDQWVXSWRGD \VDIWHUHDFKGRVH
•/RFDO5HDFWLRQV
,QWKH%17EJURXSSDLQDWWKHLQMHFWLRQVLWHZDVPRVWIUHT XHQWO\UHSRUWHGLQ
DGROHVFHQWVDQG\RXQJDGXOWVDQGIUHTXHQF\ZDVVLPLODUDIWHU'RVHDQGDIWHU'RVHRI
%17ELQDGROHVFHQWVYVDQGLQ\RXQJDGXOWVYV,QWKHSODFHERJURXSSDLQDWWKHLQMHFWLRQVLWHDIWHU'RVHVDQGZDVVLPLODULQDGROHVFHQWVDQGUHVSHFWLYHO\DQG\RXQJDGXOWVDQG UHVSHFWLYHO\090177e19744d904\A pproved\A pproved On: 11-Jun-2021 10:28 (GMT )
FDA-CBER-2021-5683-1102895
&29,'9DFFLQH%173) 5HSRUWLQJ3HULRG
'HYHORSPHQW6DIHW\8SGDWH5HSRUW'6851R $SULOWKURXJ K$SULO
&21),'(17,$/
3DJH,QWKH%17EJURXSIUHTXHQFLHVRIUHGQHVVDQGVZHOOLQJZHUH VLPLODUEHWZHHQ
DGROHVFHQWVDQG\RXQJDGXOWVDIWHU'RVHVDQG)LJXUH)UHTXHQFLHVRIUHGQHVVZHUH
JHQHUDOO\ORZDQGXQFKDQJHGIURPDIWHU'RVHFRPSDUHGZLWK'RV HRI%17ELQ
DGROHVFHQWVYVDQGLQ\RXQJDGXOWVYV )UHTXHQFLHVRIVZHOOLQJ
ZHUHVLPLODUO\ORZDQGVOLJKWO\UHGXFHGDIWHU'RVHFRPSDUHGZLWK'RVHRI%17ELQDGROHVFHQWVYVDQGLQ\RXQJDGXOWVYV ,QWKHSODFHERJURXS
UHGQHVVDQGVZHOOLQJZHUHLQIUHTXHQWLQWKHDGROHVFHQW DQG\RXQJDGXOW
JURXSVDIWHU'RVHVDQG
$IWHUWKHILUVWDQGVHFRQGGRVHDQGLQERWKDJHJURXSVPRVWORF DOUHDFWLRQVZHUHPLOGRU
PRGHUDWHLQVHYHULW\6HYHUHORFDOUHDFWLRQVZHUHUHSRUWHGLQIU HTXHQWO\DQGDWORZHU
LQFLGHQFHLQDGROHVFHQWVFRPSDUHGZLWK\RXQJDGXOWV DFURVVWKH%17E
DQGSODFHERJURXSVDIWHUDQ\GRVH1R*UDGHORFDOUHDFWLRQVZ HUHUHSRUWHGLQHLWKHUDJH
JURXS .
$FURVVDJHJURXSVPHGLDQRQVHWIRUDOOORFDOUHDFWLRQVDIWHUH LWKHUGRVHRI%17EZDV
'D\WR'D\'D\ZDVWKHGD\RIYDFFLQDWLRQDQGUHVROYHG ZLWKDPHGLDQGXUDWLRQRI
GD\V
•6\VWHPLFHYHQWV
6\VWHPLFHYHQWVZHUHJHQHUDOO\VLPLODULQIUHTXHQF\DQGVHYHULW \LQDGROHVFHQWVFRPSDUHG
ZLWK\RXQJDGXOWVZLWKIUHTXHQFLHVDQGVHYHULW\LQFUHDVLQJZLW KQXPEHURIGRVHVIRUPRVW
HYHQWVZLWKWKHH[FHSWLRQRIYRPLWLQJDQGGLDUUKHDZKLFKZHUH UHSRUWHGLQIUHTXHQWO\DQGDW
VLPLODULQFLGHQFHVDIWHUHDFKGRVHDQGPXVFOHDQGMRLQWSDLQZKLFKZDVUHSRUWHGDWKLJKHU
IUHTXHQFLHVLQWKH\RXQJDGXOWV6\VWHPLFHYHQWVLQWKHDGROHVF HQWJURXSFRPSDUHGZLWKWKH
\RXQJDGXOWJURXSLQGHFUHDVLQJRUGHURIIUHTXHQF\E\GRVH'R VHYV'RVHZHUH
•)DWLJXHDGROHVFHQWVYVFRPSDUHGWR\RXQJDGXOWV YV
•+HDGDFKHDGROHVFHQWVYVFRPSDUHGWR\RXQJDGXOWVYV
•&KLOOVDGROHVFHQWVYVFRPSDUHGWR\RXQJDGXOWV YV
•0XVFOHSDLQDGROHVFHQWVYVFRPSDUHGWR\RXQJDGX OWVYV
•-RLQWSDLQDGROHVFHQWVYVFRPSDUHGWR\RXQJDGXOW VYV
•)HYHUDGROHVFHQWVYVFRPSDUHGWR\RXQJDGXOWVYV
•9RPLWLQJUHSRUWHGLQIUHTXHQWO\LQERWKDJHJURXSVDQGVLPLODUD IWHUHLWKHUGRVH
•'LDUUKHDUHSRUWHGLQIUHTXHQWO\LQERWKJURXSVDQGVLPLODUDIWH UHDFKGRVH
6\VWHPLFHYHQWVZHUHJHQHUDOO\UHSRUWHGOHVVIUHTXHQWO\LQSODF HERYHUVXV%17EJURXSV
)ROORZLQJERWK'RVHDQG'RVHXVHRIDQWLS\UHWLFSDLQPHGLFDWLRQZDVVLPLODULQDGROHVFHQWVDQGDQGLQ\RXQJDGXOWVDQGDQGPHGLFDWLRQXVHLQFUHDVHGLQERWKDJHJURXSVDIWHU'RVHDVFRPSDUHGZLWKDIWH U'RVH8VHRI
DQWLS\UHWLFSDLQPHGLFDWLRQZDVOHVVIUHTXHQWLQWKHSODFHERJU RXSWKDQLQWKH%17E
JURXSDQGZDVVLPLODUDIWHU'RVHDQG'RVHLQWKHDGROHVFHQW DQG\RXQJDGXOWSODFHER
JURXSVUDQJLQJIURPWR090177e19744d904\A pproved\A pproved On: 11-Jun-2021 10:28 (GMT )
FDA-CBER-2021-5683-1102896
&29,'9DFFLQH%173) 5HSRUWLQJ3HULRG
'HYHORSPHQW6DIHW\8SGDWH5HSRUW'6851R $SULOWKURXJ K$SULO
&21),'(17,$/
3DJH$IWHUWKHILUVWDQGVHFRQGGRVHDQGLQERWKDJHJURXSVPRVWV\VWHPLFHYHQWVZHUHPLOGRU
PRGHUDWHLQVHYHULW\6HYHUHV\VWHPLFHYHQWVZHUHUHSRUWHGLQIU HTXHQWO\DQGDWORZHU
LQFLGHQFHLQDGROHVFHQWVFRPSDUHGZLWK\RXQJDGXOWV DFURVV%17E
DQGSODFHERJURXSVDIWHUDQ\GRVH2QHDGROHVFHQWLQWKH%17 EJURXSKDG*UDGH
S\UH[LD&RQ'D\DIWHU'RVHZLWKWHPSHUDWXUHUHWXU QLQJWRQRUPDOE\'D\LW
ZDVDOVRUHSRUWHGDVDQ$(OHDGLQJWRZLWKGUDZDO
$FURVVDJHJURXSVPHGLDQRQVHWIRUDOOV\VWHPLFHYHQWVDIWHUH LWKHUGRVHRI%17EZDV
'D\WR'D\'D\ZDVWKHGD\RIYDFFLQDWLRQ6\VWHPLFHYH QWVUHVROYHGSRVWHDFKGRVH
ZLWKDPHGLDQGXUDWLRQRIGD\H[FHSWIDWLJXHDQGFKLOOVZKLF KUHVROYHGZLWKLQDPHGLDQRI
GD\V,QVXPPDU\LQFUHDVHVLQVRPHV\VWHPLFUHDFWRJHQLFLW\HYHQWVI HYHUFKLOOVKHDGDFKH
IDWLJXHPXVFOHSDLQDQGMRLQWSDLQZHUHREVHUYHGLQWKHZHHN IROORZLQJ'RVHZKHQ
FRPSDUHGZLWKWKHZHHNIROORZLQJ'RVH7KHGLIIHUHQFHVDUHVPDOOHQRXJKWKDWWKH\DUH
XQOLNHO\WRGLVFRXUDJHYDFFLQHHVIURPFRPSOHWLQJWKHIXOOGRV HUHJLPHQIRUYDFFLQDWLRQ
QHLWKHUGRWKH\LPSDFWWKHEHQHILWULVNSURILOHRIWKHYDFFLQHRYHUDOO2YHUDOOWKHUHDFWRJHQLFLW\HYHQWVKDYHRQO\WHPSRUDU\FOLQLFDOLPSDFWRQSD WLHQWVLQUHODWLRQWRWKH
SRWHQWLDOVHYHULW\RIWKHGLVHDVHSUHYHQWHG
,PSRUWDQW ,GHQWLILHG 5LVNV
$QDSK\OD[LVKDVEHHQUHFRJQL]HGDVDQLPSRUWDQWLGHQWLILHGULVNGXULQJWKHUHSRUWLQJSHULRG
DQGZDVLQFOXGHGLQWKHLQLWLDO(8503Y'HFHPEHU $QDSK\OD[LVLVDVHULRXV
DGYHUVHUHDFWLRQWKDWDOWKRXJKYHU\UDUHFDQEHOLIHWKUHDWHQLQJ
,PSRUWDQW 3RWHQWLDO5LVNV
9DFFLQHDVVRFLDWHGHQKDQFHGGLVHDVH9$('LQFOXGLQJ9DFFLQHDVVRFLDWHGHQKDQFHG
UHVSLUDWRU\GLVHDVH9$(5'LVDQLPSRUWDQWSRWHQWLDOULVNIRU&29 ,'YDFFLQH
$OWKRXJKQRWREVHUYHGRULGHQWLILHGLQFOLQLFDOVWXGLHVZLWK&2 9,'YDFFLQHVWKHUHLVD
WKHRUHWLFDOULVNPRVWO\EDVHGRQQRQFOLQLFDOEHWDFRURQDYLUXV GDWDRI9$('RFFXUULQJ
HLWKHUEHIRUHWKHIXOOYDFFLQHUHJLPHQLVDGPLQLVWHUHGRULQYDFFLQHHVZKRKDYHZDQLQJLPPXQLW\RYHUWLPH,I9$('ZHUHWREHLGHQWLILHGDVDWUXHULV NGHSHQGLQJRQLWVLQFLGHQFH
DQGVHYHULW\LWPD\QHJDWLYHO\LPSDFWWKHRYHUDOOYDFFLQHEHQH ILWULVNDVVHVVPHQWIRUFHUWDLQ
LQGLYLGXDOV
2IQRWHWKH(8503ZDVXSGDWHGWRYGXULQJWKHUHSRUWLQJL QWHUYDODQGUHFHLYHG&+03
DSSURYDORQ$SULO$VXEVHTXHQW(8503XSGDWHYG DWHG$SULO
H[SDQGLQJWKHFRQGLWLRQDODXWKRUL]DWLRQWRDGROHVFHQWVWR \HDUVROGKDVEHHQDSSURYHG
SRVWWKH'/3RQ0D\7KHUHZHUHQRXSGDWHVWRWKHVDIHW \FRQFHUQVPDGH
%HQHILW5LVN &RQVLGHUDWLRQV
&29,'LVDVHULRXVDQGSRWHQWLDOO\IDWDORUOLIHWKUHDWHQLQJ KXPDQLQIHFWLRQ&29,'
YDFFLQHLVEHLQJGHYHORSHGIRUDFWLYHLPPXQL]DWLRQWRSUHYHQW& 29,'FDXVHGE\6$56
&R9YLUXV 7KHDYDLODEOHFOLQLFDOHYLGHQFHIRU%17EHIIH FWLYHQHVVLQFOXGHVLQGXFWLRQ
RIVWURQJLPPXQHUHVSRQVHVDQGRYHUZKHOPLQJO\KLJKYDFFLQHHIILFDF\ZLWKDVDWLVIDFWRU\090177e19744d904\A pproved\A pproved On: 11-Jun-2021 10:28 (GMT )
FDA-CBER-2021-5683-1102897
&29,'9DFFLQH%173) 5HSRUWLQJ3HULRG
'HYHORSPHQW6DIHW\8SGDWH5HSRUW'6851R $SULOWKURXJ K$SULO
&21),'(17,$/
3DJHSURILOHVXJJHVWLQJWKDWWKHYDFFLQHFRQIHUVVDIHDQGHIIHFWLYH SURWHFWLRQDJDLQVW&29,'
LQLQGLYLGXDOV\HDUVRIDJH
7KHSRWHQWLDOULVNVDUHEDVHGRQWKHREVHUYHGFOLQLFDOVWXG\VDI HW\SURILOHWRGDWHZKLFK
VKRZVPRVWO\PLOGUHDFWRJHQLFLW\ORZLQFLGHQFHRIVHYHUHRUVH ULRXVHYHQWVDQGQRQHZ
FOLQLFDOO\FRQFHUQLQJVDIHW\REVHUYDWLRQVRUVDIHW\FRQFHUQV7 KHYDFFLQHKDVEHHQVKRZQWR
EHVDIHDQGZHOOWROHUDWHGDFURVVDJHJURXSVDQGLUUHVSHFWLYHR ISULRULQIHFWLRQZLWK6$56
&R9&RQILQHPHQWRIVHYHUH&29,'FDVHVPRVWO\WRSODFHERUHFLSLHQWVYHUVXV
%17EUHFLSLHQWVDOOUHSRUWHGLQDGXOWDJHJURXSVWRGDWH VXJJHVWVQRHYLGHQFHRI
9$('RU9$(5'
3RVWDXWKRUL]DWLRQVDIHW\UHYLHZVLQFOXGLQJVSRQWDQHRXVVDIHW\ UHSRUWLQJIURPDOO
FRXQWULHVUHJLRQVLQZKLFK%17ELVDXWKRUL]HGRUFRQGLWLRQD OO\DSSURYHGRIZKLFKD
VXPPDU\UHSRUWLVVXEPLWWHGWRUHJXODWRU\DXWKRULWLHVRQDPRQWK O\EDVLVKDYHVXJJHVWHGQR
QHZLPSRUWDQWULVNVH[FHSWIRUDQDSK\OD[LVZKLFKKDVEHHQLQFOX GHGDVDQLGHQWLILHGULVNLQ
WKH(8503(IILFDF\GDWDVXJJHVWKLJKO\HIIHFWLYHSURWHFWLRQDJDLQVW&29,' LQDEURDGSRSXODWLRQRI
LQGLYLGXDOVDFURVVGHPRJUDSKLFFKDUDFWHULVWLFVLQFOXGLQJDJHDQ GSULRU6$56&R9
LQIHFWLRQZLWKWR9(REVHUYHGLQDGXOWVDQGDGROHVFHQW V\HDUVRIDJH
UHVSHFWLYHO\,PPXQREULGJLQJIRUDGROHVFHQWV\HDUVRIDJHZKRKDGQRQLQIHULRU
QHXWUDOL]LQJ*07VFRPSDUHGW R\RXQJDGXOWV \HDUVRIDJHVXSSRUWVHYLGHQFHRI
YDFFLQHHIIHFWLYHQHVVLQWKHDGROHVFHQWDJHJURXS
2YHUDOOWKHSRWHQWLDOULVNVDQGEHQHILWVDVDVVHVVHGE\WKHV DIHW\SURILOHDQGWKHHIILFDF\DQG
LPPXQRJHQLFLW\RI%17EDUHEDODQFHGLQIDYRURIWKHSRWHQW LDOEHQHILWVWRSUHYHQW
&29,'LQLPPXQL]HGDGXOWVDQGDGROHVFHQWV\HDUVRIDJH ,PSRUWDQWULVNVRI
%17EDUHGHVFULEHGLQWKH(8503DQGZLOOFRQWLQXHWREHDV VHVVHGDQGPLQLPL]HGDV
GHVFULEHGLQWKH(85037KHSXEOLFKHDOWKLPSDFWVWKDWLQFOXGHLQGLYLGXDODQGFRPPXQLW\
KHDOWKHGXFDWLRQDQGVRFLRHFRQRPLFRXWFRPHVDOVRZHLJKLQID YRURILPPXQL]LQJ
LQGLYLGXDOV\HDUVRIDJHDQGROGHUZLWK%17E
$QDSK\OD[LVLVDQLPSRUWDQWLGHQWLILHGULVNDQG9$('9$(5'DUHLPS RUWDQWSRWHQWLDOULVNV
%DVHGRQWKHDYDLODEOHVDIHW\DQGHIILFDF\GDWDIRU&29,'YD FFLQHWKHEHQHILWULVN
SURILOHRIWKHPHGLFLQDOSURGXFWUHPDLQVIDYRUDEOH 6800$5<2),03257$175,6.6
7KLVVHFWLRQVXPPDUL]HVWKHLPSRUWDQWLGHQWLILHGDQGSRWHQWLDOULVNVWKDWKDYHEHHQ
UHFRJQL]HGGXULQJWKHFRQGXFWRIWKH&29,'YDFFLQHFOLQLFDOG HYHORSPHQWSURJUDP $
VXPPDU\RIWKHLPSRUWDQWULVNVDVVRFLDWHGZLWK&29,'YDFFLQHLVSUHVHQWHGLQ 7DEOH090177e19744d904\A pproved\A pproved On: 11-Jun-2021 10:28 (GMT )
FDA-CBER-2021-5683-1102898
&29,'9DFFLQH%173) 5HSRUWLQJ3HULRG
'HYHORSPHQW6DIHW\8SGDWH5HSRUW'6851R $SULOWKURXJ K$SULO
&21),'(17,$/
3DJH7DEOH 6XPPDU\RI,PSRUWDQW5LVNVIURPWKH&29,'9DFFLQH'HYH ORSPHQW 3URJUDP
5LVN 1RQFOLQLFDO 'DWD &OLQLFDO 'DWD 0HDVXUHV LQ3ODFH DQG$FWLRQVWR E H7 DN H QD
,GHQWLILHG 5LVNV
$QDSK\OD[LV 1RGDWD 7KHUHZDVRQHUHSRUWRI
$QDSK\ODFWRLGUHDFWLRQ
WKDWRFFXUUHGGXULQJWKHRSHQODEHOSKDVHRI6WXG\&3OHDVHUHIHUWR6HFWLRQ 7DEOHIRU
FDVHGHWDLOV3KDUPDFRYLJLODQFHDFWLYLWLHVWRDGGUHVVWKHVDIHW\FRQFHUQVLQFO XGH
6WXG\&
E2QJRLQJ7KHREMHFWLYHRIWKHVWXG\LVWRHYDOXDWHWKH
VDIHW\WROHUDELOLW\LPPXQRJH QLFLW\DQGHII LFDF\RI&29,'P 51$
YDFFLQH$QXQIDYRUDEOHLPEDODQFHEHWZHHQWKHYDFFLQHDQGFRQWUROJURXSVLQWKHIUHTXHQF\RI&29,'LQSDUWLFXODUIRUVHYHUH&29,'PD\VXJJHVW
WKHRFFXUUHQFHRIYDFFLQHDVVRFLDWHGHQKDQFHGGLVHDVH6XUYHLOODQFHLV
SODQQHGIRU\HDUVIROORZLQJ'RVH
&3ODQQHGZLOOHY DOXDWHRFFXUUHQFHRIVDIHW\HYHQWVLQUHDO
ZRUOGXVHRI&29,'P51$YDFFLQH
6WXG\&3ODQQHG
FZLOOHYDOXDWHRFFXUUHQFHRIVDIHW\HYHQWVRI
LQWHUHVWLQFOXGLQJVHYHUHRUDW\SLFDO&29,'LQDFRKRUWRI SHRSOHZLWKLQ
WKH'HSDUWPHQWRI'HIHQVH+HDOWKFDUH6\VWHP
&FZLOOHYDOXDWHWKHRFFXUUHQFHRIVDIHW\HYHQWVRILQWHUHVW
LQFOXGLQJVHYHUHRUDW\SLFDO&29,'LQUHDOZRUOGXVHRI&29, '
P51$YDFFLQH$&&(669$&(8 PlannedZLOOHYDOXDWHRFFXUUHQFHRIVDIHW\HYHQWVRI
LQWHUHVWLQFOXGLQJVHYHUHRUDW\SLFDO&29,'LQUHDOZRUOGXVHRI
&29,'P5 1$YDFFLQH
3RWHQWLDO 5LVNV
9DFFLQHDVVRFLDWHGHQKDQFHGGLVHDVH9$('
LQFOXGLQJ9DFFLQH
DVVRFLDWHGHQKDQFHGUHVSLUDWRU\GLVHDVH9$(5'1RGDWD 1RGDWD $GGLWLRQDOSKDUPDFRYLJLODQFHDFWLYLWLHV
&
E
&F
&F
$&&(669$&(86HHDERYHIRUGHWDLOV
D 6RXUFH(8503YGDWHG'HFHPEHUDQG(8503YGD WHG$SULOWRUHIOHFWFXUUHQWVWXG\VWDWXV
E &DWHJRU\VWXG\LQWKH(8
F &DWHJRU\6WXG\LQWKH(8090177e19744d904\A pproved\A pproved On: 11-Jun-2021 10:28 (GMT )
FDA-CBER-2021-5683-1102899
&29,'9DFFLQH%173) 5HSRUWLQJ3HULRG
'HYHORSPHQW6DIHW\8SGDWH5HSRUW'6851R $SULOWKURXJ K$SULO
&21),'(17,$/
3DJH &21&/86,21
$QDSK\OD[LVLVDQLPSRUWDQWLGHQWLILHGULVNLGHQWLILHGGXULQJWKH UHSRUWLQJSHULRGDQG9$('
LQFOXGLQJ9$(5'DUHLPSRUWDQWSRWHQWLDOULVNV 7KHVHLPSRUWDQWULV NVZLOOFRQWLQXHWREH
FORVHO\PRQLWRUHGDV&29,'YDFFLQHGHYHORSPHQWSURJUDPSURJUHVVHV
'XULQJWKHUHSRUWLQJSHULRGWKHUHZHUHRQJRLQJFOLQLFDOWULDOV&&
&&&&%17%17% 17DQG
%176WXGLHV&&&&&DQG%17ZHUHVWLOOEOLQGHGDWWKH'/3KRZHYHUQRDGGLWLRQDOF OLQLFDOO\LPSRUWDQW
LQIRUPDWLRQKDVHPHUJHGIURPWKHVHRQJRLQJFOLQLFDOWULDOV
7KHVSRQVRUZLOOFRQWLQXHWRPRQLWRUDOOFOLQLFDOWULDOVDIHW\LQ IRUPDWLRQUHFHLYHGIURP
ZRUOGZLGHVRXUFHVDQGZLOOUHYLVHWKHSURWRFROVFRQVHQWIRUPVDQGRUSURGXFWGRFXPHQWVLI
DQHYDOXDWLRQRIVXUYHLOODQFHGDWD\LHOGVVLJQLILFDQWQHZLQIRU PDWLRQ
%DVHGRQWKHDYDLODEOHVDIHW\DQGHIILFDF\GDWDIRU&29,'YDF FLQHWKHEHQHILWULVN
SURILOHRIWKHPHGLFLQDOSURGXFWUHPDLQVIDYRUDEOH )XUWKHUGH YHORSPHQWRI&29,'
YDFFLQHLVMXVWLILHGE\WKHDQWLFLSDWHGEHQHILWVH[SHFWHGIRUSDW LHQWVZKRPD\EHH[SRVHGWR
6$56&R9LQIHFWLRQ090177e19744d904\A pproved\A pproved On: 11-Jun-2021 10:28 (GMT )
FDA-CBER-2021-5683-1102900
3DJHRI
&RQILGHQWLDOLW\ 6WDWHPHQW 7KHLQIRUPDWLRQFRQWDLQHGLQWKLVGRFXPHQWLVWKHSURSHUW\DQG FRS\ULJKWRI
%LR17HFK51$3KDUPDFHXWLFDOV *PE+7KHUHIRUHWKLVGRFXPHQWLV SURYLGHGLQFRQILGHQFHWRWKHUHFLSLHQW
1RLQIRUPDWLRQFRQWDLQHGKHUHLQVKDOOEHSXEOLVKHGGLVFORVHGR UUHSURGXFHGZLWKRXWSULRUZULWWHQDSSURYDORI
WKHSURSULHWRUV
,19(67,*$725¶6 %52&+85(
&RU9$& %17
9HUVLRQ 'DWH$35
6SRQVRU %LR17HFK51$3KDUPDFHXWLFDOV*PE+
$QGHU*ROGJUXEH
0DLQ]
*HUPDQ\
5HIHUHQFH
VDIHW\LQIRUPDWLRQIRUWKH LQYHVWLJDWLRQDOPHGLFLQDO SURGXFWV,03VLVSURYLGHG
LQ6HFWLRQ
'RFXPHQW +LVWRU\
8VH 'DWH 9HUVLRQ QXPEHU
)LUVWDSSURYHGYHUVLRQ 0$5
:LWKXSGDWHGQRQFOLQLFDOFRQWHQW $35
:LWKXSGDWHGQRQFOLQLFDOFRQWHQW $35
3DJH &21),'(17,$/090177e19744d904\A pproved\A pproved On: 11-Jun-2021 10:28 (GMT )
FDA-CBER-2021-5683-1102901
%LR17HFK51$
3KDUPDFHXWLFDOV*PE+
&RQILGHQWLDO,QYHVWLJDWRU¶V %URFKXUH
&RU9$&%173DJHRI
9HUVLRQ
'DWH$35
7$%/( 2) &217(176
6800$5<
,1752'8&7,21
%DFNJURXQG
%LR17HFK¶VGLYHUVLILHGH[SHUWLVHLQ51$WKHUDSHXWLFV
,QWURGXFWLRQWR%LR17HFK51$EDVHGYDFFLQHV
&OLQLFDOGHYHORSPHQW
6XSSRUWLYHFOLQLFDOEDFNJURXQGLQIRUPDWLRQ
3+<6,&$/&+(0,&$/$1'3+$50$&(87,&$/3523(57,(6$1'
)2508/$7,21
'HVFULSWLRQRIWKHGUXJVXEVWDQFH
3K\VLFDOFKHPLFDODQGSKDUPDFHXWLFDOSURSHUWLHVRIWKHGUXJVX EVWDQFH
'HVFULSWLRQRIWKHGUXJSURGXFW
'HVFULSWLRQRIWKHH[FLSLHQWV
'HVFULSWLRQRIWKHGLOXHQW
'HVFULSWLRQRIWKH,03
6WRUDJHDQGKDQGOLQJRIWKH,03
121&/,1,&$/678',(6
1RQFOLQLFDOSKDUPDFRORJ\
3ULPDU\3KDUPDFRG\QDPLFV
6HFRQGDU\SKDUPDFRG\QDPLFV
6DIHW\SKDUPDFRORJ\
1RQFOLQLFDOSKDUPDFRORJ\&RQFOXVLRQV
1RQFOLQLFDOSKDUPDFRNLQHWLFVDQGPHWDEROLVP
0HWKRGVRIDQDO\VLV
$EVRUSWLRQ
'LVWULEXWLRQ
0HWDEROLVPDQGH[FUHWLRQ
3KDUPDFRNLQHWLFGUXJLQWHUDFWLRQV
1RQFOLQLFDOSKDUPDFRNLQHWLFVDQGPHWDEROLVP &RQFOXVLRQV
7R[LFRORJ\
1RQFOLQLFDOGDWDIURPSULRUWR[LFRORJ\VWXGLHV
5HSHDWGRVHWR[LFRORJ\WRVXSSRU WWKHFOLQLFDOHYDOXDWLRQRI%1 7YDFFLQH
FDQGLGDWHV
*HQRWR[LFLW\
&DUFLQRJHQLFLW\
5HSURGXFWLYHDQGGHYHORSPHQWDOWR[LFLW\
3DJH &21),'(17,$/090177e19744d904\A pproved\A pproved On: 11-Jun-2021 10:28 (GMT )
FDA-CBER-2021-5683-1102902
%LR17HFK51$
3KDUPDFHXWLFDOV*PE+
&RQILGHQWLDO,QYHVWLJDWRU¶V %URFKXUH
&RU9$&%173DJHRI
9HUVLRQ
'DWH$35
/RFDOWROHUDQFH
,PPXQRWR[LFRORJ\
7R[LFRORJ\&RQFOXVLRQV
())(&76,1+80$16
6800$5<2)'$7$$1'*8,'$1&()257+(,19(67,*$725
*XLGDQFHIRUWKHLQYHVWLJDWRU
3RVRORJ\DQGPHWKRGRIDGPLQLVWUDWLRQ
5HVWULFWLRQV
,QIRUPDWLRQUHOHYDQWWRVSHFLDOSRSXODWLRQV
6SHFLDOZDUQLQJVDQGSUHFDXWLRQVIRUXVH
5HIHUHQFHVDIHW\LQIRUPDWLRQ
5LVNV
*HQHUDOULVNV
3RWHQWLDOULVNV
,GHQWLILHGULVNV
5LVNHYDOXDWLRQVXPPDU\
5()(5(1&(6
/,67 2) 7$%/(6
7DEOH %LR17HFKFOLQLFDOSODWIRUPH[SHULHQFHZLWKX51$DQGPRG51$DVR II$SULO
7DEOH *HQHUDOSURSHUWLHVRIX51$PRG51 $DQGVD51$GUXJVXEVWDQFHV
7DEOH &RPSRVLWLRQRIGUXJSURGXFWV
7DEOH /LSLGH[FLSLHQWVLQWKHGUXJSURGXFW
7DEOH 1RPHQFODWXUHRIWKHSUHFOLQLFDOO\HYDOXDWHGYDFFLQHV
7DEOH 6WXGLHVRQSULPDU\SKDUPDFRG\QDPLFHIIHFWV
7DEOH &KDUDFWHULVWLFVRIDGDSWLYHLPPXQHUHVSRQVHIRUWKHP51$IRUPDW V
7DEOH 6WXG\GHVLJQ
7DEOH ,J*DQWLERG\FRQFHQWUDWLRQDJDLQVWWKHYLUDODQWLJHQLQ:LVWDU +DQUDWV
7DEOH %LR17HFKQRQFOLQLFDOSODWIRUPH[SHULHQFH
7DEOH 'HVLJQRIWKH*/3FRPSOLDQWUHSHDWGRVHWR[LFLW\VWXG\6WXG\1R
7DEOH 3DUDPHWHUVDVVHVVHGLQWKHUHSHDWGRVHWR[LFLW\VWXG\
7DEOH 6XPPDU\RIPDFURVFRSLFILQGLQJV ±PDLQVWXG\
7DEOH *UDGLQJRIHGHPDIRUPDWLRQ
7DEOH )UHTXHQF\RIKLJKHVWHGHPDVFRUHQRWHGSRVWILUVWDQGVHFRQGYD FFLQHGRVH
LQ*/3UHSHDWHGGRVHWR[LFLW\VWXG\
3DJH &21),'(17,$/090177e19744d904\A pproved\A pproved On: 11-Jun-2021 10:28 (GMT )
FDA-CBER-2021-5683-1102903
%LR17HFK51$
3KDUPDFHXWLFDOV*PE+
&RQILGHQWLDO,QYHVWLJDWRU¶V %URFKXUH
&RU9$&%173DJHRI
9HUVLRQ
'DWH$35
/,67 2) ),*85(6
)LJXUH 2YHUYLHZRIWKHWKUHH51$SODWIRUPV
)LJXUH 51$/13EDVHG%17YDFFLQHV
