A Phase I, Single-Ascending Dose Study to Evaluate the Safety, Tolerability, and Pharmacokinetics of LOXO-305 in Healthy Adult Subjects
Phase: PHASE1
Conditions: Healthy
Sponsor: Eli Lilly and Company

Protocol J2N-OX-JZNS Version 1.0
A Phase I, Single-Ascending Dose Study to Evaluate the Safety, Tolerability, and Pharmacokinetics of LOXO-305 
in Healthy Adult Subjects
NCT06181006
Approval Date: 04-Aug-2020

 
 
Pr ot oc ol  
 
A P h ase I, Si n gle -Asce n di n g D ose St u d y t o E v al u ate t he S afet y, T oler a bilit y, a n d 
P h ar m ac o ki netics of L O X O -3 0 5 i n He alt h y A d ult S u bjects  
Pr ot oc ol Stat us: Fi nal 
Pr ot oc ol Date: 0 4 A u g ust 2 0 2 0  
Pr ot oc ol Versi o n: 1. 0 
I n vesti gati o nal Me dici nal Pr o d uct: L O X O-3 0 5  
 
Pr ot oc ol Refere nce N u m ber: L O X O -B T K -2 0 0 1 7 
C o va nce St u d y N u m ber: 8 4 2 6 6 6 5  
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 var d, S uite 4 2 0 
S o ut h Sa n Fra ncisc o, Calif or nia 9 4 0 8 0  
St u d y Site:  
C o va nce Cli nical Researc h U nit I nc. 
1 9 0 0 Mas o n A ve n ue, S uite 1 4 0 
Da yt o na Beac h, F L 3 2 1 1 7  
U S A  
 
 
 
S p o ns or Si g nat or y: 
Pri nci pal 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 ma 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.  
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I N V E S TI G A T O R A G R E E M E N T 
 
I h a ve r ea d t he pr ot oc ol a n d a gr ee t o c o n d uct t he st u d y as d escri be d h erei n. 
 
 
 
 
 
 
 
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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 var 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  
 
 
L o x o O nc ol o g y, I nc.  
Tel ( m o bile): 
 
Tel (alter nati 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 ve nt ( S A E) 
Re p orti n g  
E mail : S A EI nta ke @c o va nce.c o m 
 
 
St u d y  Site  
C o va nce Cli nical Researc h U nit ( C R U),  I nc. 
1 9 0 0 Mas o n A ve n ue, S uite 1 4 0 
Da yt o na Beac h, Fl ori da 3 2 1 1 7 
U S A  
Pri nci pal  I n vesti gat or 
 
 
C o va nce Cli nical Researc h U nit I nc. 
1 9 0 0 Mas o n A ve n ue, S uite 1 4 0 
Da yt o na Beac h, Fl ori da 3 2 1 1 7  
U S A  
Tel: 
 
Fa x: 
 
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 2  
 
Cli nical  La b orat or y  
La b C or p - H oll y w o o d 
4 2 0 0 N ort h 2 9 t h A ve n ue 
H oll y w o o d, Fl ori da 3 3 0 2 0 
U S A  
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  
Tel ( mai n): 
 
E mail : 
 
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Statisticia n  
 
C o va nce  
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C o va nce  
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E mail : 
 
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C o va nce St u d y: 8 4 2 6 6 6 5  
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Pr ot oc ol Refere nce:  L O X O -B T K -2 0 0 1 7  
Pr ot oc ol Versi o n 1. 0, 0 4 A u g ust 2 0 2 0  
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S Y N O P SI S  
 
St u d y Title  
 
A P hase I, Si n gle -Asce n di n g D ose St u d y t o E val uate t he Safet y, T olera bilit y, a n d 
P har mac o ki netics of L O X O -3 0 5 i n Healt h y A d ult 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 safet y a n d t olera bilit y of si n gle oral d oses of L O X O -3 0 5 w he n 
a d mi nistere d t o healt h y a d ult  s u bjects. 
 
T he sec o n dar y o bjecti ve of t he st u d y is:  
 
•  T o assess t he p har mac o ki netics ( P K) of si n gle oral d oses of L O X O -3 0 5 w he n 
a d mi nistere d t o healt h y a d ult  s u bjects. 
 
St u d y Desi g n  
 
T his is a n o pe n -la bel, si n gle-asce n di n g d ose st u d y t o e val uate t he safet y, t olera bilit y, a n d P K 
of L O X O -3 0 5.  
 
U p t o 4 c o h orts are pla n ne d f or e val uati o n. I n eac h c o h ort, 6 healt h y a d ult s u bjects are 
pla n ne d f or e val uati o n. S u bjects will partici pate i n o nl y 1 c o h ort. I n eac h c o h ort, s u bjects will 
recei ve a si n gle oral d ose of L O X O-3 0 5 o n Da y 1. I n eac h c o h ort, a se nti nel gr o u p of  
2 s u bjects will be d ose d at least 4 8 h o urs bef ore t he re mai ni n g 4 s u bjects i n t he c o h ort 
(f oll o wi n g re vie w of a vaila ble safet y data). Bl o o d sa m ples will be c ollecte d f or t he P K 
assess me nt of L O X O -3 0 5 i n plas ma f or 1 6 8 h o urs p ost d ose.  
 
A si n gle oral d ose of L O X O -3 0 5 will be a d mi nistere d o n Da y 1 f or eac h c o h ort as f oll o ws:  
 
•  C o h ort 1 ( Treat me nt A): 3 0 0  m g  
•  C o h ort 2 ( Treat me nt B): u p t o 6 0 0  m g  
•  C o h ort 3 ( Treat me nt C): u p t o 9 0 0  m g  
O ne a d diti o nal c o h ort ( 6 s u bjects) ma y be e nr olle d if it is dee me d a p pr o priate t o re peat a n y 
d ose le vel, or t o a d d a n i nteri m d ose le vel or le vels (e q ual t o or l o wer t ha n 9 0 0 m g), as 
deter mi ne d b y t he S p o ns or i n c o ns ultati o n wit h t he I n vesti gat or ( or desi g nee), de pe n di n g o n 
t he safet y, t olera bilit y, a n d P K res ults fr o m t he pri or c o h ort(s). D osi n g will n ot e xcee d 
9 0 0 m g i n a n y s u bject, n or will a n y s u bject be gi ve n a d ose f or w hic h t he ma xi m u m o bser ve d  
plas ma c o nce ntrati o n ( C ma x ) w o ul d e xcee d  
 n g/ m L. 
 
D ose escalati o n t o a hi g her d ose le vel (ie, ne xt c o h ort) will n ot ta ke place u ntil t he 
I n vesti gat or ( or desi g nee) a n d t he S p o ns or ha ve re vie we d all perti ne nt safet y/t olera bilit y data 
(ie, p h ysical e xa mi nati o ns, electr ocar di o gra ms [ E C Gs], vital si g n meas ure me nts, cli nical 
la b orat or y e val uati o ns, a n d a d verse e ve nts [ A Es]) t hr o u g h a mi ni m u m of 1 6 8 h o urs ( Da y 8) 
a n d ha ve deter mi ne d t hat a de q uate safet y a n d t olera bilit y fr o m t he pre vi o us l o wer d ose  
C CI

Pr ot oc ol  
C o va nce St u d y: 8 4 2 6 6 6 5  
C O N FI D E N TI A L  
Pr ot oc ol Refere nce:  L O X O -B T K -2 0 0 1 7  
Pr ot oc ol Versi o n 1. 0, 0 4 A u g ust 2 0 2 0  
Pa ge 7  of 5 8  
 
 
c o h ort has bee n de m o nstrate d t o per mit pr ocee di n g t o t he ne xt c o h ort. P har mac o ki netic data 
t hr o u g h at least 7 2 h o urs (a p pr o xi matel y 3 half-li ves) will be re vie we d t o g ui de t he 
d ose -escalati o n decisi o n. Data fr o m a mi ni m u m of 4 s u bjects will be re vie we d i n or der t o 
ma ke a d ose escalati o n decisi o n.  
 
\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 
2 8 da ys ( Da ys -2 9 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 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 n d of Treat me nt ( E O T) o n Da y 8 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 nati o n ( E T) if t he s u bject disc o nti n ues. 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 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 da ys ( ± 2 da ys) after E O T or E T.  
 
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.  
 
T he 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 ne d as t h ose s u bjects 
w h o are assi g ne d 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. 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.  
 
I n t his st u d y, p h ysical e xa mi nati o ns, 1 2-lea d E C Gs, vital si g n meas ure me nts, P K sa m pli n g, 
H o w D o Y o u Feel? 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 ( 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 pecifie 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 Es ( 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 verse 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 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 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 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 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 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 vesti gat or ( or desi 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 ne call) are t o be re p orte d.  
 
N u m ber of S u bjects  
 
T he st u d y is pla n ne d t o e nr oll u p t o 2 4 healt h y a d ult male a n d fe male s u bjects ( w o me n of 
n o n -c hil d beari n g p ote ntial o nl y). Si x s u bjects will partici pate i n eac h c o h ort.  
 
T he sa m ple size c h ose n f or t his st u d y was selecte d wit h o ut statistical c o nsi derati o ns. It has 
bee n deter mi ne d a de q uate t o meet t he st u d y o bjecti ves.  
 
E ver y atte m pt will be ma de t o e nr oll at least 1 s u bject of eac h se x i n eac h c o h ort i n t he st u d y.  

Pr ot oc ol  
C o va nce St u d y: 8 4 2 6 6 6 5  
C O N FI D E N TI A L  
Pr ot oc ol Refere nce:  L O X O -B T K -2 0 0 1 7  
Pr ot oc ol Versi o n 1. 0, 0 4 A u g ust 2 0 2 0  
Pa ge 8  of 5 8  
 
 
M ai n Criteri a f or I ncl usi o n  
 
Male s u bjects a n d fe male s u bjects 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, a n d wit hi n b o d y mass i n de x ra n ge 1 8. 0 t o 3 2. 0 k g/ m 2, i ncl usi ve. 
S u bjects will be i n g o o d ge neral healt h, base 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 n meas ure me nts, 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 desi 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 
 
L O X O -3 0 5 will be s u p plie d b y t he S p o ns or as 2 5 -m g ta blets. Li g ht bl ue o pa q ue size 0 
ca ps ules will be s u p plie d b y C o va nce. L O X O -3 0 5 ta blets will be o ver -e nca ps ulate d i nt o li g ht 
bl ue o pa q ue size 0 ca ps ules ( 4 ta blets per ca ps ule) b y C o va nce f or oral a d mi nistrati o n.  
 
C o h ort 1 ( Treat me nt A):  
•  A si n gle oral d ose of 3 0 0 m g L O X O -3 0 5 ( 1 2 × 2 5 -m g ta blets, o ver -e nca ps ulate d 
[ 3 ca ps ules]) f oll o wi n g a fast of at least 1 0 h o urs pri or t o a n d 4 h o urs after d osi n g.  
C o h ort 2 ( Treat me nt B):  
•  A si n gle oral d ose of u p t o 6 0 0 m g L O X O -3 0 5 ( 2 4 × 2 5 -m g  ta blets, 
o ver -e nca ps ulate d [ 6 ca ps ules], or less de pe n di n g o n t he d ose c h ose n) f oll o wi n g a fast 
of at least 1 0 h o urs pri or t o a n d 4 h o urs after d osi n g.  
C o h ort 3 ( Treat me nt C):  
•  A si n gle oral d ose of u p t o 9 0 0 m g L O X O -3 0 5 ( 3 6 × 2 5 -m g  ta blets, 
o ver -e nca ps ulate d [ 9 ca ps ules], or less de pe n di n g o n t he d ose c h ose n) f oll o wi n g a fast 
of at least 1 0 h o urs pri or t o a n d 4 h o urs after d osi n g.  
 
O ne a d diti o nal c o h ort ( 6 s u bjects) ma y be e nr olle d if it is dee me d a p pr o priate t o re peat a n y 
d ose le vel, or t o a d d a n i nteri m d ose le vel or le vels (e q ual t o or l o wer t ha n 9 0 0 m g), as 
deter mi ne d b y t he S p o ns or i n c o ns ultati o n wit h t he I n vesti gat or ( or desi g nee), de pe n di n g o n 
t he safet y, t olera bilit y, a n d P K res ults fr o m t he pri or c o h ort(s). D osi n g will n ot e xcee d 
9 0 0 m g i n a n y s u bject, n or will a n y s u bject be gi ve n a d ose f or w hic h t he C ma x w o ul d e xcee d  
 n g/ m L. 
 
All st u d y dr u gs will be a d mi nistere d wit h a p pr o xi matel y 2 4 0 m L of water. A n a d diti o nal 
2 4 0 m L of water ma y be a d mi nistere d if nee de d.  
 
D ur ati o n of S u bject P artici 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 2 8 da ys ( Da ys -2 9 t o -2). 
Le n gt h of C o nfi ne me nt: U p t o 9 da ys ( Da ys -1 t o 8).  
Pla n ne d St u d y C o n d uct D urati o n: U p t o 4 6 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:  
C CI

Pr ot oc ol  
C o va nce St u d y: 8 4 2 6 6 6 5  
C O N FI D E N TI A L  
Pr ot oc ol Refere nce:  L O X O -B T K -2 0 0 1 7  
Pr ot oc ol Versi o n 1. 0, 0 4 A u g ust 2 0 2 0  
Pa ge 9  of 5 8  
 
 
Serial P K bl o o d sa m ples f or t he a nal ysis of plas ma c o nce ntrati o ns of L O X O -3 0 5 will be 
c ollecte d fr o m pre d ose t hr o u g h 1 6 8 h o urs p ost -L O X O -3 0 5 a d mi nistrati o n f or eac h treat me nt.  
 
T he f oll o wi n g P K para meters will be calc ulate d, w he ne ver p ossi ble, base d o n t he plas ma 
c o nce ntrati o ns of L O X O -3 0 5 (as a p pr o priate): area u n der 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, as calc ulate d b y t he li near tra pez oi dal met h o d ( 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 h o ur 0 t o t he last meas ura ble c o nce ntrati o n 
( A U C0 -t), area u n der t he c o nce ntrati o n-ti me c ur ve fr o m ti me 0 e xtra 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), Cma x , ti me t o ma xi m u m 
o bser ve d 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 ( λZ ), a p pare nt 
s yste mic cleara nce ( C L/ F), a p pare nt v ol u me of distri b uti o n at ter mi nal p hase ( V z/ F), a n d 
a p pare nt plas ma ter mi nal eli mi nati o n half -life (t½ ). T he λZ a n d t ½ will be calc ulate d b y li near 
least s q uares re gressi o n a nal ysis usi n g t he ma xi m u m n u m ber of p oi nts i n t he ter mi nal l o g 
li near p hase (e g, 3 or m ore n o n-zer o plas ma c o nce ntrati o ns).  
 
I n di vi d ual a n d mea n plas ma c o nce ntrati 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. 
 
S afet y:  
 
Safet y will be m o nit ore d wit h A E i n q uiries, cli nical la b orat or y e val uati o ns, vital si g n 
meas ure me nts, E C Gs, c o nc o mita nt me dicati o ns, a n d p h ysical e xa mi nati o ns.  
 
St atistic al Met h o ds:  
 
P har mac o ki netics:  
 
Plas ma c o nce ntrati o ns a n d P K para meters will be 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 oefficie nt of variati 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).  
 
