A Phase I, Open-label, Fixed-sequence, Drug Interaction Study to Investigate the Effect of Multiple Oral Doses of LOXO-305 on CYP1A2, CYP2C9, and CYP2C19 Substrates Using a Probe Drug Cocktail in Healthy Subjects
Phase: PHASE1
Conditions: Healthy
Sponsor: Eli Lilly and Company

Protocol LOXO-BTK-20010 
A Phase I, Open-label, Fixed-sequence, Drug Interaction Study to Investigate the Effect 
of Multiple Oral Doses of LOXO-305 on CYP1A2, CYP2C9, and CYP2C19 Substrates 
Using a Probe Drug Cocktail in Healthy Subjects
NCT06215430 
Approval date: 10-Dec-2020 

TI T L E P A G E  
Pr ot oc ol  
A P h ase I, O pe n -l a bel, Fi xe d-se q ue nce, Dr u g I nter acti o n St u d y t o 
I n vesti g ate t he Effect of M ulti ple Or al D oses of L O X O-3 0 5 o n C Y P 1 A 2, 
C Y P 2 C 9, a n d C Y P 2 C 1 9 S u bstr ates usi n g a Pr o be Dr u g C oc kt ail i n 
He alt h y S u bjects  
Pr ot oc ol Stat us: Fi nal  
Pr ot oc ol Date: 9 Dece m b er 2 0 2 0 
Pr ot oc ol Versi o n: 1. 0 
I n v esti gati o nal Me dici nal Pr o d uct: L O X O- 3 0 5 
Pr ot oc ol Refere n ce N u m ber: L O X O -B T K - 2 0 0 1 0 
C o va nce St u d y N u m ber: 8 4 1 9 6 8 9 
I N D N u m ber: 1 3 9 8 7 6 
S p o ns or: 
L o x o O nc ol o g y, I nc. 
A w h oll y o w ne d s u bsi diar y of Eli Lill y a n d 
C o m pa n y 
7 0 1 Gate wa y B o ule v ar d, S uite 4 2 0 
S o ut h Sa n Fra ncisc o, Calif or nia 9 4 0 8 0 
U S A  
C o or di nati n g I n vesti gat or St u d y Site: 
C o va nce Cli nical Researc h U nit I nc.  
1 3 4 1 West M oc ki n g bir d La ne, S uite 2 0 0 E 
Dallas, Te xas 7 5 2 4 7 
U S A  
U p t o 2 a d diti o nal sites i n t he U nite d States 
ma y be utilize d.  
S p o ns or Si g nat or y: 
 
C o or di nati n g I n vesti gat or: 
 
I nf or mati o n descri be d herei n is c o nfi de ntial a n d m a y be discl ose d o nl y wit h t he e x press 
writte n  per missi o n of t he S p o ns or. 
P P D
P P D

Pr ot oc ol 
C O N FI D E N TI A L  
C o va nce St u d y: 8 4 1 9 6 8 9 
Pr ot oc ol Refere n ce:  L O X O -B T K - 2 0 0 1 0 
Pr ot oc ol Versi o n 1. 0, 9 Dece m b er 2 0 2 0  
Pa ge 2 of 6 8 
S P O N S O R A P P R O V A L  
I h a ve r ea d t he pr ot oc ol a n d a p pr o ve it: 
 
 
 
 
Date  
1 0 - D e c - 2 0  |  0 7 : 2 0 : 2 6  P S T
P P D

Pr ot o c ol 
C o v a n c e St u d y: 8 4 1 9 6 8 9 
C O N FI D E N TI A L 
Pr ot o c ol Refere nce: L O X O- B T K- 2 0 0 1 0 
I N V E S TI G A T O R A G R E E M E N T 
I h a v e r e a d t h e pr ot o c ol a n d a gree t o c o n d u ct t he st u d y as descri be d herei n. 
Pr ot o c ol V ersi o n 1. 0, 9 D e c e m b er 2 0 2 0 
D at e 
P a g e 3 of 6 8 
P P D

Pr ot oc ol 
C O N FI D E N TI A L  
C o va nce St u d y: 8 4 1 9 6 8 9 
Pr ot oc ol Refere n ce:  L O X O -B T K - 2 0 0 1 0 
Pr ot oc ol Versi o n 1. 0, 9 Dece m b er 2 0 2 0  
Pa ge 4 of 6 8 
S T U D Y I D E N TI FI C A TI O N  
S p o ns or 
L o x o O nc ol o g y, I nc. 
A w h oll y o w ne d s u bsi diar y of Eli Lill y a n d C o m pa n y 
7 0 1 Gate wa y B o ule v ar d, S uite 4 2 0 
S o ut h Sa n Fra ncisc o, Calif or nia 9 4 0 8 0 
U S A  
Tel ( mai n): 
 
S p o ns or’s St u d y C o ntact 
 
Direct or, Cli nical O perati o ns  
L o x o O nc ol o g y, I nc. 
Tel ( m o bile): 
 
Tel (alter n ati ve c o ntact): 
 
E mail:
 
S p o ns or’s Me dical C o ntact 
 
C o ns ulti n g t o L o x o O nc ol o g y, I nc. 
Tel ( m o bile): 
 
E mail: 
 
Seri o us A d verse E v e nt Re p orti n g 
E mail: S A EI nta ke @c o va nce.c o m  
St u d y Site(s) 
C o or di n ati n g I n vesti g at or St u d y Site  
C o va nce Cli nical Researc h U nit I nc.  
1 3 4 1 West M oc ki n g bir d La ne, S uite 2 0 0 E 
Dallas, Te xas 7 5 2 4 7 
U S A  
U p t o 2 a d diti o nal sites i n t he U nite d States ma y be 
utilize d.  
C o or di nati n g I n vesti gat or 
 
C o va nce Cli nical Researc h U nit I nc.  
1 3 4 1 West M oc ki n g bir d La ne, S uite 2 0 0 E 
Dallas, Te xas 7 5 2 4 7 
U S A  
Tel:  
 
Tel (cell): 
 
S u b-i n vesti gat or(s) 
O btai n i nf or mati o n fr o m F or m F D A 1 5 7 2s 
Cli nical La b orat or y(s) 
C o va nce Cli nical Researc h U nit I nc.  
1 3 4 1 West M oc ki n g bir d La ne, S uite 2 0 0 E 
Dallas, Te xas 7 5 2 4 7 
U S A  
Eac h a d diti o nal site will use t heir l ocal la b orat or y f or 
safet y a n al yses. 
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P P D
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Pr ot oc ol 
C O N FI D E N TI A L  
C o va nce St u d y: 8 4 1 9 6 8 9 
Pr ot oc ol Refere n ce:  L O X O -B T K - 2 0 0 1 0 
Pr ot oc ol Versi o n 1. 0, 9 Dece m b er 2 0 2 0  
Pa ge 5 of 6 8 
Bi oa nal ytical La b orat or y  
Alt uras A nal ytics, I nc. 
1 3 2 4 Alt uras Dri ve 
M osc o w, I da h o 8 3 8 4 3 
U S A  
T el ( mai n): ( 2 0 8) 8 8 3- 3 4 0 0 
E mail: jzi m mer @alt uras a nal ytics.c o m 
Statisticia n  
 
C o va nce 
T el: 
 
E mail: 
 
Pr ot oc ol Me dical Writer  
 
C o va nce 
T el: 
 
E mail:
 
P P D
P P D
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Pr ot oc ol 
C O N FI D E N TI A L  
C o va nce St u d y: 8 4 1 9 6 8 9 
Pr ot oc ol Refere n ce:  L O X O -B T K - 2 0 0 1 0 
Pr ot oc ol Versi o n 1. 0, 9 Dece m b er 2 0 2 0  
Pa ge 6 of 6 8 
S Y N O P SI S  
St u d y Title  
A P hase I, O pe n -la bel, Fi xe d-se q ue n ce, Dr u g I nteracti o n St u d y t o I n vesti gate t he Effect of 
M ulti ple Oral D oses of L O X O - 3 0 5 o n C Y P 1 A 2, C Y P 2 C 9, a n d C Y P 2 C 1 9 S u bstrates usi n g a 
Pr o be Dr u g C oc ktail i n Healt h y S u bjects  
O bjecti ves  
T he pri mar y o bjecti ve of t he st u d y is t o assess t he effect of m ulti ple oral d oses of L O X O- 3 0 5 
o n t he p har mac o ki n etic ( P K) of si n gle oral d oses of caffei ne (c yt oc hr o m e P 4 5 0 [ C Y P] 1 A 2 
s u bstrate), S-warfari n ( C Y P 2 C 9 s u bstrate), a n d o me praz ole ( C Y P 2 C 1 9 s u bstrate) i n healt h y 
s u bjects. 
T he sec o n d ar y o bjecti ve of t he st u d y is t o assess t he safet y a n d t olera bilit y of m ulti ple oral 
d oses of L O X O- 3 0 5 w he n a d mi nistere d al o ne, a n d c oa d mi nistere d wit h a si n gle oral d ose of 
pr o be dr u g c o c ktail. 
St u d y Desi g n   
T his is a P hase  1, o pe n-la bel, 2- peri o d, fi xe d-se q u e nce dr u g- dr u g i nteracti o n st u d y t o 
i n vesti gate t he eff ect of m ulti ple oral d oses of L O X O- 3 0 5 o n t he P K of si n gle oral d oses of 
caff ei ne ( C Y P 1 A 2 s u bstr ate) a n d its me ta b olite para xa nt hi ne, S- w arfari n ( C Y P 2 C 9 
s u bstrate), a n d o me praz ole ( C Y P 2 C 1 9 s u bstrate) i n healt h y s u bjects.  
I n Peri o d 1, Da y 1, 2 0 0 m g caff ei ne (ta blet), 4 0  m g o me praz ole (ca ps ule), a n d 1 0 m g 
warf ari n (ta blet) a d mi nistere d as a si n gle d ose of pr o be dr u g c o c ktail, al o n g wit h 1 0 m g 
vita mi n K (ta blets), will be a d mi nistere d i n t he m or ni n g f oll o wi n g a fast of at least 1 0  h o urs 
pre d ose a n d 2 h o urs p ost d ose. Bl o o d sa m ples f or c o nce ntrati o ns of t he s u bstrates 
(caffei ne/ para x a nt hi ne, o me praz ole, a n d S- warfari n) i n plas ma will be c ollecte d  
 
. Of t h e sa m ples c ollecte d f or c o nce ntrati o ns of eac h 
s u bstrate i n plas ma 
 p ost d ose o n Da y 1, sa m ples will be a nal yze d 
f or c o nce ntrati o n of caffei ne/ para xa nt hi ne fr o m 
 p ost d ose, f or 
c o nce ntr ati o n of o me praz ole fr o m 
 p ost d ose, a n d S-warfari n fr o m 
. 
T here will be a was h o ut peri o d of 5 da ys b et wee n a d mi nistrati o n of t he pr o be dr u g c oc kt ail 
o n Da y 1 a n d t he first d ose of L O X O- 3 0 5 o n Da y 6.  
I n Peri o d 2, o n Da ys 6 t hr o u g h 1 9, oral d oses of 2 0 0 m g L O X O - 3 0 5 will be a d mi nistere d 
o nce dail y ( Q D) f or 1 4 c o nsec uti ve da ys i n t he m or ni n g at t he act ual ti me of t he Da y 1 pr o b e 
dr u g c oc ktail d osi n g ( ± 1 h o ur). O n Da y 1 5, L O X O- 3 0 5 will be c oa d mi nistere d wit h 2 0 0 m g 
caff ei ne (ta bl et), 4 0  m g o me praz ole (ca ps ule), a n d 1 0 m g warfari n (ta blet) a d mi nistere d as a 
si n gle d ose of pr o be dr u g c oc ktail, al o n g wit h 1 0 m g of vita mi n K (ta blets) , at t he act ual t i me 
of t he Da y 1 pr o b e dr u g c oc ktail d osi n g ( ± 1 h o ur) f oll o wi n g a fast of at least 1 0 h o urs 
pre d ose a n d 2 h o urs p ost d ose. O n Da ys 7 t hr o u g h 1 1, a n d Da ys 1 3, 1 4, 1 6, 1 8, a n d 1 9, 
s u bjects will fast f or at least 2 h o urs pre d ose a n d 1 h o ur p ost d ose. O n Da ys 6, 1 2, a n d 1 7 
w here cli nical la b orat or y e val uati o ns are perf or me d, s u bjects will fast f or at least 8  h o urs 
pre d ose a n d 1 h o ur p ost d ose. Bl o o d sa m ples f or c o nce ntrati o ns of L O X O- 3 0 5 i n plas ma will 
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Pr ot oc ol 
C O N FI D E N TI A L  
C o va nce St u d y: 8 4 1 9 6 8 9 
Pr ot oc ol Refere n ce:  L O X O -B T K - 2 0 0 1 0 
Pr ot oc ol Versi o n 1. 0, 9 Dece m b er 2 0 2 0  
Pa ge 7 of 6 8 
be c ollecte d a n d a nal y ze d 
 
. Sa m ples c ollecte d 
 will be 
c ollecte d pri or t o L O X O- 3 0 5 d osi n g o n Da ys 1 6 t hr o u g h 1 9. Bl o o d sa m ples f or 
c o nce ntr ati o ns of t he s u bstrates (caff ei ne / para xa nt hi ne, o me praz ol e, a n d S-warfari n) i n 
plas ma will be 
. Of t he sa m ples 
c ollecte d f or c o nce ntrati o n s of eac h s u bstrate i n plas ma 
 
 sa m ples will be a nal yze d f or c o nce ntrati o n of caffei ne/ para xa nt hi ne fr o m 
 
, f or c o n ce ntrati o n of o me praz ole fr o m 
 
, a n d f or c o n ce ntrati o n of S- warfari n fr o m 
.  
T o assess t heir eli gi bilit y t o e nter t he s t u d y, p ote ntial s u bjects will be scree ne d wit hi n 3 4 da ys 
( Da ys - 3 5 t o - 2) a n d be a d mitte d t o t he Cli nical Researc h U nit ( C R U) o n D a y -1 ( C hec k -i n). 
S u bjects will be c o nfi ne d at t he C R U fr o m t he ti me of C hec k -i n ( Da y - 1) u ntil E n d of 
Treat me nt ( E O T) o n D a y  2 3 u p o n c o m pleti o n of all P K a n d safet y assess m e nts or Earl y 
Ter mi nati o n ( E T) if t he s u bject disc o nti n ues. D osi n g of pr o be dr u g c oc ktail will occ ur o n 
Da y 1 a n d D a y 1 5 a n d d osi n g of L O X O- 3 0 5 will o cc ur o n D a ys 6 t hr o u g h 1 9. A f oll o w- u p 
p h o ne call will occ ur f or all s u bjects w h o recei ve d at least 1  d ose of st u d y dr u g (i ncl u di n g 
s u bjects w h o ar e ter mi nate d earl y) 7 d a ys ( ±  2 da ys) after E O T or E T.  
T he start of t he st u d y is d efi ne d as t he d ate t he first s u bject w h o is e nr olle d i n t he st u d y si g ns 
a n I nf or me d C o ns e nt F or m (I C F). N ote t h at e nr oll e d s u bjects are defi n e d as t h ose s u bjects 
w h o are assi g ne d t o recei ve a d ose of st u d y dr u g; t his defi niti o n e xcl u des scree n fail ure 
s u bjects. Re place me nt s u bjects ma y be e nr olle d o nl y if dee me d necessar y b y t he S p o ns or. 
I n t his st u d y, p h ysical e x a mi nati o ns, 1 2-lea d electr ocar di o gra ms ( E C Gs), vital si g n 
meas ure me nts, H o w D o Y o u Feel? ( H D Y F?) i n q uiries, cli nical c he mistr y pa nel, c oa g ul ati o n 
para meters, he mat ol o g y pa nel, uri nal ysis ( U A; A p pe n di x 2 ), a n d rec or di n g of c o nc o mita nt 
me dicati o ns will be perf or me d at s pecifi e d ti mes d uri n g t he st u d y (f or s pecific ti me p oi nts a n d 
details o n eac h st u d y varia ble, refer t o A p p e n di x 4 ).  
A d verse e ve nts ( A Es) a n d seri o us a d vers e e v e nts ( S A Es) will be c ollecte d be gi n ni n g at 
i nf or me d c o nse nt. A d v erse e ve nts will be re p orte d t hr o u g h o ut t he st u d y (ie, fr o m si g ni n g of 
t he I C F u ntil E n d of St u d y [ E O S], or u ntil E T if t he s u bject disc o nti n ues fr o m t he st u d y a n d 
d oes n ot c o m plete a f oll o w- u p p h o ne call), eit her as s u bject me dical hist or y (if t he e ve nt is 
re p orte d as be gi n ni n g pri or t o si g ni n g of t he I C F or if t he e ve nt o cc urs pri or t o st u d y dr u g 
a d mi nistrati o n o n Da y 1 a n d is assesse d as n ot rel ate d t o st u d y pr oce d ures b y t he I n vesti gat or 
[ or desi g nee]) or as A Es (if t he e ve nt o cc urs after si g ni n g of t he I C F b ut pri or t o st u d y dr u g 
a d mi nistrati o n o n Da y 1 a n d is assesse d as relate d t o st u d y pr oce d ures b y t he I n vesti gat or [ or 
desi g nee], or if t he e v e nt occ urs after st u d y dr u g a d mi nistrati o n o n Da y 1 t hr o u g h E O T or E T 
re gar dl ess of rel ati o ns hi p t o st u d y dr u g). Fr o m E O T or E T t hr o u g h E O S, o nl y A Es assesse d 
as relate d t o st u d y dr u g b y t he I n v esti gat or ( or d esi g nee) are t o be re p orte d. All S A Es t hat 
de vel o p fr o m t he ti me of I C F si g ni n g u ntil E O S ( or E T, if t he s u bject disc o nti n ues fr o m t he 
st u d y a n d d oes n ot c o m plete a f oll o w- u p p h o n e call) are t o be re p ort e d. 
St u d y c o m pleti o n is defi ne d as t he ti me of t he last s u bject’s f oll o w- u p p h o ne call. 
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Pr ot oc ol 
C O N FI D E N TI A L  
C o va nce St u d y: 8 4 1 9 6 8 9 
Pr ot oc ol Refere n ce:  L O X O -B T K - 2 0 0 1 0 
Pr ot oc ol Versi o n 1. 0, 9 Dece m b er 2 0 2 0  
Pa ge 8 of 6 8 
N u m ber of S u bjects  
U p t o 1 6 healt h y a d ult male a n d f e male s u bjects ( w o me n of n o n-c hil d beari n g p ote ntial o nl y) 
will be e nr olle d. E ver y atte m pt will be ma de t o e nr oll at least 4  s u bjects of eac h se x i n t he 
st u d y. 
M ai n Criteri a f o r I ncl usi o n  
Male s u bjects, a n d f e mal e s u bjects of n o n -c hil d beari n g p ote ntial m ust meet t he f oll o wi n g 
criteria:  
•  Bet wee n 1 8 a n d 5 5 y ears of a ge, i ncl usi ve, at Scree ni n g  
•  Wit hi n b o d y mass i n de x ( B MI) ra n g e 1 8. 0 t o 3 2. 0 k g/ m
2, i ncl usi ve, at Scree ni n g 
•  I n g o o d g e ner al healt h, b ase d o n me dical hist or y, p h ysical e xa mi nati o n fi n di n gs, vital 
si g ns, 1 2-lea d E C G, or cli nical la b orat or y e val uati o ns at Scree ni n g a n d/ or C hec k-i n 
( Da y -1), as deter mi ne d b y t he I n vesti gat or ( or d esi g nee)  
I n vesti g ati o n al Me dici n al Pr o d ucts, D ose, a n d M o de of A d mi nistr ati o n 
S u bjects will recei ve eac h of t he f oll o wi n g treat m e nts t hr o u g h o ut t he st u d y: 
•  I n Peri o d 1, Da y 1, 2 0 0 m g caffei ne (ta blet), 4 0  m g o me praz ole (ca ps ule) , a n d 1 0 m g 
warf ari n (ta blet) will be a d mi nistere d as a si n gle d ose of pr o be dr u g c oc kt ail, al o n g 
wit h 1 0 m g vita mi n K ( 2  × 5 m g ta blets), i n t he m or ni n g f oll o wi n g a fast of at least 
1 0 h o urs pre d ose a n d 2 h o urs p ost d ose. Water will be restricte d f or 1 h o ur pri or t o a n d 
1 h o ur after d osi n g wit h t he e xce pti o n of water a d mi nistere d f or d ose a d mi nistrati o n. 
•  I n Peri o d 2, o n Da ys 6 t hr o u g h 1 9, oral d oses of 2 0 0 m g ( 2  × 1 0 0 m g ta blets) 
L O X O - 3 0 5 will be a d mi nistere d Q D f or 1 4 c o nsec uti ve da ys i n t he m or ni n g at t he 
act ual ti me of t he D a y  1 pr o be dr u g c o c ktail d osi n g ( ± 1 h o ur). O n D a y 1 5, 
L O X O - 3 0 5 will be c o a d mi nistere d wit h 2 0 0 m g caffei n e (ta blet), 4 0  m g o me praz ole 
(ca ps ule), a n d 1 0 m g warfari n (ta blet) a d mi nistere d as a si n gle d ose of pr o b e dr u g 
c oc ktail, al o n g wit h 1 0 m g vita mi n K ( 2  × 5 m g ta blets), at t he act ual ti me of t he Da y 
1 pr o be dr u g c o c ktail d osi n g ( ± 1 h o ur) f oll o wi n g a fast of at least 1 0 h o urs pre d ose 
a n d 2 h o urs p ost d ose. O n Da ys 7 t hr o u g h 1 1, a n d Da ys 1 3, 1 4, 1 6, 1 8, a n d 1 9, 
s u bjects will fast f or at least 2 h o urs pre d ose a n d 1 h o ur p ost d ose. O n Da ys 6, 1 2, a n d 
1 7 w here cli nical la b or at or y e val uati o ns are perf or me d, s u bjects will fast f or at least 
8 h o urs pre d ose a n d 1 h o ur p ost d ose. Water will be restricte d f or 1 h o ur pri or t o a n d 1 
h o ur after d osi n g wit h t h e e xce pti o n of water a d mi nistere d f or d ose a d mi nistrati o n.  
All st u d y dr u gs will be a d mi nistere d orall y wit h a p pr o xi matel y 2 4 0 m L of water. A n 
a d diti o nal 1 0 0 m L of wat er ma y be a d mi nistere d if nee de d.  
D ur ati o n of S u bject P a rtici p ati o n i n t he St u d y:  
Pla n ne d E nr oll me nt/ Scree ni n g D urati o n: A p pr o xi matel y 3 4 da ys ( Da ys - 3 5 t o - 2).  
Le n gt h of C R U C o nfi ne me nt: U p t o 2 4 da ys ( Da ys - 1 t o 2 3). 

Pr ot oc ol 
C O N FI D E N TI A L  
C o va nce St u d y: 8 4 1 9 6 8 9 
Pr ot oc ol Refere n ce:  L O X O -B T K - 2 0 0 1 0 
Pr ot oc ol Versi o n 1. 0, 9 Dece m b er 2 0 2 0  
Pa ge 9 of 6 8 
Pla n ne d St u d y C o n d uct D urati o n: U p t o 6 7 da ys ( Scree ni n g t hr o u g h f oll o w - u p call).  
Criteri a f or E v al u ati o n: 
P h ar m ac o ki netics:  
Serial bl o o d sa m ples f or plas ma c o nce ntrati o n a nal ysis of caffei n e/ para xa nt hi ne, o me praz ol e, 
a n d S- warfari n will be c ollecte d fr o m pre d ose t hr o u g h 
 
. Serial bl o o d sa m ples f or plas ma c o n ce ntrati o n a nal ysis of L O X O- 3 0 5 will be c ollecte d 
. Sa m ples 
c ollecte d 
 will be c ollecte d pri or t o L O X O- 3 0 5 
d osi n g o n Da ys 1 6 t hr o u g h 1 9. 
T he f oll o wi n g P K para m eters will be calc ulate d, w he ne ver p ossi ble,  base d o n t he plas ma 
c o nce ntr ati o ns of caffei n e / para x a nt hi ne, o me praz ole, S- warfari n, a n d L O X O- 3 0 5 (as 
a p pr o priate): ar ea u n der t he c o nce ntrati o n- ti me c ur ve ( A U C) fr o m h o ur 0 t o 2 4 h o urs 
p os t d ose ( A U C0- 2 4), A U C fr o m h o ur 0 t o t he last meas ura ble c o nce ntrati o n ( A U C 0-t), A U C 
fr o m h o ur 0 e xtr a p olate d t o i nfi nit y ( A U C0- i nf), perce nta ge e xtra p olati o n f or A U C0- i nf 
( % A U Ce xtra p), a p pare nt s yste mic clear a nce ( C L/ F), a p pare nt plas m a ter mi n al eli mi nati on 
half -life (t½ ), m a xi m u m o bser ve d plas ma c o nce ntrati o n ( Cma x ), ti me t o Cma x (tma x ), a p pare nt 
ter mi nal eli mi nati o n rate c o nsta nt ( λz), mea n resi d e nce ti me ( M R T), a p pare nt v ol u me of 
distri b uti o n at t he ter mi nal p hase ( V z/ F), a n d A U C0- 2 4 a n d A U C 0- 4 8 rati o of para xa nt hi ne t o 
caff ei ne ( M R A U C; caff ei ne / para xa nt hi ne o nl y). 
S afet y:  
Safet y will be m o nit ore d wit h H D Y F? i n q uiri es, cli nical la b orat or y e val uati o ns, vital si g n 
meas ure me nts, 1 2 -l ea d E C Gs, a n d p h ysical e xa mi nati o ns. 
St atistic al Met h o ds  
P h ar m ac o ki netics:  
T he pri mar y a n al ysis pla n ne d f or t his st u d y is a mi xe d effect m o del t hat i ncl u des treat me nt as 
a fi xe d effect a n d s u bject as a ra n d o m effect. T he a nal ysis will be perf or m e d o n t he nat ural 
l o g (l n)-tra nsf or me d P K para meters ( A U C0-t, A U C0- i nf, a n d Cma x ) a n d i ncl u de calc ul ati o n of 
least s q uare d ( L S) mea ns a n d t he differe nce bet w ee n treat me nt L S mea ns, as well as t heir 
c orres p o n di n g 9 0 % c o nfi de nce i nter v als ( CIs). T h e ge o metric mea n rati os a n d t heir 9 0 % CIs 
of t he P K para m eter f or eac h treat me nt c o m paris o n will be c o nstr ucte d usi n g t he 
e x p o ne ntiati o n of t he diff ere nce a n d t he CIs fr o m t he mi xe d effect m o del. T he c o m paris o ns 
of i nterest will be pr o be dr u gs al o ne (caffei ne a n d its meta b olite para xa nt hi ne, o me praz ole, 
a n d S- warfari n) v ers us pr o be dr u gs (caffei ne a n d its meta b olite para x a nt hi ne, o me praz ole, 
a n d S-warfari n) c oa d mi nistere d wit h L O X O - 3 0 5. T he rati o of para x a nt hi ne t o caffei ne will 
be s u m marize d.  
S afet y:  
All safet y assess me nts, i ncl u di n g A Es, S A Es, vital si g n meas ure me nts, cli nical la b orat or y 
res ults, p h ysical e xa mi nati o n res ults, c o nc o mita nt me dicati o ns, a n d 1 2-lea d E C Gs, will be 
ta b ulate d, a n d s u m marize d w her e p ossi ble, usi n g descri pti ve met h o d ol o g y b y treat me nt a n d, 
C CI
C CI
C CI

Pr ot oc ol 
C O N FI D E N TI A L  
C o va nce St u d y: 8 4 1 9 6 8 9 
Pr ot oc ol Refere n ce:  L O X O -B T K - 2 0 0 1 0 
Pr ot oc ol Versi o n 1. 0, 9 Dece m b er 2 0 2 0  
Pa ge 1 0 of 6 8 
as nee de d, b y ti me p oi nt. U nless ot her wise s pecifie d, baseli ne val ue is d efi ne d as t he last 
n o n- missi n g meas ure me nt bef ore a d mi nistrati o n of st u d y dr u g o n Da y 1, Peri o d 1. N o f or mal 
statistical a nal yses ar e pla n ne d f or t h e safet y data. All safet y data will be liste d b y s u bject. 
T he s pecific pr oce d ures will be d oc u me nte d i n t he Statistical A nal ysis Pla n.  
 