)LJXUH 5DWLRQDOHIRUWKHDGPLQLVWUDWLRQVFKHPDRI%17YDFFLQHV
)LJXUH 6FKHPDWLFOLIHFLUFOHRID&RURQDYLUXV
)LJXUH 6FKHPDWLFRYHUYLHZRIWKHRUJDQL]DWLRQRIWKH6$56&R96JO\F RSURWHLQ
)LJXUH 6FKHPDWLFRYHUYLHZRID/13
)LJXUH :HVWHUQ%ORWDQDO\VLVIRUGHWHFWLRQRIDQWLJHQH[SUHVVLRQ
)LJXUH ,PPXQRIOXRUHVFHQFHVWDLQLQJRIFHOOVWUDQVIHFWHGZLWKPRG51$HQ FRGLQJWKH
5%'RUVD51$HQFRGLQJWKH369
)LJXUH $QWLERG\UHVSRQVHHOLFLWHGE\LQIOXHQ]D+$XVLQJ/13IRUPXODWHG
PRG51$
)LJXUH 7FHOOUHVSRQVHDJDLQVWLQIOXHQ]D+$XVLQJWKH/13IRUPXODWHGP RG51$
SODWIRUP
)LJXUH $QWL6,J*UHVSRQVHDQGGDIWHULPPXQL]DWLRQZLWK 5%/
)LJXUH .LQHWLFVRIWKHDQWLERG\FRQFHQW UDWLRQDJDLQVWWKHYLUDODQWLJH Q
)LJXUH 1HXWUDOL]DWLRQRI6$56&R9SVHXGRYLUXVDQGGDIWHULPPXQL]DWLRQZLWK5%/
)LJXUH $QWL6SURWHLQ,J*UHVSRQVHDQGGDIWHULPPXQL]DWLRQZLWK5%6
)LJXUH 1HXWUDOL]DWLRQRI6$56&R9SVHXG RYLUXVGDIWHULPPXQL]DWLR QZLWK
5%6
)LJXUH $QWL6SURWHLQ,J*UHVSRQVHDQGGDIWHULPPXQL]DWLRQZLWK5%3
)LJXUH 1HXWUDOL]DWLRQRI6$56&R9SVHXG RYLUXVGDIWHULPPXQL]DWLR QZLWK
5%3
)LJXUH $QWL6SURWHLQ,J*UHVSRQVHDQGGDIWHULPPXQL]DWL RQZLWK
%17D
)LJXUH .LQHWLFVRIWKHDQWLERG\FRQFHQW UDWLRQDJDLQVWWKHYLUDODQWLJH Q
)LJXUH 1HXWUDOL]DWLRQRI6$56&R9SVHXGRYLUXVDQGGDIWHULPPXQL]DWLRQZLWK%17D
)LJXUH $QWL6,J*UHVSRQVHDQGGDIWHULPPXQL]DWLRQZLWK %17E
)LJXUH .LQHWLFVRIWKHDQWLERG\FRQFHQW UDWLRQDJDLQVWWKHYLUDODQWLJH Q
)LJXUH 1HXWUDOL]DWLRQRI6$56&R9SVHXGRYLUXVDQG GDIWHULPPXQL]DWLRQZLWK%17E
)LJXUH $QWL6,J*UHVSRQVHDQGGDIWHULPPXQL]DWLRQZLWK%17E
)LJXUH $QWL6SURWHLQ,J*UHVSRQVHDQG GDIWHULPPXQL]DWLRQ ZLWK
%17F
)LJXUH 1HXWUDOL]DWLRQRI6$56&R9SVHXGRYLUXVDQG GDIWHULPP XQL]DWLRQ
ZLWK%17F
3DJH &21),'(17,$/090177e19744d904\A pproved\A pproved On: 11-Jun-2021 10:28 (GMT )
FDA-CBER-2021-5683-1102904
%LR17HFK51$
3KDUPDFHXWLFDOV*PE+
&RQILGHQWLDO,QYHVWLJDWRU¶V %URFKXUH
&RU9$&%173DJHRI
9HUVLRQ
'DWH$35
)LJXUH (/,6$VFUHHQLQJDQDO\VLVWRGHWHFW DQWLERG\UHVSRQVHVGLUHFWHG DJDLQVWWKH
UHFRPELQDQW6$56&R9VSL NHSURWHLQ6GRPDLQ
)LJXUH (/,6$VFUHHQLQJDQDO\VLVWRGHWHFW DQWLERG\UHVSRQVHVGLUHFWHG DJDLQVWWKH
UHFRPELQDQW6$56&R9VSLNHSURWHLQ5%'GRPDLQ
)LJXUH $QWLERG\WLWHUUHVXOWLQJLQSVHXGRYLUXVQHXWUDOL]DWLRQDFWL YLW\S91
)LJXUH %LROXPLQHVFHQFHLPDJLQJ%/,PHDVXUHPHQWXVLQJWKH/13FDQGLGD WH
IRUPXODWHGPRG51$HQFRGLQJOXFLIHUDVH
)LJXUH 'HYHORSPHQWRIERG\ZHLJKWLQWKHUHSHDWGRVHWR[LFLW\VWXG\
)LJXUH 5HWLFXORF\WHVDUHGHFUHDVHGE\%17DIWHUWKHVWGRVHEXWUHFRYHUE\HQG
RI
LQOLIHLQWKHUHSHDWHG GRVHWR[LFLW\VWXG\
)LJXUH (U\WKURF\WHVDQGKHPRJORELQFRQWHQWLVQRWLQIOXHQFHGDIWHU%17
WUHDWPHQWLQWKHUHSHDWHGGRVHWR[LFLW\VWXG\
)LJXUH 1XPEHUVRIOHXNRF\WHVDQGODUJHXQFODVVLILHGFHOOVDUHLQFUHDVH GDWWKHHQG
RILQOLIH
)LJXUH 1XPEHUVRISODWHOHWVDUHVOLJKWO\GHFUHDVHGDWWKHHQGRILQOL IH
)LJXUH 6OLJKWHOHYDWLRQRI**7LQWKHUHSHDWHGGRVHWR[LFLW\VWXG\
)LJXUH 1RHOHYDWLRQRIOLYHUVSHFLILFHQ]\PHV$/$7DQG$6$7LQWKHUHS HDWHGGRVH
WR[LFLW\VWXG\
)LJXUH $FXWHSKDVHSURWHLQVDQGILEULQRJHQDUHLQFUHDVHGIRUWUHDWPHQW JURXSVLQ
WKHUHSHDWHGGRVHWR[LFLW\VWXG\
)LJXUH /RFDOUHDFWLRQVZHUHVOLJKWDIWHUILUVWLPPXQL]DWLRQEXWPRUHSURQRXQFHGDIWHU
ERRVWZLWKDUHGXFHGLPPXQL]DWLRQLQWHUYDO
)LJXUH &RXUVHRIERG\WHPSHUDWXUHGXULQJUHSHDWHGGRVHWR[LFLW\VWXG\
)LJXUH (OHYDWLRQLQF\WRNLQHOHYHOVLVVLPLODULQEXIIHUDQGYDFFLQHW UHDWHGJURXSV
3DJH &21),'(17,$/090177e19744d904\A pproved\A pproved On: 11-Jun-2021 10:28 (GMT )
FDA-CBER-2021-5683-1102905
%LR17HFK51$
3KDUPDFHXWLFDOV*PE+
&RQILGHQWLDO,QYHVWLJDWRU¶V %URFKXUH
&RU9$&%173DJHRI
9HUVLRQ
'DWH$35
/,67 2) $%%5(9,$7,216
$EEUHYLDWLRQ ([SODQDWLRQ
$( $GYHUVH(YHQW
$/$7 $ODQLQHDPLQRWUDQVIHUDVH
$6$7 $VSDUWDWHDPLQRWUDQVIHUDVH
D377 $FWLYDWHGSDUWLDOWKURPERSODVWLQWLPH
%17D %1751$/13YDFFLQHXWLOL]LQJXULGLQH51$GLIIHUHQWYDULDQW VRI WKLVSODWIRUPDUH
LQGLFDWHGDV %17D%17DHWF
%17E %1751$ /13YDFFLQHXWLOL]LQJQXFOHRVLGHPRGLILHG51$GLIIHUHQWYDULDQ WVRIWKLV
SODWIRUP DUHLQGLFDWHGDV%17E%17EHWF
%17F %1751$/13YDFFLQHXWLOL]LQJVHOIDPSOLI\LQJ51$GLIIHUHQW YDULDQWVRIWKLV
SODWIRUP DUHLQGLFDWHGDV%17F%17FHWF
&29,' &RURQDYLUXV'LVHDVH
G 'D\V
'63& GLVWHDUR\OVQJO\FHURSKRVSKRFKROLQH
(/,6$ (Q]\PH/LQNHG,PPXQRVRUEHQW$VVD\
(5 (QGRSODVPLF UHWLFXOXP
**7 *DPPD JJOXWDP\OWUDQVSHSWLGDVH
*/3 *RRG/DERUDWRU\3UDFWLFH
K +RXUV
+$ +HPDJJOXWLQLQ
+,9 +XPDQ,PPXQRGHILFLHQF\9LUXV
,&+ ,QWHUQDWLRQDO&RXQFLOIRU+DUPRQLVDWLRQ
,)1 ,QWHUIHURQ
,J* ,PPXQRJOREXOLQ*
,/ ,QWHUOHXNLQ
,0 ,QWUDPXVFXODUO\
,03 ,QYHVWLJDWLRQDO0HGLFLQDO3URGXFW
,9 ,QWUDYHQRXVO\
/13 /LSLGQDQRSDUWLFOH
P51$ PHVVHQJHU51$
PRG51$ 1XFOHRVLGHPRGLILHGPHVVHQJHU51$
S917 SVHXGRYLUXVEDVHGQHXWUDOL]DWLRQDVVD\
5%' 5HFHSWRU%LQGLQJ'RPDLQ
51$ 5LERQXFOHLFDFLG
51$/3; 51$FRPSOH[HGZLWKOLSRVRPHV
VD51$ 6HOIDPSOLI\LQJPHVVHQJHU51$
6$56 6HYHUH$FXWH5HVSLUDWRU\6\QGURPH
6$56&R9 7KHYLUXVOHDGLQJWR&29,'
3DJH &21),'(17,$/090177e19744d904\A pproved\A pproved On: 11-Jun-2021 10:28 (GMT )
FDA-CBER-2021-5683-1102906
%LR17HFK 51$
3KDUPDFHXWLFDOV*PE+
&RQILGHQWLDO,QYHVWLJDWRU¶V %URFKXUH
&RU9$&%173DJHRI
9HUVLRQ
'DWH$35
$EEUHYLDWLRQ ([SODQDWLRQ
7K 7\SH7KHOSHUFHOOV
71) 7XPRUQHFURVLVIDFWRU
X51$ 1RQPRGLILHGXULGLQHPHVVHQJHU 51$
S917 SVHXGRYLUXVEDVHGQHXWUDOL]DWLRQDVVD\
969 9HVLFXODU6WRPDWLWLV 9LUXV
:+2 :RUOG+HDOWK2UJDQL]DWLRQ
ZNV :HHNV
127(6 )25 7+( 5($'(5
7KH%LR17HFKJURXSLVDKROGLQJFR PSULVLQJVHYHUDOVXEVLGLDULHV LQFOXGLQJ%LR17HFK51$
3KDUPDFHXWLFDOV*PE+
3DJH &21),'(17,$/090177e19744d904\A pproved\A pproved On: 11-Jun-2021 10:28 (GMT )
FDA-CBER-2021-5683-1102907
%LR17HFK51$
3KDUPDFHXWLFDOV*PE+
&RQILGHQWLDO,QYHVWLJDWRU¶V %URFKXUH
&RU9$&%173DJHRI
9HUVLRQ
'DWH$35
6800$5<
7KHUHLVDQXUJHQWQHHGIRUWKHGHYHORSPHQWRI DQHZSURSK\ODFW LFYDFFLQHJLYHQ WKH
WKUHDWSRVHGE\WKHLQFUHDVLQJQXPEHURIJOREDOO\GLVWULEXWHGR XWEUHDNVRI 6HYHUH$FXWH
5HVSLUDWRU\6\QGURPH6$56&R9 LQIHFWLRQDQGWKXVLWVDVVRF LDWHGGLVHDVH
&RURQDYLUXV'LVHDVH&29,'
7KHGHYHORSPHQWRIDULERQXFOHLFDFLG51$EDVHGYDFFLQHHQFRG LQJDYLUDODQWLJHQWKDW
LVWUDQVODWHGE\WKHYDFFLQDWHGRUJDQLVPWRSURWHLQWRLQGXFHD SURWHFWLYHLPPXQH
UHVSRQVHSURYLGHVVLJQLILFDQWDGYDQWDJHVRYHUPRUHFRQYHQWLRQDO YDFFLQHDSSURDFKHV
$W%LR17HFKWKHUHDUHWKUHHGLIIHUHQW 51$SODWIRUPVXQGHUGHYH ORSPHQWQDPHO\QRQ
PRGLILHGXULGLQHFRQWDLQLQJP51$X51$QXFOHRVLGHPRGLILHGP5 1$PRG51$DQG
VHOIDPSOLI\LQJP51$VD51$7DNHQWRJHWKHUDOOWKUHH51$SODWIRUPVKDYHEHHQWHVWHGLQPRU HWKDQDGR]HQQRQ
FOLQLFDOJRRGODERUDWRU\SUDFWLF H*/3VDIHW\VWXGLHVDQGFOLQLFDOVDIHW\GDWDDUHDYDLODEOH
IRUX51$DQGPRG51$7KHVHGDWDKDYHEHHQREWDLQHGSULPDULO\ZL WK51$VIRUPXODWHG
ZLWKOLSRVRPHVDQGOLSLGQDQRSDUWLFOHVZKLFKDUHUHODWHGEXWQ RWLGHQWLFDOWRWKRVHWKDWZLOO
EHXVHGLQWKHSODQQHGFOLQLFDOWULDOV7KHQRQFOLQLFDOWR[LFLW\GDWDJHQHUDWHGE\%LR17HFKVXJJHVWD IDYRUDEOHVDIHW\SURILOHIRU
X51$PRG51$DQGVD51$IRUPXODWHGZLWKGLIIHUHQWQDQRSDUWLFOHV IRUYDULRXV
DGPLQLVWUDWLRQURXWHVLQFOXGLQJIRULQWUDYHQRXV,9LQMHFWLRQ 7KHIDYRUDEOHVDIHW\SURILOH
DIWHU,9GRVLQJLVQRWDEOHEHFDXV H,9LQMHFWLRQUHVXOWVLQDKL JKHUV\VWHPLFH[SRVXUHWKDQ
WKHLQWUDPXVFXODU,0LQMHFWLRQ SODQQHGLQWKHFOLQLFDOWULDOV 2YHUDOOWKHILQGLQJVZHUHPLOG
DQGPRVWO\UHODWHGWRWKHPRGHRIDFWLRQDQGWKH51$LQWULQVLF VWLPXODWLRQRILQQDWH
LPPXQHVHQVRUV1RXQVXVSHFWHGWDUJHWRUJDQVRIWR[LFLW\ZHUHL GHQWLILHG7KHQRQFOLQLFDO
VDIHW\SURILOHRIX51$DQGPRG51$LQURGHQWVZDVSUHGLFWLYHIRU FOLQLFDOVDIHW\
7KHQRQFOLQLFDOVDIHW\DQGWR[L FLW\RIWKH%17IDPLO\RI OLSLGQDQRSDUWLFOH/13
HQYHORSHGX51$PRG51$DQGVD51$YDFFLQH SODWIRUPVHQFRGLQJ6$ 56&R9
DQWLJHQVDUHFXUUHQWO\EHLQJDQDO\]HG LQD*/3FRPSOLDQWUHSHDW GRVHWR[LFLW\VWXG\
7KHUHDUHFXUUHQWO\QRGDWDDYDLODEOHRQWKHHIIHFWVRI DQ\RI WKH%17YDFFLQH
FDQGLGDWHVLQKXPDQV7KHSRWHQWLDOVDIHW\DQGLPPXQRJHQLFLW\RIIRXU%17YDFFLQH FDQGLGDWHV%17D
%17E%17E DQG%17FDJDLQVW6$56&R9ZLOOEHLQ YHVWLJDWHG
FOLQLFDOO\DVSDUWRIDSURJUDPWRGHYHORSDSURSK\ODFWLFYDFF LQHWRSUHYHQWLQIHFWLRQZLWK
6$56&R9DQGWKXVLWVDVVRFL DWHGGLVHDVH&29,'
7KHGDWDFXWRIIGDWHIRUWKLVGRFXPHQWLV$SULO
WK
3DJH &21),'(17,$/090177e19744d904\A pproved\A pproved On: 11-Jun-2021 10:28 (GMT )
FDA-CBER-2021-5683-1102908
%LR17HFK51$
3KDUPDFHXWLFDOV*PE+
&RQILGHQWLDO,QYHVWLJDWRU¶V %URFKXUH
&RU9$&%173DJHRI
9HUVLRQ
'DWH$35
,1752'8&7,21
%DFNJURXQG
6$56&R9LQIHFWLRQVDQGWKHGLVHDVHWKLVYLUXVFDXVHV&29,' DUHLQFUHDVLQJHYHU\
GD\DQGLVVSUHDGLQJJOREDOO\7K H:RUOG+HDOWK2UJDQL]DWLRQ: +2FODVVLILHGWKH
&29,'RXWEUHDNDVSDQGHPLFRQ 0DUFKWK7KH:+26LWXDWLRQ8SGDWH5HSRUW
GDWHG$SULOWKQRWHGFRQILUPHGFDVHVZLWKGHDWKVJORE DOO\
:+26LWXDWLRQ8SGDWH5HSRUW
7KHUHDUHFXUUHQWO\QRDSSURYHGYDFFLQHVRUDQWLYLUDOGUXJVWR SUHYHQWRUWUHDWLQIHFWLRQ
ZLWK6$56&R9RULWVDVVRFLDWHGGLVHDVH&29,' +DELE]DGHKDQG6WRQHPDQ
%LR17HFK¶V GLYHUVLILHG H[SHUWLVH LQ 51$ WKHUDSHXWLFV
%LR17HFKKDVORQJVWDQGLQJDQGGLY HUVLILHGH[SHUWLVHLQ XWLOL]LQ JPHVVHQJHU51$P51$
WRGHOLYHUJHQHWLFLQIRUPDWLRQWRFHOOVZKHUHLWLVXVHGWRH[SUHVVSURWHLQVIRU WKHWKHUDSHXWLFHIIHFW%LR17HFKKDVEHHQZRUNLQJLQWKH51$ILHOG IRUPRUHWKDQDGHFDGH
DQGLVGHYHORSLQJDSRUWIROLRRI51$WKHUDSLHVWKDWXWLOL]HIRX UGLIIHUHQWP51$IRUPDWVDQG
WKUHHGLIIHUHQWIRUPXODWLRQVWRGHULYHILYHGLVWLQFWSODWIRUPVHDFKRSWLPL]HGIRUGHOLYHULQJDSDUWLFXODUWKHUDSHXWLFPRGHRIDFWLRQ
7KHVHPRGHRIDFWLRQVLQFOXGHXVLQJP51$DVDYDFFLQHWRLQGXFH DQWLERG\DQG7FHOO
LPPXQHUHVSRQVHV7KUHHRIWKHVH SODWIRUPVDUHFXUUHQWO\LQKXP DQWHVWLQJ LQRQFRORJ\
LQGLFDWLRQVSULPDULO\DVUHSHDWHGO\,9DGPLQLVWHUHGWKHUDSHXWLFFDQFHUYDFFLQHVZKHUH
RYHUSDWLHQWVKDYHEHHQGRVHGWRGDWHIRUIXUWKHUGHWDLOV VHH6HFWLRQ 7KLV
FOLQLFDOH[SHULHQFHLQFOXGHVDODUJHQXPEHU RISDWLHQWVZKRKDY HKDGORQJWHUPH[SRVXUH
LHZKRKDYHUHFHLYHGPRUHWKDQ,9DGPLQLVWUDWLRQV
51$LVDKLJKO\YHUVDWLOHPXOWLSXUSRVHPROHFXOH:KDWPDNHVLW DWWUDFWLYHDVYDFFLQH
SODWIRUPLVWKDWLWHQDEOHVWLPHO\DQGHIIHFWLYHUHVSRQVHWRHP HUJLQJWKUHDWV 51$YDFFLQHV
FDQPLPLFDQWLJHQH[SUHVVLRQGXULQJQDWXUDOLQIHFWLRQE\GLUHFW LQJH[SUHVVLRQRIYLUWXDOO\
DQ\SDWKRJHQDQWLJHQZLWKKLJKSUHFLVLRQDQGIOH[LELOLW\RIDQW LJHQGHVLJQ51$RFFXUV
QDWXUDOO\LQWKHERG\LVPHWDEROL]HGDQGHOLPLQDWHGE\WKHERG \¶VQDWXUDOPHFKDQLVPV
GRHVQRWLQWHJUDWHLQWRWKHJHQR PHLVWUDQVLHQWO\H[SUHVVHGD QGWKHUHIRUH LVFRQVLGHUHG
VDIH9DFFLQDWLRQZLWK51$LQJHQHUDOJHQHUDWHVUREXVWLPPXQHU HVSRQVHVDV51$QRW
RQO\GHOLYHUVWKHYDFFLQHDQWLJHQEXWDOVRKDVLQWULQVLFDGMXY DQWLFLW\
7KHSURGXFWLRQRI51$UHTXLUHV RQO\DVLQJOHGHYHORSPHQWDQGPD QXIDFWXULQJSODWIRUP
LUUHVSHFWLYHRIWKHHQFRGHGSDWKRJHQDQWLJHQV7KXV51$KDVWKHSRWHQWLDORIUDSLGFRVW
HIILFLHQWKLJKYROXPHPDQXIDFWXULQJDQGIOH[LEOHVWRFNSLOLQJ ORQJWHUP VWRUDJHRIORZ
YROXPHOLEUDULHVRIIUR]HQSODVPLGDQGXQIRUPXODWHG51$ZKLFK FDQEHUDSLGO\IRUPXODWHG
DQGGLVWULEXWHG%LR17HFKKDVH[SHUWLVHLQSURGXFWLRQSURFHVVGHYHORSPHQWIRUYDULRXV51$FKHPLVWULHVDQGIRUPXODWLRQV
3DJH &21),'(17,$/090177e19744d904\A pproved\A pproved On: 11-Jun-2021 10:28 (GMT )
FDA-CBER-2021-5683-1102909
%LR17HFK51$
3KDUPDFHXWLFDOV*PE+
&RQILGHQWLDO,QYHVWLJDWRU¶V %URFKXUH
&RU9$&%173DJHRI
9HUVLRQ
'DWH$35
,QWURGXFWLRQ WR %LR17HFK 51$EDVHG YDFFLQHV
$/13IRUPXODWHG51$EDVHGYDFFLQHZRXOGSURYLGHRQHRIWKHPRV WIOH[LEOHVFDODEOH
DQGIDVWHVWDSSURDFKHVWRSURYLGHSURWHFWLRQDJDLQVW DQHZIDV WVSUHDGLQJYLUXV
LQIHFWLRQV 5DXFKHWDO 6DKLQHWDO
7KHGHYHORSPHQWRIDQ51$EDVHGYDFFLQHFDQGLGDWHHQFRGLQJDYL UDODQWLJHQWKDWLV
WUDQVODWHGE\WKHYDFFLQDWHGRUJ DQLVPWRSURWHLQWRLQGXFHDSU RWHFWLYHLPPXQHUHVSRQVH
SURYLGHVVLJQLILFDQWDGYDQWDJHVRYHUPRUHFRQYHQWLRQDOYDFFLQH DSSURDFKHV
51$YDFFLQHVDUHPROHFXODUO\GHILQHGKLJKO\SXULILHGLPPXQRJHQ V8QOLNHOLYHDWWHQXDWHG
YDFFLQHV51$YDFFLQHVGRQRWF DUU\WKHULVNVDVVRFLDWHGZLWKL QIHFWLRQDQGPD\EHJLYHQ
WRSHRSOHZKRFDQQRWEHDGPLQLVWHUHGOLYHYLUXVVXFKDVSUHJQD QWZRPHQDQG
LPPXQRFRPSURPLVHGSHUVRQV51$EDVHGYDFFLQHVDUHPDQXIDFWXUHG XVLQJDFHOOIUHH
LQ YLWURWUDQVFULSWLRQSURFHVVZKLFKDOO RZVDQHDV\DQGUDSLGSURGXFWLRQDQGWKHSURVSHFW
RISURGXFLQJKLJKQXPEHUVRIYDFFLQHGRVHVZLWKLQDVKRUWHUWLP HSHULRGWKDQSRVVLEOHZLWK
FRQYHQWLRQDOYDFFLQHDSSURDFKHV7KLVFDSDELOLW\LVSLYRWDOWR HQDEOHWKHPRVWHIIHFWLYH
UHVSRQVHLQRXWEUHDNVFHQDULRV
%LR17HFKKDVXVHGWKUHHGLIIHUHQW51$SODWIRUPVIRUWKHGHYHORS PHQWRI%17YDFFLQH
FDQGLGDWHV51$ZKLFKFRQWDLQVWKHVWDQGDUGQXFOHRVLGHXULGLQH X51$QXFOHRVLGH
PRGLILHG51$PRG51$LQZKLFK XULGLQHLVUHSODFHGE\WKHQXFO HRVLGHSVHXGRXULGLQH
DQGVHOIDPSOLI\LQJ51$VD51$ZKLFKDOVRFRQWDLQVXULGLQHQX FOHRVLGHV )LJXUH
)LJXUH 2YHUYLHZ RI WKH WKUHH 51$ SODWIRUPV
7KH51$YDFFLQHPROHFXOHVDUHFDSSHGFRQWDLQRSHQUHDGLQJIUDP HV25)VIODQNHGE\WKHXQWUDQVODWHGUHJLRQV
875DQGKDYHDSRO\$WDLODWWKH¶HQG7KH25)RIWKHX51$ DQGPRG51$YHFWRUVHQFRGHWKHYDFFLQHDQWLJHQ 7KH
VD51$KDVWZR25)V7KHILUVW25)HQFRGHVDQDOSKDYLUXVGHULYHG 51$GHSHQGHQW51$SRO\PHUDVHUHSOLFDVH
ZKLFKXSRQWUDQVODWLRQPHGLDWHVVHOIDPSOLILFDWLRQRIWKH51$ 7KHVHFRQG25)HQFRGHVWKHYDFFLQHDQWLJHQ
7K
HXWLOLW\RIHDFKRIWKHVH51$SODWIRUPVIRUWKHGHYHORSPHQW RILQIHFWLRXVGLVHDVH
YDFFLQHVLVVXSSRUWHGE\YDULRXV QRQFOLQLFDOVWXGLHVWKDWGHPR QVWUDWHGWKHHIILFLHQW
3DJH &21),'(17,$/090177e19744d904\A pproved\A pproved On: 11-Jun-2021 10:28 (GMT )
FDA-CBER-2021-5683-1102910
%LR17HFK51$
3KDUPDFHXWLFDOV*PE+
&RQILGHQWLDO,QYHVWLJDWRU¶V %URFKXUH
&RU9$&%173DJHRI
9HUVLRQ
'DWH$35
LQGXFWLRQRISRWHQWQHXWUDOL]LQJ DQWLERG\DQG7FHOOUHVSRQVHV DJDLQVWDYDULHW\RIYLUDO
SDWKRJHQVLQFOXGLQJLQIOXHQ]D(ERODKXPDQLPPXQRGHILFLHQF\YL UXV+,9DQG=LNDYLUXV
9RJHOHWDO 0R\RHWDO 3DUGLHWDO
7KHVWUXFWXUDOHOHPHQWVRIWKHYHFWRUEDFNERQHVRI%17YDFFL QH FDQGLGDWHVDUH
RSWLPL]HGIRUSURORQJHGDQGVWURQJWUDQVODWLRQRIWKHDQWLJHQH QFRGLQJ51$ FRPSRQHQW
7KHSRWHQF\RI%17YDFFLQHFDQGLGDWHVLVIXUWKHURSWLPL]HGE \HQFDSVXODWLRQRIWKH
51$FRPSRQHQWLQWR/13VZKLFKSURWHFWWKH51$IURPGHJUDGDWLRQ E\51$VHVDQG
HQDEOHWUDQVIHFWLRQRIKRVWFHOOVDIWHU,0GHOLYHU\ )LJXUH'XHWR51$¶VLQKHUHQW
DGMXYDQWDFWLYLW\PHGLDWHGE\ELQGLQJ WRLQQDWHLPPXQHVHQVRUV VXFKDVWROOOLNHUHFHSWRUV
51$/13YDFFLQHVLQGXFHDUREXVWQHXWUDOL]LQJDQWLERG\UHVSRQVH DQGDFRQFRPLWDQW7
FHOOUHVSRQVHUHVXOWLQJLQSURWH FWLYHLPPXQL]DWLRQZLWKPLQLPDO YDFFLQHGRVHV
)LJXUH 51$/13EDVHG %17 YDFFLQHV
7KH%17YDFFLQHVDUH*03JUDGH51$GUXJVXEVWDQFHVWKDWHQFR GH6$56&RYDQWLJHQV7KH51$LVIRUPXODWHG
ZLWKOLSLGVDV51$/13GUXJSURGXFW7KHYDFFLQHFDQGLGDWHVDUHVXSSOLHGDV EXIIHUHGOLTXLGVROXWLRQVIRU,0LQMHFWLRQ
7K
HWKUHH51$SODWIRUPVXVHGLQWKH%17YDFFLQHFDQGLGDWHVK DYHFRPSOHPHQWDU\
VWUHQJWKV )LJXUHX51$ZLWKKLJKLQWULQVLFDG MXYDQWLFLW\PRG51$ZLWKEOXQWHG LQQDWH
LPPXQHVHQVRUDFWLYDWLQJFDSDFLW \DQGWKXVDXJPHQWHGH[SUHVVLRQ DQGVD51$IURP
ZKLFKKLJKHUDPRXQWVRI SURWHLQSHULQMHFWHG51$WHPSODWHFDQE HSURGXFHG
7KHGLIIHUHQW%17YDFFLQHFDQGLGDWHVH[KLELWGLVWLQFWDQWLJH QH[SUHVVLRQSURILOHVDIWHU
,0LQMHFWLRQ$OO51$HQFRGHGDQWLJHQVDUHH[SUHVVHGWUDQVLHQWO \:KLOHIRU%17D
X51$DQG%17EPRG51$WKHDQWLJHQH[SUHVVLRQSHDNVVKRUWO\DIWHULQMHFWLRQIRU
%17FVD51$WKHDQWLJHQH[SUH VVLRQSHDNV ODWHUDQGLVPRUH SURORQJHGGXHWRVHOI
DPSOLILFDWLRQ
$OOYDFFLQHFDQGLGDWHVPD\EHDGPLQLVWHUHGXVLQJSULPHERRVWRU SULPHRQO\
DGPLQLVWUDWLRQUHJLPHQV )LJXUH
3DJH &21),'(17,$/090177e19744d904\A pproved\A pproved On: 11-Jun-2021 10:28 (GMT )
FDA-CBER-2021-5683-1102911
%LR17HFK51$
3KDUPDFHXWLFDOV*PE+
&RQILGHQWLDO,QYHVWLJDWRU¶V %URFKXUH
&RU9$&%173DJHRI
9HUVLRQ
'DWH$35
)LJXUH 5DWLRQDOH IRU WKH DGPLQLVWUDWLRQ VFKHPD RI %17 YDF FLQHV
&RURQDY
LUXV VSLNH SURWHLQ DV YDFFLQH WDUJHW