P har mac o ki netic d ose pr o p orti o nalit y will be assesse d f or C o h ort 1, 2, a n d 3. Nat ural  
l o g-tra nsf or me d A U C0 -2 4, A U C 0 -t, A U C0 -i nf, a n d Cma x of L O X O -3 0 5 will be e val uate d usi n g a 
p o wer m o del of t he f or m: l n( p ar a meter) = i nterce pt + sl o pe × l n( d ose) + r a n d o m err or 
 
F or eac h P K para meter se paratel y, a p o ole d esti mate (acr oss all d oses) of sl o pe, 
c orres p o n di n g 9 5 % c o nfi de nce i nter val, a n d bet wee n -s u bject C V % will be calc ulate d. 
 
Safet y:  
 
All safet y assess me nts, i ncl u di n g A Es a n d S A Es, vital si g n meas ure me nts, cli nical la b orat or y 
e val uati o ns, 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 descri 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, baseli ne val ue is defi 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 L O X O -3 0 5. N o f or mal statistical a nal yses are pla n ne d 
f or t he safet y data. All safet y data will be liste d b y s u bject. 
 
A d diti o nal details o n t he a nal yses will be i ncl u de d i n t he Statistical A nal ysis Pla n.  

Pr ot oc ol  
C o va nce St u d y: 8 4 2 6 6 6 5  
C O N FI D E N TI A L  
Pr ot oc ol Refere nce:  L O X O -B T K -2 0 0 1 7  
Pr ot oc ol Versi o n 1. 0, 0 4 A u g ust 2 0 2 0  
Pa ge 1 0  of 5 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 0  
LI S T  O F  T A B L E S  .................................................................................................................. 1 2  
LI S T  O F  A B B R E VI A TI O N S  ................................................................................................. 1 3  
1.  
I N T R O D U C TI O N .......................................................................................................... 1 5  
1. 1.  Bac k gr o u n d  ............................................................................................................... 1 5  
1. 2.  N o n -cli nical P har mac o ki netics  ................................................................................. 1 5  
1. 3.  S u m mar y of  Cli nical E x perie nce  .............................................................................. 1 7  
1. 3. 1.  
Safet y  .......................................................................................................... 1 7  
1. 3. 2.  
P har mac o ki netics  ........................................................................................ 1 8  
1. 4.  St u d y  Rati o nale  ......................................................................................................... 2 1  
1. 5.  Ris k  Assess me nt  ....................................................................................................... 2 1  
2.  
O BJ E C TI V E S  A N D  E N D P OI N T S  ................................................................................ 2 2  
2. 1.  O bjecti ves  ................................................................................................................. 2 2  
2. 1. 1.  
Pri mar y  O bjecti ve  ....................................................................................... 2 2  
2. 1. 2.  
Sec o n dar y  O bjecti ve  ................................................................................... 2 2  
2. 2.  E n d p oi nts  .................................................................................................................. 2 2  
2. 2. 1.  
Pri mar y  E n d p oi nts  ...................................................................................... 2 2  
2. 2. 2.  
Sec o n dar y  E n d p oi nts  .................................................................................. 2 2  
3.  
I N V E S TI G A TI O N A L P L A N ......................................................................................... 2 4  
3. 1.  O verall St u d y Desi g n  a n d Pla n  ................................................................................. 2 4  
3. 2.  Disc ussi o n of  St u d y Desi g n  ...................................................................................... 2 5  
3. 3.  Selecti o n of D oses i n  t he St u d y  ................................................................................ 2 5  
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  .................................................................... 2 6  
4. 1.  Scree ni n g  Pr oce d ures  ................................................................................................ 2 6  
4. 2.  C hec k -i n Pr oce d ures ( Da y -1)  .................................................................................. 2 7  
4. 3.  I ncl usi o n Criteria  ...................................................................................................... 2 7  
4. 4.  E xcl usi o n  Criteria  ..................................................................................................... 2 9  
4. 5.  S u bject N u m ber  a n d I de ntificati o n ........................................................................... 3 2  
4. 6.  Re m o val of S u bjects fr o m  St u d y Partici pati o n  ......................................................... 3 2  
5.  
S T U D Y  T R E A T M E N T S  .................................................................................................3 4  
5. 1.  Descri pti o n, St ora ge, Pac ka gi n g,  a n d La beli n g  ........................................................ 3 4  
5. 2.  St u d y  Treat me nt A d mi nistrati o n  .............................................................................. 3 4  
5. 3.  Ra n d o mizati o n  .......................................................................................................... 3 5  
5. 4.  Bli n di n g  .................................................................................................................... 3 5  

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

Pr ot oc ol  
C o va nce St u d y: 8 4 2 6 6 6 5  
C O N FI D E N TI A L  
Pr ot oc ol Refere nce:  L O X O -B T K -2 0 0 1 7  
Pr ot oc ol Versi o n 1. 0, 0 4 A u g ust 2 0 2 0  
Pa ge 1 2  of 5 8  
 
 
A p pe n di x 3: T otal  Bl o o d  V ol u me  ...................................................................................... 5 5  
A p pe n di x 4: Sc he d ule  of  Assess me nts  .............................................................................. 5 6  
 
 
LI S T O F T A B L E S  
Ta ble 1 P har mac o ki netic 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 ycle 1  Da y  8)  ............................ 1 8  
Ta ble 2 P har mac o ki netic of L O X O -3 0 5 F oll o wi n g a Si n gle 2 0 0 -m g D ose 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, C ycle 1 Da y 1)  
a n d Healt h y S u bjects  ( St u d y L O X O -B T K -2 0 0 1 4)  ............................................. 2 0  
Ta ble 3  St u d y Dr u gs  ........................................................................................................ 3 4  
 C CI

Pr ot oc ol  
C o va nce St u d y: 8 4 2 6 6 6 5  
C O N FI D E N TI A L  
Pr ot oc ol Refere nce:  L O X O -B T K -2 0 0 1 7  
Pr ot oc ol Versi o n 1. 0, 0 4 A u g ust 2 0 2 0  
Pa ge 1 3  of 5 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 nta ge e xtra p olati o n f or area u n der t he c o nce ntrati o n -ti me c ur ve 
fr o m ti me 0 e xtra 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 0 -2 4  
area u n der 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 der t he c o nce ntrati o n -ti me c ur ve fr o m ti me 0 e xtra p olate d t o 
i nfi nit y 
A U C 0 -t 
area u n der 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  
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 T K  
Br ut o n’s t yr osi ne  ki nase  
C F R  
C o de of Fe deral  Re g ulati o ns  
C K  
creati ne  ki nase  
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 ke mia 
C ma x  
ma xi m u m o bser ve d plas ma  c o nce ntrati o n  
C R U  
Cli nical Researc 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 verse E ve nts 
C V %  
c oefficie nt of  variati o n  
C Y P  
c yt oc hr o me  P 4 5 0  
E C G  
electr ocar di o gra m  
e C R F  
electr o nic Case Re p ort  F or m  
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  
H b A 1c  
he m o gl o bi n  A 1c  
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 -relate d 
HI V  
h u ma n i m m u n o deficie nc y  vir us  
H R T  
h or m o ne -re place me nt t hera p y 
I B 
I n vesti gat or’s Br oc h ure  
I C9 0  
c o nce ntrati o n re q uire d f or 9 0 %  i n hi biti o n 

Pr ot oc ol  
C o va nce St u d y: 8 4 2 6 6 6 5  
C O N FI D E N TI A L  
Pr ot oc ol Refere nce:  L O X O -B T K -2 0 0 1 7  
Pr ot oc ol Versi o n 1. 0, 0 4 A u g ust 2 0 2 0  
Pa ge 1 4  of 5 8  
 
 
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 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 
L n  
nat ural l o g  
Me d D R A  
Me dical Dicti o nar y f or Re g ulat or y Acti vities 
N H L  
n o n -H o d g ki n  l y m p h o ma 
N O E L  
n o o bser ve d effect  le vel 
P C R  
p ol y merase c hai 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 dericia’s met h o d 
R B C  
re d bl o o d cell(s) 
S A E  
seri o us a d verse e ve nt(s) 
S A P  
Statistical A nal ysis  Pla n  
S D D  
s pra y-drie d  dis persi o n  
S O C  
s yste m or ga n class 
S O P 
S U S A R  
Sta n dar d O perati n g Pr oce d ure  
s us pecte d u ne x pecte d seri o us a d verse reacti o n 
t1/ 2  
a p pare nt plas ma ter mi nal eli mi nati o n  half -life 
T E A E  
treat me nt-e mer ge nt a d verse  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/ 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 va nce St u d y: 8 4 2 6 6 6 5  
C O N FI D E N TI A L  
Pr ot oc ol Refere nce:  L O X O -B T K -2 0 0 1 7  
Pr ot oc ol Versi o n 1. 0, 0 4 A u g ust 2 0 2 0  
Pa ge 1 5  of 5 8  
 
 
1.  I N T R O D U C TI O N 
 
Refer t o t he I n vesti gat or’s Br oc h ure (I B) f or detaile 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 verse e ve nt ( A E) pr ofile 
of t he i n vesti gati o nal me dici nal pr o d uct (I M P), 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 selecti ve i n hi bit or of t he Br ut o n’s t yr osi ne 
ki nase ( B T K) bei 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 o n pr o perties, a n d n o n -c o vale nt bi n di n g m o de. 2  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 descri be d f or all a vaila ble c o vale nt i n hi bit ors.3 ,4 ,5 ,6 ,7  T hese feat ures e na ble  
L O X O -3 0 5 d ose d orall y at 1 0 0 m g a n d hi g her o nce dail y ( Q D) t o ac hie ve p har mac o ki netic 
( P K) e x p os ures t hat e xcee d t he c o nce ntrati o n re q uire d f or 9 0 % i n hi biti o n (I C9 0) of B T K-wt 
a n d B T K C 4 8 1 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 gar dless of t he i ntri nsic rate of B T K t ur n o ver. L O X O -3 0 5 is als o a hi g hl y selecti ve 
m olec ule, wit h m ore t ha n 3 0 0 -f ol d m ore selecti vit y f or B T K vers us 3 7 0 ot her ki nases teste d 
a n d n o si g nifica nt i n hi biti o n of n o n -ki nase off -tar gets at 1 μ M, t h us li miti n g t he p ote ntial f or 
off -tar get 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 pecte 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 efficac y. Of n ote, t he acti vit y of L O X O-3 0 5 i n 
di verse precli 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 desi g ne d t o bl oc k t he a de n osi ne tri p h os p hate 
bi n di n g site of t he B T K c o m petiti vel y, wit h n o e vi de nce of irre versi ble bi n di n g.  
 
1. 2.  
N o n -cli nic al  P h ar m ac o ki netics  
 
L O X O -3 0 5 ha d hi g h per 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 he 
varia bilit y i n oral a bs or pti o n, a s pra y -drie 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 de 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 ure of L O X O -3 0 5 was c o nsiste ntl y m uc h hi g her i n 
fe male rats t ha n i n males gi ve n t he sa me d ose of L O X O-3 0 5. T he se x differe nce was als o 
a p pare nt after i ntra ve n o us (I V) a d mi nistrati o n of L O X O -3 0 5. T here was n o differe nce i n t he 
P K of L O X O -3 0 5 bet wee n se xes of d o g, a n d n o ne is e x pecte d i n ot her n o n -r o de nt s pecies, 
i ncl u di n g h u ma ns. 
T he v ol u me of distri b uti o n 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 hat 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 bser ve d acr oss m o use, rat, ra b bit, a n d d o g.  
L O X O -3 0 5 was meta b olize d sl o wl y b y h u ma n micr os o mal fracti o ns a n d he pat oc ytes. T he 
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 nce i n h u ma ns. I n vitr o data wit h cl o ne d e x presse d c yt oc hr o me P 4 5 0 ( C Y P)  

Pr ot oc ol  
C o va nce St u d y: 8 4 2 6 6 6 5  
C O N FI D E N TI A L  
Pr ot oc ol Refere nce:  L O X O -B T K -2 0 0 1 7  
Pr ot oc ol Versi o n 1. 0, 0 4 A u g ust 2 0 2 0  
Pa ge 1 6  of 5 8  
 
 
e nz y mes a n d h u ma n li ver micr os o mes i n dicate t hat 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-ter m he pat oc 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 pat oc ytes were als o f or me d i n rat a n d/ or d o g he pat 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 assess me nt.  
 
Re nal cleara nce of L O X O -3 0 5 i n male a n d fe male rats was ne gli gi ble. N o data o n re nal 
cleara nce are a vaila ble i n ot her s pecies; h o we ver, t he re nal e xcreti o n pat h wa y is ofte n 
c o nser ve d acr oss s pecies, a n d t heref ore n o re nal cleara nce w o ul d be e x pecte d i n h u ma ns.  
I n a G o o d La b orat or y Practice ( G L P) i n vitr o assa y f or h u ma n et her-à-g o -g o -relate d ge ne 
( h E R G) acti vit y, t he c o nce ntrati o n res ulti n g i n 5 0 % i n hi biti o n 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 
 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 Q D. T here were n o L O X O -3 0 5 -relate d c ha n ges i n a n y car di o vasc 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 vasc ular st u d y i n t he 
c o nsci o us tele metr y -i nstr u me nte d d o g. T he ma xi m u m o bser ve d plas ma c o nce ntrati o n ( Cma x ) 
f or t his d ose was  
 n g/ m L, w hic h is a p pr o xi matel y 
 a b o ve t he pre dicte d Cma x 
plas ma L O X O -3 0 5 c o nce ntrati o n ( 
 n g/ m L) at t he pr o p ose d cli nical t hera pe utic d ose 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 peate 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 gra m ( E C G) 
rec or di n gs. T he 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 bel 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 ha 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 verse. T o get her, t hese data i n dicate 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 ve ntric ular re p olarizati 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 were 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 uate d i n 
rat f u ncti o nal o bser vati o 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 ver 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 fe male rats as part of t he G L P 2 8 -da y re peat -d ose st u d y.  
 
L O X O -3 0 5 ha d n o effect o n res pirati o n rate 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 haracterize d i n re peate 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 he 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 pecies s pecific a n d see n 
wit h ot her B T K i n hi bit ors. D o g s pecific c ha n ges 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 ose res p o nse c ur ve 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 para meters at hi g h e x p os ures.  
C CI
C CI
C CI
C CI
C CI

Pr ot oc ol  
C o va nce St u d y: 8 4 2 6 6 6 5  
C O N FI D E N TI A L  
Pr ot oc ol Refere nce:  L O X O -B T K -2 0 0 1 7  
Pr ot oc ol Versi o n 1. 0, 0 4 A u g ust 2 0 2 0  
Pa ge 1 7  of 5 8  
 
 
L O X O -3 0 5 was n ot m uta ge nic i n 2 bacterial re verse m utati o n assa ys a n d was 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 uclei via a n a ne 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 heral bl o o d l y m p h oc ytes. H o we ver, 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 rat 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 ( N O E L) 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 was 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 ne utral re d u pta ke 
p h ot ot o xicit y assa y.  
 
1. 3.  
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 bei 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 or n o n-H o d g ki n l y m p h o ma 
( N H L). T he starti n g d ose of L O X O-3 0 5 was 2 5 m g Q D.  
 
As of 0 9 A pril 2 0 2 0, safet y data were a vaila ble fr o m 1 7 2 treate d patie nts, wit h 3 0 0 m g Q D as 
t he hi g hest d ose a d mi nistere d (Secti o n 1. 3. 1 ). As of 3 0 Marc h 2 0 2 0 ( data c ut off date), P K 
data were a vaila ble fr o m 1 0 7 patie nts ( Secti o n 1. 3. 2 ). L O X O-3 0 5 was 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). L O X O -B T K -2 0 0 1 4 is 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 were gi ve n 2 0 0 m g of 
L O X O -3 0 5 o n 3 se parate da ys, eac h f oll o we d b y a was h o ut peri o d. A sec o n d st u d y is 
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), w hic h is a dr u g -dr u g i nteracti o n st u d y 
e val uati 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 here, at t he ti me of pr ot oc ol de vel o p me nt, 3 
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 parate da ys ( o ne 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 was h o ut peri o d.  
 