Pr ot oc ol 
C O N FI D E N TI A L  
C o va nce St u d y: 8 4 1 9 6 8 9 
Pr ot oc ol Refere n ce:  L O X O -B T K - 2 0 0 1 0 
Pr ot oc ol Versi o n 1. 0, 9 Dece m b er 2 0 2 0  
Pa ge 1 1 of 6 8 
T A B L E O F C O N T E N T S  
TI T L E P A G E  ............................................................................................................................. 1 
S P O N S O R A P P R O V A L  ........................................................................................................... 2 
I N V E S TI G A T O R A G R E E M E N T............................................................................................. 3 
S T U D Y I D E N TI FI C A TI O N  ..................................................................................................... 4 
S Y N O P SI S  ................................................................................................................................. 6 
T A B L E O F C O N T E N T S  ......................................................................................................... 1 1 
LI S T O F T A B L E S A N D FI G U R E S ........................................................................................ 1 3 
LI S T O F A B B R E VI A TI O N S  .................................................................................................. 1 4 
1.  
I N T R O D U C TI O N ........................................................................................................... 1 7 
1. 1.  Bac k gr o u n d ................................................................................................................ 1 7  
1. 2.  N o ncli nical P har mac o ki n etics a n d T o xic ol o g y S u m mar y ........................................ 1 7  
1. 3.  P ote ntial f or Dr u g- dr u g I nteracti o ns  .......................................................................... 1 9 
1. 4.  S u m mar y of Cli nical E x perie nce ............................................................................... 2 0  
1. 4. 1.  
Safet y  ........................................................................................................... 2 1 
1. 4. 2.  
P har mac o ki netics  ......................................................................................... 2 2 
1. 5.  St u d y Rati o nale .......................................................................................................... 2 5  
1. 6.  Ris k As sess me nt ........................................................................................................ 2 6 
2.  
O BJ E C TI V E S A N D E N D P OI N T S  ................................................................................. 2 7 
2. 1.  O bjecti ves  .................................................................................................................. 2 7 
2. 1. 1.  
Pri mar y O bj ecti ve  ........................................................................................ 2 7 
2. 1. 2.  
Sec o n dar y O bj ecti ve .................................................................................... 2 7  
2. 2.  E n d p oi nts ................................................................................................................... 2 7  
2. 2. 1.  
Pri mar y E n d p oi nts ....................................................................................... 2 7  
2. 2. 2.  
Sec o n dar y E n d p oi nts ................................................................................... 2 7  
3.  
I N V E S TI G A TI O N A L P L A N .......................................................................................... 2 8 
3. 1.  O verall St u d y Desi g n a n d Pla n .................................................................................. 2 8  
3. 2.  Disc ussi o n of St u d y Desi g n ....................................................................................... 3 0  
3. 3.  Selecti o n of D oses i n t he St u d y ................................................................................. 3 0  
3. 3. 1.  
L O X O - 3 0 5 ................................................................................................... 3 0 
3. 3. 2.  
Pr o be Dr u g C oc ktail .................................................................................... 3 0  
4.  
S E L E C TI O N O F S T U D Y P O P U L A TI O N  ..................................................................... 3 2 
4. 1.  Scree ni n g Pr oce d ures ................................................................................................. 3 2  
4. 2.  C he c k-i n Pr oce d ures ( D a y - 1) ................................................................................... 3 2 
4. 3.  I n cl usi o n Criteria ....................................................................................................... 3 3 
4. 4.  E xcl usi o n Criteria  ...................................................................................................... 3 5 
4. 5.  S u bje ct N u m ber a n d I d e ntificati o n  ............................................................................ 3 9 
4. 6.  Re m o val of S u bjects fr o m St u d y Partici pati o n  ......................................................... 3 9 
5.  
S T U D Y T R E A T M E N T S  ................................................................................................. 4 1 
5. 1.  Descri pti o n, St ora ge, Pac ka gi n g, a n d La beli n g ......................................................... 4 1  

Pr ot oc ol 
C O N FI D E N TI A L  
C o va nce St u d y: 8 4 1 9 6 8 9 
Pr ot oc ol Refere n ce:  L O X O -B T K - 2 0 0 1 0 
Pr ot oc ol Versi o n 1. 0, 9 Dece m b er 2 0 2 0  
Pa ge 1 2 of 6 8 
5. 2.  St u d y Treat me nt A d mi nistrati o n  ............................................................................... 4 1 
5. 3.  Ra n d o mizati o n ........................................................................................................... 4 2  
5. 4.  Bli n di n g ..................................................................................................................... 4 2  
5. 5.  Treat me nt C o m plia nce  ............................................................................................... 4 2 
5. 6.  Dr u g Acc o u nta bilit y .................................................................................................. 4 3  
6.  
C O N C O MI T A N T T H E R A PI E S A N D O T H E R R E S T RI C TI O N S  ................................ 4 4 
6. 1.  C o nc o mita nt T hera pies .............................................................................................. 4 4  
6. 2.  Diet, Fl ui d, a n d Acti vit y C o ntr ol ............................................................................... 4 4  
7.  
S T U D Y A S S E S S M E N T S A N D P R O C E D U R E S  ........................................................... 4 6 
7. 1.  P har mac o ki netic Assess me nts  ................................................................................... 4 6 
7. 1. 1.  
P har mac o ki netic Bl o o d Sa m ple C ollecti o n a n d Pr ocessi n g ........................ 4 6  
7. 1. 2.  
A nal ytical Met h o d ol o g y .............................................................................. 4 6  
7. 2.  Ge n ot y pi n g ................................................................................................................ 4 6  
7. 3.  Safet y a n d T oler a bilit y Assess me nts  ......................................................................... 4 6 
7. 3. 1.  
A d verse E v e nts  ............................................................................................ 4 7 
7. 3. 2.  
Cli ni cal La b orat or y E val uati o ns .................................................................. 4 8  
7. 3. 3.  
Vital Si g ns  .................................................................................................... 4 8 
7. 3. 4.  
1 2-lea d Electr ocar di o gra m ........................................................................... 4 8  
7. 3. 5.  
P h ysical E xa mi nati o n ................................................................................... 4 9 
8.  
S A M P L E SI Z E A N D D A T A A N A L Y SI S  ...................................................................... 5 0 
8. 1.  Deter mi nati o n of Sa m ple Size  ................................................................................... 5 0 
8. 2.  A nal ysis P o p ulati o ns ................................................................................................. 5 0  
8. 3.  P ha r mac o ki netic A n al ysis ......................................................................................... 5 0 
8. 3. 1.  
Descri pti ve A n al ysis  .................................................................................... 5 1 
8. 3. 2.  
Statistical Met h o d ol o g y  ............................................................................... 5 1 
8. 4.  Safet y A nal ysis  .......................................................................................................... 5 2 
8. 5.  Data Ha n dli n g a n d Rec or d Kee pi n g .......................................................................... 5 2  
8. 6.  Q ualit y C o ntr ol a n d Q ualit y Ass ura nce ..................................................................... 5 3  
9.  
A D MI NI S T R A TI V E A S P E C T S  ..................................................................................... 5 4 
9. 1.  C ha n ge i n Pr ot oc ol .................................................................................................... 5 4  
9. 2.  Site I nitiati o n Visit/I n vesti gat or Meeti n g  .................................................................. 5 4 
9. 3.  Discl os ure .................................................................................................................. 5 4  
9. 4.  M o nit ori n g ................................................................................................................. 5 4  
9. 5.  I nstit uti o nal Re vie w B oar d ........................................................................................ 5 4 
9. 6.  I nf or me d C o nse nt ...................................................................................................... 5 5 
9. 7.  Rec or ds  ...................................................................................................................... 5 5 
9. 8.  Refere n ce t o D eclarati o n of Helsi n ki/ Basic Pri nci ples  ............................................. 5 5 
9. 9.  Fi na nci n g a n d I ns ura n ce ............................................................................................ 5 6  
1 0.  R E F E R E N C E S  ................................................................................................................ 5 7 
1 1.  A P P E N DI C E S  ................................................................................................................. 5 8 

Pr ot oc ol 
C O N FI D E N TI A L  
C o va nce St u d y: 8 4 1 9 6 8 9 
Pr ot oc ol Refere n ce:  L O X O -B T K - 2 0 0 1 0 
Pr ot oc ol Versi o n 1. 0, 9 Dece m b er 2 0 2 0  
Pa ge 1 3 of 6 8 
A p pe n di x 1: A d verse E v e nt Re p orti n g ............................................................................... 5 9  
A p pe n di x 2: Cli nical La b orat or y E val uati o ns ..................................................................... 6 3  
A p pe n di x 3: T otal Bl o o d V ol u me ....................................................................................... 6 4  
A p pe n di x 4: Sc he d ule of Assess me nts  ............................................................................... 6 5 
 
LI S T O F T A B L E S A N D FI G U R E S  
Ta ble 1: P har mac o ki n etic Para meters of L O X O -3 0 5 i n Ca ncer Patie nts 
( St u d y L O X O -B T K - 1 8 0 0 1) at Stea d y State ( C ycl e 1 Da y 8) ............................. 2 3 
Ta ble  2: St u d y Dr u gs ......................................................................................................... 4 1 
Fi g ure 2: D ose- E x p os ure C orrelati o n Assesse d b y A U C 0- 8 vs D ose f or Cycle 1 Da y 8  ... 2 5 
Fi g ure 3: St u d y Sc he matic ................................................................................................. 2 9  
 
C CI

Pr ot oc ol 
C O N FI D E N TI A L  
C o va nce St u d y: 8 4 1 9 6 8 9 
Pr ot oc ol Refere n ce:  L O X O -B T K - 2 0 0 1 0 
Pr ot oc ol Versi o n 1. 0, 9 Dece m b er 2 0 2 0  
Pa ge 1 4 of 6 8 
LI S T O F A B B R E VI A TI O N S  
A b bre vi ati o n 
Defi niti o n  
% A U C
e xtra p 
perce nt a ge e xtra p olati o n f or area u n der t he c o n ce ntrati o n -ti me c ur ve 
fr o m h o ur 0 e xtr a p olate d t o i nfi nit y 
A D L  
Acti vities of Dail y Li vi n g  
A E  
a d verse e ve nt  
A U C  
area u n d er t he c o nce ntrati o n -ti me c ur ve 
A U C 0 -2 4 
area u n d er t he c o nce ntrati o n -ti me c ur ve fr o m h o ur 0 t o 2 4 h o urs p ost d ose  
A U C 0- i nf 
area u n d er t he c o nce ntrati o n -ti me c ur ve fr o m h o ur 0 e xtra p olate d t o 
i nfi nit y 
A U C 0-t 
area u n d er t he c o nce ntrati o n -ti me c ur ve fr o m h o ur 0 t o t he last 
meas ura ble c o nce ntrati o n  
A V  
atri o ve ntric ular  
B C R P  
breast ca ncer resista n ce pr otei n  
BI D  
t wice dail y 
B MI  
b o d y mass i n de x  
B P  
bl o o d press ure  
B S E P  
bile salt e x p orter p u m p  
B T K  
Br ut o n’s t yr osi ne ki nase  
C F R  
C o de of Fe d er al Re g ulati o ns  
CI  
c o nfi de nce i nter val(s)  
C K D -E PI  
C hr o nic Ki d ne y Diseas e E pi de mi ol o g y C olla b orati o n  
C L/ F  
a p pare nt s yste mic cleara nce  
C L L  
c hr o nic l y m p h oc ytic le u k e mia  
C ma x  
ma xi m u m o bser ve d plas ma c o nce ntrati o n  
C O VI D -1 9  
S A R S -C o V -2  
C R F  
Case Re p ort F or m  
C R U  
Cli nical Resea rc h U nit 
C T C A E  
C o m m o n Ter mi n ol o g y Criteria f or A d vers e E ve nts  
C V  
c oeffi cie nt of variati o n  
C Y P  
c yt oc hr o me P 4 5 0  
D DI  
dr u g -dr u g i nter acti o n  
E C G  
electr ocar di o gr a m  
e C R F 
electr o nic Cas e Re p ort F or m  
e G F R  
esti mate d gl o mer ular filtrati o n rate  
E O S  
E n d of St u d y  
E O T  
E n d of Treat me nt  
E T  
Earl y Ter mi nati o n  
F D A  
F o o d a n d Dr u g A d mi nistrati o n  
F S H  
f ollicle-sti m ulati n g h or m o ne 
G L P  
G o o d La b orat or y Practice  
H b A 1c  
he m o gl o bi n A 1c  

Pr ot oc ol 
C O N FI D E N TI A L  
C o va nce St u d y: 8 4 1 9 6 8 9 
Pr ot oc ol Refere n ce:  L O X O -B T K - 2 0 0 1 0 
Pr ot oc ol Versi o n 1. 0, 9 Dece m b er 2 0 2 0  
Pa ge 1 5 of 6 8 
H Bs A g  
he patitis B s urface a nti ge n  
H B V  
he patitis B vir us  
H C V  
he patitis C vir us  
H D Y F?  
H o w D o Y o u Feel?  
h E R G  
h u ma n et her -à-g o -g o -rel ate d ge ne 
HI V  
h u ma n i m m u n o deficie nc y vir us  
H R  
heart r ate  
H R T  
h or m o ne re place me nt t hera p y  
I B 
I n v esti gat or’s Br oc h ure 
I C5 0 
5 0 % i n hi bit or y c o nce ntrati o n  
I C9 0 
c o nce ntr ati o n re q uire d f or 9 0 % i n hi biti o n 
I C F 
I nf or me d C o nse nt F or m 
I C H 
I nter nati o nal C o u ncil f or/ C o nfere nce o n Har m o nisati o n 
I g M 
i m m u n o gl o b uli n M 
I M P 
i n vesti gati o nal me dici nal pr o d uct 
I R B 
I nstit uti o nal Re vie w B oar d 
I U D 
i ntra uteri ne de vice 
I V 
i ntra ve n o us 
L F T  
li ver f u ncti o n test(s) 
L n  
nat ural l o g  
L S  
least s q uares 
M A T E  
m ulti dr u g a n d t o xi n e xtr usi o n  pr otei n  
Me d D R A  
Me dical Dicti o nar y f or R e g ulat or y Acti vities  
m R N A  
messe n ger R N A  
M R T  
mea n resi de n ce ti me  
N H L  
n o n -H o d g ki n l y m p h o ma  
O A T  
or ga nic a ni o n tr a ns p orter 
O A T P  
or ga nic a ni o n tr a ns p orti n g p ol y pe pti de  
O A T P 1 B 1  
or ga nic a ni o n tr a ns p orti n g p ol y pe pti de 1 B 1  
O A T P 1 B 3  
or ga nic a ni o n tr a ns p orti n g p ol y pe pti de 1 B 3  
O C T  
or ga nic cati o n tra ns p orter  
P C R  
p ol y merase c h ai n reacti o n  
P -g p  
P -gl yc o pr otei n  
P K  
p har mac o ki netic(s)  
Q D  
o nce dail y  
Q Tc F  
Q T i nter val c orrecte d f or heart rate usi n g Fri d erici a’s met h o d  
R B C  
re d bl o o d cell(s) 
R P 2 D  
rec o m me n de d P has e 2 d ose 
S A D  
si n gle asce n di n g d ose 
S A E  
seri o us a d vers e e v e nt(s) 
S A P  
Statistical A nal ysis Pla n  
S D  
sta n dar d de viati o n 

Pr ot oc ol 
C O N FI D E N TI A L  
C o va nce St u d y: 8 4 1 9 6 8 9 
Pr ot oc ol Refere n ce:  L O X O -B T K - 2 0 0 1 0 
Pr ot oc ol Versi o n 1. 0, 9 Dece m b er 2 0 2 0  
Pa ge 1 6 of 6 8 
S D D  
s pra y-drie d dis p ersi o n  
S L L  
s mall l y m p h oc ytic l y m p h o ma 
S O C  
s yste m or ga n class 
S O P  
Sta n dar d O per ati n g Pr oce d ure  
S U S A R  
s us pecte d u ne x p ecte d seri o us a d verse reacti o n 
t½  
a p pare nt plas m a ter mi nal eli mi nati o n half -life 
T E A E  
treat me nt-e mer ge nt a d v erse e ve nt  
T F Ls  
ta bles, fi g ures, a n d listi n gs 
tma x  
ti me t o ma xi m u m o bser ve d plas ma c o nce ntrati o n 
T S H  
t h yr oi d-sti m ulati n g h or m o ne 
U A  
uri nal ysis  
V z 
v ol u me of distri b uti o n  
V z/ F 
a p pare nt v ol u me of distri b uti o n  
W B C  
w hite bl o o d cell(s)  
W H O  
W orl d Healt h Or ga nizati o n  
λ Z  
a p pare nt ter mi nal eli mi nati o n rate c o nsta nt  

Pr ot oc ol 
C O N FI D E N TI A L  
C o va nce St u d y: 8 4 1 9 6 8 9 
Pr ot oc ol Refere n ce:  L O X O -B T K - 2 0 0 1 0 
Pr ot oc ol Versi o n 1. 0, 9 Dece m b er 2 0 2 0  
Pa ge 1 7 of 6 8 
1.  I N T R O D U C TI O N 
Refer t o t he I n v esti gat or’s Br oc h ure (I B) f or d etaile d i nf or mati o n c o ncer ni n g t he a vaila ble 
p har mac ol o g y, t o xic ol o g y, dr u g meta b olis m, cli nical st u dies, a n d a d v erse e ve nt ( A E) pr ofile 
of t he i n vesti gati o nal me dici nal pr o d uct, L O X O- 3 0 5. 1 
1. 1.  
B ac k gr o u n d 
L O X O - 3 0 5 ( als o k n o w n as L Y 3 5 2 7 7 2 7) is a sel ecti ve i n hi bit or of t he Br ut o n’s t yr osi ne 
ki nase ( B T K) b ei n g de vel o pe d b y L o x o O nc ol o g y. L O X O- 3 0 5 is disti nct fr o m t he a p pr o ve d 
B T K i n hi bit ors (i br uti ni b, acala br uti ni b, a n d za n u br uti ni b) i n se veral i m p orta nt wa ys 
i ncl u di n g o n t he basis of its selecti vit y, fa v ora ble a bs or pti o n, distri b uti o n, meta b olis m, a n d 
e xcreti on pr o p erties, a n d n o n-c o vale nt bi n di n g m o de. 2 T h ese feat ures e n a bl e L O X O - 3 0 5 t o 
ac hie ve p h ar mac o ki netic ( P K) e x p os ures t h at e xcee d t he B T K c o nce ntrati o n res ulti n g i n 9 0 % 
i n hi biti o n (I C9 0) at tr o u g h, a n d t h us deli ver t o nic B T K tar get i n hi biti o n t hr o u g h o ut t he d osi n g 
peri o d, re g ar dless of t he i ntri nsic rate of B T K t ur n o ver. M ore o v er, t he n o n-c o vale nt bi n di n g 
m o de of L O X O- 3 0 5 is u naffecte d b y B T K C 4 8 1 s u bstit uti o ns, a c o m m o n mec ha nis m of dr u g 
resista nce d escri be d f or all a vaila ble c o vale nt i n hi bit ors.3 ,4 ,5 ,6 ,7 Fi nall y, L O X O- 3 0 5 is als o a 
hi g hl y selecti ve m olec ule t hat is m ore t ha n 3 0 0-f ol d m ore selecti ve f or B T K vers us 3 7 0 ot her 
ki nases teste d wit h n o si g nifica nt i n hi biti o n of n o n- ki nase off- tar g ets at 1 µ M, t h us li miti n g 
t he p ote ntial f or off-tar g et me diate d t o xicities. C ollecti vel y, t hese u ni q ue pr o perties of 
L O X O - 3 0 5 are e x pect e d t o deli ver m ore p ote nt, c o nti n u o us, a n d selecti ve i n hi biti o n of B T K 
i n a variet y of setti n gs, p ote ntiall y res ulti n g i n i ncrease d effi cac y. Of n ote, t he acti vit y of 
L O X O - 3 0 5 i n di vers e pr ecli nical m o del s yste ms s u p p orts t his u n derl yi n g h y p ot hesis.2 
L O X O - 3 0 5 is a s mall m olec ule t hat was d esi g ne d t o bl oc k t he a de n osi ne tri p h os p hate ( A T P) 
bi n di n g site of t he B T K ki nase c o m petiti vel y. T here is n o e vi de n ce of irre versi ble bi n di n g. 
L O X O - 3 0 5 has a m olec ular wei g ht of a p pr o xi matel y 5 0 0 g/ m ol. L O X O- 3 0 5 will be s u p plie d 
as a n i m me diate-r eleas e ta blet c o ntai ni n g 2 5 m g or 1 0 0 m g of dr u g s u bsta n ce. 
1. 2.  
N o ncli nic al P h ar m ac o ki netics a n d T o xic ol o g y S u m m ar y 
L O X O - 3 0 5 ha d hi g h p er mea bilit y i n vitr o, b ut l o w a q ue o us s ol u bilit y. T o re d uce t h e 
varia bilit y i n oral a bs or pti o n, a s pra y- dri e d dis persi o n ( S D D) ta blet f or m ulati o n was 
de vel o pe d t hat s h o we d c o nsiste nt oral bi oa vaila bilit y of a p pr o xi matel y 5 0 % i n rats a n d 8 0 % 
i n d o gs. T he bi oa vaila bilit y of t he S D D f or m ulati o n was als o n ot de pe n d e nt o n fee di n g state 
i n d o gs. 
As is c o m m o n i n r o de nts, oral e x p os ur e of L O X O- 3 0 5 was c o nsiste ntl y m uc h hi g her i n 
fe male r ats t ha n i n males gi ve n t he sa me d ose of L O X O- 3 0 5. T h e se x differe nce was als o 
a p pare nt after i ntr a ve n o us (I V) a d mi nistrati o n of L O X O- 3 0 5. T h ere w as n o differe n ce i n t he 
P K of L O X O - 3 0 5 b et wee n se xes of d o g, a n d n o n e is e x pecte d i n ot her no n -r o de nt s peci es, 
i ncl u di n g h u ma ns.  
T he v ol u me of distri b uti o n ( V z) of L O X O- 3 0 5 ra n ge d fr o m a p pr o xi matel y 2 L/ k g i n t he d o g 
t o 5 L/ k g i n t he male rat, w hic h i n dicates t hat L O X O - 3 0 5 distri b utes i nt o tiss ues. L O X O- 3 0 5 
ha d pr otei n bi n di n g of a p pr o xi matel y 9 5 % i n h u ma n plas ma. A s o me w h at l o wer e xte nt of 
bi n di n g (a p pr o xi matel y 8 2 % t o 9 2 %) was o bs er ve d acr oss m o use, rat, ra b bit, a n d d o g. 

Pr ot oc ol 
C O N FI D E N TI A L  
C o va nce St u d y: 8 4 1 9 6 8 9 
Pr ot oc ol Refere n ce:  L O X O -B T K - 2 0 0 1 0 
Pr ot oc ol Versi o n 1. 0, 9 Dece m b er 2 0 2 0  
Pa ge 1 8 of 6 8 
L O X O - 3 0 5 w as meta b oli ze d sl o wl y b y h u ma n micr os o mal fracti o ns a n d h e pat oc ytes. T h e 
l o w rates of meta b olis m i n b ot h t hese h u ma n i n vitr o s yste ms s u g gest t hat L O X O- 3 0 5 will 
ha ve l o w cleara n ce i n h u ma ns. I n vitr o d ata wit h cl o ne e x presse d c yt oc hr o me P 4 5 0 ( C Y P) 
e nz y mes a n d h u ma n li ver micr os o mes i n dicate t h at C Y P 3 A 4 is t he pri mar y C Y P e nz y me t hat 
meta b olizes L O X O - 3 0 5. It is als o a s u bstrate f or direct gl uc ur o ni dati o n. 
I n l o n g-t er m he pat o c yte i nc u bati o ns, L O X O- 3 0 5 was meta b olize d b y b ot h o xi dati o n a n d 
gl uc ur o ni dati o n. I n hi biti o n of o xi dati ve meta b olis m b y a d diti o n of t he P 4 5 0 i n hi bit or 
1-a mi n o be nz otriaz ole s h o we d t hat o xi dati ve meta b olis m is C Y P de pe n de nt. All meta b olites 
f or me d b y h u ma n he p at o c ytes wer e als o f or me d i n rat a n d/ or d o g he p at oc ytes s u p p orti n g t he 
use of rat a n d d o g f or n o ncli nical safet y ass ess me nt. 
Re nal cleara nce of L O X O - 3 0 5 i n male a n d fe mal e rats was n e gli gi ble. N o data o n re n al 
clear a nce are a vaila ble i n ot her s pecies; h o w e ver, t he re nal e xcreti o n pat h w a y is ofte n 
c o nser ve d acr oss s p ecies, a n d t heref ore n o re nal cleara n ce w o ul d b e e x pect e d i n h u ma ns.  
I n a G o o d La b orat or y Pr actice ( G L P) i n vitr o assa y f or h u ma n et her-à- g o-g o -relate d g e ne 
( h E R G) acti vit y, t he c o n ce ntrati o n r es ulti n g i n 5 0 % i n hi bit or y c o nce ntrati o n (I C5 0) f or t he 
i n hi bit or y effects of L O X O- 3 0 5 o n h E R G p otassi u m c urre nts was   μ M, w hic h is 
a p pr o xi matel y  -f ol d hi g her t ha n t he ma xi m u m u n b o u n d c o nce ntrati o n of L O X O - 3 0 5 i n 
patie nts treate d wit h t he d ose of 2 0 0 m g o nce d ail y ( Q D). T h ere w ere n o L O X O - 3 0 5-relate d 
c ha n ges i n a n y car di o v asc ular e n d p oi nts i ncl u di n g Q Tc at si n gle d oses u p t o 6 0 m g/ k g i n t he 
G L P car di o vas c ular st u d y i n t he c o nsci o us tele metr y- i nstr ume nte d d o g. T h e ma xi m u m 
o bser ve d plas ma c o nce ntrati o n ( C ma x ) f or t his d ose was 1 0 0 0 0 n g/ m L, w hi c h is 
a p pr o xi matel y  
 a b o ve t he pre dict e d C ma x  ( 
n g/ m L) at t he pr o p ose d cli nical 
t hera pe utic d os e of 2 0 0 m g Q D. F urt her m ore, t here were n o L O X O- 3 0 5-relate d 
a b n or malities i n r h yt h m or wa vef or m m or p h ol o g y i n t he G L P 2 8- da y re p eate d - d ose t o xicit y 
st u d y i n d o gs at t he l o w a n d mi d- d ose gr o u ps base d o n c o m paris o n of pre d ose a n d p ost d ose 
electr ocar di o gr a m ( E C G) rec or di n gs. T h e hi g h d ose ( 9 0/ 6 0 m g/ k g/ d ose t wice dail y [ BI D]) 
was n ot e val uate d as a ni mals i n t his gr o u p were m ori b u n d/ de bilitate d a n d were ter mi nate d o n 
Da y 1 3. Mea n Q Tc i nter val was statisticall y si g nifica ntl y pr ol o n ge d ( + 6 %; + 1 5 msec) o n 
Da y  2 6 of t he d osi n g p hase i n males a d mi nistere d 3 0/ 1 0 m g/ k g/ d ose BI D c o m pare d wit h 
c o ntr ols. T he pr ol o n gati o n i n Q Tc f or males was b el o w t he 1 0 % i ncrease or t he t hres h ol d 
re p orte d f or ca ni nes e x p ose d t o t hera pe utic c o nce ntrati o ns of dr u gs k n o w n t o ca use Q T 
pr ol o n gati o n i n h u ma ns. 8 T heref ore, t he Q Tc c h a n ges were c o nsi dere d p h ysi ol o gicall y 
u ni m p orta nt, a n d t h us n ot dee me d t o be a d v erse. T o get her, t hese d ata i n di cate t hat 
L O X O - 3 0 5 has a l o w ris k of i n d uci n g dela ye d v e ntric ular re p ol arizati o n, pr ol o n gati o n of t he 
Q Tc i nter val, a n d u nsta ble arr h yt h mias i n patie nts. 
T here w ere n o L O X O - 3 0 5-relate d fi n di n gs o n t he ce ntral ner v o us s yste m w he n e val uat e d i n 
rat f u ncti o nal o bser vatio nal batter y tests a n d l oc o m ot or acti vit y assess me nts after 4 wee ks of 
d osi n g or d uri n g rec o v er y at d oses of u p t o 5 0 0 m g/ k g/ d ose BI D i n male rats a n d 
1 7 5 m g/ k g/ d ose BI D i n f e male rats as part of t he G L P 2 8- da y re p eat -d os e st u d y.  
L O X O - 3 0 5 ha d n o eff ect o n res pirati o n rat e i n t he d o g at d oses u p t o 1 0 m g/ k g/ d ose BI D. 
Tar gets of t o xicit y were c haracteri ze d i n re p eate d - d ose st u dies c o n d ucte d i n 2 rele va nt 
t o xicit y s pecies. Certai n tar gets (t he h e mat o p oietic a n d l y m p h oi d s yste ms) were f o u n d i n 
b ot h t he rat a n d t he d o g. Rat- s pecific c ha n ges i n t he pa ncreas are s p ecies-s pecific a n d s ee n 
C CI
C CI
C CI
C CI

Pr ot oc ol 
C O N FI D E N TI A L  
C o va nce St u d y: 8 4 1 9 6 8 9 
Pr ot oc ol Refere n ce:  L O X O -B T K - 2 0 0 1 0 
Pr ot oc ol Versi o n 1. 0, 9 Dece m b er 2 0 2 0  
Pa ge 1 9 of 6 8 
wit h ot her B T K i n hi bit ors. D o g-s pecific c ha n g es i n l u n g a n d lar ge i ntesti ne were lesi o ns 
c o ntri b uti n g t o m ori b u n dit y i n hi g h- d ose a ni mals i n t he 2 8- da y st u d y. D oses e val uate d i n 
t he 2 8- da y d o g st u d y de m o nstrate d a stee p d os e-res p o nse c ur v e f or t o xicit y a n d pr o n o u nce d 
c ha n ges i n he mat ol o gic p ara meters at hi g h e x p os ures. A d diti o nall y, i n d o gs treate d f or 
3 m o nt hs, 2 male d o gs at 5 m g/ k g BI D (t he hi g hest d ose teste d) were o bser ve d t o ha ve e y e 
lesi o ns via b ot h o p ht hal mic a n d micr osc o pic e xa mi nati o n. Fi n di n gs were o bser ve d i n b ot h 
e yes of t hese a ni mals a n d c o nsiste d of ver y sli g ht t o sli g ht m ultif ocal or f ocal areas of c or neal 
o pacit y i n t he ce nter of t he c or nea al o n g wit h c o nstellati o n hist o pat h ol o gical fi n di n gs 
s u g gesti ve of mi ni mal t o mil d c or neal i nj ur y. T he ti me of o nset of t hese effects is u n k n o w n, 
as o p ht hal mic e xa ms wer e o nl y perf or m e d pri or t o t he start of d osi n g a n d d uri n g t he last 
wee k of t he st u d y; h o w e ver, n o e ye eff ects w ere o bser ve d i n t he pre vi o us 2 8- da y st u d y. N o 
oc ular fi n di n gs were o bs er ve d i n f e males. See t he I B f or a d diti o nal details. 1 
L O X O - 3 0 5 w as n ot m uta ge nic i n 2 bacterial re v erse m utati o n assa ys a n d w as ne gati ve i n a 
n o n- G L P micr o n ucle us assa y usi n g C hi nese ha mster o var y cells. L O X O- 3 0 5 was p ositi ve f or 
t he i n d ucti o n of micr o n u clei via a n a n e u ge nic mec ha nis m i n t he a bse nce a n d prese nce of t he 
e x o ge n o us meta b olic acti vati o n s yste m i n a G L P i n vitr o micr o n ucle us assa y i n h u ma n 
peri p her al bl o o d l y m p h oc ytes. H o we v er, L O X O- 3 0 5 was ne gati ve i n a G L P i n vi v o 
micr o n ucle us assa y i n r ats at d oses u p t o a n d i ncl u di n g a d ose of  
 m g/ k g. T he C ma x  at t he 
n o o bser ve d effect le vel of  
 m g/ k g was  
 n g/ m L f or males a n d  
 n g/ m L f or 
fe males. 
L O X O - 3 0 5 w as n ot f o u n d t o be p h ot ot o xic w he n e val uate d i n a n i n vitr o n e utral re d u pt a ke 
p h ot ot o xicit y assa y. 
1. 3.  
P ote nti al f or D r u g -dr u g I nter acti o ns  
L O X O - 3 0 5 s h o w e d n o d etecta ble i n hi biti o n (I C5 0 >   µ M) of C Y P 1 A 2, C Y P 2 B 6, 
C Y P 2 C 1 9, a n d C Y P 2 D 6, a n d wea k i n hi biti o n of C Y P 2 C 8, C Y P 2 C 9, a n d C Y P 3 A 4 i n h u ma n 
li ver micr os o mes. After pre-i nc u b ati o n of micr os o mes wit h L O X O- 3 0 5 a n d nic oti na mi de 
a de ni ne di n ucle oti de p h os p hate pri or t o a d diti o n of C Y P 4 5 0 pr o be s u bstrat e, t he C Y P 3 A 4 
i n hi bit or y p ote nc y of L O X O- 3 0 5 was i ncrease d, s u g gesti n g t he p ote ntial f or ti me- de pe n d e nt 
i n hi biti o n of C Y P 3 A 4. F urt her ki netic e v al uati o n c o nfir me d t hat L O X O- 3 0 5 is a 
ti me- de pe n de nt i n hi bit or of C Y P 3 A 4. 
I n a n i n vitr o he pat oc yt e assa y, L O X O- 3 0 5 i n d uce d messe n ger R N A ( m R N A) f or C Y P 3 A 4, 
C Y P 3 A 5, C Y P 2 B 6, a n d C Y P 2 C 1 9. F or b ot h C Y P 2 B 6 a n d C Y P 2 C 1 9, a n i ncreas e i n acti vit y 
was see n. F or C Y P 3 A 4, L O X O- 3 0 5 di d n ot ca us e a n i ncrease i n acti vit y, li kel y d ue t o 
c o nc urr e nt i n hi biti o n of C Y P 3 A 4 b y L O X O - 3 0 5. L O X O-3 0 5 ca use d a decrease i n m R N A f or 
C Y P 1 A 2 b ut di d n ot lea d t o a re d ucti o n of C Y P 1 A 2 acti vit y. I n t h e st u d y, C Y P 2 D 6, 
C Y P 2 C 8, a n d C Y P 2 C 9 m R N A were n ot i n d uce d. 
I n vitr o L O X O- 3 0 5 i n hi bite d P- gl yc o pr otei n ( P-g p), breast ca ncer resista nce pr otei n ( B C R P), 
m ulti dr u g a n d t o xi n e xtr usi o n pr otei n ( M A T E) 1, a n d M A T E 2 K. L O X O- 3 0 5 di d n ot i n hi bit 
or ga nic a ni o n tr a ns p orter ( O A T) 1 a n d wea kl y i n hi bite d or ga nic a ni o n tra ns p orti n g 
p ol y pe pti de ( O A T P) 1 B 1, O A T P 1 B 3, or ga nic cati o n tra ns p orter ( O C T) 1, O C T 2, O A T 3, a n d 
bile salt e x p orter p u m p ( B S E P). 
L O X O - 3 0 5 is a s u bstrat e of P- g p a n d B C R P. It is n ot a s u bstrate of t he h e p atic tra ns p orters 
O C T 1, O A T P 1 B 1, O A T P 1 B 3, or B S E P. 
C CI
C CI
C CI
C CI
C CI