&RURQDYLUXVHVOLNH6$56&R9DUH DVV51$HQYHORSHGYLUXVID PLO\WKDWHQFRGHIRUD
WRWDORIIRXUVWUXFWXUDOSURWHLQV:LWKLQWKHVHIRXUVWUXFWXUDO SURWHLQVWKHVSLNH JO\FRSURWHLQ
6SURWHLQLVWKHNH\WDUJHWIRUYDFFLQHGHYHORSPHQW6LPLODU WR WKHLQIOXHQ]DYLUXV
KHPDJJOXWLQLQ+$WKH6SURWHLQLVUHVSRQVLEOHIRUUHFHSWRUU HFRJQLWLRQDWWDFKPHQWWRWKH
FHOOYLUDOHQYHORSHIXVLRQZLWKDKRVWFHOOPHPEUDQHDQGJHQR PLFUHOHDVHGULYHQE\WKH
6SURWHLQFRQIRUPDWLRQFKDQJHOHDGLQJWRWKHIXVLRQRIYLUDODQ G KRVWFHOOPHPEUDQHV
)LJXUHDQG)LJXUH7KH6SURWHLQLVFOHDYHGE\KRVWSURWHDVHVLQWRWKH6DQG6
VXEXQLWV:KLOH6ZLWKLWVWUDQVPHPEUDQHGRPDLQLVUHVSRQVLEOHIRUPHPEUDQHIXVLRQ
WKH6GRPDLQZLWKLWV&WHUPLQD OUHFHSWRUELQGLQJGRPDLQ5%' UHFRJQL]HVWKHKRVW
UHFHSWRUDQGELQGVWRWKHWDUJHWKRVWFHOO6$56&R9DQG6$56&R9KDYHVLPLODUVWUXFWXUDOSURSHUWLHVDQGELQGWRWKHVDPHKRVWFHOOUHFHSWRU DQJLRWHQVLQFRQYHUWLQJ
HQ]\PH$&( =KRXHWDO 7KH6SURWHLQLVQRWRQO\SLYRWDOIRUKRVWFHOO
UHFRJQLWLRQDQGHQWU\EXWDOVRIRUWKHLQGXFWLRQRIYLUXVQHXWUDOL]LQJDQWLERGLHVE\WKHKRVWLPPXQHV\VWHP =DNKDUWFKRXNHWDO <RQJHWDO
3DJH &21),'(17,$/090177e19744d904\A pproved\A pproved On: 11-Jun-2021 10:28 (GMT )
FDA-CBER-2021-5683-1102912
%LR17HFK51$
3KDUPDFHXWLFDOV*PE+
&RQILGHQWLDO,QYHVWLJDWRU¶V %URFKXUH
&RU9$&%173DJHRI
9HUVLRQ
'DWH$35
)LJXUH 6FKHPDWLF OLIH FLUFOH RI D &RURQDYLUXV
6RXUFHGH:LWHWDO
6RPH
PRQRFORQDODQWLERGLHVDJDLQVW WKH6SURWHLQSDUWLFXODUO\ WKRVHGLUHFWHGDJDLQVWWKH
5%'QHXWUDOL]H6$56&R9DQG0LGGOH(DVWUHVSLUDWRU\V\QGURPH 0(56&R9LQIHFWLRQ
LQ YLWURDQGLQ YLYR+XOVZLWHWDO
7DUJHWLQJWKH6SURWHLQDVZHOODVLWV6FOHDYDJHIUDJPHQWRU WKH5%'DORQHZLWK
YDFFLQHVLVVXIILFLHQWWRLQGXFHQHXWUDOL]LQJLPPXQHUHVSRQVHV $O$PULHWDO 7KH
5%'IRUPVPHPEUDQHGLVWDO³KHDGV´RQ WKH6SURWHLQWKDWDUHFRQ QHFWHGWRWKHERG\E\D
KLQJH,QWKHQDWLYH6SURWHLQ ZKHQWKH5%'LVLQWKH³KHDGVG RZQ´FRQIRUPDWLRQWKH
QHXWUDOL]LQJHSLWRSHVDWWKHUHFHSWRUELQGLQJVLWHDUHRFFOXGHG :KHQWKH5%'LVLQWKH
³KHDGVXSFRQIRUPDWLRQ DOVRUHIHUUHGWRDVWKH³SUHIXVLRQFRQ IRUPDWLRQ´WKHQHXWUDOL]LQJ
3DJH &21),'(17,$/090177e19744d904\A pproved\A pproved On: 11-Jun-2021 10:28 (GMT )
FDA-CBER-2021-5683-1102913
%LR17HFK51$
3KDUPDFHXWLFDOV*PE+
&RQILGHQWLDO,QYHVWLJDWRU¶V %URFKXUH
&RU9$&%173DJHRI
9HUVLRQ
'DWH$35
HSLWRSHVDWWKHUHFHSWRUELQGLQJVLWHDUHH[SRVHG7KHUHIRUHD3PXWDQW³KHDGVXS´
VWDELOL]HGSUHIXVLRQFRQIRUPDWLRQYDULDQWRI6SURWHLQFDQLQGXF HDVWURQJHUQHXWUDOL]LQJ
DQWLERG\UHVSRQVHWKDQWKHQDWLYH6SURWHLQ 3DOOHVHQHWDO :UDSSHWDO
)LJXUH 6FKHPDWLF RYHUYLHZ RI W KH RUJDQL]DWLRQ RI WKH 6$56&R9 6 JO\FRSURWHLQ
7KHVHTXHQFHZLWKLQWKH6IUDJPHQWLQFOXGHV WKHVLJQDOVHTXHQF H66DQGWKHUHFHSWRUELQGLQJGRPDLQ5%'ZKLFK
LVWKHNH\VXEXQLWZLWKLQWKH 6SURWHLQWKDWLVUHOHYDQWIRUELQGL QJWRWKHKXPDQFHOOXODUUHFHSWRU$&(7KH6VXEXQLW
FRQWDLQVWKH6SURWHDVHFOHDYDJHVLWH6¶IROORZHGE\DIXVLRQSHSWLGH)3IRUPHPEUDQHIXVLRQKHSWDGUHSHDWV
+5DQG+5ZLWKDFHQWUDOKHOL[&+GRPDLQWKHWUDQVPHPEUD QHGRPDLQ70DQGDF\WRSO DVPLFWDLO&7VRXUFH
PRGLILHGIURP :UDSSHWDO
7KH%17YDFFLQHFDQGLGDWHVVHOHFWHGIRUFOLQLFDOWHVWLQJIHD WXUHWKHIROORZLQJYDFFLQH
DQWLJHQV )LJXUH
$VHFUHWHGWULPHUL]HGYDULDQWRIWKH5%'RIWKH6$56&R96SURWHLQFDOOHG9
.LUFKGRHUIHUHWDO
0HPEUDQHDQFKRUHGIXOOOHQJWK6SURWHLQZLWKWZRSRLQWPXWDWLRQVZ LWKLQWKH
FHQWUDOKHOL[GRPDLQFDOOHG9 RU90XWDWLRQRIWKHWZRDPLQ RDFLGVWRSUROLQH
.933ORFNVWKH6SURWHLQLQDQDQWLJHQLFDOO\RSWLPDOSUH IXVLRQ
FRQIRUPDWLRQ :UDSSHWDO 3DOOHVHQHWDO
/LSLG QDQRSDUWLFOH /13 IRUPXODWLRQ
7KH%17YDFFLQHFDQGLGDWH51$LVHQFDSVXODWHGLQWR/13VZKL FKSURWHFWWKH51$
IURPGHJUDGDWLRQDQGHQDEOHWUDQVIHFWLRQRIWKH51$LQWRKRVW F HOOVDIWHU,0LQMHFWLRQ7KH
VDPH/13IRUPXODWLRQLVXVHGIRUDOO RIWKH%17YDFFLQHFDQGL GDWHV)LJXUH
7KH/13VDUHFRPSRVHGRIIRXUGLIIHUHQWOLSLGVLQDGHILQHGUDWLR'XULQJPL[LQJRIWKH51$
DQGWKHGLVVROYHGOLSLGVWKHOLSLGVIRUPWKHQDQRSDUWLFOHVHQF DSVXODWLQJWKH51$$IWHU
LQMHFWLRQWKH/13VDUHWDNHQXS E\WKHFHOOVDQGWKH51$LVUHOHDVHGLQWRWKHF\WRVRO,Q
WKHF\WRVROWKH51$LVWUDQVODWHGWRWKHHQFRGHGYLUDODQWLJHQ
3DJH &21),'(17,$/090177e19744d904\A pproved\A pproved On: 11-Jun-2021 10:28 (GMT )
FDA-CBER-2021-5683-1102914
%LR17HFK51$
3KDUPDFHXWLFDOV*PE+
&RQILGHQWLDO,QYHVWLJDWRU¶V %URFKXUH
&RU9$&%173DJHRI
9HUVLRQ
'DWH$35
)LJXUH 6FKHPDWLF RYHUYLHZ RI D /13
7KHDQWLJHQPD\EHLQFRUSRUDWHGLQWRWKHFHOOXODUPHPEUDQHRUVH FUHWHGLQWRWKH
H[WUDFHOOXODUHQYLURQPHQWDQGLQGXFHDQDGDSWLYHLPPXQHUHVSRQV H,QDGGLWLRQDV
6SURWHLQLVWKHDQWLJHQWKDWUHFRJQL]HVDQGGULYHVLQIHFWLRQRI WKHKRVWFHOOV LWLVDNH\
WDUJHWRIYLUXVQHXWUDOL]LQJDQWLERGLHV )XUWKHUPRUHDV51$H[ SUHVVHG6SURWHLQLV
IUDJPHQWHGLQWUDFHOOXODUO\WKHUHVXOWLQJSHSWLGHVFDQEHSUHVHQW HGDWWKHFHOOVXUIDFH
WULJJHULQJDVSHFLILF7FHOOPHGLDWHGLPPXQHUHVSRQVHZLWKDFWLYL W\DJDLQVWWKHYLUXV
&OLQLFDO GHYHORSPHQW
)RXUGLIIHUHQW%17YDFFLQHFDQGLGDWHVEDVHGRQWKUHH51$SOD WIRUPV X51$
PRG51$DQGVD51$ZLOOEHWHVWHGFOLQLFDOO\)RUWKH%17YD FFLQHVWKH
QRPHQFODWXUHLVDVIROORZV
%17DX51$/13YLUDO6SURWHLQRIWKH6$56&R9SDUWLDOV HTXHQFH5%'
RI66SURWHLQ
%17EPRG51$/13VHFUHWHGYDULDQWRIWKH5%'RIWKH6$56& R9
6SURWHLQ
%17EPRG51$/136SURWHLQ66SURWHLQRIWKH6$56&R9 66IXOO
OHQJWKSURWHLQVHTXHQFHYDULDQW
%17FVD51$/136SURWHLQ6 6SURWHLQRIWKH6$56&R9 66IXOO
OHQJWKSURWHLQVHTXHQFHYDULDQW
7KHUHDUHFXUUHQWO\QRGDWDDYDLODEOHRQWKHHIIHFWVRIDQ\RI WKH%17YDFFLQH
FDQGLGDWHVLQKXPDQV
7KHVDIHW\DQGLPPXQRJHQLFLW\RI IRXU%17YDFFLQHFDQGLGDWHV %17D
%17E%17E%17FZLOOEHLQYHVWLJDWHGFOLQLFDOO\ DVSDUWRIDSURJUDP WR
GHYHORSDSURSK\ODFWLFYDFFLQHWRSUHYHQWLQIHFWLRQZLWK6$56&R9DQGWKXVLWV
DVVRFLDWHGGLVHDVH&29,'7KHFOLQLFDOSURJUDPZLOOVWDUWZL WKWKHLPPXQL]DWLRQRI
KHDOWK\DGXOWVERWKPHQDQGZRPHQDJHGEHWZHHQDQG \HDUV ,IWKHLPPXQL]DWLRQ
LVIRXQGWREHZHOOWROHUDWHGLPPXQL]DWLRQZLOODOVREHLQYHVW LJDWHGLQWKH ROGHUKHDOWK\
3DJH &21),'(17,$/090177e19744d904\A pproved\A pproved On: 11-Jun-2021 10:28 (GMT )
FDA-CBER-2021-5683-1102915
%LR17HFK51$
3KDUPDFHXWLFDOV*PE+
&RQILGHQWLDO,QYHVWLJDWRU¶V %URFKXUH
&RU9$&%173DJHRI
9HUVLRQ
'DWH$35
DGXOWVDQGWKHOLNHO\WDUJHWSRSXODWLRQHJDWULVNSRSXODW LRQVVXFKDVHOGHUO\ DQGRU
LPPXQRFRPSURPLVHGSRSXODWLRQV
6LQFHWKH%17YDFFLQHFDQGLGD WHVXWLOL]HWKHVDPH/13IRUPXO DWLRQWKHREVHUYHG
VDIHW\SURILOHVZLOOEHFRQVLGHUHGUHSUHVHQWDWLYHIRUDOOFDQGL GDWHYDFFLQHVLQFRPELQDWLRQ
ZLWKWKHUHVSHFWLYHSODWIRUP/LNHZLVHVLQFHVRPHRI%17YD FFLQHFDQGLGDWHVOHDG WR
H[SUHVVLRQRIWKHVDPHHQFRGHGYLUDODQWLJHQWKHREVHUYHGVDIH W\SURILOHVZLOOEH
FRQVLGHUHGUHSUHVHQWDWLYHIRUDOOFDQGLGDWHYDFFLQHVXWLOL]LQJ WKHVDPHHQFRGHGYLUDO
DQWLJHQ
6XSSRUWLYH FOLQLFDO EDFNJURXQG LQIRUPDWLRQ
:KHUHDVWKHFRPELQDWLRQRI HDFKRIWKHWKUHH51$IRUPDWVX51$ PRG51$VD51$
ZLWKWKHVSHFLILF/13FRPSRVLWLRQ XVHGLQWKH%17YDFFLQHFD QGLGDWHVKDVQRWEHHQ
WHVWHGLQKXPDQVEHIRUH%LR17HFKKDVFROOHFWHGFOLQLFDOH[SHUL HQFHRQ WZRRIWKH51$
IRUPDWVXVHGLQ%17YDFFLQHVQDPHO\X51$DQGPRG51$ %RWK5 1$IRUPDWVDUH
EHLQJXVHGLQ%LR17HFKCVLPPXQHR QFRORJ\SURJUDPVDVVXPPDUL]HG LQ7DEOH
7DEOH %LR17HFK FOLQLFDO SODWIRU P H[SHULHQFH ZLWK X51$ DQG PR G51$ DV RII $SULO
/LSRVRPDOO\IRUPXODWHG51$VZHUHIRUPXODWHGZLWKVLPLODUEXWQR WLGHQWLFDO OLSLGFRPSRVLWLRQDVWKRVHXVHGLQ%17
YDFFLQHV
SDWLHQWVGRVHGDW JRQHSDWLHQWGRVHGJ
51$ &OLQLFDO H[SHULHQFH 1
X51$ OLSRVRPDOO\ IRUPXODWHG LQWUDYHQRXV LQMHFWLRQ GRVH UDQJH WR J
HQFRGLQJYDULRXVVKDUHGWXPRUDQWLJHQVDQGLQGLYLGXDOFDQFHUP XWDWLRQV
x7ULDO1&73KDVH,LQPHODQRPDSDWLHQWV/LSR0(5,7
x7ULDO1&73KDVH ,LQWULSOHQHJDWLYHEUHDVWFDQFHUSDWLHQWV71%&0(5,7
x7ULDO1&73KDVH ,LQ+39KHDGQHFNFDQFHUSDWLHQW V+$5(
x7ULDO3KDVH,LQ SURVW DWHFDQFHUSDWLHQWV35 20(5,7
x7ULDO1&73KDVH ,LQRYDULDQFDQFHUSDWLHQWV2/,9,$
x7ULDO1&73KDVH,LQ SDWLHQWVZLWKVROLGFDQFHUV
x7ULDO1&75&73KDVH,,LQSDWLHQWVZLWKVROLGFDQFHUV
X51$ QRQOLSRVRPDOO\ IRUPXODW HG LQMHFWLRQ LQWR O\PSK QRGHV G RVH UDQJH WR J
HQFRGLQJ YDULRXVVKDUHGWXPRUDQWLJHQVDQGLQGLYLGXDOFDQFHUP XWDWLRQV
x7ULDO1&7LQPHODQRPDSDWLHQWV0(5,7
x7ULDO1&7LQPHODQRPDSDWLHQWV,9$&
X51$ QRQOLSRVRPDOO\ IRUPXODWHG SURGXFW IRU '7+ LQWUDGHUPDO LQMHFWLRQ GRVH UDQJH WR
JHQFRGLQJYDULRXVVKDUHGWXPRUDQWLJHQV
x7ULDO1&73KDVH ,LQPHODQRPDSDWLHQWV/LSR0(5,7
x7ULDO1&7LQPHODQRPDSDWLHQWV0(5,7
PRG51$ QRQOLSRVRPDOO\ IRUPXODW HG LQWUDWXPRU LQMHFWLRQ J WR J
HQFRGLQJYDULRXVF\WRNLQHV
x7ULDO1&7 LQSDWLHQWVZLWKVROLGFDQFHUV
'7+ 'HOD\HGW\SHK\SHUVHQVLWLYLW\UHDFWLRQWHVWLQJ,9 LQWU DYHQRXV,7 LQWUDWXPRUDO1 QXPEHURISDWLHQWV
3DJH &21),'(17,$/090177e19744d904\A pproved\A pproved On: 11-Jun-2021 10:28 (GMT )
FDA-CBER-2021-5683-1102916
%LR17HFK51$
3KDUPDFHXWLFDOV*PE+
&RQILGHQWLDO,QYHVWLJDWRU¶V %URFKXUH
&RU9$&%173DJHRI
9HUVLRQ
'DWH$35
X51$LQFRQMXQFWLRQZLWKDIRUPXODWLRQZKLFKLVVLPLODUEXWQRWLGHQWLFDOZLWKWKHVSHFLILF
/13FRPSRVLWLRQXVHGLQ%17D KDVEHHQLQYHVWLJDWHGE\%LR1 7HFKLQYDULRXV
RQFRORJ\FOLQLFDOWULDOVZLWKPRUHWKDQSDWLHQWVGRVHGUHSH DWHGO\
PRG51$QRQOLSRVRPDOO\IRUPXODWHGKDVEHHQDGPLQLVWHUHGWR SDWLHQWV LQDQRQJRLQJ
RQFRORJ\FOLQLFDOWULDO
7KHVXPRIWKHGDWDFROOHFWHGDFURVVWKHVHWULDOVLV VXSSRUWLYH IRUWKHULVNDVVHVVPHQWRI
%17YDFFLQHV7KHNH\REVHUYDWLRQVLQWKH FOLQLFDOWULDOVOLVWHGDERYHZHUH
X51$OLSRVRPDOO\IRUPXODWHGLQMHFWHGLQWUDYHQRXVO\KDGDIDY RUDEOHVDIHW\
SURILOH,QWKHVHWULDOVV\VWHPLFH[SRVXUHDWGRVHVXSWR JRIX51$
FRPSOH[HGZLWKOLSRVRPHV LQMHFWHG,9ZDVWROHUDWHG,QOLQHZLW KWKHWUDQVLHQW
SXOVDWLOHVHFUHWLRQRIDGLVWLQFW UDQJHRIF\WRNLQHVDWVXSUDS K\VLRORJLFDOEXWQRW
SDWKRORJLFDOSODVPDOHYHOVREVHUYHGLQWKHVHSDWLHQWV7KHDGYH UVHHYHQW$(
SURILOHZDVGRPLQDWHGE\PLOGWRPRGHUDWHIOXOLNHV\PSWRPVH JS\UH[LDDQG
FKLOOV7KHVHLPPXQHPRGXODWLRQUHODWHG$(VVWDUWHGZLWKLQ KDIWHU,9LQMHFWLRQ
ZHUHPDQDJHDEOHZLWKDQWLS\UHWL FVZHUHVHOIOLPLWLQJDQGUHVR OYHGZLWKLQ K
X51$QRQOLSLGIRUPXODWHGDGP LQLVWHUHGLQWUDGHUPDOO\RULQMH FWHGLQWRLQJXLQDO
O\PSKQRGHVZDVWROHUDWHGZLWKRQO\RFFDVLRQDODQGPLOGORFDOL QMHFWLRQVLWH
UHDFWLRQV6\VWHPLFUHDFWLRQVDIW HUORFDODSSOLFDWLRQZHUHQRW REVHUYHG
PRG51$QRQOLSLGIRUPXODWHGDGPLQLVWHUHGLQWRWXPRUOHVLRQV RIFDQFHUSDWLHQWV
ZDVWROHUDWHGZLWKRFFDVLRQDOPLOGLQMHFWLRQVLWHUHDFWLRQV6\ VWHPLFUHDFWLRQV DIWHU
ORFDODSSOLFDWLRQZHUHQRWREVHUYHG
%DVHGRQWKHDJJUHJDWHFOLQLFDOGDWDRIOLSLGIRUPXODWHGX51$D QGPRG51$FRPSRQHQWV
WKDWDUHXVHGLQWKH%17YDFF LQHVDIDYRUDEOHVDIHW\SURILO HRI%17SURGXFWVLV
H[SHFWHGZLWKPLOGORFDOL]HGDQGWUDQVLHQWHIIHFWV7KHOLVWHG ULVNVUHODWHGWR%17
YDFFLQHDUHH[SHFWHGWREHPDQDJHDEOHXVLQJURXWLQHV\PSWRPGUL YHQVWDQGDUGRIFDUHE\
WKHLQYHVWLJDWRUV,QDGGLWLRQWR%LR17HFKCVRZQGDWD GDWDIURPFOLQLFDOVWXGLHV FRQGXFWHGE\RWKHUSDUWLHV
VXSSRUWVDIDYRUDEOHULVNSURILOHRIOLSLGIRUPXODWHGDQGQRQO LSLGIRUPXODWHG 51$V
DGPLQLVWHUHGYLDYDULRXVURXWHV([HPSODU\UHSRUWHGFOLQLFDOWU LDOVDUHWKHIROORZLQJRQHV
x0RG51$V IRUPXODWHG ZLWK UHODW HG EXW QRW LGHQWLFDO OLSLG FRPSRVL WLRQV
DGPLQLVWHUHG LQWUDPXVFXODUO\ ZHUHXVHGLQWZR3KDVH,FOLQLFDOWULDOV
1&7DQG1&7SHUIRUPHGE\0RGHUQD&DPEULGJH0$86$
WRHYDOXDWHVDIHW\DQGLPPXQRJHQLFLW\DJDLQVW SRWHQWLDOO\SDQGH PLFDYLDQLQIOXHQ]D
YLUXVHVLQKHDOWK\DGXOWV )HOGPDQHWDO 'RVHVUDQJLQJIURPWRJ,0
RQHRUGHURIPDJQLWXGHKLJKHUWKDQSODQQHGIRU%17YDFFLQHV SULPHERRVW
ZNVDSDUWZHUHVDIHO\DGPLQLVWHUHG
2YHUDOOLQMHFWLRQVLWHSDLQDIWHUHLWKHUGRVHZDVWKHPRVWFRP PRQVROLFLWHGORFDO
$(7KHPRVWFRPPRQVROLFLWHGV\VWHPLF$(VDIWHUHLWKHU,0GRVH ZHUHP\DOJLD
IDWLJXHDUWKUDOJLDDQGKHDGDFKHDOOPRVWO\RIJUDGHWRLQ VHYHULW\ RIVKRUW
GXUDWLRQDQGUHVROYHGZLWKRXWLQWHUYHQWLRQ
3DJH &21),'(17,$/090177e19744d904\A pproved\A pproved On: 11-Jun-2021 10:28 (GMT )
FDA-CBER-2021-5683-1102917
%LR17HFK51$
3KDUPDFHXWLFDOV*PE+
&RQILGHQWLDO,QYHVWLJDWRU¶V %URFKXUH
&RU9$&%173DJHRI
9HUVLRQ
'DWH$35
)RUERWKWULDOVWKHUHZHUHQR$(VUHODWHGWRSRWHQWLDOO\LPPXQ HPHGLDWHGPHGLFDO
FRQGLWLRQVRUFDVHVRIQHZRQVHWRIFKURQLFLOOQHVV
x1RQOLSLG IRUPXODWHG X51$ DGPLQLVWHUHG LQWUDPXVFXODUO\ ZDVXVHGLQD3KDVH,
FOLQLFDOWULDO1&7E\&XUH9DF7ELQJHQ*HUPDQ\ IRUW HVWLQJVDIHW\DQG
LPPXQRJHQLFLW\RIDUDELHVYLUXVJO\FRSURWHLQYDFFLQH $OEHUHUHWDO ,QWKLV
WULDOKHDOWK\DGXOWVUHFHLYHGGRVHOHYHOVUDQJLQJIURP WRJ51$
DFFRUGLQJWRDGRVHSULPHERRVWVFKHPD7KHYDFFLQHZDVVDIH ZLWK D
UHDVRQDEOHWROHUDELOLW\SURILOH
0RUHRYHUVHYHUDOFOLQLFDOWULDOVZLWKVD51$EDVHGYDFFLQHV 1&7 UDELHV
YDFFLQH 1&7 FDQFHUYDFFLQHDQGZLWKOLSRVRPDOO\IRUPXODWHGPRG51$
YDFFLQHV1&7 SDUDLQIOXHQ]DYDFFLQH 1&7 FKLNXQJXQ\DYDFFLQH
DUHLQWKHUHFUXLWLQJVWDJH
3DJH &21),'(17,$/090177e19744d904\A pproved\A pproved On: 11-Jun-2021 10:28 (GMT )
FDA-CBER-2021-5683-1102918
%LR17HFK51$
3KDUPDFHXWLFDOV*PE+
&RQILGHQWLDO,QYHVWLJDWRU¶V %URFKXUH
&RU9$&%173DJHRI
9HUVLRQ
'DWH$35
3+<6,&$/ &+(0,&$/ $1' 3+$50$&(87,&$/ 3523(57,(6 $1'
)2508/$7,21
7KHIROORZLQJVHFWLRQJLYHVJHQHUDOLQIRUPDWLRQDERXWWKHSK\VLFDOFKHPLFDODQG
SKDUPDFHXWLFDOSURSHUWLHVRI WKH%17IDPLO\RI SURSK\ODFWLF 51$EDVHGYDFFLQH
FDQGLGDWHVHQFRGLQJYLUDODQWLJHQVWKDWDUHWUDQVODWHGE\WKHY DFFLQDWHGRUJDQLVPWR
SURWHLQWRLQGXFHDSURWHFWLYHLPPXQHUHVSRQVH 7KH51$FRPSRQH QWVRIWKH 51$/13
GUXJSURGXFWVRIWKHWKUHHGLIIH UHQW51$SODWIRUPVIRUFOLQLFDO LQYHVWLJDWLRQDUHWKHQRQ
PRGLILHGXULGLQHFRQWDLQLQJP51$X51$QXFOHRVLGHPRGLILHGP5 1$PRG51$DQG
VHOIDPSOLI\LQJP51$VD51$HDFKHQFRGLQJIXOOOHQJWKRUSDUW VRIWKHYLUDO6SURWHLQRI
WKH6$56&R9
'HVFULSWLRQ RI WKH GUXJ VXEVWDQFH
3K\VLFDO FKHPLFDO DQG SKDUPDFHXWLFDO SURSHUWLHV RI WKH G UXJ VXEVWDQFH
7KH51$GUXJVXEVWDQFHVRI%17 DUHKLJKO\SXULILHGVLQJOHVW UDQGHG¶FDSSHG
PHVVHQJHU51$VP51$VSURGXFHGE\ LQ YLWURWUDQVFULSWLRQIURPWKHFRUUHVSRQGLQJ'1$
WHPSODWHVHDFKHQFRGLQJIXOOOHQJWKRUSDUWVRIWKHYLUDO6SU RWHLQRI6$56&R9
1RQPRGLILHG XULGLQH P51$ X51$
7KHDFWLYHSULQFLSOHRIWKHQRQ PRGLILHGPHVVHQJHU51$X51$G UXJVXEVWDQFHLVD
VLQJOHVWUDQGHGƍFDSSHGP51$WKDWLVWUDQVODWHGXSRQHQWHULQ JWKHFHOO,QDGGLWLRQWR
WKHVHTXHQFHHQFRGLQJWKH6$56&R9DQWLJHQLHRSHQUHDGLQJIUDPHHDFKX51$
FRQWDLQVFRPPRQVWUXFWXUDOHOHPHQWVRSWLPL]HGIRU KLJKHIILFDF\RIWKH51$ZLWKUHVSHFWWRVWDELOLW\DQGWUDQVODWLRQDOHIILFLHQF\ƍFDSƍ875ƍ8 75SRO\$WDLO
1XFOHRVLGH PRGLILHG P51$ PRG51$
7KHDFWLYHSULQFLSOHRIWKHQXFOHR VLGHPRGLILHGPHVVHQJHU51$ PRG51$GUXJ
VXEVWDQFHLVDVZHOODVLQJOHVWUDQGHGƍFDSSHGP51$WKDWLV WUDQVODWHGXSRQHQWHULQJ
WKHFHOO,QDGGLWLRQWRWKHVHTXHQFHHQF RGLQJWKH 6$56&R9DQWLJHQLHRSHQUHDGLQJ
IUDPHHDFKPRG51$FRQWDLQVFRPPRQVWUXFWXUDOHOHPHQWVRSWLPL] HGIRU KLJKHIILFDF\RI
WKH51$&RPSDUHGWRWKHX51$PRG51$FRQWDLQVPHWK\OSVHXGRX ULGLQHLQVWHDGRI
XULGLQHDQGDGLIIHUHQW¶FDSVWUXFWXUH
6HOIDPSOLI\LQJ P51$ VD51$
7KHDFWLYHSULQFLSOHRIWKHVHOIDPSOLI\LQJP51$VD51$GUXJV XEVWDQFHLVDVLQJOH
VWUDQGHG¶FDSSHG51$ZKLFKVHOIDPSOLILHVXSRQHQWHULQJWKHFHOODQGWKH 6$56&R9
DQWLJHQLVWUDQVODWHGDVWKH51$VHOIDPSOLILHV,QDGGLWLRQWR WKHVHTXHQFH HQFRGLQJWKH
6$56&R9DQWLJHQLHRSHQUHD GLQJIUDPHDQGWKHFRPPRQVW UXFWXUDOHOHPHQWV LQWKH
X51$DQGPRG51$WKH VD51$YHFWRUFRQWDLQVDQDGGLWLRQDORSHQU HDGLQJIUDPHZKLFK
HQFRGHVWKH9HQH]XHODQHTXLQHHQFHSKDOLWLV9((YLUXV51$GHSH QGHQW51$
SRO\PHUDVHUHSOLFDVHDQGDVXEJHQR PLFSURPRWRUSOXVFRQVHUYHGV HTXHQFHHOHPHQWV
VXSSRUWLQJUHSOLFDWLRQDQGWUDQVODWLRQEXWQRRWKHU9((YLUXVFRGLQJVHTXHQFHV
7KHSK\VLFRFKHPLFDOSURSHUWLHVRIWKH51$GUXJVXEVWDQFHVDUHO LVWHGLQ7DEOH
3DJH &21),'(17,$/090177e19744d904\A pproved\A pproved On: 11-Jun-2021 10:28 (GMT )
FDA-CBER-2021-5683-1102919
%LR17HFK51$
3KDUPDFHXWLFDOV*PE+
&RQILGHQWLDO,QYHVWLJDWRU¶V %URFKXUH
&RU9$&%173DJHRI
9HUVLRQ
'DWH$35
7D
EOH *HQHUDO SURSHUWLHV RI X51$ PRG51$ DQG VD51$ GUXJ VXEV WDQFHV
