Clinical trial NCT03976401
Conditions: NASH - Nonalcoholic Steatohepatitis
Sponsor: Akero Therapeutics, Inc
Start date: 2019-05-28; Completion date: 2022-01-10
Enrollment: 110 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This is a multi-center evaluation of efruxifermin (EFX) in a randomized, double-blind, placebo-controlled study administered for 16 weeks in subjects with biopsy proven F1 - F4 NASH.

Detailed description:

Arms: arm 1: Main Study arm 2: Main Study arm 3: Main Study arm 4: Main Study arm 5: None arm 6: None
Interventions: intervention 1: EFX intervention 2: Placebo
Intervention descriptions: intervention 1: Administered by subcutaneous injection intervention 2: Administered by subcutaneous injection

Protocol documents:
SAP_002.pdf: 
 
 
 
 
 
 
ST ATISTI C AL A N ALYSIS
ST ATISTI C AL A N ALYSIS PL A N
PL A N  
Pr ot o c ol Titl e:  
A P H A S E 2 A, R A N D O MI Z E D, D O U B L E -B LI N D, 
P L A C E B O -C O N T R O L L E D  S T U D Y E V A L U A TI N G T H E 
S A F E T Y A N D E F FI C A C Y O F E F R U XI F E R MI N  I N 
S U B J E C T S  WI T H N O N A L C O H O LI C 
S T E A T O H E P A TI TI S ( N A S H)  
 
Pr ot o c ol N u m b er:  
A K -U S -0 0 1 -0 1 0 1  
Pr ot o c ol V er si o n/ D at e:  
V er si o n 1 . 0 / 2 6  M ar c h 2 0 1 9  
V er si o n 2. 0  / 1 0  A pril 2 0 1 9  
A m e n d m e nt 1  / 0 5 J u n e 2 0 1 9  
A m e n d m e nt 2  / 1 3 S e pt e m b er 2 0 1 9  
A m e n d m e nt 3 / 0 2 O ct o b er 2 0 1 9  
A m e n d m e nt 4  / 0 8 J a n u ar y 2 0 2 0  
A m e n d m e nt 5  / 2 9 M a y 2 0 2 0  
A m e n d m e nt 6  / 0 8 O ct o b er 2 0 2 0  
 
I n v e sti g ati o n al Pr o d u ct: Efr u xif er mi n  ( E F X) 
 
 
S p o n s or:  
A k er o T h er a p e uti c s, I n c  
 
 
 
 
S A P V er si o n / D at e: 
C o h ort C V er si o n 2. 0  / 0 5 M ar c h 2 0 2 1  
 
C O N FI D E N TI A L  
I nf or m ati o n c o nt ai n e d i n t hi s S A P  i s pr o pri et ar y a n d c o nfi d e nti al i n n at ur e a n d m a y n ot b e u s e d, 
di v ul g e d, p u bli s h e d, or ot h er wi s e di s cl o s e d t o ot h er s e x c e pt t o t h e e xt e nt n e c e s s ar y t o o bt ai n 
a p pr o v al of t h e I n stit uti o n al R e vi e w B o ar d or a s r e q uir e d b y l a w.  P er s o n s t o w h o m t hi s 
i nf or m atio n i s di s cl o s e d s h o ul d b e i nf or m e d t h at t hi s i nf or m ati o n i s c o nfi d e nti al a n d m a y n ot b e 
f urt h er di s cl o s e d wit h o ut t h e e x pr e s s p er mi s si o n of A k er o T h er a p e uti c s, I n c. 
 
 




A k er o T h er a p e uti c s, I n c  
C O N FI D E N TI A L  
St ati sti c al A n al y si s Pl a n  
A K -U S -0 0 1 -0 1 0 1  
 
C o h ort C V er si o n 2. 0 , 0 5 M ar c h 2 0 2 1  
P a g e 3  of 2 8  
 
V E R SI O N HI S T O R Y
V E R SI O N HI S T O R Y  
V er si o n  
V er si o n D at e  
D e s cri pti o n  
1. 0  
0 4 J a n u ar y 2 0 2 1  
Ori gi n al si g n e d v er si o n  
1. 1  
2 6  J a n u ar y 2 0 2 1  
A dj u st l a n g u a g e f or Li v er Bi o p s y 
E v al u a bl e A n al y si s S et  
1. 2  
1 0  F e br u ar y  2 0 2 1  
U p d at e d p er S p o n or r e q u e st:  
I n di c at e t w o s et s of bi o p s y d at a  (l o c al 
r e a d v. s. c e ntr al r e a d); 
A d d e d a n  a n al y si s f or E L F W e e k 1 2 d at a 
if a v ail a bl e, a n d a dj u st a n al y si s  vi sit 
wi n d o w n f or W e e k 1 2 E L F;  
F 4 S af et y S et a d d e d f or s el e ct e d s af et y 
a n al y si s  
2. 0  
0 5 M ar c h 2 0 2 1  
S e c o n d si g n e d v er si o n  
 
 


A k er o T h er a p e uti c s, I n c  
C O N FI D E N TI A L  
St ati sti c al A n al y si s Pl a n  
A K -U S -0 0 1 -0 1 0 1  
 
C o h ort C V er si o n 2. 0 , 0 5 M ar c h 2 0 2 1  
P a g e 4  of 2 8  
 
T A BL E O F C O N T E N T S
T A BL E O F C O N T E N T S  
1  
I ntr o d u cti o n ......................................................................................................................... 8  
2  
St u d y O v er vi e w  ................................................................................................................... 8  
2. 1  
St u d y O bj e cti v e s  .......................................................................................................... 8  
2. 1. 1  
Pri m ar y O bj e cti v e  ................................................................................................. 8  
2. 1. 2  
S e c o n d ar y O bj e cti v e s  ........................................................................................... 8  
2. 1. 3  
E x pl or at or y O bj e cti v e s  .......................................................................................... 8  
2. 2  
St u d y D e si g n  ............................................................................................................... 9  
2. 2. 1  
O v er vi e w  ............................................................................................................... 9  
2. 2. 2  
S a m pl e Si z e D et er mi n ati o n  ................................................................................... 9  
2. 3  
St u d y E n d p oi nt s  ..........................................................................................................1 0  
2. 3. 1  
S e c o n d ar y Effi c a c y E n d p oi nt s  .............................................................................1 0  
2. 3. 2  
E x pl or at or y Effi c a c y E n d p oi nt s  ............................................................................1 0  
2. 3. 3  
S af et y E n d p oi nt s  ..................................................................................................1 1  
3  
St ati sti c al M et h o d ol o g y  ......................................................................................................1 1  
3. 1  
G e n er al C o n si d er ati o n s  ..............................................................................................1 1  
3. 1. 1  
A n al y si s D a y  ........................................................................................................1 1  
3. 1. 2  
A n al y si s Vi sit s  ......................................................................................................1 1  
3. 1. 3  
D efi niti o n of B a s eli n e  ...........................................................................................1 2  
3. 1. 4  
S u m m ar y St ati sti c s  ..............................................................................................1 3  
3. 1. 5  
H y p ot h e si s T e sti n g  ..............................................................................................1 3  
3. 1. 6  
H a n dli n g of Dr o p o ut s a n d Mi s si n g D at a  ...............................................................1 3  
3. 2  
A n al y si s P o p ul ati o n s  ...................................................................................................1 3  
3. 2. 1  
F ull A n al y si s S et ( F A S)  ........................................................................................1 3  
3. 2. 2  
S af et y S et  ............................................................................................................1 4  
3. 2. 3  
F 4 S af et y S et  .......................................................................................................1 4  
3. 2. 4  
P K A n al y si s S et  ...................................................................................................1 4  
3. 2. 5  
Bi o m ar k er A n al y si s S et  ........................................................................................1 4  
3. 2. 6  
P er Pr ot o c ol A n al y si s S et ( P P A S)  ........................................................................1 4  
3. 2. 7  
Li v e r Stiff n e s s E v al u a bl e A n al y si s S et .................................................................1 4  
3. 2. 8  
Li v er Bi o p s y E v al u a bl e A n al y si s S et  ....................................................................1 4  
3. 2. 9  
Str atifi c ati o n  .........................................................................................................1 4  
3. 3  
S u bj e ct D at a a n d St u d y C o n d u ct  ................................................................................1 5  
3. 3. 1  
S u bj e ct Di s p o siti o n  ..............................................................................................1 5  
3. 3. 2  
Pr ot o c ol D e vi ati o n s  ..............................................................................................1 5  
3. 3. 3  
A n al y si s P o p ul ati o n s  ............................................................................................1 5  
3. 3. 4  
D e m o gr a p hi c a n d B a s eli n e C h ar a ct eri sti c s  ..........................................................1 5  
3. 3. 5  
M e di c al Hi st or y  ....................................................................................................1 6  
3. 3. 6  
C o n c o mit a nt M e di c ati o n s  .....................................................................................1 6  
3. 3. 7  
St u d y Dr u g E x p o s ur e a n d C o m pli a n c e  ................................................................1 7  


A k er o T h er a p e uti c s, I n c  
C O N FI D E N TI A L  
St ati sti c al A n al y si s Pl a n  
A K -U S -0 0 1 -0 1 0 1  
 
C o h ort C V er si o n 2. 0 , 0 5 M ar c h 2 0 2 1  
P a g e 5  of 2 8  
 
3. 4  
Effi c a c y A s s e s s m e nt  ...................................................................................................1 7  
3. 4. 1  
S e c o n d ar y Effi c a c y E n d p oi nt s  .............................................................................1 7  
3. 4. 2  
E x pl or at or y Effi c a c y E n d p oi nt s  ............................................................................1 8  
3. 4. 3  
S u b gr o u p s  ...........................................................................................................2 2  
3. 5  
S af et y A s s e s s m e nt  .....................................................................................................2 2  
3. 5. 1  
A d v er s e E v e nt s  ....................................................................................................2 2  
3. 5. 2  
Cli ni c al L a b or at or y T e st s  .....................................................................................2 3  
3. 5. 3  
Vit al Si g n s  ............................................................................................................2 5  
3. 5. 4  
1 2 -L e a d El e ctr o c ar di o gr a m s  ................................................................................2 5  
3. 5. 5  
Ot h er S af et y A s s e s s m e nt s  ...................................................................................2 5  
3. 6  
P h ar m a c o ki n eti c ( P K) A s s e s s m e nt  .............................................................................2 5  
3. 7  
P h ar m a c o d y n a mi c ( P D) A s s e s s m e nt  ..........................................................................2 5  
3. 8  
B o n e Bi o m ar k er A s s e s s m e nt  ......................................................................................2 6  
4  
D at a M o nit ori n g C o m mitt e e ( D M C)  ....................................................................................2 6  
5  
I nt eri m A n al y si s .................................................................................................................2 6  
6  
C h a n g e s fr o m Pr ot o c ol -S p e cifi e d St ati sti c al A n al y s e s  .......................................................2 6  
7  
Pr o gr a m mi n g S p e cifi c ati o n s  ..............................................................................................2 7  
A p p e n di x A:  R ef er e n c e s  ..........................................................................................................2 8  
 
 
 


A k er o T h er a p e uti c s, I n c  
C O N FI D E N TI A L  
St ati sti c al A n al y si s Pl a n  
A K -U S -0 0 1 -0 1 0 1  
 
C o h ort C V er si o n 2. 0 , 0 5 M ar c h 2 0 2 1  
P a g e 6  of 2 8  
 
LI S T O F A B B R E VI A TI O N
LI S T O F A B B R E VI A TI O NS 
A b br e vi ati o n  
D efi niti o n  
A D A  
A nti -dr u g A nti b o di e s  
A E  
A d v er s e E v e nt  
A E SI  
A d v er s e E v e nt of S p e ci al I nt er e st  
A L P  
Al k ali n e P h o s p h at a s e  
A L T  
Al a ni n e A mi n otr a n sf er a s e  
A N C O V A  
A n al y si s of C o v ari a n c e  
A S T  
A s p art at e A mi n otr a n sf er a s e  
A T C  
A n at o mi c al T h er a p e uti c C h e mi c al  
B L Q  
B el o w Li mit of Q u a ntifi c ati o n  
B MI  
B o d y M a s s I n d e x  
B S A P  
B o n e S p e cifi c Al k ali n e P h o s p h at a s e  
C 3 M  
N e o -e pit o p e of M M P -9 M e di at e d D e gr a d ati o n of T y p e III 
C oll a g e n  
C L D Q -N A F L D  
C hr o ni c Li v er Di s e a s e Q u e sti o n n air e -N o n al c o h oli c F att y 
Li v er Di s e a s e  
C P  
C hil d P u g h  
C R N  
Cli ni c al R e s e ar c h N et w or k  
C R F  
C a s e R e p ort F or m  
C S R  
Cli ni c al St u d y R e p ort  
c T 1  
C orr e ct e d T 1  
C T C A E  
C o m m o n T er mi n ol o g y Crit eri a f or A d v er s e E v e nt s  
DI LI  
Dr u g -I n d u c e d Li v er I nj ur y 
D M C  
D at a M o nit ori n g C o m mitt e e  
D X A  
D u al E n er g y X -r a y A b s or pti o m etr y 
e DI S H  
E v al u ati o n of Dr u g -I n d u c e d S eri o u s H e p at ot o xi cit y 
E C G  
El e ctr o c ar di o gr a m  
E F X  
Efr u xif er mi n  
E L F ™ 
E n h a n c e d Li v er Fi br o si s P a n el  
E O T  
E n d of Tr e at m e nt  
F A S  
F ull A n al y si s S et  
G G T  
G a m m a Gl ut a m yl Tr a n sf er a s e  
H R Q o L  
H e alt h -R el at e d Q u alit y of Lif e  
I N R 
I nt er n ati o n al N or m ali z e d R ati o 
L L O Q  
L o w Li mit of Q u a ntifi c ati o n  
M e d D R A  
M e di c al Di cti o n ar y f or R e g ul at or y A cti viti e s  
M E L D  
M o d el f or E n d -St a g e Li v er Di s e a s e  
M M R M  
Mi x e d -M o d el R e p e at e d -M e a s ur e s  
N A b  
N e utr ali zi n g A nti b o d y  
N A F L D  
N o n al c o h oli c F att y Li v er Di s e a s e  
N A S  
N A F L D A cti vit y S c or e  
N A S H  
N o n al c o h oli c St e at o h e p atiti s  
P K  
P h ar m a c o ki n eti c s  
P P A S  
P er Pr ot o c ol A n al y si s S et  
S A E  
S eri o u s A d v er s e E v e nt  
S A P  
St ati sti c al A n al y si s Pl a n  
S F -3 6  
S h ort F or m 3 6 H e alt h S ur v e y  


A k er o T h er a p e uti c s, I n c  
C O N FI D E N TI A L  
St ati sti c al A n al y si s Pl a n  
A K -U S -0 0 1 -0 1 0 1  
 
C o h ort C V er si o n 2. 0 , 0 5 M ar c h 2 0 2 1  
P a g e 7  of 2 8  
 
A b br e vi ati o n  
D efi niti o n  
S O C  
S y st e m Or g a n Cl a s s  
T B  
T ot al Bilir u bi n  
T E A E  
Tr e at m e nt -E m er g e nt A d v er s e E v e nt  
T E S A E  
Tr e at m e nt -E m er g e nt S eri o u s A d v er s e E v e nt  
T F L s  
T a bl e s, Fi g ur e s, a n d Li sti n g s  
W H O  
W orl d H e alt h Or g a ni z ati o n  
W P AI  
W or k Pr o d u cti vit y a n d A cti vit y I m p air m e nt  
 
 


A k er o T h er a p e uti c s, I n c  
C O N FI D E N TI A L  
St ati sti c al A n al y si s Pl a n  
A K -U S -0 0 1 -0 1 0 1  
 