1. 3. 1.  
S afet y  
 
As of 0 9 A pril 2 0 2 0, 1 7 2 patie nts were treate d i n t he first -i n-h u ma n st u d y  
( L O X O-B T K -1 8 0 0 1) a n d recei ve d L O X O -3 0 5 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. A f ull s u m mar y of treat me nt -e mer ge nt a d verse e ve nts ( T E A Es) f or patie nts i n t his 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 he 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  
O verall, T E A Es were re p orte d i n 1 2 3 of 1 7 2 treate d patie nts i n t he safet y p o p ulati o n a n d 
were mil d or m o derate se verit y ( Gra de 1 or 2) i n 8 9 of 1 2 3 ( 5 1. 7 %) patie nts a n d were 
Gra de 3 or 4 i n se verit y i n 3 3 of 1 2 3 ( 1 9. 2 %) patie nts. T he m ost fre q ue ntl y re p orte d T E A Es 
occ urri n g i n ≥ 1 0 % of patie nts were fati g ue ( 1 2. 8 % t otal, 7. 0 % relate d) a n d diarr hea ( 1 0. 5 % 
t otal, 6. 4 % relate d). T he m ost fre q ue ntl y re p orte d dr u g-relate d T E A Es (t h ose i n > 5 % of 
patie nts) were fati g ue ( 7. 0 %), diarr hea ( 6. 4 %), a n d c o nt usi o n ( 5. 2 %). All ot her dr u g -relate d 
T E A Es occ urre d i n < 5 % of patie nts eac h. T he m ost fre q ue ntl y re p orte d Gra de ≥ 3  T E A Es  
i ncl u de d ne utr o pe nia ( 4. 1 % t otal; 2. 9 % relate d), ne utr o p hil c o u nt decrease d ( 2. 3 % t otal; 1. 2 % 
relate d), a ne mia ( 1. 7 % t otal; 0. 6 % relate d), fati g ue a n d platelet c o u nt decrease d (eac h 1. 2 % 
t otal; eac h 0. 6 % relate d), a n d h y p o kale mia ( 1. 2 % t otal; n o ne relate d). 
C CI
C CI
C CI
C CI

Pr ot oc ol  
C o va nce St u d y: 8 4 2 6 6 6 5  
C O N FI D E N TI A L  
Pr ot oc ol Refere nce:  L O X O -B T K -2 0 0 1 7  
Pr ot oc ol Versi o n 1. 0, 0 4 A u g ust 2 0 2 0  
Pa ge 1 8  of 5 8  
 
 
Fi ve patie nts ( 2. 9 % of all 1 7 2 patie nts treate d) disc o nti n ue d L O X O -3 0 5 beca use of T E A Es; 
2 of t he 5 patie nts ( 1. 2 % of all patie nts treate d) disc o nti n ue d L O X O -3 0 5 beca use of a 
treat me nt-relate d e ve nt. O ne of t hese patie nts wit h ma ntle cell l y m p h o ma treate d i n t he 
1 0 0 m g Q D gr o u p disc o nti n ue d d ue t o Gra de 3 le u k oc yt osis c o nsi dere d relate d t o st u d y dr u g. 
St u d y t hera p y was hel d f or res ol uti o n of le u k oc yt osis a n d t he patie nt s u bse q ue ntl y pr o gresse d 
a n d st u d y t hera p y was n ot res u me d; t he e ve nt of le u k oc yt osis was rec or de d as 
rec o vere d/res ol ve d. T he sec o n d patie nt treate d i n t he 1 5 0 m g Q D gr o u p disc o nti n ue d d ue t o 
Gra de 2 m yal gia; t he m yal gia was o n g oi n g. T he patie nt ha d pre vi o usl y recei ve d i br uti ni b 
w hic h was disc o nti n ue d after 3 m o nt hs of treat me nt f or A Es.  
 
A t otal of 5 deat hs ha ve bee n re p orte d f or patie nts treate d i n t his st u d y, L O X O -B T K -1 8 0 0 1. 
N o deat hs were c o nsi dere d relate d t o L O X O -3 0 5.  
 
Fr o m preli mi nar y A E data 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, all T E A Es ( hea dac he, na usea, a n d v o miti n g) 
were Gra de 1 i n se verit y a n d c o nsi dere d 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 pri or t o E n d of Treat me nt ( E O T; data o n file at t he ti me of pr ot oc ol 
de vel o p me nt). T here were n o 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 3 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 fr o m preli mi nar y data a vaila ble ( data o n file at 
t he ti me of pr ot oc ol de vel o p me nt). 
 
1. 3. 2.  
P h ar m ac o ki netics  
 
As of Marc h 3 0, 2 0 2 0, P K data were a vaila ble fr o m 1 0 7 patie nts e nr olle d i n  
L O X O -B T K -1 8 0 0 1. Stea d y -state P K para meters of L O X O-3 0 5 i n t hese ca ncer patie nts c o ul d 
be deri ve d fr o m data c ollecte d o n C ycle 1 Da y 8 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 ntrati 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 ue 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 ose sa m ple, lea di n g t o a n esti mate d plas ma half -life of 
a p pr o xi matel y 2 0 h o urs. F oll o wi n g a d mi nistrati o n of d oses of 1 0 0 m g Q D or hi g her, mea n 
tr o u g h plas ma le vels of L O X O-3 0 5 e xcee de d t he 
 of B T K i n vitr o  
(Fi g ure 1 ). 
 
T a ble 1 P h ar m ac o ki netic P ar a meters 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 me a n 
( % C V) 
 
T m a x  ( h) 
Me di a n 
( mi n, m a x) 
A U C 0 -2 4  
( n g * h/ m L) 
Ge o me a n 
( % C V) 
C L/ F  
( L/ h) 
Ge o me a n 
( % C V) 
t1/ 2 
( h) 
Ge o me a n 
( % C V) 
2 5 m g Q D  
5 0 m g Q D  
1 0 0 m g Q D  
C CI
C CI

Pr ot oc ol  
C o va nce St u d y: 8 4 2 6 6 6 5  
C O N FI D E N TI A L  
Pr ot oc ol Refere nce:  L O X O -B T K -2 0 0 1 7  
Pr ot oc ol Versi o n 1. 0, 0 4 A u g ust 2 0 2 0  
Pa ge 1 9  of 5 8  
 
 
 
 
 
 
D ose Le vel  
 
 
 
N  
C m a x 
( n g/ m L) 
Ge o me a n 
( % C V) 
 
T m a x  ( h) 
Me di a n 
( mi n, m a x) 
A U C 0 -2 4  
( n g * h/ m L) 
Ge o me a n 
( % C V) 
C L/ F  
( L/ h) 
Ge o me a n 
( % C V) 
t1/ 2 
( h) 
Ge o me a n 
( % C V) 
1 5 0 m g Q D  
2 0 0 m g Q D  
2 5 0 m g Q D  
3 0 0 m g Q D  
A b bre viati o ns: 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 bjects;  
P K = p har mac o ki netic; Q D = o nce dail y; % C V = c oefficie nt of variati o n i n perce nt; t 1/ 2 =  half -life; tma x  = ti me of 
ma xi mal plas ma c o nce ntrati o n.  
a N = 5; b N = 8; c N = 1 8; d N = 1 6; e N = 2 0; f N = 1 6; g N = 1 5  
Data c ut off date: Marc h 3 0, 2 0 2 0.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
0  
2 5 m g  ( N = 5) 
5 0 m g  ( N = 6) 
1 0 0 m g  ( N = 1 0) 
1 5 0 m g  ( N = 2 0) 
2 0 0 m g  ( N = 2 9) 
2 5 0 m g  ( N = 2 4) 
             3 0 0 m g  ( N = 1 8) 
 
 
0  
2  
4  
6  
8  
Ti m e ( h)  
M e a n C o n c e ntr ati o n  ( n g/ m L) 
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI

Pr ot oc ol  
C o va nce St u d y: 8 4 2 6 6 6 5  
C O N FI D E N TI A L  
Pr ot oc ol Refere nce:  L O X O -B T K -2 0 0 1 7  
Pr ot oc ol Versi o n 1. 0, 0 4 A u g ust 2 0 2 0  
Pa ge 2 0  of 5 8  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
0  
0  
2  
4  
6  
8  
Ti m e ( h)  
 
Data c ut off date: Marc h 3 0, 2 0 2 0  
 
Si n gle d oses of 2 0 0 m g L O X O -3 0 5 were i n vesti gate d i n a 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, Pil ot F o o d Effect st u d y) i n w hic h t he P K was deter mi ne d. F oll o wi n g a 
si n gle d ose of 2 0 0 m g L O X O-3 0 5 t o patie nts or healt h y s u bjects, A U C fr o m 0 t o 8 h o urs was 
si milar bet wee n t he t w o gr o u ps a n d C ma x was a p pr o xi matel y 
% hi g her i n healt h y s u bjects, 
as s h o w n i n t he ta ble bel o w ( data o n file at t he ti me of pr ot oc ol de vel o p me nt).  
 
T a ble 2 P h ar m ac o ki netic of L O X O -3 0 5 F oll o wi n g a Si n gle 2 0 0 -m g D ose 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, C ycle 1 D a y 1) a n d He alt h y 
S u bjects ( St u d y L O X O -B T K -2 0 0 1 4)  
He alt h y  V ol u nteers a  
C a ncer P atie nts b  
P ar a meter  
 
Ge o metric  Me a n  
C V  
n  
Ge o metric  Me a n  
C V  
n  
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 0 t o 8 h o urs; C V =c oefficie nt of variati o n; 
C ma x = ma xi m u m c o nce ntrati o n; n = n u m ber of s u bjects.  
a L O X O-B T X -2 0 0 1 4, 2 0 0 m g si n gle d ose, faste d 
b L O X O -B T K -1 8 0 0 1, 2 0 0 m g si n gle d ose, faste d  
 
I n healt h y v ol u nteers, t he ge o metric mea n si n gle-d ose C ma x of a p pr o xi matel y  
 n g/ m L 
f oll o wi n g a 2 0 0-m g si n gle d ose is 
 bel o w t he N O E L (i n rat, Cma x 
 n g/ m L) f or 
micr o n uclei i n d ucti o n.  
2 5 m g  ( N = 5) 
5 0 m g  ( N = 6) 
1 0 0 m g ( N = 9)  
1 5 0 m g  ( N = 2 0) 
2 0 0 m g  ( N = 2 4) 
2 5 0 m g  ( N = 2 5) 
3 0 0 m g  ( N = 1 6) 
M e a n  C o n c e nt ati o n  ( n g/ m L) 
C CI
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 va nce St u d y: 8 4 2 6 6 6 5  
C O N FI D E N TI A L  
Pr ot oc ol Refere nce:  L O X O -B T K -2 0 0 1 7  
Pr ot oc ol Versi o n 1. 0, 0 4 A u g ust 2 0 2 0  
Pa ge 2 1  of 5 8  
 
 
1. 4.  
St u d y  R ati o n ale  
 
W he n de vel o pi n g ne w dr u gs f or cli nical i n dicati o ns, it is necessar y t o c ollect data o n t he 
safet y, t olera bilit y, a n d P K i n or der t o s u p p ort f urt her de vel o p me nt of t he c o m p o u n d as a 
usef ul cli nical ca n di date a n d deter mi ne d ose le vels a n d d ose i nter vals f or s u bse q ue nt st u dies. 
T his st u d y will assess t he safet y, t olera bilit y, a n d P K of L O X O -3 0 5 i n healt h y s u bjects at 
hi g her d ose le vels t ha n pre vi o usl y a d mi nistere d i n t his p o p ulati o n t o deter mi ne t he si n gle 
d ose of L O X O -3 0 5 nee de d t o reac h t hera pe utic a n d s u prat hera pe utic e x p os ures of  
L O X O -3 0 5 t o desi g n a p ote ntial cli nical st u d y t o deter mi ne t he effect of L O X O -3 0 5 i n t he 
Q T i nter val.  
 
1. 5.  
Ris k  Assess me 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 ( be y o n d t hat of a n assess me 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 pati 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.  
 
D oses of L O X O -3 0 5 u p t o 3 0 0 m g Q D are c urre ntl y bei n g i n vesti gate d i n t he o n g oi n g gl o bal 
P hase 1/ 2 st u d y i n ca ncer patie nts, L O X O -B T K -1 8 0 0 1. Si n gle d oses of 2 0 0 m g L O X O -3 0 5 
were i n vesti gate d i n a st u d y c o n d ucte d i n healt h y v ol u nteers ( L O X O -B T K -2 0 0 1 4).  
L O X O -B T K -2 0 0 1 4 is a pil ot f o o d effect st u d y e val uati n g t he effects of f o o d a n d of 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. Si n gle d oses of 2 0 0 m g 
L O X O -3 0 5 are c urre ntl y bei n g i n vesti gate d i n a st u d y c o n d ucte d 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 0 6 is a dr u g -dr u g i nteracti o n st u d y e val uati 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.  
 
Fr o m A E data 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 1 0 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, all T E A Es ( hea dac he, na usea, a n d v o miti n g) were Gra de 1 i n 
se verit y a n d c o nsi dere d relate d t o L O X O-3 0 5. All 3 e ve nts occ urre d were re p orte d b y  
1 s u bject a n d res ol ve d b y E O T ( data o n file at t he ti me of pr ot oc ol de vel o p me nt). T here were 
n o 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 3 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 fr o m preli mi nar y data a vaila ble ( data o n file at t he ti me of pr ot oc ol 
de vel o p me nt).  
 
T he d oses of L O X O -3 0 5 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 t o s u bjects partici pati n g i n t his st u d y. 
 
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 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 be f o u n d i n t he I B. 1  
T he d ose -escalati o n pr oce d ures a n d safet y m o nit ori n g practices e m pl o ye d b y t his pr ot oc ol 
(ie, re vie wi n g A E re p orti n g, c o n d ucti n g p h ysical e xa mi nati o ns a n d cli nical la b orat or y 
e val uati o ns, meas uri n g vital si g ns, a n d perf or mi n g 1 2 -lea d E C Gs) are c o nsi dere d a de q uate t o 
pr otect t he s u bjects’ safet y.  

Pr ot oc ol  
C o va nce St u d y: 8 4 2 6 6 6 5  
C O N FI D E N TI A L  
Pr ot oc ol Refere nce:  L O X O -B T K -2 0 0 1 7  
Pr ot oc ol Versi o n 1. 0, 0 4 A u g ust 2 0 2 0  
Pa ge 2 2  of 5 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 safet y a n d t olera bilit y of si n gle oral d oses of L O X O -3 0 5 w he n 
a d mi nistere d t o healt h y a d ult  s u bjects. 
2. 1. 2.  
Sec o n d ar y  O bjecti ve  
 
T he sec o n dar y o bjecti ve of t he st u d y is:  
 
•  T o assess t he P K of si n gle oral d oses of L O X O -3 0 5 w he n a d mi nistere d t o healt h y 
a d ult  s u bjects. 
 