3DUDPHWHU9DOXH'HVFULSWLRQ
X51$PRG51$ VD51$
$SSHDUDQFH &OHDUFRORUOHVVOLTXLG
7KHRUHWLFDO OHQJWK aWRQXFOHRWLGHV
aWRQXFOHRWLGHV
&RQFHQWUDWLRQ PJP/
([WLQFWLRQ FRHIILFLHQW DW QP /JîFP
S+
'HSHQGLQJRQWKHILQDOO\VHOHFWHGDQWLJHQ
'HVFULSWLRQ RI WKH GUXJ SURGXFW
7KHGUXJSURGXFWLVDSUHVHUYDWLYHIUHHVWHULOHGLVSHUVLRQRI 51$IRUPXODWHGLQOLSLG
QDQRSDUWLFOHV/13LQDTXHRXVFU\RSURWHFWDQWEXIIHUIRU ,0DGP LQLVWUDWLRQ7KH51$GUXJ
VXEVWDQFHLVWKHRQO\DFWLYHLQJUHGLHQWLQWKHGUXJSURGXFW7K HSURGXFWLVVWRUHGIUR]HQDW
WR&7KHGUXJSURGXFWLVILOOHGDWPJP/LQ JODVVYLDOVDQGFORVHGZLWK
VWRSSHUVDQGIOLSRIIFULPSLQJFDSV
7KHFRPSRVLWLRQRI51$GUXJSURGXFWVIRUXVHLQWKHSODQQHGFOLQLFDOWULDOVDQGWKH
IXQFWLRQRIWKHUHVSHFWLYHFRPSRQHQWVDUHJLYHQLQ 7DEOH7KH/13FRPSRVLWLRQLVWKH
VDPHIRUDOOIRXU%17YDFFLQHFDQGLGDWHV
7DEOH &RPSRVLWLRQ RI GUXJ SURGXFWV
&RPSRQHQW 4XDOLW\VWDQGDUG )XQFWLRQ
'UXJVXEVWDQFH ,QKRXVH $FWLYH
$/&>@,QKRXVH )XQFWLRQDOOLSLG
$/&>@,QKRXVH )XQFWLRQDOOLSLG
'63&>@,QKRXVH 6WUXFWXUDOOLSLG
&KROHVWHURO 3K(XU 6WUXFWXUDOOLSLG
6XFURVH 1)3K(XU &U\RSURWHFWDQW
1D&O 8633K(XU %XIIHU
.&O 8633K(XU %XIIHU
1D+32 8633K(XU %XIIHU
.+32 1)3K(XU %XIIHU
:DWHUIRULQMHFWLRQ 3K(XU 6ROYHQW9HKLFOH
>@$/& K\GUR[\EXW\OD ]DQHG L\OELVKH[DQHGL\OELVKH[\OGHFDQRDWH
>@$/& >SRO\HWK\OHQHJO\FRO@ 11GLWHWUD GHF\ODFHWDPLGH
>@'63& GLVWHDUR\O VQJO\F HURSKRVSKRFKROLQH
TV TXDQWXPVDWLVDVPXFKDVPD\VXIILFH
3DJH &21),'(17,$/090177e19744d904\A pproved\A pproved On: 11-Jun-2021 10:28 (GMT )
FDA-CBER-2021-5683-1102920
%LR17HFK51$
3KDUPDFHXWLFDOV*PE+
&RQILGHQWLDO,QYHVWLJDWRU¶V %URFKXUH
&RU9$&%173DJHRI
9HUVLRQ
'DWH$35
'HVFULSWLRQ RI WKH H[FLSLHQWV
$OOH[FLSLHQWVXVHGLQWKHIRUPXODWLRQRIWKHGUXJSURGXFWDUH OLVWHGLQ7DEOH
7KHGUXJSURGXFWFRQWDLQVWKHWZRIXQFWLRQDOOLSLGV $/&DQ G$/&DQGWKHWZR
VWUXFWXUDOOLSLGV'63&GLVWHDUR\O VQJO\FHURSKRVSKRFKROLQHDQGFKROHVWHURO
3K\VLFRFKHPLFDOSURSHUWLHVDQG WKHVWUXFWXUHVRIWKHIRXUOLSLG VDUHVKRZQLQ 7DEOH
7DEOH /LSLG H[FLSLHQWV LQ WKH GUXJ SURGXFW
/LSLG
&$6
QXPEHU0ROHFXODU
ZHLJKW>'D@0ROHFXODU IRUPXOD3K\VLFDO
VWDWHDQG
VWRUDJH
FRQGLWLRQ&KHPLFDO QDPH V\QRQ\PV DQG VWUXFWXUH
$/&
QRW
DSSOLFDEOH &+12 /LTXLG
RLO
&K\GUR[\EXW\OD]DQHGL\OELVKH[DQH
GL\OELVKH[\OGHFDQRDWH
$/&
a
&+12&+2Q2&+
Q
6ROLG
&>SRO\HWK\OHQHJO\FRO@11
GLWHWUDGHF\FODFHWDPLGH
'63&
&+123 6ROLG
&'LVWHDUR\O VQJO\FHURSKRVSKRFKROLQH
&KROHVWHURO
&+2 6ROLG
&
&$6 &KHPLFDO$EVWUDFWV6HUYLFH'63& GLVWHDUR\OVQJO\F HURSKRVSKRFKROLQH
'HVFULSWLRQ RI WKH GLOXHQW
)RUWKHGLOXWLRQRIGUXJSURGXFWVIRU,0LQMHFWLRQLVRWRQLF1D&OVROXWLRQLVVRXUFHG
DVDQDSSURYHGPHGLFLQDOSURGXFW7KHFRPSRVLWLRQLVDFFRUGLQJ WRWKHVXSSOLHU¶V
VSHFLILFDWLRQV
3DJH &21),'(17,$/090177e19744d904\A pproved\A pproved On: 11-Jun-2021 10:28 (GMT )
FDA-CBER-2021-5683-1102921
%LR17HFK51$
3KDUPDFHXWLFDOV*PE+
&RQILGHQWLDO,QYHVWLJDWRU¶V %URFKXUH
&RU9$&%173DJHRI
9HUVLRQ
'DWH$35
'HVFULSWLRQ RI WKH ,03
,03 QDPH %17YDFFLQH FDQGLGDWHV$QWLYLUDO51$YDFFLQHVIRUDFWLYH LPPXQL]DWLRQ
DJDLQVW&29,'
,03 W\SH 51$/13YDFFLQHFDQGLGDWHVXWLOL]LQJGLIIHUHQW%LR17HFK51$IRU PDWVLH
X51$SURGXFWFRGH %17DPRG51$SURGXFWFRGH%17E
%17EVD51$SURGXFWFRGH%17F
,03 DGPLQLVWUDWLRQ
URXWH6ROXWLRQIRU,0LQMHFWLRQ
'RVDJH IUHTXHQF\ 7KH%17YDFFLQHV ZLOOEHDGPLQLVWHUHGHLWKHUXVLQJVLQJOHGR VHRU
SULPHERRVWUHJLPHQV
6WRUDJH DQG KDQGOLQJ RI WKH ,03
7KHGUXJSURGXFWLVDVXSSOLHGDVVWHULOHGLVSHUVLRQRI51$IRU PXODWHGLQ/13LQDQ
DTXHRXVFU\RSURWHFWDQWEXIIHUIRU ,0DGPLQLVWUDWLRQ3ULRUWRL QMHFWLRQWKH51$/13
SURGXFWVDUHGLOXWHGZLWKLVRWRQLF1D&OVROXWLRQWRWKH LQWHQGHGFRQFHQWUDWLRQ
DFFRUGLQJWRWKH3KDUPDF\0DQXDODQGDGPLQLVWHUHGWRWKHWULDO VXEMHFW
'XHWRWKHSDQGHPLFXUJHQF\GHWDLOVRQUHFRQVWLWXWLRQVDQGDSS OLFDWLRQVFKHPHDWWKH
KRVSLWDOVLWHDUHFXUUHQWO\XQGHUGHYHORSPHQW,QXVHDVZHOOD VGUXJSURGXFWVWDELOLW\
VWXGLHVKDYHEHHQVWDUWHGGHWDLOVDUHSURYLGHGLQWKH,QYHVWLJ DWLRQDO0HGLFLQDO3URGXFW
'RVVLHU,03'DQGRUUHOHYDQW,QYHVWLJDWLRQDO1HZ'UXJ,1'V HFWLRQV
3DJH &21),'(17,$/090177e19744d904\A pproved\A pproved On: 11-Jun-2021 10:28 (GMT )
FDA-CBER-2021-5683-1102922
%LR17HFK51$
3KDUPDFHXWLFDOV*PE+
&RQILGHQWLDO,QYHVWLJDWRU¶V %URFKXUH
&RU9$&%173DJHRI
9HUVLRQ
'DWH$35
121&/,1,&$/ 678',(6
51$YDFFLQHVKDYHVKRZQJUHDWSRWHQWLDOLQJHQHUDWLQJLPPXQHUHVSRQVHV LQDQLPDO
PRGHOVDQGFRQIHUSURWHFWLRQDJ DLQVWYDULRXVYLUXVHVVXFKDV=LND+,9DQG,QIOXHQ]D
9RJHOHWDO 0R\RHWDO 3DUGLHWDO 8QSXEOLVKHGLPPXQRJHQLFLW\GDWD
IURP51$EDVHGYDFFLQHVDJDLQVWRWKHUYLUXVHVVXFKDV(EROD0D UEXUJDQG/DVVDYLUXV
LQGLFDWHWKDWWKHUDQJHRIDSSOLFDWLRQVIRUDQWLYLUDO51$YDFFLQHVLVEURDGGDWDRQILOH
,QWKHSODQQHGFOLQLFDOWULDOV IRXU%17YDFFLQHFDQGLGDWHV EDVHGRQWKUHH51$
SODWIRUPVZLOOEHHYDOXDWHGIRUGHWDLOVVHH 6HFWLRQ LH%17D%17E
%17EDQG%17F7KHSULPDU\SKDUPDFRORJ\RI WKH%17YDFFLQHVZDVHYDOXDWHGL QDUDQJHRIQRQ
FOLQLFDOSKDUPDFRORJ\VWXGLHV LQ YLWURDQGLQ YLYR([SUHVVLRQRI51$HQFRGHGDQWLJHQV
WKHVHFUHWHGWULPHUL]HGUHFHSWRU ELQGLQJGRPDLQ5%'YDULDQW ³9´DQGWKH3PXWDQW
³KHDGVXS´SUHIXVLRQVWDELOL]HGIXOOOHQJWKVSLNH6SURWHLQ 36³99´ZDVVWXGLHG
LQ YLWUR7KHWZRYHUVLRQV9DQG9HQFRGHIRUWKHVDPHDQWLJHQZLWKW KHLGHQWLFDODPLQR
DFLGVHTXHQFHEXWGLIIHULQWKHQXFOHRWLGHFRGLQJVHTXHQFH,QLPPXQRJHQLFLW\VWXGLHVRIWKH%17YDFFLQHFDQGLGDWHVDQW LJHQELQGLQJ
LPPXQRJOREXOLQ*,J*UHVSRQVHVDUHGHWHFWHGE\DQHQ]\PHOLQN HGLPPXQRVRUEHQW
DVVD\(/,6$)XQFWLRQDODQWLERG\UHVSRQVHV WRWKHYDFFLQHFDQGLGDWHVDUHGHW HFWHGE\DSVHXGRYLUXV
EDVHGQHXWUDOL]DWLRQDVVD\S9177KHS917XVHVDYHVLFXODUVW RPDWLWLVYLUXV969
YHFWRUWKDWH[SUHVVHVDIOXRUHVFHQWPDUNHUDQGODFNVWKH969* JO\FRSURWHLQ7KH
SVHXGRW\SHYLUXVLQVWHDGEHDUVW KH6$56&R96SURWHLQZKLFK PHGLDWHVFHOOHQWU\
7KHUHIRUHWKHSVHXGRYLUXVFDQEHLQDFWLYDWHGE\QHXWUDOL]LQJD QWLERGLHVWKDWELQG6$56
&R96
,Q YLYRVWXGLHVZHUHSHUIRUPHGWREHQFKPDUNGLIIHUHQWYDFFLQHDQWLJHQV DOOGHULYHGIURP
6$56&R96DQGWRSURYLGHSURRIRIFRQFHSWLHWRGHPRQVW UDWHWKDW%17
YDFFLQHVFDQLQGXFHDQDQWL6$56&R9LPPXQHUHVSRQVHDQGDUH VDIH VXSSRUWLQJ
FOLQLFDOLQYHVWLJDWLRQLQKXPDQV
7DEOHVXPPDUL]HVWKHQRPHQFODWXUHXVHGIRUWKH%17YDFFLQHFDQGLGDWHVWR
IDFLOLWDWHWKHUHYLHZRIWKHSURYLGHGQRQFOLQLFDOLQIRUPDWLRQ,QVRPHRIWKHH[SHULPHQWVGHVFULEHGEHORZWHVWLWHPVDUH/13I RUPXODWLRQVRIRQHRIWKH
WKUHH51$SODWIRUPVLQFRQMXQFWLRQZLWK
DQRQ6$56&R9GHULYHGYLUDOJHQHVXFKDV,QIOXHQ]D+$HJ
RQHRIWKHWZR6$56&R9GHULYHGYDFFLQHDQWLJHQVEXWQRWW KHRQHXVHGIRUWKH
UHVSHFWLYHFOLQLFDOFDQGLGDWHHJ
7KHGDWDREWDLQHGLQWKRVHH[SHULPHQWVDUHFRQVLGHUHGUHSUHVHQW DWLYHIRUWKHVDIHW\SURILOH
RIWKHUHVSHFWLYH/1351$SODWIRUPDQGLWVFDSDELOLW\WRLQGXFH LPPXQHUHVSRQVHV DQGDV
LQGHSHQGHQWRIWKHHQFRGHGDQWLJHQ DQGDUHWKHUHIRUHSUHVHQWHG DVVXSSRUWLYHGDWD
3DJH &21),'(17,$/090177e19744d904\A pproved\A pproved On: 11-Jun-2021 10:28 (GMT )
FDA-CBER-2021-5683-1102923
%LR17HFK51$
3KDUPDFHXWLFDOV*PE+
&RQILGHQWLDO,QYHVWLJDWRU¶V %URFKXUH
&RU9$&%173DJHRI
9HUVLRQ
'DWH$35
7D
EOH 1RPHQFODWXUH RI WKH SUHFOLQLFDOO\ HYDOXDWHG YDFFLQHV
3URGXFW &RGH 51$ SODWIRUP $QWLJHQ 7UDQVODWHG 3URWHLQ 9DULDQW FRGH
%17D X51$ 9 6HFUHWHG5%'YDULDQWZLWKD&WHUPLQDOWULPHUL]DWLRQ
GRPDLQ5%/
%17D X51$ 9 0HPEUDQHDQFKRUHGPXWDWHGIXOOOHQJWK6SURWHLQ 5%/
%17E PRG51$ 9 6HFUHWHG5%'YDULDQWZLWKD&WHUPLQDOWULPHUL]DWLRQ
GRPDLQ5%3
%17E PRG51$ 9 0HPEUDQHDQFKRUHGPXWDWHGIXOOOHQJWK6SURWHLQ 5%3
%17E PRG51$ 9 0HPEUDQHDQFKRUHGPXWDWHGIXOOOHQJWK6SURWHLQ 5%3
%17F VD51$ 9 6HFUHWHG5%'YDULDQWKDUERULQJD& WHUPLQDO
WULPHUL]DWLRQGRPDLQ5%6
%17F VD51$ 9 0HPEUDQHDQFKRUHGIXOOOHQJWK6SURWHLQPXWDWHG 5%6
1RQFOLQLFDO SKDUPDFRORJ\
3ULPDU\ 3KDUPDFRG\QDPLFV
7DEOHVXPPDUL]HVWKHVWXGLHVRQSULPDU\SKDUPDFRG\QDPLFV
3DJH &21),'(17,$/090177e19744d904\A pproved\A pproved On: 11-Jun-2021 10:28 (GMT )
FDA-CBER-2021-5683-1102924
%LR17HFK51$
3KDUPDFHXWLFDOV*PE+
&RQILGHQWLDO,QYHVWLJDWRU¶V %URFKXUH
&RU9$&%173DJH 25RI81
9HUVLRQ
'DWH$35
7D
EOH 6WXGLHV RQ SULPDU\ SKDUPDFRG\QDPLF HIIHFWV
$OOVWXG\W\SHVDUHEDVHGRQWKHDQDO\VLVRI6VSHFLILFLPPXQH UHVSRQVHVHOLFLWHGLQ%$/%FPLFH6RPHRIWKHVHVWXGLHVDUHRQ JRLQJ
6WXG\
QXPEHU6WXG\7\SH 6SHFLHV
7HVW
6\VWHP7HVW ,WHP 'RVH >J@ 5HVXOWV &URVV UHIHUHQFH
%17 YDFFLQH VWXGLHV
5 ,Q YLWURDQWLJHQ
H[SUHVVLRQDQG
ORFDOL]DWLRQ+(.7
FHOOV%17D5%/
%17E5%3%17E
5%3
%17F5%6 $OOWHVWHGLWHPVH[SUHVVHGWKHHQFRGHG6SURWHLQ
GHULYHGDQWLJHQ 6HFWLRQ
5 ,Q YLYRLPPXQRJHQLFLW\ 0LFH%$/%F %17D5%/ ,PPXQRJHQLFLW\ZDVVKRZQLQDOOWHVWHGGRVHV 6HFWLRQ
5 ,Q YLYRLPPXQRJHQLFLW\ 0LFH%$/%F %17E5%3 ,PPXQRJHQLFLW\ZDVVKRZQLQDOOWHVWHGGRVHV 6HFWLRQ
5 ,Q YLYRLPPXQRJHQLFLW\ 0LFH%$/%F %17E5%3 ,PPXQRJHQLFLW\ZDVVKRZQLQDOOWHVWHGGRVHV 6HFWLRQ
5 ,Q YLYRLPPXQRJHQLFLW\ 0LFH%$/%F %17F5%6 ,PPXQRJHQLFLW\ZDVVKRZQLQDOOWHVWHGGRVHV 6HFWLRQ
6XSSRUWLYH VWXGLHV
5 ,QYLYRLPPXQRJHQLFLW\ 0LFH%$/%F PRG51$HQFRGLQJD
QRQ6$56&R9 YLUDO
DQWLJHQ 7KHYLUDODQWLJHQGHOLYHUHGE\WKH/13IRUPXODWHG
PRG51$SODWIRUPLQGXFHGD VWURQJDQWERG\
LPPXQHUHVSRQVHDQGDQWLJHQ VSHFLILF7FHOO
DFWLYLW\6HFWLRQ
5 ,Q YLYRLPPXQRJHQLFLW\ 0LFH%$/%F 5%/ ,PPXQRJHQLFLW\ZDVVKRZQLQDOOWHVWHGGRVHV 6HFWLRQ
5 ,Q YLYRLPPXQRJHQLFLW\ 0LFH%$/%F 5%6 ,PPXQRJHQLFLW\ZDVVKRZQLQDOOWHVWHGGRVHV 6HFWLRQ
5 ,Q YLYRLPPXQRJHQLFLW\ 0LFH%$/%F %17E5%3 ,PPXQRJHQLFLW\ZDVVKRZQLQDOOWHVWHGGRVHV 6HFWLRQ
5 ,Q YLYRLPPXQRJHQLFLW\ 0LFH%$/%F 5%6 ,PPXQRJHQLFLW\ZDVVKRZQLQDOOWHVWHGGRVHV 6HFWLRQ
5 ,Q YLYRGLVWULEXWLRQ 0LFH%$/%F PRG51$HQFRGLQJ
OXFLIHUDVH 7KHVXUURJDWHRIWKH%17ESODWIRUPZDV
H[SUHVVHGLQPLFHZLWKGLVWULEXWLRQLQWKHPXVFOH
LQMHFWLRQVLWHDQGOLYHU6HFWLRQ
QD QRWDSSOLFDEOH
3DJH &21),'(17,$/090177e19744d904\A pproved\A pproved On: 11-Jun-2021 10:28 (GMT )
FDA-CBER-2021-5683-1102925
%LR17HFK51$
3KDUPDFHXWLFDOV*PE+
&RQILGHQWLDO,QYHVWLJDWRU¶V %URFKXUH
&RU9$&%173DJHRI
9HUVLRQ
'DWH$35
In vitro H[SUHVVLRQ RI %17 YDFFLQH 51$FRPSRQHQWV
7RDQDO\]HZKHWKHU5%'YDULDQW 9DQGWKHPXWDWHGIXOOOHQJW K6SURWHLQ99DUH
UREXVWO\WUDQVODWHGIURPWKHUHVSHFWLYH51$GUXJVXEVWDQFHV LQ YLWURDVVD\VZHUH
SHUIRUPHGDQGDQWLJHQH[SUHVVLRQDVVHVVHGE\ZHVWHUQEORW )LJXUHRULPPXQH
IOXRUHVFHQFHDQDO\VLV )LJXUH
)LJXUH :HVWHUQ %ORW DQDO\VLV IRU GHWHFWLRQ RI DQWLJHQ H[SUHVVL RQ
+(.7FHOOVZHUHWUDQVIHFWHG XVLQJ5LER-XLFHP51$WUDQVIHFW LRQUHDJHQW0HUFN0LOOLSRUH ZLWKJRIWKH51$
VXEVWDQFHV$X51$HQFRGLQJ9PRG51$HQFRGLQJ9DQGVD51$HQFRGLQJ9%)RUWKHFRQVWUXFWWHVWLQJ
HQFRGLQJ99YHUVLRQX51$PRG51$DQGVD51$ZDVWHVWHGDQG KDIWHUWUDQVIHFWLRQFHOOO\VDWHVZHUH
WUDQVIHUUHGWRDVRGLXPGRGHF\OVXOIDWH6'6±SRO\DFU\ODPLGHJHOHOHFWURSKRUHVLV3$*(V\VWHPIROORZHGE\ ZHVWHUQ
EORWDQDO\VLVXVLQJDSRO\FORQDO6$56&RURQDYLUXV6SLNH66XEXQL W3URWHLQ$QWLERG\$OOVDPSOHVVKRZHGVSHFLILF
DQWLJHQH[SUHVVLRQDQGVSHFLILF EDQGVZHUHGHWHFWHGIRUWKH9HQFRGLQJFRQVWUXFWVDWN'DZKLOHWKH9HQFRGHG
SURWHLQUXQVDWDQH[SHFWHGVL]HRIN'D5HFRPELQDQWSURWHLQ V5%'>QJ@FRQWUROH[SHFWHGVL]HN'D6
FRQWURO>QJ@H[SHFWHGVL]HN'DZHUHXVHGDVDVVD\FRQWURO V 1RWHWKDW9FRQVWUXFWVZHUHVHSDUDWHGZLWKD
SRO\DFU\ODPLGHJHO$UHFRPELQDQW 6$56&295%'SURWHLQN 'DZDVXVHGDVDSRVLWLYHFRQWURO)RU9DQG9
FRQVWUXFWVVHSDUDWLRQZDVSHUIRUPHGZLWKD±SRO\DFU\ODPLG HJHO$UHFRPELQDQW6$56 &R966XEXQLWSURWHLQ
N'DZDVXVHGDVDSRVLWLYHFRQWURO
51$FRQVWUXFWVHQFRGLQJWKH9KDYHDSUHGLFWHGVL]HRI N'DDQGIRU9DQG9
FRQVWUXFWVWKHVL]HSUHGLFWLRQLVN'D:HVWHUQEORWDQDO\ VLVFRQILUPHGWKH
H[SUHVVLRQDQGVL]HRIDOOWHVWHG51$VLQFHOOO\VDWHVRI+(. 7FHOOV LQGLFDWLQJFRUUHFW
H[SUHVVLRQLQDHXNDU\RWLFV\VWHP
&RORFDOL]DWLRQRIWKH5%'DQWLJHQFRQVWUXFWDQGWKHIXOOOHQJWK 6SURWHLQFRQVWUXFWVZLWK
DQHQGRSODVPLFUHWLFXOXP(5PDUNHUZDVVKRZQE\LPPXQRIOXRUHVFHQFHH[SHULPHQWVLQ
+(.7FHOOVH[SUHVVLQJ%17E PRG51$HQFRGLQJ9DQG%17 FVD51$
HQFRGLQJ9UHVSHFWLYHO\7KHVHUHVXOWVVXJJHVWWKDWERWK5% 'DQGIXOOOHQJWK6 SURWHLQ
DUHSURFHVVHGZLWKLQWKH(5IRUVXUIDFHH[SUHVVLRQRUVHFUHWLRQ ZKLFKLV DSUHUHTXLVLWHIRU
LQFUHDVHGELRDYDLODELOLW\DQGLPSURYHG LQGXFWLRQRILPPXQHUHVS RQVH
3DJH &21),'(17,$/090177e19744d904\A pproved\A pproved On: 11-Jun-2021 10:28 (GMT )
FDA-CBER-2021-5683-1102926
%LR17HFK51$
3KDUPDFHXWLFDOV*PE+
&RQILGHQWLDO,QYHVWLJDWRU¶V %URFKXUH
&RU9$&%173DJHRI
9HUVLRQ
'DWH$35
)LJXUH ,PPXQRIOXRUHVFHQFH VWDLQ LQJ RI FHOOV WUDQVIHFWHG ZLWK PRG51$ HQFRGLQJ WKH 5%' RU
VD51$ HQFRGLQJ WKH 3 69
+(.7FHOOVZHUHWUDQVIHFWHGZLWKJRIPRG51$HQFRGLQJWK H5%'9 RUVD51$HQFRGLQJWKHPHPEUDQH
DQFKRUHGPXWDWHGIXOOOHQJWK6SURWHLQ9XVLQJ5LER-XLFH51$ WUDQVIHFWLRQUHDJHQW0HUFN0LOOLSRUH$IWHUKLQ
FXOWXUHFHOOVZHUHIL[HGDQGVWDLQHGIRUWKH HQGRSODVPLFUHWLF XOXP(5&RQFDQDYDOLQ$$OH[D)OXRUFRQMXJDWH
UHGWKH6SURWHLQVXEGRPDLQXVLQJDSRO\FORQDO WKDWDQWLERG\ DOVRUHFRJQL]LQJWKH UHFHSWRUELQGLQJGRPDLQ5%'
GRPDLQDQWL6DQWLERG\DQGIRU$OH[D)OXRUJUHHQDQGGHR[\ULERQXFOHLFDFLG'1$WRGHILQHWKHQXFOH XV
+RHFKVWEOXH7KHPHUJHGFRORUHGSLFWXUHVKRZWKDWWKH5%'H [SUHVVHGE\PRG51$9DQGWKH36H[SUHVVHGE\
VD51$9HDFKFRORFDOL]HZLWKWKH(5PDUNHUORFDOL]DWLRQVFDOH P$FRQWUROXVLQJQRQWUDQVIHFWHGFHOOVLV
VKRZQDWWKHWRS
In vivo data 6XSSRUWLYH LPPXQRJHQLFLW\ VWXGLHV
7KHP51$IRUPDWVX51$PRG51$VD51$XVHGIRUGHYHORSPHQWRI%17YDFFLQHV
KDYHEHHQSUHYLRXVO\HYDOXDWHGLQVWXGLHVZLWKRWKHUYLUDODQWLJHQVDVLPPXQRJHQV 9RJHO
HWDO 3DUGLHWDO 3DUGLHWDO
9DFFLQHVEDVHGRQWKHVHP51$SODWIRUPVZHUHVKRZQWRLQGXFHVWU RQJDQWLERG\
UHVSRQVHVDQGSULPHDQGH[SDQGPXOWLIXQFWLRQDO&'DQG&'7FHOOV7KHSURSHUWLHVRI
DQWLJHQVSHFLILFLPPXQHUHVSRQVHVLQGXFHGE\YDFFLQDWLRQZLWKW KHVHP51$IRUPDWVZHUH
VWXGLHGLQVHYHUDOVSHFLHVVHH 7DEOH9DFFLQDWLRQZLWKQXFOHRVLGHPRGLILHGPRG51$
LVFKDUDFWHUL]HGE\WKHVWURQJ H[SDQVLRQRI7KVNHZHGDQWLJHQ VSHFLILF7IROOLFXODUKHOSHU
7IKFHOOV7KHVHFHOOVVWLPXODWHDQGH[SDQGJHUPLQDOFHQWHU% FHOOVZKLFKUHVXOWVLQ
SDUWLFXODUO\VWURQJORQJOLYHGKLJKDIILQLW\DQWLERG\UHVSRQVH V7KHX51$DQGVD51$
IRUPDWVDUH7/5DJRQLVWVDQGH[KLELWDKLJKHULPPXQHVWLPXOD WRU\DFWLYLW\ZKLFK
3DJH &21),'(17,$/090177e19744d904\A pproved\A pproved On: 11-Jun-2021 10:28 (GMT )
FDA-CBER-2021-5683-1102927
%LR17HFK51$
3KDUPDFHXWLFDOV*PE+
&RQILGHQWLDO,QYHVWLJDWRU¶V %URFKXUH
&RU9$&%173DJHRI
9HUVLRQ
'DWH$35
UHVXOWVLQW\SH,LQWHUIHURQUHOHDVHDQGDVWURQJO\7KELDVHG &'7FHOOUHVSRQVHDVZHOO
DVVWURQJH[
SDQVLRQRIF\WRWR[LF7FHOOV6DKLQHWDO 'XHWRVHOIDPSOLILFDWLRQDQG
SURORQJHGWUDQVODWLRQVD51$LVDEOHWRLQGXFHVWURQJ&'DQG&'7FHOOUHVSRQVHVE\
DSU
LPHRQO\DGPLQLVWUDWLRQVFKHGXOH 9RJHOHWDO
7DEOH &KDUDFWHULVWLFV RI DGDSWLYH LPPXQH UHVSRQVH IRU WKH P51$ IRUP DWV
X51$ PRG51$ VD51$
6RXUFH3DUGLHWDO
9RJHOHWDO .UDQ]HWDO
6RXUFH9RJHOHWDO .UDQ]
HWDO3DUGLHWDO
6RXUFH9RJHOHWDO
0R\RHWDO
&'7 FHOO
UHVSRQV
Hx,QGXFWLRQRIPXOWLIXQFWLRQDO
VWURQJO\7K VNHZHGLPPXQH
UHVSRQVHZLWKLQGXFWLRQRI ,)1
Ȗ71)Į,/&'7FHOOV
x6WURQJH[SDQVLRQRIIROOLFXODU
KHOSHU7IKFHOOVZLWKDQ ,)1Ȗ
7I+FHOOVPRXVHKXPDQ 1+3x6WURQJLQGXFWLRQRIPXOWL
IXQFWLRQDO7KVNHZHG
LPPXQHUHVSRQVHZLWK
LQGXFWLRQRI,)1Ȗ71)Į
,/&'7FHOOV
x6WURQJH[SDQVLRQRIIROOLFXODU
KHOSHU7IKFHOOVZLWKDQ ,)1
Ȗ7I+FHOOVPRXVH KXPDQ
1+3x([SDQVLRQRID
VWURQJO\
7KVNHZHG
LPPXQHUHVSRQVHZLWK
PXOWLIXQFWLRQDO7K
,)1Ȗ71)Į,/
&'7FHOOVPRXVH
&'7 FHOO
UHVSRQV
Hx([SDQVLRQRIPXOWLIXQFWLRQDO
&'F\WRWR[LFHIIHFWRUDQGORQJ
OLYHGPHPRU\7FHOOV ZLWKDQ
,)1Ȗ71)Į&'
SKHQRW\SHPRXVH KXPDQx([SDQVLRQRIPXOWLIXQFWLRQDOF\
WRWR[LFHIIHFWRUDQGORQJ
OLYHGPHPRU\ &'7FHOOVZLWK
DQ,)1Ȗ71) Į&'
SKHQRW\SHPRXVH KXPDQx6WURQJH[SDQVLRQRI
ORQJOLYHGHIIHFWRUDQG
FHQWUDOPHPRU\&'
7FHOOVZLWKDQ,)1 Ȗ
71)Į&'
SKHQRW\SHPRXVH
$QWLERG\