C o h ort C V er si o n 2. 0 , 0 5 M ar c h 2 0 2 1  
P a g e 8  of 2 8  
 
1  I N T R O D U C TI O N
I N T R O D U C TI O N 
T h e p ur p o s e of t hi s St ati sti c al A n al y si s Pl a n ( S A P) i s t o pr o vi d e a d e s cri pti o n of t h e st ati sti c al 
m et h o d s t o b e i m pl e m e nt e d f or t h e a n al y si s of t h e C o h ort  C  d at a fr o m A k er o  T h er a p e uti c s,  I n c. 
Pr ot o c ol  A K -U S -0 0 1 -0 1 0 1 .  A s e p ar at e S A P  h a s b e e n  pr o vi d e d f or t h e a n al y si s of M ai n St u d y  
d at a fr o m A k er o T h er a p e uti c s, I n c. Pr ot o c ol  A K -U S -0 0 1 -0 1 0 1 .  T h e S A P will b e fi n ali z e d pri or t o 
u n bli n di n g of t h e C o h ort C  d at a b a s e .  A n y d e vi ati o n s fr o m t h e S A P aft er d at a b a s e u n bli n di n g  
will b e d o c u m e nt e d i n t h e fi n al Cli ni c al St u d y R e p ort ( C S R).  
2  S T U D Y 
S T U D Y O V E R VI E W
O V E R VI E W  
2. 1
2. 1  St u dy 
St u dy O bj ectiv es
O bj ectiv es  
2. 1. 1  Pri m ary O bj ectiv e  
T h e pri m ar y o bj e cti v e of t hi s st u d y i s:  
•  
T o a s s e s s t h e s af et y a n d t ol er a bilit y of E F X  i n N A S H s u bj e ct s wit h c o m p e n s at e d 
cirr h o si s  
2. 1. 2  S ec o n d ary O bj ectiv es  
T h e s e c o n d ar y o bj e cti v e s of t hi s st u d y ar e:  
•  
T o e v al u at e t h e c h a n g e fr o m b a s eli n e i n li v er stiff n e s s a s e v al u at e d b y Fi br o S c a n ® at  
W e e k 1 6  
•  
T o e v al u at e t h e c h a n g e fr o m b a s eli n e i n n o n -i n v a si v e pl a s m a ( s er u m) fi br o si s 
bi o m ar k er s  i n cl u di n g li v er fi br o si s b y E L F ™ T e st s c or e a n d pr o-C 3 l e v el s  
2. 1. 3  Ex pl or at ory O bj ectiv es  
T h e e x pl or at or y o bj e cti v e s of t hi s st u d y ar e:  
•  
C h a n g e fr o m b a s eli n e i n m ar k er s of li v er i nj ur y a n d f u n cti o n i n cl u di n g al a ni n e 
a mi n otr a n sf er a s e (A L T ), a s p art at e a mi n otr a n sf er a s e ( A S T), al k ali n e p h o s p h at a s e ( A L P),  
g a m m a gl ut a m yl tr a n sf er a s e ( G G T), bilir u bi n, I nt er n ati o n al N or m ali z e d R ati o (I N R),  
al b u mi n, M o d el f or E n d -St a g e Li v er Di s e a s e ( M E L D) s c or e, a n d C hil d P u g h ( C P) s c or e 
•  
C h a n g e fr o m b a s eli n e i n b o d y w ei g ht a n d w ai st -t o-hi p r ati o  
•  
C h a n g e fr o m b a s eli n e i n b o n e mi n er al d e n sit y of t h e l u m b ar s pi n e, f e m or al n e c k, a n d 
t ot al hi p a s m e a s ur e d b y D u al E n er g y X -r a y A b s or pti o m etr y (D X A )  
•  
T h e pr o p orti o n of s u bj e ct s –  w h o s e fi br o si s r e gr e s s e s b y ≥ 1 -st a g e a c c or di n g t o t h e 
N A S H C R N cl a s sifi c ati o n  
•  
T h e pr o p orti o n of s u bj e ct s w h o h a d n o w or s e ni n g i n N A S wit h i m pr o v e m e nt i n fi br o si s 
st a g e  
•  
T h e pr o p orti o n of s u bj e ct s w h o h a d at l e a st 2 p oi nt s i m pr o v e m e nt i n N A S wit h n o 
w or s e ni n g i n fi br o si s st a g e  
•  
T h e pr o p orti o n of s u bj e ct s w h o h a d ≥ 1 p oi nt i m pr o v e m e nt i n N A S, fi br o si s, st e at o si s , 
l o b ul ar i nfl a m m ati o n or h e p at o c ell ul ar b all o o ni n g 


A k er o T h er a p e uti c s, I n c  
C O N FI D E N TI A L  
St ati sti c al A n al y si s Pl a n  
A K -U S -0 0 1 -0 1 0 1  
 
C o h ort C V er si o n 2. 0 , 0 5 M ar c h 2 0 2 1  
P a g e 9  of 2 8  
 
•  
C h a n g e s fr o m b a s eli n e i n h e alt h -r el at e d q u alit y of lif e ( H R Q o L) 
•  
C h a n g e s fr o m b a s eli n e i n li p o pr ot ei n pr ofil e a n d m ar k er s of li pi d m et a b oli s m, i n s uli n 
s e n siti vit y a n d gl y c e mi c c o ntr ol  
•  
C h a n g e fr o m b a s eli n e i n b o d y f at di stri b uti o n a s m e a s ur e d b y D X A t ot al b o d y 
c o m p o siti o n  
•  
Pl a s m a c o n c e ntr ati o n s of E F X  
•  
T o e v al u at e d e c o m p e n s at e d li v er d i s e a s e e v e nt s i n cl u di n g a s cit e s, h e p ati c 
e n c e p h al o p at h y  ( H E), or v ari c e al bl e e di n g 
2. 2
2. 2  St u dy 
St u dy D esi g n
D esi g n  
2. 2. 1  Ov ervi e w  
T hi s i s a P h a s e 2 a, r a n d o mi z e d, d o u bl e -bli n d, pl a c e b o -c o ntr oll e d st u d y e v al u ati n g t h e s af et y 
a n d effi c a c y of  E F X  i n s u bj e ct s wit h N A S H. 
C o h ort C will e nr oll a p pr o xi m at el y 3 0 s u bj e ct s wit h bi o p s y -pr o v e n N A S H.   All s u bj e ct s i n  
C o h ort  C  will h a v e F 4 fi br o si s.   S u bj e ct s m e eti n g t h e st u d y’ s e ntr y crit eri a will b e r a n d o ml y 
a s si g n e d i n a 1: 2  r ati o i nt o 2 tr e at m e nt gr o u p s as s h o w n i n t h e fi g ur e b el o w: 
 
T h er e will b e n o str atifi c ati o n f or C o h ort C .  St u d y dr u g will b e a d mi ni st er e d s u b c ut a n e o u sl y 
o n c e w e e kl y ( Q W) f or a t ot al  of 1 6 w e e k s.  Aft er 1 6 w e e k s of tr e at m e nt, a s af et y f oll o w -u p vi sit 
will o c c ur at W e e k 2 0.   F oll o wi n g 1 6 w e e k s of tr e at m e nt, s u bj e ct s will b e gi v e n t h e o pti o n t o 
c oll e ct a n e n d of tr e at m e nt bi o p s y.  
T hi s st u d y will b e c o n d u ct e d at a p pr o xi m at el y 3 0  sit e s i n t h e U. S .  A d diti o n al sit e s m a y b e 
a d d e d, d e p e n di n g o n s u bj e ct a c cr u al r at e s.  
2. 2. 2  S a m pl e Siz e D et er mi n ati o n  
Si n c e t h e pri m ar y o bj e cti v e i s t o a s s e s s t h e s af et y a n d t ol er a bilit y of E F X  i n N A S H s u bj e ct s wit h 
c o m p e n s at e d cirr h o si s, t h e s a m pl e si z e i s d et er mi n e d b a s e d o n cli ni c al  c o n si d er ati o n s, a n d t h e 
tr e at m e nt c o m p ari s o n s of effi c a c y m e a s ur e m e nt s ar e not p o w er e d.  


A k er o T h er a p e uti c s, I n c  
C O N FI D E N TI A L  
St ati sti c al A n al y si s Pl a n  
A K -U S -0 0 1 -0 1 0 1  
 
C o h ort C V er si o n 2. 0 , 0 5 M ar c h 2 0 2 1  
P a g e 1 0  of 2 8  
 
2. 3
2. 3  St u dy E n d p oi nts
St u dy E n d p oi nts  
2. 3. 1  S ec o n d ary Effic acy E n d p oi nts  
T h e s e c o n d ar y e n d p oi nt s ar e:  
•  
C h a n g e fr o m b a s eli n e i n li v er stiff n e s s a s e v al u at e d b y Fi br o S c a n ® at W e e k 1 6  
•  
C h a n g e s fr o m b a s eli n e i n n o n -i n v a si v e bi o m ar k er s i n cl u di n g Pr o-C 3 at 
W e e k s
 1 2,  1 6  a n d 2 0 , a n d li v er fi br o si s b y E L F ™ T e st s c or e at W e e k s 6, 1 2 a n d 1 6  
2. 3. 2  Ex pl or at ory Effic acy E n d p oi nts  
T h e e x pl or at or y e n d p oi nt s  ar e:  
•  
C h a n g e fr o m b a s eli n e i n m ar k er s of li v er i njur y  a n d f u n cti o n i n cl u di n g A L T, A S T,  A L P, 
G G T, bilir u bi n, I N R, al b u mi n, M E L D s c or e, a n d C P s c or e  at W e e k s 1 2, 1 6 a n d 2 0  
•  
C h a n g e fr o m b a s eli n e i n b o d y w ei g ht a n d w ai st -t o-hi p r ati o  at W e e k s 1 2, 1 6 a n d 2 0  
•  
C h a n g e fr o m b a s eli n e i n b o n e mi n er al d e n sit y of t h e l u m b ar s pi n e, f e m or al n e c k, a n d 
t ot al hi p a s m e a s ur e d b y D X A at W e e k 1 6  
•  
T h e pr o p orti o n of s u bj e ct s at W e e k 1 6 w h o s e fi br o si s r e gr e s s e s b y ≥ 1 -st a g e a c c or di n g 
t o t h e N A S H C R N cl a s sifi c ati o n  
•  
T h e pr o p orti o n of s u bj e ct s at W e e k 1 6 w h o h a d n o w or s e ni n g i n N A S wit h i m pr o v e m e nt 
i n fi br o si s st a g e  
•  
T h e pr o p orti o n of s u bj e ct s at W e e k 1 6 w h o h a d at l e a st 2 p oi nt s i m pr o v e m e nt i n N A S  
•  
T h e pr o p orti o n of s u bj e ct s at W e e k 1 6 w h o h a d ≥ 1 p oi nt i m pr o v e m e nt i n N A S, fi br o si s, 
st e at o si s l o b ul ar i nfl a m m ati o n or h e p at o c ell ul ar b all o o ni n g  
•  
T h e pr o p orti o n of s u bj e ct s at W e e k 1 6 w h o h a d N A S H r e s ol uti o n ( 0 -1 P oi nt 
I nfl a m m ati o n, 0 P oi nt B all o o ni n g) 
•  
T h e  pr o p orti o n of s u bj e ct s at W e e k 1 6 w h o h a d fi br o si s i m pr o v e m e nt ≥ 2 -st a g e  
•  
C h a n g e s fr o m b a s eli n e i n H R Q o L  ( S F-3 6, C L D Q -N A F L D, W P AI) at W e e k s 1 2 a n d 1 6  
•  
C h a n g e s fr o m b a s eli n e i n li p o pr ot ei n pr ofil e a n d m ar k er s of li pi d m et a b oli s m, i n s uli n 
s e n siti vit y a n d gl y c e mi c c o ntr ol  at W e e k s 1 2, 1 6 a n d 2 0  
•  
C h a n g e fr o m b a s eli n e i n b o d y f at di stri b uti o n a s m e a s ur e d b y D X A t ot al b o d y 
c o m p o siti o n  at W e e k 1 6  
•  
Pl a s m a c o n c e ntr ati o n s of E F X  
•  
T h e i n ci d e n c e a n d s e v erit y of a n y d e c o m p e n s at e d li v er di s e a s e e v e nt s i n cl u di n g a s cit e s, 
h e p a ti c e n c e p h al o p at h y ( H E), or v ari c e al bl e e di n g 
•  
C h a n g e s fr o m b a s eli n e i n  N e o -e pit o p e of M M P -9 M e di at e d D e gr a d ati o n of T y p e III 
C oll a g e n (C 3 M )  
•  
C h a n g e s fr o m b a s eli n e i n  pl at el et s  at W e e k s 1 2, 1 6 a n d 2 0  
•  
C h a n g e fr o m b a s eli n e i n li v er st e at o si s a s e v al u at e d b y Fi br o S c a n ® ( C A P) at W e e k 1 6  


A k er o T h er a p e uti c s, I n c  
C O N FI D E N TI A L  
St ati sti c al A n al y si s Pl a n  
A K -U S -0 0 1 -0 1 0 1  
 
C o h ort C V er si o n 2. 0 , 0 5 M ar c h 2 0 2 1  
P a g e 1 1  of 2 8  
 
2. 3. 3  S af ety E n d p oi nts  
T h e s af et y e n d p oi nt i s t h e s af et y a n d t ol er a bilit y of E F X  i n N A S H s u bj e ct s wit h c o m p e n s at e d 
cirr h o si s . 
S af et y a n al y s e s i n cl u d e: s u m m ari e s of e xt e nt of e x p o s ur e, a d v er s e e v e nt s ( A E s), l a b or at or y 
e v al u ati o n s, el e ctr o c ar di o gr a m ( E C G) , vit al si g n a s s e s s m e nt s, b o d y w ei g ht, a nti -dr u g a nti b o d y 
( A D A) a n d n e utr ali zi n g a nti b o d y (N A b ) a s s e s s m e nt s, a n d c o n c o mit a nt m e di c ati o n u s a g e. 
3  S T A TI S TI C AL M E T H O D OL
S T A TI S TI C AL M E T H O D OL O G Y
O G Y  
3. 1
3. 1  G e n er al 
G e n er al C o nsi d er ati o ns
C o nsi d er ati o ns  
3. 1. 1  A n alysis D ay  
A n al y si s d a y will b e c al c ul at e d fr o m t h e d at e of fir st d o s e of st u d y dr u g .  T h e d a y of t h e fir st 
d o s e of st u d y dr u g will b e D a y 1 , a n d t h e d a y i m m e di at el y b ef or e D a y 1  will b e D a y -1 .  T h er e 
will b e n o D a y 0 , i n ali g n m e nt wit h int er n ati o n al d at a st a n d ar d s f or cli ni c al tri al s .  A n al y si s d a y 
will b e c al c ul at e d a s ( d at e of cli ni c al e v e nt –  d at e of fir st d o s e of st u d y dr u g) + 1 if t h e d at e of 
t h e e v e nt i s o n or aft er t h e d at e of fir st d o s e a n d a s ( d at e of cli ni c al e v e nt –  d at e of fir st d o s e of 
st u d y dr u g) if t h e d at e of e v e nt i s b ef or e t h e d at e of fir st d o s e.  
3. 1. 2  A n alysis Visits  
S c h e d ul e d vi sit s will b e a s si g n e d t o a n al y si s vi sit s a s r e c or d e d o n t h e C a s e R e p ort F or m  (C R F ).  
U n s c h e d ul e d a n d e arl y t er mi n ati o n vi sit s f or E L F ™ will b e a s si g n e d t o a n al y si s vi sit s a c c or di n g 
t o t h e f oll o wi n g vi sit wi n d o w s: 
A n al y si s Vi sit  
T ar g et A n al y si s D a y  L o w A n al y si s D a y  
Hi g h A n al y si s D a y  
W e e k 6  
4 3  
2 2  
6 4  
W e e k 1 2  
8 5  
6 5  
9 9  
W e e k 1 6  
1 1 3  
1 0 0  
1 4 1  
N ot e: if t h e  u n s c h e d ul e d c oll e cti o n or  e arl y t er m c oll e cti o n i s > 2 1  d a y s aft er t h e l a st d o s e 
of st u d y dr u g, it will n ot b e u s e d i n a n al y s e s.  
F or A L T, m ar k er s of li v er i nj ur y a n d f u n cti o n , w ai st -t o-hi p r ati o , bi o m ar k er s , pr o-C 3  a n d H R Q o L , 
u n s c h e d ul e d a n d e arl y t er mi n ati o n vi sit s will b e a s si g n e d t o a n al y si s vi sit s a c c or di n g t o t h e 
f oll o wi n g vi sit wi n d o w s: 
A n al y si s Vi sit  
T ar g et A n al y si s D a y  L o w A n al y si s D a y  
Hi g h A n al y si s D a y  
W e e k 1  
8  
2  
1 5  
W e e k 4  
2 9  
1 6  
4 3  
W e e k 8  
5 7  
4 4  
7 1  
W e e k 1 2  
8 5  
7 2  
9 9  
W e e k 1 6  
1 1 3  
1 0 0  
1 2 7  
W e e k 2 0 S af et y 
f oll o w-u p  
1 4 1  
1 2 8  
E O S  
N ot e : if t h e u n s c h e d ul e d c oll e cti o n or  e arl y t er m c oll e cti o n i s > 1 4 d a y s aft er t h e l a st d o s e 
of st u d y dr u g, it will n ot b e u s e d i n a n al y s e s.  
F or b o d y w ei g ht , u n s c h e d ul e d a n d e arl y t er mi n ati o n vi sit s will b e a s si g n e d t o a n al y si s vi sit s 
a c c or di n g t o t h e f oll o wi n g vi sit wi n d o w s:  


A k er o T h er a p e uti c s, I n c  
C O N FI D E N TI A L  
St ati sti c al A n al y si s Pl a n  
A K -U S -0 0 1 -0 1 0 1  
 