Pr ot oc ol 
C O N FI D E N TI A L  
C o va nce St u d y: 8 4 1 9 6 8 9 
Pr ot oc ol Refere n ce:  L O X O -B T K - 2 0 0 1 0 
Pr ot oc ol Versi o n 1. 0, 9 Dece m b er 2 0 2 0  
Pa ge 2 0 of 6 8 
1. 4.  
S u m m ar y of Cli nic al E x perie nce  
L O X O - 3 0 5 is c urre ntl y b ei n g st u die d i n a n o n g oi n g gl o bal P hase 1/2 first -i n- h u ma n st u d y, 
L O X O -B T K - 1 8 0 0 1 (t he B R UI N St u d y), i n patie nts wit h pre vi o usl y treate d c hr o nic 
l y m p h oc ytic le u ke mia ( C L L)/ s mall l y m p h oc ytic l y m p h o ma ( S L L) or n o n- H o d g ki n 
l y m p h o ma ( N H L). T he st arti n g d ose of L O X O- 3 0 5 was 2 5 m g Q D.  
As of Se pte m ber 2 7, 2 0 2 0, safet y data were a vaila ble fr o m a t otal of 3 3 0 patie nts treate d i n 
t he L O X O -B T K - 1 8 0 0 1 st u d y. T his i ncl u des 3 2 4 patie nts treate d at d os es ra n gi n g fr o m 2 5 m g 
Q D t o  3 0 0 m g Q D i n P hase 1/ 2 M o n ot hera p y c o h orts, a n d 6 patie nts treat e d i n P hase 1 b 
C o m bi na ti o n Ar m A ( L O X O- 3 0 5 2 0 0 m g Q D pl us ve net ocla x 4 0 0 m g Q D [after ra m p - u p] 
Secti o n  1. 4. 1 ).  
As of Se pte m ber 3 0, 2 0 2 0, P K data were a v aila ble fr o m 1 8 1 pat ie nts e nr olle d i n t he 
L O X O -B T K - 1 8 0 0 1 st u d y (Secti o n  1. 4. 2 ). 
As of N o ve m ber 2 3, 2 0 2 0, L O X O- 3 0 5 ha d b ee n rece ntl y i n vesti gate d i n 1 st u d y i n healt h y 
v ol u nteers ( L O X O- B T K- 2 0 0 1 4), w hic h was c o m plete d. L O X O- B T K - 2 0 0 1 4 was a pil ot 
f o o d-effect cr oss o ver st u d y e val uati n g t he effects of f o o d a n d a pr ot o n p u m p i n hi bit or 
( o me praz ole) o n t he P K of L O X O- 3 0 5 w here 1 0 healt h y v ol u nteers w ere gi ve n 2 0 0 m g of 
L O X O - 3 0 5 o n 3 se p arat e da ys, eac h f oll o we d b y a was h o ut peri o d.  
As of N o ve m ber 2 3, 2 0 2 0, f o ur a d diti o nal st u dies were o n g oi n g i n healt h y v ol u nteers 
( L O X O-B T K - 2 0 0 0 6, L O X O-B T K - 2 0 0 1 7, L O X O-B T K - 2 0 0 0 7, a n d L O X O-B T K - 2 0 0 0 8).  
L O X O -B T K - 2 0 0 0 6 is a dr u g- dr u g i nteracti o n ( D DI) st u d y e val u ati n g t he effects of a str o n g 
C Y P 3 A 4 i n hi bit or (itrac o naz ole) a n d a str o n g C Y P 3 A 4 i n d ucer (rifa m pi n) o n t he P K of 
L O X O - 3 0 5 w h ere, at t he ti me of t his pr ot oc ol’s de vel o p me nt, 3 healt h y v ol u nteers were 
gi ve n 1 d ose of 2 0 0 m g of L O X O - 3 0 5, 1 2 h ealt h y v ol u nteers were gi ve n 2 0 0 m g of 
L O X O - 3 0 5 o n 2 se p arat e da ys ( 1 of w hic h was c o-a d mi nistere d wit h itrac o naz ole), eac h 
f oll o we d b y a w as h o ut peri o d, a n d 1 2 healt h y v ol u nteers were gi ve n 2 0 0 m g of L O X O - 3 0 5 
o n 3 se parat e da ys ( 2 of w hic h wer e c o -a d mi nistere d wit h rifa m pi n) , eac h f oll o we d b y a 
was h o ut peri o d.  
L O X O -B T K - 2 0 0 1 7 is a si n gle asce n di n g d ose ( S A D) st u d y e val uati n g t he s afet y a n d 
t olera bilit y of L O X O- 3 0 5 at 3 0 0 m g, 6 0 0 m g, 8 0 0 m g, a n d 9 0 0 m g d oses, w here, at t he ti me 
of t his pr ot oc ol’s de vel o p me nt, 6 healt h y v ol u nteers were gi ve n a si n gle d ose of 3 0 0 m g 
L O X O - 3 0 5, 6 healt h y v ol u nteers wer e gi ve n a si n gle d ose of 6 0 0 m g L O X O - 3 0 5, 6 healt h y 
v ol u nteers were gi ve n a si n gle d ose of 8 0 0 m g L O X O - 3 0 5, a n d 6 h ealt h y v ol u nteers were 
gi ve n a si n gle d ose of 9 0 0 m g L O X O - 3 0 5.  
L O X O -B T K - 2 0 0 0 7 is a 2- part st u d y of t he a bs or pti o n, meta b olis m, e xcreti o n, a n d t he 
a bs ol ute bi oa vaila bilit y of [ 1 4C] -L O X O - 3 0 5 w here, at t he ti me of t his pr ot oc ol’s 
de vel o p me nt, 4 s u bjects were gi ve n a si n gle oral d ose of 2 0 0 m g of [ 1 4C] -L O X O - 3 0 5 
(c o ntai ni n g ~ 2 0 0 µ Ci) as a n oral s ol uti o n a n d 5 s u bjects were gi ve n a si n gl e oral d ose of 
2 0 0 m g L O X O - 3 0 5 as 2 × 1 0 0-m g ta blets f oll o we d 2  h o urs later b y a si n gl e d ose of < 1 0 0 µ g 
of [ 1 4C] -L O X O - 3 0 5 (c o ntai ni n g ~ 1  µ Ci of ra di oacti vit y [ micr otracer]) a d mi nistere d as a n I V  
p us h o ver a p pr o xi matel y 2 mi n utes.  

Pr ot oc ol 
C O N FI D E N TI A L  
C o va nce St u d y: 8 4 1 9 6 8 9 
Pr ot oc ol Refere n ce:  L O X O -B T K - 2 0 0 1 0 
Pr ot oc ol Versi o n 1. 0, 9 Dece m b er 2 0 2 0  
Pa ge 2 1 of 6 8 
L O X O -B T K - 2 0 0 0 8 is a D DI st u d y e val uati n g t he effects of L O X O- 3 0 5 o n t he P K of a 
se nsiti ve C Y P 3 A 4 s u bstrate ( mi daz ola m) w here, at t he ti me of t his pr ot oc ol’s de vel o p me nt, 
1 5 healt h y v ol u nteers w ere gi ve n 2 0 0 m g Q D of L O X O- 3 0 5 o n 1 3 c o ns ec uti ve da ys ( 1 da y of 
w hic h was c o -a d mi nister e d wit h I V mi daz ola m a n d 1 da y of w hic h w as c o-a d mi nistere d wit h 
oral mi daz ola m).  
1. 4. 1.  
S afet y  
As of Se pte m ber 2 7, 2 0 2 0, 3 3 0 patie nts were treat e d i n t he L O X O- B T K - 1 8 0 0 1 st u d y a n d 
recei v e d L O X O- 3 0 5. T his i ncl u des 3 2 4 patie nts treate d at d oses ra n gi n g fr o m 2 5 m g Q D 
t o 3 0 0 m g Q D i n P hase 1/ 2 M o n ot hera p y c o h orts, a n d 6 patie nts treat e d i n P hase 1 b 
C o m bi nati o n Ar m A ( L O X O- 3 0 5 2 0 0 m g Q D pl us ve net ocla x 4 0 0 m g Q D [after v e net ocla x 
ra m p- u p]). A f ull s u m mar y of treat me nt-e mer g e nt a d verse e ve nts ( T E A Es) f or patie nts i n t he 
st u d y is pr o vi de d i n t he L O X O- 3 0 5 I B a n d t h e I n vesti gat or is directe d t o t he safet y 
i nf or mati o n descri be d i n t hat d oc u me nt.1 A s u m mar y of safet y f or L O X O - 3 0 5 gi ve n as 
m o n ot hera p y t o patie nts i n t he L O X O- B T K - 1 8 0 0 1 st u d y is pr o vi de d bel o w.  
•  I n t he 3 2 4 patie nts i n t he P hase 1/ 2 M o n ot hera p y c o h orts, T E A Es re p ort e d i n ≥ 1 0 % 
of patie nts ( n = 3 3 or m ore) w ere fati g ue ( 2 0. 1 % t otal, 8. 3 % relate d), diarr hea ( 1 7. 0 % 
t otal, 8. 6 % relate d), a n d c o nt usi o n ( 1 3. 0 % t otal, 9. 0 % relate d). Dr u g-relat e d T E A Es 
were re p orte d i n 1 5 6 of 3 2 4 patie nts ( 4 8. 1 %) i n t h e P hase 1/ 2 M o n ot hera p y c o h orts. 
T he m ost fre q ue ntl y r e p orte d dr u g- relate d T E A Es f or L O X O- 3 0 5 (t h ose i n > 5 % of 
patie nts o verall) w ere c o nt usi o n ( 9. 0 %), diarr h ea ( 8. 6 %), a n d fati g ue ( 8. 3 %). All 
ot her dr u g- r elate d T E A Es were re p orte d i n < 5 % of patie nts (ie, < 1 7 p atie nts eac h). 
Treat me nt - e mer ge nt A Es of se verit y Gra de 3 or 4 were re p orte d i n 8 7 of 3 2 4 patie nts 
( 2 6. 9 %) i n t he P hase 1/ 2 M o n ot hera p y c o h orts, wit h 4 1 ( 1 2. 7 %) of t hes e Gra de 3 or 4 
A Es re p orte d as rel ate d t o st u d y dr u g.  
•  O n -st u d y deat h ( d eat h wit hi n 2 8 da ys of t he last d ose of st u d y dr u g) d ue t o a Gra d e 5 
(fatal) A E was r e p orte d i n 4 of 3 2 4 patie nts ( 1. 2 %) i n t he P hase 1/ 2 M o n ot hera p y 
c o h orts . O ne Gra de 5 A E, E nter oc occ us f aeci u m -relate d se ptic s h oc k, was c o nsi dere d 
t o be relate d t o st u d y dr u g (f urt her d etails are pr o vi de d i n t he L O X O-3 0 5 I B 1). All 
ot her Gra d e 5 A Es w ere c o nsi dere d t o be n ot relat e d t o st u d y dr u g; t hese i ncl u de d 
p ne u m o nia f u n gal, s h oc k, a n d ple ural eff usi o n. 
Treat me nt - e mer ge nt A Es re p orte d f oll o wi n g L O X O- 3 0 5 a d mi nistrati o n i n healt h y v ol u nteers 
i n t he L O X O-B T K - 2 0 0 1 4 st u d y ( hea dac he, na us ea, a n d v o miti n g), were all Gra de 1 i n 
se verit y a n d c o nsi dere d t o be relate d t o L O X O- 3 0 5. All 3 e ve nts were re p orte d b y 1 s u bject 
a n d res ol ve d wit hi n 1 t o 1. 5 da ys.  
Treat me nt - e mer ge nt A Es re p orte d f oll o wi n g L O X O- 3 0 5 a d mi nistrati o n i n healt h y v ol u nteers 
i n t he L O X O-B T K - 2 0 0 0 6 st u d y (i nter mitte nt belc hi n g, bl oati n g, i nsect bite, a p ht h o us ulcer, 
na usea, i nter mitte nt diarr hea [ x 2], m us cle t witc h), were all Gra d e 1 i n se verit y, a n d bl oati n g, 
1 i nsta nce of i nter mitte nt diarr hea, a n d i nt er mitte nt belc hi n g were c o nsi dere d t o be relat e d t o 
L O X O - 3 0 5 a n d rifa m pi n. All 7 A Es were re p ort e d b y 3 s u bjects a n d all e v e nts res ol ve d pri or 
t o E n d of Treat me nt ( E O T; preli mi nar y data o n fil e at t he ti me of t his pr ot oc ol’s 
de vel o p me nt).  

Pr ot oc ol 
C O N FI D E N TI A L  
C o va nce St u d y: 8 4 1 9 6 8 9 
Pr ot oc ol Refere n ce:  L O X O -B T K - 2 0 0 1 0 
Pr ot oc ol Versi o n 1. 0, 9 Dece m b er 2 0 2 0  
Pa ge 2 2 of 6 8 
Treat me nt -e mer gent A Es re p orte d f oll o wi n g L O X O- 3 0 5 a d mi nistrati o n i n healt h y v ol u nteers 
i n t he L O X O-B T K - 2 0 0 1 7 st u d y ( hea dac he [ o bs er ve d at t he 3 0 0 m g L O X O - 3 0 5 d ose], a n d 
hea dac he [ x 2], i nter mitte nt hea dac h e, a n d p etec hi al ras h left t hi g h [ o bser ve d at t he 9 0 0 m g 
L O X O - 3 0 5 dose]), w ere all Gra de 1 i n se v erit y. O ne i nsta nce of h ea d ac he o bser ve d at t he 
3 0 0 m g L O X O - 3 0 5 d ose a n d 1 i nsta nce o bser ve d at t he 9 0 0 m g L O X O - 3 0 5 d ose, t he 
i nter mitte nt hea dac h e, a n d t he petec hial ras h left t hi g h were c o nsi d ere d t o be relate d t o 
L O X O - 3 0 5. All fi ve A Es were re p orte d b y 4 s u bjects a n d res ol ve d wit hi n 2 h o urs t o 5 da ys 
of o nset ( preli mi nar y d ata o n file at t he ti me of t his pr ot oc ol’s de vel o p me nt).  
Treat me nt - e mer ge nt A Es re p orte d f oll o wi n g L O X O- 3 0 5 a d mi nistrati o n i n healt h y v ol u nteers 
i n Part 1 of t he L O X O- B T K - 2 0 0 0 7 st u d y ( bl o o d y n ose, hea dac he, l o ose st o ol [ x 2], re d 
b u m ps o n left k nee, s mall a brasi o n t o ri g ht el b o w), were all Gra d e 1 i n se verit y a n d hea dac he 
was c o nsi der e d t o be r elate d t o L O X O- 3 0 5. All 7 A Es were re p orte d b y 4 s u bjects a n d al l 
e ve nts res ol ve d wit hi n 1 t o 2 da ys ( preli mi nar y data o n file at t he ti me of t his pr ot oc ol’s 
de vel o p me nt).  
Treat me nt - e mer ge nt A Es re p orte d f oll o wi n g L O X O- 3 0 5 a d mi nistrati o n i n healt h y v ol u nteers 
i n Part 2 of t he L O X O-B T K - 2 0 0 0 7 st u d y (te n der n ess at left ve ni p u nct ure site [ x 2], br uisi n g 
t o left a ntec u bital sec o n d ar y t o p hle b ot o m y [ x 2], br uisi n g t o ri g ht a ntec u bital sec o n dar y t o 
p hle b ot o m y, a n d aller gic reacti o n), were all Gra de 1 i n se verit y a n d n o e v e nts were 
c o nsi dere d t o be relate d t o L O X O- 3 0 5. All 6 A Es were re p orte d b y 4 s u bjects a n d all e ve nts 
res ol ve d wit hi n 1 t o 2 da ys ( preli mi nar y data o n file at t he ti me of t his pr ot oc ol’s 
de vel o p me nt).  
Treat me nt - e mer ge nt A Es re p orte d f oll o wi n g L O X O- 3 0 5 a d mi nistrati o n i n healt h y v ol u nteers 
i n t he L O X O-B T K - 2 0 0 0 8 st u d y (i njecti o n site pai n, nasal c o n gesti o n, flat ule nce, 
c o nsti pati o n, i ncrease d uri nar y fr e q ue n c y, facial ras h, a n d s ki n tear fr o m ta pe at I V site), were 
all Gra de 1 i n se v erit y, a n d flat ule nce, c o nsti pati o n, a n d i ncrease d uri nar y fre q ue nc y were 
c o nsi dere d  t o be relate d t o L O X O- 3 0 5. All 7 A Es were re p orte d b y 3 s u bjects a n d all e ve nts 
res ol ve d wit hi n 1 t o 8 da ys ( preli mi nar y data o n file at t he ti me of t his pr ot oc ol’s 
de vel o p me nt). 
As part of eac h cli nical trial c o n d ucte d i n patie nts or healt h y v ol u nteers, E C G a n d vital si g ns 
are perf or m e d at i nter vals s pecifie d b y pr ot oc ol. F or st u d y L O X O- B T K - 1 8 0 0 1 c o n d ucte d i n 
patie nts, n o cli nicall y si g nifica nt fi n di n gs of Q Tc pr ol o n gati o n ha ve bee n i de ntifie d i n 3 3 0 
patie nts as of Se pte m ber 2 7, 2 0 2 0 ( L O X O- 3 0 5 I B 1). I n a d diti o n, t here ha ve bee n n o cli nicall y 
si g nifica nt a b n or mal fi n di n gs i n vital si g ns a n d E C G data i n t he st u dies i n vesti gati n g 
L O X O - 3 0 5 c o n d u cte d i n healt h y v ol u nteers as of N o ve m ber 2 3, 2 0 2 0 ( preli mi nar y data o n 
file at t he ti me of t his pr ot oc ol’s de vel o p me nt). 
1. 4. 2.  
P h ar m ac o ki netics  
As of Se pte m ber 3 0, 2 0 2 0, P K data were a v aila ble fr o m 1 8 1 patie nts e nr olle d i n t he 
L O X O -B T K - 1 8 0 0 1 st u d y. Stea d y-state P K para meters of L O X O-3 0 5 i n t h ese ca n cer patie nts 
c o ul d be deri ve d fr o m data c ollecte d o n C ycle 1 D a y 8 ( Fi g ure 1 ), a n d are s h o w n i n Ta ble 1 . 
T hese data s h o w t hat L O X O -3 0 5 is a bs or be d after oral a d mi nistrati o n wit h a me dia n ti me t o 
ma xi m u m o bser ve d plas ma c o nce ntr ati o n (t ma x ) of a p pr o xi matel y 2 h o urs a n d l o w cleara nce 
(Ta ble 1 ). D u e t o t he li mite d sa m pli n g i nter val ( 0- 8 h o urs), i m p utati o n f or t he 2 4- h o ur sa m ple 
was ma de fr o m C ycle 1 Da y 8 pre d os e sa m ple, lea di n g t o a n esti mate d plas ma half- life of 

Pr ot oc ol 
C O N FI D E N TI A L  
C o va nce St u d y: 8 4 1 9 6 8 9 
Pr ot oc ol Refere n ce:  L O X O -B T K - 2 0 0 1 0 
Pr ot oc ol Versi o n 1. 0, 9 Dece m b er 2 0 2 0  
Pa ge 2 3 of 6 8 
a p pr o xi matel y 2 0 h o urs. Ma xi m u m o bser ve d plas ma c o nce ntrati o n a n d area u n der t he plas m a 
c o nce ntr ati o n -ti me c ur ve ( A U C) of L O X O- 3 0 5 s h o we d i ncrease pr o p orti o nal t o d ose 
(Fi g ure 2 ). F oll o wi n g a d mi nistrati o n of t he rec o m me n de d P hase 2 d ose ( R P 2 D) 2 0 0 m g Q D, 
mea n tr o u g h plas ma le v els of L O X O- 3 0 5 e x cee de d t he c o nce ntrati o n re q uire d f or 9 6 % 
i n hi biti o n of B T K i n vitr o (I C5 0  =  
n g/ m L, I C9 6 =  
 n g/ m L). F urt h er details ma y be 
f o un d i n t he I B. 1 
P har mac o ki netic dat a f oll o wi n g oral a d mi nistrati o n of a 2 0 0- m g d ose of L O X O- 3 0 5 i n ta blet 
f or m i n healt h y v ol u nteers i n t he L O X O-B T K -2 0 0 1 4 st u d y i n dicate t hat t here was little effect 
of eit her a sta n d ar d meal or t he pr ot o n p u m p i n hi bit or o me praz ole o n t h e P K of L O X O- 3 0 5.  
T a ble 1 : P h ar m ac o ki netic P ar a m eters of L O X O- 3 0 5 i n C a ncer P atie nts 
( St u d y L O X O -B T K - 1 8 0 0 1) at Ste a d y St ate ( C ycle 1 D a y 8) 
D ose Le vel  
N  
C m a x 
( n g/ m L) 
Ge o m e a n 
( % C V) 
tm a x  ( h) 
Me di a n  
( mi n, m a x) 
A U C 0- 8 
( n g * h/ m L) 
Ge o m e a n 
( % C V) 
A U C 0- 2 4 
( n g * h/ m L) 
Ge o m e a n 
( % C V) 
C L/ F ( L/ h)  
Ge o m e a n 
( % C V) 
t1/ 2 ( h) 
Ge o m e a n 
( % C V) 
R ati o  
A U C 0- 8  
D a y 
8/ D a y 1  
Ge o 
m e a n 
( % C V) 
2 5  m g Q D  
5 
7 3 4 
( 1 1. 0 %) 
2 ( 1, 8)  
4 2 4 0 
( 1 2. 4 %) 
9 8 0 0 
( 2 5. 8 %) 
1. 5 5 a 
( 6 9. 6 %) 
1 8. 2 a 
( 6 0. 1 %) 
1. 4 4 
( 2 3. 0 %) 
5 0  m g Q D  
6 
1 4 2 0 
( 1 9. 2 %) 
1. 5 ( 1, 4)  
8 6 6 0 
( 2 4. 7 %) 
2 0 1 0 0 
( 3 4. 9 %) 
2. 6 2 b 
( 3 6. 7 %) 
1 7. 6 b 
( 3 9. 6 %) 
1. 5 1 
( 2 5. 9 %) 
1 0 0  m g Q D  
9 
3 9 1 0 
( 3 5. 6 %) 
2 ( 1, 4)  
2 2 0 0 0 
( 3 7. 2 %) 
5 2 4 0 0 
( 3 9. 7 %) 
0. 9 6 8 c 
( 6 3. 0 %) 
2 2. 2 c 
( 3 3. 9 %) 
1. 8 8 
( 4 2. 8 %) 
1 5 0  m g Q D  
2 0  
4 6 8 0 
( 2 9. 1 %) 
2 ( 1, 8)  
2 8 0 0 0 
( 2 9. 6 %) 
6 4 4 0 0 
( 3 9. 6 %) 
1. 3 6 d  
( 6 6. 7 %) 
1 8. 1 d  
( 5 1. 8 %) 
1. 7 4 
( 2 4. 9 %) 
2 0 0  m g Q D  
9 9  
5 7 7 0 
( 4 7. 7 %) 
2 ( 1, 8)  
3 6 9 0 0  
( 4 0. 8 %) 
9 1 0 0 0 
( 4 2. 0 %) 
1. 1 4 e 
( 6 1. 8 %) 
1 9. 9 e 
( 5 6. 2 %) 
1. 6 9 h 
( 2 9. 6 %) 
2 5 0  m g Q D  
2 5  
8 1 0 0 
( 2 8. 1 %) 
2 ( 1, 4)  
4 9 7 0 0 
( 3 1. 3 %) 
1 1 1 0 0 0 
( 3 8. 7 %) 
1. 2 6 f 
( 1. 0 8 %) 
1 7. 4 f 
( 5 0. 6 %) 
1. 6 8 
( 2 4. 5 %) 
3 0 0  m g Q D  
1 7  
1 0 7 0 0 
( 2 6. 6 %)  
2 ( 1, 4)  
6 5 8 0 0 
( 3 5. 9 %) 
1 5 8 0 0 0 
( 4 9. 2 %) 
1. 6 3 g  
( 4 2. 5 %) 
3 0. 1 g  
( 1 0 2 %) 
2. 1 5 
( 3 1. 2 %) 
A b bre viati o ns: A U C 0- 8 = area u n der t he c o nce ntrati o n -ti me c ur ve fr o m ti me 0 t o 8 h o urs; A U C 0- 2 4 = area u n der 
t he c o nce ntrati o n-ti me c ur ve fr o m ti me 0 t o 2 4 h o urs; C L/ F  = a p pare nt oral cleara nce; C ma x  = ma xi m u m dr u g 
c o nce ntrati o n; Ge o mea n = Ge o metrical mea n; N = n u m ber of s u bjec ts; Q D = o nce dail y; C V = c oefficie nt of 
variati o n; t1/ 2 = half -life; tma x  = ti me of ma xi mal plas ma c o nce ntrati o n.  
a N =  4, b N =  5, c N =  8, d N =  1 8, e N = 6 4, f N =  2 1, g N =  1 6, h N =  7 3  
S D T M Tra nsfer: Se pte m ber 3 0, 2 0 2 0  
C CI
C CI

Pr ot oc ol 
C O N FI D E N TI A L  
C o va nce St u d y: 8 4 1 9 6 8 9 
Pr ot oc ol Refere n ce:  L O X O -B T K - 2 0 0 1 0 
Pr ot oc ol Versi o n 1. 0, 9 Dece m b er 2 0 2 0  
Pa ge 2 4 of 6 8 
 
C CI
C CI
C CI

Pr ot oc ol 
C O N FI D E N TI A L  
C o va nce St u d y: 8 4 1 9 6 8 9 
Pr ot oc ol Refere n ce:  L O X O -B T K - 2 0 0 1 0 
Pr ot oc ol Versi o n 1. 0, 9 Dece m b er 2 0 2 0  
Pa ge 2 5 of 6 8 
S D T M Tra nsfer: Se pte m ber 3 0, 2 0 2 0  
Preli mi nar y a n d i nteri m plas ma c o nce ntrati o n dat a fr o m o n g oi n g st u d y L O X O- B T K - 2 0 0 0 8 
i n dicate t hat t he d ose of 2 0 0 m g Q D i n healt h y v ol u nteers pr o d uces a L O X O- 3 0 5 stea d y-stat e 
ge o metric mea n C ma x  of 
 n g/ m L a n d A U C fr o m h o ur 0 t o 2 4 h o urs p ost d ose ( A U C0- 2 4) 
of a p pr o xi matel y  
 n g * h/ m L. T hese res ults i n dicate t hat t he d ose of 2 0 0 m g Q D i n t his 
st u d y will pr o vi de e x p os ure i n t he ra n g e of t he R P 2 D of L O X O- 3 0 5 s ee n i n patie nts, w hile 
re mai ni n g well u n der t h e n o o bser ve d a d v erse effect le vel Cma x  f or ge n ot o xicit y of 
a p pr o xi matel y  
 n g/ m L.  
1. 5.  
St u d y R ati o n ale 
T he o bjecti ve of D DI st u dies is t o deter mi ne w het her p ote ntial i nteracti o ns bet wee n a n 
i n vesti gati o nal dr u g a n d ot her dr u gs e xist. Dr u g- dr u g i nteracti o n st u dies ha ve a n i m p orta nt 
r ole i n dr u g de vel o p me nt,9 a n d t his st u d y is bei n g perf or me d as part of t he de vel o p me nt 
pr o gra m f or L O X O - 3 0 5. 
L O X O - 3 0 5 s h o w e d n o d etecta ble i n hi biti o n (I C5 0  
 μ M) of C Y P 1 A 2, C Y P 2 B 6, 
C Y P 2 C 1 9, a n d C Y P 2 D 6, a n d wea k i n hi biti o n of C Y P 2 C 8, C Y P 2 C 9, a n d C Y P 3 A 4 wit h 
i n hi bit or y c o nsta nt ( Ki) val ues ra n gi n g fr o m  
 μ M i n h u ma n li ver micr os o mes. 
After pr e -i nc u b ati o n of micr os o mes wit h L O X O- 3 0 5 a n d nic oti na mi de a d e ni ne di n ucle oti de 
p h os p hate f or 3 0 mi n utes pri or t o a d diti o n of C Y P 4 5 0 pr o be s u bstrate, t he C Y P 3 A 4 
i n hi bit or y p ote nc y of L O X O- 3 0 5 was i ncrease d, s u g gesti n g t he p ote ntial f or ti me- de pe n d e nt 
i n hi biti o n of C Y P 3 A 4. F urt her ki netic e v al uati o n c o nfir me d t hat L O X O- 3 0 5 is a 
ti me- de pe n de nt i n hi bit or of C Y P 3 A 4 wit h a Ki val ue of  
 μ M a n d a ki nact ( ma xi mal 
i nacti vati o n rate c o nsta nt) val ue of  
. 1 5 h- 1 res ulti n g i n a Cli nact val ue (i nacti vati o n 
clear a nce) of 8. 6 4 mi n - 1 m M - 1. 
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI

Pr ot oc ol 
C O N FI D E N TI A L  
C o va nce St u d y: 8 4 1 9 6 8 9 
Pr ot oc ol Refere n ce:  L O X O -B T K - 2 0 0 1 0 
Pr ot oc ol Versi o n 1. 0, 9 Dece m b er 2 0 2 0  
Pa ge 2 6 of 6 8 
I n a n i n vitr o he pat oc yt e assa y, L O X O- 3 0 5 i n d uce d m R N A f or C Y P 3 A 4, C Y P 3 A 5, 
C Y P 2 B 6, a n d C Y P 2 C 1 9. F or b ot h C Y P 2 B 6 a n d C Y P 2 C 1 9, a n i ncreas e i n acti vit y was see n. 
F or C Y P 3 A 4, L O X O - 3 0 5 di d n ot ca use a n i ncrease i n acti vit y, li kel y d ue t o c o nc urre nt 
i n hi biti o n of C Y P 3 A 4 b y L O X O- 3 0 5. L O X O-3 0 5 ca use d a d ecreas e i n m R N A  f or C Y P 1 A 2 
b ut di d n ot lea d t o a re d u cti o n of C Y P 1 A 2 acti vit y. I n t he st u d y, C Y P 2 D 6, C Y P 2 C 8, a n d 
C Y P 2 C 9 m R N A were n ot i n d uce d. 
L O X O - 3 0 5 ma y h a ve t he p ote ntial t o raise plas ma c o nce ntrati o ns of dr u gs t hat are s u bstrates 
of C Y P 2 C 8, C Y P 2 C 9, a n d C Y P 3 A 4 or l o w er plas ma c o nce ntrati o ns t hat are meta b olize d b y 
C Y P 1 A 2, C Y P 2 B 6, C Y P 2 C 1 9, or C Y P 3 A 4. T his st u d y is desi g ne d t o deter mi ne t he effect of 
L O X O - 3 0 5 o n t he P K of caff ei ne ( C Y P 1 A 2 s u bstrate), S- warfari n ( C Y P 2 C 9 s u bstrate), a n d 
o me praz ole ( C Y P 2 C 1 9 s u bstrate). T he effects of L O X O - 3 0 5 o n t he P K of ot her C Y P 4 5 0 
s u bstrates will be e x pl ore d i n se parate cli nical st u dies. Caffei ne, warfari n, a n d o me praz ole 
are c o m m o nl y use d as i n de x s u bstrates f or C Y P 4 5 0 e nz y mes i n D DI st u di es. 9 
1. 6.  
Ris k Assess m e nt  
S u bjects i n t he c urre nt st u d y will n ot recei ve a n y healt h be nefit ( b e y o n d t h at of a n assess m e nt 
of t heir me dical stat us) fr o m partici pati n g i n t he st u d y. T he ris ks of partici p ati o n are 
pri maril y t h ose ass ociate d wit h a d verse reacti o ns t o t he st u d y treat me nts, alt h o u g h t here ma y 
als o be s o me disc o mf ort fr o m c ollecti o n of bl o o d sa m ples a n d ot her st u d y pr oce d ures. T he 
d ose of L O X O- 3 0 5 a d mi nistere d i n t his st u d y is n ot a ntici pate d t o i n d uce a n y p ote ntial ris k t o 
s u bjects partici pati n g i n t his st u d y as t he d ose d oes n ot e xcee d t he hi g h est d ose safel y 
a d mi nistere d i n first -i n- h u ma n st u d y or healt h y v ol u nteer st u dies.1 M ore i nf or mati o n a b o ut 
t he k n o w n a n d e x p ecte d be nefits, ris ks, a n d reas o na bl y a ntici pate d A Es ass ociate d wit h 
L O X O - 3 0 5 ma y b e f o u n d i n t he I B. 1 
T here is a p ote ntial ris k t hat m ulti ple d oses of L O X O - 3 0 5 ma y lea d t o decreases i n w hite 
bl o o d cells i ncl u di n g ne utr o p hils, l y m p h oc ytes, m o n oc ytes, a n d e osi n o p hils. T heref ore, t o 
miti gate a n y p ote ntial i m m u n os u p pressi ve ris ks d uri n g t he o n g oi n g S A R S- C o V- 2 
( C O VI D-1 9) pa n de mic, s u bjects will re mai n i n t he Cli nical Researc h U nit ( C R U) f or 
9 6 h o urs p ost d ose ( Da y 2 3) t o all o w f or L O X O - 3 0 5 eli mi nati o n. I n a d diti o n, s u bject’s 
he mat ol o g y la b orat or y r es ults will be re vie we d pri or t o disc har ge fr o m t he C R U. M ore 
i nf or mati o n a b o ut t he k n o w n a n d e x pecte d be n efits, ris ks, a n d reas o na bl y a ntici pate d A Es 
ass ociate d wit h L O X O - 3 0 5 ma y be f o u n d i n t he I B.1 
T he d ose of caff ei ne, o m e praz ol e, vita mi n K, a n d warfari n a d mi nistere d i n t his st u d y are n ot 
a ntici pate d t o i n d uce a n y p ote ntial ris k or be nefit t o s u bjects partici pati n g i n t his st u d y, as 
t he y are si n gle d oses a d mi nistere d acc or di n g t o t he d osi n g rec o m me n d ati o ns i n t he f ull 
prescri bi n g i nf or mati o n.  
T he safet y m o nit ori n g pr actices e m pl o ye d will i ncl u de A E re p orti n g, vital si g n 
meas ure me nts, 1 2 -l ea d E C Gs, cli nical la b orat or y e val uati ons, a n d p h ysical e xa mi nati o ns, a n d 
are c o nsi d ere d a de q uat e t o pr otect t he s u bjects’ s afet y.  
 