UHVSRQVHx+LJKWLWHUKLJKDIILQLW\ORQJOLYHGQHXWUDOL]
LQJDQWLERG\UHVSRQVHV
DIWHUSULPH RQO\ERRVWPRXVH
UDWV1+3
x$'&&DFWLYLW\UDEELWV
x0RXVH,J*a,J*Dx+LJKWLWHUKLJKDIILQLW\ORQJ
OLYHGQHXWUDOL]LQJDQWLERG\
UHVSRQVHVDIWHUSULPH ERRVW
RQO\PRXVHUDWV1+3
x$'&&DFWLYLW\UDEELWV
x0RXVH,J*a,J*Dx+LJKWLWHUQHXWUDOL]LQJ
DQWLERG\UHVSRQVHV
DIWHUSULPHRQO\
PRXVHUDWVSLJ
1+3
x0RXVH,J*D!!,J*
$'&& $QWLERG\GHSHQGHQW FHOOXODU F\WRWR[LFLW\ ,J* ,PPXQRJO REXOLQ * ,/ LQWHUOHXNLQ ,)1 ,QWHUIHURQ 1+3 1RQ
KXPDQSULPDWH7IK 7IROOLFXODUKHOSHU71) 7XPRUQHFURVLV IDFWRU
,PPXQRJHQLFLW\ XVLQJ LQIOXHQ]D KHPDJJOXWLQLQ DV D PRG HO DQWLJHQ
,QPXULQHLQIOXHQ]DYLUXVFKDOOHQJHPRGHOVDOOWKUHHP51$IRUP DWVX51$PRG51$
VD51$KDYHEHHQVKRZQWRFRQIH UVWURQJSURSK\ODFWLFYDFFLQHDF WLYLW\
2QHVWXG\XVHGDPRG51$/13YDFFLQHWKDWHQFRGHVLQIOXHQ]D+$ 0LFHZHUHLQMHFWHG
,0ZLWKJRQGD\VDQGZLWKWKH+$HQFRGLQJIRUPXODWHG 51$2QGD\VDQG
EORRGVDPSOHVZHUHGUDZQDQGZHUHWKHQWHVWHGIRUDQWLERG\ DQGFHOOXODUUHVSRQVHV WR
IOX+$7KHDQDO\VLVVKRZHGDKLJKVHUXPDQWLERG\UHVSRQVHGHP RQVWUDWHGE\YHU\KLJK
OHYHOVRIDQWLJHQVSHFLILF,J*LQVHUXPDQGKLJK LQIOXHQ]DYLUX VQHXWUDOL]DWLRQWLWHUV
)LJXUH0RUHRYHUVWURQJ7K&'DQG&'7FHOOUHVSRQVHV )LJX UHZHUH
LQGXFHGE\WKHPRG51$YDFFLQH
3DJH &21),'(17,$/090177e19744d904\A pproved\A pproved On: 11-Jun-2021 10:28 (GMT )
FDA-CBER-2021-5683-1102928
%LR17HFK51$
3KDUPDFHXWLFDOV*PE+
&RQILGHQWLDO,QYHVWLJDWRU¶V %URFKXUH
&RU9$&%173DJHRI
9HUVLRQ
'DWH$35
)LJXUH $QWLERG\ UHVSRQVH HOLFLW HG E\ LQIOXHQ]D +$ XVLQJ /13IR UPXODWHG PRG51$
%$/%FPLFHZHUHLPPXQL]HGWZLFH ,0ZLWKJRIWKHYDFFLQHFDQGLGDWH +$VSHFLILF,J*ZDVPHDVXUHGE\(/,6$
7KHIXQFWLRQDOLW\RIWKHDQWLERGLHVZDVPHDVXUHGE\LQIOXHQ]DYLUXVQHXWUDOL]DWLRQ
)LJXUH 7 FHOO UHVSRQVH DJDLQVW LQIOXHQ]D +$ XVLQJ WKH /13IRU PXODWHG PRG51$ SODWIRUP
%$/%FPLFHZHUHLPPXQL]HG,0ZLWK JRIWKHYDFFLQHFDQGLGDWH WZLFH7KH7FHOOUHVSRQVHZDVDQDO\]HGXVLQJ
DQWLJHQVSHFLILFSHSWLGHV WRVWLPXODWH7FHOOVUHFRYHUHGIURPWKH VSOHHQ ,QWHUIHURQ,)1 JUHOHDVHZDVPHDVXUHGDIWHU
SHSWLGHVWLPXODWLRQXVLQJDQ(/,6SRWDVVD\
7UHDWPHQWZLWKWKH/13IRUPXODWHGPRG51$LQGXFHGDVWURQJLPPXQ HUHVSRQVHDFURVV
WKHREVHUYDWLRQSHULRGRI GDIWHURQHLPPXQL]DWLRQDQGDVHFRQGLPPXQL]DWLRQ VWURQJO\
ERRVWHGWKHDQWL+$,J*DQWLERG\JHQHUDWLRQ )LJXUH
3DJH &21),'(17,$/090177e19744d904\A pproved\A pproved On: 11-Jun-2021 10:28 (GMT )
FDA-CBER-2021-5683-1102929
%LR17HFK51$
3KDUPDFHXWLFDOV*PE+
&RQILGHQWLDO,QYHVWLJDWRU¶V %URFKXUH
&RU9$&%173DJHRI
9HUVLRQ
'DWH$35
6LPLODUWRWKHDQWLERG\UHVSRQVHWKH/13IRUPXODWHGPRG51$HQF RGLQJIRU+$LQGXFHGD
KLJK7FHOOUHVSRQVH )LJXUH
9DULRXVRWKHULPPXQRJHQLFLW\VWXG LHVLQPLFHKDYHGRFXPHQWHGWK HLQGXFWLRQRI
QHXWUDOL]LQJDQWLERGLHVDQGDQWLJHQVSHFLILF7KW\SH7FHOOUHVSRQVHVZLWKX51$DQG
VD51$YDFFLQHVHQFRGLQJLQIOXHQ]D+$ 9RJHOHWDO
,PPXQRJHQLFLW\ VWXG\ RI WKH /13IRUPXODWHG X51$ HQFRG LQJ 3 69
5%/%17D
7KHSRWHQF\RIWKH/13IRUPXODWHGX51$FRGLQJIRU3695%/ ZDVWHVWHGLQ
PLFH2IQRWHLQWKHFOLQLFDOWULDOX51$HQFRGLQJWKH5%'DORQ H%17DEXWQRW36
9LVXVHG
$QLPDOVZHUHLPPXQL]HGZHHNO\EOHGDQGDWGD\ VDFULILFHGIR UWKHILQDOEOHHGLQJWLPH
SRLQWDQG,)1\UHOHDVH7FHOODQDO\VLVYLD(/,6SRW7KH(/,6$G DWDVKRZDQHDUO\GRVH
GHSHQGHQW,J*UHVSRQVHUHFRJQL]LQJ6DQGWKH5%'7KHSRWHQF\ RIWKH/13IRUPXODWHG
X51$FRGLQJIRU369%17D 5%/ZDVWHVWHGLQPLFH IRUGHWDLOVVHHWKH
ILJXUHOHJHQGIRU )LJXUH7KHILQDODQDO\VLVLVSHQGLQJ
%$/%FPLFHZHUHLPPXQL]HG,0RQFHDVRXWOLQHGLQ 7DEOH$WGD\DQLPDOVZHUH
VDFULILFHGIRUWKHILQDOEOHHGLQJ WLPHSRLQWDQG,)1\UHOHDVH7 FHOODQDO\VLVYLD(/,6SRW
7KHILQDODQDO\VLVLVSHQGLQJ7KH(/,6$GDWDVKRZDQHDUO\GRVHGHSHQGHQW,J*UHVSRQVHUHFRJ QL]LQJ6$56&R9
66XEXQLWSURWHLQ6DQGWKH5%' )LJXUH6HUDREWDLQHGDQGGDIWHU
LPPXQL]DWLRQVKRZGRVHGHSHQGHQW6$56&R9SVHXGRYLUXVQHXWUDO L]DWLRQ)LJXUH
7KHVWXG\LVRQJRLQJ
3DJH &21),'(17,$/090177e19744d904\A pproved\A pproved On: 11-Jun-2021 10:28 (GMT )
FDA-CBER-2021-5683-1102930
%LR17HFK51$
3KDUPDFHXWLFDOV*PE+
&RQILGHQWLDO,QYHVWLJDWRU¶V %URFKXUH
&RU9$&%173DJHRI
9HUVLRQ
'DWH$35
)LJXUH $QWL6 ,J* UHVSRQVH DQG G DIWHU LPPXQL]DWLR Q ZLWK 5%/
%$/%FPLFHZHUHLPPXQL]HG,0RQFHZLWKRU JRI/13IRU PXODWHG5%/ 2QDQGGDIWHU
LPPXQL]DWLRQDQLPDOVZHUHEOHGDQGWKHVHUXPVDPSOHVZHUHDQDO\ ]HGIRUDQWL6OHIWDQGDQWL5%'ULJKWDQWLJHQ
VSHFLILF,J*E\(/,6$)RUGD\GD\GD\ DQGGUHVXOWVIURPGLIIHUHQWVHUXP
GLOXWLRQVDUHGHSLFWHGRQWKHJUDSKV2QHSRLQWLQWKHJUDSKVWDQ GVIRURQHPRXVH(YHU\PRXVHVHUXPZDVPHDVXUHGLQ
GXSOLFDWH*URXSVL]HQ 0HDQ6(0DUHGHSLFWHGE\WKHKRUL]RQ WDOOLQHVZLWKZKLVNHUVIRUHDFK JURXS
$QWLERG\FRQFHQWUDWLRQVLQWKHVHUXPVDPSOHVZHUHFDOFXODWHGIR UWKHLQGLYLGXDOVDPSOLQJ
GD\VDQGWKHNLQHWLFVRI,J*VDJDLQVW6DQG5%'SURWHLQVLVVK RZQLQ)LJXUH
$QWLERG\FRQFHQWUDWLRQVDJDLQVW6 )LJXUH$ DQG5%' )LJXUH% LQFUHDVHGLQD
GRVHGHSHQGHQWPDQQHURYHUWLPH
3DJH &21),'(17,$/090177e19744d904\A pproved\A pproved On: 11-Jun-2021 10:28 (GMT )
FDA-CBER-2021-5683-1102931
%LR17HFK51$
3KDUPDFHXWLFDOV*PE+
&RQILGHQWLDO,QYHVWLJDWRU¶V %URFKXUH
&RU9$&%173DJHRI
9HUVLRQ
'DWH$35
)LJXUH .LQHWLFV RI WKH DQW LERG\ FRQFHQWUDWLRQ DJDLQVW WK HYLUDODQWLJHQ
)RU LQGLYLGXDO ǻ2' YDOXHV WKH DQWLERG\ FRQFHQWUDWLRQV LQ WKH VHUXP VDPSOHV ZHUH FDOFXODWHG 7KH VHUXP VDPSOHV ZHUH
WHVWHGDJDLQVW$WKH6SURWHLQ DQG%5%'*URXSPHDQDQWLE RG\FRQFHQWUDWLRQVDUHVKRZQ6(0
3DJH &21),'(17,$/090177e19744d904\A pproved\A pproved On: 11-Jun-2021 10:28 (GMT )
FDA-CBER-2021-5683-1102932
%LR17HFK51$
3KDUPDFHXWLFDOV*PE+
&RQILGHQWLDO,QYHVWLJDWRU¶V %URFKXUH
&RU9$&%173DJHRI
9HUVLRQ
'DWH$35
)LJXUH 1HXWUDOL]DWLRQ RI 6$56 &R9 SVHXGRYLUXV DQG G DIWHU LPPXQL]DWLRQ ZLWK
5%/
%$/%FPLFHZHUHLPPXQL]HG,0RQFHZLWKRU JRI/13IRU PXODWHG5%/ 2QDQGGDIWHU
LPPXQL]DWLRQDQLPDOVZHUHEOHGDQGWKHVHUDZHUHWHVWHGIRU6$5 6&R9SVHXGRYLUXVQHXWUDOL]DWLRQ*UDSKVGHSLFW
S91VHUXPGLOXWLRQVUHGXFWLRQRILQIHFWLRXVHYHQWVFRPSDUHGW RSRVLWLYHFRQWUROVZLWKRXWVHUXP2QHSRLQWLQ
WKHJUDSKV VWDQGV IRURQHPRXVH(YHU\PRXVHVDPSOHZDVPHDVXUHG LQGXSOLFDWH*URXSVL]HQ 0HDQ6(0LV
VKRZQE\KRUL]RQWDOEDUVZLWKZKLVNHUVIRUHDFK JURXS//24ORZ HUOLPLWRITXDQWLILFDWLRQ8/24XSSHUOLPLWRI
TXDQWLILFDWLRQ
,PPXQRJHQLFLW\ VWXG\ RI WKH /13IRUPXODWHG VD51$HQFRG LQJ WKH
UHFHSWRU ELQGLQJ GRPDLQ 5%6
7RGLVVHFWWKHSRWHQF\RIWKH/13IRUPXODWHGVD51$%$/%FPLFH ZHUHLPPXQL]HG ,0
ZLWK5%/HQFRGLQJIRUWKHYLUDO5%'RQFHDVRXWOLQHGLQ 7DEOHDQGWKHDQWLERG\
LPPXQHUHVSRQVHZLOOEHDQDO\]HG
7KLVVWXG\LVRQJRLQJ$WWKLVWLPHSRLQW(/,6$GDWDDQG GDIWHUWKHLPPXQL]DWLRQ
DUHDYDLODEOHWKDWVKRZDQHDUO\ GRVHGHSHQGHQWLPPXQHDFWLYDW LRQDJDLQVWWKH
3DJH &21),'(17,$/090177e19744d904\A pproved\A pproved On: 11-Jun-2021 10:28 (GMT )
FDA-CBER-2021-5683-1102933
%LR17HFK51$
3KDUPDFHXWLFDOV*PE+
&RQILGHQWLDO,QYHVWLJDWRU¶V %URFKXUH
&RU9$&%173DJHRI
9HUVLRQ
'DWH$35
6SURWHLQDQGWKHUHFHSWRUELQGLQJGRPDLQ )LJXUH)XUWKHUPRUHS917HOLFLWV
QHXWUDOL]LQJDQWLERGLHVDOUHDG\GDIWHULPPXQL]DWLRQ )LJXUH
)LJXUH $QWL6 SURWHLQ ,J* UHVSR QVH DQG G DIWHU LPPXQL] DWLRQ ZLWK 5%6
%$/%FPLFHZHUHLPPXQL]HG,0RQF HZLWKRUJRI/13IR UPXODWHG5%6DQGGDIWHU
LPPXQL]DWLRQDQLPDOVZHUHEOHGDQ GWKHVHUXPVDPSOHVZHUHDQDO\]HGIRUWRWDODPRXQWRIDQWL6OHIWDQGDQWL5%'
ULJKWDQWLJHQVSHFLILFLPPXQRJOREXOLQ*,J*PHDVXUHGYLD(/ ,6$)RUGD\GD\DQGGD\V
GLIIHUHQWVHUXPGLOXWLRQZHUHLQFOXGHGLQWKHJUDSK2QHSRLQWLQWKHJUDSKVWDQGVIRURQHPRXVHHYHU\PRXVH
VDPSOHZDVPHDVXUHGLQGXSOLFDWHVJURXSVL]HQ PHDQ 6(0LV LQFOXGHGIRUWKHJURXSV
3DJH &21),'(17,$/090177e19744d904\A pproved\A pproved On: 11-Jun-2021 10:28 (GMT )
FDA-CBER-2021-5683-1102934
%LR17HFK51$
3KDUPDFHXWLFDOV*PE+
&RQILGHQWLDO,QYHVWLJDWRU¶V %URFKXUH
&RU9$&%173DJHRI
9HUVLRQ
'DWH$35
)LJXUH 1HXWUDOL]DWLRQ RI 6$56 &R9 SVHXGRYLUXV G DIWHU LP PXQL]DWLRQ ZLWK 5%6
%$/%FPLFHZHUHLPPXQL]HG,0RQFHZLWK RUJRI/13IRU PXODWHG5%62QGDIWHULPPXQL]DWLRQ
DQLPDOVZHUHEOHGDQGWKHVHUDZHUHWHVWHGIRU6$56&R9SVHXG RYLUXVQHXWUDOL]DWLRQ*UDSKVGHSLFWS91 VHUXP
GLOXWLRQVUHGXFWLRQRILQIHFWLRXVHYHQWVFRPSDUHGWRSRVL WLYHFRQWUROVZLWKRXWVHUXP2QHSRLQWLQWKHJUDSKV
VWDQGVIRURQHPRXVH(YHU\PRXVHVDPSOHZDVPHDVXUHGLQGXSOLFDWH*URXSVL]HQ 0HDQ 6(0LVVKRZQE\
KRUL]RQWDOEDUVZLWKZKLVNHUVIRUHDFKJURXS//24ORZHUOLPLWRITXDQWLILFDWLRQ8/24XSSHUOLPLWRITXDQWLILFDWLRQ
,PPXQRJHQLFLW\ VWXG\ RI WKH /13IRUPXODWHG PRG51$ HQFR GLQJ WKH
YLUDO 6 SURWHLQ9 5%3
7RGLVVHFWWKHSRWHQF\RIWKH/13IRUPXODWHGPRG51$DYHUVLRQF RGLQJIRUWKHYLUDO6
SURWHLQ95%3ZDVLQYHVWLJDWHG)RUWKLVSXUSRVHDGRVH WLWUDWLRQVWXG\LQ%$/%F
PLFHZDVLQLWLDWHGZKHUHWKHLPPXQHUHVSRQVHZLOOEHDQDO\]HGIRFXVLQJRQWKHDQWLERG\
LPPXQHUHVSRQVH
7KLVVWXG\LVRQJRLQJ$WWKLVWLPHSRLQW(/,6$GDWDDQG G DIWHUWKHILUVWLPPXQL]DWLRQ
DUHDYDLODEOHWKDWVKRZDQHDUO\GRVHGHSHQGHQWLPPXQHDFWLYDW LRQDJDLQVWWKH
6SURWHLQDQGWKH5%' )LJXUH
3DJH &21),'(17,$/090177e19744d904\A pproved\A pproved On: 11-Jun-2021 10:28 (GMT )
FDA-CBER-2021-5683-1102935
%LR17HFK51$
3KDUPDFHXWLFDOV*PE+
&RQILGHQWLDO,QYHVWLJDWRU¶V %URFKXUH
&RU9$&%173DJHRI
9HUVLRQ
'DWH$35
)LJXUH $QWL6 SURWHLQ ,J* UHVSR QVH DQG G DIWHU LPPXQL ]DWLRQ ZLWK 5%3
%$/%FPLFHZHUHLPPXQL]HG,0RQFHZLWKRU JRI/13IR UPXODWHGPRG51$5%3DQGGDIWHU
LPPXQL]DWLRQDQLPDOVZHUHEOHGDQ GWKHVHUXPVDPSOHVZHUHDQDO\]HGIRUWRWDODPRXQWRIDQWL6OHIWDQGDQWL5%'
ULJKWDQWLJHQVSHFLILFLPPXQRJOREXOLQ*,J*PHDVXUHGYLD(/ ,6$)RUGD\GD\DQGGD\
GLIIHUHQWVHUXPGLOXWLRQZHUHLQFOXGHGLQWKHJUDSK2 QHSRLQWLQWKHJUDSKVWDQGVIRURQHPRXVHHYHU\PRXVH
VDPSOHZDVPHDVXUHGLQGXSOLFDWHVJURXSVL]H Q PHDQ6(0LV LQFOXGHGIRUWKHJURXSV
&XUUHQWO\6$56&R9S917GDWDD UHDYDLODEOHIRUGD\DIWHUL PPXQL]DWLRQZKLFK
VKRZHGGRVHGHSHQGHQWSVHXGRYLUXVQHXWUDOL]DWLRQDFWLYLW\RIWK HVHUXPVDPSOHV
)LJXUH7KHVWXG\LVRQJRLQJ
3DJH &21),'(17,$/090177e19744d904\A pproved\A pproved On: 11-Jun-2021 10:28 (GMT )
FDA-CBER-2021-5683-1102936
%LR17HFK51$
3KDUPDFHXWLFDOV*PE+
&RQILGHQWLDO,QYHVWLJDWRU¶V %URFKXUH
&RU9$&%173DJHRI
9HUVLRQ
'DWH$35
)LJXUH 1HXWUDOL]DWLRQ RI 6$56 &R9 SVHXGRYLUXV G DIWHU LP PXQL]DWLRQ ZLWK 5%3
%$/%FPLFHZHUHLPPXQL]HG,0RQFHZLWK RUJRI/13IRUPXODWHGPRG51$5%32QGDIWHU
LPPXQL]DWLRQDQLPDOVZHUHEOHGDQGWKHVHUDZHUHWHVWHGIRU6$56&R9SVHXGRYLUXVQHXWUDOL]DWLRQ*UDSKVGHSLFW
S91VHUXPGLOXWLRQVUHGXFWLRQRILQIHFWLRXVHYHQWVFRPSDUHGW RSRVLWLYH FRQWUROVZLWKRXWVHUXP2QHSRLQWLQ
WKH JUDSKV VWDQGV IRURQHPRXVH(YHU\PRXVHVDPSOHZDVPHDVXUHG LQGXSOLFDWH*URXSVL]HQ 0HDQ6(0LV
VKRZQE\KRUL]RQWDOEDUVZLWKZKLVNHUV IRUHDFKJURXS//24ORZ HUOLPLWRITXDQWLILFDWLRQ8/24XSSHUOLPLWRI
TXDQWLILFDWLRQ
In vivoLPPXQRJHQLFLW\ VWXGLHV IRU %17 YDFFLQH FDQGLGDWHV
7KHLPPXQRJHQLFLW\VWXGLHVDQGWKHLUDQDO\VLVDUHFXUUHQWO\RQJR LQJIRUDOO%17
YDFFLQHVLQFOXGLQJ%17D%17 E%17E DQG%17F$ QWLERG\UHVSRQVH
GDWDDQDO\]LQJWRWDO,J*EXWDOVRSVHXGRYLUXVQHXWUDOL]LQJDQWL ERG\WLWHUV IURPGLIIHUHQW
SRVWYDFFLQDWLRQWLPHSRLQWVDUHDYDLODEOHIRUDOOFDQGLGDWHVDQG VKRZLPPXQRJHQLFLW\IRU
ERWK6SURWHLQDQWLJHQVQDPHO\WKH5%'9LH%17D%17 EDQGWKH369
LH%17D%17E'DWDDYDLODEOHDWWKHSRLQWRIWLPH RIFRPSOHWLQJWKLV,%LV
UHSRUWHGEHORZDQGXSGDWHVZLOOEHSURYLGHGDVWKH\EHFRPHDYDL ODEOH
7DEOH 6WXG\ GHVLJQ
*URXS
QR1R RI
DQLPDOV9DFFLQH
GRVH,PPXQL]DWLRQ
GD\'RVH YROXPH >/@
URXWH%ORRG FROOHFWLRQ
GD\(QG RI LQOLIH SKDVH
EXIIHU ,0
/RZ ,0
0HGLXP ,0
+LJK ,0
,PPXQRJHQLFLW\ VWXG\ RI WKH %17D 5%/
7RDVVHVVWKHSRWHQF\RIWKH/13IRUPXODWHGX51$YDFFLQHFDQGLGDWH%17DZKLFK
HQFRGHVWKH5%'9%$/%FPLFHZHUHLPPXQL]HG,0RQFHDVRXWOLQ HGLQ7DEOH
(/,6$GDWDIURPVHUDREWDLQHGDQGGDIWHUWKHLPPXQL]D WLRQVKRZDQHDUO\
GRVHGHSHQGHQW,J*UHVSRQVHUHFRJQL]LQJ6DQGWKH5%' )LJXUH&RUUHVSRQGLQJ
VKRZHGRQO\PLQLPDOWRDEVHQWSVHXGRYLUXVQHXWUDOL]DWLRQDFWLYL W\RIWKHVHUXPVDPSOHV
DFURVVDOOWLPHSRLQWVDQDO\]HG )LJXUH+RZHYHUWKLVPLJKWEHGXHWRWKHVLQJOH
3DJH &21),'(17,$/090177e19744d904\A pproved\A pproved On: 11-Jun-2021 10:28 (GMT )
FDA-CBER-2021-5683-1102937
%LR17HFK51$
3KDUPDFHXWLFDOV*PE+
&RQILGHQWLDO,QYHVWLJDWRU¶V %URFKXUH
&RU9$&%173DJHRI
9HUVLRQ
'DWH$35
DGPLQLVWUDWLRQRI%17D LQPLFHVLQFHLQUDWVS917GDWDVKRZ HGSURQRXQFHG
SVHXGRYLUXVQHXWUDOL]DWLRQDIWHUWKUHHZHHNO\LPPXQL]DWLRQURXQ GV 6HFWLRQ 7KH
PRXVHVWXG\ZLOOEHUHSHDWHGZLWKDVPDOOHUJURXS
)LJXUH $QWL6 SURWHLQ ,J* UHVSRQVH DQG G DIWHU LPPXQ L]DWLRQ ZLWK %17D
%$/%FPLFHZHUHLPPXQL]HG,0RQFHZLWKRUJRI/13IRUP XODWHG5%/2QDQG GDIWHU
LPPXQL]DWLRQDQLPDOVZHUHEOHGDQGWKHVHUDZHUHDQDO\]HGIRU DQWL6OHIWDQGDQWL5%'ULJKWDQWLJHQVSHFLILF,J*
E\(/,6$2QDQGGDIWHULPPXQL]DWLRQDQLPDOVZHUHE OHGDQGWKHVHUDZHUHDQDO\]HGIRUDQWL6OHIWDQG
DQWL5%'ULJKWDQWLJHQVSHFLILF,J*E\(/,6$)RUDOOWLPHSRL QWVYDOXHVIRUDVHUXPGLOXWLRQRIZHUHLQFOXGHGRQ
WKHJUDSKV)RUDOOWLPHSRLQWVYDOXHVIRUDVHUXPGLOXWLRQRI ZHUHLQFOXGHGRQWKHJUDSKV2QHSRLQWLQWKHJUDSK
VWDQGVIRURQHPRXVH(YHU\PRXVHVDPSOHZDVPHDVXUHGLQGXSOLF DWH*URXSVL]HQ 0HDQ6(0LVGHSLFWHGDVD
KRUL]RQWDOOLQHZLWKZKLVNHUVIRUHDFK JURXSV
$QWLERG\FRQFHQWUDWLRQVLQWKHVHUXPVDPSOHVZHUHFDOFXODWHGIRUWKHLQGLYLGXDOVDPSOLQJ
GD\VDQGWKHNLQHWLFVRI,J*VDJDLQVW6DQG5%'SURWHLQVLVVKR ZQ LQ)LJXUH
3DJH &21),'(17,$/090177e19744d904\A pproved\A pproved On: 11-Jun-2021 10:28 (GMT )
FDA-CBER-2021-5683-1102938
%LR17HFK51$
3KDUPDFHXWLFDOV*PE+
&RQILGHQWLDO,QYHVWLJDWRU¶V %URFKXUH
&RU9$&%173DJHRI
9HUVLRQ
'DWH$35
$QWLERG\FRQFHQWUDWLRQVDJDLQVW6 )LJXUH$DQG5%' )LJXUH%LQFUHDVHGLQD
GRVHGHSHQGHQWPDQQHURYHUWLPH
)LJXUH .LQHWLFV RI WKH DQWLERG\ FRQFHQWUDWLRQ DJDLQVW WKH YLU DO DQWLJHQ
)RULQGLYLGXDOǻ2'YDOXHVWKHDQWLERG\FRQFHQWUDWLRQVLQWKHVHUXPVDPSOHVZHUHFDOFXODWHG7KHVHUXPVDPSOHVZHUH
WHVWHGDJDLQVW$WKH6SURWHLQ DQG%5%'*URXSPHDQDQWLE RG\FRQFHQWUDWLRQVDUHVKRZQ6(0 1RWHWKDWIRUWKH
6DQGWKH5%'PJP/SURWHLQZHUHFRDWHGRQWRDZHOOSODWH %17EHQFRGHVIRUWKHUHFHSWRUELQGLQJGRPDLQ
RQO\$VWKH5%'KDVDVPDOOHUVL]HWKDQWKH6PRUHDQWLERG\ELQGLQJVLWHVDUHDYDLODEOHZLWKLQPJP/RI5%'
FRPSDUHGWR6ZKLFKFRXOGH[SODLQWKHKLJKHUDQWLERG\FRQFHQWUDWLRQFDOFXODWHGDJDLQVW5%'
3DJH &21),'(17,$/090177e19744d904\A pproved\A pproved On: 11-Jun-2021 10:28 (GMT )
FDA-CBER-2021-5683-1102939
%LR17HFK51$
3KDUPDFHXWLFDOV *PE+
&RQILGHQWLDO,QYHVWLJDWRU¶V %URFKXUH
&RU9$&%173DJHRI
9HUVLRQ
'DWH$35
)LJXUH 1HXWUDOL]DWLRQ RI 6$56 &R9 SVHXGRYLUXV DQG G DIWHU LPPXQL]DWLRQ ZLWK
%17D
%$/%FPLFHZHUHLPPXQL]HG,0RQFHZLWKRU JRI%17D 2QDQGGDIWHULPPXQL]DWLRQDQLPDOV
ZHUHEOHGDQGWKHVHUDZHUHWHVW HGIRU6$56&R9SVHXGRYLUXV QHXWUDOL]DWLRQ*UDSKVGHSLFWS91 VHUXPGLOXWLRQV
UHGXFWLRQRILQIHFWLRXVHYHQWVFRPSDUHGWRSRVLWLYHFRQWU ROVZLWKRXWVHUXP2QHSRLQWLQWKHJUDSKVVWDQGVIRURQH
PRXVH(YHU\PRXVHVDPSOHZDVPHDVXUHGLQGXSOLFDWH*URXSVL]HQ 0HDQ 6(0LVVKRZQE\KRUL]RQWDOEDUVZLWK
ZKLVNHUVIRUHDFKJURXS//24ORZHUOLPLWRITXDQWLILFDWLRQ8 /24XSSHUOLPLWRITXDQWLILFDWLRQ
,PPXQRJHQLFLW\ VWXG\ RI WKH %17E 5%3
7RDVVHVVWKHSRWHQF\RIWKH/13 IRUPXODWHGPRG51$YDFFLQHFDQG LGDWH%17E
ZKLFKHQFRGHV5%'9%$/%FPLFHZHUHLPPXQL]HG,0RQFHDVRXWOLQHGLQ 7DEOH7R
DVVHVVWKHSRWHQF\RIWKH/13IRUPXODWHGPRG51$YDFFLQHFDQGLGDW H%17EZKLFK
HQFRGHV5%'%$/%FPLFHZHUHLP PXQL]HG,0RQFHDVRXWOLQHGLQ 7DEOH(/,6$GDWD
IURPVHUDREWDLQHGDQGGDIWHULPPXQL]DWLRQVKRZDQHDUO \GRVHGHSHQGHQW,J*
UHVSRQVHUHFRJQL]LQJ6DQGWKH5%'
3DJH &21),'(17,$/090177e19744d904\A pproved\A pproved On: 11-Jun-2021 10:28 (GMT )
FDA-CBER-2021-5683-1102940
%LR17HFK51$
3KDUPDFHXWLFDOV*PE+
&RQILGHQWLDO,QYHVWLJDWRU¶V %URFKXUH
&RU9$&%173DJHRI
9HUVLRQ
'DWH$35
)LJXUH $QWL6 ,J* UHVSRQVH DQG G DIWHU LPPXQL]DWLRQ ZLWK %17E