C o h ort C V er si o n 2. 0 , 0 5 M ar c h 2 0 2 1  
P a g e 1 2  of 2 8  
 
A n al y si s Vi sit  
T ar g et A n al y si s D a y  L o w A n al y si s D a y  
Hi g h A n al y si s D a y  
W e e k 1  
8  
2  
1 1  
W e e k  2  
1 5  
1 2  
1 8  
W e e k  3  
2 2  
1 9  
2 5  
W e e k 4  
2 9  
2 6  
3 2  
W e e k  5  
3 6  
3 3  
3 9  
W e e k  6  
4 3  
4 0  
4 6  
W e e k  7  
5 0  
4 7  
5 3  
W e e k 8  
5 7  
5 4  
6 0  
W e e k  9  
6 4  
6 1  
6 7  
W e e k  1 0  
7 1  
6 8  
7 4  
W e e k  1 1  
7 8  
7 5  
8 1  
W e e k 1 2  
8 5  
8 2  
8 8  
W e e k  1 3  
9 2  
8 9  
9 5  
W e e k  1 4  
9 9  
9 6  
1 0 2  
W e e k  1 5  
1 0 6  
1 0 3  
1 0 9  
W e e k 1 6  
1 1 3  
1 1 0  
1 2 7  
W e e k 2 0 S af et y 
f oll o w-u p  
1 4 1  
1 2 8  
E O S  
N ot e: if t h e u n s c h e d ul e d c oll e cti o n or  e arl y t er m c oll e cti o n i s > 1 4 d a y s aft er t h e l a st d o s e 
of st u d y dr u g, it will n ot b e u s e d i n a n al y s e s.  
T h e effi c a c y a s s e s s m e nt s fr o m tw o  Fi br o S c a n ®  (S cr e e ni n g a n d W e e k 1 6 ) a n d t h e s af et y 
a s s e s s m e nt s fr o m t w o D X A S c a n s  ( S cr e e ni n g a n d W e e k 1 6 ) will b e c o n si d er e d f or t h e a n al y si s 
r e g ar dl e s s of w h e n t h e s e c o n d a s s e s s m e nt  or bi o p s y  t a k e s pl a ce .  U n s c h e d ul e d vi sit s  aft er t h e 
fir st d o s e of st u d y dr u g a n d e arl y t er mi n ati o n vi sit s will b e  a s si g n e d a s p o st -b a s eli n e.  
F or P K c o n c e ntr ati o n s u m m ari e s, a c o n c e ntr ati o n t h at i s i nt e n d e d a s pr e d o s e will b e e x cl u d e d 
fr o m a n al y si s if it i s > 2 4 h o ur s b ef or e a d o s e or aft er t h e c urr e nt d o s e.  B e y o n d t hi s r ul e, P K 
c o n c e ntr ati o n s m u st b e wit hi n t h e vi sit wi n d o w t o b e i n cl u d e d i n s u m m ar y st ati sti c s of P K.  
Wit hi n a n a n al y si s vi sit wi n d o w,  t h e m e a s ur e m e nt fr o m t h e s c h e d ul e d vi sits  will  b e u s e d if 
a v ail a bl e.  If n o s c h e d ul e d vi sit o c c ur s , t h e m e a s ur e m e nt fr o m t h e vi sit cl o s e st t o t h e d efi n e d 
t ar g et a n al y si s d a y  wit hi n t h e wi n d o w  will b e u s e d.   If t h er e i s m or e t h a n o n e m e a s ur e m e nt wit h 
e q u al di st a n c e t o t h e d efi n e d t ar g et a n al y si s d a y , t h e l att er will b e u s e d.   If n o vi sit s o c c ur wit hi n 
a vi sit wi n d o w, t h e m e a s ur e m e nt f or t hi s vi sit will b e tr e at e d a s mi s si n g.  
3. 1. 3  D efi niti o n of B as eli n e  
F or all v ari a bl e s e x c e p t li pi d s a n d li v er e n z y m e s v ari a bl e s, p r e-d o s e m e a s ur e m e nt s o n B a s eli n e 
vi sit ( D a y 1)  will b e c o n si d er e d t h e b a s eli n e v al u e s .  If t h e m e a s ur e m e nt at t hi s vi sit i s n ot 
a v ail a bl e,  t h e l a st m e a s ur e m e nt pri or t o t h e fir st d o s e of st u d y dr u g m a y b e u s e d a s t h e 
b a s eli n e v al u e  u nl e s s it i s st at e d ot h er wi s e.   T h e s c h e d ul e d b a s eli n e vi sit f or Fi br o S c a n, li v er 
bi o p s y , D X A s c a n , a n d E L F ™ i s S cr e e ni n g.  B a s eli n e li pi d v ari a bl e s i n cl u di n g T ot al C h ol e st er ol, 
H D L -C, L D L -C , Tri gl y c eri d e s, n o n -H D L c h ol e st er ol  will b e t h e a v er a g e of S cr e e ni n g  a n d 
B a s eli n e vi sit ( D a y 1)  v al u e s.   B a s eli n e li v er e n z y m e s v ari a bl e s i n cl u di n g A L T a n d A S T  will b e 
t h e a v er a g e of Pr e -B a s eli n e  a n d B a s eli n e vi sit  ( D a y 1) v al u e s .  If o n e i s mi s si n g f or li pi d s a n d 
li v er e n z y m e s v ari a bl e s, t h e a v ail a bl e o n e will b e u s e d.   


A k er o T h er a p e uti c s, I n c  
C O N FI D E N TI A L  
St ati sti c al A n al y si s Pl a n  
A K -U S -0 0 1 -0 1 0 1  
 
C o h ort C V er si o n 2. 0 , 0 5 M ar c h 2 0 2 1  
P a g e 1 3  of 2 8  
 
3. 1. 4  S u m m ary St atistics  
C at e g ori c al d at a will g e n er all y b e s u m m ari z e d wit h c o u nt s a n d p er c e nt a g e s of s u bj e ct s .  T h e 
d e n o mi n at or u s e d f or t h e p er c e nt a g e c al c ul ati o n will b e cl e arl y d efi n e d .  C o nti n u o u s d at a will 
g e n er all y b e s u m m ari z e d wit h d e s cri pti v e st ati sti c s i n cl u di n g n ( n u m b er of n o n -mi s si n g v al u e s), 
m e a n, m e di a n, st a n d ar d d e vi ati o n, mi ni m u m, a n d m a xi m u m .  F or c ert ai n c o nti n u o u s d at a, it w ill 
b e s u m m ari z e d wit h d e s cri pti v e st ati sti c s i n cl u di n g n ( n u m b er of n o n -mi s si n g v al u e s), arit h m eti c 
m e a n, arit h m eti c st a n d ar d d e vi ati o n, g e o m etri c m e a n, g e o m etri c c o effi ci e nt of v ari ati o n, 
m e di a n, mi ni m u m, a n d m a xi m u m.   P K c o n c e ntr ati o n s will b e s u m m ari z e d wit h t h e s et of 
c o nti n u o u s p ar a m et er s i n cl u di n g g e o m etri c m e a n a n d will a d d t h e st ati sti c of n u m b er of 
s a m pl e s b el o w t h e li mit of q u a ntifi c ati o n ( n bl q).  
All i n di vi d u al s u bj e ct d at a will b e li st e d a s m e a s ur e d.  
3. 1. 5  Hy p ot h esis T esti n g  
T h e  st ati sti c al h y p ot h e s e s  will b e t e st e d at t h e 2 -si d e d , 0. 0 5  si g nifi c a n c e f or t h e p ar a m et er s wit h 
n e utr al dir e cti o n  u nl e s s  s p e cifi e d  ot h er wi s e . 
3. 1. 6   H a n dli n g of Dr o p o uts a n d Missi n g D at a  
Mi s si n g d at a c a n h a v e a n i m p a ct o n t h e i nt er pr et ati o n of t h e tri al d at a .  I n g e n er al, v al u e s f or 
mi s si n g d at a will n ot b e i m p ut e d.  
W h er e a p pr o pri at e, s af et y d at a f or s u bj e ct s t h at di d n ot c o m pl et e t h e st u d y will b e i n cl u d e d i n 
s u m m ar y st ati sti c s .  F or e x a m pl e, if a s u bj e ct r e c ei v e d st u d y dr u g, t h e s u bj e ct will b e i n cl u d e d i n 
a s u m m ar y of A E s a c c or di n g t o t h e tr e at m e nt r e c ei v e d; ot h er wi s e, if t h e s u bj e ct i s n ot d o s e d 
t h e n t h e y will b e e x cl u d e d fr o m t h e s u m m ar y.  If s af et y l a b or at or y r e s ult s f or a s u bj e ct ar e 
mi s si n g f or a n y r e a s o n at a ti m e p oi nt, t h e s u bj e ct will b e e x cl u d e d fr o m t h e c al c ul a ti o n of 
s u m m ar y st ati sti c s f or t h at ti m e p oi nt .  If t h e s u bj e ct i s mi s si n g a pr e-d o s e v al u e, t h e n t h e 
s u bj e ct will b e e x cl u d e d fr o m t h e c al c ul ati o n of s u m m ar y st ati sti c s f or t h e pr e -d o s e v al u e a n d 
t h e c h a n g e fr o m pr e-d o s e v al u e s.  
V al u e s f or mi s si n g s af et y l a b or at or y d at a will n ot b e i m p ut e d; h o w e v er, a mi s si n g b a s eli n e r e s ult 
will b e r e pl a c e d wit h a s cr e e ni n g r e s ult, if a v ail a bl e .  If n o pr e-tr e at m e nt l a b or at or y v al u e i s 
a v ail a bl e, t h e b a s eli n e v al u e will b e a s s u m e d t o b e n or m al (i. e., n o gr a d e [ Gr a d e 0]) f or t h e 
s u m m ar y of gr a d e d l a b or at or y a b n or m aliti e s.  
V al u e s f or mi s si n g vit al si g n s d at a will n ot b e i m p ut e d; h o w e v er, a mi s si n g b a s eli n e r e s ult will b e 
r e pl a c e d wit h a s cr e e ni n g r e s ult, if a v ail a bl e. 
B el o w li mit of q u a ntifi c ati o n (B L Q ) P K c o n c e ntr ati o n at p r e-d o s e at B a s eli n e will b e i m p ut e d a s 
z er o a n d t h e ot h er pr e -d o s e B L Q P K c o n c e ntr ati o n s will b e i m p ut e d a s h alf of t h e l o w li mit of 
q u a ntifi c ati o n (0. 5* L L O Q ).   
3. 2
3. 2  A n alysis P o p ul ati o ns
A n alysis P o p ul ati o ns  
3. 2. 1  F ull A n alysis S et ( F AS)  
T h e F A S will i n cl u d e all s u bj e ct s w h o w er e r a n d o mi z e d i nt o t h e st u d y.  T h e F A S will b e t h e 
pri m ar y a n al y si s s et f or effi c a c y a n al y s e s . 


A k er o T h er a p e uti c s, I n c  
C O N FI D E N TI A L  
St ati sti c al A n al y si s Pl a n  
A K -U S -0 0 1 -0 1 0 1  
 
C o h ort C V er si o n 2. 0 , 0 5 M ar c h 2 0 2 1  
P a g e 1 4  of 2 8  
 
S u bj e ct s w h o r e c ei v e a d o s e of st u d y dr u g ot h er t h a n t h at t o w hi c h t h e y w er e r a n d o mi z e d f or 
t h e e ntir e d ur ati o n of tr e at m e nt will b e a n al y z e d a c c or di n g t o tr e at m e nt gr o u p t o w hi c h t h e y 
w er e r a n d o mi z e d.  
3. 2. 2  S af ety S et 
T h e S af et y S et will i n cl u d e all s u bj e ct s  w h o r e c ei v e d at l e a st o n e d o s e of st u d y dr u g .  T h e 
S af et y S et will b e t h e pri m ar y a n al y si s s et f or s af et y a n al y s e s .   
S u bj e ct s w h o r e c ei v e d a d o s e of st u d y dr u g ot h er  t h a n t h at t o w hi c h t h e y w er e r a n d o mi z e d f or 
t h e e ntir e d ur ati o n of tr e at m e nt will b e a n al y z e d a c c or di n g t o t h e d o s e of st u d y dr u g r e c ei v e d.  
All d at a c oll e ct e d d uri n g tr e at m e nt pl u s 3 0 d a y s aft er l a st d o s e of st u d y dr u g will b e i n cl u d e d  i n 
t h e s af et y s u m mari e s.   
3. 2. 3  F 4 S af ety S et 
T h e F 4 S af et y S et will b e a s u b s et of t h e S af et y S et.  It will e x cl u d e  S af et y S et s u bj e ct s  w h o ar e 
n ot  c o nfir m e d F 4 fi br o si s  b y hi st ol o g y c e ntr al r e a d s .   
3. 2. 4  P K A n alysis S et  
T h e P K A n al y si s S et will i n cl u d e all r a n d o mi z e d s u bj e ct s w h o t o o k at l e a st o n e d o s e of st u d y 
dr u g a n d f or w h o m c o n c e ntr ati o n d at a of E F X  i s a v ail a bl e. 
3. 2. 5  Bi o m ark er A n alysis S et  
T h e Bi o m ar k er A n al y si s S et will i n cl u d e d at a fr o m s u bj e ct s i n t h e S af et y S et w h o h a v e t h e 
b a s eli n e a n d at l e a st o n e o n -st u d y m e a s ur e m e nt t o pr o vi d e i nt er pr et a bl e r e s ult s f or E L F ™ T e st 
s c or e or  pr o -C 3  l e v el s. 
3. 2. 6  P er Pr ot oc ol  A n alysis S et  ( P P AS) 
T h e P P A S i s d efi n e d a s a n y s u bj e ct w h o i s r a n d o mi z e d, r e c ei v e s at l e a st o n e d o s e of st u d y 
dr u g  wit h o ut a n y m aj or pr ot o c ol d e vi ati o n s .  A f ull d et ail of i n cl u si o n s a n d e x cl u si o n s fr o m P P A S 
will b e i n t h e cl a s sifi c ati o n s s p e cifi c ati o n s a n d fi n ali z e d b ef or e u n bli n di n g.  
3. 2. 7  Liv er Stiff n ess Ev al u a bl e  A n al ysis S et 
T h e Li v er Stiff n e s s E v al u a bl e A n al y si s S et will b e a s u b s et of t h e F A S.   It will i n cl u d e all F A S 
s u bj e ct s w h o h a v e B a s eli n e a n d W e e k 1 6  li v er stiff n e s s a s e v al u at e d b y Fi br o S c a n. 
3. 2. 8  Liv er Bi o psy Ev al u a bl e  A n a lysis S et 
Li v er Bi o p s y E v al u a bl e A n al y si s S et will b e a s u b s et of t h e F A S.  It will i n cl u d e all F A S s u bj e ct s 
wit h c o nfir m e d F 4 fi br o si s  at b a s eli n e b y c e ntr al r e a d s w h o h a v e B a s eli n e a n d W e e k 1 6  li v er 
bi o p s y r e s ult s.  It will b e t h e a n al y si s p o p ul ati o n f or  t h e r e s p o n d er s b a s e d o n hi st ol o gi c 
e v al u ati o n of N A S s y st e m a n d fi br o si s st a g e.  
3. 2. 9  Str atific ati o n  
N ot A p pli c a bl e.  


A k er o T h er a p e uti c s, I n c  
C O N FI D E N TI A L  
St ati sti c al A n al y si s Pl a n  
A K -U S -0 0 1 -0 1 0 1  
 
C o h ort C V er si o n 2. 0 , 0 5 M ar c h 2 0 2 1  
P a g e 1 5  of 2 8  
 
3. 3
3. 3  S u bj ect D at a
S u bj ect D at a  a n d St u dy C o n d uct
a n d St u dy C o n d uct  
3. 3. 1  S u bj ect Dis p ositi o n  
C o u nt s a n d p er c e nt a g e s of s u bj e ct s w h o w er e s cr e e n e d ( si g n e d i nf or m e d c o n s e nt),  
di s c o nti n u e d e arl y d uri n g s cr e e ni n g ( s cr e e n f ail ur e s), a n d r a n d o mi z e d will b e s u m m ari z e d i n 
t ot al b a s e d o n all s cr e e n e d s u bj e ct s.  R e a s o n s f or e arl y di s c o nti n u ati o n will al s o b e 
s u m m ari z e d .  I n a d diti o n, di s c o nti n u ati o n c o ntri b ut e d b y C O VI D -1 9 will b e s u m m ari z e d.  
C o u nt s a n d p er c e nt a g e s of s u bj e ct s i n e a c h of t h e f oll o wi n g di s p o siti o n c at e g ori e s will b e 
pr e s e nt e d b y tr e at m e nt a n d i n t ot al b a s e d o n all r a n d o mi z e d s u bj e ct s : 
•  
S u bj e ct s w h o w er e  r a n d o mi z e d 
•  
S u bj e ct s w h o st art e d  st u d y dr u g  
•  
S u bj e ct s w h o c o m pl et e d  t h e tr e at m e nt 
•  
S u bj e ct s w h o wit h dr e w fr o m t h e tr e at m e nt 
•  
S u bj e ct s w h o c o m pl et e d  t h e st u d y 
•  
S u bj e ct s w h o wit h dr e w fr o m t h e st u d y  
F or r a n d o mi z e d s u bj e ct s w h o wit h dr a w fr o m  t h e tr e at m e nt a n d wit h dr a w fr o m t h e st u d y, t h e 
pri m ar y r e a s o n f or t h e wit h dr a w al will b e  s u m m ari z e d .  I n a d diti o n, e arl y di s c o nti n u ati o n fr o m 
t h e tr e at m e nt c o ntri b ut e d b y C O VI D -1 9 a n d e arl y di s c o nti n u ati o n fr o m t h e st u d y c o ntri b ut e d b y 
C O VI D -1 9 will b e s u m m ari z e d.   
3. 3. 2  Pr ot oc ol D evi ati o ns  
Pr ot o c ol d e vi ati o n s will b e d efi n e d i n t h e Pr ot o c ol D e v i ati o n Pl a n .  C o u nt s a n d p er c e nt a g e s of 
s u bj e ct s wit h  C S R r e p ort a bl e  pr ot o c ol d e vi ati o n s b y d e vi ati o n c at e g or y will b e s u m m ari z e d b y 
tr e at m e nt a n d i n t ot al b a s e d o n all r a n d o mi z e d s u bj e ct s.  All pr ot o c ol d e vi ati o n s a n d C O VI D -1 9 
r el at e d pr ot o c ol d e vi ati o n s will b e li st e d. 
3. 3. 3  A n alysis P o p ul ati o ns  
C o u nt s a n d p er c e nt a g e s of s u bj e ct s i n e a c h a n al y si s p o p ul ati o n will b e s u m m ari z e d b y 
tr e at m e nt a n d i n t ot al b a s e d o n all r a n d o mi z e d s u bj e ct s. 
3. 3. 4  D e m o gr a p hic  a n d B as eli n e C h ar act eristics  
T h e f oll o wi n g d e m o gr a p hi c a n d b a s eli n e c h ar a ct eri sti c s will b e s u m m ari z e d:  
•  
A g e ( y e ar s) a n d a g e c at e g ori e s ( < 4 5 y e ar s, ≥4 5 t o < 6 5 y e ar s, ≥6 5 y e ar s)  
•  
S e x  
•  
R a c e  
•  
Et h ni cit y  
•  
H ei g ht ( c m)  at S cr e e ni n g  
•  
W ei g ht ( k g)  at B a s eli n e  
•  
B o d y m a s s i n d e x ( B MI) ( k g/ m
2 ) at B a s eli n e  a n d B MI c at e g ori e s  at B a s eli n e  ( < 3 0 k g/ m2 , 
≥3 0 k g/ m 2 ) 
•  
W ai st cir c u mf er e n c e (c m ) at B a s eli n e  
•  
Hi p  cir c u mf er e n c e (c m ) at B a s eli n e  