2. 2.  
E n d p oi nts  
2. 2. 1.  
Pri m ar y E n d p oi nts 
S afet y  
T he pri mar y e n d p oi nt of t his st u d y is t o assess t he safet y a n d t olera bilit y of L O X O -3 0 5 at 
si n gle d oses ≥ 3 0 0 m g. T his st u d y will i n vesti gate t he safet y a n d t olera bilit y of si n gle d oses 
(ie, p ote ntial t hera pe utic a n d s u prat hera pe utic e x p os ures) of L O X O-3 0 5 w he n a d mi nistere d 
t o healt h y s u bjects. Asce n di n g d oses u p t o a n d p ossi bl y i ncl u di n g 9 0 0 m g will be 
i n vesti gate d. 
 
Safet y a n d t olera bilit y will be assesse d b y m o nit ori n g A Es a n d c o nc o mita nt me dicati o ns, 
perf or mi n g p h ysical e xa mi nati o ns a n d cli nical la b orat or y e val uati o ns, meas uri n g vital si g ns, 
a n d perf or mi n g 1 2 -lea d E C Gs. T hese safet y a n d t olera bilit y e n d p oi nts are dee me d a de q uate 
t o detect a n y safet y si g nals w he n t he pla n ne d d ose ra n ge of L O X O-3 0 5 is a d mi nistere d t o 
healt h y s u bjects.  
 
2. 2. 2.  
Sec o n d ar y E n d p oi nts 
P h ar m ac o ki netic  
T he f oll o wi n g P K para meters will be calc ulate d, w he ne ver p ossi ble, base d o n t he plas ma 
c o nce ntrati o ns of L O X O -3 0 5 (as a p pr o priate):  
 
•  area u n der 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 C0 -2 4) 
•  area u n der 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 U C0 -t) 
•  area u n der t he c o nce ntrati o n -ti me c ur ve fr o m ti me 0 e xtra 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 C 0 -i nf ( % A U Ce xtra p) 

Pr ot oc ol  
C o va nce St u d y: 8 4 2 6 6 6 5  
C O N FI D E N TI A L  
Pr ot oc ol Refere nce:  L O X O -B T K -2 0 0 1 7  
Pr ot oc ol Versi o n 1. 0, 0 4 A u g ust 2 0 2 0  
Pa ge 2 3  of 5 8  
 
 
•  C ma x  
•  ti me t o ma xi m u m o bser ve d plas ma c o nce ntrati o n (tma x ) 
•  a p pare nt ter mi nal eli mi nati o n rate c o nsta nt  ( λZ ) 
•  a p pare nt s yste mic cleara nce  ( C L/ F) 
•  a p pare nt v ol u me of distri b uti o n at ter mi nal p hase  ( Vz/F)  
•  a p pare nt plas ma ter mi nal eli mi nati o n half -life (t½ ). 
I n di vi d ual a n d mea n plas ma c o nce ntrati 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 Cli nical St u d y Re p ort. 

Pr ot oc ol  
C o va nce St u d y: 8 4 2 6 6 6 5  
C O N FI D E N TI A L  
Pr ot oc ol Refere nce:  L O X O -B T K -2 0 0 1 7  
Pr ot oc ol Versi o n 1. 0, 0 4 A u g ust 2 0 2 0  
Pa ge 2 4  of 5 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 n o pe n -la bel, si n gle-asce n di n g d ose st u d y t o e val uate t he safet y, t olera bilit y, a n d P K 
of L O X O -3 0 5.  
 
U p t o 4 c o h orts are pla n ne d f or e val uati o n. I n eac h c o h ort, 6 healt h y a d ult s u bjects are 
pla n ne d f or e val uati o n. S u bjects will partici pate i n o nl y 1 c o h ort. I n eac h c o h ort, s u bjects will 
recei ve a si n gle oral d ose of L O X O-3 0 5 o n Da y 1. Eac h c o h ort will i ncl u de a se nti nel gr o u p 
of 2 s u bjects will be d ose d at least 4 8 h o urs bef ore t he re mai ni n g 4 s u bjects (f oll o wi n g 
re vie w of all a vaila ble safet y data).  
 
A si n gle oral d ose of L O X O -3 0 5 will be a d mi nistere d o n Da y 1 f or eac h c o h ort as f oll o ws:  
 
•  C o h ort 1 ( Treat me nt A): 3 0 0  m g  
•  C o h ort 2 ( Treat me nt B): u p t o 6 0 0  m g  
•  C o h ort 3 ( Treat me nt C): u p t o 9 0 0  m g.  
O ne a d diti o nal c o h ort ( 6 s u bjects) ma y be e nr olle d if it is dee me d a p pr o priate t o re peat a n y 
d ose le vel, or t o a d d a n i nteri m d ose le vel or le vels (e q ual t o or l o wer t ha n 9 0 0 m g), as 
deter mi ne d b y t he S p o ns or i n c o ns ultati o n wit h t he I n vesti gat or ( or desi g nee), de pe n di n g o n 
t he safet y, t olera bilit y, a n d P K res ults fr o m t he pri or c o h ort(s). D osi n g will n ot e xcee d 
9 0 0 m g i n a n y s u bject, n or will a n y s u bject be gi ve n a d ose f or w hic h t he C ma x w o ul d e xcee d  
 n g/ m L. 
 
D ose escalati o n t o a hi g her d ose le vel (ie, ne xt c o h ort) will n ot ta ke place u ntil t he 
I n vesti gat or ( or desi g nee) a n d t he S p o ns or ha ve re vie we d all perti ne nt safet y/t olera bilit y data 
(ie, p h ysical e xa mi nati o ns, E C Gs, vital si g n meas ure me nts, cli nical la b orat or y e val uati o ns, 
a n d a d verse e ve nts [ A Es]) t hr o u g h a mi ni m u m of 1 6 8 h o urs ( Da y 8) a n d ha ve deter mi ne d 
t hat a de q uate safet y a n d t olera bilit y fr o m t he pre vi o us, l o wer d ose, c o h ort has bee n 
de m o nstrate d t o per mit pr ocee di n g t o t he ne xt c o h ort. P har mac o ki netic data t hr o u g h at least 
7 2 h o urs (a p pr o xi matel y 3 half -li ves) after d osi n g will be re vie we d t o g ui de t he 
d ose -escalati o n decisi o n. Data fr o m a mi ni m u m of 4 s u bjects will be re vie we d i n or der t o 
ma ke a d ose escalati o n decisi o n. D ose -escalati o n criteria a n d st o p pi n g r ules are descri be d i n 
Secti o n 5. 5 . 
 
Eac h treat me nt ( A, B, a n d C) 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 a n d 4 h o urs after d osi n g. 
 
T he P K sa m pli n g will be o btai ne d f or 1 6 8 h o urs after a d mi nistrati o n of eac h d ose of 
L O X O -3 0 5.  
 
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 2 8 da ys 
( Da ys 2 9 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 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 8 
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 nati o n ( E T) if t he s u bject 
disc o nti n ues. 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 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 da ys ( ± 2 da ys) after E O T or E T. T he  
C CI

Pr ot oc ol  
C o va nce St u d y: 8 4 2 6 6 6 5  
C O N FI D E N TI A L  
Pr ot oc ol Refere nce:  L O X O -B T K -2 0 0 1 7  
Pr ot oc ol Versi o n 1. 0, 0 4 A u g ust 2 0 2 0  
Pa ge 2 5  of 5 8  
 
 
d urati o n of partici pati o n is e x pecte d t o be a p pr o xi matel y 4 6 da ys ( Scree ni n g t hr o u g h 
f oll o w-u p p h o ne call).  
 
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.  
 
T he 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 ne d as t h ose s u bjects 
w h o are assi g ne d 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.  
 
I n t his st u d y, p h ysical e xa 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 pecifie 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 Es ( 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 verse 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 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 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 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 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 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 vesti gat or ( or desi 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 ne call) are t o be re p orte d.  
 
A Sc he d ule of Assess 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.  
 
3. 2.  
Disc ussi o n of St u d y  Desi g n  
 
W he n de vel o pi n g ne w dr u gs f or cli nical i n dicati o ns, it is necessar y t o c ollect data o n t he 
safet y, t olera bilit y, a n d P K t o s u p p ort f urt her de vel o p me nt of t he c o m p o u n d as a usef ul 
cli nical ca n di date a n d deter mi ne d ose le vels a n d d ose i nter vals f or s u bse q ue nt st u dies. T his 
st u d y will assess t he safet y, t olera bilit y, a n d P K of L O X O-3 0 5 i n healt h y s u bjects at hi g her 
d ose le vels t ha n pre vi o usl y a d mi nistrate d i n t his p o p ulati o n s o as t o deter mi ne t he si n gle d ose 
of L O X O -3 0 5 nee de d t o reac h t hera pe utic a n d s u prat hera pe utic e x p os ures of L O X O -3 0 5 t o 
desi g n a p ote ntial cli nical st u d y t o deter mi ne t he effect of L O X O -3 0 5 o n t he Q T i nter val.  
 
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 nc o mita nt me dicati o ns. 
 
3. 3.  
Selecti o n of D oses i n t he  St u d y  
 
T he t hree pla n ne d si n gle d oses of 3 0 0 m g, 6 0 0 m g, a n d 9 0 0 m g i n t his st u d y are desi g ne d t o 
yiel d a C ma x of L O X O -3 0 5 u p t o 
 hi g her t ha n t he t hera pe utic Cma x  ( 
 n g/ m L, 
Ta ble 1 ) at t he rec o m me n de d P hase 2 d ose of 2 0 0 m g Q D t hat ma y arise fr o m i ntri nsic or  
C CI
C CI

Pr ot oc ol  
C o va nce St u d y: 8 4 2 6 6 6 5  
C O N FI D E N TI A L  
Pr ot oc ol Refere nce:  L O X O -B T K -2 0 0 1 7  
Pr ot oc ol Versi o n 1. 0, 0 4 A u g ust 2 0 2 0  
Pa ge 2 6  of 5 8  
 
 
e xtri nsic fact ors t hat lea d t o hi g her e x p os ures i n ca ncer patie nts. A f o urt h o pti o nal d ose le vel, 
n ot t o e xcee d 9 0 0 m g, ma y be use d if necessar y, t o f urt her defi ne t he d ose -e x p os ure 
relati o ns hi p. 
 
T he starti n g si n gle d ose of 3 0 0 m g i n t his st u d y is e x pecte d t o pr o d uce a C ma x t hat is 
a p pr o xi matel y  
 n g/ m L (
 t hera pe utic). As L O X O-3 0 5 s h o ws ge nerall y li near P K 
i n ca ncer patie nts (Ta ble 1 ), if e x p os ure als o i ncreases li nearl y wit h d ose i n healt h y s u bjects, 
t he pr o p ose d si n gle d oses of 6 0 0 m g a n d 9 0 0 m g w o ul d pr o d uce Cma x val ues of  
 a n d 
, res pecti vel y. As t he P K li nearit y of 
d oses greater t ha n 3 0 0 m g is n ot k n o w n, t he P K of L O X O -3 0 5 f oll o wi n g eac h d ose will be 
e val uate d pri or t o a d mi nisteri n g hi g her d oses, a n d n o d ose will be gi ve n f or w hic h t he 
ge o metric mea n C ma x is pre dicte d t o e xcee d 
 
base d o n t he P K o bser ve d at l o wer d oses.  
 
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 ures 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 2 8 da ys of st u d y e ntr y (ie, pri or t o C hec k -i n [ Da y -1]):  
 
I ncl usi o n/e xcl usi o n criteria 
I nf or me d c o nse nt 
De m o gra p hic data  
Me dical hist or y (i ncl u di n g re vie w of me dicati o n[s]) 
Hei g ht, wei g ht, a n d b o d y mass i n de x ( B MI)  
1 2 -lea d E C G meas ure d after t he s u bject has 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. 2. 4 ) 
Vital si g n meas ure me nts (i ncl u di n g o x y ge n sat urati o n, oral te m perat ure, res pirat or y 
rate, 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 least 5 mi n utes]; Secti o n 7. 2. 3 ) 
H D Y F? i n q uir y, A E, S A E, a n d c o nc o mita nt me dicati o n e val uati o ns ( Secti o n 7. 2. 1 ) 
Cli nical la b orat or y e val uati o ns ( Secti o n 7. 2. 2 ; cli nical c he mistr y pa nel [faste d at least 
8 h o urs], c oa g ulati o n para meters, he mat ol o g y pa nel, a n d U A; A p pe n di x 2 ) 
Scree ns f or he patitis C vir us ( H C V) a nti b o d y, he patitis B s urface a nti ge n ( H Bs A g), 
he patitis B vir us ( H B V) 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 S A R S -C o V -2 ( C O VI D -1 9) via p ol y merase c hai n reacti o n testi n g 
([ P C R] or e q ui vale nt (A p pe n di x 2 ) 
He m o gl o bi n A 1c ( H b A 1c) test ( A p pe n di x 2 ) 
Scree n f or selecte 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 ( A p pe n di x 2 ) 
Esti mate d gl o mer ular filtrati o n rate ( A p pe n di x 2 ) 
Ser u m pre g na nc y test (f or fe male s u bjects o nl y; A p pe n di x 2 ) 
C CI
C CI
C CI
C CI
C CI

Pr ot oc ol  
C o va nce St u d y: 8 4 2 6 6 6 5  
C O N FI D E N TI A L  
Pr ot oc ol Refere nce:  L O X O -B T K -2 0 0 1 7  
Pr ot oc ol Versi o n 1. 0, 0 4 A u g ust 2 0 2 0  
Pa ge 2 7  of 5 8  
 
 
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 male s u bjects o nl y; 
A p pe n di x 2 ) 
T h yr oi d -sti m ulati n g h or m o ne ( T S H) test (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 ( Da 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:  
 
Re vie w of i ncl usi o n/e xcl usi o n criteria  
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) 
Wei g ht a n d B MI  
C o m plete p h ysical e xa mi nati o n ( Secti o n 7. 2. 5 ) 
1 2 -lea d E C G meas ure d after t he s u bject has 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. 2. 4 ) 
Vital si g n meas ure me nts (i ncl u di n g o x y ge n sat urati o n, oral te m perat ure, res pirat or y 
rate, 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. 2. 3 ) 
H D Y F? i n q uir y, A E, S A E, a n d c o nc o mita nt me dicati o n e val uati o ns ( Secti o n 7. 2. 1 ) 
Cli nical la b orat or y e val uati o ns ( Secti o n 7. 2. 2 ; cli nical c he mistr y pa nel [faste d at least 
8 h o urs], c oa g ulati o n para meters, he mat ol o g y pa nel, a n d U A; A p pe n di x 2 ) 
Scree n f or C O VI D -1 9 via P C R or e q ui vale nt  
Scree n f or selecte 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 ( A p pe n di x 2 ) 
Esti mate d gl o mer ular filtrati o n rate ( A p pe n di x 2 ) 
Ser u m pre g na nc y test (f or fe male s u bjects o nl y; A p pe n di x 2 ) 
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 ( Da 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 plia 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 val uati o ns f or p ote ntial s u bjects 
pri or t o e nr oll me nt. 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 bjects selecte d f or 
e nr oll me nt b y t he I n vesti gat or ( or desi 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 vesti gat or ( or desi g nee) 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 ( Da 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:  

Pr ot oc ol  
C o va nce St u d y: 8 4 2 6 6 6 5  
C O N FI D E N TI A L  
Pr ot oc ol Refere nce:  L O X O -B T K -2 0 0 1 7  
Pr ot oc ol Versi o n 1. 0, 0 4 A u g ust 2 0 2 0  
Pa ge 2 8  of 5 8  
 