%$/%FPLFHZHUHLPPXQL]HG,0RQFHZLWK RUJRI/13IR UPXODWHGPRG51$YDFFLQHFDQGLGDWHHQFRGLQJWKH
5%'%17E2QDQGGDIWHULPPXQL]DWLRQDQLPDOVZHUHEOHGDQGWKHVHUDZHUHDQDO\]HGIRUDQWL6
OHIWDQGDQWL5%'ULJKWDQWLJHQVSHFLILF,J*E\(/,6$)RUGD \GD\GD\DQGGD\
GDWDIURPGLIIHUHQWVHUXPGLOXWLRQVZHUHLQFOXGHGRQWKH JUDSKV2QHSRLQWRQWKHJUDSKV VWDQGV IRURQH
PRXVH(YHU\VHUXPVDPSOHZDVPHDVXUHGLQGXSOLFDWH*URXSVL]HQ 0HDQ6(0LVGHSLFWHGE\DKRUL]RQWDOOLQH
ZLWKZKLVNHUVIRUHDFKJURXS
$QWLERG\FRQFHQWUDWLRQVLQWKHV HUXPVDPSOHVZHUHFDOFXODWHGIRUWKHLQGLYLGXDOVDPSOLQJ
GD\VDQGWKHNLQHWLFVRI,J*VDJDLQVW6DQG5%'SURWHLQVLVVKRZQLQ )LJXUH
$QWLERG\FRQFHQWUDWLRQVDJDLQVW6 )LJXUH$ DQG5%' )LJXUH% LQFUHDVHGLQD
GRVHGHSHQGHQWPDQQHURYHUWLPH
3DJH &21),'(17,$/090177e19744d904\A pproved\A pproved On: 11-Jun-2021 10:28 (GMT )
FDA-CBER-2021-5683-1102941
%LR17HFK51$
3KDUPDFHXWLFDOV*PE+
&RQILGHQWLDO,QYHVWLJDWRU¶V %URFKXUH
&RU9$&%173DJHRI
9HUVLRQ
'DWH$35
)LJXUH .LQHWLFV RI WKH DQWLERG\ FRQFHQWUDWLRQ DJDLQVW WKH YLU DO DQWLJHQ
)RULQGLYLGXDOǻ2'YDOXHVWKHDQWLERG\FRQFHQWUDWLRQVLQWKHVHUXPVDPSOHVZHUHFDOFXODWHG7KHVHUXPVDPSOHVZHUH
WHVWHGDJDLQVW$WKH6SURWHLQ DQG%5%'*URXSPHDQDQWLE RG\FRQFHQWUDWLRQVDUHVKRZQ6(01RWHWKDWIRUWKH
6DQGWKH5%'PJP/SURWHLQZHUHFRDWHGRQWRDZHOOSODWH %17EHQFRGHVIRUWKHUHFHSWRUELQGLQJGRPDLQ
RQO\$VWKH5%'KDVDVPDOOHUVL]HWKDQWKH6PRUHDQWLERG\ ELQGLQJVLWHVDUHDYDLODEOHZLWKLQPJP/RI5%'
FRPSDUHGWR6ZKLFKFRXOGH[SODLQWKHKLJKHUDQWLERG\FRQFHQWU DWLRQFDOFXODWHGDJDLQVW5%'
6HUDREWDLQHGDQGGDIWHULPPXQL]DWLRQVKRZKLJK6$56&R9 SVHXGRYLUXV
QHXWUDOL]DWLRQHVSHFLDOO\VHUDIURPPLFHLPPXQL]HGZLWKRU J%17E DQG
FRUUHODWLQJZLWKWKHVWURQJLQFUHDVHRI,J*DQWLERG\WLWHUV )LJXUH
3DJH &21),'(17,$/090177e19744d904\A pproved\A pproved On: 11-Jun-2021 10:28 (GMT )
FDA-CBER-2021-5683-1102942
%LR17HFK51$
3KDUPDFHXWLFDOV*PE+
&RQILGHQWLDO,QYHVWLJDWRU¶V %URFKXUH
&RU9$&%173DJHRI
9HUVLRQ
'DWH$35
)LJXUH 1HXWUDOL]DWLRQ RI 6$56 &R9 SVHXGRYLUXV DQG G DIWHU LPPXQL]DWLRQ ZLWK
%17E
%$/%FPLFHZHUHLPPXQL]HG,0RQFHZLWK RUJRI%17E 2QDQGGDIWHULPPXQL]DWLRQ DQLPDOV
ZHUHEOHGDQGWKHVHUDZHUHWHVWHGIRU6$56&R9SVHXGRYLUXVQ HXWUDOL]DWLRQ*UDSKVGHSLFWS91 VHUXPGLOXWLRQV
UHGXFWLRQRILQIHFWLRXVHYHQWVFRPSDUHGWRSRVLWLYHFRQWU ROVZLWKRXWVHUXP2QHSRLQWLQWKH JUDSKVVWDQGVIRURQH
PRXVH(YHU\PRXVHVDPSOHZDVPHDVXUHGLQGXSOLFDWH*URXSVL]H Q 0HDQ 6(0LVVKRZQE\KRUL]RQWDOEDUVZLWK
ZKLVNHUVIRUHDFKJURXS//24ORZHUOLPLWRITXDQWLILFDWLRQ8/2 4XSSHUOLPLWRITXDQWLILFDWLRQ
,PPXQRJHQLFLW\VW XG\ RI %17E 5%3
7RGLVVHFWWKHSRWHQF\RI%17EWKHLPPXQRJHQLFLW\YDFFLQHF DQGLGDWH ZDV
LQYHVWLJDWHG)RUWKLVSXUSRVHDGRVHWLWUDWLRQVWXG\LQ%$/% FPLFHZDVLQLWLDWHG LQZKLFK
WKHLPPXQHUHVSRQVHZLOOEHDQDO\]HGIRFXVLQJRQWKHDQWLERG\L PPXQHUHVSRQVH
7KLVVWXG\LVRQJRLQJ$WWKLVWL PHSRLQW(/,6$GDWDDQG GDIWHUWKHILUVW
LPPXQL]DWLRQDUHDYDLODEOHWKDWVKRZDQHDUO\GRVHGHSHQGHQWL PPXQHDFWLYDWLRQDJDLQVW
WKH6SURWHLQDQGWKHUHFHSWRUELQGLQJGRPDLQ )LJXUH
3DJH &21),'(17,$/090177e19744d904\A pproved\A pproved On: 11-Jun-2021 10:28 (GMT )
FDA-CBER-2021-5683-1102943
%LR17HFK51$
3KDUPDFHXWLFDOV*PE+
&RQILGHQWLDO,QYHVWLJDWRU¶V %URFKXUH
&RU9$&%173DJHRI
9HUVLRQ
'DWH$35
)LJXUH $QWL6 ,J* UHVSRQVH DQG G DIWHU LPPXQL]DWLRQ ZLWK %17E
%$/%FPLFHZHUHLPPXQL]HG,0RQFHZLWKRUJRI/13I RUPXODWHGPRG51$YDFFLQHFDQGLGDWHHQFRGLQJWKH
369%17E2QDQGGDIWHULPPXQL]DWLRQDQLPDOVZHUHEOHGDQGWKHVHUDZHUHDQDO\]HGIRUDQWL6OHIW
DQGDQWL5%'ULJKWDQWLJHQVSHFLILF,J*E\(/,6$)RUGD\ DQGGD\G DWDIURPGLIIHUHQWVHUXP
GLOXWLRQVZHUHLQFOXGHGRQWKHJUDSKV2QHSRLQWRQWKHJUDSKV VWDQGVIRURQHPRXVH(YHU\VHUXPVDPSOHZDV
PHDVXUHGLQGXSOLFDWH*URXSVL]HQ 0HDQ 6(0LVGHSLFWHGE\ DKRUL]RQWDOOLQHZLWKZKLVNHUVIRUHDFKJURXS
,PPXQRJHQLFLW\ VWXG\ RI %17F 5%6
7RGLVVHFWWKHSRWHQF\RI WKHVD51$YDFFLQHFDQGLGDWHHQFRGLQJ WKH369
%17F %$/%FPLFHZHUHLPPXQL]HG,0RQFHDVRXWOLQHGLQ 7DEOH7KHPLFHZLOO
EHEOHGDQGLPPXQRJHQLFLW\RIWKH51$YDFFLQHZLOOEHLQYHVWLJDWHGE\IRFXVLQJRQWKH
DQWLERG\LPPXQHUHVSRQVH7KHVHUDDUHEHLQJWHVWHGIRUDQWLJHQ ELQGLQJDQG6$56&R9
SVHXGRYLUXVQHXWUDOL]DWLRQ 1H[WWRDQ(/,6$DQDO\VLVWKHVH UDDUHEHLQJWHVWHGIRU
DQWLJHQELQGLQJDQG6$56&R9SVHXGRYLUXVQHXWUDOL]DWLRQ7KLV VWXG\LVRQJRLQJ
$WWKLVWLPHSRLQW(/,6$GDWD DQG GDIWHUWKHLPPXQL]DWLRQ DUHDYDLODEOHWKDWVKRZDQ
HDUO\GRVHGHSHQGHQWLPPXQHDFWLYDWLRQDJDLQVWWKH6 SURWHLQD QGWKHUHFHSWRUELQGLQJ
GRPDLQ)LJXUH)XUWKHUPRUHS917HOLFLWVQHX WUDOL]LQJDQWLERGLHVDOUHDG\ GDIWHU
LPPXQL]DWLRQLQDOODQLPDOVLQFOXGLQJDOOVHUXPVDPSOHVIURPPL FHLPPXQL]HGZLWK J
RI %17FRQO\ )LJXUH
3DJH &21),'(17,$/090177e19744d904\A pproved\A pproved On: 11-Jun-2021 10:28 (GMT )
FDA-CBER-2021-5683-1102944
%LR17HFK51$
3KDUPDFHXWLFDOV*PE+
&RQILGHQWLDO,QYHVWLJDWRU¶V %URFKXUH
&RU9$&%173DJHRI
9HUVLRQ
'DWH$35
)LJXUH $QWL6 SURWHLQ ,J* UHVSRQVH DQG G DIWHU LPPXQL ]DWLRQ ZLWK %17F
%$/%FPLFHZHUHLPPXQL]HG,0RQFHZLWKRU JRI/13IR UPXODWHGVD51$YDFFLQHFDQGLGDWHHQFRGLQJWKH3
69%17FDQGGDIWHULPPXQL]DWLRQDQLPDOVZHUH EOHGDQGWKHVHUXPVDPSOHVZHUHDQDO\]HGIRUWRWDO
DPRXQWRIDQWL6OHIWDQGDQWL5%'ULJKWDQWLJHQVSHFLILF LPPXQRJOREXOLQ*,J*PHDVXUHGYLD(/,6$)RUGD\
GD\DQGGD\GLIIHUHQWVHUXPGLOXWL RQVZHUHLQFOXGHGLQWKHJUDSK2QHSRLQWLQWKHJUDSK
VWDQGVIRURQHPRXVHHYHU\PRXVHVDPSOHZDVPHDVXUHGLQGXSOLF DWHVJURXSVL]HQ PHDQ 6(0LVLQFOXGHGIRU
WKHJURXSV
6$56&R9S917GDWDDUHDYDLODE OHIRUGD\VDQGDIWHULPP XQL]DWLRQZKLFK
VKRZHGSRWHQWGRVHGHSHQGHQWSVHXGRYLUXVQHXWUDOL]DWLRQDFWLYLW \RIWKHVHUXPVDPSOHV
)LJXUH
3DJH &21),'(17,$/090177e19744d904\A pproved\A pproved On: 11-Jun-2021 10:28 (GMT )
FDA-CBER-2021-5683-1102945
%LR17HFK51$
3KDUPDFHXWLFDOV*PE+
&RQILGHQWLDO,QYHVWLJDWRU¶V %URFKXUH
&RU9$&%173DJHRI
9HUVLRQ
'DWH$35
)LJXUH 1HXWUDOL]DWLRQ RI 6$56 &R9 SVHXGRYLUXV DQG G D IWHU LPPXQL]DWLRQ ZLWK
%17F
%$/%FPLFHZHUHLPPXQL]HG,0RQFHZLWK RUJRI%1WF 2QDQGGDIWHULPPXQL]DWLRQDQLPDOV
ZHUHEOHGDQGWKHVHUDZHUHWHVWHGIRU6$56&R9SVHXGRYLUXVQH XWUDOL]DWLRQ *UDSKV GHSLFWS91 VHUXPGLOXWLRQV
UHGXFWLRQRILQIHFWLRXVHYHQWVFRPSDUHGWRSRVLWLYHFRQWU ROVZLWKRXWVHUXP2QHSRLQWLQWKH JUDSKVVWDQGVIRURQH
PRXVH(YHU\PRXVHVDPSOHZDVPHDVXUHGLQ GXSOLFDWH*URXSVL]HQ 0HDQ6(0LVVKRZQE\KRUL]RQWDOEDUVZLWK
ZKLVNHUVIRUHDFKJURXS//24ORZHUOLPLWRITXDQWLILFDWLRQ8/24XSSHUOLPLWRITXDQWLILFDWLRQ
,PPXQRJHQLFLW\ RI %17 YDFFLQH FDQGLGDWHV LQ UDWV DI WHU UHSHDWHG
GRVLQJ
,QWKH*/3FRPSOLDQWUHSHDWGRVHWR[LFLW\VWXG\LQUDWVVHFWLR Q6WXG\1R
WKHLPPXQRJHQLFLW\RIWKHDGPLQLVWHUHG51$YDFFLQHV%17D% 17E%17E
DQG%17FZDVLQYHVWLJDWHG6HUXPVDPSOHVZHUHFROOHFWHGIUR PUHSHDWHGO\GRVHG
PDLQVWXG\DQLPDOVDWGD\%17FRUDWGD\DIWHUILUV WLPPXQL]DWLRQ
%17D%17EDQG%17EDQGWKHHOLFLWHGDQWLERG\LPPXQHUHVSRQVH
DQDO\]HGE\6GRPDLQ )LJXUHDQG5%'VXEGRPDLQ )LJXUHVSHFLILF(/,6$DV
ZHOODV6$56&R96SVHXGRYLUXVQHXWUDOL]DWLRQDVVD\ )LJXUH
3DJH &21),'(17,$/090177e19744d904\A pproved\A pproved On: 11-Jun-2021 10:28 (GMT )
FDA-CBER-2021-5683-1102946
%LR17HFK51$
3KDUPDFHXWLFDOV*PE+
&RQILGHQWLDO,QYHVWLJDWRU¶V %URFKXUH
&RU9$&%173DJHRI
9HUVLRQ
'DWH$35
)LJXUH (/,6$ VFUHHQLQJ DQDO\VLV WR GHWHFW DQWLERG\ UHVSRQVH V GLUHFWHG DJDLQVW WKH UHFRPELQDQW
6$56&R9 VSLNH SURWHLQ 6 GRPDLQ
:LVWDU+DQUDWVZHUHLPPXQL]HG,0ZLWKWKUHHZHHNO\LQMHFWLRQV RIRUJ%17DRUJ%17E
J%17ERUWZRZHHNO\LQMHFWLRQVRIJ%17F2QGD\ %17FRUGD\DOORWKHUFRKRUWVDQLPDOV
ZHUHEOHGDQGWKHVHUDZHUHWHVWHGIRUWRWDODPRXQWRIDQWL6 DQWLJHQVSHFLILFLPPXQRJOREXOLQ*,J*PHDVXUHGYLD
(/,6$'LIIHUHQWVHUXPGLOXWLRQVZHUHWHVWHGUDQJLQJIURP WR 2QHSRLQWLQWKHJUDSKVWDQGVIRUWKHǻ2'
JURXSPHDQYDOXHDWDSDUWLFXODUJLYHQVHUXPGLOXWLRQJURXSVL ]HQ
)LJXUH (/,6$ VFUHHQLQJ DQDO\VLV WR GHWHFW DQWLERG\ UHVSRQVH V GLUHFWHG DJDLQVW WKH UHFRPELQDQW
6$56&R9 VSLNH SURWHLQ 5%' GRPDLQ
:LVWDU+DQUDWVZHUHLPPXQL]HG,0ZLWKWKUHHZHHNO\LQMHFWLRQV RIRUJ%17DRU J%17E
J%17ERUWZRZHHNO\LQMHFWLRQVRIJ%17F2QGD\ %17FRUGD\DOORWKHUFRKRUWVDQLPDOV
ZHUHEOHGDQGWKHVHUDZHUHWHVWHG IRUWRWDODPRXQWRIDQWL5%' DQWLJHQVSHFLILFLPPXQRJOREXOLQ*,J*PHDVXUHGYLD
(/,6$'LIIHUHQWVHUXPGLOXWLRQVZHUHWHVWHGUDQJLQJIURP WR2QHSRLQWLQWKHJUDSKVWDQGVIRUWKH ǻ2'
JURXSPHDQYDOXHDWDSDUWLFXODUJLYHQVHUXPGLOXWLRQJURXSVL ]HQ
7U
HDWPHQWRIUDWVZLWKHDFKRIWKH%17YDFFLQHFDQGLGDWHVUH VXOWHG LQWKHIRUPDWLRQRI
DQWLERGLHVRIWKH,J*LVRW\SHDJDLQVWWKH6GRPDLQDVZHOODV WKH5%'VXEGRPDLQRIWKH
6$56&R9VSLNHSURWHLQ )LJXUHDQG)LJXUH 7KHDQDO\VLVVKRZHGDZHDN
DQWLERG\LPPXQHUHVSRQVHIRU%17FWUHDWHG DQLPDOVDWGD\ DPRGHUDWHDQWLERG\9HKLFOH%XIIHU&RQWURO
%17DJ
%17DJ
%17EJ
%17EJ
%17FJ%17EJGD\
GD\
9HKLFOH%XIIHU&RQWURO
%17DJ
%17DJ
%17EJ
%17EJ
%17FJ%17EJGD\
GD\
3DJH &21),'(17,$/090177e19744d904\A pproved\A pproved On: 11-Jun-2021 10:28 (GMT )
FDA-CBER-2021-5683-1102947
%LR17HFK51$
3KDUPDFHXWLFDOV*PE+
&RQILGHQWLDO,QYHVWLJDWRU¶V %URFKXUH
&RU9$&%173DJHRI
9HUVLRQ
'DWH$35
LPPXQHUHVSRQVHIRU%17DWUHDWHGDQLPDOVDWGD\DQGDV WURQJDQWLERG\LPPXQH
UHVSRQVHIRUERWKPRG51$EDVHGYDFFLQHV%17EDQG%17E DWGD\
LUUHVSHFWLYHRIWKHYDFFLQHDQWLJHQXVHG
$QWLERG\FRQFHQWUDWLRQVLQWKHVHUXPVDPSOHVZHUHFDOFXODWHGIRUWKHLQGLYLGXDOVDPSOHV
DQGWKH,J*FRQFHQWUDWLRQDJDLQVW6DQG5%'SURWHLQVLVJLYHQ LQ7DEOH$QWLERG\
FRQFHQWUDWLRQVDJDLQVW6DQG5%'LQFUHDVHGLQDGRVHGHSHQGHQW PDQQHURYHUWLPH RQO\
IRUWKHPRG51$EDVHGYDFFLQH %17E,QUDWVWKHORZHUFRQFH QWUDWLRQRI%17D
LQGXFHGDVOLJKWO\KLJKHU,J*FRQFHQWUDWLRQDJDLQVWWKHWZRDQW LJHQVLQFRPSDULVRQWRWKH
JRI%17D
7DEOH ,J* DQWLERG\ FRQFHQWUD WLRQ DJDLQVW WKH YLUDO DQWLJHQ L Q :LVWDU +DQ UDWV
)RULQGLYLGXDOǻ2'YDOXHVWKHDQWLERG\FRQFHQWUDWLRQVLQWKHVHUXPVDPSOHVZHUHFDOFXODWHG7KHVHUXPVDPSOHVZHUH
WHVWHGDJDLQVWWKH6SURWHLQDQG5%'*URXSPHDQDQWLERG\FRQF HQWUDWLRQVDUHVKRZQ6(0WKDWZHUHJUDSKHGLQ
)LJXUH DQG)LJXUH)RUWKHLQGLYLGXDOWLWHU
,J* WRWDO
>JP/@ GDI
WHU ILUVW LPPXQL]DWLRQ G DIWHU ILUVW
LPPXQL]DWLRQ
%17D
J%17D
J%17E
J%17E
J%17E
J%17F
J
$JDLQVW6
$JDLQVW5%'
6HUDRI
DOOLPPXQL]HGDQLPDOVVKRZ6$56&R9SVHXGRYLUXVQHXWU DOL]DWLRQ WRDYDU\LQJ
H[WHQW)LJXUH,QOLQHZLWK(/,6$GDWDDZ HDNQHXWUDOL]LQJDFWLYLW\LVLQG XFHGE\
%17FWUHDWPHQWDWGD\DPRGHUDWHQHXWUDOL]LQJDFWLYLW\ LVLQGXFHGE\%17D
WUHDWPHQWDWGD\DQGDKLJKYLUDOQHXWUDOL]DWLRQDFWLYLW\L VLQGXFHGE\%17EDQG
%17EWUHDWPHQWDWGD\DIWHUILUVWLPPXQL]DWLRQ
3DJH &21),'(17,$/090177e19744d904\A pproved\A pproved On: 11-Jun-2021 10:28 (GMT )
FDA-CBER-2021-5683-1102948
%LR17HFK51$
3KDUPDFHXWLFDOV*PE+
&RQILGHQWLDO,QYHVWLJDWRU¶V %URFKXUH
&RU9$&%173DJHRI
9HUVLRQ
'DWH$35
)LJXUH $QWLERG\ WLWHU UHVXOW LQJ LQ SVHXGRYLUXV QHXWUDOL]D WLRQ DFWLYLW\ S91
:LVWDU+DQUDWVZHUHLPPXQL]HG,0ZLWKWKUHHZHHNO\LQMHFWLRQVR IRU J%17DRU J%17E
J%17ERUWZRZHHNO\LQMHFWLRQVRI J%17F2QG D\%17FRUGD\DOORWKHUFRKRUWV
DQLPDOVZHUHEOHGDQGWKHVHUD ZHUHWHVWHGIRU6$56&R9SVHXG RYLUXVQHXWUDOL]DWLRQ *UDSKVGHSLFWS91 VHUXP
GLOXWLRQVUHGXFWLRQRILQIHFWLRXVHYHQWVFRPSDUHGWRSRVL WLYHFRQWUROVZLWKRXWVHUXP2QHSRLQWLQWKHJUDSKV
VWDQGVIRURQHUDW(YHU\UDWVDPSOHZDVPHDVXUHGLQGXSOLFDWH *URXSVL]HQ PDOHDQGQ IHPDOHUDWV 0HDQ6(0
LVVKRZQE\KRUL]RQWDOEDUVZLWKZKLVNHUVIRUHDFKJURXS//24 ORZHUOLPLWRITXDQWLILFDWLRQ8/24XSSHUOLPLWRI
TXDQWLILFDWLRQ
6HFRQGDU\ SKDUPDFRG\QDPLFV
1RVHFRQGDU\SKDUPDFRG\QDPLFVVWXGLHVZHUHFRQGXFWHGIRUWKH%17 YDFFLQH
FDQGLGDWHV
6DIHW\ SKDUPDFRORJ\
1RVDIHW\SKDUPDFRORJ\VWXGLHVZHUHFRQGXFWHGDVWKH\DUHQRWFRQVLGHUHGQHFHVVDU\
DFFRUGLQJWRWKH:+2JXLGHOLQH :+27HFKQLFDO5HSRUW6HULHV1R ³$QQH[:+2
JXLGHOLQHVRQQRQFOLQLFDOHYDOXDWLRQRIYDFFLQHV´
1RQFOLQLFDO SKDUPDFRORJ\ &RQFOXVLRQV
$OOQRQFOLQLFDOSKDUPDFRORJ\VWXGLHV DQGWKHLUDQDO\VLVDUHVWLOORQJRLQJ
7KHFXUUHQWO\DYDLODEOHGDWDGHPRQVWUDWHWKDWYDFFLQHVEDVHGRQ DOOWKUHH51$SODWIRUPV
X51$PRG51$DQGVD51$LQFRQMXQ FWLRQZLWKERWKWKH5%'ZLWKD WULPHUL]DWLRQ
GRPDLQ³9´DQGWKHPXWDWHGIXOOOHQJWK6SURWHLQ³9´´9´LQFOX GLQJWKHFOLQLFDO
YDFFLQHFDQGLGDWHV%17D%17E%17EDQG%17F DUHFDSDEOHRI
LQGXFLQJUREXVWLPPXQHUHVSRQVHV LQPLFHDQGUDW
,QPLFHWKHDQWLERG\UHVSRQVHZDVGHWHFWHGDWDYHU\HDUO\WLPH SRLQWE\,J*DQDO\VLVRQ
GSRVWLPPXQL]DWLRQ7KHLQGXFWLRQRIDQDQWLERG\UHVSRQVHE\D YHU\ORZLPPXQL]DWLRQ1$9 G
JPRG51$9 G
J VD51$9 GJPRG51$9 G//248/24%17E %17F %17E
3DJH &21),'(17,$/090177e19744d904\A pproved\A pproved On: 11-Jun-2021 10:28 (GMT )
FDA-CBER-2021-5683-1102949
%LR17HFK51$
3KDUPDFHXWLFDOV*PE+
&RQILGHQWLDO,QYHVWLJDWRU¶V %URFKXUH
&RU9$&%173DJHRI
9HUVLRQ
'DWH$35
GRVHRIJZLWKWKHPRG51$SODWIRUP%17E%17EDQ GWKHVD51$
SODWIRUP%17FLQGLFDWHKLJKYDFFLQHSRWHQF\$OVRLPPXQHUHVSRQVHVE\6$56
&R9SVHXGRYLUXVQHXWUDOL]DWLRQDUHGHWHFWDEOH GSRVWLPPXQL]DWLRQLQWKHPLFHLPPXQL]HGZLWKLQWHUPHGLDWHGRVH V6LPLODUUHVXOWVLQGLFDWLQJL PPXQRJHQLFLW\ZHUH
REWDLQHGLQDQDFFHVVRU\VWXG\WRWKH*/3FRPSOLDQWUHSHDWGRVH WR[LFRORJ\VWXG\LQUDWV
6WXG\1R
$VERWKDQWLJHQYDULDQWV5%'DQGIXOOOHQJWK6 SURWHLQDUHLP PXQRJHQLFLQFOXGLQJWKH
LQGXFWLRQRIYLUXVQHXWUDOL]LQJDQWLERGLHVDQGDOO51$SODWIRU PVKDYHDOUHDG\VKRZQ
LPPXQRJHQLFLW\IRURWKHUYLUDO DQWLJHQVWKHVHSUHOLPLQDU\GDWD VXSSRUWWKHFOLQLFDOWHVWLQJ
RIHDFKRIWKHVHYDFFLQHFDQGLGDWHV
$FRPSDULVRQRIWKHWK UHH51$SODWIRUPVZLWKUHJDUGWRWKHLULP PXQRJHQLFLW\LQPLFH DQG
UDWVPD\QRWEHSUHGLFWLYHIRUWKHLUUHODWLYHLPPXQRJHQLFLW\LQ KXPDQVGXHWRVSHFLHV
VSHFLILFGLIIHUHQFHVLQLQQDWH LP PXQLW\PHFKDQLVPVWKHUHIRUH WKLVGLIIHUHQWLDWLRQZLOO
UHTXLUHFOLQLFDOLQYHVWLJDWLRQLQKXPDQV
1RQFOLQLFDO SKDUPDFRNLQHWLFV DQG PHWDEROLVP
1RSKDUPDFRNLQHWLFVWXGLHVZHUHFRQGXFWHGIRUWKH%17YDFFLQ HFDQGLGDWHVDVWKH\
DUHFRQVLGHUHGQRWQHFHVVDU\DFFRUGLQJWRWKH:+2JXLGHOLQH :+27HFKQLFDO5HSRUW
6HULHV1R ³$QQH[:+2JXLGHOLQHVRQQR QFOLQLFDOHYDOXDWLRQRIYDFFLQH V´
0HWKRGV RI DQDO\VLV
1RWDSSOLFDEOH
$EVRUSWLRQ
7KHDGPLQLVWUDWLRQURXWHIRUWKH%17YDFFLQHVLV LQWUDPXVFXO DUVR QRDEVRUSWLRQ
VWXGLHVZHUHFRQGXFWHG
'LVWULEXWLRQ
1RELRGLVWULEXWLRQVWXGLHVZHUHSHUIRUPHG ZLWKWKH%17YDFFLQHFDQGLGDWHV7KHELRGLVWULEXWLRQRIOXFLIHUDVHDVDVXUURJDWHPDUNHUSURWHLQ IRUWKHDQWLJHQVHQFRGHGLQ
WKH%17YDFFLQHFDQGLGDWHVZDVDVVHVVHGXVLQJDQ51$HQFRGLQ JOXFLIHUDVH
IRUPXODWHGOLNHWKH%17YDFFLQHV%DVHGRQH[WHQVLYHSULRUH[SHULHQFHZLWK 51$WKHUDSHXWLFVZHU RXWLQHO\WHVWQHZGUXJ
FDQGLGDWHVIRUWKHLUDELOLW\WRGHOLYHU51$ LQ YLYRXVLQJOXFLIHUDVHHQFRGLQJ51$DV
UHSRUWHU/XFLIHUDVHH[SUHVVLRQ FDQEHGHWHFWHG LQ YLYRDIWHULQMHFWLRQRIOXFLIHULQE\
PHDVXULQJWKHOXPLQHVFHQFH LQ YLYR8VLQJWKLVPHWKRGRORJ\ZHGHPRQVWUDWHGWKDWWKH
PRG51$DVUHSUHVHQWDWLYHIRUDOOWKUHH51$SODWIRUPVLQGXFHVDKLJKDQGORQJOXFLIHUDVH
H[SUHVVLRQ)LJXUH
3DJH &21),'(17,$/090177e19744d904\A pproved\A pproved On: 11-Jun-2021 10:28 (GMT )
FDA-CBER-2021-5683-1102950
%LR17HFK51$
3KDUPDFHXWLFDOV*PE+
&RQILGHQWLDO,QYHVWLJDWRU¶V %URFKXUH
&RU9$&%173DJHRI
9HUVLRQ
'DWH$35
)LJXUH %LROXPLQHVFHQFH LPDJLQJ %/, PHDVXUHPHQW XVLQJ WKH /13 FDQGLGDWH IRUPXODWHG
PRG51$ HQFRGLQJ OXFLIHUDVH
%$/%FPLFHZHUHLQMHFWHG ,0ZLWKJRI/13IRUPXODWHGPRG51$HQ FRGLQJOXFLIHUDVHLQHDFKKLQGOHJ$WWLPHSRLQWV
DIWHULQMHFWLRQWKHOXFLIHUDVHH[SUHVVLRQ LQ YLYRZDVPHDVXUHGE\OXFLIHULQDSSOLFDWLRQ$IWHUGOXFLIHUDVHH[SUHVVLRQ
GURSSHGWREDFNJURXQGOHYHOV
%DVHGRQRXUSUHYLRXVH[SHULHQFHZHDQWLFLSDWH WKDWWKHELRGLV WULEXWLRQRIWKHDQWLJHQ
HQFRGHGE\WKH51$FRPSRQHQWVRIWKH%17YDFFLQHFDQGLGDWHV ZLOOEHGHSHQGHQWRQ
WKH/13GLVWULEXWLRQ7KHUHIRUHWKHPRG51$UHVXOWVVKRZQEHORZ DUHFRQVLGHUHGWREH
UHSUHVHQWDWLYHIRUDOOWKUHH%1751$SODWIRUPV
([SUHVVLRQRIWKHOXFLIHUDVHUHSRUWHUZDVREVHUYHGDWWKHVLWHRILQMHFWLRQDQGWRDOHVVHU