A k er o T h er a p e uti c s, I n c  
C O N FI D E N TI A L  
St ati sti c al A n al y si s Pl a n  
A K -U S -0 0 1 -0 1 0 1  
 
C o h ort C V er si o n 2. 0 , 0 5 M ar c h 2 0 2 1  
P a g e 1 6  of 2 8  
 
•  
W ai st -t o-hi p r ati o  at B a s eli n e  
•  
T y p e 2 di a b et e s st at u s at S cr e e ni n g   
•  
St ati n U s e at B a s eli n e  
•  
Vit a mi n E/ T hi a z oli di n e di o n e U s e at B a s eli n e  
•  
Fi br o si s st a g e (l o c al r e a d) at S cr e e ni n g  
•  
Bi o p s y di a g n o si s (l o c al r e a d) at S cr e e ni n g  
•  
N A S  a n d N A S c o m p o n e nt s  (l o c al r e a d) at S cr e e ni n g   
•  
Fi br o si s st a g e ( c e ntr al r e a d) at S cr e e ni n g  
•  
Bi o p s y di a g n o si s ( c e ntr al r e a d) at S cr e e ni n g  
•  
N A S  a n d N A S c o m p o n e nt s  ( c e ntr al r e a d) at S cr e e ni n g  
•  
Li v er Stiff n e s s a s E v al u at e d b y Fi br o S c a n at S cr e e ni n g  ( kil o P a s c al s  [k P a ])  
•  
Li v er St e at o si s a s E v al u at e d b y Fi br o S c a n at S cr e e ni n g  (C o ntr oll e d Att e n u ati o n 
P ar a m et er  [C A P ])  
•  
Al a ni n e a mi n otr a n sf er a s e (U/ L ) a n d A s p art at e A mi n otr a n sf er a s e (U/ L ) at B a s eli n e  
•  
Tri gl y c eri d e  (m g/ d L ), T ot al C h ol e st er ol  (m g/ d L ), L D L-C  (m g/ d L ), H D L-C (m g/ d L ), a n d  
n o n -H D L -C  (m g/ d L ) at B a s eli n e  
•  
H e m o gl o bi n A 1 c (% ) at B a s eli n e  
•  
E n d o g e n o u s F G F 2 1 at B a s eli n e  
•  
M E L D  S c or e at B a s eli n e  
•  
C P  S c or e at B a s eli n e  
•  
E L F  S c or e at B a s eli n e  
•  
Pr o -C 3  (u g/ L ) at B a s eli n e  
•  
A L T > = 3 x U L N at B a s eli n e   
•  
A S T > = 3 x U L N at B a s eli n e  
D e m o gr a p hi c a n d b a s eli n e c h ar a ct eri sti c s  will b e s u m m ari z e d wit h d e s cri pti v e st ati sti c s or 
c o u nt s a n d p er c e nt a g e s of s u bj e ct s a s a p pr o pri at e b y tr e at m e nt a n d i n t ot al f or all r a n d o mi z e d 
s u bj e ct s  a n d e a c h d efi n e d a n al y si s p o p ul ati o n  if t h e a n al y si s p o p ul ati o n  c o m p o siti o n i s diff er e nt 
t h a n all  r a nd o mi z e d s u bj e ct s . 
3. 3. 5  M e dic al Hist ory  
M e di c al hi st or y will b e c o d e d t o s y st e m or g a n cl a s s  ( S O C) a n d pr ef err e d t er m  u si n g t h e M e di c al 
Di cti o n ar y f or R e g ul at or y A cti viti e s ( M e d D R A) v er si o n 2 2. 0 .  C o u nt s a n d p er c e nt a g e s of 
s u bj e ct s wit h m e di c al hi st or y b y S O C  a n d  pr ef err e d t er m will b e s u m m ari z e d b y tr e at m e nt a n d 
i n t ot al b a s e d o n all r a n d o mi z e d s u bj e ct s. 
3. 3. 6  C o nc o mit a nt M e dic ati o ns  
C o n c o mit a nt m e di c ati o n s will b e c o d e d t o a n at o mi c al t h er a p e uti c c h e mi c al ( A T C) cl a s s a n d 
pr ef err e d t er m u si n g t h e W orl d H e alt h Or g a ni z ati o n ( W H O) Dr u g Di cti o n ar y v er si o n 2 0 1 9 G B 3 .  
F or s u m m ar y p ur p o s e s, m e di c ati o n s will b e c o n si d er e d pri or m e di c ati o n s if t h e y st o p p e d pri or t o 
t h e fir st d o s e of st u d y dr u g a n d c o n c o mit a nt m e di c ati o n s if t h e y w er e t a k e n at a n y ti m e o n or  
aft er t h e fir st d o s e of st u d y dr u g  (i. e. st art e d pri or t o t h e fir st d o s e of st u d y dr u g a n d w er e 
o n g oi n g or st art e d aft er t h e fir st d o s e of st u d y dr u g) . 
C o u nt s a n d p er c e nt a g e s of s u bj e ct s t a ki n g c o n c o mit a nt m e di c ati o n s b y A T C cl a s s a n d 
pr ef err e d t er m will b e s u m m ari z e d b y tr e at m e nt a n d i n t ot al b a s e d o n t h e S af et y S et .  T h e u s e 
of a n y pri or m e di c ati o n or c o n c o mit a nt m e di c ati o n will b e li st e d f or all r a n d o mi z e d s u bj e ct s . 


A k er o T h er a p e uti c s, I n c  
C O N FI D E N TI A L  
St ati sti c al A n al y si s Pl a n  
A K -U S -0 0 1 -0 1 0 1  
 
C o h ort C V er si o n 2. 0 , 0 5 M ar c h 2 0 2 1  
P a g e 1 7  of 2 8  
 
3. 3. 7  St u dy Dr u g Ex p os ur e a n d C o m pli a nc e  
W e e k s  of e x p o s ur e t o st u d y dr u g will b e c al c ul at e d a s : 
(d at e of l a st d o s e of st u d y dr u g - d at e of fir st d o s e of st u d y dr u g +  1 ) / 7 
W e e k s  of e x p o s ur e t o st u d y dr u g will b e s u m m ari z e d b y tr e at m e nt b a s e d o n t h e S af et y S et  wit h 
d e s cri pti v e st ati sti c s a n d wit h c o u nt s a n d p er c e nt a g e s of s u bj e ct s wit h e x p o s ur e i n t h e f oll o wi n g 
c at e g ori e s:  
•  
> 0  t o ≤4 w e e k s  
•  
> 4 t o ≤8 w e e k s  
•  
> 8 t o ≤1 2 w e e k s   
•  
> 1 2  t o ≤1 6  w e e k s  
•  
> 1 6  w e e k s  
T h e t ot al n u m b er of i nj e cti o n s a d mi ni st er e d will b e c al c ul at e d f or e a c h s u bj e ct. A c o nti n g e n c y 
t a bl e will b e pr o vi d e d t o di s pl a y t h e n u m b er a n d p er c e nt a g e of s u bj e ct s i n e a c h tr e at m e nt gr o u p 
wit h t h e f oll o wi n g n u m b er of i nj e cti o n s: 1 -3 , 4 -6 , 7 -9 , 10 -1 2 , 13 -1 5 , > = 1 6 . 
S u bj e ct s t h at mi s s 2 or m or e d o s e s of st u d y dr u g o v er t h e c o ur s e of st u d y p arti ci p ati o n  ar e 
c o n si d er e d n o n c o m pli a nt. T h e fr e q u e n c y a n d p er c e nt a g e of s u bj e ct s w h o ar e c o m pli a nt a n d 
n o n c o m pli a nt will b e s u m m ari z e d b y tr e at m e nt gr o u p.  
3. 4
3. 4  Effic acy Ass ess m e nt
Effic acy Ass ess m e nt  
Effi c a c y d at a will b e s u m m ari z e d a n d a n al y z e d b y r a n d o mi z e d tr e at m e nt b a s e d o n t h e F A S  
u nl e s s ot h er wi s e s p e cifi e d .  F or t h e s e c o n d ar y e n d p oi nt s, t h e b o x p l ot s o v er ti m e will b e 
pr o vi d e d.  
3. 4. 1  S ec o n d ary Effic acy E n d p oi nts  
3. 4. 1. 1  
C h a n g e fr o m b as eli n e i n liv er stiff n ess as ev al u at e d by Fi br oSc a n ® at W e ek 1 6  
Li v er stiff n e s s will b e a s s e s s e d u si n g Fi br o S c a n ®  at S cr e e ni n g  a n d W e e k 1 6 .  S u m m ar y 
st ati sti c s at all vi sit s  f or t h e v al u e s, c h a n g e fr o m b a s eli n e a n d p er c e nt c h a n g e fr o m b a s eli n e will 
b e pr o vi d e d . 
T h e c h a n g e a n d p er c e nt c h a n g e fr o m b a s elin e at W e e k 1 6 i n li v er stiff n e s s e x pr e s s e d i n k P a  
will b e a n al y z e d wit h a n a n al y si s of c o v ari a n c e ( A N C O V A) m o d el wit h tr e at m e nt gr o u p a s a 
f a ct or a n d b a s eli n e li v er stiff n e s s a s e v al u at e d b y Fi br o S c a n ® a s a c o v ari at e  u si n g t h e F A S .  
T h e tr e at m e nt eff e ct e sti m at e, 9 5 % CI a n d p v al u e s will b e pr o vi d e d.   Mi s si n g v al u e s  at W e e k 1 6 
will b e i m p ut e d u si n g t h e  l a st-o b s er v e d -c arri e d -f or w ar d ( L O C F) m et h o d.  T h e s a m e a n al y si s 
will b e r e p e at e d o n t h e Li v er Stiff n e s s E v al u a bl e A n al y si s S et  a n d t h e P P A S , a n d n o 
i m p ut ati o n will b e p erf or m e d. 
T h e S A S s a m pl e c o d e i s li st e d:  
* * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * *   
  T R E A T M E N T :  0  ( P l a c e b o ) ,  1  ( E F X  5 0  m g )  
  B A S E :  B a s e l i n e  l i v e r  s t i f f n e s s  a s  e v a l u a t e d  b y  F i b r o S c a n  
  C H G :  C h a n g e  f r o m  b a s e l i n e  t o  W e e k  1 6  i n  l i v e r  s t i f f n e s s  
* * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * ;   


A k er o T h er a p e uti c s, I n c  
C O N FI D E N TI A L  
St ati sti c al A n al y si s Pl a n  
A K -U S -0 0 1 -0 1 0 1  
 
C o h ort C V er si o n 2. 0 , 0 5 M ar c h 2 0 2 1  
P a g e 1 8  of 2 8  
 
p r o c  g l m ;   
  c l a s s  T R E A T M E N T ;   
  m o d e l  C H G  =  T R E A T M E N T  B A S E  /  p ;   
  l s m e a n s  T R E A T M E N T  /  s t d e r r  p d i f f  c l ;   
  e s t i m a t e  " E F X  5 0  m g  :  P l a c e b o "  T R E A T M E N T  - 1  1 ;  
r u n ;  
T h e S h a pir o -Wil k n or m alit y t e st will b e p erf or m e d f or t h e r e si d u al s fr o m t h e m o d el a b o v e.  If t h e 
p -v al u e i s < 0. 0 1, t h e n n o n-p ar a m etri c a n al y s e s will b e e x pl or e d.  
3. 4. 1. 2  
C h a n g es fr o m b as eli n e i n n o n -i nv asiv e bi o m ark ers i ncl u di n g Pr o-C 3 at W e eks 1 2, 1 6 a n d 2 0 , a n d 
liv er fi br osis by EL F ™ T est sc or e at W e eks 6, 1 2 a n d 1 6  
E L F ™ T e st s c or e  a n d it s c o m p o n e nt s i n cl u di n g h y al ur o ni c a ci d ( H A), pr o c oll a g e n III a mi n o 
t er mi n al p e pti d e ( PIII N P), ti s s u e i n hi bit or of m et all o pr ot ei n a s e 1 ( TI M P-1)  will b e m e a s ur e d at 
S cr e e ni n g, W e e k 6 a n d W e e k 1 6 .  V al u e s a n d c h a n g e s fr o m b a s eli n e i n E L F ™ T e st s c or e  a n d 
it s c o m p o n e nt s will b e s u m m ari z e d d e s cri pti v el y.  A N C O V A m o d el wit h tr e at m e nt gr o u p a s a 
f a ct or a n d b a s eli n e  v al u e  a s a c o v ari at e  b a s e d o n t h e F A S w ill b e u s e d f or a n al y zi n g t h e 
c h a n g e fr o m b a s eli n e t o W e e k 1 6.  L S m e a n s, 9 5 %  c o nfi d e n c e i nt er v al s a n d p -v al u e s will b e 
pr e s e nt e d .  Mi s si n g v al u e s  will b e i m p ut e d u si n g t h e  L O C F m et h o d.   T h e s a m e a n al y si s will b e 
r e p e at e d o n t h e Bi o m ar k er A n al y si s S et a n d t h e P P A S, a n d n o i m p ut ati o n will b e p erf or m e d.  
T h e S h a pir o -Wil k n or m alit y t e st will b e p erf or m e d f or t h e r e si d u al s fr o m t h e m o d el a b o v e.  If t h e 
p -v al u e i s < 0. 0 1, t h e n n o n -p ar a m etri c a n al y s e s will b e e x pl or e d .  W e e k 1 2 of E L F  T e st s c or e 
a n d it s c o m p o n e nt s will b e i n cl u d e d i n t h e s u m m ar y a n d t h e c h a n g e fr o m b a s eli n e t o W e e k 1 2 
will b e a n al y z e d u si n g t h e s a m e A N C O V A m o d el if t h e d at a i s a v ail a bl e.  
Pr o -C 3 will b e m e a s ur e d at S cr e e ni n g, B a s eli n e ( D a y 1), W e e k 1, W e e k 4, W e e k 8, W e e k  1 2, 
W e e k 1 6 a n d W e e k 2 0 S af et y f oll o w -u p.  V al u e s a n d c h a n g e s fr o m b a s eli n e i n Pr o -C 3 will b e 
s u m m ari z e d d e s cri pti v el y.  T h e c h a n g e  a n d p er c e nt c h a n g e  fr o m b a s eli n e t o W e e ks, 4, 8,  1 2 , 
1 6 a n d 2 0  will b e a n al y z e d u si n g A N C O V A m o d el i n a m a n n er si mil ar t o t h e E L F ™ T e st s c or e 
a n d it s c o m p o n e nt s.  
3. 4. 2  Ex pl or at ory Effic acy E n d p oi nts  
T h e e x pl or at or y effi c a c y e n d p oi nt s ar e d efi n e d i n S e cti o n 2. 3. 3 .  D e s cri pti v e st ati sti c s at e a c h 
s c h e d ul e d vi sit f or t h e v al u e s a n d c h a n g e s fr o m b a s eli n e of t h e e x pl or at or y effi c a c y e n d p oi nt s 
will b e s u m m ari z e d.   F or c ert ai n effi c a c y e n d p oi nt s, l o g arit h mi c tr a n sf or m ati o n m a y b e 
p erf or m e d pri or t o fitti n g t h e A N C O V A m o d el.   Si n c e t h e s e e n d p oi nt s ar e f or e x pl or at or y 
p ur p o s e s, all t h e a n al y si s will b e b a s e d o n t h e o b s er v e d v al u e s a n d n o a dj u st m e nt s f or 
m ulti pli cit y will b e m a d e  e x p c e pt f or l i v er st e at o si s a s e v al u at e d b y Fi br o S c a n ® e x pr e s s e d i n 
C A P . 
3. 4. 2. 1  
M ark ers of liv er i nj ury a n d f u ncti o n  
M ar k er s of li v er i nj ur y a n d f u n cti o n i n cl u di n g A L T, A S T, A L P, G G T, bilir u bi n, I N R, al b u mi n, 
M E L D s c or e, a n d C P s c or e will b e m e a s ur e d at S cr e e ni n g, Pr e -B a s eli n e, B a s eli n e  ( D a y 1) , 
W e e k  1 , W e e k  4 , W e e k  8 , W e e k  1 2 , W e e k  1 6 a n d  W e e k  2 0  S af et y  f oll o w-u p .   
C P s c or e  will b e c al c ul at e d a s b el o w , r a n gi n g fr o m 5-1 5 : 
 
1 p oi nt  
2  p oi nt  
3  p oi nt  
Bilir u bi n  ( T ot al)  
< 2  m g/ d L ( < 3 4. 2 µ m ol/ L)  
2 -3  m g/ d L ( 3 4. 2 -5 1. 3  µ m ol/ L)  
> 3  m g/ d L ( > 5 1. 3  µ m ol/ L)  
Al b u mi n  
> 3. 5 g/ d L ( > 3 5 g/ L)  
2. 8 -3. 5 g/ d L ( 2 8 -3 5 g/ L)  
< 2. 8  g/ d L ( < 2 8 g/ L)  
I N R  
< 1. 7  
1. 7 -2. 2   
> 2. 2  


A k er o T h er a p e uti c s, I n c  
C O N FI D E N TI A L  
St ati sti c al A n al y si s Pl a n  
A K -U S -0 0 1 -0 1 0 1  
 