 

Pr ot oc ol 
C O N FI D E N TI A L  
C o va nce St u d y: 8 4 1 9 6 8 9 
Pr ot oc ol Refere n ce:  L O X O -B T K - 2 0 0 1 0 
Pr ot oc ol Versi o n 1. 0, 9 Dece m b er 2 0 2 0  
Pa ge 2 7 of 6 8 
2.  O B J E C TI V E S A N D E N D P OI N T S  
2. 1.  
O bjecti ves  
2. 1. 1.  
Pri m ar y O bjecti ve  
T he pri mar y o bjecti ve of t he st u d y is t o assess t he effect of m ulti ple oral d oses of L O X O- 3 0 5 
o n t he P K of si n gle oral d oses of caffei ne ( C Y P 1 A 2 s u bstrate), S- w arfari n ( C Y P 2 C 9 
s u bstrate), a n d o me praz ole ( C Y P 2 C 1 9 s u bstrate) i n healt h y s u bjects. 
2. 1. 2.  
Sec o n d ar y O bjecti ve  
T he sec o n d ar y o bjecti ve of t he st u d y is t o assess t he safet y a n d t olera bilit y of m ulti ple oral 
d oses of L O X O- 3 0 5 w he n a d mi nistere d al o ne, a n d c oa d mi nistere d wit h a si n gle oral d ose of 
pr o be dr u g c o c ktail. 
2. 2.  
E n d p oi nts  
2. 2. 1.  
Pri m ar y E n d p oi nts  
T he f oll o wi n g P K para m eters will be calc ulate d w he ne ver p ossi ble, b ase d o n t he plas ma 
c o nce ntr ati o ns of caffei n e/ para x a nt hi ne, o me praz ole, S- warfari n, a n d L O X O- 3 0 5 (as 
a p pr o priate): 
•   A U C 0- 2 4 
•  A U C fr o m h o ur 0 t o t he l ast meas ura ble c o nce ntrati o n ( A U C 0-t) 
•  A U C fr o m h o ur 0 e xtr a p olate d t o i nfi nit y ( A U C 0- i nf) 
•  perce nt a ge e xtra p olati o n f or A U C 0- i nf ( % A U Ce xtra p) 
•  a p pare nt s yste mic cleara nce ( C L/ F) 
•  a p pare nt plas m a ter mi nal eli mi nati o n half -life (t½ ) 
•  C ma x  
•  tma x  
•  a p pare nt ter mi nal eli mi nati o n rate c o nsta nt ( λ z) 
•  a p pare nt v ol u me of distri b uti o n at t he ter mi nal p hase ( V z/ F) 
•  mea n resi de n ce ti me ( M R T)  
•  A U C 0- 2 4 a n d A U C 0- 4 8 rati o of para x a nt hi ne t o caffei ne ( M R A U C; 
caff ei ne/ par a xa nt hi ne o nl y). 
2. 2. 2.  
Sec o n d ar y E n d p oi nts  
Safet y a n d t oler a bilit y will be assesse d b y m o nit ori n g A Es, perf or mi n g p h ysical e xa mi nati o ns 
a n d cli nical la b or at or y e v al uati o ns, meas uri n g vital si g ns, a n d rec or di n g 1 2- lea d E C Gs.  

Pr ot oc ol 
C O N FI D E N TI A L  
C o va nce St u d y: 8 4 1 9 6 8 9 
Pr ot oc ol Refere n ce:  L O X O -B T K - 2 0 0 1 0 
Pr ot oc ol Versi o n 1. 0, 9 Dece m b er 2 0 2 0  
Pa ge 2 8 of 6 8 
3.  I N V E S TI G A TI O N A L P L A N 
3. 1.  
O ver all St u d y Desi g n a n d Pl a n  
T his is a P hase  1, o pe n-la bel, 2- peri o d, fi xe d-se q u e nce D DI st u d y t o i n vesti gate t he effect of 
m ulti ple oral d oses of L O X O- 3 0 5 o n t he P K of si n gle oral d oses of caffei ne ( C Y P 1 A 2 
s u bstrate) a n d its meta b olite para xa nt hi ne, S- w arfari n ( C Y P 2 C 9 s u bstrate), a n d o me praz ole 
( C Y P 2 C 1 9 s u bstrate) i n healt h y s u bjects.  
I n Peri o d 1, Da y 1, 2 0 0 m g caff ei ne (ta blet), 4 0  m g o me praz ole (ca ps ule), a n d 1 0 m g 
warf ari n  (ta blet) a d mi nistere d as a si n gle d ose of pr o be dr u g c o c ktail, al o n g wit h 1 0 m g 
vita mi n K (ta blets), will be a d mi nistere d i n t he m or ni n g f oll o wi n g a fast of at least 1 0  h o urs 
pre d ose a n d 2 h o urs p ost d ose. Bl o o d sa m ples f or c o nce ntrati o ns of t he s u bstrates 
(caffei ne/ para x a nt hi ne, o me praz ole, a n d S-warfar i n) i n plas ma will be c ollecte d  
 
. Of t h e sa m ples c ollecte d f or c o nce ntrati o ns of eac h 
s u bstrate i n plas ma 
, sa m ples will be a nal yze d 
f or c o nce ntrati o n of caffei ne/ para xa nt hi ne fr o m 
, f or 
c o nce ntr ati o n of o me praz ole fr o m 
, a n d c o nce ntrati o ns of 
S- warf ari n fr o m 
. 
T here will be a was h o ut peri o d of 5 da ys b et wee n a d mi nistrati o n of t he pr o be dr u g c oc kt ail 
o n Da y 1 a n d t he first d ose of L O X O- 3 0 5 o n Da y 6.  
I n Peri o d 2, o n Da ys 6 t hr o u g h 1 9, oral d oses of 2 0 0 m g L O X O - 3 0 5 will be a d mi nistere d Q D 
f or 1 4 c o nsec uti ve da ys i n t he m or ni n g at t he act u al ti me of t he Da y 1 pr o b e dr u g c oc kt ail 
d osi n g ( ± 1 h o ur). O n Da y 1 5, L O X O- 3 0 5 will be c oa d mi nistere d wit h 2 0 0 m g caffei ne 
(ta blet), 4 0 m g o me praz ole (ca ps ule ), a n d 1 0 m g warfari n (ta blet) a d mi nistere d as a si n gle 
d ose of pr o be dr u g c oc kt ail, al o n g wit h 1 0 m g of vita mi n K (ta blets) at t he act ual ti me of t he 
Da y 1 pr o be dr u g c oc kt ail d osi n g ( ± 1 h o ur) f oll o wi n g a fast of at least 1 0 h o urs pre d ose a n d 
2 h o urs p ost d ose. O n Da ys 7 t hr o u g h 1 1, a n d Da ys 1 3, 1 4, 1 6, 1 8, a n d 1 9, s u bjects will fast 
f or at least 2 h o urs pre d ose a n d 1- h o ur p ost d ose. O n Da ys 6, 1 2, a n d 1 7 w here cli nical 
la b orat or y e v al uati o ns ar e perf or me d, s u bjects will fast f or at least 8 h o urs pre d ose a n d 1 h o ur 
p ost d ose. Bl o o d sa m ples f or c o nce ntrati o ns of L O X O- 3 0 5 i n plas ma will be c ollecte d a n d 
a nal yze d 
 
 
 Bl o o d sa m ples f or c o n ce ntrati o ns of t he s u bstrates 
(caffei ne/ para x a nt hi ne, o me praz ole, a n d S-warfari n)  i n plas ma 
 
 Of t h e sa m ples c ollecte d f or c o nce ntrati o ns of eac h 
s u bstrate i n plas ma pre d ose 
, sa m ples will be a nal yze d 
f or c o nce ntrati o n of caffei ne/ para xa nt hi ne 
, f or 
c o nce ntr ati o n of o me praz ole 
, a n d f or c o nce ntrati o n 
of S - warf ari n 
. 
T he sc he matic of t he st u d y desi g n is dis pla ye d i n Fi g ure 3 . T h e start of t he st u d y is defi ne d as 
t he date t he first s u bject w h o is e nr olle d i n t he st u d y si g ns a n I nf or me d C o nse nt F or m (I C F). 
N ote t hat e nr olle d s u bjects are defi n e d as t h ose s u bjects w h o are assi g ne d t o recei v e a d ose of 
st u d y dr u g; t his defi niti on e xcl u des scree n fail ure s u bjects. Re place me nt s u bjects ma y be 
e nr olle d o nl y if dee m e d necessar y b y t he S p o ns or. 
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI

Pr ot oc ol 
C O N FI D E N TI A L  
C o va nce St u d y: 8 4 1 9 6 8 9 
Pr ot oc ol Refere n ce:  L O X O -B T K - 2 0 0 1 0 
Pr ot oc ol Versi o n 1. 0, 9 Dece m b er 2 0 2 0  
Pa ge 2 9 of 6 8 
S u bjects w h o are d eter mi ne d t o be scr ee n fail ures are per mitte d t o be re -s cree ne d if t he 
I n v esti gat or ( or d esi g nee), wit h a gree me nt fr o m t he S p o ns or, feels t hat t he s u bject ma y meet 
eli gi bilit y criteria u p o n re -scr ee n. Re-s cree ne d s u bjects will be pr o vi de d a ne w s u bject 
n u m ber. 
T o assess t heir eli gi bilit y t o e nter t he st u d y, p ote ntial s u bjects will be scree ne d wit hi n 3 4  da ys 
( Da ys - 3 5 t o - 2) a n d be a d mitte d t o t he C R U o n Da y -1 ( C hec k -i n). 
S u bjects will be c o nfi ne d at t he C R U fr o m t he ti me of C hec k -i n ( Da y - 1) u ntil E O T o n 
Da y  2 3 u p o n c o m pleti o n of all P K a n d safet y assess me nts or Earl y Ter mi n ati o n ( E T) if t he 
s u bject disc o nti n ues. D osi n g of pr o be dr u g c oc ktail will occ ur o n Da y 1 a n d Da y 1 5 a n d 
d osi n g of L O X O- 3 0 5 will occ ur o n Da ys 6 t hr o u g h 1 9. A f oll o w- u p p h o ne call will occ ur f or 
all s u bjects w h o recei ve d at least 1  d ose of st u d y dr u g (i ncl u di n g s u bjects w h o are ter mi nate d 
earl y) 7 d a ys ( ± 2 da ys) after E O T or E T. T he d urati o n of partici pati o n is e x pecte d t o be 
a p pr o xi matel y 6 7 da ys ( Scree ni n g t hr o u g h f oll o w- u p p h o ne call). 
Fi g ure  3: St u d y Sc he m atic 
 
I n t his st u d y, p h ysical e x a mi nati o ns, 1 2-lea d E C Gs, vital si g n meas ure me nts, H o w D o Y o u 
Feel ? ( H D Y F?) i n q uiries, cli nical c he mistr y pa nel, c oa g ulati o n para meters, he mat ol o g y 
pa nel, uri nal ysis ( U A; A p pe n di x 2 ), a n d rec or di n g of c o nc o mita nt me dicati o ns will be 
perf or me d at s pecifi e d ti mes d uri n g t he st u d y (f or s pecific ti me p oi nts a n d details o n eac h 
st u d y varia ble, refer t o A p pe n di x 4 ).  
A d verse e ve nts a n d seri o us a d verse e ve nts ( S A Es) will be c ollecte d be gi n ni n g at i nf or me d 
c o nse nt. A d vers e e v e nts will be re p orte d t hr o u g h o ut t he st u d y (ie, fr o m si g ni n g of t he I C F 
u ntil E n d of St u d y [ E O S], or u ntil E T if t he s u bject disc o nti n ues fr o m t he st u d y a n d d oes n ot 
c o m plete a f oll o w - u p p h o ne call), eit her as s u bject me dical hist or y (if t he e ve nt is re p orte d as 
be gi n ni n g pri or t o si g ni n g of t he I C F or if t he e ve nt occ urs pri or t o st u d y dr u g a d mi nistrati o n 
o n Da y 1 a n d is assess e d as n ot relate d t o st u d y pr oce d ures b y t h e I n vesti gat or [ or desi g nee]) 
or as A Es (if t he e ve nt occ urs after si g ni n g of t he I C F b ut pri or t o st u d y dr u g a d mi nistrati o n 
o n Da y 1 a n d is assess e d as relate d t o st u d y pr o ce d ures b y t he I n v esti gat or [ or desi g nee], or if 
t he e ve nt occ urs aft er st u d y dr u g a d mi nistrati o n o n Da y 1 t hr o u g h E O T or E T re gar dless of 
relati o ns hi p t o st u d y dr u g). Fr o m E O T or E T t hr o u g h E O S, o nl y A Es assesse d as relat e d t o 
st u d y dr u g b y t he I n vesti gat or ( or desi g n ee) are t o be re p ort e d. All S A Es t hat de vel o p fr o m 

Pr ot oc ol 
C O N FI D E N TI A L  
C o va nce St u d y: 8 4 1 9 6 8 9 
Pr ot oc ol Refere n ce:  L O X O -B T K - 2 0 0 1 0 
Pr ot oc ol Versi o n 1. 0, 9 Dece m b er 2 0 2 0  
Pa ge 3 0 of 6 8 
t he ti me of I C F si g ni n g u ntil E O S ( or E T, if t he s u bject disc o nti n ues fr o m t he st u d y a n d d oes 
n ot c o m plete a f oll o w- u p p h o ne call) are t o be re p orte d. 
A Sc he d ule of Ass ess me nts is prese nte d i n A p pe n di x 4 . St u d y c o m pleti o n is defi ne d as t he 
ti me of t he last s u bject’s f oll o w- u p p h o ne call. 
3. 2.  
Disc ussi o n of St u d y Desi g n  
Meta b olic r o utes of eli mi nati o n, i ncl u di n g m ost of t h ose occ urri n g t hr o u g h t he C Y P fa mil y of 
e nz y mes, ca n be i n hi bite d or i n d uce d b y c o n c o mita nt dr u g treat me nt. C ha n ges arisi n g fr o m 
meta b olic D DI ca n be si g nifica nt a n d c o ntri b ute t o i ncreas es or decreases i n t he bl o o d a n d 
tiss ue c o nce ntrati o ns of t he pare nt dr u g or acti ve meta b olite. I n crease d or decrease d 
c o nce ntr ati o ns of a pare nt dr u g or its meta b olites ca n alter t he s afet y a n d efficac y pr ofile of a 
dr u g.  
T he pr o be dr u gs c h ose n i n t his st u d y all o w i n vesti gati o n of D DIs me diate d t hr o u g h C Y P 4 5 0 
e nz y mes. L O X O - 3 0 5 s h o we d n o detecta ble i n hi biti o n (I C 5 0  
 μ M) of C Y P 1 A 2, 
C Y P 2 B 6, a n d C Y P 2 D 6 a n d s h o we d wea k i n hi biti o n of C Y P 2 C 8, C Y P 2 C 9, C Y P 2 C 1 9, a n d 
C Y P 3 A 4.  I n vitr o L O X O- 3 0 5 i n d uce d C Y P 3 A 4, C Y P 2 C 1 9, a n d C Y P 2 B 6 a n d d o w n 
re g ulate d C Y P 1 A 2. T h e pr o be dr u gs w ere c h ose n as t he y are k n o w n t o be s e nsiti ve s u bstrates 
of C Y P 1 A 2 (caffei ne), a n d C Y P 2 C 9 ( warfari n), a n d C Y P 2 C 1 9 ( o me praz ol e). Vita mi n K will 
be a d mi nistere d wit h warfari n t o c o u nteract its a ntic oa g ula nt effect.  
T he fi xe d si n gle-se q u e nce desi g n use d i n t his st u d y is t y pical f or dr u g i nteracti o n st u dies, 
beca use it all o ws i ntra -s u bject c o m paris o ns. A si n gle se q ue nce will be use d t o a v oi d carr y 
o ver effects. T his st u d y will be o pe n-la bel beca us e t he pri mar y e n d p oi nts are n ot c o nsi dere d 
s u bjecti ve. 
C o n d ucti n g t he st u d y i n healt h y a d ult s u bjects miti gates t he p ote ntial c o nf o u n di n g effects of 
t he disease state a n d c o n c o mita nt me dicati o ns. 
3. 3.  
Selecti o n of D oses i n t he St u d y  
3. 3. 1.  
L O X O - 3 0 5 
M ulti ple oral d oses of 2 0 0 m g L O X O - 3 0 5 Q D will be a d mi nistere d o n Da ys 6 t hr o u g h 
Da y  1 5 t o ac hie v e L O X O - 3 0 5 stea d y state, e ns uri n g t he ma xi mal effect of L O X O- 3 0 5 w h e n 
c oa d mi nistere d wit h t he pr o be dr u g c o c ktail o n D a y 1 5. L O X O- 3 0 5 2 0 0 m g Q D will 
c o nti n ue o n Da y 1 6 t hr o u g h Da y 1 9 t o mai ntai n stea d y state of L O X O- 3 0 5. W hile d oses of 
2 5 m g Q D t o 3 0 0 m g Q D ha ve bee n e val u ate d, L O X O - 3 0 5 2 0 0 m g gi ve n Q D has bee n 
c h ose n as t he R P 2 D f or t he o n g oi n g gl o bal P hase 1/ 2 first -i n- h u ma n st u d y, 
L O X O -B T K - 1 8 0 0 1 i n p atie nts wit h pre vi o usl y treate d C L L/ S L L or N H L. T he a vaila ble d ata 
de m o nstrate t hat L O X O -3 0 5 a p pears s afe a n d well t olerate d at t hese d os es. At all e val uate d 
d oses, n o d ose- li miti n g t o xicities ha ve bee n i d e ntifie d i n h u ma ns.1  
3. 3. 2.  
Pr o be Dr u g C oc kt ail  
T he select e d d oses of t he pr o be dr u gs caffei ne, o me praz ole,  an d warfari n  were b ase d o n 
t y pical d oses f or t hese dr u gs w he n t he y are use d as i n de x s u bstrates i n D DI st u dies, a n d are 
c o nsi dere d t o be hi g h e n o u g h t o pr o vi de s ufficie nt plas ma c o nce ntrati o ns t o ac hie ve t h e 
C CI

Pr ot oc ol 
C O N FI D E N TI A L  
C o va nce St u d y: 8 4 1 9 6 8 9 
Pr ot oc ol Refere n ce:  L O X O -B T K - 2 0 0 1 0 
Pr ot oc ol Versi o n 1. 0, 9 Dece m b er 2 0 2 0  
Pa ge 3 1 of 6 8 
o bjecti ves of t he st u d y.  T he reas o n f or t he a d mi nistrati o n of t he d ose of vita mi n K selecte d is 
t o o verc o me t he a nti-c oa g ula nt effects of warfari n base d o n t y pical d oses use d f or D DI 
st u dies. 
 

Pr ot oc ol 
C O N FI D E N TI A L  
C o va nce St u d y: 8 4 1 9 6 8 9 
Pr ot oc ol Refere n ce:  L O X O -B T K - 2 0 0 1 0 
Pr ot oc ol Versi o n 1. 0, 9 Dece m b er 2 0 2 0  
Pa ge 3 2 of 6 8 
4.  S E L E C TI O N O F S T U D Y P O P U L A TI O N  
4. 1.  
Scree ni n g Pr oce d ures  
T he f oll o wi n g scree ni n g pr oce d ur es will be perf or me d f or all p ote ntial s u bjects at a visit 
c o n d ucte d wit hi n 3 5 da ys of st u d y e ntr y (ie, pri or t o C hec k- i n [ Da y -1]):  
1.  I n cl usi o n/ E xcl usi o n criteria 
2.  I nf or me d c o ns e nt 
3.  De m o gra p hic d ata  
4.  Me dical hist or y (i ncl u di n g re vie w of m e dicati o n[s]) 
5.  Hei g ht, wei g ht, a n d b o d y mass i n d e x ( B MI)  
6.  1 2-lea d E C G meas ure d after t he s u bject h as bee n resti n g i n t he s u pi ne p ositi o n f or at 
least 1 0 mi n utes ( Secti o n  7. 3. 4 ) 
7.  Vital si g n meas ure me nts (i ncl u di n g b o d y te m perat ure, res pirat or y rate, o x y ge n 
sat urati o n, a n d s u pi ne bl o o d press ure [ B P] a n d p ulse rate [ meas ure d after t he s u bject 
has bee n s u pi ne f or at lea st 5 mi n utes]; Secti o n  7. 3. 3 ) 
8.  H D Y F? i n q uir y, A E, S A E, a n d c o nc o mita nt me di cati o n e val uati o ns ( Secti o n  7. 3. 1 ) 
9.  Cli nical la b orat or y e val u ati o ns ( Secti o n  7. 3. 2 ; cli nical c he mistr y pa n el [faste d at least 
8 h o urs], c oa g ul ati o n par a meters, he m at ol o g y pa n el, a n d U A;  A p pe n di x 2 ) 
1 0.  Scree ns f or he patitis C vir us ( H C V) a nti b o d y, he p atitis B s urface a nti ge n ( H Bs A g), 
he patitis B vir us ( H B V) i m m u n o gl o b uli n M (I g M) c ore a nti b o d y, h u ma n 
i m m u n o deficie nc y vir us ( HI V) a nti b o d y, a n d C O VI D - 1 9 via p ol y merase c hai n 
reacti o n ( P C R) testi n g or e q ui vale nt (A p pe n di x 2 ) 
1 1.  He m o gl o bi n A 1c ( H b A 1 c) test ( A p pe n di x 2 ) 
1 2.  Uri ne dr u g scree n f or sel ecte d dr u gs of a b use (i ncl u di n g c oti ni ne) a n d alc o h ol scree n 
( breat h or uri ne; A p pe n di x 2 ) 
1 3.  Esti mate d gl o mer ular filtr ati o n rate (e G F R) cal c ulate d usi n g t he  C hr o nic Ki d ne y 
Disease E pi de mi ol o g y C olla b orati o n ( C K D- E PI)  e q uati o n (A p pe n di x 2 ) 
1 4.  Ser u m pre g na n c y test (f or fe male  s u bjects o nl y; A p pe n di x 2 ) 
1 5.  F ollicle -sti m ulati n g h or m o ne ( F S H) test (f or p ost-me n o pa usal fe m ale s u bjects o nl y; 
A p pe n di x 2 ) 
1 6.  T h yr oi d- sti m ulati n g h or m o ne ( T S H) test (A p p e n di x 2 ) 
1 7.  Bl o o d sa m ple f or ge n ot y pi n g ( A p pe n di x 2 ) 
4. 2.  
C hec k -i n Pr oce d ures ( D a y - 1) 
At C hec k -i n ( D a y -1), s u bjects will re p ort t o t he C R U  a n d t he f oll o wi n g pr oce d ures will be 
perf or me d:  
1.  Re vie w of i ncl usi o n/e xcl usi o n criteria 
2.  I nteri m me dical hist or y, i ncl u di n g c o nc o mita nt me dicati o n(s) 

Pr ot oc ol 
C O N FI D E N TI A L  
C o va nce St u d y: 8 4 1 9 6 8 9 
Pr ot oc ol Refere n ce:  L O X O -B T K - 2 0 0 1 0 
Pr ot oc ol Versi o n 1. 0, 9 Dece m b er 2 0 2 0  
Pa ge 3 3 of 6 8 
3.  Wei g ht a n d B MI 
4.  C o m plete p h ysical e xa mi nati o n ( Secti o n  7. 3. 5 ) 
5.  1 2-lea d E C G meas ure d after t he s u bject h as bee n resti n g i n t he s u pi ne p ositi o n f or at 
least 1 0 mi n utes ( Secti o n  7. 3. 4 ) 
6.  Vital si g n m eas ure me nts (i ncl u di n g b o d y te m perat ure, res pirat or y rate, o x y ge n 
sat urati o n, a n d s u pi ne B P a n d p ulse rate [ meas ure d after t he s u bject has bee n s u pi ne 
f or at least 5 mi n utes]; Secti o n  7. 3. 3 ) 
7.  H D Y F? i n q uir y, A E, S A E, a n d c o nc o mita nt me di cati o n e val uati o ns ( Secti o n  7. 3. 1 ) 
8.  Cli nical la b orat or y e val u ati o ns (Secti o n  7. 3. 2 ; cli nical c he mistr y pa n el [faste d at least 
8 h o urs], c oa g ul ati o n par a meters, he m at ol o g y pa n el, a n d U A; A p pe n di x 2 ) 
9.  Scree n f or C O VI D - 1 9 via P C R test ( or e q ui vale nt; A p pe n di x 2 ) 
1 0.  Uri ne dr u g scree n f or sel ecte d dr u gs of a b use (i ncl u di n g c oti ni ne) a n d alc o h ol scree n 
( breat h or uri ne; A p pe n di x 2 ) 
1 1.  e G F R calc ulate d usi n g t h e C K D - E PI e q u ati o n (A p pe n di x 2 ) 
1 2.  Ser u m pre g na n c y test (f or fe male s u bjects o nl y; A p pe n di x 2 ) 
1 3.  C o m plia nce wit h c o nc o mita nt me dicati o ns a n d e xcl usi o nar y restricti o ns ( Secti o n  6 ) 
F or s u bjects t o c o nti n ue t heir partici pati o n i n t he st u d y, t he i ncl usi o n/e xcl usi o n criteria m ust 
c o nti n ue t o be met at C hec k -i n ( D a y -1 [as a p pr o priate; # 1 , Secti o n  4. 2 ]). I n a d diti o n, 
c o nti n ue d c o m pli a nce wit h c o nc o mita nt me dicati o n a n d ot her restricti o ns will be verifie d.  
T he S p o ns or will re vie w me dical hist or y a n d all scree ni n g e v al uati o ns f or p ote ntial s u bjects 
pri or t o C hec k-i n ( D a y - 1). Pri or t o d osi n g, t he S p o ns or will pr o vi de a p pr o val of s u bject s 
selecte d f or e nr oll me nt b y t he I n v esti gat or ( or d esi g nee). 
S u bjects w h o meet all t he i ncl usi o n criteria a n d f or w h o m n o ne of t he e xcl usi o n criteria a p pl y 
will be eli gi ble t o be e nr olle d i nt o t he st u d y. Safet y e val uati o ns ma y be re peate d at t he 
discreti o n  of t he I n v esti gat or ( or desi g n ee) or S p o ns or. 
4. 3.  
I ncl usi o n Criteri a 
S u bjects w h o meet t he f oll o wi n g criteria at Scree ni n g a n d C hec k -i n ( D a y - 1), u nless 
ot her wise s pecifie d, ma y be i ncl u de d i n t he st u d y: 
1.  Males, a n d fe m ales of n o n -c hil d beari n g p ote ntial, bet wee n 1 8 a n d 5 5 years of a ge, 
i ncl usi ve, at Scree ni n g. 
2.  Wit hi n B MI ra n g e 1 8. 0 t o 3 2. 0 k g/ m
2, i ncl usi ve. 
3.  I n g o o d h ealt h, deter mi ne d b y n o cli nicall y si g nifica nt fi n di n gs fr o m me dical hist or y, 
p h ysical e xa mi nati o n, 1 2- lea d E C G, vital si g n meas ure me nts, or cli nical la b orat or y 
e val uati o ns (A p pe n di x 4 ) at Scree ni n g a n d/ or C hec k-i n ( Da y - 1) as assesse d b y t he 
I n v esti gat or ( or d esi g nee). 
4.  Fe male s u bjects of n o n- c hil dbeari n g p ote ntial, defi ne d as bei n g per m a ne ntl y sterile 
(ie, d ue t o h ysterect o m y, bilateral t u bal li gati o n, bilateral sal pi n gect o m y, bil ateral 
o o p h orect o m y, or c o nfir me d t u bal occl usi o n m ore t ha n 6 m o nt hs pri or t o Da y 1) or 

Pr ot oc ol 
C O N FI D E N TI A L  
C o va nce St u d y: 8 4 1 9 6 8 9 
Pr ot oc ol Refere n ce:  L O X O -B T K - 2 0 0 1 0 
Pr ot oc ol Versi o n 1. 0, 9 Dece m b er 2 0 2 0  
Pa ge 3 4 of 6 8 
p ost- me n o pa usal ( defi ne d as at l east 1 2 m o nt hs p ost-cessati o n of me nses wit h o ut a n 
alter nati ve me dical ca us e). P ost - me n o pa usal stat us will be c o nfir me d wit h a scree ni n g 
ser u m F S H le vel c o nsiste nt wit h p ost- me n o pa usal stat us per t he la b orat or y’s refere nce 
ra n ges. All fe m ale s u bjects m ust ha ve a ne gati ve q ualitati ve ser u m pre g n a n c y test 
(ser u m h u ma n c h ori o nic g o na d otr o pi n; ser u m q ua ntitati ve h u ma n c h ori o nic 
g o na d otr o pi n tests ma y be use d f or c o nfir mati o n as nee de d) at Scree ni n g a n d 
C hec k -i n ( Da y -1). Fe male s u bjects are re q uire d t o refrai n fr o m d o nati o n of o va fr o m 
C hec k -i n ( Da y - 1) u ntil 6 m o nt hs after Da y 1 9 ( or last a d mi nistrati o n of st u d y dr u g if 
s u bject ter mi nates fr o m t he st u d y earl y).  
5.  Male s u bjects w h o are ca pa ble of fat heri n g a c hil d m ust a gree t o use 1 of t h e 
f oll o wi n g met h o ds of c o ntrace pti o n: 
a. Male sterilizati o n, wit h d oc u me nte d c o nfir mati o n of s ur gical s uccess. Male 
s u bjects will be s ur gicall y sterile f or at least 9 0 da ys pri or t o C hec k-i n 
( Da y - 1), or 
b.  If d oc u me ntati o n of s ur gi cal sterilizati o n is n ot a vaila ble, male s u bjects m ust 
f oll o w 1 of t he c o ntrace pti o n met h o ds bel o w fr o m Da y 1 t hr o u g h 6 m o nt hs 
after D a y 1 9 ( or l ast a d mi nistrati o n of st u d y dr u g if s u bject ter mi nates fr o m 
t he st u d y earl y): 
i. Male c o n d o m wit h s per mici de, or 
ii. A male s u bject m ust e ns ure t hat t heir fe male part ner me ets 1 of t he 
f oll o wi n g criteria: 
1.  i ntra uteri ne de vice (I U D) ( h or m o nal I U D; e g, Mire na® ). 
C o p per I U Ds are acce pta ble (e g, Para Gar d ® ); or 
2.  esta blis he d use of oral, i m pla nte d, i njecte d, tra ns der mal, 
i ntra va gi nal, or h or m o nal met h o d of c o ntrace pti o n ass ociate d 
wit h i n hi biti o n of o v ulati o n; or 
3.  n o n-c hil d beari n g p ote nti al, defi ne d as b ei n g per m a ne ntl y sterile 
(ie, d ue t o h ysterect o m y, bilateral t u bal li gati o n, bilateral 
sal pi n gect o m y, bilateral o o p h orect o m y, or c o nfir me d t u bal 
occl usi o n m ore t ha n 6 m o nt hs pri or t o Da y 1 f or male part ner); 
or 
4.  be p ost- me n o pa usal wit h a me n orr h ea f or at least 1  year pri or t o 
Da y 1 a n d F S H ser u m le vels c o nsiste nt wit h p ost- me n o pa usal 
stat us. 
Male s u bjects w h o pr acti ce tr ue a bsti ne nce b eca us e of a lifest yle c h oice (i e, d o n ot 
bec o me a bsti ne nt j ust f or t he p ur p ose of st u d y partici pati o n) are e xe m pt fr o m 
c o ntrace pti ve re q uir e me nts. Peri o dic a bsti ne nce b y a fe male p art ner (e g, cal e n dar, 
o v ulati o n, s y m pt ot her mal, p ost- o v ulati o n met h o ds) a n d wit h dra w al are n ot acce pta ble 
met h o ds of c o ntrace pti o n. If a male s u bject is a bsti ne nt at t he ti me of si g ni n g t he I C F 
b ut bec o mes se x uall y acti ve fr o m C hec k-i n ( Da y - 1) t hr o u g h 6 m o nt hs after Da y 1 9 
( or last a d mi nistrati o n of st u d y dr u g if s u bject ter mi nates fr o m t he st u d y earl y), he 
m ust a gree t o  use c o ntrace pti o n as descri be d a b o v e. 
F or male s u bjects, se x ual i nterc o urse wit h fe male part ners w h o are pre g n a nt, or 
breastfee di n g s h o ul d be a v oi de d fr o m C hec k-i n ( D a y - 1) t hr o u g h 6 m o nt hs after 