 
Males, a n d fe males 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. 
Wit hi n B MI ra n ge 1 8. 0 t o 3 2. 0 k g/ m
2, i ncl usi ve. 
I n g o o d healt 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 vesti gat or ( or desi g nee). 
Fe male s u bjects of n o n -c hil d beari n g p ote ntial, defi ne d as bei n g per ma 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 st u d y dr u g 
a d mi nistrati o n) or p ost -me n o pa usal ( defi ne d as at least 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 use). 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 ≥ 4 0 mI U/ m L. All fe male s u bjects m ust 
ha ve a ne gati ve q ualitati ve ser u m pre g na nc 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 
a d mi nistrati o n of st u d y dr u g.  
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 he 
f oll o wi n g met h o ds of c o ntrace pti o n fr o m t he ti me of t he d ose a d mi nistrati o n t hr o u g h 
6 m o nt hs after t he last d ose of L O X O -3 0 5 a d mi nistrati 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). If d oc u me ntati 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:  
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 meets 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 ® ); 
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 ntial, defi ne d as bei n g per ma 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 male part ner’s st u d y 
dr u g a d mi nistrati o n);  or  
4.  be p ost -me n o pa usal wit h a me n orr hea f or at least 1 year pri or t o 
d osi n g 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 practice tr ue a bsti ne nce beca use of a lifest yle c h oice (ie, 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  

Pr ot oc ol  
C o va nce St u d y: 8 4 2 6 6 6 5  
C O N FI D E N TI A L  
Pr ot oc ol Refere nce:  L O X O -B T K -2 0 0 1 7  
Pr ot oc ol Versi o n 1. 0, 0 4 A u g ust 2 0 2 0  
Pa ge 2 9  of 5 8  
 
 
c o ntrace pti ve re q uire me nts. Peri o dic a bsti ne nce b y a fe male part ner (e g, cale 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 wal 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 t hr o u g h 6 m o nt hs after st u d y dr u g a d mi nistrati o n, he 
m ust a gree t o use c o ntrace pti o n as descri be d a b o ve.  
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 na nt, or 
breastfee di n g s h o ul d be a v oi de d. Male s u bjects are re q uire d t o refrai n fr o m d o nati o n 
of s per m fr o m C hec k -i n ( Da y -1) u ntil 6 m o nt hs after a d mi nistrati o n of st u d y dr u g.  
F or s u bjects w h o are e xcl usi vel y i n sa me -se x relati o ns hi ps, c o ntrace pti ve 
re q uire me nts d o n ot a p pl y. 
A ble t o s wall o w m ulti ple ca ps ules.  
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.  
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 8 -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:  
 
Hist or y or prese nce of a n y of t he f oll o wi n g, dee me d cli nicall y si g nifica nt b y t he 
I n vesti gat or ( or desi 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 ucti o n  s ur ger y 
g.  hist or y or prese nce 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 ular t hr o m b oe m b olis m wit hi n 
6 m o nt hs pri or t o t he first d ose a d mi nistrati o n ( 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 t he first d ose 
a d mi nistrati o n ( Da y  1)  
iii. Ne w Y or k Heart Ass ociati o n Class ≥ 2 c o n gesti ve heart fail ure wit hi n 
6 m o nt hs pri or t o t he first d ose a d mi nistrati o n ( 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 pre -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 xcl 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 
vii.  Ve ntric ular d ysf u ncti o n or ris k fact ors f or T orsa des de P oi ntes (e g, 
heart fail ure, car di o m y o pat h y, fa mil y hist or y of L o n g Q T  S y n dr o me)  

Pr ot oc ol  
C o va nce St u d y: 8 4 2 6 6 6 5  
C O N FI D E N TI A L  
Pr ot oc ol Refere nce:  L O X O -B T K -2 0 0 1 7  
Pr ot oc ol Versi o n 1. 0, 0 4 A u g ust 2 0 2 0  
Pa ge 3 0  of 5 8  
 
 
viii.  Si g nifica nt scree ni n g E C G  a b n or malities:  
1.  left b u n dle bra nc h bl oc k  
2.  sec o n d de gree atri o ve ntric 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 usi n g Fri dericia’s met h o d 
( Q Tc F) is > 4 5 0 msec  
4.  E C G fi n di n gs dee me d a b n or mal wit h cli nical si g nifica nce b y 
t he I n vesti gat or ( or desi g nee) at Scree ni n g, C hec k-i n ( Da y -1), 
or pri or t o d osi n g o n Da y  1.  
S u bjects wit h o ut -of -ra n ge, 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 ( Da y -1), or pri or t o d osi n g o n Da y 1, 
i ncl u di n g: 
a. oral b o d y te m perat ure >  3 7. 5° C;  
b.  p ulse rate < 5 0 or > 9 9 beats 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) 
F or t hese para meters, o ut -of -ra n ge val ues t hat are n ot cli nicall y si g nifica nt (as 
deter mi ne d b y t he I n vesti gat or [ or desi g nee]) ma y be re peate d t wice 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. N ote: Rec hec ks of p ulse rate 
a n d B P val ues will be per mitte d u p t o 2 ti mes t o c o nfir m eli gi bilit y f or st u d y 
partici pati o n. S u bjects ma y be eli gi ble f or partici pati o n i n t he st u d y base d o n 
rec hec ke d p ulse rate a n d/ or B P val ues if t he val ues fall wit hi n t he ra n ges state d a b o ve. 
A b n or mal la b orat or y val ues ( he mat ol o g y pa nel, U A, cli nical c he mistr y pa nel [faste d 
at least 8 h o urs], e xcl u di n g t h ose f urt her defi ne d i n e xcl usi o n criteria # 5 , # 6 , # 7 , a n d 
# 8  bel o w) deter mi ne d t o be cli nicall y si g nifica nt b y t he I n vesti gat or ( or desi g nee), 
a n d S p o ns or at Scree ni n g a n d/ or C hec k -i n ( Da y -1) as c o nfir me d b y re peat 
assess me nt. 
Cli nicall y si g nifica nt a b n or malit y, as deter mi ne d b y t he I n vesti gat or ( or desi g nee), 
fr o m p h ysical e xa mi nati o n at C hec k-i n ( Da y -1).  
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 nsferase, a n d ser u m (t otal a n d direct) bilir u bi n, as well as a m ylase 
a n d li pase a b o ve t he u p per li mit of t he n or mal ra n ge at Scree ni n g or C hec k -i n 
( Da y -1). Rec hec ks of L F Ts, a m ylase, a n d li pase will be per mitte d u p t o 2 ti mes t o 
c o nfir m eli gi bilit y f or st u d y partici pati o n if t he val ues fall wit hi n n or mal  ra n ges. 
A n y cli nicall y si g nifica nt de viati o ns fr o m n or mal ra n ges i n creati ne ki nase ( C K) 
u nless a p pr o ve d b y t he I n vesti gat or ( or desi g nee) a n d S p o ns or. Rec hec ks of C K will 
be per mitte d u p t o 2 ti mes t o c o nfir m eli gi bilit y f or st u d y partici pati o n if t he  
o ut -of -ra n ge val ues are sta ble or tre n di n g d o w n a n d t he I n vesti gat or ( or desi g nee) a n d 
t he S p o ns or dee m t hat t he res ults are n ot cli nicall y si g nifica nt a n d will n ot i m pact 
st u d y c o n d uct. 

Pr ot oc ol  
C o va nce St u d y: 8 4 2 6 6 6 5  
C O N FI D E N TI A L  
Pr ot oc ol Refere nce:  L O X O -B T K -2 0 0 1 7  
Pr ot oc ol Versi o n 1. 0, 0 4 A u g ust 2 0 2 0  
Pa ge 3 1  of 5 8  
 
 
Esti mate d gl o mer ular filtrati o n rate ≤ 9 0 m L/ mi n ute/ 1. 7 3 m 2 at Scree ni n g or C hec k -i n 
( Da y -1) 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 
e q uati o n. 
He m o gl o bi n, w hite bl o o d cell c o u nt, a n d platelet c o u nts bel o w t he l o wer li mit of 
n or mal ra n ge at Scree ni n g or C hec k -i n ( Da y -1). Rec hec ks of he m o gl o bi n, w hite 
bl o o d cell c o u nt, a n d platelet c o u nts will be per mitte d u p t o 2 ti mes t o c o nfir m 
eli gi bilit y f or st u d y partici pati o n if t he val ues fall wit hi n n or mal ra n ges.  
P ositi ve ser ol o gic test f or H Bs A g, H B V c ore a nti b o d y, H C V, 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 C V b y a nti b o d y will re q uire c o nfir mati o n 
b y P C R bef ore e nr oll me nt t o detect prese nce of acti ve vir us. S u bjects w h o are H C V 
P C R 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.  
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 her details re gar di n g C O VI D -1 9 testi n g (i ncl u di n g pr oce d ures 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 pecifie d i n se parate d oc u me nts.  
S u bjects wit h k n o w n o n g oi n g alc o h ol a n d/ or dr u g a b use wit hi n 2 years pri or t o 
Scree ni n g, or e vi de nce of s uc h a b use 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 ( Da y -1). Tests f or dr u gs of a b use m ust be ne gati ve at b ot h Scree ni n g a n d 
C hec k -i n ( Da y -1).  
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.  
C o ns u m pti o n of alc o h ol - or caffei ne -c o ntai ni n g f o o ds or be vera ges 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, u nless dee me d acce pta ble b y t he 
I n vesti gat or ( or desi g nee) a n d S p o ns or. 
Stre n u o us e xercise 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.  
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 nce, u nless a p pr o ve d b y t he I n vesti gat or ( or desi g nee). 
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 hic he ver is 
l o n ger, pri or t o t he first d ose a d mi nistrati o n ( Da y 1). 
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), str o n g P-gl yc o pr otei n  
( 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, her bal pr o d ucts, nat ural or her bal s u p ple me nts, a n d 
h or m o ne -re place me nt t hera p y [ H R T]) wit hi n 1 4 da ys pri or t o t he first d ose 
a d mi nistrati o n ( Da y 1) a n d t hr o u g h E O T or E T, u nless dee me d acce pta ble b y t he 
I n vesti gat or ( or desi g nee) a n d S p o ns or. 
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.  
Hist or y or prese nce, 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 vesti gat or ( or desi g nee), w o ul d i nterfere wit h t he 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.  

Pr ot oc ol  
C o va nce St u d y: 8 4 2 6 6 6 5  
C O N FI D E N TI A L  
Pr ot oc ol Refere nce:  L O X O -B T K -2 0 0 1 7  
Pr ot oc ol Versi o n 1. 0, 0 4 A u g ust 2 0 2 0  
Pa ge 3 2  of 5 8  
 
 
P o or peri p heral ve n o us access.  
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.  
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 ( Da y -1).  
Use of t o bacc o, s m o ki n g cessati o n pr o d ucts, or pr o d ucts c o ntai ni n g 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.  
Si g nifica 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, he 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 car diac fail ure), ne ur ol o gical, or 
ps yc hiatric dis or der (as deter mi ne d b y t he I n vesti gat or [ or desi g nee]), or ca ncer 
wit hi n t he past 5 years (e xce pt l ocalize d basal cell, s q ua m o us, or i n sit u ca ncer of t he 
s ki n). N ote: s u bjects wit h a hist or y of a p pe n dect o m y a n d/ or her nia re pairs will be 
acce pta ble. 
Hist or y of dia betes mellit us; H b A 1c ≥ 6. 5 %.  
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).  
Ha ve pre vi o usl y c o m plete d or wit h dra w n fr o m a n y ot her st u d y i n vesti gati n g 
L O X O -3 0 5 a n d ha ve pre vi o usl y recei ve d t he i n vesti gati o nal pr o d uct.  
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 vesti gat or ( or desi g nee), a n d as c o nfir me d b y t he S p o ns or, wit hi n t he 3 0 da ys pri or 
t o t he first d osi n g a n d t hr o u g h E O T or E T. 
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 partici pate 
i n t his st u d y. 
4. 5.  
S u bject N u m ber a n d  I de ntific 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 set of 3 di gits will i de ntif y t he s u bject (e g, 0 0 1 -1 0 1). If s u bjects are 
wit h dra w n b y t he I n vesti gat or ( or desi g nee) or v ol u ntaril 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 dee me d necessar y b y t he S p o ns or. If 
necessar y, as deter mi ne 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 data ma y be re place d. Re place 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 5 0 t o t he last 3 di gits of t he s u bject n u m ber f or t he s u bject t he y are 
re placi n g (e g, S u bject N u m ber 0 0 1-1 5 1 re places S u bject N u m ber 0 0 1 -1 0 1).  
 
4. 6.  
Re m o v al 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 vesti gat or ( or desi g nee) 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 vesti 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 beca use of t he f oll o wi n g: 
 
•  c ha n ge i n c o m plia nce 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  safet y 
•  occ urre nce of  A Es  

Pr ot oc ol  
C o va nce St u d y: 8 4 2 6 6 6 5  
C O N FI D E N TI A L  
Pr ot oc ol Refere nce:  L O X O -B T K -2 0 0 1 7  
Pr ot oc ol Versi o n 1. 0, 0 4 A u g ust 2 0 2 0  
Pa ge 3 3  of 5 8  
 
 
•  occ urre nce of  pre g na nc y  
•  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 wal will i m me diatel y be ma de t o t he S p o ns or. I n case of wit h dra wal, 
eff orts will be ma de t o perf or m all fi nal st u d y da y assess me nts ( A p pe n di x 4 ). T he date 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 wit h dra wal will be rec or de d o n t he 
s u bject’s electr o nic Case 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 
assesse 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 me 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 vesti gat or ( or desi g nee) or 
S p o ns or, base d o n t he occ urre nce of t he 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 nat ure, se verit y, a n d/ or  d urati o n;  
•  i ncrease d fre 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;  
•  me dical or et hical reas o ns affecti n g t he c o nti n ue d perf or ma nce 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 vel 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 nce 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 va nce St u d y: 8 4 2 6 6 6 5  
C O N FI D E N TI A L  
Pr ot oc ol Refere nce:  L O X O -B T K -2 0 0 1 7  
Pr ot oc ol Versi o n 1. 0, 0 4 A u g ust 2 0 2 0  
Pa ge 3 4  of 5 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 vesti gat or ( or desi g nee) wit h a de q uate 
q ua ntities of t he L O X O -3 0 5.  
 
T a ble 3 St u d y Dr u gs  
 
St u d y Dr u g  
L O X O -3 0 5  
F or m a  
Ta blet  
Stre n gt h  
2 5 m g  
S u p plier  
L o x o O nc ol o g y, I nc.  
M a n uf act urer  
Be n d Researc h, I nc.  
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). 
 
T he ta blets c o ntai ni n g 2 5 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 st ore d acc or di n g t o t he i nstr ucti o ns o n t he la bel.  
 
Size 0 li g ht bl ue o pa q ue ca ps ules t o o ver -e nca ps ulate L O X O -3 0 5 ta blets will be s u p plie d b y 
C o va nce. L O X O -3 0 5 ta blets will be o ver -e nca ps ulate d ( wit h 4 ta blets of L O X O -3 0 5 bei n g 
place d i n eac h ca ps ule) acc or di n g t o C o va nce C R Us Sta n dar d O perati n g Pr oce d ures ( S O Ps) 
a n d rele va nt pr ocesses.  
 
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 da nce wit h nati o nal 
la ws a n d re g ulati o ns. T he st u d y dr u g will be tra nsferre 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 ner will be a p pr o priatel y 
la bele d. 
 