C o h ort C V er si o n 2. 0 , 0 5 M ar c h 2 0 2 1  
P a g e 1 9  of 2 8  
 
A s cit e s   
A b s e nt   
Sli g ht  
M o d er at e  
E n c e p h al o p at h y  
N o  E n c e p h al o p at h y  
Gr a d e 1 -2  
Gr a d e 3 -4   
Cl a s s A  = 5 -6 p oi nt s  
Cl a s s B = 7 -9 p oi nt s  
Cl a s s C = 1 0 -1 5 p oi nt s  
A N C O V A m o d el wit h tr e at m e nt gr o u p a s a f a ct or a n d b a s eli n e v al u e a s a c o v ari at e will b e u s e d 
f or a n al y zi n g t h e c h a n g e fr o m b a s eli n e t o W e e ks  4, 8,  1 2 , 1 6, a n d 2 0, a s w ell a s t h e p er c e nt 
c h a n g e fr o m b a s eli n e t o W e e k s  4, 8,  1 2,  1 6 a n d 2 0 .  L S m e a n s, 9 5 % c o nfi d e n c e i nt er v al s a n d 
p -v al u e s will b e pr e s e nt e d . 
3. 4. 2. 2  
B o dy w ei g ht a n d w aist -t o-hi p r ati o  
B o d y w ei g ht , w ai st  cir c u mf er e n c e a n d hi p cir c u mf er e n c e will b e m e a s ur e d at all vi sit s.    
A N C O V A m o d el wit h tr e at m e nt gr o u p a s a f a ct or a n d b a s eli n e v al u e a s a c o v ari at e  will b e u s e d 
f or a n al y zi n g t h e c h a n g e fr o m b a s eli n e a n d p er c e nt c h a n g e fr o m b a s eli n e  t o W e e ks  4, 8, 1 2,  
1 6, a n d 2 0 .  L S m e a n s, 9 5 % c o nfi d e n c e i nt er v al s a n d p-v al u e s will b e pr e s e nt e d.  
3. 4. 2. 3  
Bi o m ark er s 
L i pi d m et a b oli s m bi o m ar k er s  a n d i n s uli n s e n siti vit y & gl y c e mi c c o ntr ol  bi o m ar k er s  will b e 
m e a s ur e d at B a s eli n e ( D a y 1) , W e e k  1 , W e e k  4 , W e e k  8 , W e e k  1 2 , W e e k  1 6 a n d  W e e k  2 0  
S af et y  f oll o w-u p . 
A N C O V A m o d el wit h tr e at m e nt gr o u p  a s a f a ct or a n d b a s eli n e  v al u e  a s a c o v ari at e  will  b e u s e d 
f or a n al y zi n g t h e c h a n g e fr o m b a s eli n e t o W e e k 1 2 , t h e c h a n g e fr o m b a s eli n e t o W e e k 1 6, a n d  
t h e c h a n g e fr o m b a s eli n e t o W e e k 2 0 , a s w ell a s t h e p er c e nt c h a n g e fr o m b a s eli n e t o W e e k 1 2,  
1 6 a n d 2 0 .  L S m e a n s, 9 5 % c o nfi d e n c e i nt er v al s a n d p -v al u e s will b e pr e s e nt e d . 
3. 4. 2. 4  
D X A sc a n  m e as ur e m e nts  
D X A s c a n s m e a s ur e m e nt s i n cl u di n g b o n e mi n er al d e n sit y of t h e l u m b ar s pi n e, f e m or al n e c k,  
t ot al hi p a n d b o d y f at di stri b uti o n will b e p erf or m e d at B a s eli n e ( D a y 1) a n d W e e k 1 6 .   
A n a n al y si s will b e p erf or m e d o n t h e c h a n g e fr o m b a s eli n e t o W e e k 1 6 i n D X A S c a n 
m e a s ur e m e nt s u si n g A N C O V A m o d el wit h tr e at m e nt gr o u p  a s a f a ct or a n d b a s eli n e  v al u e  a s a 
c o v ari at e .  L S m e a n s, 9 5 % c o nfi d e n c e i nt er v al s a n d  p -v al u e s will b e pr e s e nt e d . 
3. 4. 2. 5  
Liv er bi o psy  
•  
T h e pr o p orti o n of s u bj e ct s at W e e k 1 6 w h o s e fi br o si s r e gr e s s e s b y ≥ 1 -st a g e a c c or di n g 
t o t h e N A S H C R N cl a s sifi c ati o n  
•  
T h e pr o p orti o n of s u bj e ct s at W e e k 1 6 w h o h a d n o w or s e ni n g i n N A S wit h i m pr o v e m e nt 
i n fi br o si s st a g e  
•  
T h e pr o p orti o n of s u bj e ct s at W e e k 1 6 w h o h a d at l e a st 2 p oi nt s i m pr o v e m e nt i n N A S  
•  
T h e pr o p orti o n of s u bj e ct s at W e e k 1 6 w h o h a d ≥ 1  p oi nt i m pr o v e m e nt i n N A S, fi br o si s, 
st e at o si s l o b ul ar i nfl a m m ati o n or h e p at o c ell ul ar b all o o ni n g  
•  
T h e pr o p orti o n of s u bj e ct s at W e e k 1 6 w h o h a d N A S H r e s ol uti o n ( 0-1 P oi nt 
I nfl a m m ati o n, 0 P oi nt B all o o ni n g) 
•  
T h e pr o p orti o n of s u bj e ct s at W e e k 1 6 w h o h a d fi br o si s i m pr o v e m e nt ≥ 2 -st a g e  
F oll o wi n g 1 6 w e e k s of tr e at m e nt, s u bj e ct s will b e gi v e n t h e o pti o n t o c oll e ct a n e n d of tr e at m e nt 
bi o p s y .  C o u nt s a n d p er c e nt a g e s of s u bj e ct s will b e pr e s e nt e d b y tr e at m e nt gr o u p  b a s e d o n t h e 
Li v er Bi o s y E v al u a bl e A n al y si s S et  u si n g c e ntr al r e a d s . 


A k er o T h er a p e uti c s, I n c  
C O N FI D E N TI A L  
St ati sti c al A n al y si s Pl a n  
A K -U S -0 0 1 -0 1 0 1  
 
C o h ort C V er si o n 2. 0 , 0 5 M ar c h 2 0 2 1  
P a g e 2 0  of 2 8  
 
3. 4. 2. 6  
H R Q oL  
H R Q o L  i n cl u di n g S h ort F or m 3 6 H e alt h S ur v e y ( S F -3 6) , C hr o ni c Li v er Di s e a s e Q u e sti o n n air e -
N o n al c o h oli c F att y Li v er Di s e a s e ( C L D Q-N A F L D) a n d  W or k Pr o d u cti vit y a n d A cti vit y 
I m p air m e nt ( W P AI) will b e c oll e ct e d at B a s eli n e ( D a y 1) , W e e k  1 , W e e k  4 , W e e k  8 , W e e k  1 2 , 
a n d  W e e k  1 6.   
A N C O V A m o d el wit h tr e at m e nt gr o u p  a s  a  f a ct or a n d b a s eli n e  v al u e  a s a c o v ari at e  will b e u s e d  
f or a n al y zi n g t h e c h a n g e fr o m b a s eli n e t o W e e k 1 2  a n d t h e c h a n g e fr o m b a s eli n e t o W e e k 1 6 .  
L S m e a n s, 9 5 % c o nfi d e n c e i nt er v al s a n d p -v al u e s will b e pr e s e nt e d . 
S F -3 6 : T h e S F -3 6 a s k s 3 6 q u e sti o n s t o m e a s ur e f u n cti o n al h e alt h a n d w ell -b ei n g fr o m t h e 
s u bj e ct’ s p oi nt of vi e w.   It c o n si st s of ei g ht h e alt h d o m ai n s i n t h e t a bl e b el o w.  T h e s e h e alt h 
d o m ai n s c al e s c o ntri b ut e t o t h e p h y si c al h e alt h a n d m e nt al h e alt h s u m m ar y m e a s ur e s.   
T h e s c or e s ar e w ei g ht e d s u m s of t h e q u e sti o n s i n e a c h d o m ai n. All t h e  r a w s c or e s  will b e 
tr a n sf or m e d t o s c or e s r a n gi n g fr o m 0 - 1 0 0.  Hi g h er s c or e s r e pr e s e nt  b ett er h e alt h.   P h y si c al 
C o m p o n e nt S u m m ar y ( P C S)  i s c al c ul at e d b y p o siti v el y w ei g hti n g t h e f o ur s u b s c al e s i n t h e 
p h y si c al d o m ai n ( P F , R P , B P  a n d G H ) a n d t h e r e m ai ni n g p s y c h ol o gi c al d o m ai n s u b s c al e s 
n e g ati v el y .  I n c o ntr a st, t h e M e nt al C o m p o n e nt S u m m ar y ( M C S)  i s c al c ul at e d b y p o siti v el y 
w ei g hti n g t h e f o ur m e nt al d o m ai n s u b s c al e s ( V T , S F , R E  a n d M H ), a n d n e g ati v el y w ei g hti n g t h e 
f o ur p h y si c al d o m ai n s u b s c al e s. 
D o m ai n s  
N u m b er of It e m s 
It e m s 
P h y si c al f u n cti o ni n g  ( P F) 
1 0  
3 , 4 , 5 , 6 , 7 , 8 , 9 , 1 0 , 1 1 , 1 2  
R ol e -p h y si c al  ( R P) 
4  
1 3 , 1 4 , 1 5 , 1 6  
B o dil y p ai n  ( B P) 
2  
2 1 , 2 2  
G e n er al h e alt h  ( G H) 
5  
1 , 3 3 , 3 4 , 3 5 , 3 6  
Vit alit y  ( V T) 
4  
2 3 , 2 7 , 2 9 , 3 1  
S o ci al f u n cti o ni n g  ( S F) 
2  
2 0 , 3 2  
R ol e -e m oti o n al  ( R E) 
3  
1 7 , 1 8 , 1 9  
M e nt al h e alt h  ( M H) 
5  
2 4 , 2 5 , 2 6 , 2 8 , 3 0  
C L D Q -N A F L D : T h e C L D Q-N A F L D a s k s q u e sti o n s r el at e d t o li v er di s e a s e a n d s p e cifi c all y 
N A F L D, t o m e a s ur e h e alt h r el at e d q u alit y of lif e i n s u bj e ct s wit h c hr o ni c li v er di s e a s e.    
T h e q u e sti o n n air e h a s  3 6 it e m s gr o u p e d i nt o si x d o m ai n s: A b d o mi n al S y m pt o m s, A cti vit y, 
E m oti o n al, F ati g u e, S y st e mi c S y m pt o m s, a n d W orr y.   It e m s ar e s c or e d b y a  7 -p oi nt  r ati n g s c al e  
fr o m 1 (all of t h e ti m e ) t o 7  (n o n e of t h e ti m e ).  T h e  hi g h er it e m v al u e s i n di c at e b ett er h e alt h.   
T h e d o m ai n  s c or e will b e c al c ul at e d a s  di vi di n g t h e s u m of t h e d o m ai n’ s it e m s b y t h e n u m b er of 
it e m s wit hi n t h at d o m ai n.  T h e t ot al s c or e will b e c al c ul at e d a s a n a v er a g e of t h e si x d o m ai n 
s c or e s.    
D o m ai n s  
N u m b er of It e m s  
It e m s 
A b d o mi n al S y m pt o m s ( A S)  
3  
1, 5, 1 7  
F ati g u e ( F A)  
6  
2, 4, 8, 1 1, 1 3 , 3 5 
S y st e mi c S y m pt o m s ( S S)  
6  
3, 6, 2 1, 2 3, 2 7 , 3 6 
A cti vit y ( A C)  
5  
7, 9, 1 4 , 3 0, 3 1 
E m oti o n al F u n cti o n ( E F)  
9  
1 0, 1 2, 1 5, 1 6, 1 9, 2 0, 2 4, 2 6 , 3 4 
W orr y ( W O)  
7  
1 8, 2 2, 2 5, 2 8, 2 9 , 3 2, 3 3 
W P AI : T h e q u e sti o n n air e a s k s q u e sti o n s r e g ar di n g t h e eff e ct of N A S H o n a p er s o n’ s a bilit y t o 
w or k a n d p erf or m r e g ul ar a cti viti e s . 
T h e W P AI c o n si st s of si x q u e sti o n s:  1 = c urr e ntl y e m pl o y e d ; 2 = h o ur s mi s s e d d u e t o s p e cifi e d 
pr o bl e m ; 3 = h o ur s mi s s e d ot h er r e a s o n s ; 4  = h o ur s a ct u all y w or k e d ; 5 = d e gr e e pr o bl e m 
aff e ct e d pr o d u cti vit y w hil e w or ki n g ; 6 = d e gr e e pr o bl e m aff e ct e d r e g ul ar a cti viti e s.  W P AI 


A k er o T h er a p e uti c s, I n c  
C O N FI D E N TI A L  
St ati sti c al A n al y si s Pl a n  
A K -U S -0 0 1 -0 1 0 1  
 
C o h ort C V er si o n 2. 0 , 0 5 M ar c h 2 0 2 1  
P a g e 2 1  of 2 8  
 
o ut c o m e s ar e e x pr e s s e d a s i m p air m e nt p er c e nt a g e s, wit h hi g h er n u m b er s i n di c ati n g gr e at er 
i m p air m e nt a n d l e s s pr o d u cti vity .  F o ur m ai n o ut c o m e s c a n b e g e n er at e d a n d e x pr e s s e d i n 
p er c e nt a g e s b y m ulti pl yi n g t h e f oll o wi n g s c or e s b y 1 0 0:  
•  
P er c e nt w or k ti m e mi s s e d d u e t o pr o bl e m:   Q 2  / ( Q 2 +  Q 4)  
•  
P er c e nt i m p air m e nt w hil e w or ki n g d u e t o pr o bl e m:  Q 5  / 1 0  
•  
P er c e nt o v er all w or k i m p air m e nt d u e t o pr o bl e m:   
Q 2  / ( Q 2 +  Q 4)  +  [( 1 - ( Q 2 / ( Q 2 +  Q 4)))  x ( Q 5 / 1 0)]  
F or t h o s e w h o mi s s e d w or k a n d di d n ot a ct u all y w or k i n t h e p a st s e v e n d a y s, t h e p er c e nt 
o v er all w or k i m p air m e nt d u e t o pr o bl e m will b e e q u al t o t h e p er c e nt w or k ti m e mi s s e d 
d u e t o pr o bl e m. 
•  
P er c e nt a cti vit y i m p air m e nt d u e t o pr o bl e m:  Q 6  / 1 0  
3. 4. 2. 7  
Li p o pr ot ei n pr ofil e a n d fr e e f atty aci ds 
Li p o pr ot ei n pr ofil e  i n cl u di n g T ot al C h ol e st er ol , H D L -C , L D L -C , Tri gl y c eri d e s , a n d f r e e fatt y a ci d s  
will b e m e a s ur e d at S cr e e ni n g, B a s eli n e  ( D a y 1) , W e e k  1 , W e e k  4 , W e e k  8 , W e e k  1 2 , W e e k  1 6 
a n d  W e e k  2 0  S af et y  f oll o w-u p .   
N o n -H D L c h ol e st er ol  will b e c al c ul at e d a s  T ot al C h ol e st er ol  - H D L -C . 
A N C O V A m o d el wit h tr e at m e nt gr o u p  a s a f a ct or a n d b a s eli n e  v al u e  a s a c o v ari at e  will b e u s e d  
f or a n al y zi n g t h e c h a n g e fr o m b a s eli n e a n d p er c e nt c h a n g e fr o m b a s eli n e t o W e e k s 4, 8, 1 2, 
1 6, a n d 2 0 .  L S m e a n s, 9 5 % c o nfi d e n c e i nt er v al s a n d p -v al u e s will b e pr e s e nt e d . 
3. 4. 2. 8  
C 3 M  a n d P R O -C 3/ C 3 M  R ati o  
C 3 M will b e m e a s ur e d at  B a s eli n e  ( D a y 1 ), W e e k 4, W e e k 8, W e e k  1 2 , W e e k  1 6 , a n d W e e k 2 0.  
P R O -C 3/ C 3 M R ati o  will b e d eri v e d at all a v ail a bl e ti m e p oi nt s.   A N C O V A m o d el w it h tr e at m e nt 
gr o u p  a s a f a ct or a n d b a s eli n e  v al u e  a s a c o v ari at e  will b e u s e d  f or a n al y zi n g t h e c h a n g e fr o m 
b a s eli n e t o W e e k 1 2, a n d t h e c h a n g e fr o m b a s eli n e t o W e e k 1 6.  L S m e a n s, 9 5 % c o nfi d e n c e 
i nt er v al s a n d p-v al u e s will b e pr e s e nt e d . 
3. 4. 2. 9  
Pl at el ets  
Pl at el et s  will b e m e a s ur e d at S cr e e ni n g, B a s eli n e  ( D a y 1) , W e e k  1 , W e e k  4 , W e e k  8 , W e e k  1 2 , 
W e e k  1 6 a n d  W e e k  2 0  S af et y  f oll o w-u p . 
A N C O V A m o d el wit h tr e at m e nt gr o u p a s a f a ct or a n d b a s eli n e v al u e a s a c o v ari at e will b e u s e d 
f or a n al y zi n g t h e c h a n g e fr o m b a s eli n e a n d p er c e nt c h a n g e fr o m b a s eli n e  t o W e e ks  4, 8, 1 2,  
1 6, a n d 2 0 .  L S m e a n s, 9 5 % c o nfi d e n c e i nt er v al s a n d p -v al u e s will b e pr e s e nt e d.  
3. 4. 2. 1 0  Liv er st e at osis as ev al u at e d by Fi br oSc a n ® at W e ek 1 6  ex pr ess e d i n C A P  
Li v er st e at o si s  will b e a s s e s s e d u si n g Fi br o S c a n ®  at S cr e e ni n g  a n d W e e k 1 6 .  S u m m ar y 
st ati sti c s at all vi sit s  f or t h e v al u e s, c h a n g e fr o m b a s eli n e a n d p er c e nt c h a n g e fr o m b a s eli n e will 
b e pr o vi d e d . 
T h e c h a n g e a n d p er c e nt c h a n g e fr o m b a s eli n e at W e e k 1 6 i n li v er st e at o si s e x pr e s s e d i n C A P  
will b e a n al y z e d wit h a n a n al y si s of c o v ari a n c e ( A N C O V A) m o d el wit h tr e at m e nt gr o u p a s a 
f a ctor a n d b a s eli n e li v er st e at o si s  a s e v al u at e d b y Fi br o S c a n ®  a s a c o v ari at e  u si n g t h e F A S.  
T h e tr e at m e nt eff e ct e sti m at e, 9 5 % CI a n d p v al u e s will b e pr o vi d e d.   Mi s si n g v al u e s at W e e k 1 6 
will b e i m p ut e d u si n g t h e  L O C F  m et h o d.  T h e s a m e a n al y si s will b e r e p e a t e d o n t h e Li v er 
Stiff n e s s E v al u a bl e A n al y si s S et  a n d t h e P P A S , a n d n o i m p ut ati o n will b e p erf or m e d. 