Pr ot oc ol 
C O N FI D E N TI A L  
C o va nce St u d y: 8 4 1 9 6 8 9 
Pr ot oc ol Refere n ce:  L O X O -B T K - 2 0 0 1 0 
Pr ot oc ol Versi o n 1. 0, 9 Dece m b er 2 0 2 0  
Pa ge 3 5 of 6 8 
Da y  1 9 ( or last a d mi nistrati o n of st u d y dr u g if s u bject ter mi nates fr o m t he st u d y 
earl y), u nless t he m ale s u bject uses a c o n d o m wit h s per mici de. Male s u bjects are 
re q uire d t o r efr ai n fr o m d o nati o n of s per m fr o m C hec k-i n ( D a y - 1) u ntil 6 m o nt hs 
after D a y 1 9 ( or l ast a d mi nistrati o n of st u d y dr u g if s u bject ter mi nates fr o m t he st u d y 
earl y).  
F or s u bjects w h o are e xcl usi vel y i n sa me-se x rel ati o ns hi ps, c o ntrace pti ve 
re q uire me nts d o n ot a p pl y. 
6.  A ble t o u n dersta n d a n d pr o vi de writte n i nf or me d c o nse nt. 
7.  A ble t o c o m pl y wit h all st u d y pr oce d ures, i ncl u di n g t he 2 3- ni g ht sta y at t he C R U a n d 
f oll o w- u p p h o ne call. 
4. 4.  
E xcl usi o n Criteri a  
T he f oll o wi n g will e xcl u de p ote ntial s u bjects fr o m t he st u d y: 
1.  Hist or y or prese n ce of a n y of t he f oll o wi n g, dee m e d cli nicall y si g nifica nt b y t he 
I n v esti gat or ( or d esi g nee), a n d/ or S p o ns or: 
a. li ver disease 
b.  pa ncreatitis  
c. pe ptic ulcer disease  
d.  i ntesti nal mala bs or pti o n 
e. c h olec ystect o m y  
f. gastric re d u cti o n s ur ger y 
g.  hist or y or pres e n ce of cli nicall y si g nifica nt car di o vasc ular disease:  
i. m y ocar dial i nfarcti o n or cere br o vasc ul ar t hr o m b o e m b olis m wit hi n 
6 m o nt hs pri or t o Da y 1  
ii. s y m pt o matic a n gi na pect oris wit hi n 6 m o nt hs pri or t o Da y 1 
iii. c o n gesti ve heart fail ure ≥ sta ge 2 per N e w Y or k H eart Ass ociati o n 
Classificati o n wit hi n 6  m o nt hs pri or t o Da y 1 
i v. c o n ge nital pr ol o n ge d Q T s y n dr o me  
v.  ve ntric ular pr e- e xcitati o n s y n dr o me ( W olff- Par ki ns o n W hite 
s y n dr o me) 
vi.  arr h yt h mia (e x cl u di n g be ni g n si n us arr h yt h mia) or hist or y of 
arr h yt h mia re q uiri n g me dical i nter ve nti o n wit hi n 6 m o nt hs pri or t o 
Da y 1  
vii.  ve ntric ular d ysf u n cti o n or ris k fact ors f or T ors a des de P oi ntes (e g, 
heart f ail ure, car di o m y o p at h y, fa mil y hist or y of L o n g Q T S y n dr o me)  
viii.  E C G a b n or malities t hat are cli nicall y si g nifica nt at Scree ni n g, 
C hec k -i n ( Da y -1),  or pre d ose o n Da y 1, i ncl u di n g, b ut n ot li mite d t o: 
1.  c o m plete left b u n dle- bra nc h bl oc k  

Pr ot oc ol 
C O N FI D E N TI A L  
C o va nce St u d y: 8 4 1 9 6 8 9 
Pr ot oc ol Refere n ce:  L O X O -B T K - 2 0 0 1 0 
Pr ot oc ol Versi o n 1. 0, 9 Dece m b er 2 0 2 0  
Pa ge 3 6 of 6 8 
2.  sec o n d- de gree atri o ve ntri c ular ( A V) bl oc k, t y pe 2, or 
t hir d- de gree A V bl oc k 
3.  Q T i nter val c orrecte d f or heart rate ( H R) usi n g Fri dericia’s 
met h o d ( Q Tc F) > 4 5 0 ms ec  
S u bjects wit h o ut- of-ra n g e E C G val ues or a b n or m al E C G 
fi n di n gs t hat are n ot cli nicall y si g nifica nt will be per mitte d t o 
ha ve E C Gs re p eate d u p t o 2 ti mes d uri n g Scree ni n g, C hec k-i n 
( Da y - 1), a n d pre d ose o n Da y 1 t o c o nfir m eli gi bilit y f or st u d y 
partici pati o n,  if t he re p eat val ue(s) are n or mal/fall o utsi de of 
t he ra n ges state d a b o ve. 
2.  S u bjects wit h o ut- of- ra n g e, at-rest (ie, s u pi ne f or at least 5 mi n utes) vital si g n 
meas ure me nts at Scree ni n g, C hec k -i n ( D a y - 1), or pri or t o d osi n g o n Da y 1. 
O ut - of-r a n ge vital si g n meas ure m e nts are d efi ne d as:  
a. b o d y te m perat ur e > 3 7. 5° C; 
b.  p ulse rate <  5 0 or > 9 9 b eats per mi n ute ( b p m); 
c. s yst olic B P < 8 9 or > 1 3 9 m m H g;  
d.  diast olic B P <  5 0 or > 8 9 m m H g;  
e. o x y ge n sat urati o n < 9 5 % (r o o m air).  
S u bjects wit h o ut- of- ra n g e val ues f or t h ese para meters t hat are n ot cli nicall y 
si g nifica nt will be per mitte d t o ha ve vital si g n meas ure me nts re peat e d u p t o 2 ti mes 
d uri n g Scree ni n g, C hec k-i n ( Da y - 1), a n d pre d ose o n Da y 1 t o c o nfir m eli gi bilit y f or 
st u d y partici pati o n if t he re peat v al ue(s) are n or mal/fall o utsi de of t he ra n ges state d 
a b o ve.  
3.  Hist or y or prese n ce of cli nicall y si g nifica nt me dical or ps yc hiatric c o n diti o n or 
disease i n t he o pi ni o n of t he I n v esti gat or ( or d esi g nee), or m e ntall y or le gall y 
i nca pacitate d or has si g nifica nt e m oti o nal pr o ble ms at t he ti me of t he Scree ni n g visit 
or e x pect e d d uri n g t he c o n d uct of t he st u d y. 
4.  Cli nicall y si g nifica nt a b n or malit y, as deter mi ne d b y t he I n v esti gat or ( or d esi g nee), 
fr o m p h ysical e xa mi nati o n at C hec k-i n ( D a y -1).  
5.  A b n or mal la b orat or y v al ues ( he mat ol o g y pa n el, U A, cli nical c h e mistr y pa nel [faste d 
at least 8 h o urs]) t hat are cli nicall y si g nifica nt e xcl u di n g t h ose f urt her defi ne d i n 
e xcl usi o n criteria # 6 , # 7 , a n d # 8  at Scree ni n g a n d/ or C hec k-i n ( D a y - 1). S u bjects wit h 
o ut- of- ra n g e cli nical la b orat or y res ults t hat are n ot cli nicall y si g nifica nt (e x cl u di n g 
t h ose f urt her d efi ne d i n e xcl usi o n criteria #6 , # 7 , a n d # 8 ) ma y ha ve la b orat or y 
assess me nts re peate d at t he I n vesti gat or ( or desi g nee)’s discreti o n u p t o 2 ti mes 
d uri n g Scree ni n g a n d C h ec k-i n ( D a y - 1) t o c o nfir m eli gi bilit y f or st u d y partici pati o n 
if t he re peat val ue(s) fall wit hi n n or mal ra n ges or are sta bilizi n g. 
6.  A b n or mal li ver f u ncti o n tests ( L F Ts ) as defi ne d b y as partate a mi n otra nsferase , 
ala ni ne a mi n otra nsf eras e, a n d ser u m (t otal a n d direct) bilir u bi n, as well as a m ylase, or 
li pase a b o ve t he u p p er li mit of t he n or mal ra n ge p er t he la b orat or y’s refere nce ra n g es 
at Scree ni n g or C hec k -i n ( Da y - 1). S u bjects wit h o ut- of-ra n g e L F Ts, a m ylase, a n d 
li pase val ues a b o v e t he u p per li mit of n or mal t hat are n ot cli nicall y si g nifica nt will be 
per mitte d t o ha ve L F Ts, a m ylase, or li pase assess me nts re peat e d u p t o 2 ti mes d uri n g 

Pr ot oc ol 
C O N FI D E N TI A L  
C o va nce St u d y: 8 4 1 9 6 8 9 
Pr ot oc ol Refere n ce:  L O X O -B T K - 2 0 0 1 0 
Pr ot oc ol Versi o n 1. 0, 9 Dece m b er 2 0 2 0  
Pa ge 3 7 of 6 8 
Scree ni n g a n d C hec k-i n ( Da y - 1) t o c o nfir m eli gi bilit y f or st u d y partici pati o n if t he 
re peat v al ue(s) fall wit hi n n or mal ra n ges.  
7.  Creati ne ki nase v al ues a b o ve t he u p per li mit of t he n or mal ra n ge p er t he la b orat or y’s 
refere nce r a n ges t hat are cli nicall y si g nifica nt at Scree ni n g or C hec k-i n ( Da y - 1). 
S u bjects wit h o ut- of- ra n g e creati ne ki nase v al ues t hat are n ot cli nicall y si g nifica nt 
will be per mitte d t o ha ve t he creati ne ki nase ass ess me nts re peate d u p t o 2  ti mes 
d uri n g Scree ni n g a n d C h ec k-i n ( D a y - 1) t o c o nfir m eli gi bilit y f or st u d y partici pati o n 
if t he re peat val ue(s) ar e sta ble or n or malizi n g. 
8.  Esti mate d gl o mer ular filtrati o n rate (e G F R) ≤ 8 0 m L/ mi n ute/ 1. 7 3 m2 calc ulate d usi n g 
t he C K D-E PI e q uati o n at Scree ni n g  or C hec k-i n ( Da y - 1). S u bjects wit h o ut- of- ra n g e 
e G F R val u es t hat are n ot cli nicall y si g nifica nt will be per mitte d t o ha ve e G F R 
assess me nts re peate d u p t o 2 ti mes d uri n g Scree ni n g a n d C hec k-i n ( Da y - 1) t o 
c o nfir m eli gi bilit y f or st u d y partici pati o n if t he re p eat val ue(s) fall a b o v e t h e ra n ge 
state d a b o ve.  
9.  H b A 1c ≥ 6. 5 % at Scree ni n g. S u bjects wit h o ut- of- ra n ge H b A 1c val u es t hat are n ot 
cli nicall y si g nifica nt will be per mitte d t o ha ve H b A 1c assess me nts re peat e d u p t o 2 
ti mes d uri n g Scree ni n g t o c o nfir m eli gi bilit y f or st u d y partici pati o n if t he re peat 
val ue(s) f all bel o w t he r a n ge state d a b o ve. 
1 0.  P ositi ve ser ol o gic test f or H Bs A g, H B V I g M c ore a nti b o d y, H C V a nti b o d y, or HI V 
a nti b o d y at Scree ni n g. S u bjects w h o are p ositi ve f or H B V I g M c ore a nti b o d y or H C V 
a nti b o d y re q uire c o nfir m ati o n b y P C R bef ore e nr o ll me nt t o detect prese nce of acti ve 
vir us. S u bjects w h o are H B V c ore a nti b o d y or H C V a nti b o d y p ositi ve or f or w h o m a 
P C R is u na ble t o be o btai ne d will n ot be eli gi ble. 
1 1.  P ositi ve P C R test ( or e q ui vale nt) f or C O VI D- 1 9 at Scree ni n g or C hec k-i n ( Da y - 1). 
F urt he r d etails re g ar di n g C O VI D- 1 9 testi n g (i ncl u di n g pr oce d ures f or s u bjects w h o 
test p ositi ve at a n y ti me t hr o u g h o ut C R U c o nfi ne me nt) are s p ecifie d i n a se parat e 
d oc u me nt.   
1 2.  Hist or y of c o n ge nital n o n- he m ol ytic h y per bilir u bi ne mia (e g, Gil bert’s s y n dr o me). 
1 3.  Si g nif ica nt hist or y or cli nical ma nifestati o n of a n y aller gic, der mat ol o gical, biliar y, 
he patic, gastr oi ntesti nal, re nal, meta b olic, h e mat ol o gical , p ul m o nar y, car di o vasc ular 
(i ncl u di n g a n y pri or hist or y of car di o m y o pat h y or heart fail ure), n e ur ol o gical, or 
ps yc hiatric dis or der (as d eter mi ne d b y t he I n v esti gat or [ or desi g n ee]), or ca ncer 
wit hi n t he past 5  years ( e xce pt l ocalize d b asal cell, s q ua m o us, or i n sit u ca ncer of t h e 
s ki n). N ote: s u bjects wit h a hist or y of a p pe n d ect o m y a n d/ or her nia re pairs will be 
acce pta ble.  
1 4.  Hist or y or prese n ce, u p o n cli nical e val uati o n, of a n y ill ness t hat, i n t he o pi ni o n of t he 
I n v esti gat or ( or d esi g nee), w o ul d i nterfere wit h t h e a bilit y t o pr o vi de i nf or me d 
c o nse nt or c o m pl y wit h st u d y i nstr ucti o ns, or t hat mi g ht c o nf o u n d t he i nter pretati o n 
of t he st u d y res ults, or p ut t he s u bject at u n d ue ris k. 
1 5.  Hist or y of a maj or s ur gical pr oce d ure wit hi n 3 0 da ys pri or t o Scree ni n g. 
1 6.  K n o w n o n g oi n g alc o h ol a n d/ or dr u g a b us e wit hi n 2 years pri or t o Scree ni n g, or 
e vi de nce of s uc h a b us e as i n dicate d b y t he la b orat or y assa ys f or dr u gs of a b use 
(i ncl u di n g c oti ni ne a n d alc o h ol) c o n d ucte d d uri n g Scree ni n g a n d/ or at C hec k-i n 

Pr ot oc ol 
C O N FI D E N TI A L  
C o va nce St u d y: 8 4 1 9 6 8 9 
Pr ot oc ol Refere n ce:  L O X O -B T K - 2 0 0 1 0 
Pr ot oc ol Versi o n 1. 0, 9 Dece m b er 2 0 2 0  
Pa ge 3 8 of 6 8 
( Da y - 1). Tests f or dr u gs of a b use m ust be ne g ati ve at b ot h Scree ni n g a n d C hec k-i n 
( Da y -1).  
1 7.  Use of t o bacc o, s m o ki n g-cessati o n pr o d u cts, or pr o d ucts c o ntai ni n g nic oti ne a n d 
e-ci garettes ( nic oti ne a n d n o n- nic oti ne), wit hi n 3 m o nt hs pri or t o Scree ni n g a n d 
t hr o u g h E O T or E T. 
1 8.  Use or i nte nti o n t o use a n y prescri pti o n or o ver-t he-c o u nter me dicati o ns (i ncl u di n g 
b ut n ot li mite d t o a n y m o derate or str o n g C Y P 3 A 4 a n d/ or C Y P 3 A 5 i n hi bit ors or 
i n d ucers [i ncl u di n g her bal pr o d ucts s uc h as St. J o h n’s w ort], C Y P 2 C 8 s u bstrates, 
str o n g P- g p i n hi bit ors, pr ot o n p u m p i n hi bit ors, a ntaci ds, H 2-rece pt or a nta g o nists, a n d 
dr u gs t hat pr ol o n g Q T/ Q Tc i nter val, vita mi n s u p ple m e nts, caffei ne [ wit h t he 
e xce pti o n of caff ei ne a d mi nistere d f or t he p ur p os es of t his st u d y/i n acc or d a nce wit h 
t he pr ot oc ol], her b al pr o d ucts, nat ural or her bal s u p ple me nts, a n d 
h or m o ne- re pl ace m e nt t hera p y [ H R T]) fr o m 1 4 da ys pri or t o Da y 1 or 5 half-li ves (if 
k n o w n, w hic he ver is l o n ger [e x ce pt f or paracet a m ol/aceta mi n o p he n ma xi m u m of 
2 g/ da y f or u p t o 3 c o nsec uti ve da ys d uri n g t he st u d y]) t hr o u g h E O T or E T, u nless 
dee me d acce pta ble b y t h e I n vesti gat or ( or desi g nee) a n d S p o ns or. 
1 9.  C o ns u m pti o n of gra pefr uit/ gra pefr uit j uice or Se ville ora n ges or its j uice wit hi n 
7 da ys pri or t o C hec k- i n ( Da y - 1) a n d t hr o u g h E O T or E T. 
2 0.  C o ns u m pti o n of alc o h ol-c o ntai ni n g f o o ds or be vera ges or caffei ne-c o ntai ni n g f o o ds 
or be ver a ges (i n cl u di n g b ut n ot li mite d t o teas [i ncl u di n g decaf fei nate d teas], c offees 
[i ncl u di n g decaffei nat e d c offees], c ol as [i ncl u di n g decaffei nat e d c olas], e ner g y 
dri n ks, g u m c o ntai ni n g caffei n e, c h oc ol ate, a n d f o o ds a n d be vera ges c o ntai ni n g 
c h oc olate) wit hi n 7 2 h o urs pri or t o C hec k- i n ( Da y - 1) a n d t hr o u g h E O T or E T.  
2 1.  Hist or y of si g nifica nt h y perse nsiti vit y, i nt olera nce, or aller g y t o a n y dr u g c o m p o u n d, 
f o o d, or ot her s u bsta n ce, u nless a p pr o ve d b y t he I n vesti gat or ( or desi g nee). 
2 2.  Has bee n o n a diet i nc o m pati ble wit h t he o n-st u d y diet, i n t he o pi ni o n of t he 
I n v esti gat or ( or d esi g nee), wit hi n t he 3 0 da ys pri or t o Da y 1 a n d t hr o u g h E O T or E T. 
2 3.  Partici pati o n i n a n y ot her i n vesti gati o nal st u d y dr u g trial i n v ol vi n g a d mi nistrati o n of 
a n y i n vesti gati o nal dr u g i n t he past 3 0 da ys or 5 half-li ves (if k n o w n), w hi c he ver is 
l o n ger, pri or t o Da y 1. 
2 4.  Has pre vi o usl y recei ve d L O X O- 3 0 5 i n a n y ot her st u d y i n vesti gati n g L O X O- 3 0 5, 
wit hi n 3 0 da ys pri or t o Da y 1. 
2 5.  Stre n u o us e xer cise wit hi n 5 da ys pri or t o C hec k- i n ( Da y - 1) a n d t hr o u g h E O T or E T. 
2 6.  P o or peri p her al ve n o us access. 
2 7.  D o nati o n of bl o o d fr o m 5 6 da ys pri or t o Scree ni n g, plas ma or platelets fr o m 4 wee ks 
pri or t o Scree ni n g. 
2 8.  Recei pt of bl o o d pr o d ucts wit hi n 2 m o nt hs pri or t o C hec k- i n ( D a y -1).  
2 9.  S u bjects w h o, i n t he o pi ni o n of t he I n vesti gat or ( or desi g nee), s h o ul d n ot p artici pate 
i n t his st u d y. 
3 0.  S u bject w h o are n o n- a n d sl o w C Y P 2 C 9 ( C Y P 2 C 9 * 2/ * 3 or C Y P 2 C 9 * 3/ * 3 
ge n ot y pes) a n d C Y P 2 C 1 9 ( C Y P 2 C 1 9 * 2/ * 2, C Y P 2 C 1 9 * 2/ * 3, or C Y P 2 C 1 9 * 3/ * 3 
ge n ot y pes) meta b olizers as deter mi ne d b y g e n ot y pi n g at Scree ni n g.  

Pr ot oc ol 
C O N FI D E N TI A L  
C o va nce St u d y: 8 4 1 9 6 8 9 
Pr ot oc ol Refere n ce:  L O X O -B T K - 2 0 0 1 0 
Pr ot oc ol Versi o n 1. 0, 9 Dece m b er 2 0 2 0  
Pa ge 3 9 of 6 8 
4. 5.  
S u bject N u m ber a n d I de nt ific ati o n 
S u bject n u m bers will c o nsist of 6 di gits i n w hic h t he first set of 3 di gits will i de ntif y t he site 
a n d t he sec o n d s et of 3 di gits will i de ntif y t he s u bject (e g, 0 0 1- 1 0 1).  
F or s u bjects w h o are wit h dra w n b y t he I n v esti gat or ( or desi g nee) or v ol u nt aril y wit h dra w 
pre mat urel y fr o m t he st u d y, re place me nt s u bjects will be e nr olle d o nl y if d ee me d necessar y 
b y t he S p o ns or.  
If necessar y, as deter mi n e d b y t he S p o ns or, s u bjects w h o fail t o c o m plete t he treat me nt or 
ha ve i ns ufficie nt P K dat a ma y be re place d.  Re pl ace me nt s u bjects will be assi g ne d a s u bject 
n u m ber b y a d di n g 2 0 0 t o t he last 3 di gits of t he s u bject n u m ber f or t h e s u bject t he y are 
re placi n g ( e g, S u bject N u m ber 0 0 1- 3 0 1 re places S u bject N u m ber 0 0 1- 1 0 1). 
S u bjects w h o are d eter mi ne d t o be scr ee n fail ures are per mitte d t o be re -s cree ne d if t he 
I n v esti gat or ( or d esi g nee), wit h a gree me nt fr o m t he S p o ns or, feels t hat t he s u bject ma y meet 
eli gi bilit y criteria u p o n re -scr ee n. Re-s cree ne d s u bjects will be pr o vi de d a ne w s u bject 
n u m ber as defi n e d a b o ve. 
4. 6.  
Re m o v a l of S u bjects fr o m St u d y P artici p ati o n 
S u bjects will be i nf or me d t hat t he y are free t o wit h dra w fr o m t he st u d y at a n y ti me a n d f or 
a n y reas o n. T he I n v esti gat or ( or desi g n ee) ma y re m o ve a s u bject fr o m t he st u d y if, i n t he 
I n v esti gat or’s ( or desi g nee’s) o pi ni o n, it is n ot i n t he best i nterest of t he s u bject t o c o nti n ue 
t he st u d y. S u bjects ma y be wit h dra w n b eca us e of t he f oll o wi n g:  
•  c ha n ge i n c o m plia n ce wit h i ncl usi o n/e xcl usi o n criteri o n t hat is cli nicall y rele va nt a n d 
affects s u bject saf et y  
•  occ urr e nce of A Es  
•  occ urr e nce of pr e g na nc y 
•  n o n- c o m plia nce wit h st u d y restricti o ns  
•  i nta ke of n o n-per mitte d c o nc o mita nt me dicati o n t hat mi g ht affect s u bject safet y or 
st u d y assess me nts/ o bjecti ves, etc. 
N otificati o n of wit h dra w al will i m me diatel y be ma de t o t he S p o ns or. I n cas e of wit h dra w al, 
eff orts will be ma d e t o perf or m all E T assess me nts ( A p pe n di x 4 ). T he d ate t he s u bject is 
wit h dra w n fr o m t he st u d y a n d t he reas o n f or wi t h dra wal will be rec or d e d o n t he s u bject’s 
electr o nic Cas e Re p ort F or m (e C R F). All wit h dra w n s u bjects wit h A Es t hat are assess e d as 
relate d t o st u d y dr u g a n d w hic h are o n g oi n g at E T ma y c o nti n ue t o be f oll o we d u ntil t he 
s y m pt o ms or val ue(s) ret ur n t o n or mal, or acce pta ble le vels, as j u d ge d b y t he I n vesti gat or ( or 
desi g nee) a n d c o nfir m e d b y t he S p o ns or. 
T he e ntire st u d y ma y be disc o nti n ue d at t he discreti o n of t he I n v esti gat or ( or desi g nee) or 
S p o ns or, base d o n t he occ urre n ce of t h e f oll o wi n g: 
•  A Es u n k n o w n t o date wit h res pect t o t heir n at ure, se verit y, a n d/ or d urati o n 
•  i ncreas e d fr e q ue nc y a n d/ or se verit y a n d/ or d urati o n of k n o w n A Es 

Pr ot oc ol 
C O N FI D E N TI A L  
C o va nce St u d y: 8 4 1 9 6 8 9 
Pr ot oc ol Refere n ce:  L O X O -B T K - 2 0 0 1 0 
Pr ot oc ol Versi o n 1. 0, 9 Dece m b er 2 0 2 0  
Pa ge 4 0 of 6 8 
•  me dical or et hical reas o ns affecti n g t he c o nti n ue d perf or ma n ce of t he st u d y  
•  diffic ulties i n t he recr uit me nt of s u bjects  
•  ca ncellati o n of dr u g de v el o p me nt. 
I n t he e ve nt t hat t he st u d y is ter mi nate d earl y, t he S p o ns or or its desi g nee will pr o vi de 
s pecific g ui da n ce t o t he C R U re gar di n g t he E O S pr oce d ures. 
 
 

Pr ot oc ol 
C O N FI D E N TI A L  
C o va nce St u d y: 8 4 1 9 6 8 9 
Pr ot oc ol Refere n ce:  L O X O -B T K - 2 0 0 1 0 
Pr ot oc ol Versi o n 1. 0, 9 Dece m b er 2 0 2 0  
Pa ge 4 1 of 6 8 
5.  S T U D Y T R E A T M E N T S  
5. 1.  
Descri pti o n, St or a ge, P ac k a gi n g, a n d L a beli n g 
T he S p o ns or ( or desi g nee) will pr o vi de t he I n v esti gat or ( or desi g nee) wit h a de q uate 
q ua ntities of L O X O - 3 0 5. C o va nce will pr oc ure a d e q uate q ua ntities of caffei ne, o me praz ol e, 
warf ari n , a n d vita mi n K (Ta ble  2). 
T a ble 2: St u d y Dr u gs  
St u d y Dr u g  
F or m a 
Stre n gt h  
S u p plier  
M a n uf act urer
b 
L O X O - 3 0 5 
Ta blet  
2 × 1 0 0 m g  
L o x o 
O nc ol o g y, I nc.  
Catale nt Sa n Die g o or L o nza 
P har ma & Bi otec h  
C affei ne  
Ta blet  
2 0 0 m g  
Mc Kess o n  
Me da C o ns u mer Healt h  
O me pr az ole 
Ca ps ule 
4 0 m g  
Mc Kess o n  
Sa n d oz 
W arf ari n 
Ta blet  
1 0 m g  
Mc Kess o n  
Tar o  
Vit a mi n K  
Ta blets  
2 × 5 m g  
Mc Kess o n  
Valea nt P har mace uticals  
 a S pecific i n gre die nts/ p urit y will be i de ntifie d i n t he Certificate of A nal ysis ( or e q ui vale nt) t hat is s u p plie d wit h 
t he st u d y dr u g(s). 
b T he ma n ufact urer will be c o nfir me d b y t he site at t he ti me of dr u g pr oc ure me nt.  
T he ta blets c o ntai ni n g 1 0 0 m g L O X O - 3 0 5 will be s u p plie d b y t he S p o ns or ( or desi g nee), 
al o n g wit h t he batc h/l ot n u m bers a n d Certificate of A nal ysis. It will be pr o vi de d i n 
hi g h- de nsit y p ol yet h yle ne b ottles a n d will be st ore d acc or di n g t o t he i nstr ucti o ns o n t he la bel. 
T he pr o be dr u g c oc ktail st u d y dr u gs will be s u p plie d b y C o va nce, al o n g wit h t he l ot n u m bers. 
T he pr o be dr u g c oc ktail st u d y dr u gs will be pr o vi de d i n hi g h- de nsit y p ol yet h yle ne b ottles 
( o me praz ole a n d w arf ari n) a n d blister pac ks (caffei ne) a n d will be st ore d acc or di n g t o t he 
i nstr ucti o ns o n t he pac ka ge i nsert.  
Vita mi n K ta blets will be s u p plie d b y C o va nce, al o n g wit h t he l ot n u m bers. T he vita mi n K 
ta blets will be pr o vi de d i n hi g h- de nsit y p ol yet h yle ne b ottles a n d will be st ore d acc or di n g t o 
t he i nstr ucti o ns o n t he pac ka ge i nsert.  
St u d y dr u gs will be st ore d at t he C R U i n a l ocati o n t hat is l oc ke d wit h restricte d access. 
T he b ul k dr u g c o ntai ner a n d u nit d ose c o ntai ners will be la bele d i n acc or d a nce wit h nati o nal 
la ws a n d re g ul ati o ns. T he st u d y dr u gs will be st ore d i n acc or da nce wit h t he la beli n g. T he 
st u d y dr u gs will be tra nsf erre d fr o m b ul k s u p plies i nt o t he s u bject’s d ose c o ntai ner b y 
q ualifie d C R U e m pl o yees. Eac h u nit d ose c o ntai n er will be a p pr o priatel y l a bele d. 
5. 2.  
St u d y Tre at m e nt A d mi nistr ati o n  
S u bjects will r ecei ve eac h of t he f oll o wi n g treat m e nts t hr o u g h o ut t he st u d y: 
•  I n Peri o d 1, Da y 1, 2 0 0 m g caffei ne (ta blet), 4 0  m g o me praz ole (ca ps ule), a n d 1 0 m g 
warf ari n (ta blet)  will be a d mi nistere d as a si n gle d ose of pr o be dr u g c oc kt ail, al o n g 
wit h 1 0 m g vita mi n K ( 2  × 5 m g ta blets), i n t he m or ni n g f oll o wi n g a fast of at least 

Pr ot oc ol 
C O N FI D E N TI A L  
C o va nce St u d y: 8 4 1 9 6 8 9 
Pr ot oc ol Refere n ce:  L O X O -B T K - 2 0 0 1 0 
Pr ot oc ol Versi o n 1. 0, 9 Dece m b er 2 0 2 0  
Pa ge 4 2 of 6 8 
1 0 h o urs pre d ose a n d 2 h o urs p ost d ose. Water will be restricte d f or 1 h o ur pri or t o a n d 
1 h o ur after d osi n g wit h t he e xce pti o n of water a d mi nistere d f or d ose a d mi nistrati o n. 
•  I n Peri od 2, o n Da ys 6 t hr o u g h 1 9, oral d oses of 2 0 0 m g ( 2  × 1 0 0 m g ta blets) 
L O X O - 3 0 5 will be a d mi nistere d Q D f or 1 4 c o nsec uti ve da ys i n t he m or ni n g at t he 
act ual ti me of t he D a y  1 pr o be dr u g c o c ktail d osi n g ( ± 1 h o ur). O n D a y 1 5, 
L O X O -3 0 5 will be c o a d mi nistere d w it h 2 0 0 m g caffei n e (ta blet), 4 0  m g o me praz ole 
(ca ps ule), a n d 1 0 m g warfari n (ta blet) a d mi nistere d as a si n gle d ose of pr o b e dr u g 
c oc ktail, al o n g wit h 1 0 m g vita mi n K ( 2  × 5 m g ta blets), at t he act ual ti me of t he Da y 
1 pr o be dr u g c o c ktail d osi n g ( ± 1 h o ur) f oll o wi n g a fast of at least 1 0 h o urs pre d ose 
a n d 2 h o urs p ost d ose. O n Da ys 7 t hr o u g h 1 1, a n d Da ys 1 3, 1 4, 1 6, 1 8, a n d 1 9, 
s u bjects will fast f or at least 2 h o urs pre d ose a n d 1 h o ur p ost d ose. O n Da ys 6, 1 2, a n d 
1 7 w here cli nical la b or at or y e val uati o ns are perf or me d, s u bjects will fast f or at least 
8 h o urs pre d ose a n d 1 h o ur p ost d ose. Water will be restricte d f or 1 h o ur pri or t o a n d 1 
h o ur after d osi n g wit h t h e e xce pti o n of water a d mi nistere d f or d ose a d mi nistrati o n. 
All st u d y dr u gs will be a d mi nistere d orall y wit h a p pr o xi matel y 2 4 0 m L of water . A n 
a d diti o nal 1 0 0 m L of wat er ma y be a d mi nistere d if nee de d. Water will be restricte d f or 
1- h o ur pre d os e a n d 1- h o ur p ost d ose, wit h t he e xce pti o n of water a d mi nistere d f or d os e 
a d mi nistrati o n.  
Eac h u nit d ose will be pr e pare d b y q u alifie d C R U staff.  
A p pr o priate u nit d ose(s), as descri be d a b o ve, will be a d mi nistere d t o s u bjects. Alt h o u g h t he 
ti mi n g of e ve nts re q uires t hat eac h s u bject will be a d mi nistere d t he a p pr o priate d ose at a 
s pecific ti me, t he e x act d ose ti me of su bjects ma y be sta g gere d t o o b viate t he nee d t o ha v e all 
s u bjects o n precisel y t he sa me st u d y sc he d ule. F or eac h d ose, t h e s u bject’s act ual d ose ti me 
will be rec or d e d i n t he s o urce d oc u m e nts a n d tra ns cri be d i nt o t he e C R F. 
S u bjects will be i nstr ucte d n ot t o  cr us h, s plit, or c he w t he st u d y dr u gs. 
S u bjects will n ot la y s u pi ne f or 4 h o urs f oll o wi n g L O X O- 3 0 5 d ose a d mi nistrati o n, e xce pt as 
necessitate d b y t he o cc urre nce of a n A E(s) a n d/ or st u d y pr oce d ure(s). 
5. 3.  
R a n d o miz ati o n 
T his is a n o n-ra n d o mize d st u d y. T he st u d y has a fi xe d treat me nt se q u e nce.  
5. 4.  
Bli n di n g  
T his is a n o pe n-la bel st u d y. 
5. 5.  
Tre at m e nt C o m pli a nce  
T he f oll o wi n g meas ur es will be e m pl o ye d t o e ns ure treat me nt c o m plia nce: 
•  All d oses will be a d mi nistere d u n der t he s u per visi o n of s uita bl y q ualifie d C R U staff. 
•  I m me diat el y after oral d ose a d mi nistrati o n, a vis ual i ns pecti o n of t he m o ut h a n d 
ha n ds will be perf or me d f or eac h s u bject. 