5. 2.  
St u d y Tre at me nt  A d mi nistr ati o n  
C o h ort 1 ( Treat me nt A):  
•  A si n gle oral d ose of 3 0 0 m g L O X O -3 0 5 ( 1 2 × 2 5 -m g ta blets, o ver -e nca ps ulate d 
[ 3 ca ps ules]) f oll o wi n g a fast of at least 1 0 h o urs pri or t o a n d 4 h o urs after d osi n g.  
C o h ort 2 ( Treat me nt B):  
•  A si n gle oral d ose of u p t o 6 0 0 m g L O X O -3 0 5 ( 2 4 × 2 5 -m g  ta blets, 
o ver -e nca ps ulate d [ 6 ca ps ules], or less de pe n di n g o n t he d ose c h ose n) f oll o wi n g a fast 
of at least 1 0 h o urs pri or t o a n d 4 h o urs after d osi n g.  
C o h ort 3 ( Treat me nt C):  
•  A si n gle oral d ose of u p t o 9 0 0 m g L O X O -3 0 5 ( 3 6 × 2 5 -m g  ta blets, 
o ver -e nca ps ulate d [ 9 ca ps ules], or less de pe n di n g o n t he d ose c h ose n) f oll o wi n g a fast 
of at least 1 0 h o urs pri or t o a n d 4 h o urs after d osi n g.  

Pr ot oc ol  
C o va nce St u d y: 8 4 2 6 6 6 5  
C O N FI D E N TI A L  
Pr ot oc ol Refere nce:  L O X O -B T K -2 0 0 1 7  
Pr ot oc ol Versi o n 1. 0, 0 4 A u g ust 2 0 2 0  
Pa ge 3 5  of 5 8  
 
 
O ne a d diti o nal c o h ort ( 6 s u bjects) ma y be e nr olle d if it is dee me d a p pr o priate t o re peat a n y 
d ose le vel, or t o a d d a n i nteri m d ose le vel or le vels (e q ual t o or l o wer t ha n 9 0 0 m g), as 
deter mi ne d b y t he S p o ns or i n c o ns ultati o n wit h t he I n vesti gat or ( or desi g nee), de pe n di n g o n 
t he safet y, t olera bilit y, a n d P K res ults fr o m t he pri or c o h ort(s). D osi n g will n ot e xcee d 
9 0 0 m g i n a n y s u bject, n or will a n y s u bject be gi ve n a d ose f or w hic h t he C ma x w o ul d e xcee d  
 n g/ m L. 
 
All st u d y dr u gs will be a d mi nistere d wit h a p pr o xi matel y 2 4 0 m L of water. A n a d diti o nal 
2 4 0 m L of water ma y be a d mi nistere d if nee de d.  
 
Eac h u nit d ose will be pre pare d b y q ualifie d C R U staff. Eac h u nit d ose c o ntai ner will be 
a p pr o priatel y la belle d.  
 
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 c o nsiste ntl y a d mi nistere d t he a p pr o priate 
d ose at a s pecific ti me, t he e xact d ose ti me of s u bjects ma y be sta g gere d t o o b viate t he nee d 
t o ha ve 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 he s u bject’s act ual 
d ose ti me will be rec or de d i n t he s o urce d oc u me nts a n d tra nscri 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 occ 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 nra n d o mize d st u d y.  
 
5. 4.  
Bli n di n g  
 
T his is a n o pe n -la bel st u d y. 
 
5. 5.  
D ose Esc al ati o n Criteri a a n d St o p pi n g  R ules  
 
D ose escalati o n t o t he ne xt d ose le vel (ie, ne xt c o h ort) will n ot ta ke place u ntil t he 
I n vesti gat or ( or desi g nee) a n d t he S p o ns or ha ve deter mi ne d t hat a de q uate safet y a n d 
t olera bilit y data (ie, p h ysical e xa mi nati o ns, E C Gs, vital si g n meas ure me nts, cli nical 
la b orat or y e val uati o ns, a n d A Es t hr o u g h 1 6 8 h o urs [ Da y 8] f oll o wi n g d osi n g o n Da y 1) fr o m 
t he pre vi o us, l o wer d ose, c o h ort has bee n de m o nstrate d t o per mit pr ocee di n g t o t he ne xt 
c o h ort. A s ufficie nt peri o d of ti me will be all o we d bet wee n d osi n g ( 1 6 8 h o urs [ Da y 8], 
f oll o wi n g d osi n g o n Da y 1) of t he pri or c o h ort a n d t he d osi n g of t he ne xt c o h ort i n or der f or 
t he I n vesti gat or ( or Desi g nee) a n d t he S p o ns or t o a de q uatel y re vie w t he safet y a n d 
t olera bilit y data fr o m t he pri or c o h ort. P har mac o ki netic data t hr o u g h at least 7 2 h o urs 
(a p pr o xi matel y 3 half-li ves) will be re vie we d t o g ui de d ose-escalati o n decisi o ns or f or 
selecti o n of a n alter nate d ose f or e val uati o n, a n d/ or t o c o nfir m t he sa m pli n g sc he d ule. Data 
fr o m a mi ni m u m of 4 s u bjects will be re vie we d i n or der t o ma ke a d ose escalati o n decisi o n. 
 
T he I n vesti gat or ( or desi g nee) a n d t he S p o ns or will ma ke 1 of t he f oll o wi n g deter mi nati o ns: 
T o c o nti n ue wit h t he st u d y as pla n ne d.  
C CI

Pr ot oc ol  
C o va nce St u d y: 8 4 2 6 6 6 5  
C O N FI D E N TI A L  
Pr ot oc ol Refere nce:  L O X O -B T K -2 0 0 1 7  
Pr ot oc ol Versi o n 1. 0, 0 4 A u g ust 2 0 2 0  
Pa ge 3 6  of 5 8  
 
 
T o c o nti n ue wit h t he st u d y a n d a d d a d diti o nal safet y e val uati o ns t o s u bse q ue nt 
c o h orts. 
I n t he e ve nt of t he f oll o wi n g occ urre nce: 
a. O ne s u bject at a gi ve n d ose le vel e x perie nces a dr u g -relate d C o m m o n 
Ter mi n ol o g y Criteria f or A d verse E ve nts ( C T C A E) gra de ≥ 3 t o xicit y ( w hic h 
is n ot a n S A E), w hic h is dee me d cli nicall y si g nifica nt b y t he I n vesti gat or ( or 
desi g nee), wit h a gree me nt fr o m t he S p o ns or, a decisi o n will be ma de as 
f oll o ws: 
o  A dj ust t o a n i nter me diate d ose bet wee n t he c urre nt d ose a n d t he ne xt 
pla n ne d  d ose;  
o  A dj ust t o a n i nter me diate d ose bet wee n t he c urre nt d ose a n d t he pre vi o us 
l o wer d ose;  
o  D ose a d mi nistrati o n ma y be per mitte d t o c o nti n ue as dee me d b y t he 
I n vesti gat or ( or desi g nee), wit h a gree me nt fr o m t he S p o ns or, w here t he 
safet y para meter assesse d d oes n ot p ose a s u bject safet y ris k base d o n 
safet y k n o wle d ge fr o m pri or L O X O-3 0 5  st u dies. 
b.  T w o or m ore s u bjects i n a d ose le vel e x perie nce a dr u g -relate d C T C A E gra de  
≥ 3 t o xicit y ( w hic h is n ot a n S A E), w hic h are dee me d cli nicall y si g nifica nt b y 
t he I n vesti gat or ( or desi g nee), wit h a gree me nt fr o m t he S p o ns or, a decisi o n 
will be ma de as f oll o ws:  
o  D ose a d mi nistrati o n ma y be per mitte d t o c o nti n ue as pla n ne d if dee me d 
acce pta ble b y t he I n vesti gat or ( or desi g nee), wit h a gree me nt fr o m t he 
S p o ns or, w here t he safet y para meter assesse d d oes n ot p ose a s u bject 
safet y ris k base d o n safet y k n o wle d ge fr o m pri or L O X O-3 0 5  st u dies; 
o  E val uate a n alter nati ve d ose  le vel; 
o  T he st u d y ma y be ter mi nate d wit h n o a d diti o nal d ose a d mi nistrati o n t o a n y 
s u bjects. 
c. O ne or m ore s u bject(s) i n a d ose le vel has a C ma x of >  
 n g/ m L or a 
pre dicte d C ma x of ≥  
 n g/ m L i n a s u bse q ue nt d ose le vel, a decisi o n will  
be ma de as  f oll o ws: 
o  A dj ust t o a n i nter me diate d ose bet wee n t he c urre nt d ose a n d t he pre vi o us 
l o wer d ose;  
o  T he st u d y ma y be ter mi nate d wit h n o a d diti o nal d ose a d mi nistrati o n t o a n y 
s u bjects. 
5. 6.  
Tre at me nt  C o m pli a nce  
 
T he f oll o wi n g meas ures 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 diatel 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. 
C CI
C CI

Pr ot oc ol  
C o va nce St u d y: 8 4 2 6 6 6 5  
C O N FI D E N TI A L  
Pr ot oc ol Refere nce:  L O X O -B T K -2 0 0 1 7  
Pr ot oc ol Versi o n 1. 0, 0 4 A u g ust 2 0 2 0  
Pa ge 3 7  of 5 8  
 
 
•  At eac h d ose pre parati 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 
will be perf or me d, as  a p pr o priate. 
5. 7.  
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 t he st u d y 
s u p plies (i ncl u di n g L O X O-3 0 5 ta blets a n d ca ps ules t o o ver -e nca ps ulate L O X O -3 0 5) recei ve d 
or pr oc ure d b y C o va nce. I n a d diti o n, a n acc urate dr u g dis p ositi o n rec or d will be ke 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 vie w b y t he S p o ns or 
u p o n re q uest.  
 
F or eac h batc 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 s u p plies (i ncl u di n g all I M P) will be dis p ose d of b y 
t he C R U, per t he S p o ns or’s writte n i nstr ucti o ns a n d/ or i n acc or da nce wit h 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 a n d t he C R Us S O Ps.  

Pr ot oc ol  
C o va nce St u d y: 8 4 2 6 6 6 5  
C O N FI D E N TI A L  
Pr ot oc ol Refere nce:  L O X O -B T K -2 0 0 1 7  
Pr ot oc ol Versi o n 1. 0, 0 4 A u g ust 2 0 2 0  
Pa ge 3 8  of 5 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 mit a nt  T her a pies  
 
Paraceta 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 nc 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 d ose a d mi nistrati o n ( Da y 1).  
 
All prescri pti o n/ n o n prescri pti o n me dicati o ns a n d o ver -t he-c o u nter me dicati o ns (i ncl u di n g 
H R T, her bal pr o d ucts, nat ural or her bal s u p ple me nts, e xce pt f or paraceta m ol/aceta mi n o p he n 
as refere nce d a b o ve) are pr o hi bite d f or 1 4 da ys pri or t o d ose a d mi nistrati o n ( Da y 1) a n d 
t hr o u g h E O T or E T, u nless dee me d acce pta ble b y t he I n vesti gat or ( or desi g nee) a n d S p o ns or. 
T his i ncl u des, b ut is 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), 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. 
 
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 vesti 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 case, t he 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 re q uire d t o refrai 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 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 ges c o ntai ni n g 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 will n ot be 
all o we d u nless dee me d acce pta ble b y t he I n vesti gat or ( or desi g nee) a n d S p o ns or.  
 
C o ns u m pti o n of alc o h ol - or caffei ne -c o ntai ni n g f o o ds or be vera ges 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 u nless dee me d acce pta ble b y 
t he I n vesti gat or ( or desi g nee) a n d S p o ns or. 
 
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 xercise pr o gra m or 
partici pate i n a n y u n us uall y stre n u o us p h ysical e xerti o n).  
 
W hile c o nfi ne d at t he C R U, s u bjects will recei ve a sta n dar d diet at sc he 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. 
 
Fasti n g re q uire me nt i n relati o n t o d osi n g are descri be d i n Secti o n 3. 1  a n d Secti o n 5. 2 . 

Pr ot oc ol  
C o va nce St u d y: 8 4 2 6 6 6 5  
C O N FI D E N TI A L  
Pr ot oc ol Refere nce:  L O X O -B T K -2 0 0 1 7  
Pr ot oc ol Versi o n 1. 0, 0 4 A u g ust 2 0 2 0  
Pa ge 3 9  of 5 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 me 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 nal ysis of 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 xact 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 de 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 parate La b orat or y Ma 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 ytic al  Met h o d ol o g y  
 
C o nce ntrati o ns of L O X O -3 0 5 i n plas ma will be deter mi ne d usi n g a vali date d bi oa nal ytical 
met h o d. 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 me nt.  
 
7. 2.  
S afet y a n d T oler a bilit y  Assess me nts  
 
Safet y e val uati o ns ma y be 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 de t o sc he d ule a n d perf 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 me 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 desce n di n g or der of pri orit y): 
 
•  d osi n g  
•  P K bl o o d  sa m pli n g 
•  1 2 -lea d E C Gs  
•  vital si g n  meas ure me nts  
•  bl o o d a n d uri ne sa m ples f or cli nical la b orat or y  e val uati o ns 
•  p h ysical  e xa mi nati o n. 
7. 2. 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 ures f or re p orti n g S A Es are detaile d i n A p pe 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 uesti o n s uc h as “ Ha ve 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 me p oi nts s pecifie d 
i n A p pe n di x 4  (ie, at Scree 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 da 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.  

Pr ot oc ol  
C o va nce St u d y: 8 4 2 6 6 6 5  
C O N FI D E N TI A L  
Pr ot oc ol Refere nce:  L O X O -B T K -2 0 0 1 7  
Pr ot oc ol Versi o n 1. 0, 0 4 A u g ust 2 0 2 0  
Pa ge 4 0  of 5 8  
 
 
A d verse e ve nts, w het her v ol u nteere d, i de ntifie d b y t he s u bject’s res p o nses 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 val uati o ns, will be rec or de 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 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 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 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 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 vesti gat or ( or desi 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 ne call) are 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 relate d t o st u d y dr u g b y t he I n vesti gat or ( or desi g nee) w hic 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 he S p o ns or. T he 
I n vesti gat or ( or desi g nee) s h o ul d use a p pr o priate 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 me 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) after 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 nce t he E O T or E T visit. 
 
At all ti mes, a s u bject ma y be re q uire 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 vesti gat or ( or desi g nee). 
 
A n y e ve nt t hat meets t he criteria of a s us pecte d u ne x pecte d seri o us a d verse 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 desi 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 nce 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 e x pecte d a d verse reacti o ns.  
7. 2. 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 uati o ns (cli nical c he mistr y pa nel [faste d at least 8 h o urs; at E O T or 
E T, s u bjects are n ot re 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 oa 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], esti mate d 
gl o mer ular filtrati o n rate [ 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 B V c ore a nti b o d y, H Bs A g, 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 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 he discreti o n of t he I n vesti gat or ( or desi g nee). F urt her details  

Pr ot oc ol  
C o va nce St u d y: 8 4 2 6 6 6 5  
C O N FI D E N TI A L  
Pr ot oc ol Refere nce:  L O X O -B T K -2 0 0 1 7  
Pr ot oc ol Versi o n 1. 0, 0 4 A u g ust 2 0 2 0  
Pa ge 4 1  of 5 8  
 
 
re gar di n g C O VI D-1 9 testi n g (i ncl u di n g pr oce d ures 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 pecifie d i n se parate d oc u me nts.  
 
A uri ne dr u g scree n f or selecte 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) will be 
perf or me d at Scree ni n g a n d re peate 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 test (fe male 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 test ( 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 are prese 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. 2. 3.  
Vit al  Si g ns  
 
Vital si g n meas ure me nts (i ncl u di n g o x y ge n sat urati o n, oral te m perat ure, res pirat or y rate, a n d 
s u pi ne B P, a n d p ulse rate) will be o btai ne 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 rea di n g a n d meas ure me nts s h o ul d be ta ke n after t he s u bject has bee n resti n g i n t he 
s u pi ne p ositi o n f or at least 5 mi n utes. 
 