A k er o T h er a p e uti c s, I n c  
C O N FI D E N TI A L  
St ati sti c al A n al y si s Pl a n  
A K -U S -0 0 1 -0 1 0 1  
 
C o h ort C V er si o n 2. 0 , 0 5 M ar c h 2 0 2 1  
P a g e 2 2  of 2 8  
 
3. 4. 3  S u b gr o u ps  
S u b gr o u p a n al y s e s will  b e p erf or m e d f or t h e s e c o n d ar y  effi c a c y e n d p oi nt .  T h e g r o u p v ari a bl e s 
i n cl u d e st ati n u s e, T y p e 2 di a b et e s st at u s a n d b a s eli n e E n d o g e n o u s F G F 2 1 .  
T h e gl y c e mi c c o ntr ol bi o m ar k er s will b e  s u m m ari z e d a n d a n al y z e d b y t h e f oll o wi n g s u b gr o u p: 
t y p e 2 di a b et e s st at u s .  
T h e li p o pr ot ei n pr ofil e will b e s u m m ari z e d a n d a n al y z e d b y t h e f oll o wi n g s u b gr o u p: st ati n u s e .  
3. 5
3. 5  S af ety Ass ess m e nt
S af ety Ass ess m e nt  
T h e s af et y of E F X  will b e a s s e s s e d d uri n g t h e st u d y t hr o u g h t h e r e p orti n g of A E s,  cli ni c al 
l a b or at or y t e st s, E C G, vit al si g n a s s e s s m e nt s, b o d y w ei g ht, A D A a n d N A b a s s e s s m e nt s, a n d 
c o n c o mit a nt m e di c ati o n u s a g e.  
All s af et y d at a c oll e ct e d o n or aft er t h e d at e t h at st u d y dr u g s w er e fir st di s p e n s e d u p t o t h e d at e 
of l a st d o s e of st u d y dr u g s pl u s 3 0 d a y s will b e s u m m ari z e d b y tr e at m e nt gr o u p .  D at a f or t h e 
f oll o w-u p p eri o d will b e i n cl u d e d i n d at a li sti n g s.  
S af et y d at a will b e s u m m ari z e d b y a ct u al tr e at m e nt r e c ei v e d ( a n d i n t ot al f or s el e ct e d a n al y s e s) 
b a s e d o n t h e S af et y S et  u nl e s s ot h er wi s e s p e cifi e d .  S el e ct e d s af et y d at a will b e r e p e at e d o n 
F 4 S af et y S et . 
3. 5. 1  A dv ers e Ev e nts  
All A E s will b e c o d e d t o s y st e m or g a n cl a s s  a n d pr ef err e d t er m u si n g M e d D R A  v er si o n 2 2. 0  or 
t h e l at e st v er si o n. 
Tr e at m e nt -e m er g e nt a d v er s e e v e nt s ( T E A E s) ar e d efi n e d a s o n e or b ot h of t h e f oll o wi n g:  
•  
A n y A E s wit h a n o n s et d at e /ti m e o n or aft er t h e st u d y dr u g s st art d at e /ti m e a n d n o l at er 
t h a n 3 0 d a y s aft er p er m a n e nt di s c o nti n u ati o n of st u d y dr u g s 
•  
A n y A E s l e a di n g t o pr e m at ur e di s c o nti n u ati o n of st u d y dr u g s .   
Inj e cti o n sit e r e a cti o n s , di arr h e a , h y p o gl y c e mi a  a n d dr u g -i n d u c e d li v er i nj uri e s ( DI LI) will b e 
m o nit or e d a s A E s of s p e ci al i nt er e st s  ( A E SI s) d uri n g t hi s st u d y .  D uri n g t h e c o ur s e of t h e st u d y, 
a d diti o n al A E SI s m a y b e i d e ntifi e d b y t h e S p o n s or.  
A n o v er vi e w of A E s will b e pr o vi d e d i n cl u di n g c o u nt s a n d p er c e nt a g e s of s u bj e ct s wit h t h e 
f oll o wi ng:  
•  
A n y T E A E s ( o v er all a n d b y m a xi m u m s e v erit y)  
•  
A n y st u d y dr u g r el at e d T E A E s ( o v er all a n d b y m a xi m u m s e v erit y)  
•  
A n y st u d y pr o c e d ur e r el at e d T E A E s ( o v er all a n d b y m a xi m u m s e v erit y)  
•  
A n y T E A E s of s p e ci al i nt er e st  ( o v er all, i nj e cti o n sit e r e a cti o n s, di arr h e a , h y p o gl y c e mi a , 
DI LI)  
•  
A n y T E A E of d e c o m p e n s at e d li v er di s e a s e e v e nt s i n cl u di n g a s cit e s, h e p ati c 
e n c e p h al o p at h y ( H E), or v ari c e al bl e e di n g  
•  
A n y s eri o u s A E s  ( S A E s) 
•  
A n y tr e at m e nt -e m er g e nt s eri o u s A E s ( T E S A E s)  






A k er o T h er a p e uti c s, I n c  
C O N FI D E N TI A L  
St ati sti c al A n al y si s Pl a n  
A K -U S -0 0 1 -0 1 0 1  
 
C o h ort C V er si o n 2. 0 , 0 5 M ar c h 2 0 2 1  
P a g e 2 5  of 2 8  
 
F or  t h e ot h er p ar a m et er s, t h e i n ci d e n c e of a b n or m aliti e s ( a s d efi n e d b y n or m al r a n g e s) pri or t o 
t h e fir st d o s e of st u d y dr u g a n d aft er t h e fir st d o s e of st u d y dr u g will b e s u m m ari z e d wit h c o u nt s 
a n d p er c e nt a g e s of s u bj e ct s.  
T h e i n ci d e n c e of tr e at m e nt -e m er g e nt l a b or at or y a b n or m aliti e s, d efi n e d a s v al u e s t h at i n cr e a s e 
at l e a st o n e t o xi cit y gr a d e fr o m b a s eli n e at a n y ti m e p o st b a s eli n e u p t o a n d i n cl u di n g t h e d at e 
of l a st d o s e of st u d y dr u g s pl u s 3 0 d a y s , will b e s u m m ari z e d wit h c o u nt s a n d p er c e nt a g e s of 
s u bj e ct s  b y tr e at m e nt gr o u p .  If b a s eli n e d at a ar e mi s si n g, t h e n a n y gr a d e d a b n or m alit y (i. e., at 
l e a st a Gr a d e 1) will b e c o n si d er e d tr e at m e nt-e m er g e nt .  If n o pr e-tr e at m e nt l a b or at or y v al u e i s 
a v ail a bl e, t h e b a s eli n e v al u e will b e a s s u m e d t o b e n or m al (i. e., n o gr a d e [ Gr a d e 0]) f or t h e 
s u m m ar y of gr a d e d l a b or at or y a b n or m aliti e s.  
E v al u ati o n of dr u g -i n d u c e d s eri o u s h e p at ot o xi cit y ( e DI S H) pl ot will b e pr o vi de d t o di s pl a y p e a k 
s er u m A L T a n d T ot al Bilir u bi n ( T B) l e v el s f or e a c h s u bj e ct.   T h e p e a k s er u m A S T v er s u s T B 
l e v el s f or e a c h s u bj e ct will  al s o b e  pr o vi d e d . 
3. 5. 3  Vit al Si g ns  
H ei g ht will b e m e a s ur e d wit h o ut s h o e s at S cr e e ni n g.  Ot h er v it al si g n s (b o d y w ei g ht , B MI , 
s y st oli c a n d di a st oli c bl o o d pr e s s ur e, p ul s e, r e s pir ati o n r at e  a n d or al t e m p er at ur e)  will b e 
m e a s ur e d at e a c h vi sit .  Tri pli c at e bl o o d pr e s s ur e a n d h e art r at e  will b e m e a s ur e d at B a s eli n e 
( D a y 1) a n d at 4 8 - 9 6 h o ur s p o st -d o s e o n W e e k s 4 a n d W e e k 8 .  
V al u e s  a n d  c h a n g e s fr o m b a s eli n e t o e a c h vi sit  a n d ti m e p oi nt  f or vit al si g n s will b e s u m m ari z e d  
d e s cri pti v el y.   Tri pli c at e m e a s ur e m e nt s will b e a v er a g e d pri or t o s u m m ar y.  
3. 5. 4  1 2 -L e a d El ectr oc ar di o gr a ms  
1 2 -l e a d E C G will b e m e a s ur e d at S cr e e ni n g, B a s eli n e ( D a y 1)  a n d  W e e k  1 6 . 
V al u e s  a n d c h a n g e s fr o m b a s eli n e of E C G p ar a m et er s (h e art  r at e, P R i nt er v al, Q R S I nt er v al, 
Q T i nt er v al, Q T c B  i nt er v al, Q T cF  i nt er v al a n d R R i nt er v al) a n d o v er all i nt er pr et ati o n will b e 
s u m m ari z e d  b y vi sit .  T h e n u m b er a n d p er c e nt a g e of s u bj e ct s wit h a b s ol ut e Q T c i nt er v al v al u e s 
i n t h e pr e-s p e cifi e d c at e g ori e s ( > 4 5 0, > 4 8 0, a n d > 5 0 0 m s e c), a n d Q T c i nt er v al c h a n g e ( > 3 0 a n d 
> 6 0 m s e c) will b e s u m m ari z e d.   
3. 5. 5  Ot h er S af ety Ass ess m e nts  
A D A , N A b a n d ot h er s af et y d at a wi ll b e li st e d.  A d diti o n all y, t h e s u bj e ct vi sit s i m p a ct e d b y 
C O VI D -1 9  will b e li st e d.  
3. 6
3. 6  P h ar m ac oki n etic
P h ar m ac oki n etic  ( P K)
( P K) Ass ess m e nt
Ass ess m e nt  
P K s a m pli n g will b e o bt ai n e d pr e -d o s e at  B a s eli n e ( D a y 1) , W e e k  1 , W e e k  4 , W e e k  8 , W e e k  1 2 , 
W e e k  1 6 , W e e k  2 0  S af et y  f oll o w-u p , a n d at 4 8 -9 6 h o ur s p o st -d o s e o n W e e k 4 a n d W e e k 8 . 
Pl a s m a E F X  c o n c e ntr ati o n s  will b e li st e d a n d s u m m ari z e d b y tr e at m e nt gr o u p , vi sit, a n d ti m e 
p oi nt  f or t h e P K A n al y si s  S et.  
3. 7
3. 7  P h ar m ac o dy n a mic 
P h ar m ac o dy n a mic (P D
P D ) Ass ess m e nt
) Ass ess m e nt 
S ali v a c orti s ol t e sti n g will b e o bt ai n e d pr e -d o s e at  B a s eli n e ( D a y 1) , W e e k  1 , W e e k  4 , W e e k  8 , 
W e e k  1 2 , W e e k  1 6, W e e k  2 0  S af et y  f oll o w-u p , a n d at 4 8 -9 6 h o ur s p o st -d o s e o n W e e k 4 a n d 
W e e k 8 . 


A k er o T h er a p e uti c s, I n c  
C O N FI D E N TI A L  
St ati sti c al A n al y si s Pl a n  
A K -U S -0 0 1 -0 1 0 1  
 
C o h ort C V er si o n 2. 0 , 0 5 M ar c h 2 0 2 1  
P a g e 2 6  of 2 8  
 
V al u e s of S ali v a c orti s ol a n d c h a n g e s fr o m b a s eli n e t o e a c h vi sit will b e s u m m ari z e d 
d e s cri pti v el y  o n S af et y  S et . 
A N C O V A m o d el wit h tr e at m e nt gr o u p  a s a f a ct or a n d b a s eli n e  v al u e  a s a c o v ari at e  will b e u s e d  
f or a n al y zi n g t h e a b s ol ut e c h a n g e  fr o m b a s eli n e t o W e e k 1 6.  L S m e a n s, 9 5 % c o nfi d e n c e 
i nt er v al s a n d p-v al u e s will b e pr e s e nt e d .  T h e a n al y si s will b e b a s e d o n t h e o v b s er v e d v al u e s 
a n d n o a dj u st m e nt s f or m ulti pli cit y will b e m a d e .  
3. 8
3. 8  B o n e 
o n e Bi o m ark er
Bi o m ark er  Ass ess m e nt
Ass ess m e nt  
B o n e bi o m ar k er s  s a m pl e s (O st e o c al ci n , P 1 N P , C T X -1 , B S A P , P T H, a n d Vit a mi n D ) will b e 
c oll e ct e d  at  B a s eli n e ( D a y 1) , W e e k  1 , W e e k  4 , W e e k  8 , W e e k  1 2 , W e e k  1 6 a n d W e e k  2 0  
S af et y  f oll o w-u p . 
V al u e s of b o n e bi o m ar k er s  a n d c h a n g e s fr o m b a s eli n e t o e a c h vi sit will b e s u m m ari z e d 
d e s cri pti v el y  o n S af et y  S et . 
A N C O V A m o d el wit h tr e at m e nt gr o u p  a s a f a ct or a n d b a s eli n e  v al u e  a s a c o v ari a t e will b e u s e d  
f or a n al y zi n g t h e a b s ol ut e c h a n g e  fr o m b a s eli n e t o W e e k 1 6.  L S m e a n s, 9 5 % c o nfi d e n c e 
i nt er v al s a n d p-v al u e s will b e pr e s e nt e d .  T h e a n al y si s will b e b a s e d o n t h e o v b s er v e d v al u e s 
a n d n o a dj u st m e nt s f or m ulti pli cit y will b e m a d e .  
4  D A T A M O NI T O RI N G C O M M
D A T A M O NI T O RI N G C O M M I T T E E
I T T E E (D M C
D M C ) 
A n e xt er n al D M C t h at c o n si st s of t w o h e p at ol o gi st s, o n e c ar di ol o gi st a n d a st ati sti ci a n will 
r e vi e w t h e pr o gr e s s of t h e st u d y.   
T h e D M C’ s s p e cifi c a cti viti e s will b e d efi n e d b y a m ut u all y a gr e e d c h art er, w hi c h will d efi n e t h e 
D M C’ s m e m b er s hi p, c o n d u ct, a n d m e eti n g s c h e d ul e.  
W hil e t h e D M C will b e a s k e d t o a d vi s e A k er o r e g ar di n g f ut ur e c o n d u ct of t h e st u d y, i n cl u di n g 
p o s si b l e e arl y st u d y t er mi n ati o n b a s e d o n t h e st o p pi n g r ul e s fr o m t h e pr ot o c ol , A k er o r et ai n s 
fi n al d e ci si o n-m a ki n g a ut h orit y o n all a s p e ct s of t h e st u d y.    
5  I N T E RI M A N AL Y SI S
I N T E RI M A N AL Y SI S 
N o  f or m al i nt eri m a n al y si s i s pl a n n e d.   
6  C H A N G E S F R O M P R O T O C O
C H A N G E S F R O M P R O T O C O L-S P E CI FI E D S T A TI S TI
S P E CI FI E D S T A TI S TI C AL A N A
C AL A N A L Y S E S
L Y S E S 
T h e  f oll o wi n g e x pl or at or y e n d p oi nt s  r el at e d t o li v er bi o s y ar e a d d e d f or  C o h ort C : 
•  
T h e pr o p orti o n of s u bj e ct s at W e e k 1 6 w h o h a d N A S H r e s ol uti o n ( 0-1 P oi nt 
I nfl a m m ati o n, 0 P oi nt B all o o ni n g) 
•  
T h e pr o p orti o n of s u bj e ct s at W e e k 1 6 w h o h a d fi br o si s i m pr o v e m e nt ≥ 2 -st a g e  
T h e e x pl or at or y e n d p oi nt r el at e d t o li v er bi o s y i s u p d at e d  f or C o h ort C “T h e pr o p orti o n of 
s u bj e ct s at W e e k 1 6 w h o h a d at l e a st 2 p oi nt s i m pr o v e m e nt i n N A S ” fr o m “T h e pr o p orti o n o f 
s u bj e ct s w h o h a d 2 p oi nt s i m pr o v e m e nt i n N A S wit h n o w or s e ni n g i n fi br o si s st a g e ” 
T h e s u b gr o u p a n al y si s i s a d d e d f or  li p o pr ot ei n pr ofil e b y st ati n u s e , a n d f or gl y c e mi c c o ntr ol 
bi o m ar k er s b y t y p e 2 di a b et e s st at u s. 
W e e k 1 2 will b e a n al y z e d f or E L F a n d it s c o m p o n e nt s if t h e d at a i s a v ail a bl e.  