Pr ot oc ol 
C O N FI D E N TI A L  
C o va nce St u d y: 8 4 1 9 6 8 9 
Pr ot oc ol Refere n ce:  L O X O -B T K - 2 0 0 1 0 
Pr ot oc ol Versi o n 1. 0, 9 Dece m b er 2 0 2 0  
Pa ge 4 3 of 6 8 
•  At eac h d ose pre p arati o n occasi o n, a pre d ose a n d p ost d ose i n ve nt or y of L O X O- 3 0 5 , 
caff ei ne, w arf ari n, vita mi n K, a n d o me praz ole  will be per f or me d. 
5. 6.  
Dr u g Acc o u nt a bilit y  
T he I n vesti gat or ( or desi g nee) will mai ntai n a n acc urate rec or d of t he recei pt of L O X O - 3 0 5, 
caff ei ne, w arf ari n, a n d vita mi n K ta blets, a n d t he o me praz ole ca ps ules recei ve d . I n a d diti o n, 
a n acc urate dr u g dis p ositi o n rec or d will be k e pt, s pecif yi n g t he a m o u nt dis pe nse d t o eac h 
s u bject a n d t he date of dis pe nsi n g. T his dr u g acc o u nta bilit y rec or d will be a vaila ble f or 
i ns pecti o n at a n y ti me. At t he c o m pleti o n of t he st u d y, t he ori gi nal dr u g acc o u nta bilit y rec or d 
will be a vaila ble f or re vi e w b y t he S p o ns or u p o n re q uest. 
F or eac h bat c h of u nit d oses, t he e m pt y use d u nit d ose c o ntai ners will be discar de d u p o n 
satisfact or y c o m pleti o n of t he c o m plia nce a n d acc o u nta bilit y pr oce d ures. A n y u n use d 
asse m ble d u nit d oses will be retai ne d u ntil c o m pleti o n of t he st u d y. 
At t he c o m pleti o n of t he st u d y, all u n use d L O X O- 3 0 5 ta blets will be dis p ose d of b y t he C R U, 
i n acc or d a nce wit h t he C R U’s Sta n dar d O perati n g Pr oce d ures ( S O Ps) a n d l ocal/state/fe deral 
g ui deli nes g o ver ni n g waste dis p osal of i n vesti gati o nal dr u gs, f oll o wi n g t he S p o ns or’s writte n 
a ut h orizati o n. T he caff ei ne,  warfari n, a n d vita mi n K ta blets a n d o me praz ol e ca ps ules will be 
dis p ose d of b y t he C R U i n acc or d a nce wit h t he C R U’s S O Ps.  
 

Pr ot oc ol 
C O N FI D E N TI A L  
C o va nce St u d y: 8 4 1 9 6 8 9 
Pr ot oc ol Refere n ce:  L O X O -B T K - 2 0 0 1 0 
Pr ot oc ol Versi o n 1. 0, 9 Dece m b er 2 0 2 0  
Pa ge 4 4 of 6 8 
6.  C O N C O MI T A N T T H E R A PI E S A N D O T H E R R E S T RI C TI O N S  
6. 1.  
C o nc o mi t a nt T her a pies 
Paracet a m ol/aceta mi n o p he n ( ma xi m u m of 2  g/ da y f or u p t o 3 c o nsec uti ve da ys) is a n 
acce pta ble c o n c o mita nt me dicati o n.  
S u bjects will refrai n fr o m partici pati o n i n a n y ot her i n vesti gati o nal st u d y dr u g trial i n w hic h 
recei pt of a n y i n vesti gati o nal dr u g occ urs wit hi n 5 half -li ves (if k n o w n) or 3 0 da ys, 
w hic he ver is l o n ger, pri or t o Da y 1. 
All prescri pti o n me dicati o ns a n d o ver- t h e-c o u nter me dicati o ns i ncl u di n g b ut n ot li mite d t o: 
m o derate or str o n g C Y P 3 A 4 a n d/ or C Y P 3 A 5 i n hi bit ors or i n d ucers (i ncl u di n g her bal 
pr o d ucts s uc h as St. J o h n’s w ort), C Y P 2 C 8 s u bstrates, str o n g P- g p i n hi bit ors, pr ot o n p u m p 
i n hi bit ors, a ntaci ds, H2-rece pt or a nta g o nists, a n d dr u gs t hat pr ol o n g Q T/ Q Tc i nter val, her bal 
pr o d ucts, vita mi n s u p ple me nts,  nat ural or her bal s u p ple me nts, caffei ne ( wit h t he e xce pti o n of 
caff ei ne a d mi nistere d f or t he p ur p oses of t his st u d y/i n acc or da n ce wit h t he pr ot oc ol), a n d 
H R T are pr o hi bite d f or 1 4 da ys or 5 half-li ves (if k n o w n; e xce pt f or 
paraceta m ol/aceta mi n o p he n as refer e nce d a b o ve), w hic he ver is l o n ger, pri or t o Da y 1 a n d 
t hr o u g h E O T or E T, u nless dee me d acce pt a ble b y t he, I n v esti gat or ( or d esi g nee), a n d 
S p o ns or. A n y me dicati o n ta ke n b y a s u bject d uri n g t he c o urse of t he st u d y, i ncl u di n g details 
of its d osa ge, a d mi nistrati o n, a n d t he reas o n f or its use, will be d oc u me nte d i n t he e C R F. 
T he a d mi nistrati o n of a n y c o nc o mita nt me dicati o n d uri n g t he st u d y is pr o hi bite d wit h o ut 
pri or a p pr o val of t he I n v esti gat or ( or desi g nee) a n d S p o ns or, u nless its use is dee me d 
necessar y i n a me dical e mer ge nc y. I n t his c ase, t h e use of t he c o nc o mita nt me dicati o n will be 
re p orte d as s o o n as is practical. 
6. 2.  
Diet, Fl ui d, a n d Acti vit y C o ntr ol 
S u bjects are r e q uire d t o r efrai n fr o m use of t o bacc o, s m o ki n g-cessati o n pr o d ucts, a n d 
nic oti ne-c o ntai ni n g pr o d ucts a n d e- ci garettes ( nic oti ne a n d n o n- nic oti ne) wit hi n 3  m o nt hs 
pri or t o Scree ni n g t hr o u g h E O T or E T. 
C o ns u m pti o n of f o o ds or be vera g es c o ntai ni n g gra pefr uit/ gra p efr uit j uice or Se ville ora n ges 
or its j uice wit hi n 7  da ys pri or t o C hec k-i n ( D a y - 1) a n d t hr o u g h E O T or E T will n ot be 
all o we d.  
C o ns u m pti o n of alc o h ol-c o ntai ni n g f o o ds or be vera ges or caffei ne-c o ntai ni n g f o o ds or 
be vera g es (i ncl u di n g b ut n ot li mite d t o teas [i ncl u di n g decaffei nate d teas], c offees [i ncl u di n g 
decaffei nat e d c offees], c olas [i ncl u di n g decaffei n ate d c olas], e ner g y dri n ks, g u m c o ntai ni n g 
caff ei ne, c h o c olate, a n d f o o ds a n d be vera ges c o ntai ni n g c h oc olate) wit hi n 7 2 h o urs pri or t o 
C hec k -i n ( Da y - 1) a n d t hr o u g h E O T or E T will n ot be all o we d. 
S u bjects will refrai n fr o m stre n u o us e xercise fr o m 5  da ys pri or t o C hec k-i n ( Da y -1) a n d 
d uri n g t he peri o d of c o nfi ne me nt at t he C R U a n d will ot her wise mai ntai n t heir n or mal le vel 
of p h ysical acti vit y t hr o u g h E O T or E T (ie, s h o ul d n ot be gi n a ne w e x ercis e pr o gra m or 
partici pate i n a n y u n us u all y stre n u o us p h ysical e x erti o n).  

Pr ot oc ol 
C O N FI D E N TI A L  
C o va nce St u d y: 8 4 1 9 6 8 9 
Pr ot oc ol Refere n ce:  L O X O -B T K - 2 0 0 1 0 
Pr ot oc ol Versi o n 1. 0, 9 Dece m b er 2 0 2 0  
Pa ge 4 5 of 6 8 
W hile c o nfi ne d at t he C R U, s u bjects will recei v e a sta n dar d diet at sc h e d ule d ti mes t hat d o 
n ot c o nflict wit h ot her st u d y- relate d acti vities. All st u d y dr u gs will be a d mi nistere d orall y 
wit h a p pr o xi matel y 2 4 0 m L of water . A n a d diti o nal 1 0 0 m L of  water m a y be a d mi nistere d if 
nee de d.  
Fasti n g re q uir e me nts a n d water r estricti o ns i n relati o n t o d osi n g are descri b e d i n Secti o n  3. 1  
a n d Secti o n  5. 2 .  
 

Pr ot oc ol 
C O N FI D E N TI A L  
C o va nce St u d y: 8 4 1 9 6 8 9 
Pr ot oc ol Refere n ce:  L O X O -B T K - 2 0 0 1 0 
Pr ot oc ol Versi o n 1. 0, 9 Dece m b er 2 0 2 0  
Pa ge 4 6 of 6 8 
7.  S T U D Y A S S E S S M E N T S A N D P R O C E D U R E S  
7. 1.  
P h ar m ac o ki netic Assess m e nts  
7. 1. 1.  
P h ar m ac o ki netic Bl o o d S a m ple C ollecti o n a n d Pr ocessi n g  
Bl o o d sa m ples f or P K a n al ysis of eac h s u bstrate (caffei ne / para xa nt hi ne, o me praz ole, a n d 
S- warf ari n) a n d L O X O -3 0 5 plas ma le vels will be c ollecte d at t he ti me p oi nts s pecifie d i n 
A p pe n di x 4 . T he e x act ti me of t he st u d y dr u g a d mi nistrati o n a n d t he act ual ti me of bl o o d 
sa m pli n g f or P K a nal ysis will be rec or d e d o n t he e C R F. 
Pr ocessi n g, st ora ge, a n d s hi p pi n g i nstr ucti o ns f or t hese P K bl o o d sa m ples will be pr o vi de d i n 
a se par ate La b orat or y M a n ual. T he n u m ber of bl o o d sa m ples a n d t otal bl o o d v ol u me re q uire d 
f or P K testi n g is prese nte d i n A p pe n di x 3 . 
7. 1. 2.  
A n al y tic al Met h o d ol o g y 
Plas ma c o nce ntr ati o ns of eac h s u bstrat e (caffei ne / para xa nt hi ne, o m e praz ol e, a n d S-warfari n) 
a n d L O X O- 3 0 5 will be deter mi ne d usi n g vali date d bi oa nal ytical met h o ds. S pecifics of t he 
bi oa nal ytical met h o ds will be pr o vi de d i n a se parate d oc u m e nt.  
7. 2.  
Ge n ot y pi n g  
A bl o o d sa m ple f or ge n ot y pi n g t o e xcl u de s u bjects w h o are n o n- a n d sl o w C Y P 2 C 9  
( C Y P 2 C 9 * 2/ * 3 or C Y P 2 C 9 * 3/ * 3 ge n ot y pes) a n d C Y P 2 C 1 9 (C Y P 2 C 1 9 * 2/ * 2, C Y P 2 C 1 9 
* 2/ * 3, or C Y P 2 C 1 9 * 3/ * 3 ge n ot y pes) meta b olizers  will be c ollecte d at t he Scree ni n g.  
Bl o o d v ol u me re q uire d f or ge n ot y pi n g is prese nte d i n A p pe n di x 3 .  
7. 3.  
S afet y a n d T oler a bilit y Assess me nts 
Safet y e val uati o ns ma y b e re peate d at t he discreti o n of t he I n vesti gat or ( or desi g nee) or 
S p o ns or. 
E ver y eff ort will be ma d e t o sc he d ule a n d p erf or m t he pr oce d ures i n acc or da nce wit h t he 
n o mi nal ti me, gi vi n g c o nsi derati o ns t o a p pr o priate p ost ure c o n diti o ns, practical restricti o ns, 
a n d a n y ot her pr oce d ures t o be perf or m e d at t he sa me ti me p oi nt. T he or der of pri orit y f or 
sc he d uli n g pr oce d ures ar o u n d a ti me p oi nt is (i n or der of pri orit y): 
•  d osi n g 
•  P K bl o o d sa m pli n g 
•  vital si g n meas ure me nts *  
•  1 2- lea d E C Gs * 
•  bl o o d a n d uri ne sa m ples f or cli nical la b orat or y e v al uati o ns 
•  p h ysical e xa mi nati o n. 
* W he n vital si g n meas ur e me nts a n d 1 2- lea d E C Gs are sc h e d ule d at t he s a me ti me as P K 
bl o o d sa m pli n g, t he P K bl o o d sa m pli n g will be o btai ne d at t he sc h e d ule d ti me p oi nt, a n d t he 

Pr ot oc ol 
C O N FI D E N TI A L  
C o va nce St u d y: 8 4 1 9 6 8 9 
Pr ot oc ol Refere n ce:  L O X O -B T K - 2 0 0 1 0 
Pr ot oc ol Versi o n 1. 0, 9 Dece m b er 2 0 2 0  
Pa ge 4 7 of 6 8 
vital si g n meas ure me nts f oll o we d b y 1 2- lea d E C Gs will be o btai ne d pri or t o a n d as cl ose as 
p ossi ble t o t he sc he d ule d P K bl o o d sa m pli n g. 
7. 3. 1.  
A d verse E ve nts  
A d verse e ve nt defi niti o ns; assi g n me nt of se verit y, ca usalit y, acti o n ta ke n, a n d o utc o me; a n d 
pr oce d ur es f or re p orti n g S A Es are detaile d i n A p p e n di x 1 . 
S u bjects will be as ke d a n o n-lea di n g H D Y F? q u esti o n s uc h as “ Ha v e t here bee n a n y c ha n ges 
i n y o ur healt h stat us si nce Scree ni n g/si nce y o u were last as ke d ?” at t he ti m e p oi nts s pecifie d 
i n A p pe n di x 4  (ie, at Scr ee ni n g [after t he I C F is si g ne d], at C hec k-i n [ Da y -1], at eac h 
p ost d ose vital si g n meas ure me nt, a n d at a n a p pr o priate ti me f or all ot her d a ys). S u bjects will 
als o be e nc o ura ge d t o v ol u ntaril y re p ort A Es occ urri n g at a n y ot her ti me t hr o u g h t he E O S. 
A d verse e ve nts, w het h er v ol u nteere d, i de ntifie d b y t he s u bject’s res p o ns es t o H D Y F? 
i n q uiries, or n ote d o n p h ysical e xa mi nati o n, E C G, vital si g n meas ure me nts, or cli nical 
la b orat or y e v al uati o ns, will be rec or d e d t hr o u g h o ut t he st u d y (ie, fr o m si g ni n g of t he I C F 
u ntil E O S [ or E T if t he s u bject disc o nti n ues fr o m t he st u d y a n d d oes n ot c o m plete a 
f oll o w- u p p h o ne call]), eit her as s u bject me dical hist or y (if t he e ve nt is re p orte d as be gi n ni n g 
pri or t o si g ni n g of t he I C F or if t he e ve nt occ urs pri or t o st u d y dr u g a d mi nistrati o n o n Da y 1 
a n d is assesse d as n ot r el ate d t o st u d y pr oce d ures b y t he I n vesti gat or [ or d esi g nee]) or as A Es 
(if t he e ve nt o cc urs after si g ni n g of t he I C F b ut pri or t o st u d y dr u g a d mi nistrati o n on Da y  1 
a n d is assesse d as relate d t o st u d y pr oce d ures b y t he I n vesti gat or [ or desi g nee], or if t h e e ve nt 
occ urs after st u d y dr u g a d mi nistrati o n o n Da y 1 t hr o u g h E O T or E T re gar dless of relati o ns hi p 
t o st u d y dr u g). Fr o m E O T or E T t hr o u g h E O S, o nl y A Es assesse d as relate d t o st u d y dr u g b y 
t he I n v esti gat or ( or d esi g nee) are t o be re p ort e d. All S A Es t hat de vel o p fr o m t he ti me of I C F 
si g ni n g u ntil E O S ( or E T, if t he s u bject disc o nti n ues fr o m t he st u d y a n d d o es n ot c o m plete a 
f oll o w- u p p h o ne call) ar e t o be re p orte d. 
U nless a s u bject wit h dra ws c o nse nt or is wit h dra w n fr o m t he st u d y a n d d oes n ot c o m plete t he 
f oll o w- u p p h o ne call, all s u bjects m ust be f oll o we d u ntil E O S. S u bjects wit h A Es t hat are 
assesse d as r elate d t o st u d y dr u g b y t he I n vesti gat or ( or desi g nee) w hi c h are o n g oi n g at E O S 
ma y c o nti n ue t o be f oll o we d u ntil t he s y m pt o ms or val ue(s) ret ur n t o n or mal, or acce pta ble 
le vels, as j u d ge d b y t he I n vesti gat or ( or desi g nee) a n d c o nfir me d b y t h e S p o ns or. T he 
I n v esti gat or ( or d esi g nee) s h o ul d use a p pr o pri ate j u d g me nt i n or deri n g a d diti o nal tests as 
necessar y t o m o nit or t he res ol uti o n of e ve nts. T he S p o ns or ma y re q uest t hat a d diti o nal safet y 
tests be perf or m e d. 
S u bjects will recei ve a f oll o w- u p p h o ne call 7 da ys ( ±  2 da ys) aft er E O T or E T t o deter mi ne 
if a n y S A E or dr u g-relate d A E has occ urre d si n ce t he E O T or E T visit. 
At all ti mes, a s u bject ma y be re q uir e d t o re mai n at t he C R U f or l o n ger at t he discreti o n of 
t he I n v esti gat or ( or d esi g nee). 
A n y e ve nt t hat meets t he criteria of a s us pect e d u n e x pecte d s eri o us a d vers e reacti o n 
( S U S A R) will be re p orte d t o t he I nstit uti o nal Re vie w B oar d (I R B) acc or di n g t o C R U p olic y 
b y t he I n vesti gat or ( or d esi g nee) a n d t o re g ulat or y a ut h orities b y t he S p o ns or ( or S p o ns or 
desi g nee) acc or di n g t o re g ulat or y a ut h orit y re q uire me nts. Refer t o Refere n ce Safet y 
I nf or mati o n i n t he c urre nt I B1 f or L O X O- 3 0 5 f or a d diti o nal safet y i nf or mati o n. 

Pr ot oc ol 
C O N FI D E N TI A L  
C o va nce St u d y: 8 4 1 9 6 8 9 
Pr ot oc ol Refere n ce:  L O X O -B T K - 2 0 0 1 0 
Pr ot oc ol Versi o n 1. 0, 9 Dece m b er 2 0 2 0  
Pa ge 4 8 of 6 8 
7. 3. 2.  
Cli nic al L a b or at or y E v al u ati o ns 
Cli nical la b orat or y e val u ati o ns (cli nical c he mistr y pa nel [faste d at least 8  h o urs; at E T or t he 
da y bef or e E O T, s u bjects are n ot r e q uire d t o be faste d pri or t o cli nical la b orat or y 
e val uati o ns], c o a g ulati o n para meters, he mat ol o g y pa nel, T S H [ Scree ni n g o nl y], H b A 1c 
[ Scree ni n g o nl y], e G F R [ Scree ni n g a n d C hec k -i n ( Da y -1)],  a n d U A) will be c ollecte d at t he 
ti me p oi nts s pecifie d i n A p pe n di x 4 . 
Scree ns f or H C V a nti b o d y, H Bs A g, H B V I g M c ore a nti b o d y, a n d HI V a nti b o d y will be 
perf or me d at Scree ni n g .  
Testi n g f or C O VI D- 1 9 via P C R ( or e q ui vale nt) will be perf or me d at t he ti me p oi nts s pecifie d 
i n A p pe n di x 4 . Testi n g f or C O VI D- 1 9 ma y als o b e c o n d ucte d p eri o dicall y d uri n g t he 
s u bject’s C R U c o nfi ne m e nt, at t he discreti o n of t h e I n vesti gat or ( or desi g nee). F urt her det ails 
re gar di n g C O VI D- 1 9 testi n g (i ncl u di n g pr oce d ures f or s u bjects w h o test p ositi ve at a n y ti me 
t hr o u g h o ut C R U c o nfi ne me nt) are s p ecifie d i n a se parat e d oc u me nt.  
A uri ne dr u g scree n f or s electe d dr u gs of a b use (i ncl u di n g c oti ni ne) a n d a n alc o h ol scree n 
( uri ne or br eat h) will be perf or me d at Scree ni n g a n d re peat e d at C hec k-i n ( Da y -1) f or all 
s u bjects. A ser u m q ualitati ve pre g na nc y t est (fe m ale s u bjects o nl y [ser u m q ua ntitati ve ma y 
be use d f or c o nfir mati o n, if nee de d]) a n d a n F S H t est ( p ost- me n o pa usal fe male s u bjects o nl y) 
will be perf or me d at t he ti me p oi nts s pecifie d i n  A p pe n di x 4 . 
T he n u m ber of bl o o d sa m ples a n d t otal bl o o d v ol u me re q uire d f or cli nical la b orat or y 
e val uati o ns ar e pres e nte d i n A p pe n di x 3 . A list of t he s pecific e val uati o ns is i n A p pe n di x 2 . 
7. 3. 3.  
Vit al Si g ns  
Vital si g n meas ure me nts (i ncl u di n g b o d y te m perat ure, res pirat or y rate, o x y ge n sat urati o n, 
a n d s u pi ne B P a n d p ulse rate) will be o btai n e d at t he ti me p oi nts s pecifie d i n  A p pe n di x 4 . 
Bl o o d press ure a n d p ulse rate meas ure me nts s h o ul d be perf or me d usi n g t he sa me ar m f or 
eac h r ea di n g a n d m eas ur e me nts s h o ul d be ta ke n after t he s u bject h as bee n resti n g i n t he 
s u pi ne p ositi o n for at least 5  mi n utes.  
W he n vital si g n meas ure me nts are sc h e d ule d at t h e sa me ti me as P K bl o o d dra ws, t he P K 
bl o o d dra ws will be o btai ne d at t he sc he d ul e d ti me p oi nt, a n d t he vital si g n meas ure me nts will 
be o btai ne d pri or t o a n d as cl ose as p ossi ble t o t he sc he d ule d P K bl o o d dra w. 
7. 3. 4.  
1 2- le a d Electr oc a r di o gr a m 
A 1 2 -lea d E C G (i n cl u di n g H R, P R, R R, Q R S, a n d Q T i nter val para meters) will be o btai ne d 
after t he s u bject has bee n resti n g f or at least 1 0  mi n utes i n t he s u pi ne p ositi o n at t he 
ti me p oi nts s pecifie d i n A p pe n di x 4 . T he Q T i nter v al will be c orrecte d f or H R b y Fri dericia’s 
( Q Tc F = Q T/[ R R] 1/ 3) f or m ula. 
W he n 1 2- lea d E C Gs ar e sc he d ule d at t he s a me ti me as P K bl o od dra ws, t he P K bl o o d dra ws 
will be o btai ne d at t he sc he d ule d ti me p oi nt, a n d t he 1 2-lea d E C Gs will be o btai ne d pri or t o 
a n d as cl ose as p ossi ble t o t he sc he d ule d P K bl o o d dra w. 

Pr ot oc ol 
C O N FI D E N TI A L  
C o va nce St u d y: 8 4 1 9 6 8 9 
Pr ot oc ol Refere n ce:  L O X O -B T K - 2 0 0 1 0 
Pr ot oc ol Versi o n 1. 0, 9 Dece m b er 2 0 2 0  
Pa ge 4 9 of 6 8 
7. 3. 5.  
P h ysic al E x a mi n ati o n 
A c o m plete or a b bre viat e d p h ysical e xa mi nati o n will be per f or me d at t he ti me p oi nts s pecifie d 
i n A p pe n di x 4 . C o m plete p h ysical e xa mi nati o ns will e val uate ge neral a p p eara nce a n d t he 
f oll o wi n g b o d y s yste ms/ or ga ns: der mat ol o gical; h ea d a n d e yes; ears, n ose, m o ut h, a n d t hr oat; 
p ul m o nar y; car di o vas c ular; a b d o mi nal; l y m p hatic; m usc ul os keletal/e xtre mities; a n d 
ne ur ol o gical. Wei g ht a n d hei g ht will be re p orte d ( hei g ht o nl y re p orte d d uri n g Scree ni n g). 
A b bre viate d p h ysical e xa mi nati o ns will e val uate ge neral a p peara n ce a n d t h e f oll o wi n g b o d y 
s yste ms/ or ga ns: der mat ol o gical; p ul m o nar y; car di o vasc ular; a b d o mi nal; a n d ne ur ol o gical. 