H[WHQWLQWKHOLYHU'LVWULEXWLRQWRWKHOLYHULVFRQVLGHUHGWR EHPHGLDWHGE\/13VHQWHULQJ
WKHEORRGVWUHDP
0HWDEROLVP DQG H[FUHWLRQ
51$LQFOXGLQJSVHXGRXULGLQHPRGLILHG51$DQGVD51$LVGHJUDGHG E\FHOOXODU51DVHV
DQGVXEMHFWWRQXFOHLFDFLGPHWDEROLVP1XFOHRWLGHPHWDEROLVPR FFXUVFRQWLQXRXVO\ZLWKLQ
WKHFHOOZLWKWKHQXFOHRVLGHEHLQJGHJUDGHGWRZDVWHSURGXFWV DQGH[FUHWHGRUUHF\FOHG
IRUQXFOHRWLGHV\QWKHVLV3URWHLQVHQFRGHGE\WKH51$ LQWKH%17YDFFLQHFDQGLGDWHVDUH SURWHRO\WLFDOO\
GHJUDGHGMXVWOLNHRWKHUHQGRJHQRXVSURWHLQV7KHUHIRUHQR51$ RUSURWHLQPHWDEROLVP
RUH[FUHWLRQVWXGLHVZLOOEHFRQGXFWHG2IWKHIRXUOLSLGVXVHGDVH[FLSLHQWVLQWKH/13IRUPXODWLRQWZRDUHQDWXUDOO\RFFXUULQJ
FKROHVWHURODQG'63&DQG ZLOOWKHUHIRUHEHPHWDEROL]HG DQGH[ FUHWHGOLNHRWKHU
3DJH &21),'(17,$/090177e19744d904\A pproved\A pproved On: 11-Jun-2021 10:28 (GMT )
FDA-CBER-2021-5683-1102951
%LR17HFK51$
3KDUPDFHXWLFDOV*PE+
&RQILGHQWLDO,QYHVWLJDWRU¶V %URFKXUH
&RU9$&%173DJHRI
9HUVLRQ
'DWH$35
HQGRJHQRXVOLSLGV7KHSKDUPDFRNLQHWLFSURILOHRIWKHWZRQRYHOOLSLGV$/&DQG
$/&ZLOOEHFKDUDFWHUL]HGDWDODWHUVWDJHRI QRQFOLQLFD OGHYHORSPHQW
)RUWKHDERYHQRWHGUHDVRQVQRP HWDEROLVPRUH[FUHWLRQVWXGLHV ZHUHFRQGXFWHG
3KDUPDFRNLQHWLF GUXJ LQWHUDFWLRQV
1RSKDUPDFRNLQHWLFGUXJLQWHUDF WLRQVWXGLHVZHUHSHUIRUPHG
1RQFOLQLFDO SKDUPDFRNLQHWLFV DQG PHWDEROLVP &RQFOXVLRQ V
3KDUPDFRNLQHWLFVWXGLHVZHUHFRQGXFWHGXVLQJDOXFLIHUDVHUHSRU WHU51$DQGSURWHLQ
H[SUHVVLRQDIWHU,0LQMHFWLRQZDVGHPRQVWUDWHG LQ YLYR7KHOXFLIHUDVHELRGLVWULEXWLRQ
SURILOHUHVHPEOHVWKDWRIVLPLODU51$SURGXFWVGHYHORSHGE\%LR17HFKVRPHRIZKLFK
KDYHEHHQVDIHO\WHVWHGDWKLJKHUGRVHV QRQFOLQLFDOO\DQGFOLQ LFDOO\XVLQJ,9
DGPLQLVWUDWLRQ$OWKRXJKOLYHUSDU DPHWHUVZLOOEHFDUHIXOO\PRQ LWRUHGGXULQJWKHFOLQLFDO
GHYHORSPHQWRIWKH%17YDFFLQH VSULRUFOLQLFDOH[SHULHQFHZ LWKVLPLODU51$SURGXFWV
GHYHORSHGE\%LR17HFKLQGLFDWHVWKDWWKHGLVWULEXWLRQWRWKHOL YHUGRHVQRWSRVHDVDIHW\
ULVN
7R[LFRORJ\
7RHQDEOHWKHUDSLGGHYHORSPHQW RIDSURSK\ODFWLF YDFFLQHGXULQJDSXEOLFKHDOWK
HPHUJHQF\DVLVWKHFDVHIRUWKHFXUUHQW6$56&R9RXWEUHDN WKH:+2KDVSXEOLVKHG
UHFRPPHQGDWLRQVRQWKHFRQWHQWRIDPLQLPXPQRQFOLQLFDOVDIHW\ SDFNDJHWRVXSSRUW
LQLWLDWLRQRIFOLQLFDOWHVWLQJVHH³ :+27HFKQLFDO5HSRUW6HULHV1R ´³$QQH[
*XLGHOLQHVRQWKHTXDOLW\VDIHW\DQGHIILFDF\RI(ERODYDFFLQH V´:+27HFKQLFDO
5HSRUW6HULHV1R$FFRUGLQJWR:+2UHFRPPHQGDWLRQ LQWHULPGDWDIURPD
*/3UHSHDWGRVHWR[LFLW\VWXG\PD\VXSSRUWFOLQLFDOWHVWLQJRIDYDFFLQHLQDQRXWEUHDNVLWXDWLRQ
)RUWKH%LR17HFK51$SODWIRUPVHQFRGLQJGLIIHUHQWSURWHLQVH[L VWLQJQRQFOLQLFDODQG
FOLQLFDOVDIHW\GDWDVXJJHVWD IDYRUDEOHVDIHW\SURILOH
1RQFOLQLFDO GDWD IURP SULRU WR[LFRORJ\ VWXGLHV,QSULRUVWXGLHVWKHFRPSDQ\KDVJHQHUDWHGQRQFOLQLFDOWR[LFR ORJ\GDWDIRUPXOWLSOH
UHODWHG51$EDVHGWKHUDSHXWLFV9DULRXVQRQFOLQLFDOVWXGLHVWHVWLQJX51$PRG51$DQG
VD51$IRUPDWVZLWKGLIIHUHQWIRUPXODWLRQVKDYHEHHQFRQGXFWHGDQRYHUYLHZLVJLYHQLQ7DEOH,QWKHVHVWXGLHVGLIIHUHQWUR XWHVRIDGPLQLVWUDWLRQLQFOXG LQJ,0,1LQWUDQRGDO
,7LQWUDWXPRUDODQG,9ZHUHXVHG6RIDUGDWDIURPQRQFOLQLFDOWR[LFLW\VWXGLHVVXJJHVWDIDYRUDEOHVDIHW\SURILOHIRU,9DGPLQLVWHUHGX51$DVXVHGIR U%17DDQGPRG51$
DVXVHGIRU%17EDQG%17EDVZHOODV,0LQMHFWHGVD5 1$DVXVHGIRU
%17FIRUPXODWHGZLWKGLIIHUHQWQDQRSDUWLFOHV 2YHUDOOWK HILQGLQJVIRUGLIIHUHQWOLSLG
IRUPXODWHG51$IRUPDWVLQWKHWR[LFLW\VWXGLHVZHUHPLOGDQGP RVWO\UHODWHGWRWKH51$
LQWULQVLFLPPXQRVWLPXODWRU\FDSDFLW\$OOFKDQJHVDWWULEXWHGWR LPPXQHVWLPXODWLRQZHUH
IXOO\UHYHUVLEO\IRUDOO51$IRUPDWV0RVWQRWDEO\ WKHQRQFOL QLFDOVDIHW\SURILOHRIX51$
DVXVHGIRU%17DDQGPRG51$DVXVHGIRU%17EZDVSUHGLFWLYHRIFOLQLFDOVDIHW\ZKHQHQFRGLQJFDQFHU±UHODWHGDQWLJHQVRUF\WRNLQHV
3DJH &21),'(17,$/090177e19744d904\A pproved\A pproved On: 11-Jun-2021 10:28 (GMT )
FDA-CBER-2021-5683-1102952
%LR17HFK51$
3KDUPDFHXWLFDOV*PE+
&RQILGHQWLDO,QYHVWLJDWRU¶V %URFKXUH
&RU9$&%173DJHRI
9HUVLRQ
'DWH$35
7DEOH %LR17HFK QRQFOLQLFDO SODWIRUP H[SHULHQFH
51$ 5HOHYDQW QRQFOLQLFDO VDIHW\ VWXGLHV
X51$ */3WR[LFLW\VWXGLHV LQ PRXVH
xVWXGLHVWHVWLQJX51$IRUPXODWHGLQ5LQJHUVROXWLRQ,1
xVWXGLHVWHVWLQJX51$IRUPXODWHGLQ OLSRVRPHFRQWDLQLQJ OLSR SOH[HV51$/3;,9
1RQ*/36WXG\LQ F\QRPROJXV
xVWXGLHVWHVWLQJX51$IRUPXODWHGLQ OLSRVRPHFRQWDLQLQJ OLSR SOH[HV51$/3;,9
5RXWH,9LQWUDQRGDO
'RVHXSWR JPRXVHXSWRDSSUR[ JNJLQF\QRPROJXVPRQNH\V
2YHUDOO
VDIHW\FRQFOXVLRQ
,9LQMHFWLRQRIPXOWLSOHOLSRVRPHIRUPXODWHGYDFFLQHDQWLJHQVZ DVYHU\ZHOOWROHUDWHGLQPLFHZLWKGRVHVDW
OHDVWIROGRYHUWKHWDUJHWGRVHLQWKHFOLQLFDOWULDOV0RGHUDWHDQG WUDQVLHQWO\PSKRSHQLDFRQVLGHUHGWR
EHWULJJHUHGE\LQ WROOOLNHUHFHSWRU7/5PHGLDWHGF\WRNLQHLQGXFWLRQ±DQLQWHQ GHGSKDUPDFRORJLFDO
HIIHFW0RVWILQGLQJVDUHWKHUH VXOWRIDGDSWLYHFKDQJHVWRWKHLPPXQHV\VWHPZKLFKZHUHUHYHUVLEOHDQG
DUHWKXVFRQVLGHUHGFRQVLVWHQWZLWKWHVWDUWLFOHSKDUPDFRORJ\
PRG51$ */3 WR[LFLW\VWXGLHV LQ PRXVH
xVWXGLHVWHVWLQJPRG51$IRUPXODWHGLQ/13V,9
xVWXGLHVWHVWLQJPRG51$IRUPXODWHGLQ5LQJHUVROXWLRQ,7DQ G,9
1RQ*/3 VDIHW\VWXGLHV LQ F\QRPROJXV
xVWXGLHVWHVWLQJPRG51$IRUPXODWHGLQ/13V,9
5RXWH,9 ,7LQWUDWXPRUDORWKHUURXWHVLQ5 'VWXGLHV
'RVHXSWR JPRXVHXSWRPJNJLQF\QRPROJXVPRQNH\V
2Y
HUDOO VDIHW\ FRQFOXVLRQV
1RWHVWLWHPUHODWHGILQGLQJVZHUHQRWHGIRU5LQJHUVROXWLRQIRUPXODWH GPRG51$DIWHU,9DQG,7
DGPLQLVWUDWLRQ,9DGPLQLVWUDWLRQRIKLJKGRVHVRI/13IRUPXODWHGPRG51$ZDVJHQHUDOO\ZHOO WROHUDWHG
6OLJKWWRPRGHUDWHHIIHFWVRQKHPDWRORJ\FOLQLFDOSDUDPHWHUV OLYHUHQ]\PHVDQGRQO\PSKRLGRUJDQV
VSOHHQOLYHUZHUHQRWHGEXWZHUHDPHOLRUDWHGDIWHUD ZNUHFRYHU\SHULRG
,QVWXGLHVLQF\QRPROJXVPRQNH\VDOPRVWQRWHVW LWHPUHODWHGIL QGLQJVZHUHQRWHGRQVDIHW\SDUDPHWHUV
6OLJKWEXWUHYHUVLEOHHIIHFWVRQKHPDWRORJ\ZHUHGHWHFWHGWKD WZHUHDWWULEXWHGWRWKHPRGHRIDFWLRQRI
WKHHQFRGHGSURWHLQV
VD51$ */3 WR[LFLW\VWXGLHV LQ UDEELW
VW
XG\WHVWLQJS RO\SOH[IRUPXODWHGVD51$
5RXWHLQWUDPXVFXODU
'RVHXSWR JUDEELW
2YHUDOOVDIHW\FRQFOXVLRQV
1RWHVWLWHPUHODWHGILQGLQJVZHUHQRWHGIRUSRO\SOH[IRUPXODWHGVD51$
,1 LQWUDQRGDO,7 LQWUDWXPRUDO,9 LQWUDYHQRXV
3ULRU LPPXQRWR[LFR O
RJ\ H[SHULHQFH
8QPRGLILHGDQGPRGLILHG51$VHQFRGLQJDQWLJHQVRUIXQFWLRQDOSURWHLQVZHUHHYDOXDWHGLQ
DQXPEHURIUHSHDWGRVHWR[LFRORJ\VWXGLHVDIWHULQWUDYHQRXVRU LQWUDWXPRUDO
DGPLQLVWUDWLRQ,PPXQRWR[LFRORJLFDOLQVSHFWLRQVZHUHLPSOHPHQWH GLQWKHVHVWXGLHV
LQFOXGLQJDOOWKUHH51$SODWIRUPV5HOHYDQWSDUDPHWHUVZHUHPHDVXUHGIRUH[DPSOH
3DJH &21),'(17,$/090177e19744d904\A pproved\A pproved On: 11-Jun-2021 10:28 (GMT )
FDA-CBER-2021-5683-1102953
%LR17HFK51$
3KDUPDFHXWLFDOV*PE+
&RQILGHQWLDO,QYHVWLJDWRU¶V %URFKXUH
&RU9$&%173DJHRI
9HUVLRQ
'DWH$35
FOLQLFDOVLJQVV\VWHPLFWROHUDQFHERG\ZHLJKWPDFURVFRSLFDQG KLVWRSDWKRORJLFDO
DVVHVVPHQWRIO\PSKDWLFRUJDQVERQHPDUURZVPHDUVDEVROXWHDQ GUHODWLYHGLIIHUHQWLDO
EORRGFRXQWDOEXPLQLPPXQRJOREXOLQUDWLRDQGFRDJXODWLRQSDUD PHWHUV
7KH51$VZHUHIRUPXODWHGZLWKHLW KHUVDOWEXIIHUVRUOLSRVRPDO IRUPXODWLRQV,QJHQHUDO
FKDQJHVREVHUYHGLQWKHVHVWXGLHVZHUHPLOGDQGPRVWO\UHODWHG WRLQIODPPDWRU\
UHVSRQVHVHJWUDQVLHQWF\WRNLQHLQFUHDVHKHPDWRORJLFDOFKD QJHVDQGHIIHFWVRQ
O\PSKRLGRUJDQV
)LQGLQJVLQWKHVHWR[LFLW\VWXGLHVZHUHPDLQO\UHODWHGWRWKHP RGHRIDFWLRQRI WKHHQFRGHG
SURWHLQRUGHSHQGHQWRQWKHLPPXQHVWLPXODWRU\FDSDFLW\RI51$ LWVHOI'RVHVRIXSWR
JDQLPDOX51$RUJDQLPDOPRG51$ZHUHWHVWHGZLWKRXWD Q\VLJQRI
XQSUHGLFWDEOHRYHUVWLPXODWLRQRIWKHLPPXQHV\VWHPLQPLFH6RIDUFOLQLFDOGDWDVXJJHVWWKDWWKHQRQFOLQLFDOLPPXQRWR[LF LW\SURILOHZDVSUHGLFWLYHIRU
WKHFOLQLFDOVHWWLQJDOWKRXJKWK HURGHQWPRGHOLVOHVVVHQVLWL YHIRUVRPH
LPPXQRWR[LFRORJLFDOSDUDPHWHUVVXFKDVF\WRNLQHV
&RQFOXVLRQV IURP SULRU WR[LFRORJ\ H[SHULHQFH
9DULRXVQRQFOLQLFDOVWXGLHVWHVWLQJX51$PRG51$DQGVD51$FR PSRQHQWV ZLWK
GLIIHUHQWIRUPXODWLRQVKDYHEHHQFRQGXFWHG6RIDUGDWDIURP W KHQRQFOLQLFDOWR[LFLW\
VWXGLHVVXJJHVWDIDYRUDEOHVDIHW\SURILOHRI,9DGPLQLVWHUHGX 51$DQGPRG51$DVZHOO
DVLQWUDPXVFXODUO\LQMHFWHGVD51$IRUPXODWHGZLWKGLIIHUHQWQDQ RSDUWLFOHV
)RUX51$DQGPRG51$HQFRGLQJYDULRXVDQWLJHQVDQGSURWHLQVWKH QRQFOLQLFDOVDIHW\
SURILOHZDVSUHGLFWLYHIRUWKHFOLQLFDOVDIHW\SURILOHVHHQZKH Q%LR17HFKWHVWHGWRWDOGRVHV
RIXSWRJX51$DQGPJPRG51$LQGLIIHUHQWFOLQLFDOWULD OV7KHVHUHVXOWVVXSSRUW
WKHFRQVLVWHQWVDIHW\SURILOHVDFURVVHDFKSODWIRUP7KHKLJKHV WDEVROXWHGRVHVRIX51$
VXFKDVLQ%17DDQGPRG51$VXFKDVLQ%17EWKDWZLOO EHXVHGLQWKH
SODQQHGFOLQLFDOWULDOVZLOOEHDWOHDVWIROGORZHUWKDQWKH KLJKHVWGRVHVRIX51$DQG
PRG51$DGPLQLVWHUHGFOLQLFDOO\VRIDU
%DVHGRQ%LR17HFK¶VQRQFOLQLFDODQGFOLQLFDOH[SHULHQFH ZLWKW KH51$FRPSRQHQWVDQG
JLYHQWKDWWKHVDPH/13IRUPXODWLRQLQWKH%17YDFFLQHFDQGL GDWHVLV DOUHDG\EHLQJ
HYDOXDWHGFOLQLFDOO\ZLWKDQRWKHU51$FRQWDLQLQJLQIHFWLRXVGLV HDVHYDFFLQH FDQGLGDWH
%17YDFFLQHFDQGLGDWHVDUHDQWLFLSDWHGWRKDYHDIDYRUDEOHV DIHW\EHQHILWEDODQFH
5HSHDWGRVH WR[LFRORJ\ WR VXSSRUW WKH FOLQLFDO HYDOXDWLRQ RI %17 YDFFLQH
FDQGLGDWHV
7R[LFRORJ\RI%17YDFFLQHFDQGLGDWHVZDVVWXGLHGLQD */3FR PSOLDQWUHSHDWGRVH
VWXG\
7KHVWXG\GHVLJQLVEDVHGRQJXLGHOLQHUHFRPPHQGDWLRQV³ :+27HFKQLFDO5HSRUW6HULHV
1R´³$QQH[:+2JXLGHOLQHVRQ QRQF OLQLFDOHYDOXDWLRQRIYDFFLQH V´7KH
VWXG\GHVLJQLVVXPPDUL]HGLQ 7DEOH
3DJH &21),'(17,$/090177e19744d904\A pproved\A pproved On: 11-Jun-2021 10:28 (GMT )
FDA-CBER-2021-5683-1102954
%LR17HFK51$
3KDUPDFHXWLFDOV*PE+
&RQILGHQWLDO,QYHVWLJDWRU¶V %URFKXUH
&RU9$&%173DJHRI
9HUVLRQ
'DWH$35
7D
EOH 'HVLJQ RI WKH */3 FRPSOLDQW UHSHDWGRVH WR[LFLW\ VWXG\ 6WXG\ 1R
7HVW ,WHPVx%17DX51$/135%'RIWKH6$56&R96 SURWHLQ
x%17EPRG51$/135%'RIWKH6$56&R96SURWHLQ
x%17EPRG51$/13PXWDWHGIXOOOHQJWK6SURWHLQRIWKH6$5 6&R96 SURWHLQ
³9´YDULDQW´
x%17FVD51$/135%'RI WKH6$56&R9 6SURWHLQ
6SHFLHVDJH :LVWDU+DQUDWZNV
$GPLQLVWUDWLRQV7KUHH%17D%17EDQG%17ERUWZR%17FDGPLQ LVWUDWLRQVRQGD\
DQGLIDSSOLFDEOHIROORZHGE\DZHHNUHFRYHU\SHULRG
5RXWH ,QWUDPXVFXODULQWRWKH 0 ELFHSV IHPRULV
'RVH JURXSV 7HVW ,WHP 'RVH OHYHO
&RQWURO %XIIHU
%17D X51$5%'J
J
%17E PRG51$5%'J
J
%17F VD51$5%' J
%17E PRG51$PXWDWHGIXOOOHQJWK6SURWHLQ J
6DWHOOLWH JURXS 6$ 6$IRUF\WRNLQHUHVSRQVHDQDO\VLV VH[JURXS
*URXS VL]H *URXS UHFRYHU\VH[JURXS
$UHOHYDQW
DQLPDOPRGHOIRUWR[LFLW\DVVHVVPHQWRIYDFFLQHVLV RQHWKDWGHYHORSVDQ
LPPXQHUHVSRQVHVLPLODUWRWKHH[SHFWHGKXPDQUHVSRQVHDIWHUYD FFLQDWLRQZKLOHDOVR
DOORZLQJDGPLQLVWUDWLRQRIW KHDEVROXWHFOLQLFDOGRVH :+27HFKQLFDO5HSRUW6HULHV1R
³$QQH[:+2JXLGHOLQHVRQQRQFOLQLFDOHYDOXDWLRQRIYDFFLQ HV´ 6LQFHWKH
UDWGHYHORSVDQLPPXQHUHVSRQVHVVLPLODUWRWKHH[SHFWHGKXPDQUHVSRQVHDIWHU 51$
YDFFLQDWLRQDQGLVDFRPPRQO\XVHGVSHFLHVLQYDFFLQHWR[LFRORJ \VWXGLHVLWZDVFKRVHQ
DVWKHDQLPDOPRGHOIRUWR[LFLW\DVVHVVPHQWRIWKH%17YDFFL QHV
7KHUHSHDWGRVHVWXG\LQYHVWLJDWHGWRZKDWH[WHQWDQ\REVHUYHG VLGHHIIHFWLVUHODWHGWR
WKH51$SODWIRUPX51$PRG51$DQGVD51$
WKH/13IRUPXODWLRQLQFRPELQDWLRQZLWKWKHUHVSHFWLYHSODWIRU P
WKHYDFFLQHGRVHDQGRU
WKHHQFRGHGDQWLJHQ
([DPSOHVIRUHDFKRIWKHWKUHH51$SODWIRUPVX51$PRG51$DQG VD51$ XVHGLQWKH
%17YDFFLQHFDQGLGDWHVZHUHLQYHVWLJDWHG XWLOL]LQJWKHVDPH /13IRUPXODWLRQDQG
WKHUHIRUHWKHREVHUYHGVDIHW\SURILOHVDUH FRQVLGHUHGUHSUHVHQW DWLYHIRUDOOFDQGLGDWH
YDFFLQHVEDVHGRQWKHVH51$SODWIRUPV
3DJH &21),'(17,$/090177e19744d904\A pproved\A pproved On: 11-Jun-2021 10:28 (GMT )
FDA-CBER-2021-5683-1102955
%LR17HFK51$
3KDUPDFHXWLFDOV*PE+
&RQILGHQWLDO,QYHVWLJDWRU¶V %URFKXUH
&RU9$&%173DJHRI
9HUVLRQ
'DWH$35
'LIIHUHQWYDFFLQHGRVHVFRYHULQJWKHKLJKHVWDQWLFLSDWHGFOLQL FDOGRVHV ZHUHWHVWHGIRUWKH
PRG51$DQGX51$SODWIRUPV)RUP RG51$WKHGRVHVWHVWHGZHUH JDQGJ
)RUX51$WKHGRVHVJDQGJZHUHWHVWHG)RUWKHVD51$ DJGRVHZDV
WHVWHG$OOWKUHH51$SODWIRUPVZHUHHYDOXDWHGIRUDWOHDVWRQH HQFRGHGDQWLJHQ5%'
DQGIRUPRG51$S6 SURWHLQDVZHOO
)RUWKHYDFFLQHFDQGLGDWHVWKDWXVHWKHGD\SULPHERRVWGRVL QJUHJLPHQVWKHGRVLQJ
SULPHERRVWLQWHUYDOZDVGHOLEHUDW HO\VKRUWHQHGWRGWRH[DJJ HUDWHYDFFLQHH[SRVXUH
7KHSULPDU\VWXG\HQGSRLQWLVVDIHW\HYDOXDWLRQRIWKHWKUHHGL IIHUHQW51$SODWIRUPV
X51$PRG51$DQGVD51$HQFDSVXODWHGLQWKHVDPH/13DIWHU,0 DGPLQLVWUDWLRQ$Q
DGGLWLRQDOHQGSRLQWLVWKHVDIHW\HYDOXDWLRQRIWKHLPPXQRJHQV HQFRGHGE\WKHUHVSHFWLYH
YDFFLQHV7KHSDUDPHWHUVDVVHVVHGLQWKHUHSHDWGRVHWR[LFLW\VWXG\DUHV XPPDUL]HGLQ 7DEOH
%DVHGRQSUHYLRXVQRQFOLQLFDODQGFOLQLFDOH[SHULHQFHZLWKWKH GLIIHUHQW51$SODWIRUPVD
WUDQVLHQWSURLQIODPPDWRU\F\WRNLQHUHVSRQVHLVDQWLFLSDWHGGXH WRWKHLPPXQHVWLPXOXV
7KLVPLJKWOHDGWRORFDOUHDFWLRQVVXFKDVVZHOOLQJHGHPDRUU HGQHVVDQGERG\
WHPSHUDWXUHLQFUHDVH7KHUHIRUHVSHFLDODWWHQWLRQZDVSDLGWR WKHGXUDWLRQDQGH[WHQWRI
F\WRNLQHUHOHDVHRIWKHIROORZLQJF\WRNLQHV,)1Ȗ71)Į,/ ȕ,/,/$WWKHHQGRI
LQOLIHDQGDIWHUUHFRYHU\IXOOKLVWRSDWKRORJLFDODQDO\VLVZLO OEHSHUIRUPHGDFFRUGLQJWR
JXLGDQFH (0$*XLGHOLQHRQ5HSHDWHG'RVH7R[LFLW\ :+2*XLGHOLQHVRQ1RQFOLQLFDO
(YDOXDWLRQRI9DFFLQHV
7KHUHSHDWGRVHVWXG\LVVWLOORQJRLQJSUHOLPLQDU\UHVXOWVDUH VXPPDUL]HGLQ 7DEOH
7KHVHUHVXOWVDUHSUHOLPLQDU\DQGPD\EHVXEMHFWWRFKDQJH
7DEOH 3DUDPHWHUV DVVHVVHG LQ WKH UHSHDWGRVH WR[LFLW\ VWXG\
3DUDPHWHU 7LPH RI DVVHVVPHQW 2EVHUYDWLRQ
0RUWDOLW\ $WOHDVWWZLFHGDLO\ 8QWLOGSRVWVWLPPXQL]DWLRQQRPRUWDOLW\ZDVREVHUYHGLQDQ\JURXS
&OLQLFDO VLJQV $WOHDVWWZLFHGDLO\8QWLOGSRVWVWLPPXQL]DWLRQQRV\VWHPLFLQWROHUDQFHZDVREVHUYHG
LQDQ\JU
RXS
%RG\ZHLJKW
DOVR VHH
6HFWLRQ7ZLFHZHHNO\
SULRUDQGRQHGD\
SRVWHDFK
DGPLQLVWUDWLRQ$VOLJKWUHGXFWLRQRIERG\ZHLJKWZDVVHHQ KDIWHUWKHDGPLQLVWUDWLRQV
LQDQLPD
OVRIDOOWUHDWPHQWJURXSVXSWRaFRPSDUHGWRSUH GRVH
YDOXHV1RVXFKUHGXFWLRQZDVQRWHGIRUWKH FRQWUROJURXS%RG\
ZHLJKWJDLQEHWZHHQWKHDGPLQLVWUDWLRQVZDVFRPSDUDEOHWRWKHF RQWURO
JURXS
)RRG FRQVXPSWLRQ
DOVR VHH
6HFWLRQ:HHNO
\$VOLJKWUHGXFWLRQLQIRRGFRQVXPSWLRQZDVVHHQLQDQLPDOV UHFH LYLQJ
J%17DJ%17DJ%17EJ
%17EDQGJ%17F RILQFRPSDULVRQZLWKFRQWUROJ URXS
GXULQJWHVWZHHNZKLFK LPSURYHGGXULQJWKHIROORZLQJWHVWZH HN
3DJH &21),'(17,$/090177e19744d904\A pproved\A pproved On: 11-Jun-2021 10:28 (GMT )
FDA-CBER-2021-5683-1102956
%LR17HFK51$
3KDUPDFHXWLFDOV*PE+
&RQILGHQWLDO,QYHVWLJDWRU¶V %URFKXUH
&RU9$&%173DJHRI
9HUVLRQ
'DWH$35
3DUDPHWHU 7LPH RI DVVHVVPHQW 2EVHUYDWLRQ
/RFDO WROHUDQFH
DOVR VHH
6HFWLRQKDQGKSRVW
HDFKDGPLQLVWUDWLRQ*URXSVKRZHGQRORFDOUHDFWLRQ
$OODQLPDOVRIWKHWUHDWPHQWJURXSVGHYHORSHG PDLQO\VOLJKWWR PRGHUDWH
HGHPDDWWKHLQMHFWLRQVLWH KDIWHUVWGRVH,QPRVWRIWKHDQLPDOV
WKHVHLQMHFWLRQVLWHUHDFWLRQV RQO\RFFXUUHGDIWHUWKHVHFRQGGRVH ZKHUH
PRGHUDWHWRVHYHUHHU\WKHPDZDVVHHQLQPDQ\UDWVLQUHFHLYLQJ J
%17D%17EJ %17EDQGJ%17FDW
KUDIWHUWKHQGGRVH )RUUDWVJLYHQDWKLUGGRVHDOOILQGLQ JV
UHVROYHGSULRUWRWKHWKLUGDGPLQLVWUDWLRQ
%RG\WHPSHUDWXUH
DOVR VHH
6HFWLRQKDQGKSRVW
HDFKDGPLQLVWUDWLRQ
ZHHNO\GXULQJ
UHFRYHU\$VOLJKWLQFUHDVHRIERG\WHPSHUDWXUHZDVQRWHG KSRVWDGPLQ LVWUDWLRQ
FRPSDUHGWR KYDOXHVDSSUR[& LQDOODQLPDOVLQFOXGLQJFRQWUROV
,WZDVPRUHSURQRXQFHGLQWKHWUHDWPHQWJURXSV )RUVLQJOHDQLPDOV
WHPSHUDWXUHUHDFKHG&EXWZDVUHGXFHGDJDLQ KODWHU
&\WRNLQHV3ULRUWRDQGKSRVW
HDFKGRVLQJDQGDW
WKHHQGRILQOLIH/HYHOVRI,)1 Ȗ 71)Į ,/ ȕ,/,/ ZHUHFRPSDUDEOHLQEXIIHUDQG
YDFFLQHDGPLQLVWHUHGDQLPDOV
+HPDWRORJ\
DOVR VHH
6HFWLRQGSRVWILUVW
DGPLQLVWUDWLRQDQGDW
WKHHQGRILQ
OLIHUHFRYHU\0RVWKHPDWRORJLFDOSDUDPHWHUVUHPDLQHGXQFKDQJHG GDIWHUWKH ILUVW
DQGGDIWHUWKHODVWGRVH
$GRVHGHSHQGHQWGHFUHDVH ZDVQRWHGIRUUHWLFXORF\WHV GDIWHUVWGRVH
LQDOOWUHDWPHQWJURXSVZKLFKZDVOHVVSURQRXQFHGDIWHUWKHOD VWGRVH
+HPRJORELQRUHU\WKURF\WHYDOXHV ZHUHXQDIIHFWHG
7KHDEVROXWHQXPEHURISODWHOHWVLVVOLJKWO\UHGXFHGDWWKHHQG RIWKH
PDLQVWXG\
:KLWHEORRGFHOOVQHXWURSKLOVDQGPRQRF\WHVZHUHLQFUHDVHGLQDOO