A k er o T h er a p e uti c s, I n c  
C O N FI D E N TI A L  
St ati sti c al A n al y si s Pl a n  
A K -U S -0 0 1 -0 1 0 1  
 
C o h ort C V er si o n 2. 0 , 0 5 M ar c h 2 0 2 1  
P a g e 2 7  of 2 8  
 
T h e  f oll o wi n g e x pl or at or y e n d p oi nt s ar e a d d e d f or C o h ort C:  
•  
A L T i s a d d e d a s o n e of t h e m ar k er s of li v er i nj ur y a n d f u n cti o n . 
•  
C 3 M   
•  
P R O -C 3/ C 3 M r ati o  
•  
C h a n g e  fr o m b a s eli n e i n pl at el et s at W e e k s 1 2, 1 6 a n d 2 0  
•  
C h a n g e fr o m b a s eli n e i n li v er st e at o si s a s e v al u at e d b y Fi br o S c a n ® ( C A P) at W e e k 1 6  
7  P R O G R A M MI N G S P E CI FI C
P R O G R A M MI N G S P E CI FI C A TI O NS
A TI O NS  
A n al y s e s will b e p erf or m e d u si n g S A S ®  v er si o n 9. 4  or hi g h er .  All a v ail a bl e d at a will b e 
pr e s e nt e d i n s u bj e ct d at a li sti n g s w hi c h will b e s ort e d b y s u bj e ct a n d vi sit d at e a s a p pli c a bl e .  
D et ail e d Pr o gr a m mi n g S p e cifi c ati o n s will b e pr o vi d e d i n a s e p ar at e d o c u m e nt.  
 
 


A k er o T h er a p e uti c s, I n c  
C O N FI D E N TI A L  
St ati sti c al A n al y si s Pl a n  
A K -U S -0 0 1 -0 1 0 1  
 
C o h ort C V er si o n 2. 0 , 0 5 M ar c h 2 0 2 1  
P a g e 2 8  of 2 8  
 
A P P E N DI X A:  R E F E R E N
A P P E N DI X A:  R E F E R E N C E S
C E S  
S a n y al A, C h arl e s E D, N e u s c h w a n d er -T etri B A, L o o m b a R, H arri s o n S A, A b d el m al e k M F, et al. 
P e g b elf er mi n ( B M S -9 8 6 0 3 6), a P E G yl at e d fi br o bl a st gr o wt h f a ct or 2 1 a n al o g u e, i n p ati e nt s wit h 
n o n -al c o h oli c st e at o h e p atiti s: a r a n d o mi s e d, d o u bl e -bli n d, pl a c e b o -c o ntr oll e d, p h a s e 2 a tri al. 
L a n c et. 2 0 1 9; 3 9 2( 1 0 1 6 5) : 2 7 0 5 -2 7 1 7.  

Prot_000.pdf: 




EFX 
Clinical Trial Protocol: AK-US-001-0101 
Page 3 of 98 
Akero Therapeutics, Inc. 
Confidential 
Amendment 6, 08Oct2020 
SYNOPSIS 
Name of Sponsor Company: Akero Therapeutics, Inc. 
Name of Test Product and Dosage: EFX 70 mg, 50 mg, and 28 mg 
Title of Study: 
A Phase 2a, Randomized, Double-Blind, Placebo-Controlled Study Evaluating the Safety and Efficacy of 
EFX in Subjects with Nonalcoholic Steatohepatitis (NASH) 
Investigator and Study Centers:  
Approximately 30 centers in the United States (U.S.) 
Study Period: 
Main Study: 
Participation can last up to 30 weeks, which includes: 
•
Screening: 6 weeks
•
On-Treatment: 16 weeks
•
Safety Follow-up: 4 weeks
•
Repeat Liver Biopsy: 4 weeks (in eligible subjects)
Cohort C: 
Participation can last up to 26 weeks, which includes: 
•
Screening: 6 weeks
•
On-Treatment: 16 weeks
•
Safety Follow-up: 4 weeks
Phase of Development: 
Phase 2a 
Objectives:  
Main Study: 
The primary objective of this study is: 
•
To evaluate absolute change from baseline in hepatic fat fraction assessed by Magnetic
Resonance Imaging - Proton Density Fat Fraction (MRI-PDFF) at Week 12
The secondary objectives of this study are: 
•
To evaluate percent change from baseline in hepatic fat fraction assessed by MRI-PDFF at
Week 12
•
To evaluate the responder: subjects who achieved a clinically meaningful relative reduction of
at least 30% in liver fat content as measured by MRI-PDFF at Week 12
•
To evaluate the responder based on NAFLD Activity Score (NAS) system: subjects who had a
decrease of ≥ 2 points in NAS with at least a 1-point reduction in either lobular inflammation or
hepatocellular ballooning and with no concurrent worsening of fibrosis stage
•
To evaluate the change from baseline in ALT at Week 12
•
To assess the safety and tolerability of EFX in subjects with NASH
Cohort C: 
The primary objective of this study is: 
•
To assess the safety and tolerability of EFX in NASH subjects with compensated cirrhosis
The secondary objectives of this study are: 
•
To evaluate the change from baseline in liver stiffness as evaluated by FibroScan® at Week 16
•
To evaluate the change from baseline in non-invasive plasma (serum) fibrosis biomarkers
including liver fibrosis by ELF™ Test score and pro-C3 levels


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Study Design: 
This is a Phase 2a, randomized, double-blind, placebo-controlled study evaluating the safety and efficacy of 
EFX in subjects with NASH.  
Main Study: 
Subjects meeting the study’s entry criteria will be randomly assigned in 1:1:1:1 ratio into 4 treatment groups 
as shown in the figure below:  
Cohort C: 
Subjects meeting the study’s entry criteria will be randomly assigned in 1:2 ratio into 2 treatment groups as 
shown in the figure below: 
Following 16 weeks of treatment, subjects will be given the option to collect an end of treatment biopsy. 
Randomization:  


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Main Study: 
Randomization will be stratified by baseline hepatic fat fraction (< 15% vs ≥ 15%) and F1 fibrosis 
score. 
Study drug will be administered subcutaneously once weekly (QW) for a total of 16 weeks. 
Eligible subjects will be randomized to one of four treatment groups with a ratio 1:1:1:1: 
Group A: 
Placebo 
Group B:  
28 mg EFX 
Group C:  
50 mg EFX 
Group D: 
70 mg EFX 
After 16 weeks of treatment, a Safety Follow-up Visit will occur at Week 20. Subjects with ≥ 30% 
relative fat reduction on MRI-PDFF at Week 12 will be required to return between Weeks 22 - 24 
for a repeat liver biopsy and MRI-PDFF.  
Cohort C: 
Study drug will be administered subcutaneously once weekly (QW) for a total of 16 weeks. 
Eligible subjects will be randomized to one of two treatment groups with a ratio 1:2: 
Group A: 
Placebo 
Group B: 
50 mg EFX 
After 16 weeks of treatment, a Safety Follow-up Visit will occur at Week 20. 
Number of Subjects Planned:  
Total 110: Approximately 80 subjects in the Main Study and approximately 30 subjects in Cohort C. 


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Target Population: 
Males and non-pregnant, non-lactating females between 18 – 80 years of age with biopsy proven F1 - F3 
NASH. Limit F1 fibrosis to ≤ 20% of total subject population. 
Diagnosis and Main Criteria for Inclusion: 
Key Inclusion Criteria for the Main Study:  
2.
Body mass index (BMI) > 25 kg/m2 (unless the subject has biopsy-proven NASH documented within the
last 2 years).
3.
Must have confirmation of ≥ 10% liver fat content on MRI-PDFF at screening.
4.
Biopsy-proven NASH. Must have had a liver biopsy within 180 days of randomization with fibrosis
stage 1 to 3 and a non-alcoholic fatty liver disease (NAFLD) activity score (NAS) of ≥ 4 with at least a
score of 1 in each of the following NAS components:
a.
Steatosis (scored 0 to 3),
b.
Ballooning degeneration (scored 0 to 2), and
c.
Lobular inflammation (scored 0 to 3).
5.
Must have no evidence of worsening of ALT and AST (within 50%) measurements at the screening (- 6
weeks) and pre-baseline (-2 weeks) visits.
6.
Screening laboratory parameters, as determined by the central laboratory:
a.
Estimated glomerular filtration rate (eGFR) ≥ 60 mL/min, as calculated by the Cockcroft-
Gault equation;
b.
HbA1c ≤ 9.5% (or serum fructosamine ≤ 381 µmol if HbA1c is unable to be resulted);
c.
Hemoglobin ≥ 11 g/dL;
d.
INR ≤ 1.3, unless due to therapeutic anticoagulation;
e.
Direct bilirubin ≤ 0.3 mg/dL;
f.
Total bilirubin ≤ 1.3 x upper limit of normal (ULN), unless due to an alternate etiology
such as Gilbert’s syndrome or hemolytic anemia;
g.
Creatinine kinase < 3 x ULN;
h.
Platelet count ≥ 150,000/µL;
i.
Serum triglyceride level ≤ 500 mg/dL;
j.
ALT < 5 x ULN;
k.
AST < 5 x ULN;
l.
AST > 20u/L (only required for subjects without a historical biopsy in the last 2 years
confirming fibrosis 1-3 and a NAS ≥ 4);
m. ALP < 2 x ULN.
7.
FibroScan® measurement > 7.0 kPa.
Key Inclusion Criteria for Cohort C: 
2.
Compensated cirrhosis (Fibrosis Stage 4) due to NASH documented by a local pathologist within 24
months of Screening with no evidence of competing etiology, and at least one co-existing or historic
metabolic comorbidity. If a historical biopsy is not available within 24 months of Screening, the subject
may undergo a liver biopsy to be assessed by the local or central reader and confirm to have
compensated cirrhosis (Fibrosis Stage 4).
3.
FibroScan® measurement > 13.1 kPa.
4.
Enhanced Liver Fibrosis (ELF) score of > 9.8.
5.
Must have no evidence of worsening of ALT and AST (within 50%) measurements at the screening
(-6 weeks) and pre-baseline (-2 weeks) visits.
a.
A single retest of the pre-baseline labs is permitted only if there is reason to believe the
initial value was erroneous due to a sample processing error or due to an extenuating
circumstance. An average of the screening and pre-baseline value will be used and
compared to the retest value. The retest value must have no evidence of worsening within
50% of the average of the screening and pre-baseline value.


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6.
Screening laboratory parameters, as determined by the central laboratory:
a.
Estimated glomerular filtration rate (eGFR) ≥ 60 mL/min, as calculated by the Cockcroft-
Gault equation;
b.
HbA1c ≤ 9.5% (or serum fructosamine ≤ 381 µmol if HbA1c is unable to be resulted);
c.
Hemoglobin ≥ 11 g/dL;
d.
INR ≤ 1.3, unless due to therapeutic anticoagulation;
e.
Direct bilirubin ≤ 0.3 mg/dL;
f.
Total bilirubin ≤ 1.3 x upper limit of normal (ULN), unless due to an alternate etiology
such as Gilbert’s syndrome or hemolytic anemia;
g.
Creatinine kinase < 3 x ULN;
h.
Platelet count ≥ 125,000/µL;
i.
Serum triglyceride level ≤ 500 mg/dL;
j.
ALT ≤ 5 x ULN;
k.
AST < 5 x ULN;
l.
ALP < 2 x ULN;
m. Albumin ≥ 3.5 g/dL.
Key Exclusion Criteria for the Main Study: 
1.
Weight gain or loss > 5% in the 3 months prior to randomization or > 10% in the 6 months prior to
screening.
2.
Type 1 and insulin-dependent Type 2 diabetes.
3.
Presence of cirrhosis on liver biopsy (stage 4 fibrosis).
4.
Poorly controlled hypertension (blood pressure [BP] > 160/100).
5.
Prior history of decompensated liver disease including ascites, hepatic encephalopathy (HE), or variceal
bleeding.
6.
Chronic hepatitis B virus (HBV) infection (hepatitis B surface antigen [HBsAg] positive).
7.
Chronic hepatitis C virus (HCV) infection (HCV antibody [Ab] and HCV ribonucleic acid [RNA]
positive). Subjects cured of HCV infection less than 2 years prior (based on date of RNA polymerase
chain reaction [PCR] negative confirmation following conclusion of treatment) to the screening visit are
not eligible.
8.
Prior or planned (during the study period) bariatric surgery (e.g., gastroplasty, roux-en-Y gastric
bypass), surgery reversal or removal of intragastric balloon > 2 years prior to enrollment would be
eligible.
9.
Other causes of liver disease based on medical history and/or centralized review of liver histology,
including but not limited to: alcoholic liver disease, autoimmune disorders (e.g., primary biliary
cholangitis [PBC], primary sclerosing cholangitis [PSC], autoimmune hepatitis), drug-induced
hepatotoxicity, Wilson disease, clinically significant iron overload, or alpha-1-antitryspin deficiency
requiring treatment.
10. Subjects with osteoporosis, defined as a T-score of -2.5 or lower at screening.
11. History of liver transplantation.
12. Current or prior history of hepatocellular carcinoma (HCC).
13. Alcohol intake above an average limit of 2 drinks per day for women and 3 drinks per day for men
assessed by alcohol use disorders identification test (AUDIT-C) questionnaire.
14. Human immunodeficiency virus (HIV) infection.
15. Unstable cardiovascular disease in the 6 months prior to screening.
16. Life expectancy less than 2 years.
Key Exclusion Criteria for Cohort C:
1.
Weight gain or loss > 5% in the 3 months prior to randomization or > 10% in the 6 months prior to
screening.
2.
Type 1 and insulin-dependent Type 2 diabetes.
3.
Prior history of or current decompensated liver disease including ascites, hepatic encephalopathy (HE),
or variceal bleeding.


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4.
Child-Pugh Score > 6 (Class B or C), as determined at screening, unless due to therapeutic anti-
coagulation.
5.
MELD score > 12, as determined at screening, unless due to therapeutic anti-coagulation.
6.
Poorly controlled hypertension (blood pressure [BP] > 160/100).
7.
Chronic hepatitis B virus (HBV) infection (hepatitis B surface antigen [HBsAg] positive).
8.
Chronic hepatitis C virus (HCV) infection (HCV antibody [Ab] and HCV ribonucleic acid [RNA]
positive). Subjects cured of HCV infection less than 2 years prior (based on date of RNA polymerase
chain reaction [PCR] negative confirmation following conclusion of treatment) to the screening visit are
not eligible.
9.
Prior or planned (during the study period) bariatric surgery (e.g., gastroplasty, roux-en-Y gastric
bypass), surgery reversal or removal of intragastric balloon > 2 years prior to enrollment would be
eligible.
10. Other causes of liver disease based on medical history and/or centralized review of liver histology,
including but not limited to: alcoholic liver disease, autoimmune disorders (e.g., primary biliary
cholangitis [PBC], primary sclerosing cholangitis [PSC], autoimmune hepatitis), drug-induced
hepatotoxicity, Wilson disease, clinically significant iron overload, or alpha-1-antitryspin deficiency
requiring treatment.
11. Subjects with osteoporosis, defined as a T-score of -2.5 or lower at screening.
12. History of liver transplantation.
13. Current or prior history of hepatocellular carcinoma (HCC).
14. Alcohol intake above an average limit of 2 drinks per day for women and 3 drinks per day for men
assessed by alcohol use disorders identification test (AUDIT-C) questionnaire.
15. Human immunodeficiency virus (HIV) infection.
16. Unstable cardiovascular disease in the 6 months prior to screening.
17. Life expectancy less than 2 years.
Investigational Product, Dosage, and Mode of Administration: 
EFX is an IgG1Fc-fibroblast growth factor 21 (FGF21) fusion protein. 
Main Study: 
EFX or Placebo is administered subcutaneously as follows: 
•
Placebo QW for 16 weeks (n = 20)
•
28 mg EFX QW for 16 weeks (n = 20)
•
50 mg EFX QW for 16 weeks (n = 20)
•
70 mg EFX QW for 16 weeks (n = 20)
Cohort C: 
EFX or Placebo is administered subcutaneously as follows: 
•
Placebo QW for 16 weeks (n = 10)
•
50 mg EFX QW for 16 weeks (n = 20)
Criteria for Evaluation: 
Safety:  
The safety of EFX will be assessed during the study through the reporting of adverse events (AEs), clinical 
laboratory tests, electrocardiogram (ECG), vital sign assessments, body weight, anti-drug antibody (ADA) 
and neutralizing antibody (NAB) assessments, and concomitant medication usage. 
An external Data Monitoring Committee (DMC) that consists of two hepatologists, one cardiologist, and a 
statistician will review the progress of the study. The DMC will convene after 20 subjects (approximately 5 
per treatment group in the Main Study) have completed the Week 4 assessments. The DMC will receive all 
reports of serious adverse events (SAEs) and convene as needed to monitor for safety. 