Pr ot oc ol 
C O N FI D E N TI A L  
C o va nce St u d y: 8 4 1 9 6 8 9 
Pr ot oc ol Refere n ce:  L O X O -B T K - 2 0 0 1 0 
Pr ot oc ol Versi o n 1. 0, 9 Dece m b er 2 0 2 0  
Pa ge 5 0 of 6 8 
8.  S A M P L E SI Z E A N D D A T A A N A L Y SI S  
8. 1.  
Deter mi n ati o n of S a m ple Size  
U p t o 1 6 healt h y a d ult male a n d f e male s u bjects ( w o me n of n o n-c hil d beari n g p ote ntial o nl y) 
will be e nr olle d. T he sa m ple size c h ose n f or t his st u d y was select e d wit h o ut statistical 
c o nsi derati o ns b ut is c o nsiste nt wit h pre vi o us st u dies of a si milar desi g n. U p t o 1 6 s u bjects 
are a ntici p ated t o be s ufficie nt t o pr o vi de a relia ble esti mate of t he ma g nit u de a n d vari a bilit y 
of t he i nteracti o n. Re place me nt s u bjects ma y be e nr olle d o nl y if dee me d n ecessar y b y t he 
S p o ns or. E ver y atte m pt will be ma de t o e nr oll at least 4  s u bjects of eac h s e x i n t he st u d y.  
8. 2.  
A n al ysis P o p ul ati o ns 
T he  P K P o p ul ati o n will c o nsist of all s u bjects w h o ha ve recei ve d a d ose of L O X O- 3 0 5 or 
t he pr o be c o c ktail dr u gs, ha ve at least 1 q ua ntifia ble plas ma c o nce ntrati o n, a n d f or w h o m at 
least 1 P K para met er ca n be c o m p ute d. A s u bjec t ma y be e xcl u d e d fr o m t h e P K s u m mar y 
statistics a n d statistical a nal ysis if t he s u bject has a n A E of v o miti n g t hat occ urs at or b ef ore 
tma x . T he i m pact of pr ot oc ol de viati o ns o n t he P K p o p ulati o n will be e val uate d o n a 
case- b y-cas e basis.  
T he  S afet y P o p ul ati o n will c o nsist of all s u bjects w h o ha ve recei v e d at least 1  d ose of st u d y 
dr u g ( pr o be c oc ktail dr u gs a n d/ or L O X O- 3 0 5). S u bjects will be classifie d i nt o gr o u ps base d 
o n act ual treat me nt recei ve d.  
8. 3.  
P h ar m ac o ki netic A n al ysis  
Serial bl o o d sa m ples f or plas ma c o nce ntrati o n a nal ysis will be a nal yze d usi n g sa m ples 
c ollecte d at t he f oll o wi n g ti me p oi nts:  
•  Caffei ne / para x a nt hi ne: 
o  
 f oll o wi n g a d mi nistrati o n al o ne o n 
 
  
•  O me praz ol e:  
o  
 f oll o wi n g a d mi nistrati o n al o ne o n 
 
 
•  S- War f ari n: 
o  
 f oll o wi n g a d mi nistrati o n al o ne o n 
 
 
•  L O X O - 3 0 5:  
o  
 f oll o wi n g a d mi nistrati o n al o ne o n 
 
o  
 f oll o wi n g a d mi nistrati o n wit h  
 
  
 
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI

Pr ot oc ol 
C O N FI D E N TI A L  
C o va nce St u d y: 8 4 1 9 6 8 9 
Pr ot oc ol Refere n ce:  L O X O -B T K - 2 0 0 1 0 
Pr ot oc ol Versi o n 1. 0, 9 Dece m b er 2 0 2 0  
Pa ge 5 1 of 6 8 
W he ne v er p ossi ble, t he f oll o wi n g P K para meters f or eac h s u bstrate (caffei ne/ para x a nt hi ne, 
o me praz ole , a n d S-warfari n) a n d L O X O -3 0 5 will be calc ul ate d f or eac h s u bject base d o n t he 
plas ma c o nce nt rati o ns (as a p pr o priate): 
•  area u n d er t he c o nce ntrati o n ti me c ur ve ( A U C ) fr o m h o ur 0 t o 2 4 h o urs p ost d ose 
( A U C0- 2 4) 
•  A U C fr o m h o ur 0 t o t he l ast meas ura ble c o nce ntrati o n ( A U C 0-t) 
•  A U C fr o m h o ur 0 e xtr a p olate d t o i nfi nit y ( A U C 0- i nf) 
•  perce nt a ge e xtra p olati o n f or A U C 0- i nf ( % A U Ce xtra p) 
•  a p pare nt s yste mic cleara nce ( C L/ F)  
•  C ma x  
•  mea n resi de n ce ti me ( M R T)  
•  a p pare nt plas m a ter mi nal eli mi nati o n half -life (t½ ) w here v er p ossi ble, w here t 1/ 2  = 
nat ural l o g ( 2)/ λ Z  
•  ti me t o ma xi m u m o bser ve d plas ma c o nce ntrati o n (t ma x ) 
•  a p pare nt ter mi nal eli mi nati o n rate c o nsta nt ( λ Z ) 
•  a p pare nt v ol u me of distri b uti o n at ter mi nal p hase ( V z/F)  
•  A U C 0- 2 4 a n d A U C 0- 4 8 rati o of para x a nt hi ne t o caffei ne ( M R A U C; 
caff ei ne/ par a xa nt hi ne o nl y) 
P har mac o ki netic calc ulati o ns will be pe rf or me d usi n g c o m mercial s oft ware s uc h as P h oe ni x™ 
Wi n N o nli n
®  Versi o n  8. 1 or hi g her ( Cert ara U S A I nc.).  
Ot her par a meters m a y be a d de d as a p pr o priate. Fi nal P K para meters re p orte d will be detaile d 
i n t he Statistical A nal ysis Pla n ( S A P). 
P har mac o ki netic a n a l ysis will use act ual ti mes as rec or de d o n t h e e C R F. All statistical 
a nal yses will be perf or m e d usi n g S A S  Versi o n  9. 4 or great er. M ore details o n t he a nal yses 
will be i ncl u de d i n t he S A P. 
8. 3. 1.  
Descri pti ve A n al ysis  
Plas ma c o nce ntr ati o ns a n d P K para meters will b e s u m marize d wit h descri pti ve statistics 
( n u m ber, arit h metic mea n, sta n dar d de viati o n, c o efficie nt of v ariati o n [ C V %], ge o metric 
mea n, ge o metric C V %, me dia n, mi ni m u m, a n d ma xi m u m). 
I n di vi d ual a n d m ea n plas ma c o nce ntr ati o n-ti me c ur ves ( b ot h li near a n d l o g li near) will be 
i ncl u de d i n t he fi nal re p ort. 
8. 3. 2.  
St atistic al Met h o d ol o g y 
T he pri mar y a n al ysis pla n ne d f or t his st u d y is a mi xe d effect m o del t hat i ncl u des treat me nt as 
a fi xe d effect a n d s u bject as a ra n d o m effect. T he a nal ysis will be perf or m e d o n t he nat ural 
l o g (l n)-tra nsf or me d P K para meters ( A U C0-t, A U C0- i nf, a n d Cma x ) a n d i ncl u de calc ul ati o n of 

Pr ot oc ol 
C O N FI D E N TI A L  
C o va nce St u d y: 8 4 1 9 6 8 9 
Pr ot oc ol Refere n ce:  L O X O -B T K - 2 0 0 1 0 
Pr ot oc ol Versi o n 1. 0, 9 Dece m b er 2 0 2 0  
Pa ge 5 2 of 6 8 
least s q uare d ( L S) mea ns a n d t he differe nce bet w ee n treat me nt L S mea ns, as well as t heir 
c orres p o n di n g 9 0 % c o nfi de nce i nter v als ( CIs). T h e ge o metric mea n  rati os a n d t heir 9 0 % CIs 
of t he P K para m eter f or eac h treat me nt c o m paris o n will be c o nstr ucte d usi n g t he 
e x p o ne ntiati o n of t he diff ere nce a n d t he CIs fr o m t he mi xe d effect m o del. T he c o m paris o ns 
of i nterest will be pr o be dr u gs al o ne (caffei ne a n d its meta b olite para xa nt hi ne, o me praz ole, 
a n d S- warfari n) v ers us pr o be dr u gs (caffei ne a n d its meta b olite para x a nt hi ne, o me praz ole, 
a n d S-warfari n) c oa d mi nistere d wit h L O X O - 3 0 5. T he rati o of para x a nt hi ne t o caffei ne will 
be s u m marize d.  
8. 4.  
S afet y A n al ysis 
All safet y assess me nts, i ncl u di n g A Es, S A Es, vital si g n meas ure me nts, cli nical la b orat or y 
res ults, p h ysical e xa mi nati o n res ults, c o nc o mita nt me dicati o ns, a n d 1 2-lea d E C Gs, will be 
ta b ulate d a n d s u m marize d w here p ossi ble, usi n g d escri pti ve met h o d ol o g y, as nee de d, b y 
ti me p oi nt. U nless ot her wise s pecifie d, bas eli ne val ue is defi ne d as t he l ast n o n-missi n g 
meas ure me nt b ef or e a d mi nistrati o n of st u d y dr u g o n Da y 1, Peri o d 1. N o f or mal statistical 
a nal yses ar e pla n ne d f or t he safet y d ata. All safet y data will be  liste d b y s u bject. 
C o nc o mita nt me dicati o ns will be c o de d usi n g t he W orl d Healt h Or ga nizati o n ( W H O) Dr u g 
Dicti o nar y ( W H O Dr u g Gl o bal B 3, Se pte m ber 2 0 1 9). A d vers e e ve nts will be c o de d usi n g 
Me dical Dicti o nar y f or R e g ulat or y Acti vities ( Me d D R A) Versi o n 2 2. 1 ( or hi g her). T he 
i nci de nce of A Es will be prese nte d b y s e verit y a n d b y relati o ns hi p t o st u d y dr u g as 
deter mi ne d b y t he I n v esti gat or or desi g nee ( A p p e n di x 1  f or A E re p orti n g). All T E A Es will be 
s u m marize d b y s yste m or ga n class a n d preferre d t er m. 
8. 5.  
D at a H a n dli n g a n d Rec or d Kee pi n g  
A n y c ha n ges t o i nf or mati o n i n t he trial pr o gress n otes a n d ot her s o urce d oc u me nts will be 
i nitiale d a n d date d o n t he da y t he c han g e is ma de b y a C R U staff me m ber a ut h orize d t o ma ke 
t he c ha n ge. C ha n g es will be ma de b y stri ki n g a si n gle li ne t hr o u g h err o n e o us data a n d clearl y 
e nteri n g t he c orrect data (e g, wr o n g d ata ri g ht dat a). If t he reas o n f or t he c ha n ge is n ot 
a p pare nt, a brief e x pla nati o n f or t he c ha n g e will be writte n a djace nt t o t he c ha n ge b y t he 
C R U staff me m ber.  
T he Data M a na ge m e nt Pla n will be a p pr o ve d b y t he S p o ns or. 
Data will be vali date d d uri n g data e ntr y b y t he C R U a n d verifi e d b y t he St u d y M o nit or. Data 
will t he n be re vie w e d b y t he data ma na g e me nt gr o u p t o res ol ve a n y o utsta n di n g iss ues. 
Listi n gs will be ge nerate d after t he d ata bas e is clea ne d b y data m a na ge m e nt a n d will be 
re vie we d b y t h e C o va nce scie ntific tea m. T he e C R F a n d a n cillar y data will be c o n vert e d i nt o 
fi nal S A S ®  datasets f oll o wi n g St u d y Data Ta b ulati o n M o del or S p o ns or- pr o vi de d 
s pecificati o ns. T he fi nal datasets str uct ure will be verifie d usi n g We b S u b missi o n Data 
Ma na ger
® , w hile t he d ataset c o nte nt will be peer re vie we d b y a n i n de pe n d e nt pr o gra m mer. 
T he ta b les, fi g ur es, a n d listi n gs ( T F Ls) will be pr o gra m me d per t h e fi nal S A P. All T F Ls will 
be peer re vie we d b y a n i n de pe n de nt pr o gra m mer. I n a d diti o n, draft T F Ls will be re vie we d b y 
t he C o va nce sci e ntific tea m d uri n g t he dr y r u n a n d data re vie w meeti n gs. 
T he peer re vie w will be perf or me d b y i n d e pe n de nt pr o gra m mers f oll o wi n g t he q ualit y c o ntr ol 
pr ocess a n d pr o gra m mi n g c hec klists. 

Pr ot oc ol 
C O N FI D E N TI A L  
C o va nce St u d y: 8 4 1 9 6 8 9 
Pr ot oc ol Refere n ce:  L O X O -B T K - 2 0 0 1 0 
Pr ot oc ol Versi o n 1. 0, 9 Dece m b er 2 0 2 0  
Pa ge 5 3 of 6 8 
8. 6.  
Q u alit y C o ntr ol a n d Q u alit y Ass ur a nce 
Q ualit y c o ntr ol a n d q ualit y ass ura nce will be perf or me d acc or di n g t o C o va nce S O Ps or per 
S p o ns or re q uest, a n d as a p plica ble, acc or di n g t o t he c o ntract bet wee n C o va nce a n d t he 
S p o ns or. 
 

Pr ot oc ol 
C O N FI D E N TI A L  
C o va nce St u d y: 8 4 1 9 6 8 9 
Pr ot oc ol Refere n ce:  L O X O -B T K - 2 0 0 1 0 
Pr ot oc ol Versi o n 1. 0, 9 Dece m b er 2 0 2 0  
Pa ge 5 4 of 6 8 
9.  A D MI NI S T R A TI V E A S P E C T S  
9. 1.  
C h a n ge i n Pr ot oc ol 
T here will be n o alterati o ns i n t he pr ot oc ol wit h o ut a gree me nt b et wee n t h e S p o ns or a n d t he 
I n v esti gat or ( or d esi g nee).  
T here will be n o alterati o ns i n t he pr ot oc ol affecti n g s u bject safet y wit h o ut t he e x press 
writte n a p pr o val of t h e S p o ns or, I n vesti gat or ( or d esi g nee), a n d t he I R B (see F or m 
F D A  1 5 7 2). 
9. 2.  
Site I niti ati o n Visit/I n vesti g at or Meeti n g  
Pri or t o t he start  of t he cli nical st u d y, t he re pres e ntati ve(s) of t he S p o ns or a n d/ or S p o ns or will 
meet wit h t he I n vesti gat or ( or desi g nee) a n d a p pr o priate C R U staff t o fa miliarize t he 
I n v esti gat or ( or d esi g nee) a n d C R U staff wit h t he materials necessar y f or c o n d ucti n g t he 
cli nical st u d y.  
9. 3.  
Discl os ure  
All i nf or mati o n pr o vi de d re gar di n g t he st u d y, as well as all i nf or mati o n 
c ollecte d/ d oc u me nte d d uri n g t he st u d y, will be re gar de d as c o nfi de ntial. T he I n vesti gat or ( or 
desi g nee) a grees n ot t o discl ose s uc h i nf or mati o n i n a n y wa y w it h o ut pri or writte n per missi o n 
fr o m t he S p o ns or. 
A n y p u blicati o n of t he res ults, i n part or i n t otal (e g, articles i n j o ur nals or n e ws pa pers, oral 
prese ntati o ns, a bstracts) b y t he I n vesti gat or ( or d esi g nee) or t heir re prese nt ati ve(s), s hall 
re q uire pri or n otificati o n a n d re vie w, wit hi n a reas o na ble ti mefra me, b y t he S p o ns or, a n d 
ca n n ot be ma d e i n vi olati o n of t he S p o ns or’s c o nfi de ntialit y restricti o ns or t o t he detri me nt of 
t he S p o ns or’s i ntellect ual pr o pert y ri g hts. 
9. 4.  
M o nit ori n g  
T he S p o ns or will desi g nate a St u d y M o nit or(s) w h o will be res p o nsi ble f or m o nit ori n g t his 
cli nical trial. T he S p o ns or’s St u d y M o nit or(s) will m o nit or t he st u d y c o n d uct, pr o per e C R F 
a n d s o urce d o c u me ntati o n c o m pleti o n a n d rete nti o n, a n d acc urate st u d y dr u g acc o u nta bilit y. 
T o t his e n d, t he S p o ns or’s St u d y M o nit or(s) will visit t he C R Us at s uita ble i nter vals ( or ma y 
perf or m acti vities re m otel y as per t he M o nit ori n g Pla n f or t his st u d y) a n d be i n fre q u e nt 
c o ntact t hr o u g h ver bal a n d writte n c o m m u nicati o n. It is esse ntial t hat t he S p o ns or’s St u d y 
M o nit or(s) has access t o all d oc u me nts (relat e d t o t he st u d y a n d t he i n di vi d ual partici pa nts) at 
a n y ti me t hese ar e re q u este d. I n t ur n, t he S p o ns or’s St u d y M o nit or(s) will a d here t o all 
re q uire me nts f or s u bject c o nfi de ntialit y as o utli ne d i n t he I C F. T he I n v esti gat or ( or desi g n ee) 
a n d I n vesti gat or’s staff will be e x pecte d t o c o o p erate wit h t he S p o ns or’s St u d y M o nit or(s), t o 
be a vaila ble d uri n g a p orti o n of t he m o nit ori n g visit t o a ns wer q uesti o ns, a n d t o pr o vi de a n y 
missi n g i nf or mati o n.  
9. 5.  
I nstit uti o n al Re vie w B o ar d  
I n acc or da n ce wit h U S Title 2 1 C o de of Fe d eral R e g ulati o ns ( C F R) 5 6, t he pr ot oc ol, 
a d vertise me nt, I C F, a n d ot her i nf or mati o n pr o vi d e d t o s u bjects will be re vie we d a n d 

Pr ot oc ol 
C O N FI D E N TI A L  
C o va nce St u d y: 8 4 1 9 6 8 9 
Pr ot oc ol Refere n ce:  L O X O -B T K - 2 0 0 1 0 
Pr ot oc ol Versi o n 1. 0, 9 Dece m b er 2 0 2 0  
Pa ge 5 5 of 6 8 
a p pr o ve d b y t he I R B. T h e S p o ns or will s u p pl y rele va nt material f or t he I n v e sti gat or ( or 
desi g nee) t o s u b mit t o t he  I R B f or t he pr ot oc ol’s re vie w a n d a p pr o val. V erificati o n of t he 
I R B u nc o n diti o nal a p pr o val of t he pr ot oc ol a n d t h e writte n I C F stat e me nt will be tra ns mitte d 
t o t he I n v esti gat or ( or d esi g nee). 
T he I R B will be i nf or me d  b y t he I n vesti gat or ( or desi g nee) of s u bs e q ue nt pr ot oc ol 
a me n d me nts a n d of seri o us a n d u ne x pecte d A Es. A p pr o val f or pr ot oc ol a me n d me nts will be 
tra ns mitte d i n writi n g t o t he I n vesti gat or ( or desi g nee). If re q u este d, t he I n vesti gat or ( or 
desi g nee) will per mit a u dits b y t he I R B a n d re g ul at or y i ns pecti o ns b y pr o vi di n g direct access 
t o s o urce data/ d o c u me nts. 
T he I n vesti gat or ( or desi g nee) will pr o vi de t he I R B wit h pr o gress re p orts at a p pr o priate 
i nter vals ( n ot t o e xcee d 1 year) a n d a St u d y Pr o gress Re p ort f oll o wi n g t he c o m pleti o n, 
ter mi nati o n, or disc o nti n uati o n of t he I n vesti gat or’s ( or desi g nee’s) p artici pati o n i n t he st u d y. 
9. 6.  
I nf or m e d C o nse nt 
Writte n i nf or me d c o ns e nt f or t he st u d y will be o btai ne d fr o m all s u bjects b ef ore 
pr ot oc ol- s pecifi c pr oce d ures ar e carrie d o ut. T h e I C F will be a p pr o v e d (al o n g wit h t he 
pr ot oc ol) b y t he I R B a n d will be acce pta ble t o t he S p o ns or. 
T he I n vesti gat or ( or desi g nee) will e x plai n t he n at ure of t he st u d y a n d t he acti o n of t he test 
pr o d uct. T he s u bjects will be i nf or me d t hat partici pati o n is v ol u ntar y a n d t hat t he y ca n 
wit h dra w fr o m t he st u d y at a n y ti me. I n acc or da nce wit h 2 1 C F R 5 0, t he i nf or me d c o nse nt 
pr ocess s hall be d o c u me nte d b y t he use of a writte n I C F a p pr o ve d b y t he I R B a n d si g ne d b y 
t he s u bject pri or t o pr ot o c ol-s pecific proce d ures b ei n g perf or m e d. 
T he s u bject will si g n 2 c o pies of t he I C F. O n e c o p y will be gi ve n t o t he s u bject, a n d t he ot her 
will be mai ntai ne d wit h t he s u bject’s r ec or ds.  
9. 7.  
Rec or ds  
T he res ults fr o m dat a c ollecte d at Scr ee ni n g a n d d uri n g t he st u d y will be rec or de d i n t he 
s u bject’s e C R F. T o mai ntai n c o nfi de ntialit y, t he s u bjects will be i de ntifie d o nl y b y n u m bers. 
T he c o m plete d e C R Fs will be tra nsferre d t o t he S p o ns or ( or desi g nee). C o pi es of eac h e C R F 
will be retai ne d b y t he I n vesti gat or ( or desi g nee). All s o urce d oc u me nts, rec or ds, a n d re p orts 
will be retai ne d b y t he C R U i n acc or d a nce wit h 2 1 C F R 3 1 2. 6 2(c). 
All pri mar y data, or c o pies t here of (e g, la b orat or y rec or ds, e C R Fs, data s h eets, 
c orres p o n d e nce, p h ot o gr a p hs, a n d c o m p uter rec or ds), w hic h are a res ult of t he ori gi nal 
o bser vati o ns a n d acti vities of t he st u d y a n d are necessar y f or t he rec o nstr ucti o n a n d 
e val uati o n of a n y st u d y r e p ort, will be retai n e d i n t he C R U arc hi ves. 
9. 8.  
Refere nce t o Decl ar ati o n of Helsi n ki/ B asic Pri nci ples  
T he st u d y pr oce d ures o utli ne d i n t his pr ot oc ol will be c o n d ucte d i n acc or da nce wit h t he U S 
C F R g o ver ni n g Pr otecti o n of H u ma n S u bjects ( 2 1 C F R 5 0), Fi na n cial Discl os ure b y Cli nical 
I n v esti gat ors ( 2 1 C F R 5 4), I R Bs ( 2 1 C F R 5 6), a n d I n v esti gati o nal Ne w Dr u g A p plicati o n 
( 2 1 C F R  3 1 2), as a p pr o priate. As s uc h, t hes e secti o ns of U S Title 2 1 C F R, al o n g wit h t he 

Pr ot oc ol 
C O N FI D E N TI A L  
C o va nce St u d y: 8 4 1 9 6 8 9 
Pr ot oc ol Refere n ce:  L O X O -B T K - 2 0 0 1 0 
Pr ot oc ol Versi o n 1. 0, 9 Dece m b er 2 0 2 0  
Pa ge 5 6 of 6 8 
a p plica ble I C H G ui d eli nes, are c o m m o nl y k n o w n as G o o d Cli nical Practices, w hic h are 
c o nsiste nt wit h t he Declarati o n of Helsi n ki.  
9. 9.  
Fi n a nci n g a n d I ns ur a nce  
Fi na nci n g a n d i ns ur a nce will be a d dress e d i n a s e parate a gree me nt.  
 
 

Pr ot oc ol 
C O N FI D E N TI A L  
C o va nce St u d y: 8 4 1 9 6 8 9 
Pr ot oc ol Refere n ce:  L O X O -B T K - 2 0 0 1 0 
Pr ot oc ol Versi o n 1. 0, 9 Dece m b er 2 0 2 0  
Pa ge 5 7 of 6 8 
1 0.  R E F E R E N C E S  
1.   L o x o O nc ol o g y, I nc. L O X O- 3 0 5 - I n v esti gat or’s Br oc h ure ( Versi o n 4. 0). 2 9 Oct o ber 
2 0 2 0.  
2.   Bra n d h u ber B, G o mez E, S mit h S, Ear y T, S pe ncer S, R ot he n ber g S M, et al. A ne xt 
ge nerati o n r e versi ble B T K I n hi bit or, f or o verc o mi n g ac q uire d resista nce t o irre versi ble 
B T K i n hi bit ors. Cli n L y m p h o ma M yel o ma Le u k. 2 0 1 8; 1 8; S 2 1 6.  
3.   B yr d J C, F ur ma n R R, C o utre S E, Fli n n I W, B ur ger J A, Bl u m K A, et al. Tar geti n g B T K 
wit h i br uti ni b i n rela pse d c hr o nic l y m p h oc ytic le u ke mia. N E n gl J Me d. 2 0 1 3 J ul 
4; 3 6 9( 1): 3 2 – 4 2.  
4.  W o yac h J A, R u p pert A S, G ui n n D, Le h ma n A, Bl ac hl y J S, L oza ns ki A, et al. 
B T K C 4 8 1 S- Me diate d Resista nce t o I br uti ni b i n C hr o nic L y m p h oc ytic Le u ke mia. J Cli n 
O nc ol. 2 0 1 7 Ma y 1; 3 5( 1 3): 1 4 3 7 – 4 3.  
5.   W o yac h J, H u a n g Y, R o gers K, B hat S A, Gre v er M R, L oza ns ki A, et al. Resista nce t o 
acala br uti ni b i n C L L is me diate d pri maril y b y B T K m utati o ns. Bl o o d. 
2 0 1 9; 1 3 4( S u p ple me nt _ 1).  
6.   C hir o n D, Di Li bert o M, Marti n P, H ua n g X, S har ma n J, Blec ua P, et al. Cell- c ycle 
re pr o gr a m mi n g f or PI 3 K i n hi biti o n o verri des a rel a pse-s pecific C 4 8 1 S B T K m utati o n 
re veal e d b y l o n git u di nal f u ncti o nal ge n o mics i n ma ntle cell l y m p h o ma. Ca ncer Disc o v. 
2 0 1 4 Se p; 4( 9): 1 0 2 2 – 3 5.  
7.   X u L, Tsa k ma klis N, Ya n g G, C he n J G, Li u X, D e m os M, et al. Ac q uire d m utati o ns 
ass ociate d wit h i br uti ni b resista nce i n Wal d e nstr ö m macr o gl o b uli ne mia. Bl o o d. 2 0 1 7 
0 4; 1 2 9( 1 8): 2 5 1 9 – 2 5.  
8.   T o y os hi ma S, Ka n n o A, Kita ya ma T, Se ki ya K, N a kai K, Har u na M, et al. Q T 
P R O D A C T: I n Vi v o Q T Assa y i n t he C o nsci o us D o g f or Assessi n g t he P ote ntial f or Q T 
I nter val Pr ol o n gati o n b y H u ma n P har mace uticals [I nter net]. J o ur nal of p h ar mac ol o gical 
scie nces. 2 0 0 5 [cite d 2 0 2 0 J u n 1 0]. A vaila ble fr o m: 
htt ps:// p u b me d. nc bi. nl m. ni h. g o v/ 1 6 4 9 3 1 8 7/ 
9.   F o o d a n d Dr u g A d mi nistrati o n. G ui da nce f or I n d ustr y: Cli nical Dr u g I nteracti o n St u dies 
- C yt oc hr o me P 4 5 0 E nz yme - a n d Tra ns p orter- Me diate d Dr u g I nteracti o ns G ui da nce f or 
I n d ustr y [I nter n et]. F o o d a n d Dr u g A d mi nistrati o n; 2 0 2 0 [cite d 2 0 2 0 Se p 2 5]. A vaila ble 
fr o m: htt ps:// w w w.f da. g o v/ me dia/ 1 3 4 5 8 1/ d o w nl oa d 
 

Pr ot oc ol 
C O N FI D E N TI A L  
C o va nce St u d y: 8 4 1 9 6 8 9 
Pr ot oc ol Refere n ce:  L O X O -B T K - 2 0 0 1 0 
Pr ot oc ol Versi o n 1. 0, 9 Dece m b er 2 0 2 0  
Pa ge 5 8 of 6 8 
1 1.  A P P E N DI C E S  

Pr ot oc ol 
C O N FI D E N TI A L  
C o va nce St u d y: 8 4 1 9 6 8 9 
Pr ot oc ol Refere n ce:  L O X O -B T K - 2 0 0 1 0 
Pr ot oc ol Versi o n 1. 0, 9 Dece m b er 2 0 2 0  
Pa ge 5 9 of 6 8 
A p pe n di x  1: A d verse E ve nt Re p orti n g  
A d verse E ve nts  
Defi niti o n of A d vers e E v e nts 
A n a d vers e e ve nt ( A E; or a d verse e x peri e nce) is  defi ne d as a n y u nt o war d me dical occ urre n ce 
e x perie n ce d b y a p atie nt or healt h y a d ult s u bject, w het her or n ot c o nsi dere d dr u g- relat e d b y 
t he I n v esti gat or ( or d esi g nee). A tr eat me nt-e mer g e nt a d vers e e ve nt ( T E A E) is a n A E t hat 
starts o n or after t he first a dmi nistrati o n of st u d y dr u g. 
T he f oll o wi n g are all A Es: 
•  
u nfa v ora bl e c ha n g es i n ge neral c o n diti o n 
•  
s u bjecti ve or o bjecti ve si g ns/s y m pt o ms 
•  
c o nc o mita nt diseases or acci de nts  
•  
cli nicall y si g nifica nt a d v erse c h a n ges i n la b orat or y para meters o bser v e d i n a s u bject 
d uri n g a cli nical st u d y 
A d verse e ve nts c o m prise all dist ur ba nces of g e neral healt h stat us, s u bjecti ve a n d o bjecti ve 
disease s y m pt o ms (i ncl u di n g la b orat or y a b n or m alities t hat are dee m e d cli nicall y si g nifica nt 
b y t he I n vesti gat or [ or d esi g nee]), a n d acci de nts o bser ve d i n t he c o nt e xt of a cli nical trial, 
irres pecti ve of a p ossi ble ca usal r elati o ns hi p wit h t he a d mi nistrati o n of t he trial s u bsta nce. 
Cate g orizati o n of A d v ers e E ve nts 
T he se verit y of A Es will be cate g orize d b ase d o n t he Nati o nal Ca ncer I nstit ute C o m m o n 
Ter mi n ol o g y Criteria f or A d verse E v e nts ( C T C A E) Versi o n 5. 0 as f oll o ws: 
•  
Gr a de  1 Mil d:  As y m pt o matic or mil d s y m pt o ms; cli nical or dia g n ostic 
o bser vati o ns o nl y; i nter ve nti o n n ot i n dicate d 
•  
Gr a de  2 M o der at e:  Mi ni mal, l ocal, or n o ni n vasi ve i nter ve nti o n i n dicate d; li miti n g 
a ge-a p pr o priate i nstr u me ntal Acti vities of Dail y Li vi n g ( A D L) *  
•  
Gr a de  3 Severe o r m e dic all y si g nific a nt b ut n ot i m me di atel y life -t hre ate ni n g: 
H os pitalizati o n or pr ol o n gati o n of h os pitalizati o n i n dicate d; disa bli n g; li miti n g 
self-care A D L * *  
•  
Gr a de  4 Life -t hre ate ni n g c o nse q ue nces: A n e v e nt t hat p uts t he s u bject at 
i m me diate ris k of deat h  
•  
Gr a de  5: Deat h relate d t o A E  
N ote: N ot all gra d es are a p pr o priate f or all A Es. T h eref ore, s o me A Es are liste d wit hi n t h e C T C A E wit h fe wer t h a n 
5 o pti o ns f or gra d e selecti o n. Gra d e 5 ( d eat h) is n ot a p pr o priate f or s o me A Es a n d t h eref ore is n ot a n o pt i o n. 
* I nstr u me ntal A D L refer t o pre pari n g meals, s h o p pi n g f or gr o ceries, or cl ot h es, usi n g t h e tele p h o n e, ma n a gi n g m o n e y, etc. 
* * Self -car e A D L refer t o b at hi n g, dressi n g a n d u n dressi n g, fee di n g self, usi n g t h e t oilet, ta ki n g me dicati o ns, a n d n ot 
be dri d de n . 