YDFFLQDWHGJURXSVODUJHXQFODVVLILHGFHOOV LQDOOEXW%17F
YDFFLQDWHGDQLPDOV DWWKHHQGRIWKHLQOLIHSKDVH
&OLQLFDO FKHPLVWU\
LQFO DFXWH SKDVH
SURWHLQV
DOVR VHH
6HFWLRQGSRVW
ILUVW
DGPLQLVWUDWLRQDQGDW
WKHHQGRILQ
OLIHUHFRYHU\&OLQLFDOFKHPLVWU\SDUDPHWHUVZHUHQRWDIIHFWHGH[FHSWIRUDV OLJKW
LQFUHDVHLQȖ JOXWDP\OWUDQVSHSWLGDVHIRUDOOWUHDWPHQWJURXSV G DIWHUVW
GRVH
DQGGDIWHUWKHODVWGRVH
$FXWHSKDVHSURWHLQVDOSKD DFLGJO\FRSURWHLQDOSKDPDFURJOREXOLQDQG
ILEULQRJHQZHUHLQFUHDVHGLQDOOWUHDWPHQWJURXSV GDIWHUWKHVWGRVHRU
DWWKHHQGRILQOLIHUHVSHFWLYHO\
&RDJXODWLRQ$WWKHHQGRILQ
OLIHUHFRYHU\6OLJKWSURORQJDWLRQRIDFWLYDWHGSDUWLDOWKURPERSODVWLQWLPH D 377LQ
DOPRVWDOOYDFFLQHWUHDWHGJURXSV FRQVLGHUHGWREHGHSHQGHQWR QDFXWH
SKDVHUHVSRQVH
2SKWKDOPRORJ\
$XGLWRU\$WWKHHQGRILQ
OLIHUHFRYHU\1RILQGLQJVLQDQ\JURXS
8ULQH FRPSRVLWLRQ$WWKHHQGRILQ
OLIHUHFRYHU\1RFKDQJHVLQS+ZHUHREVHUYHGWKHUHODWLYHXULQHYROXPHZDV
GHFUHDVHGLQDOOYDFFLQDWHGDQLPDOV
2UJDQ ZHLJKW$WWKHHQGRILQ
OLIHUHFRYHU\,QWKHPDMRULW\RIRUJDQVQ RGLIIHUHQFHLQUHODWLYHDQGDEVROXWH ZHLJKW
ZDVREVHUYHG6SOHHQZHLJKWZDVLQFUHDVHGLQIHPDOHVDQGPDOHV RIDOO
YDFFLQDWHGDQLPDOVZKHQFRPSDUHGZLWKEXIIHUWUHDWHGDQLPDOV
0DFURVFRSLF
SDWKRORJ\$WWKHHQG
RILQ
OLIHUHFRYHU\$WKLFNHQHGLQMHFWLRQVLWHZDVWKHPRVWFRPPRQREVHUYDWLRQLQD OO
YDFFLQHWUHDWHGDQLPDOVIRUJ%17DLQIRU J
%17DIRUJ%17EIRUJ%17E
LQJ%17F DQGIRU%17E 6RPHDQLPDOVDOVR
GLVSOD\HGHQODUJHGLOLDFO\PSKQRGHVDQGRUHQODUJHGVSOHHQV
+LVWRSDWKRORJ\$WWKHHQGRILQ
OLIHUHFRYHU\1RW\HWDYDLODEOH
3DJH &21),'(17,$/090177e19744d904\A pproved\A pproved On: 11-Jun-2021 10:28 (GMT )
FDA-CBER-2021-5683-1102957
%LR17HFK51$
3KDUPDFHXWLFDOV*PE+
&RQILGHQWLDO,QYHVWLJDWRU¶V %URFKXUH
&RU9$&%173DJHRI
9HUVLRQ
'DWH$35
3DUDPHWHU 7LPH RI DVVHVVPHQW 2EVHUYDWLRQ
'RVH H[SRVXUH
VHURORJ\
DOVR VHH
6HFWLRQ $WWKHHQGRILQ
OLIHUHFRYHU\7UHDWPHQWZLWKDOO%17YDFFLQHFDQGLGDWHVUHVXOWHGLQWKHIR UPDWLRQ
RIQHXWUDOL]LQJDQWLERGLHVSURWHFWLQJDJDLQVWSVHXGRYLUXVLQIHF WLRQ1R
QHXWUDOL]DWLRQZD VREVHUYHGLQEXIIHUFRQWUROWUHDWHGDQLPDOV
0RUWDOLW\ DQG FOLQLFDO VLJQV
,QWKHUHSHDWGRVHWR[LFLW\VWXG\ QRPRUWDOLW\ZDVREVHUYHGWK URXJKRXWWKHFRXUVHRIWKH
PDLQVWXG\RULQWKHUHFRYHU\SKDVHXQWLOGDWDFXWRIIGDWH$O OVFKHGXOHGDGPLQLVWUDWLRQV
IRUPDLQDQGUHFRYHU\DQLPDOVKDYHEHHQSHUIRUPHG1RFOLQLFDO VLJQVZHUHQRWHGXQWLO
GDWDFXWRIIDIWHUWKHVWLPPXQL]DWLRQLQDQ\JURXS
%RG\ ZHLJKW DQG IRRG FRQVXPSWLRQ
,QWKHUHSHDWGRVHWR[LFLW\VWXG\WKHERG\ZHLJKWZDVGHFUHDVH GKDIWHUWKH
DGPLQLVWUDWLRQVLQDOOWUHDWPHQWJURXSVFRPSDUHGWRSUHGRVHOH YHOVXSWRDSSUR[
1RUHGXFWLRQZDVQRWHGIRUWKHFRQWURO*URXS%RG\ZHLJKWJDL QEHWZHHQWKH
DGPLQLVWUDWLRQVZDVFRPSDUDEOHWRWKHFRQWUROJURXS )LJXUH
$VOLJKWUHGXFWLRQLQIRRGFRQVXPSWLRQZDVVHHQLQDQLPDOVRI * URXSVDQGLQ
FRPSDULVRQZLWKFRQWURO*URXSGXULQJWHVWZHHNZKLFKLPSUR YHGGXULQJWKHIROORZLQJ
WHVWZHHN
)LJXUH 'HYHORSPHQ W RI ERG\ ZHLJKW LQ WKH UHSHDWGRVH WR[LFL W\ VWXG\
:LVWDU+DQUDWVQ PDOHDQGIHPDOHZHUHLQMHFWHG ,0ZLWKEX IIHUFRQWURO>EODFN@RUJDQLPDO%17D
X51$5%'>GDUNJUHHQ@RU JDQLPDO%17EPRG51$5 %'>OLJKWJUHHQ@ JDQLPDO%17E
PRG51$PXW6>OLJKWJUHHQ@RU J%17FVD51$5%'>WXUTXRLVH@ DWWKHLQGLFDWHGWLPHSRLQWV%RG\ZHLJKWZDV
3DJH &21),'(17,$/090177e19744d904\A pproved\A pproved On: 11-Jun-2021 10:28 (GMT )
FDA-CBER-2021-5683-1102958
%LR17HFK51$
3KDUPDFHXWLFDOV*PE+
&RQILGHQWLDO,QYHVWLJDWRU¶V %URFKXUH
&RU9$&%173DJHRI
9HUVLRQ
'DWH$35
PHDVXUHGWZLFHZHHNO\$ULWKPHWLFPHDQ6(0ERG\ZHLJKWREVHUYH GLQWKH*/3WR[LFLW\VWXG\6WXG\1R RI
DOOJURXSVLVGHSLFWHG
+HPDWRORJ\
,QWKHUHSHDWGRVHWR[LFLW\VW XG\PRVWKHPDWRORJLFDOSDUDPHWHUV UHPDLQHGXQFKDQJHG G
DIWHUWKHILUVWGRVHDQGGDIWHUWKHODVWGRVH$GRVHGHSHQGHQWGHFUHDVHZDVQRWHGIRUUHWLFXORF\WHV GDIWHU
VWGRVHLQDOOWUHDWPHQW
JURXSVZKLFKZDVOHVVSURQRXQFHGGDIWHUWKHODVWGRVHIRUDOO JURXSVWUHDWHGZLWK
JDQLPDO )LJXUH7KHUHWLFXORF\WHGHFUHDVHZDVQRWDFFRPSDQLHGE\DUHGXFWLRQ
RIHU\WKURF\WHFRXQWVRUKHPRJORELQFRQWHQW )LJXUH
)LJXUH 5HWLFXORF\WHV DUH GHFUHDVHG E\ %17 DIWHU WKH VWGRVH EXW UHFRYHU E\ HQG RI LQOLIH LQ
WKH UHSHDWHGGRVH WR[LFLW\ VWXG\
:LVWDU+DQUDWVQ PDOHDQGIHPDOHZHUHLQLQMHFWHG,0ZLWKE XIIHUFRQWURO >EODFN@RUJDQLPDO%17D
X51$5%'>GDUNJUHHQ@RUJDQLPDO%17EPRG51$5%' >OLJKWJUHHQ@JDQLPDO%17E
PRG51$PXW6>OLJKWJUHHQ@RUJ%17FVD51$5%'>WXUTXRLVH@DWGD\VDQG+HPDWRORJ\SDUDPHWHUV
ZHUHDVVHVVHGGDIWHUWKHVWGRVHDQG GDIWHUWKHODVWGRVH$ULWKPHWLFPHDQYDOXHVRIDEVRO XWHUHWLFXORF\WHFRXQWV
6(0REVHUYHGLQWKH*/3WR[LFLW\VWXG\6WXG\1R DUHV KRZQ5DQJHRIVWDQGDUGODERUDWRU\YDOXHVLVJLYHQ
DVGDVKHGOLQHV
3DJH &21),'(17,$/090177e19744d904\A pproved\A pproved On: 11-Jun-2021 10:28 (GMT )
FDA-CBER-2021-5683-1102959
%LR17HFK51$
3KDUPDFHXWLFDOV*PE+
&RQILGHQWLDO,QYHVWLJDWRU¶V %URFKXUH
&RU9$&%173DJHRI
9HUVLRQ
'DWH$35
)LJXUH (U\WKURF\WHV DQG KHPR JORELQ FRQWHQW LV QRW LQIOXHQFHG D IWHU %17 WUHDWPHQW LQ WKH
UHSHDWHGGRVH WR[LFLW\ VWXG\
:LVWDU+DQUDWVQ PDOHDQGIHPDOHZHUHLQLQMHFWHG,0ZLWKE XIIHUFRQWURO >EODFN@RUJDQLPDO%17D
X51$5%'>GDUNJUHHQ@RUJDQLPDO%17EPRG51$5%' >OLJKWJUHHQ@JDQLPDO%17E
PRG51$PXW6>OLJKWJUHHQ@RUJ%17FVD51$5%'>WXUTXRLV H@DWGD\VDQG+HPDWRORJ\SDUDPHWHUV
ZHUHDVVHVVHGGDIWHUWKHVWGRVHDQGGDIWHUWKHODVWGRVH5DQJHRIVWDQGDUGODERUDWRU\Y DOXHVLVJLYHQDVGDVKHG
OLQHV$ULWKPHWLFPHDQYDOXHVRIDEVROXWHUHWLFXORF\WHFRXQWV 6(0DUHVKRZQ*/3WR[LFLW\VWXG\6WXG\1R
:KLWHEORRGFHOOVQHXWURSKLOV DQGPRQRF\WHVZHUHLQFUHDVHG LQ QXPEHULQDOOYDFFLQDWHG
JURXSVDQGWKHQXPEHURIODUJHXQFODVVLILHGFHOOV ZDVHOHYDWHGL QDOOEXWEXIIHUDQG
%17FWUHDWHGDQLPDOV )LJXUH
3DJH &21),'(17,$/090177e19744d904\A pproved\A pproved On: 11-Jun-2021 10:28 (GMT )
FDA-CBER-2021-5683-1102960
%LR17HFK51$
3KDUPDFHXWLFDOV*PE+
&RQILGHQWLDO,QYHVWLJDWRU¶V %URFKXUH
&RU9$&%173DJHRI
9HUVLRQ
'DWH$35
)LJXUH 1XPEHUV RI OHXNRF\WHV D QG ODUJH XQFODVVLILHG FHOOV DUH LQFUHDVHG DW WKH HQG RI LQOLIH
:LVWDU+DQUDWVQ PDOHDQGIHPDOHZHUHLQLQMHFWHG,0ZLWK EXIIHUFRQWURO>EODFN@RU JDQLPDO%17D
X51$5%'>GDUNJUHHQ@RU JDQLPDO%17EPRG51$5% '>OLJKWJUHHQ@ JDQLPDO%17E
PRG51$PXW6>OLJKWJUHHQ@RU J%17FVD51$5%'>WXUTXRLVH@DWGD\VDQG+HPDWRORJ\SDUDPHWHUV
ZHUHDVVHVVHGGDIWHUWKHVWGRVHDQGGDIWHUWKHODVWGRVH$ULWKPHWLFPHDQYDOXHVRIDEVRO XWHUHWLFXORF\WHFRXQWV
6(0DUHVKRZQ*/3WR[LFLW\VWXG\6WXG\1R
/DVWO\DWWKHHQGRILQOLIHGSRVWODVWLPPXQL]DWLRQDVOLJKWGHFUHDVHLQSODWHOHWFRXQWV
ZDVREVHUYHG )LJXUH
)LJXUH 1XPEHUV RI SODWHOHWV DUH VOLJKWO\ GHFUHDVHG DW WKH HQG RI LQOLIH
:LVWDU+DQUDWVQ PDOHDQGIHPDOHZHUHLQLQMHFWHG,0ZLWK EXIIHUFRQWURO>EODFN@RU JDQLPDO%17D
X51$5%'>GDUNJUHHQ@RU JDQLPDO%17EPRG51$5% '>OLJKWJUHHQ@ JDQLPDO%17E
PRG51$PXW6>OLJKWJUHHQ@RUJ%17FVD51$5%'>WXUTX RLVH@DWGD\VDQG+HPDWRORJ\SDUDPHWHUV
ZHUHDVVHVVHGGDIWHUWKHVWGRVHDQGGDIWHUWKHODVWGRVH$ULWKPHWLFPHDQYDOXHVRIDEVR OXWHUHWLFXORF\WHFRXQWV
6(0DUHVKRZQ*/3WR[LFLW\VWXG\6WXG\1R
3DJH &21),'(17,$/090177e19744d904\A pproved\A pproved On: 11-Jun-2021 10:28 (GMT )
FDA-CBER-2021-5683-1102961
%LR17HFK51$
3KDUPDFHXWLFDOV*PE+
&RQILGHQWLDO,QYHVWLJDWRU¶V %URFKXUH
&RU9$&%173DJHRI
9HUVLRQ
'DWH$35
&OLQLFDO FKHPLVWU\ DQG DFXWH SKDVH SURWHLQV
,QWKHUHSHDWGRVHWR[LFLW\VWXG\ DOPRVWDOOFOLQLFDOFKHPLVWU\ SDUDPHWHUVZHUH XQFKDQJHG
2QO\DVOLJKWPRVWSUREDEO\GRVHGHSHQGHQWLQFUHDVHLQȖJOXWD P\OWUDQVSHSWLGDVH**7
ZDVQRWHGIRUDOOWUHDWPHQWJURXSVGDIWHUVWGRVHDQGGDIWHUWKHODVWGRVH )LJXUH
2IQRWHWKLVILQGLQJZDVQRWDFFRPSDQLHGE\WKHHOHYDWLRQRIRWKHUOLYHUSDUDPHWHUVDV
DODQLQHDPLQRWUDQVIHUDVH$/$7DQGDVSDUWDWHDPLQRWUDQVIHUDVH$6$7 )LJXUH
)LJXUH 6OLJKW HOHYDWLRQ RI **7 LQ WKH UHSHDWHGGRVH WR[LFLW\ VWXG\
:LVWDU+DQUDWVQ PDOHDQGIHPDOHZHUHLQLQMHFWHG,0ZLWK EXIIHUFRQWURO>EODFN@ RUJDQLPDO%17D
X51$5%'>GDUNJUHHQ@RU JDQLPDO%17EPRG51$5% '>OLJKWJUHHQ@ JDQLPDO%17E
PRG51$PXW6>OLJKWJUHHQ@RU J%17FVD51$5%'>WXUTXRLVH@DWGD\VDQG&OLQLFDOFKHPLVWU\
SDUDPHWHUVZHUHDVVHVVHGGDIWHUWKHVWGRVHDQGGDIWHUWKHODVWGRVH$ULWKPHWLFPHDQYDOXHVRI **7 YDOXHV
6(0REVHUYHGLQWKH*/3WR[LFLW\VWXG\6WXG\1RDUH VKRZQLQ8/
3DJH &21),'(17,$/090177e19744d904\A pproved\A pproved On: 11-Jun-2021 10:28 (GMT )
FDA-CBER-2021-5683-1102962
%LR17HFK51$
3KDUPDFHXWLFDOV* PE+
&RQILGHQWLDO,QYHVWLJDWRU¶V %URFKXUH
&RU9$&%173DJHRI
9HUVLRQ
'DWH$35
)LJXUH 1R HOHYDWLRQ RI OLYHUVSHFLILF HQ]\PHV $/$7 DQG $6$7 LQ WKHU HSHDWHGGRVH WR[LFLW\
VWXG\
:LVWDU+DQUDWVQ PDOHDQGIHPDOHZHUHLQLQMHFWHG,0ZLWK EXIIHUFRQWURO >EODFN@RUJDQLPDO%17D
X51$5%'>GDUNJUHHQ@RUJDQLPDO%17EPRG51$5 %'>OLJKWJUHHQ@JDQLPDO%17E
PRG51$PXW6>OLJKWJUHHQ@RUJ%17FVD51$5%'>WXUT XRLVH@DWGD\VDQG&OLQLFDOFKHPLVWU\
SDUDPHWHUVZHUHDVVHVVHGGDIWHUWKHVWGRVHDQGGDIWHUWKHODVWGRVH$ULWKPHWLFPHDQYDOXHVRIDE VROX WH $/$7
DQG$6$7YDOXHV6(0REVHUYHGLQWKH*/3WR[LFLW\VWXG\6WXG \1R DUHVKRZQLQ8/
$FXWHSK
DVHSURWHLQVDOSKDDFLGJO\FRSURWHLQDOSKDPDFURJORE XOLQDQGILEULQRJHQZHUH
PHDVXUHGWRDVVHVVYDFFLQHLQGXFHGLQIODPPDWRU\UHDFWLRQV7KH PDUNHUVZHUHLQFUHDVHG
LQWKHWUHDWPHQWJURXSV GDIWHUWKHVWGRVHRUDWWKHHQGRIWKHLQOLIHSKDVHUHVSHFWLYHO\
)LJX
UH
3DJH &21),'(17,$/090177e19744d904\A pproved\A pproved On: 11-Jun-2021 10:28 (GMT )
FDA-CBER-2021-5683-1102963
%LR17HFK51$
3KDUPDFHXWLFDOV*PE+
&RQILGHQWLDO,QYHVWLJDWRU¶V %URFKXUH
&RU9$&%173DJHRI
9HUVLRQ
'DWH$35
)LJXUH $FXWH SKDVH SURWHLQV D QG ILEULQRJHQ DUH LQFUHDVHG IRU WUHDWPHQW JURXSV LQ WKH UHSHDWHG
GRVH WR[LFLW\ VWXG\
:LVWDU+DQUDWVQ PDOHDQGIHPDOHZHUHLQLQMHFWHG,0ZLWKE XIIHUFRQWURO >EODFN@RUJDQLPDO%17D
X51$5%'>GDUNJUHHQ@RUJDQLPDO%17EPRG51$5%' >OLJKWJUHHQ@JDQLPDO%17E
PRG51$PXW6>OLJKWJUHHQ@RUJ%17FVD51$5%'>WXUTXRLV H@DWGD\VDQG$%$FXWHSKDVH
SURWHLQVDOSKDDFLGJO\FRSURWHLQDQGDOSKDPDFURJOREXOLQZHUH DVVHVVHGGDIWHUWKHVWGRVHQ PDOHVDQG
IHPDOHV&)EULQRJHQZDVPHDVXUHG LQWKH*/3WR[LFLW\VWXG\6 WXG\1RDWQHFURSV\GDIWHUWKHODVWGRVH
Q PDOHVDQGIHPDOHV$ULWKPHWLFPHDQYDOXHVRI WKHSURWHLQ V6(0DUHVKRZQLQJP/
&RDJXODWLRQ
&RDJXODWLRQSDUDPHWHUVSURWKURPELQWLPH37D377DQGILEULQRJ HQZHUHPHDVXUHGDW
WKHHQGRILQOLIHSKDVH)LEULQRJHQZDVHOHYDWHGLQDOOYDFFLQ HWUHDWHGJURXSVDURXQG
IROGFRPSDUHGWRFRQWURO )LJXUH7KLVLQGXFWLRQLVPRVWSUREDEO\GXHWRWKHYDFFLQH
LQGXFHGLQIODPPDWRU\UHDFWLRQD377ZDVVOLJKWO\HOHYDWHGLQ*URXSVDQGFRPSDUHGW RWKHFRQWUROJURXS7KH
VOLJKWLQFUHDVHLVFRQVLGHUHGWREHVHFRQGDU\WRWKHDFXWHSKDVHUHVSRQVH
2SKWKDOPRORJLFDO DQG DXGLWRU\ DVVHVVPHQWV
([DPLQDWLRQVRIWKHH\HDUHSHUIR UPHGRQDOODQLPDOVEHIRUHILU VWGRVLQJDQGDWWKHHQGRI
WKHPDLQVWXG\DQGIRUDOOUHFRY HU\DQLPDOVDW WKHHQGRIWKH UHFRYHU\SHULRG
7KHSXSLOODU\UHIOH[DGQH[DRFXOLLHOLGVODFULPDODSSDUDWXVFRQMXQFWLYDFRUQHD
DQWHULRUFKDPEHUOHQVYLWUHRXVERG\IXQGXVUHWLQDRSWLFGL VFDUHH[DPLQHGDQGVFRUHG
,QDGGLWLRQDXGLWRU\DFXLW\LV FKHFNHGZLWKDVLPSOHQRLVHWHVW
3DJH &21),'(17,$/090177e19744d904\A pproved\A pproved On: 11-Jun-2021 10:28 (GMT )
FDA-CBER-2021-5683-1102964
%LR17HFK51$
3KDUPDFHXWLFDOV*PE+
&RQILGHQWLDO,QYHVWLJDWRU¶V %URFKXUH
&RU9$&%173DJHRI
9HUVLRQ
'DWH$35
3ULRUWRDQGDWWKHHQGRIGRVLQJSHULRGRSKWKDOPRORJLFDODQGDXGLWRU\DVVHVVPHQWV
UHVXOWHGLQGHWHFWLRQRIQRFKDQJHV
8ULQH FRPSRVLWLRQ
$WWKHHQGRILQOLIHXULQHZDVFROOHFWHGRYHUDSHULRGRI KIURPPDLQVWXG\DQLPDOV1R
FKDQJHVLQS+ZHUHREVHUYHGEXWW KHUHODWLYHXULQHYROXPHZDV GHFUHDVHGDQGVSHFLILF
JUDYLW\VOLJKWO\LQFUHDVHGLQDOOYDFFLQDWHGDQLPDOV
0DFURVFRSLF SDWKRORJ\
0DLQVWXG\ DQL
PDOVZHUHGLVVHFWHGIROORZLQJDUDQGRPL]DWLRQVFK HPH GDIWHUWKHODVW
DGPLQLVWUDWLRQ
7KHPRVWFRPPRQREVHUYDWLRQ LQDOOWUHDWPHQWJURXSVZDVDWKLFN HQHGLQMHFWLRQVLWH
DQGRULQGXUDWLRQDWWKHLQMHFWHGPXVFOHVHH 7DEOHIRUDOOILQGLQJV7KLVILQGLQJLVWHVW
LWHPUHODWHGDQGLVFDXVHGE\WKH ORFDOLQIODPPDWLRQSURFHVV)XUWKHUPRUHHQODUJHG
VSOHHQDQGLOLDFO\PSKQRGHVZHUHQRWHGLQDQXPEHURIDQLPDOV LQWKHWHVWLWHPWUHDWHG
JURXSV7KHHIIHFWVRQWKHO\PSKRLGRUJDQV DUHPRVWSUREDEO\HI IHFWVRI WKHLQGXFWLRQRI
DQLQIODPPDWRU\UHVSRQVHE\WKHYDFFLQH
6LQJOHIHPDOHDQLPDOVIURP*URXSVDQGZHUHUHSRUWHGW RKDYHDGLODWHGXWHUXV
ILOOHGZLWKFOHDUOLTXLG7KLVFKDQJHLVFRQVLGHUHGWREHDQRUPDOYDULDWLRQDVVRFLDWHGZLWK
UHSURGXFWLYHF\FOLQJ$OORWKHUILQGLQJVDUHFRQVLGHUHGUDQGRP DVWKH\RQO\DSSHDUHGLIDW
DOOLQVLQJOHDQLPDOV
6SHFLDODWWHQWLRQZLOOEHSD\HGWRWKHKLVWRSDWKRORJ\GDWD RIW KHPHQWLRQHGRUJDQVWKDWLV
QRW\HWDYDLODEOHWRLQWHUSUHWWKHILQGLQJVIXUWKHU
7DEOH 6XPPDU\ RI PDFURVF RSLF ILQGLQJV ± PDLQ VWXG\
*URXS )LQGLQJV LQ PDOH DQG IHPDOH DQLPDOV
x(PSK\VHPDWRXVOXQJDQLPDOV
x5HGGHQHGWK\PXVDQLPDOV
x7KLFNHQHGKDUGHQHGLQMHFWLRQVLWHDQGRUPXVFOHDQLPD OV
x(QODUJHGVSOHHQDQLPDOV
x(QODUJHGLOLDFO\PSKQRGHVDQLPDOV
x'LODWHGXWHUXVDQLPDOV
x(QODUJHGDGUHQDOJODQGDQLPDOV
x3URVWDWHUHGXFHGLQVL]HDQLPDOV
x6HPLQDOYHVLFOHUHGXFHGLQVL]HDQLPDOV
x7KLFNHQHGKDUGHQHGLQMHFWLRQVLWHDQGRUPXVFOHDQLPD OV
x(QODUJHGVSOHHQDQLPDOV
x(QODUJHGLOLDFO\PSKQRGHVDQLPDOV
x'LODWHGXWHUXVDQLPDOV
x(QODUJHGDGUHQDOJODQGDQLPDOV
3DJH &21),'(17,$/090177e19744d904\A pproved\A pproved On: 11-Jun-2021 10:28 (GMT )
FDA-CBER-2021-5683-1102965
%LR17HFK51$
3KDUPDFHXWLFDOV*PE+
&RQILGHQWLDO,QYHVWLJDWRU¶V %URFKXUH
&RU9$&%173DJHRI
9HUVLRQ
'DWH$35
x7KLFNHQHGKDUGHQHGLQMHFWLRQVLWHDQGRUPXVFOH DQLPD OV
x(QODUJHGVSOHHQDQLPDOV
x(QODUJHGLOLDFO\PSK QRGHVDQLPDOV
x'LODWHGXWHUXVDQLPDOV
x7KLFNHQHGKDUGHQHGLQMHFWLRQVLWHDQGRUPXVFOH DQLPD OV
x(QODUJHGVSOHHQDQLPDOV
x(QODUJHGLOLDFO\PSKQRGHVDQLPDOV
x(QODUJHGDGUHQDOJODQGDQLPDOV
x7KLFNHQHGKDUGHQHGLQMHFWLRQVLWHDQGRUPXVFOH DQLPD OV
x(QODUJHGVSOHHQDQLPDOV
x(QODUJHGLOLDFO\PSKQRGHVDQLPDOV
x7KLFNHQHGKDUGHQHGLQMHFWLRQVLWHDQGRUPXVFOH DQLPDOV
x(QODUJHGVSOHHQDQLPDOV
x(QODUJHGLOLDFO\PSKQRGHVDQLPDOV
x'LODWHGXWHUXVDQLPDOV
2UJDQ ZHLJKW
,QWKHPDMRULW\RIZHLJKHGRUJDQVQRGLIIHUHQFHLQUHODWLYHDQG DEVROXWH RUJDQZHLJKW
EHWZHHQYDFFLQDWHGDQGEXIIHUWUHD WHGDQLPDOVZHUHREVHUYHG&R QJUXHQWZLWKWKH
PDFURVFRSLFREVHUYDWLRQV6HFWL RQWKHDYHUDJHVSOHHQ ZHLJKWZDVLQFUHDVHGLQ
PDOHDQGIHPDOHDQLPDOVYDFFLQDWHGZLWKWKH%17YDFFLQHFDQG LGDWHV
*HQRWR[LFLW\
7KHFRPSRQHQWVRIDOO%17YDFFLQHH[FLSLHQWVOLSLGVDQG51$ DUHQRWVXVSHFWHGWR
KDYHJHQRWR[LFSRWHQWLDO1RLP SXULW\RUFRPSRQHQWRIWKHGHOLY HU\V\VWHPZDUUDQWV
JHQRWR[LFLW\WHVWLQJ,QDFFRUGDQFHZLWKWKH:+2JXLGHOLQH :+27HFKQLFDO5HSRUW
6HULHV1R ³$QQH[:+2JXLGHOLQHVRQQR QFOLQLFDOHYDOXDWLRQRIYDFFLQH V´
QRJHQRWR[LFLW\VWXGLHVZHUHSHUIRUPHG
&DUFLQRJHQLFLW\
51$LWVHOIDQGWKHOLSLGVXVHGLQWKH%17YDFFLQHVKDYHQR FDUFLQRJHQLFRU
WXPRULJHQLFSRWHQWLDO)XUWKHUPRUHDFFRUGLQJWR,&+6$,&+6$*XLGHOLQH³*XLGHOLQH
RQWKH1HHGIRU&DUFLQRJHQLFLW\6WXGLHVRI3KDUPDFHXWLFDOV´1R YHPEHUQR
FDUFLQRJHQLFLW\VWXGLHVDUHUHTXLUHGIRUWKHUDSHXWLFVWKDWDUH QRWFRQWLQXRXVO\
DGPLQLVWHUHG
5HSURGXFWLYH DQG GHYHORSPHQWDO WR[LFLW\
0DFURVFRSLFDQGPLFURVFRSLFHYDOXDWLRQRIPDOHDQGIHPDOHUHSUR GXFWLYHWLVVXHVZHUH
LQFOXGHGLQDOOSUHYLRXV*/3WR[LFLW\VWXGLHVRIDOOWKUHH51$SODWIRUPV DQGDUHLQFOXGHGLQ
WKHRQJRLQJ*/3UHSHDWGRVHWR[LFLW\VWXG\WHVWLQJ%17D%1 7E%17E
DQG%17F6HFWLRQ 3UHYLRXV*/3WR[LFLW\VWXGLHVVKRZHGQRFKDQJHVLQ
UHSURGXFWLYHRUJDQV6LQFHHIIHFWVRQUHSURGXFWLRQFDQQRWEHH[ FOXGHGDWWKLVVWDJH
ZRPHQRIFKLOGEHDULQJSRWHQWLDODQGPHQRIUHSURGXFWLYHSRWHQWL DO DUHUHTXLUHGWRXVH
3DJH &21),'(17,$/090177e19744d904\A pproved\A pproved On: 11-Jun-2021 10:28 (GMT )
FDA-CBER-2021-5683-1102966
%LR17HFK51$
3KDUPDFHXWLFDOV*PE+
&RQILGHQWLDO,QYHVWLJDWRU¶V %URFKXUH
&RU9$&%173DJHRI
9HUVLRQ
'DWH$35
HIIHFWLYHFRQWUDFHSWLRQGXULQJ WKHSODQQHGFOLQLFDOWULDOV
…[truncated]