W he n vital si g n meas ure me nts are sc he d ule d at t he sa me ti me as bl o o d dra ws, t he 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 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 bl o o d dra w.  
 
7. 2. 4.  
1 2 -le a d Electr oc ar di o gr a m  
 
A 1 2 -lea d E C G (i ncl u di n g 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 val will be c orrecte d f or heart rate 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 are sc he d ule d at t he sa me ti me as bl o o d dra ws, t he 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 bl o o d dra w.  
 
7. 2. 5.  
P h ysic al  E x a mi n ati o n  
 
A c o m plete or a b bre viate d p h ysical e xa mi nati o n 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 . C o m plete p h ysical e xa mi nati o ns will e val uate ge neral a p peara 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; hea 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 vasc 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 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; 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 va nce St u d y: 8 4 2 6 6 6 5  
C O N FI D E N TI A L  
Pr ot oc ol Refere nce:  L O X O -B T K -2 0 0 1 7  
Pr ot oc ol Versi o n 1. 0, 0 4 A u g ust 2 0 2 0  
Pa ge 4 2  of 5 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  
 
T his st u d y is pla n ne d t o e nr oll u p t o 2 4 healt h y a d ult male a n d fe male s u bjects ( w o me n of 
n o n -c hil d beari n g p ote ntial o nl y). Si x s u bjects will partici pate i n eac h c o h ort.  
 
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. 
E ver y atte m pt will be ma de t o e nr oll at least 1 s u bject of eac h se x i n eac h c o h ort.  
N o f or mal statistical assess me nt of sa m ple size has bee n c o n d ucte d. T he sa m ple size c h ose n 
f or t his st u d y is c o m m o n i n si n gle-asce n di n g d ose st u dies a n d is c o nsi dere d s ufficie nt t o 
ac hie ve t he o bjecti ves of t he st u d y.  
 
8. 2.  
A n al ysis  P o p ul ati o ns  
8. 2. 1.  
St u d y  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 recei ve d at least 1 d ose of L O X O -3 0 5, 
ha ve at least 1 q ua ntifia ble P K c o nce ntrati o n, a n d f or w h o m at least 1 P K para meter ca n be 
c o m p ute d. A s u bject ma y be e xcl u de d fr o m t he 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 bef ore 2 ti mes t he me dia n 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 case-b y -case 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 recei ve d 1 d ose of 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 P K bl o o d sa m ples f or t he a nal ysis of plas ma c o nce ntrati o ns of L O X O -3 0 5 will be 
c ollecte d fr o m pre d ose t hr o u g h 1 6 8 h o urs p ost -L O X O -3 0 5 d ose f or Treat me nts A, B, a n d C.  
 
W he ne ver p ossi ble, t he f oll o wi n g P K para meters will be calc ulate d f or eac h s u bject, base d o n 
t he plas ma c o nce ntrati o ns of L O X O-3 0 5 (as  a p pr o priate): 
 
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 h o ur 0 t o 2 4 h o urs p ost d ose, as 
calc ulate d b y t he li near tra pez oi dal  met h o d  
A U C 0 -t 
area 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 t he last 
meas ura ble c o nce ntrati o n, calc ulate d usi n g t he li near tra pez oi dal r ule f or 
i ncreasi n g a n d decreasi n g c o nce ntrati o ns  
A U C 0 -i nf 
A U C fr o m ti me 0 e xtra p olate d t o i nfi nit y, calc ulate d usi n g t he  f or m ula: 
C t 
A U C 0 -i nf = A U C 0 -t +  
z 
w here C t is t he last meas ura ble c o nce ntrati o n a n d λZ is t he a p pare nt ter mi nal 
eli mi nati o n rate c o nsta nt  
% A U C
e xtra p  
perce nta ge e xtra p olati o n f or A U C 0 -i nf 
C ma x  
ma xi m u m o bser ve d plas ma  c o nce ntrati o n  
tma x  
ti me t o ma xi m u m o bser ve d plas ma c o nce ntrati o n  
λ  

Pr ot oc ol  
C o va nce St u d y: 8 4 2 6 6 6 5  
C O N FI D E N TI A L  
Pr ot oc ol Refere nce:  L O X O -B T K -2 0 0 1 7  
Pr ot oc ol Versi o n 1. 0, 0 4 A u g ust 2 0 2 0  
Pa ge 4 3  of 5 8  
 
 
λ Z  
a p pare nt ter mi nal eli mi nati o n rate c o nsta nt, w here Z is t he ma g nit u de of t he 
sl o pe of t he li near re gressi o n of t he l o g c o nce ntrati o n vers us ti me pr ofile 
d uri n g t he ter mi nal  p hase  
C L/ F  
a p pare nt s yste mic  cleara nce  
t½  
a p pare nt plas ma ter mi nal eli mi nati o n half -life ( w he ne ver p ossi ble), w here 
t½ =  l n( 2)/ λZ  
V z/ F 
a p pare nt v ol u me of distri b uti o n at ter mi nal  p hase  
 
P har mac o ki netic calc ulati o ns will be perf 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 ( Certara U S A I nc.).  
T he λ Z a n d t ½ will be calc ulate d b y li near least s q uares re gressi o n a nal ysis usi n g t he 
ma xi m u m n u m ber of p oi nts i n t he ter mi nal l o g li near p hase (e g, 3 or m ore n o n -zer o plas ma 
c o nce ntrati o ns). Ot her para meters ma 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 nal ysis will use act ual ti mes as rec or de d o n t he e C R F. All statistical 
a nal ysis will be perf or me d usi n g S A S  Versi o n 9. 4 or greater. 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 ntrati o ns a n d P K para meters will be 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 oefficie nt of variati 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 mea n plas ma c o nce ntrati 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  
 
P har mac o ki netic d ose pr o p orti o nalit y will be assesse d f or C o h orts 1, 2, a n d 3. Nat ural  
l o g-tra nsf or me d A U C0 -2 4, A U C 0 -t, A U C0 -i nf, a n d Cma x of L O X O -3 0 5 will be e val uate d usi n g a 
p o wer m o del of t he f or m:  
 
l n( p ar a meter) = i nterce pt + sl o pe × l n( d ose) + r a n d o m err or 
 
F or eac h P K para meter se paratel y, a p o ole d esti mate (acr oss all d oses) of sl o pe, 
c orres p o n di n g 9 5 % c o nfi de nce i nter val, a n d bet wee n -s u bject C V % will be calc ulate d. 
 
8. 4.  
S afet y  A n al ysis  
 
All safet y assess me nts, i ncl u di n g A Es a n d S A Es, vital si g n meas ure me nts, cli nical la b orat or y 
e val uati o ns, 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 descri 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, baseli ne val ue is defi 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 L O X O -3 0 5. N o f or mal statistical a nal yses are pla n ne d 
f or t he safet y data. All safet y data will be liste d b y s u bject. 

Pr ot oc ol  
C o va nce St u d y: 8 4 2 6 6 6 5  
C O N FI D E N TI A L  
Pr ot oc ol Refere nce:  L O X O -B T K -2 0 0 1 7  
Pr ot oc ol Versi o n 1. 0, 0 4 A u g ust 2 0 2 0  
Pa ge 4 4  of 5 8  
 
 
C o nc o mita nt me dicati o ns will be c o de d usi n g t he 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 n d A Es will be c o de d usi n g 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 se 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 vesti gat or ([ or desi g nee], A p pe 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 ter 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 ha n ge 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 ges will be ma de b y stri ki n g a si n gle li ne t hr o u g h err o ne o us data a n d clearl y 
e nteri n g t he c orrect data (e g, wr o n g data  ri g ht data). 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 ge will be writte n a djace nt t o t he c ha n ge b y t he 
cli nicia n. 
 
T he Data Ma na ge me 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 verifie d b y t he St u d y M o nit or. Data 
will t he n be re vie we d b y t he data ma na ge 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 data base is clea ne d b y data ma na ge me nt a n d will be 
re vie we d b y t he C o va nce scie ntific tea m. T he e C R F a n d a ncillar y data will be c o n verte 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 clie nt -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 
dataset c o nte nt will be peer re vie we d b y a n i n de pe n de nt pr o gra m mer.  
 
T he ta bles, fi g ures, a n d listi n gs ( T F Ls) will be pr o gra m me d per t he 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 scie 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 de 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.  
 
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 sta n dar d 
o perati n g pr oce d ures or per clie nt 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 va nce St u d y: 8 4 2 6 6 6 5  
C O N FI D E N TI A L  
Pr ot oc ol Refere nce:  L O X O -B T K -2 0 0 1 7  
Pr ot oc ol Versi o n 1. 0, 0 4 A u g ust 2 0 2 0  
Pa ge 4 5  of 5 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 bet wee n t he S p o ns or a n d t he 
I n vesti gat or ( or desi 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 he S p o ns or, I n vesti gat or ( or desi 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 prese ntati ve(s) of t he 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 vesti gat or ( or 
desi 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 wit 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 ne ws pa pers, oral 
prese ntati o ns, a bstracts) b y t he I n vesti gat or ( or desi g nee) or t heir re prese ntati 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 de 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 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 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 oc 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 will visit t he C R U at s uita ble i nter vals a n d be i n 
fre q ue 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 has access t o all d oc u me nts (relate 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 are re q ueste d. I n t ur n, t he S p o ns or’s St u d y M o nit or 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 vesti gat or ( or 
desi g nee) a n d I n vesti gat or’s staff will be e x pecte d t o c o o perate wit h t he S p o ns or’s St u d y 
M o nit or, 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 nce wit h U S Title 2 1 C o de of Fe deral Re 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 de d t o s u bjects will be re vie we d a n d 
a p pr o ve d b y t he I R B. T he S p o ns or will s u p pl y rele va nt material f or t he I n vesti 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. Verificati o n of t he  

Pr ot oc ol  
C o va nce St u d y: 8 4 2 6 6 6 5  
C O N FI D E N TI A L  
Pr ot oc ol Refere nce:  L O X O -B T K -2 0 0 1 7  
Pr ot oc ol Versi o n 1. 0, 0 4 A u g ust 2 0 2 0  
Pa ge 4 6  of 5 8  
 
 
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 he writte n I C F state me nt will be tra ns mitte d 
t o t he I n vesti gat or ( or desi 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 bse 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 ueste 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 ulat or y i ns pecti o ns b y pr o vi di n g direct access 
t o s o urce data/ d oc 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) partici pati o n i n t he st u d y. 
 
9. 6.  
I nf or me d C o nse nt  
 
Writte n i nf or me d c o nse nt f or t he st u d y will be o btai ne d fr o m all s u bjects bef ore 
pr ot oc ol -s pecific pr oce d ures are carrie d o ut. T he I C F will be a p pr o ve 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 nat 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 oc 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 oc ol-s pecific pr oce d ures bei n g perf or me d. 
 
T he s u bject will si g n 2 c o pies of t he I C F. O ne 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 rec or ds.  
 
9. 7.  
Rec or ds  
 
T he res ults fr o m data c ollecte d at Scree 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 pies 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 da 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 heets, 
c orres p o n de nce, p h ot o gra 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 re p ort, will be retai ne 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 ncial Discl os ure b y Cli nical 
I n vesti gat ors ( 2 1 C F R 5 4), I R Bs ( 2 1 C F R 5 6), I n vesti gati o nal Ne w Dr u g A p plicati o n 
( 2 1 C F R 3 1 2), A p plicati o ns f or F D A A p pr o val t o Mar ket a Ne w Dr u g ( 2 1 C F R 3 1 4), a n d 
Ra di oacti ve Dr u gs f or Certai n Researc h Uses ( 2 1 C F R 3 6 1. 1), as a p pr o priate. As s uc h, t hese  

Pr ot oc ol  
C o va nce St u d y: 8 4 2 6 6 6 5  
C O N FI D E N TI A L  
Pr ot oc ol Refere nce:  L O X O -B T K -2 0 0 1 7  
Pr ot oc ol Versi o n 1. 0, 0 4 A u g ust 2 0 2 0  
Pa ge 4 7  of 5 8  
 
 
secti o ns of U S Title 2 1 C F R, al o n g wit h t he a p plica ble I C H G ui deli 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 ura nce will be a d dresse d i n a se parate a gree me nt.  

Pr ot oc ol  
C o va nce St u d y: 8 4 2 6 6 6 5  
C O N FI D E N TI A L  
Pr ot oc ol Refere nce:  L O X O -B T K -2 0 0 1 7  
Pr ot oc ol Versi o n 1. 0, 0 4 A u g ust 2 0 2 0  
Pa ge 4 8  of 5 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 vesti gat or’s Br oc h ure ( Versi o n 3. 1). 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 re 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.  
 
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, Blac 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 ua n g Y, R o gers K, B hat S A, Gre ver 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.  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 gra m mi n g f or PI 3 K i n hi biti o n o verri des a rela pse-s pecific C 4 8 1 S B T K m utati o n 
re veale 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, De 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 de 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, Na 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 har 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/  

Pr ot oc ol  
C o va nce St u d y: 8 4 2 6 6 6 5  
C O N FI D E N TI A L  
Pr ot oc ol Refere nce:  L O X O -B T K -2 0 0 1 7  
Pr ot oc ol Versi o n 1. 0, 0 4 A u g ust 2 0 2 0  
Pa ge 4 9  of 5 8  
 
 
1 1.  A P P E N DI C E S  

Pr ot oc ol  
C o va nce St u d y: 8 4 2 6 6 6 5  
C O N FI D E N TI A L  
Pr ot oc ol Refere nce:  L O X O -B T K -2 0 0 1 7  
Pr ot oc ol Versi o n 1. 0, 0 4 A u g ust 2 0 2 0  
Pa ge 5 0  of 5 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 verse E ve nts  
 
A n a d verse e ve nt ( A E; or a d verse e x perie nce) is defi ne d as a n y u nt o war d me dical occ urre nce 
e x perie nce d b y a patie 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 -relate d b y 
t he I n vesti gat or ( or desi g nee). A treat me nt-e mer ge nt a d verse e ve nt ( T E A E) is a n A E t hat 
starts o n or after t he first a d mi 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 ble c ha n ges 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 rele va nt a d verse c ha n ges i n la b orat or y para meters o bser ve 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 ge 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 malities t hat are dee me d cli nicall y si g nifica nt 
b y t he I n vesti gat or [ or desi g nee]), a n d acci de nts o bser ve d i n t he c o nte xt of a cli nical trial, 
irres pecti ve of a p ossi ble ca usal relati 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 verse E ve nts  
 
T he se verit y of A Es will be cate g orize d base d o n t he Nati o nal Ca ncer I nstit ute 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 ate: 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 Se vere or me 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 ve 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 des are a p pr o priate f or all A Es. T heref ore, s o me A Es are liste d wit hi n t he C T C A E wit h fe wer t ha n 
5 o pti o ns f or gra de selecti o n. Gra de 5 ( deat h) is n ot a p pr o priate f or s o me A Es a n d t heref ore is n ot a n o pti 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 oceries or cl ot hes, usi n g t he tele p h o ne, ma na gi n g m o ne y, etc. 
* * Self -care A D L refer t o bat hi n g, dressi n g a n d u n dressi n g, fee di n g self, usi n g t he 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 va nce St u d y: 8 4 2 6 6 6 5  
C O N FI D E N TI A L  
Pr ot oc ol Refere nce:  L O X O -B T K -2 0 0 1 7  
Pr ot oc ol Versi o n 1. 0, 0 4 A u g ust 2 0 2 0  
Pa ge 5 1  of 5 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 wee 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 urre nce or w orse ni n g of t he A E r ules o ut a ca usal 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 nce or w orse ni n g of t he A E is c o nsiste nt wit h a ca usal relati 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 here is a reas o na ble p ossi bilit y t hat t he 
e x perie nce ma y ha 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 na nc y (i ncl u di n g pre g na nc y i n fe male part 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 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 prese 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 pre 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 desi g nee) u ntil c o m pleti o n of t he pre g na nc y. If t he pre g na nc y e n ds f or 
a n y reas o n bef ore t he a ntici pate d date, t he I n vesti gat or ( or desi g nee) 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 prese ntati ve. At t he c o m pleti o n of t he pre g na nc y, t he 
I n vesti gat or ( or desi g nee) will d oc u me nt t he o utc o me of t he pre g na nc y. If t he o utc o me of t he 
pre g na nc y meets t he criteria f or i m me diate classificati o n as a n 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 vesti 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 i m me diatel y if t he y disc o ver t heir 
se x ual 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 ore 
pre g na nc y i nf or mati o n ca n be c ollecte d. W he n a C R U bec o mes a ware t hat t he fe male part 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 vesti gat or ( or desi g nee) i m me diatel 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 he 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 prese ntati ve via e mail.  
 