Pr ot oc ol 
C O N FI D E N TI A L  
C o va nce St u d y: 8 4 1 9 6 8 9 
Pr ot oc ol Refere n ce:  L O X O -B T K - 2 0 0 1 0 
Pr ot oc ol Versi o n 1. 0, 9 Dece m b er 2 0 2 0  
Pa ge 6 0 of 6 8 
T he I n vesti gat or ( or desi g nee) will ma ke a deter mi nati o n of t he relati o ns hi p of t he A E t o t he 
st u d y dr u g usi n g a 2-cate g or y s yste m acc or di n g t o t he f oll o wi n g g ui deli nes: 
•  
N O T R E L A T E D  = T he ti me c o urse bet w ee n t he a d mi nistrati o n of i n vesti gati o nal 
pr o d uct a n d t he occ urr e n ce or w orse ni n g of t he A E r ules o ut a ca us al relati o ns hi p 
a n d a n ot her ca use (e g, c o nc o mita nt dr u gs, t hera pies, c o m plicati o ns, c o m or bi dities) 
is s us pecte d 
•  
R E L A T E D  = T he ti me c o urse bet wee n a d mi nistrati o n of i n vesti gati o nal pr o d uct 
a n d t he occ urre n ce or w orse ni n g of t he A E is c o nsiste nt wit h a ca usal rel ati o ns hi p 
a n d n o ot her ca use ( e g, c o nc o mita nt dr u gs, t hera pies, c o m plicati o ns, c o m or bi dities) 
ca n be i de ntifie d  
A n A E is ass ociate d wit h t he use of t he dr u g if t h ere is a reas o na ble p ossi bilit y t hat t he 
e x perie n ce ma y h a ve bee n ca use d b y t he dr u g. 
Pre g na nc y  
As i nf or mati o n is a vaila ble, a pre g n a nc y (i n cl u di n g pre g na nc y i n fe male p art ners of male 
s u bjects) dia g n ose d t hr o u g h E n d of St u d y ( E O S) or Earl y Ter mi nati o n ( E T; if t he s u bject 
disc o nti n ues fr o m t he st u d y a n d d oes n ot c o m plete a f oll o w- u p p h o ne call)  a n d f or u p t o 
9 0 da ys after st u d y dr u g a d mi nistrati o n o n Da y 1 9 ( or last a d mi nistrati o n of st u d y dr u g if 
s u bject ter mi nates fr o m t he st u d y earl y) s h o ul d be re p orte d b y t he I n vesti gat or ( or desi g nee) 
via e mail t o C o va nce or t he S p o ns or’s Cli nical Safet y Re prese ntati ve wit hi n 2 4 h o urs of 
bei n g n otifie d. C o va nce or t he S p o ns or’s Cli nical Safet y Re pres e ntati ve will t he n f or war d t he 
Pre g na nc y F or m t o t he I n vesti gat or ( or desi g nee) f or c o m pleti o n. 
e m ail: S A EI nt a ke @ C o v a nce.c o m 
A s u bject bec o mi n g pr e g na nt w hile o n st u d y dr u g will i m me diatel y be wit h dra w n fr o m t he 
st u d y a n d E T st u d y pr oce d ures will be perf or me d. T he s u bject or part ner s h o ul d be f oll o we d 
b y t he I n vesti gat or ( or d esi g nee) u ntil c o m pleti o n of t he pre g n a nc y. If t he pre g na nc y e n ds f or 
a n y reas o n b ef or e t he a ntici pate d date, t he I n vesti gat or ( or desi g n ee) s h o ul d n otif y C o va nce 
or t he S p o ns or’s Cli nical Safet y Re pres e ntati ve. At t he c o m pleti o n of t he pre g na nc y, t he 
I n v esti gator ( or d esi g nee) will d oc u me nt t he o utc o me of t he pre g n a nc y. If t he o utc o me of t he 
pre g na nc y m eets t he criteria f or i m me diat e classificati o n as a seri o us a d verse e ve nt ( S A E; ie, 
p ost part u m c o m plicati o n, s p o nta ne o us a b orti o n, still birt h, ne o natal deat h, or c o n ge nital 
a n o mal y), t he I n v esti gat or ( or desi g nee) s h o ul d f oll o w t he pr oce d ures f or re p orti n g a n S A E. 
Male s u bjects will be i nstr ucte d t o n otif y t he I n vesti gat or ( or desi g nee) i m me diatel y if t he y 
disc o ver t heir se x u al part ner is pre g na nt. I n t his i nsta nce, t he part ner m ust pr o vi de writte n 
c o nse nt bef or e pr e g na nc y i nf or mati o n ca n be c ollecte d. W h e n a Cli nical Researc h U nit 
( C R U) bec o mes a war e t h at t he fe male p art ner of a male s u bject is pre g na nt, t he y are t o 
c o ntact t he I n v esti gat or ( or desi g nee) i m me diat el y ( wit hi n 2 4 h o urs of t he C R U staff 
bec o mi n g a ware of t h e e ve nt) i n a d diti o n t o n otif yi n g C o va nce or t he S p o ns or’s Cli nical 
Safet y Re pres e ntati ve via e mail.  
All pre g na ncies s h o ul d b e rec or de d o n t he A E electr o nic Case Re p ort F or m (e C R F; as 
a p pr o priate), i n a d diti o n t o c o m pleti o n of t he re q uire d pre g n a nc y f or ms. If t he I n vesti gat or 
( or desi g nee) s us pects t h at a pre g n a nc y w as t he res ult of a n i nteracti o n bet wee n t he st u d y 

Pr ot oc ol 
C O N FI D E N TI A L  
C o va nce St u d y: 8 4 1 9 6 8 9 
Pr ot oc ol Refere n ce:  L O X O -B T K - 2 0 0 1 0 
Pr ot oc ol Versi o n 1. 0, 9 Dece m b er 2 0 2 0  
Pa ge 6 1 of 6 8 
treat me nt a n d t he c o ntrace pti ve met h o d, i n a d diti o n t o t he pre g na nc y t h e dr u g i nteracti o n 
s h o ul d als o be ca pt ure d as a se par ate A E. 
Defi niti o n of Seri o us A d verse E ve nts 
A n S A E b y t he F o o d a n d Dr u g A d mi nistrati o n ( F D A) defi niti o n is a n y a d v erse dr u g 
e x perie n ce occ urri n g at a n y d ose t hat res ults i n a n y of t he f oll o wi n g o utc o mes: 
•  
Deat h  
•  
A life -t hreate ni n g a d vers e dr u g e x perie nce (ie, o n e t hat places t he s u bj ect, i n t he 
vie w of t he I n v esti gat or [ or desi g nee], at i m me diate ris k of deat h) 
•  
I n p atie nt h os pitalizati o n or pr ol o n gati o n of e xisti n g h os pitalizati o n 
•  
A persiste nt or si g nifica nt disa bilit y/i nca pacit y  
•  
A c o n ge nital a n o mal y/ birt h defect 
•  
A n i m p orta nt me dical e v e nt t hat ma y re q uire me dical or s ur gical i nter ve nti o n t o 
pre ve nt 1 of t he a b o ve o utc o mes 
I m p ort a nt me dical e v e nts t hat ma y n ot res ult i n deat h, be life-t hreate ni n g, or re q uire 
h os pitalizati o n ma y be c o nsi dere d S A Es w he n, b ase d o n a p pr o priate me di cal j u d g me nt, t he y 
ma y je o par dize t he patie nt or s u bject a n d ma y re q uire me dical or s ur gical i nter ve nti o n t o 
pre ve nt 1 of t he o ut c o mes liste d i n t his defi niti o n. 
U ne x pect e d A d verse Dr u g Reacti o n  
A n A E or s us pect e d a d verse dr u g r eacti o n is c o nsi dere d ‘ u n e x pecte d’ if t he e ve nt is n ot liste d 
i n t he Refere n ce Safet y I nf or mati o n secti o n of t he I n v esti gat or’s Br oc h ure (I B) or if it is n ot 
liste d at t he s pecificit y or se verit y t hat has bee n o bser ve d f or a n u na p pr o ve d i n vesti gati o nal 
me dici nal pr o d uct (I M P). 
Re p orti n g 
T he F D A -r e p orta ble A Es are A Es t hat are ass ociat e d wit h t he use of t he dr u g a n d re prese nt 
e ve nts t hat ar e assesse d as seri o us, relate d, a n d u n e x pecte d. T h e F D A -re p orta ble A Es will be 
re p orte d b y t he C R U t o t he S p o ns or a n d t he res p o nsi ble I nstit uti o nal Re vie w B oar d (I R B). 
Fi nal deter mi nati o n of w het her a n e ve nt re pres e nts a s us pecte d u n e x pecte d seri o us a d vers e 
reacti o n ( S U S A R) will b e t he res p o nsi bilit y of t he S p o ns or. 
Wit hi n 2 4 h o urs of w he n a n A E t hat is p ote ntiall y F D A-re p ort a ble is first rec o g nize d or 
re p orte d, a n d wit hi n 2 4 h o urs of a n y S A E (re gar dless of w het her t he e v e nt is assesse d as 
relate d or u nrelate d t o st u d y dr u g) bei n g first rec o g nize d or re p orte d, C o va n ce or t he 
S p o ns or’ s Cli nical Safet y Re prese ntati ve will be n otifie d b y t he I n vesti gat or ( or desi g nee) i n 
writi n g usi n g t he f oll o wi n g e mail a d dress: 
e m ail: S A EI nt a ke @ C o v a nce.c o m 
T o re p ort t he S A E, t he c o m plete d re p ort f or m s h o ul d be se nt b y e mail t o C o va nce or t h e 
S p o ns or’s Cli nical Safet y Re prese ntati ve wit hi n 2 4  h o urs of a w are n ess. I nc o mi n g re p orts are 

Pr ot oc ol 
C O N FI D E N TI A L  
C o va nce St u d y: 8 4 1 9 6 8 9 
Pr ot oc ol Refere n ce:  L O X O -B T K - 2 0 0 1 0 
Pr ot oc ol Versi o n 1. 0, 9 Dece m b er 2 0 2 0  
Pa ge 6 2 of 6 8 
re vie we d d uri n g n or mal b usi ness h o urs. A d diti o nal re p orti n g i nstr ucti o ns a n d t he S A E Re p ort 
F or m ar e pr o vi de d i n t he St u d y Ma n ual. 
T he I R B will be n otifie d of a n y F D A-r e p orta ble A E wit hi n t he ti mefra me re q uire d b y t he 
I R B. T he I R B Seri o us a n d U ne x pect e d A d verse E x perie nce S u b missi o n F or m will be 
c o m plete d a n d s u b mitte d wit h t he c o p y of t he writte n c o nfir mati o n or s u m mar y of t he A E. 
 
 

Pr ot oc ol 
C O N FI D E N TI A L  
C o va nce St u d y: 8 4 1 9 6 8 9 
Pr ot oc ol Refere n ce:  L O X O -B T K - 2 0 0 1 0 
Pr ot oc ol Versi o n 1. 0, 9 Dece m b er 2 0 2 0  
Pa ge 6 3 of 6 8 
A p pe n di x  2: Cli n ic al L a b or at or y E v al u ati o ns 
Cli nic al C he mistr y P a nel 
( F aste d): 
He m at ol o g y P a nel: 
Ot her Tests:  
Ala ni ne a mi n otra nsferase ( A L T)  
Al b u mi n 
Al kali ne p h os p hatase ( A L P)  
A m ylase  
As partate a mi n otra nsferase 
( A S T) 
Bilir u bi n ( direct a n d t otal)  
Bl o o d urea nitr o ge n  
Calci u m  
C hl ori de 
C h olester ol 
Creati ne ki nase  
Creati ni ne  
Gl uc ose 
Ir o n 
Li pase  
Ma g nesi u m  
P h os p h or us 
P otassi u m  
S o di u m 
T otal pr otei n  
Tri gl yceri des 
Uric aci d  
He mat ocrit  
He m o gl o bi n  
Mea n c or p usc ular he m o gl o bi n  
Mea n c or p usc ular he m o gl o bi n 
c o nce ntrati o n 
Mea n c or p usc ular v ol u me  
Platelet c o u nt 
Re d bl o o d cell ( R B C) c o u nt 
R B C distri b uti o n wi dt h  
W hite bl o o d cell ( W B C) c o u nt  
W B C differe ntial ( perce nt a n d 
a bs ol ute): 
    Bas o p hils 
    E osi n o p hils 
    L y m p h oc ytes 
    M o n oc ytes 
    Ne utr o p hils 
He m o gl o bi n A 1c ( H b A 1c) b 
T h yr oi d- sti m ulati n g h or m o ne 
( T S H)b 
Esti mate d gl o mer ular filtrati o n 
ratea, d 
S A R S -C o V -2 ( C O VI D -1 9) test  
C o a g ul ati o n P ar a meters: 
Partial t hr o m b o plasti n ti me  
Pr ot hr o m bi n ti me  
I nter nati o nal n or malize d rati o 
Ser ol o g y: b 
He patitis B s urface a nti ge n 
( H Bs A g) 
He patitis B vir us ( H B V) 
i m m u n o gl o b uli n M (I g M) c ore 
a nti b o d y 
He patitis C vir us ( H C V) 
a nti b o d y 
H u ma n i m m u n o deficie nc y vir us 
( HI V) a nti b o d y 
F or Fe m ale S u bjects O nl y:  
Pre g na nc y test (ser u m 
q ualitati ve, ser u m q ua ntitati ve 
ma y be use d f or c o nfir mati o n if 
nee de d) c 
F ollicle -sti m ulati n g h or m o ne 
( p ost-me n o pa usal fe male 
s u bjects o nl y) b 
 
Uri n al ysis:  
Bilir u bi n  
C ol or a n d a p peara nce  
Gl uc ose 
Ket o nes 
Le u k oc yte esterase  
Nitrite  
Occ ult bl o o d 
p H a n d s pecific gra vit y  
Pr otei n  
Ur o bili n o ge n 
Micr osc o pic e xa mi nati o n 
i ncl u di n g bacteria, casts, 
cr ystals, e pit helial cells, R B Cs, 
a n d W B Cs (if pr otei n, le u k oc yte 
esterase, nitrite, or occ ult bl o o d 
is p ositi ve) 
Uri ne Dr u g Scree n: a 
I ncl u di n g b ut n ot li mite d t o t he 
f oll o wi n g: 
Alc o h ol (et ha n ol) e 
A m p heta mi nes  
Bar bit urates  
Be nz o diaze pi nes  
Ca n na bi n oi ds 
C ocai ne ( meta b olite)  
Met ha d o ne  
O piates  
P he nc ycli di ne 
C oti ni ne  
a. Perf or me d at Scree ni n g a n d C hec k -i n ( Da y -1) o nl y.  
b.  Perf or me d at Scree ni n g o nl y.  
c. Perf or me d at Scree ni n g, C hec k -i n ( Da y -1), a n d Da y 2 2 f or E n d of Treat me nt ( E O T) or Earl y Ter mi nati o n 
( E T) o nl y. 
d.  Calc ulate d usi n g t he C hr o nic Ki d ne y Disease E pi de mi ol o g y C olla b orati o n ( C K D -E PI) e q uati o n.  
e. Uri ne or breat h test.  

Pr ot oc ol 
C O N FI D E N TI A L  
C o va nce St u d y: 8 4 1 9 6 8 9 
Pr ot oc ol Refere n ce:  L O X O -B T K - 2 0 0 1 0 
Pr ot oc ol Versi o n 1. 0, 9 Dece m b er 2 0 2 0  
Pa ge 6 4 of 6 8 
A p pe n di x  3: T ot al Bl o o d V ol u m e 
T he f oll o wi n g bl o o d v ol u mes will be wit h dra w n f or eac h s u bj ect: 
a F or P K sa m ples f or a n al ysis of eac h s u bstrate ( caffei n e/ p ara x a nt hi n e , o me praz ole, a n d S-warfari n) a  si n gle bl o o d sa m ple will 
be c ollecte d . 
b T h yr oi d -sti m ulati n g h or m o n e ( T S H) a n d esti mate d gl o mer ular filtrati o n rate (e G F R) will b e assesse d as p art of t h e cli nical 
c he mistr y sa m ple.  
If e xtra bl o o d s a m ples ar e re q uir e d, t he ma xi m u m bl o o d v ol u me t o be wit h dra w n per s u bject 
will n ot e xcee d 5 0 0 m L.  
Assess me nt  
A p pr o xi m ate 
Bl o o d V ol u me per 
S a m ple ( m L)  
M a xi m u m N u m ber of 
Bl o o d S a m ples  
A p pr o xi m ate 
T ot al 
V ol u me 
( m L) 
Ser ol o g y  
8. 0  
1  
8. 0  
He m o gl o bi n A 1c ( H b A 1c)  
4. 0  
1  
4. 0  
Pr o be d r u g coc ktail  p har mac o ki netic  
(P K ) sa m pli n ga 
4. 0  
3 6 
1 4 4. 0 
L O X O -3 0 5 P K sa m pli n g  
4. 0  
3 0  
1 2 0 . 0 
Cli nical la b orat or y e val uati o ns:  
    He mat ol o g y  
    Cli nical c he mistr y b 
    C oa g ulati o n  
4. 0 
4. 0 
3. 0  
9 
9 
9  
9 9. 0 
Ser u m pre g na nc y test (fe male s u bjects 
o nl y)  
4. 0 
3 
1 2. 0 
Ser u m f ollicle -sti m ulati n g h or m o ne 
( p ost- me n o pa usal fe male s u bjects o nl y)  
4. 0 
1 
4. 0 
Ge n ot y pi n g  
1 4. 0  
1  
1 4. 0  
T ot al:  4 0 5 . 0 m L  

Pr ot oc ol 
C O N FI D E N TI A L  
C o va nce St u d y: 8 4 1 9 6 8 9 
Pr ot oc ol Refere n ce:  L O X O -B T K - 2 0 0 1 0 
Pr ot oc ol Versi o n 1. 0, 9 Dece m b er 2 0 2 0  
Pa ge 6 5 of 6 8 
A p pe n di x  4: Sc he d ule of Assess m e nts

Pr ot oc ol 
C O N FI D E N TI A L  
C o va nce St u d y: 8 4 1 9 6 8 9  
Pr ot oc ol Refere n ce:  L O X O -B T K - 2 0 0 1 0 
Pr ot oc ol Versi o n 1. 0, 9 Dece m b er 2 0 2 0  
Pa ge 6 6 of 6 8 
 
 
St u d y Pr o ce d ures a 
Scree ni n g  
( D a ys -3 5 
t o -2)  
C hec k -i n 
( D a y -1)  
Peri o d  1 
Peri o d 2  
Cli nic 
Disc h ar ge 
E O T/ E T u  
F oll o w -u p 
p h o ne c all  
( E O S) 
1 
2 
3 
4 
5 
6 
7 
8 
9 
1 0  1 1  1 2  1 3  1 4  1 5  1 6  1 7  1 8  1 9  2 0  2 1  2 2  
2 3  
7 ( ± 2) d a ys 
p ost E O T/ E T v  
C o nfi ne d t o t he C R U  
 
X  
X  X  X  X  X  X  X  X  X  X  X  X  X  X  X  X  X  X  X  X  X  X  
X  
 
I ncl usi o n/ E xcl usi o n Criteria 
X  
X  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
I nf or me d C o nse nt 
X  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
De m o gra p hics  
X  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Me dical Hist or y  
X  
X b 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Hei g ht/ Wei g ht/ B MI  
X  
X c 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
e G F R  
X  
X  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Ge n ot y pi n g  
X  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
P h ysical E xa mi n ati o n d 
 
X  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X  
 
1 2 -lea d E C Ge 
X  
X  
X   
 
 
X  X  
 
 
 
 
 
X  
 
 
X  
 
X  
 
 
X  
 
 
X  
 
Vital Si g n Meas ure me nts f, g, h 
X  
X  
X   
 
 
X  X  
 
 
 
 
 
X  
 
 
X  
 
X  
 
 
X  
 
 
X  
 
H D Y F? I n q uir y i 
X  
X  
X  X  X  X  X  X  X  X  X  X  X  X  X  X  X  X  X  X  X  X  
 
 
X  
X  
A Es/ S A Es j 
X  
X  
X  X  X  X  X  X  X  X  X  X  X  X  X  X  X  X  X  X  X  X  
 
 
X  
X  
Pr o be Dr u g C oc ktail D osi n g k 
 
 
X   
 
 
 
 
 
 
 
 
 
 
 
 
X  
 
 
 
 
 
 
 
 
 
L O X O -3 0 5 D osi n g l 
 
 
 
 
 
 
 
X  X  X  X  X  X  X  X  X  X  X  X  X  X  
 
 
 
 
 
Cli nical La b orat or y 
E val uati o ns o 
X 
X 
 X 
 
 
 
X 
 
 
 
 
 
X 
 
 
X 
 
X 
 
 
X 
 
X 
X 
 
He patitis a n d HI V Scree n  
X  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
C O VI D -1 9 Test p 
X  
X  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
H b A 1c Test  
X  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Dr u g Scree n q 
X  
X  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pri or a n d C o nc o mita nt 
Me dicati o ns
r 
X 
X 
X  X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Ser u m Pre g na nc y Test s 
X  
X  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X  
X  
 
F S H Test t 
X  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
T S H Test  
X  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
C CI

Pr ot oc ol 
C O N FI D E N TI A L  
C o va nce St u d y: 8 4 1 9 6 8 9  
Pr ot oc ol Refere n ce:  L O X O -B T K - 2 0 0 1 0 
Pr ot oc ol Versi o n 1. 0, 9 Dece m b er 2 0 2 0  
Pa ge 6 7 of 6 8 
A b bre viati o ns: A E  = a d v erse e v e nt; B MI = b o d y mass i n d e x; B P  = bl o o d press ure; C O VI D -1 9  = S A R S - C o V-2; C R F = Case Re p ort F or m; C R U  = Cli nical Researc h U nit; 
E C G = ele ctr ocar di o gra m; e G F R = esti mate d gl o mer ular filtrati o n rate; E O S  = E n d of St u d y; E O T  = E n d of Treat me nt; E T  = Earl y Ter mi nati o n; F S H  = f ollicle-sti m ulati n g h or m o ne; H b A 1c = 
he m o gl o bi n A 1c; H D Y F?  = H o w D o Y o u Fee l?; HI V = h u ma n i m m u n o d eficie n c y vir us; I C F  = I nf or me d C o nse nt F or m; P K = p har mac o ki netic; S A E  = seri o us a d verse e ve nt; 
T S H  = t h yr oi d-sti m ulati n g h or m o n e; U A = uri n al ysis.  
a. F or details o n st u d y pr o ce d ures, see Secti o n  7 . 
b.  I nteri m me dical hist or y o nl y. 
c. Hei g ht c ollecte d at Scree ni n g o nl y; B MI calc ulate d b ase d o n Scree ni n g h ei g ht . 
d.  A c o m plete p h ysical e x a mi n ati o n will b e p erf or me d at C h ec k -i n ( Da y -1). A n a b bre viate d p h ysical e x a mi n ati o n will b e perf or me d at Da y 2 3 ( E O T) or at E T.  
e. 1 2 -lea d E C Gs will b e o btai n e d at Scree ni n g a n d C h ec k-i n ( Da y -1), Da y  1 ( pre d ose), Da y 5 ( 9 6  h o urs p ost d ose o n Da y 1), Da y  6 ( pre d ose a n d 2  h o urs  p ost d ose), Da y 1 2 ( pre d ose), Da y 1 5 
( pre d ose a n d 2 h o urs p ost d ose), Da y 1 7 ( pre d ose), a n d Da y 2 0 ( 2 4  h o urs p ost d ose o n Da y 1 9), a n d Da y 2 3 ( 9 6  h o urs p ost d ose o n Da y 1 9 [ E O T]) or E T. 1 2 -lea d E C Gs will be c ollecte d after 
t he s u bject h as reste d i n t h e s u pi ne p ositi o n f or at least 1 0  mi n utes. W h e n sc h e d ule d at t h e sa me ti me as P K bl o o d dra ws, 1 2 -lea d E C Gs will be o btai ne d pri or t o a n d as cl ose as p ossi ble t o 
ha vi n g bl o o d dra w n. T h e all o we d sa m pli n g wi n d o w f or 1 2 -lea d E C Gs is ± 3 0  mi n utes fr o m t h e n o mi n al ti me p oi nt f or all p ost d ose 1 2 -lea d E C Gs a n d n o less t ha n 1 0 mi n utes pri or t o d osi n g 
f or pre d ose 1 2-lea d E C Gs. 
f. Vital si g n meas ure me nts (s u pi n e B P a n d p ulse rate) will b e o btai n e d at Scree ni n g, C h ec k -i n ( Da y -1), Da y  1 ( pre d ose), Da y 5 ( 9 6  h o urs p ost d ose o n Da y 1 ), Da y 6 ( pre d ose a n d 2  h o urs 
p ost d ose), Da y 1 2 ( pre d ose), Da y 1 5 ( pre d ose a n d 2  h o urs p ost d ose), Da y 1 7 ( pre d ose), a n d Da y 2 0 ( 2 4  h o urs p ost d ose o n Da y 1 9), a n d Da y 2 3 ( 9 6  h o urs p ost d ose o n Da y 1 9 [ E O T]) or E T. 
Bl o o d press ure a n d p ulse rate will b e meas ure d usi n g t h e sa me ar m f or eac h rea di n g after t h e s u bject h as b ee n s u pi n e f or at least 5  mi n utes. W he n sc he d ule d at t he sa me ti me as P K bl o o d 
dra ws, vital si g n meas ure me nts s h o ul d b e carrie d o ut pri or t o a n d as cl ose as p ossi ble t o h a vi n g bl o o d dra w n. T h e all o we d sa m pli n g wi n d o w f or vital si g n meas ure me nts is ±  3 0  mi n utes fr o m 
t he n o mi nal ti me p oi nt f or all p ost d ose vital si g n meas ure me nts a n d n o less t h a n 1 0 mi n utes pri or t o d osi n g f or pre d ose vital si g n meas ure me nts.  
g.  Res pirat or y rate a n d b o d y te m p erat ure will b e o btai n e d at Scree ni n g, C h ec k -i n ( Da y -1), a n d Da y 2 3 ( 9 6  h o urs p ost d ose o n Da y 1 9 [ E O T]) or E T.  
h.  O x y ge n sat urati o n will b e meas ure d via p ulse o xi metr y at Scree ni n g, C h ec k -i n ( Da y -1), pre d ose o n Da y 1, a n d Da y 2 3 ( 9 6  h o urs p ost d ose o n Da y 1 9 [ E O T]) o r E T. T he all o we d sa m pli n g 
wi n d o w f or o x y g e n sat urati o n meas ure me nts is ±  3 0  mi n utes fr o m t h e n o mi n al ti me p oi nt f or all p ost d ose o x y g e n sat urati o n meas ure me nts a n d n o less t ha n 1 0  mi n utes pri or t o d osi n g f or 
pre d ose o x y g e n sat urati o n meas ure me nts.  
i. A H D Y F? i n q uir y will b e p erf or me d at Scree ni n g (after t h e I C F is si g n e d), at C h ec k-i n ( Da y -1), at eac h p ost d ose vital si g n meas ure me nt, a n d at a n a p pr o priate ti me f or all ot her da ys.  
j. A d verse e ve nts a n d S A Es will b e c ollecte d b e gi n ni n g at i nf or me d c o nse nt. A d v erse  e v e nts will b e rec or d e d t hr o u g h o ut t he st u d y (ie, fr o m si g ni n g of t he I C F u ntil E O S, or u ntil E T if t he 
s u bject disc o nti n u es fr o m t h e st u d y a n d d o es n ot c o m plete a f oll o w-u p p h o n e call), eit h er as s u bject me dical hist or y (if t he e ve nt is re p orte d as be gi n ni n g pri or t o si g ni n g of t he I C F or if t he 
e ve nt occ urs pri or t o st u d y dr u g a d mi nistrati o n o n Da y 1 a n d is assesse d as n ot relate d t o st u d y pr o ce d ures b y t h e I n v esti gat or [ or desi g nee]) or as A Es (if t he e ve nt occ urs after si g ni n g of t he 
I C F b ut pri or t o st u d y dr u g a d mi nistrati o n o n Da y 1 a n d is assesse d b y t h e I n v esti g at or [ or d esi g n ee]) as relate d t o st u d y pr oce d ures, or if t he e ve nt occ urs after st u d y dr u g a d mi nistrati o n o n 
Da y  1 t hr o u g h E O T or E T re g ar dless of relati o ns hi p t o st u d y dr u g). Fr o m E O T or E T  t hr o u g h E O S, o nl y A Es assesse d as relate d t o st u d y dr u g are t o be rec or de d. All S A Es t hat de vel o p fr o m 
t he ti me of I C F si g ni n g u ntil E O S ( or E T if t h e s u bject disc o nti n u es fr o m t h e st u d y a n d d o es n ot c o m plete a f oll o w-u p p h o ne call) are t o be re p orte d.  
k.  O n  Da y  1 a n d Da y 1 5, t h e pr o b e dr u g c o c ktail ( 2 0 0  m g caffei n e [ta blet], 4 0  m g o me praz ole [ca ps ule], a n d 1 0 m g warfari n [ta blet]) a n d  1 0  m g vita mi n K (ta blets) will be a d mi nistere d orall y 
i n t he m or ni n g f oll o wi n g a fast of at least 1 0 h o urs pri or t o d osi n g a n d 2  h o urs p ost d ose ( wit h water restricte d f or 1 h o ur pri or t o a n d 1 h o ur p ost d ose a d mi nistrati o n). 
l. O n Da y 6 t hr o u g h Da y 1 9, oral d oses of 2 0 0  m g L O X O -3 0 5 will be a d mi nistere d Q D i n t h e m or ni n g at t h e act u al ti me of t he Da y 1 pr o be dr u g c oc ktail d osi n g ( ±  1 h o ur). O n Da ys 7 t hr o u g h 
1 1, a n d Da ys 1 3, 1 4, 1 6, 1 8, a n d 1 9, s u bjects will b e faste d f or at least 2  h o urs pre d ose a n d 1 h o ur p ost d ose. O n d a ys w here cli nical la b orat or y e val uati o ns are perf or me d ( Da y 2, Da y 6, Da y 
1 2, a n d Da y 1 7) s u bjects will b e faste d f or 8  h o urs pre d ose a n d 1 h o ur p ost d ose. O n Da y 1 5, 2 0 0  m g L O X O -3 0 5 will b e c oa d mi nistere d wit h pr o be dr u g c oc ktail ( 2 0 0  m g caffei ne [ta blet], 
4 0  m g o me pra z ole [ca ps ule], a n d 1 0  m g warfari n [ta blet]) a n d 1 0  m g vita mi n K (ta blets) i n t h e m or ni n g at t h e act u al ti me of t he Da y 1 pr o be dr u g c oc ktail d osi n g ( ± 1 h o ur), f oll o wi n g a fast 
of 1 0  h o urs pri or t o d osi n g  a n d 2  h o urs p ost d ose ( wit h water restricte d f or 1 h o ur pri or  t o a n d 1 h o ur p ost d ose).  
m.  C CI

Pr ot oc ol 
C O N FI D E N TI A L  
C o va nce St u d y: 8 4 1 9 6 8 9  
Pr ot oc ol Refere n ce:  L O X O -B T K - 2 0 0 1 0 
Pr ot oc ol Versi o n 1. 0, 9 Dece m b er 2 0 2 0  
Pa ge 6 8 of 6 8 
n.  
o.  Cli n ical c he mistr y p a n el (faste d f or at least 8 h o urs), c o a g ulati o n par a meters, h e mat ol o g y p a n el, a n d U A will b e p erf or me d at Scree ni n g, C hec k -i n (Da y -1), Da y 2 ( 2 4  h o urs p ost d ose 
o n  Da y  1), Da y  6 ( pre d ose), Da y 1 2 ( pre d ose), Da y  1 5 ( pre d ose), Da y 1 7 ( pre d ose), Da y 2 0 ( 2 4 h o urs p ost d ose o n Da y 1 9), a n d Da y 2 2 ( 7 2  h o urs p ost d ose o n Da y 1 9, if t he s u bject 
c o m pletes t he st u d y [ E O T]), or o n t h e d a y of E T. At E T or t h e d a y b ef ore E O T ( Da y 2 2), s u bjects are n ot re q uire d t o b e faste d  pri or t o cli nical la b orat or y e val uati o ns.  
p.  Testi n g f or C O VI D -1 9 will b e c o n d u cte d at a mi ni m u m at Scree ni n g a n d C h ec k -i n ( Da y -1). Testi n g f or C O VI D -1 9 ma y als o be c o n d ucte d peri o dicall y d uri n g t he s u bject’s C R U 
c o nfi ne me nt, at t h e discreti o n of t h e I n v esti g at or ( or d esi g n ee). Tests will b e p erf or me d b y ra pi d p ol y merase c h ai n reacti o n or e q ui vale nt.  
q.  Uri n e dr u g scree n f or dr u gs of a b use (i n cl u di n g c oti ni n e) a n d alc o h ol scree n ( uri n e or breat h).  
r. Pri or a n d c o n c o mita nt me dicati o n a d mi nistrati o n will b e rec or d e d be gi n ni n g at i nf or me d c o nse nt. I n a d diti o n, all I n v esti gat or -a p pr o ve d prescri pti o n a n d o ver -t he-c ou nter me dicati o ns ta ke n 
b y a s u bject wit hi n 1 4  d a ys or 5 half -li v es (if k n o w n), w hic h e v er is l o n g er, pri or t o Da y 1 will b e rec or d e d o n t h e s u bject’s electr o nic C R F. 
s. Fe male s u bjects o nl y. Perf or me d at Scree ni n g, C h ec k -i n ( Da y -1), a n d Da y 2 2 ( 7 2  h o urs p ost d ose o n Da y 1 9), if t h e s u bject c o m pletes t he st u d y ( E O T) or o n t he da y of E T.  
t. P ost -me n o pa usal fe male s u bjects o nl y.  
u.  E n d of Treat me nt is d efi n e d as w h e n t h e s u bject is release d fr o m t h e C R U f oll o wi n g c o m pleti o n of all assess m e nts t hr o u g h Da y  2 3. Earl y Ter mi nati o n is defi ne d as w he n t he s u bject is 
release d fr o m t h e C R U if t h e s u bject ter mi n ates t h e st u d y earl y. Vital si g n meas ure me nts, E C G, a n d a b bre viate d p h ysical e xa mi nati o n res ults are t o be a vaila ble f or re vie w b y t he I n vesti gat or  
( or desi g nee) pri or t o s u bject release fr o m t h e C R U o n Da y 2 3 ( E O T) or E T. Cli nical la b orat or y res ults (f or cli nical c h e mistr y, he mat ol o g y, c oa g ulati o n, a n d U A) a n d ser u m pre g na nc y test 
res ults (fe male s u bjects o nl y) are t o b e a v aila ble f or re vie w b y t h e I n v esti g at or ( or d esi g n ee) pri or t o s u bject release fr o m t he C R U at t he E O T visit a n d pri or t o s u bject release fr o m t he C R U 
at t he E T visit if a v aila ble. 
v.  T o be c o n d ucte d 7  d a ys ( ±  2 d a ys) f oll o wi n g E O T or E T. E n d of St u d y is d efi n e d as w h e n t h e s u bject is c o ntacte d b y t he C R U f o r a f oll o w-u p p h o ne call 7  da ys ( ±  2 da ys) after t he E O T visit 
or E T visit t o d eter mi n e if a n y S A E or st u d y dr u g -relate d A E h as o cc urre d si n ce t h e E O T or E T visit. All s u bjects w h o recei ve d L O X O-3 0 5 or pr o be dr u g c oc ktail (i ncl u di n g s u bjects w h o 
are ter mi nate d earl y) will recei v e a f oll o w -u p p h o n e call.  
w.  De n otes pre d ose sa m ple c ollecti o n o nl y.  
C CI