All pre g na ncies s h o ul d be rec or de d o n t he A E 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 na nc y f or ms. If t he I n vesti gat or ( or desi g nee) s us pects t hat a 
pre g na nc y was t he res ult of a n i nteracti o n bet wee n t he st u d y 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 he dr u g i nteracti o n s h o ul d als o be ca pt ure d as a 
se parate A E. 

Pr ot oc ol  
C o va nce St u d y: 8 4 2 6 6 6 5  
C O N FI D E N TI A L  
Pr ot oc ol Refere nce:  L O X O -B T K -2 0 0 1 7  
Pr ot oc ol Versi o n 1. 0, 0 4 A u g ust 2 0 2 0  
Pa ge 5 2  of 5 8  
 
 
Defi niti o n of Seri o us A d verse E ve nts  
 
A n S A E ( b y F D A defi niti o n) is a n y a d verse dr u g e x perie nce 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 verse dr u g e x perie nce (ie, o ne t hat places t he s u bject, i n t he 
vie w of t he I n vesti gat or [ or desi g nee], at i m me diate ris k of  deat h);  
•  
I n patie 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 ve 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 orta nt me dical e ve 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, base d o n a p pr o priate me dical 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 utc o mes liste d i n t his defi niti o n.  
 
U ne x pecte d A d verse Dr u g Reacti o n  
 
A n A E or s us pecte d a d verse dr u g reacti o n is c o nsi dere d ‘ u ne x pecte d’ if t he e ve nt is n ot liste d 
i n t he Refere nce Safet y I nf or mati o n secti o n of t he I n vesti gat or’s Br oc h ure 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.  
 
Re p orti n g  
 
T he F D A -re p orta ble A Es are A Es t hat are ass ociate d wit h t he use of t he dr u g a n d re prese nt 
e ve nts t hat are assesse d as seri o us, relate d, a n d u ne x pecte d. T he 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. Fi nal 
deter mi nati o n of w het her a n e ve nt re prese nts a s us pecte d u ne x pecte d seri o us a d verse reacti o n 
will be 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 orta 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 ve 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 nce 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 he 
S p o ns or’s Cli nical Safet y Re prese ntati ve wit hi n 2 4 h o urs of a ware ness. I nc o mi n g re p orts are 
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 are pr o vi de d i n t he St u d y Ma n ual.  

Pr ot oc ol  
C o va nce St u d y: 8 4 2 6 6 6 5  
C O N FI D E N TI A L  
Pr ot oc ol Refere nce:  L O X O -B T K -2 0 0 1 7  
Pr ot oc ol Versi o n 1. 0, 0 4 A u g ust 2 0 2 0  
Pa ge 5 3  of 5 8  
 
 
T he I R B will be n otifie d of a n y F D A -re 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 pecte 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 va nce St u d y: 8 4 2 6 6 6 5  
C O N FI D E N TI A L  
Pr ot oc ol Refere nce:  L O X O -B T K -2 0 0 1 7  
Pr ot oc ol Versi o n 1. 0, 0 4 A u g ust 2 0 2 0  
Pa ge 5 4  of 5 8  
 
 
A p pe n di x 2: Cli nic 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 
S A R S -C o V -2 ( C O VI D -1 9)  
Testi n g  
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  
H u ma n i m m u n o deficie nc y vir us 
( HI V) a nti b o d y 
He patitis B s urface a nti ge n 
( H Bs A g) 
He patitis B vir us ( H B V)  c ore 
a nti b o d y 
He patitis C vir us  ( H C 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 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) 
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 E n d of Treat me nt ( E O T) or Earl y Ter mi nati o n ( E T)  o nl y.  

Pr ot oc ol  
C o va nce St u d y: 8 4 2 6 6 6 5  
C O N FI D E N TI A L  
Pr ot oc ol Refere nce:  L O X O -B T K -2 0 0 1 7  
Pr ot oc ol Versi o n 1. 0, 0 4 A u g ust 2 0 2 0  
Pa ge 5 5  of 5 8  
 
 
A p pe n di x 3: T ot al Bl o o d V ol u me  
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 bject:  
 
 
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  
L O X O -3 0 5 p har mac o ki netic sa m pli n g  
4. 0  
2 0  
8 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 
C oa g ulati o n para meters  
 
4. 0  
4. 0  
3. 0  
 
4  
 
4 4. 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 ( F S H; 
p ost -me n o pa usal fe male s u bjects o nl y) 
a n d t h yr oi d -sti m ulati n g h or m o ne ( T S H) 
 
4. 0  
 
1  
 
4. 0  
T ot al:  
1 5 2. 0 m L  
 
If e xtra bl o o d sa m ples are re q uire 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 2 0 0 m L.  

Pr ot oc ol  
C o va nce St u d y: 8 4 2 6 6 6 5  
C O N FI D E N TI A L  
Pr ot oc ol Refere nce:  L O X O -B T K -2 0 0 1 7  
Pr ot oc ol Versi o n 1. 0, 0 4 A u g ust 2 0 2 0  
Pa ge 5 6  of 5 8  
 
 
A p pe n di x 4: Sc he d ule of Assess me nts  

Pr ot oc ol  
C o va nce St u d y: 8 4 2 6 6 6 5  
C O N FI D E N TI A L  
Pr ot oc ol Refere nce:  L O X O -B T K -2 0 0 1 7  
Pr ot oc ol Versi o n 1. 0, 0 4 A u g ust 2 0 2 0  
Pa ge 5 7  of 5 8  
 
 
 
 
 
 
 
St u d y Pr oce d ures a  
 
 
Scree ni n g 
( D a ys -2 9  
t o -2)  
 
 
 
C hec k -i n 
( D a y -1)  
St u d y C o n d uct  
Cli nic Disc h ar ge/ 
E O T/ E T t 
F oll o w -u p P h o ne 
C all ( E O S)  
1  
2  
3  
4  
5  
6  
7  
8  
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  
 
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 c 
X c 
 
 
 
 
 
 
 
 
 
P h ysical E xa mi nati o n d  
 
X  
 
 
 
 
 
 
 
X  
 
1 2 -lea d E C Ge 
X  
X  
X  
X  
 
X  
 
 
 
X  
 
Vital Si g ns f 
X g, h  
X g, h  
X h  
X  
X  
X  
X  
X  
X  
X g, h  
 
H D Y F? I n q uir y i 
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  
L O X O -3 0 5 A d mi nistrati o n  
 
 
X k  
 
 
 
 
 
 
 
 
Cli nical La b orat or y E val uati o ns n  
X  
X  
 
 
 
X  
 
 
X u  
X u  
 
Esti mate d Gl o mer ular Filtrati o n Rate  
X  
X  
 
 
 
 
 
 
 
 
 
He patitis a n d HI V Scree n  
X  
 
 
 
 
 
 
 
 
 
 
C O VI D -1 9 Testi n g o  
X  
X  
 
 
 
 
 
 
 
 
 
H b A 1c Test  
X  
 
 
 
 
 
 
 
 
 
 
Dr u g Scree n p  
X  
X  
 
 
 
 
 
 
 
 
 
Pri or a n d C o nc o mita nt Me dicati o ns q  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
Ser u m Pre g na nc y Test r 
X  
X  
 
 
 
 
 
 
X u  
X u  
 
F S H Test s 
X  
 
 
 
 
 
 
 
 
 
 
T S H Test  
X  
 
 
 
 
 
 
 
 
 
 
A b bre viati o ns: A E = a d verse e ve nt; B MI = b o d y mass i n de x; B P = bl o o d press ure; C O VI D -1 9 = S A Rs C or o na vir us 1 9; C R U = Cli nical Researc h U nit; E C G = electr ocar di o gra m; 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 Feel?; HI V = h u ma n i m m u n o deficie nc 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 ne; U A = uri nal ysis. 
a. F or details o n st u d y pr oce 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 o d y mass i n de x base d o n Scree ni n g  hei g ht.  
d.  A  c o m plete  p h ysical  e xa mi nati o n will  be  perf or me d  at C hec k -i n ( Da y -1).  A n  a b bre viate d  p h ysical  e xa mi nati o n  will  be  perf or me d  o n  Da y  8  ( E n d of  Treat me nt  [ E O T]) or  Earl y  Ter mi nati o n 
( E T). 
e. 1 2 -lea d electr ocar di o gra ms ( 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 bl o o d dra ws at Scree ni n g an d C hec k -i n ( Da y -1), a n d at t he f oll o wi n g ti mes relate d t o 
a d mi nistrati o n of eac h Treat me nt: Da y 1 ( pre d ose a n d 2 a n d 4 h o urs after L O X O -3 0 5 d osi n g), Da y 2, Da y 4, a n d Da y 8 ( E O T) or E T. 1 2 -lea d E C Gs will be c ollecte d after t he s u bject has 
reste d i n t he s u pi ne p ositi o n f or at least 1 0 mi n utes.  
C CI

Pr ot oc ol  
C o va nce St u d y: 8 4 2 6 6 6 5  
C O N FI D E N TI A L  
Pr ot oc ol Refere nce:  L O X O -B T K -2 0 0 1 7  
Pr ot oc ol Versi o n 1. 0, 0 4 A u g ust 2 0 2 0  
Pa ge 5 8  of 5 8  
 
 
 
f. Vital si g n meas ure me nts (s u pi ne bl o o d press ure [ B P] a n d p ulse rate) will be o btai ne d at Scree ni n g a n d C hec k -i n ( Da y -1), at t he f oll o wi n g ti mes relate d t o a d mi nistrati o n of eac h Treat me nt: 
pre d ose ( wit hi n 4 5 mi n utes pri or t o d osi n g), 4 5 mi n utes p ost d ose, a n d 2, 4, 2 4, 4 8, 7 2, 9 6, 1 2 0, 1 4 4, a n d 1 6 8 h o urs p ost d ose ( Da y 8 [ E O T]) or E T. Vital si g n meas ure me nts s h o ul d be carrie d 
o ut  pri or  t o a n d as cl ose as p ossi ble  t o t he sc he d ule d bl o o d  dra w.  B P  a n d p ulse  rate will be meas ure d usi n g  t he sa me ar m f or eac h rea di n g after t he s u bject has  bee n  s u pi ne f or at least 
5  mi n utes.  
g.  Oral te m perat ure a n d res pirat or y rate will be o btai ne d at Scree ni n g a n d C hec k -i n ( Da y -1) a n d o n Da y 8 ( E O T) or  E T.  
h.  O x y ge n sat urati o n will be meas ure d via p ulse o xi metr y o nce at Scree ni n g, C hec k -i n ( Da y -1), pre d ose o n Da y 1, a n d Da y 8 ( E O T) or  E T.  
i. A H o w D o Y o u Feel? i n q uir y will be perf or me d at Scree 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 
da ys.  
j. A d verse e ve nts ( A Es) a n d seri o us A Es ( 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 verse e ve nts will be rec or de 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 nf or me d 
C o nse nt F or m [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 assesse d as n ot 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 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 he I n vesti gat or [ or desi g nee]) 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 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 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 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. 
k.  S u bjects will be assi g ne d t o 1 c o h ort o nl y, C o h ort 1 ( Treat me nt A/ 3 0 0 m g L O X O -3 0 5), C o h ort 2 ( Treat me nt B/ 6 0 0 m g L O X O -3 0 5), or C o h ort 3 ( Treat me nt C/ 9 0 0 m g  L O X O -3 0 5)  
n.  Cli nical c he mistr y pa nel (faste d f or at least 8 h o urs), c oa g ulati o n para meters, he mat ol o g y pa nel, a n d uri nal ysis ( U A) will be  perf or me d.  
o.  Testi n g f or C O VI D -1 9 will be c o n d ucte d at a mi ni m u m at Scree ni n g a n d C hec 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 he discreti o n of t he I n vesti gat or ( or desi g nee). Tests will be perf or me d b y ra pi d p ol y merase c hai n reacti o n or  e q ui vale nt.  
p.  Dr u gs of a b use uri ne test, i ncl u di n g c oti ni ne a n d alc o h ol. Res ults fr o m t he dr u gs of a b use tests will be use d t o deter mi ne s u bject eli gi bilit y per t he i ncl usi o n/e xcl usi o n  criteria. 
q.  Pri or a n d c o nc o mita nt me dicati o n a d mi nistrati o n will be rec or de 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 vesti gat or -a p pr o ve d me dicati o ns ta ke n b y a s u bject wit hi n 1 4 da ys pri or t o 
st u d y dr u g a d mi nistrati o n ( Da y 1) f or prescri pti o n me dicati o ns a n d n o n -prescri pti o n me dicati o n, will be rec or de d o n t he s u bject’s electr o nic Case Re p ort  F or m.  
r. Fe male s u bjects  o nl y.  
s. P ost -me n o pa usal fe male s u bjects  o nl y.  
t. E O T is defi ne d as w he n t he s u bject is release d fr o m t he C R U f oll o wi n g c o m pleti o n of all assess me nts t hr o u g h Da y 8. E T is defi ne d as w he n t he s u bject is release d fr o m t he C R U if t he 
s u bject ter mi nates t he 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 he C R U at t he E O T visit. Cli nical la b orat or y e val uati o ns f or cli nical c he mistr y, he mat ol o g y, c oa g ulati o n, a n d UA a n d pre g na nc y test res ults (fe male s u bjects o nl y) 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 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 vaila ble. 
u.  Cli nical la b orat or y e val uati o ns a n d pre g na nc y test (fe male s u bjects o nl y) will be perf or me d o n t he da y pri or t o s u bject relea se fr o m t he C R U ( Da y 7) if t he s u bject c o m pletes t he st u d y 
( E O T). Cli nical  la b orat or y e val uati o ns  a n d pre g na nc y  test (fe male s u bjects o nl y)  will  be  perf or me d  o n  t he da y  of  s u bject release fr o m t he C R U if t he s u bject ter mi nates earl y ( E T). 
v.  T o be c o n d ucte d 7 da ys ( ± 2 da ys) f oll o wi n g E O T or E T. E O S is defi ne d as w he n t he s u bject atte n ds t he C R U f or 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 
deter mi ne if a n y S A E or st u d y dr u g -relate d A E has occ urre d si nce t he E O T or E T visit. All s u bjects w h o recei ve d L O X O-3 0 5 (i ncl u di n g s u bjects w h o are ter mi nate d earl y) will recei ve a 
f oll o w-u p p h o ne  call. 
C CI