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Pharmacokinetics: 
Blood for pharmacokinetics (PK) will be collected at specified timepoints after dosing as outlined in the 
Schedule of Assessments (Appendix A and Appendix B) and will be used to estimate steady state PK 
parameters (i.e., Tmax, Cmax, Ctrough, AUC0-t, t½ , CL/F, Vz/F) following subcutaneous (SC) administration of 
EFX. 
Efficacy: 
Main Study: 
The efficacy will be assessed via the absolute change from baseline in hepatic fat fraction measured 
by MRI-PDFF at Week 12. 
Cohort C: 
The efficacy will be assessed via the change from baseline in liver stiffness as evaluated by 
FibroScan® at Week 16 and non-invasive plasma (serum) fibrosis biomarkers including Liver 
Fibrosis by ELF™ Test score and pro-C3 levels. 
Sample Size Calculation: 
Main Study:  
With the following assumptions, the power for N = 20 subjects with active treatment is 
approximately 91% to detect: 
•
a true, baseline-adjusted, mean decrease from baseline in MRI-PDFF-estimated hepatic fat 
content of 5% (absolute) compared to placebo,
•
with a one-sided t-test for decrease from placebo,
•
at a 5% significance level,
•
20 subjects receiving placebo, and
•
a standard deviation estimated as 5.2% (Sanyal et al. 2019).
Cohort C: 
Since the primary objective for Cohort C is to assess the safety and tolerability of EFX in NASH 
subjects with compensated cirrhosis, the sample size of Cohort C is determined based on clinical 
considerations, and the treatment comparisons of efficacy measurements are not powered. 
Statistical Methods: 
Efficacy Analysis: 
Primary Efficacy Analysis (Main Study Only): 
The primary efficacy variable will be the absolute change from baseline hepatic 
fat fraction measured by MRI-PDFF at Week 12. Summary statistics (number of 
subjects, mean, standard deviation, median, minimum, and maximum) at all 
visits, and change from baseline will be provided. The primary efficacy variable 
will be analyzed using an analysis of covariance (ANCOVA) model with 
treatment group and F1 fibrosis score as factors and baseline hepatic fat fraction 
(absolute %) measured by MRI-PDFF as a covariate. For any subjects in the full 
analysis set (FAS) with a missing primary efficacy value, the primary efficacy 
variable will be imputed with multiple imputation method. The specification of 
the multiple imputation method will be provided in the SAP. Fixed hypothesis 
testing sequence will be used to control the multiplicity for each active dose to 
be compared with placebo.  
Secondary Efficacy Analysis: 
Main Study: 
For the continuous secondary efficacy variables related to hepatic fat fraction, 
like percent change from baseline in fat fraction assessed by MRI-PDFF at Week 


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12, the same ANCOVA model used for primary efficacy variable will be used. 
For the other continuous secondary efficacy variables, the ANCOVA model with 
treatment group, baseline hepatic fat fraction (< 15% vs ≥ 15%), and F1 fibrosis 
score as factors will be used. Normality will be tested for the model residuals. 
For certain efficacy variables, logarithmic transformation may be performed 
prior to fitting the ANCOVA model.  
For the responder(s) based on MRI-PDFF, logistic regression will be used for 
the analysis. The analyses will include the treatment group and F1 fibrosis score 
as factors and baseline hepatic fat fraction assessed by MRI-PDFF as a 
covariate. The missing value will be imputed as a non-responder. 
For the responder(s) based on the NAS system, Fisher’s exact test will be used 
for the analyses. Odds ratios, 95% confidence intervals and p-values will be 
provided. The missing value will be imputed as a non-responder. 
Cohort C: 
Summary statistics (number of subjects, mean, standard deviation, median, 
minimum, and maximum) at all visits and change from baseline will be 
provided. The efficacy variables will be analyzed with an ANCOVA model with 
treatment group as a factor and baseline value as a covariate. The effect of Type 
2 diabetes status will be explored. Normality will be tested for the model 
residuals. 
Exploratory Efficacy Analyses: 
The same analyses used for the secondary efficacy variables will be used for the 
exploratory efficacy variables. 
Pharmacokinetic 
Analysis: 
Plasma concentrations of EFX will be listed and summarized. 
Detailed description of data analysis and statistical methods to be used will be outlined separately in a 
Statistical Analysis Plan (SAP). 
This study will be conducted in accordance with the guidelines of Good Clinical Practice 
(GCP) including archiving of essential documents. 


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TABLE OF CONTENTS 
STUDY ACKNOWLEDGEMENT SIGNATURE PAGE ........................................................2 
SYNOPSIS .................................................................................................................................3 
TABLE OF CONTENTS .........................................................................................................11 
LIST OF TABLES ...................................................................................................................15 
LIST OF FIGURES .................................................................................................................15 
LIST OF APPENDICES ..........................................................................................................16 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS ..........................................16 
1.
BACKGROUND AND RATIONALE ..........................................................................21 
1.1. 
Background ..................................................................................................................21 
1.1.1. 
FGF21 ....................................................................................................................21 
1.2. 
EFX Background .........................................................................................................22 
1.3. 
Nonclinical Findings ....................................................................................................23 
1.3.1. 
Pharmacology ........................................................................................................23 
1.3.2. 
Pharmacokinetics ...................................................................................................24 
1.3.3. 
Toxicology .............................................................................................................24 
1.3.3.1. 
Repeated-dose Toxicology Studies ..................................................................24 
1.3.3.2. 
Genotoxicity (Mutagenicity) ............................................................................26 
1.3.3.3. 
Carcinogenicity ................................................................................................27 
1.3.3.4. 
Developmental and Reproductive Toxicity .....................................................27 
1.3.3.5. 
Ongoing/Planned Toxicology Studies of EFX ................................................27 
1.3.3.6. 
Margin of Safety for Clinical Dose of EFX .....................................................27 
1.4. 
Clinical Trials of EFX ..................................................................................................28 
1.4.1. 
Study 20100015 - Phase 1a Single Ascending Dose Study in Diabetic 
Patients ...................................................................................................................28 
1.4.1.1. 
Subject Disposition ..........................................................................................29 
1.4.1.2. 
Pharmacokinetic Results ..................................................................................29 
1.4.1.3. 
Pharmacodynamic Results ...............................................................................29 
1.4.1.4. 
Safety Results...................................................................................................29 
1.4.1.5. 
Conclusion .......................................................................................................30 
1.4.2. 
Study 20100018 - Phase 1b Multiple Ascending Dose Study in Diabetic 
Patients ...................................................................................................................31 
1.4.2.1. 
Subject Disposition ..........................................................................................31 
1.4.2.2. 
Pharmacokinetic Results ..................................................................................31 
1.4.2.3. 
Pharmacodynamic Results ...............................................................................32 
1.4.2.4. 
Safety Results Describing the Combined Q2W and QW Datasets ..................33 


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1.4.2.5. 
Conclusion .......................................................................................................34 
1.5. 
Rationale for this Study ...............................................................................................35 
1.6. 
Rationale for Selection of Dose ...................................................................................37 
1.7. 
Compliance ..................................................................................................................38 
2.
STUDY OBJECTIVES ..................................................................................................39 
2.1. 
Primary Objectives.......................................................................................................39 
2.2. 
Secondary Objectives...................................................................................................39 
2.3. 
Exploratory Objectives ................................................................................................39 
3.
INVESTIGATIONAL PLAN ........................................................................................41 
3.1. 
Overall Study Design and Plan ....................................................................................41 
3.2. 
Study Duration and Number of Centers .......................................................................42 
3.3. 
End of Study ................................................................................................................42 
3.4. 
Early Termination ........................................................................................................42 
3.5. 
Post Study Care ............................................................................................................43 
4.
STUDY POPULATION SELECTION ..........................................................................44 
4.1. 
Study Population ..........................................................................................................44 
4.2. 
Inclusion Criteria .........................................................................................................44 
4.3. 
Exclusion Criteria ........................................................................................................46 
5.
INVESTIGATIONAL MEDICINAL PRODUCTS (IMP) ............................................50 
5.1. 
Randomization, Blinding and Treatment Codes ..........................................................50 
5.1.1. 
Procedures for Breaking Treatment Codes ............................................................50 
5.2. 
Investigational Product(s) ............................................................................................50 
5.2.1. 
Storage and Handling .............................................................................................51 
5.2.2. 
Dosage and Administration....................................................................................52 
5.3. 
Prior and Concomitant Medications ............................................................................52 
5.4. 
Investigational Medicinal Product Accountability ......................................................54 
5.4.1. 
Investigational Medicinal Product Return or Disposal ..........................................54 
6.
STUDY PROCEDURES ................................................................................................55 
6.1. 
Screening and Informed Consent .................................................................................55 
6.2. 
Demographics and Medical History ............................................................................55 
6.3. 
Physical Examination...................................................................................................55 


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6.4. 
Vital Signs, Weight, Hip and Waist Circumference ....................................................56 
6.5. 
12-Lead Electrocardiography .......................................................................................56 
6.6. 
FibroScan® ...................................................................................................................57 
6.7. 
Liver Biopsy.................................................................................................................57 
6.8. 
MRI-PDFF ...................................................................................................................58 
6.9. 
DXA Scan ....................................................................................................................58 
6.10. Health Related Quality of Life Questionnaires ............................................................59 
6.10.1. 
Short Form 36 Health Survey (SF-36) ...................................................................59 
6.10.2. 
Chronic Liver Disease Questionnaire-Nonalcoholic Fatty Liver Disease 
(CLDQ-NAFLD) ...................................................................................................59 
6.10.3. 
Work Productivity and Activity Impairment (WPAI) ...........................................59 
6.11. Alcohol Use Disorders Identification Test (AUDIT-C) ..............................................59 
6.12. Lifestyle Modification .................................................................................................59 
6.13. Clinical Laboratory Tests .............................................................................................60 
6.13.1. 
Laboratory Parameters ...........................................................................................60 
6.14. Sample Collection, Storage, and Shipping ..................................................................62 
6.15. Pharmacokinetic Assessments .....................................................................................62 
6.16. Anti-Drug Antibody and Neutralizing Antibody Sampling.........................................62 
6.17. Blood Storage...............................................................................................................62 
6.18. Biomarkers ...................................................................................................................62 
6.19. Criteria for Discontinuation of Study Drug .................................................................63 
6.20. Interruption of Study Drug...........................................................................................64 
6.21. Adverse Events ............................................................................................................64 
6.21.1. 
Severity ..................................................................................................................65 
6.21.2. 
Relationship ...........................................................................................................65 
6.21.3. 
Overdose ................................................................................................................66 
6.21.4. 
Serious Adverse Events .........................................................................................66 
6.21.4.1. 
Definition .........................................................................................................66 
6.21.5. 
Reporting Adverse Events .....................................................................................66 
6.21.5.1. 
Reporting Procedures for Non-Serious Adverse Events ..................................66 
6.21.5.2. 
Reporting Procedures Serious Adverse Events ................................................67 
6.22. Adverse Events of Special Interest ..............................................................................69 
6.23. Clinical Laboratory Abnormalities and Other Abnormal Assessments as 
Adverse Events or Serious Events ...............................................................................69 
6.24. Observation for Drug Induced Liver Injury (DILI) .....................................................71 
6.24.1. 
Subjects with Normal Liver Transaminases and Bilirubin at Baseline .................71 
6.24.2. 
Subjects with Elevations in Liver Transaminases or Bilirubin at Baseline ...........71 


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6.24.3. 
Close Observation for Suspected Drug-Induced Liver Injury ...............................72 
6.25. Removal of Subjects from the Study ...........................................................................73 
7.
PLANNED STATISTICAL METHODS .......................................................................74 
7.1. 
Endpoints .....................................................................................................................74 
7.1.1. 
Efficacy Endpoints .................................................................................................74 
7.1.1.1. 
Primary Endpoint .............................................................................................74 
7.1.1.2. 
Secondary Efficacy Endpoints .........................................................................74 
7.1.1.3. 
Exploratory Efficacy Endpoints .......................................................................74 
7.1.2. 
Safety Endpoints ....................................................................................................75 
7.2. 
Analysis Conventions ..................................................................................................76 
7.3. 
Analysis Sets ................................................................................................................76 
7.3.1. 
Efficacy ..................................................................................................................76 
7.3.2. 
Safety .....................................................................................................................76 
7.3.2.1. 
Pharmacokinetics .............................................................................................76 
7.3.2.2. 
Biomarkers .......................................................................................................76 
7.4. 
Data Handling Conventions .........................................................................................76 
7.5. 
Demographic Data and Baseline Characteristics .........................................................77 
7.6. 
Efficacy Analysis .........................................................................................................77 
7.6.1. 
Primary Efficacy Analysis .....................................................................................77 
7.6.2. 
Secondary Efficacy Analysis .................................................................................77 
7.6.3. 
Exploratory Efficacy Analysis ...............................................................................78 
7.7. 
Safety Analysis ............................................................................................................78 
7.7.1. 
Extent of Exposure .................................................................................................78 
7.7.2. 
Adverse Events ......................................................................................................78 
7.7.3. 
Laboratory Evaluations ..........................................................................................79 
7.8. 
Pharmacokinetic Analysis ............................................................................................79 
7.9. 
Biomarker Analysis .....................................................................................................79 
7.10. Sample Size ..................................................................................................................80 
7.11. Data Monitoring Committee ........................................................................................80 
7.11.1. 
Stopping Rules .......................................................................................................81 
7.12. Adjudication Committee ..............................................................................................81 


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8.
ADMINISTRATIVE CONSIDERATIONS ..................................................................82 
8.1. 
Investigator Responsibilities ........................................................................................82 
8.1.1. 
Good Clinical Practice ...........................................................................................82 
8.1.2. 
Institutional Review Board (IRB)/Independent Ethics Committee (IEC)/ 
Ethics Committee (EC) Review and Approval ......................................................82 
8.1.3. 
Informed Consent...................................................................................................82 
8.1.4. 
Confidentiality .......................................................................................................83 
8.1.5. 
Study Files and Retention of Records ....................................................................83 
8.1.6. 
Electronic Case Report Forms ...............................................................................84 
8.1.7. 
Inspections .............................................................................................................85 
8.1.8. 
Protocol Compliance ..............................................................................................85 
8.2. 
Sponsor Responsibilities ..............................................................................................85 
8.2.1. 
Protocol Modifications...........................................................................................85 
8.2.2. 
Study Report and Publications ...............................................................................85 
8.3. 
Joint Investigator/Sponsor Responsibilities .................................................................86 
8.3.1. 
Payment Reporting.................................................................................................86 
8.3.2. 
Access to Information for Auditing or Inspections................................................86 
8.3.3. 
Study Discontinuation ............................................................................................86 
9.
REFERENCE LIST ........................................................................................................87 
10.
APPENDICES ................................................................................................................90 
LIST OF TABLES 
Table 1. 
Systemic Exposures in Monkey, Rat, and Humans at the 
NOAEL and Margin of Safety in Humans ..........................................28 
Table 2. 
Treatment-Related Adverse Events and Withdrawals .........................34 
Table 3. 
Clinical Laboratory Assessments .........................................................61 
LIST OF FIGURES 
Figure 1. 
EFX Schematic Structure with Disulfide Bonds and Chains...............23 
Figure 2. 
Study Schema – Main Study ................................................................41 
Figure 3. 
Study Schema – Cohort C ....................................................................42 


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LIST OF APPENDICES 
Appendix A. 
Schedule of Assessments- Main Study ................................................90 
Appendix B. 
Schedule of Assessments- Cohort C ....................................................93 
Appendix C. 
Pregnancy Precautions, Definition for Female of Childbearing 
Potential, and Contraceptive Requirements .........................................96 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
ADA 
anti-drug antibodies 
AE 
adverse event 
AESI 
adverse event of special interest 
ALP 
alkaline phosphatase 
ALT 
alanine aminotransferase (SGPT) 
ANC 
absolute neutrophil count 
ANCOVA 
analysis of covariance 
aPTT 
activated partial thromboplastin time 
AST 
aspartate aminotransferase (SGOT) 
AUC 
area under the time-concentration curve 
AUDIT-C 
alcohol use disorders identification test 
BMI 
body mass index 
BSAP 
bone specific alkaline phosphatase 
BUN 
blood urea nitrogen 
CAP 
controlled attenuation parameter 
CFR 
Code of Federal Regulations 
CI 
confidence interval 
Cmax 
maximum plasma drug concentration 
Cmin 
minimum plasma drug concentration 
CP 
Child-Pugh 
CRF 
case report form 
cT1 
Corrected T1 
CTCAE 
Common Terminology Criteria for Adverse Events 


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CV 
coefficient of variation 
DILI 
drug-induced liver injury 
DNA 
deoxyribonucleic acid 
DXA 
Dual Energy X-ray Absorptiometry 
ECG 
electrocardiogram 
eCRF 
electronic Case Report Form 
EFX 
efruxifermin 
eGFR 
estimated Glomerular Filtration Rate 
ELF™ 
Enhanced Liver Fibrosis Panel 
FAS 
full analysis set 
FDA 
Food and Drug Administration 
FGF 
fibroblast growth factor 
FGFR 
fibroblast growth factor receptor 
FVB 
Friend Virus B 
GCP 
Good Clinical Practice 
GGT 
gamma glutamyl transferase 
GLP 
Good Laboratory Practice 
HbA1c 
hemoglobin A1c 
HBcAb 
total hepatitis B core antibody 
HBsAg 
hepatitis B surface antigen 
HBV 
hepatitis B virus 
HCC 
hepatocellular carcinoma 
Hct 
hematocrit 
HCV 
hepatitis C virus 
HDL 
high-density lipoprotein cholesterol 
Hgb 
hemoglobin 
HIPAA 
Health Information Portability and Accountability Act 
HITECH 
Health Information Technology for Economic and Clinical Health 
HIV 
human immunodeficiency virus 


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HLGT 
high-level group term 
HLT 
high-level term 
HOMA 
homeostasis model assessment of insulin resistance, (HOMA-IR) and 
beta cell function (HOMA-B) 
HRQoL 
health-related quality of life 
ICF 
informed consent form 
ICH 
International Council for Harmonisation  
IEC 
Independent Ethics Committee 
IgG1 
human immunoglobulin G1  
IMP 
investigational medicinal product 
IND 
Investigational New Drug  
INR 
International Normalized Ratio 
IP 
investigational product 
IRB 
Institutional Review Board 
IRT 
interactive response technology 
ITT 
intent-to-treat 
IV 
intravenous 
KO 
knock-out 
LDH 
lactate dehydrogenase 
LDL 
low-density lipoprotein cholesterol 
LLT 
low-level term 
LOCF 
last observation carried forward 
mAb 
monoclonal antibody 
MedDRA 
Medical Dictionary for Regulatory Activities 
MELD 
Model for End-Stage Liver Disease 
MRE 
magnetic resonance elastography 
MRI 
magnetic resonance imaging 
MRI-PDFF 
magnetic resonance imaging – proton density fat fraction 
NAFLD 
non-alcoholic fatty liver disease 
NAS 
non-alcoholic fatty liver disease activity score 


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NASH 
nonalcoholic steatohepatitis 
NOAEL 
no-observed-adverse-effect-level 
PBC 
primary biliary cholangitis 
PD 
pharmacodynamics 
PI 
principal investigator 
PK 
pharmacokinetics 
PSC 
primary sclerosing cholangitis 
PT 
preferred term 
PT 
prothrombin time 
Q2W 
every 2 weeks 
QW 
every week 
RBC 
red blood cell (count) 
RNA 
ribonucleic acid 
SC 
subcutaneous 
SAE 
serious adverse event 
SAP 
Statistical Analysis Plan 
SD 
standard deviation 
SE 
standard error  
SGOT 
serum glutamate oxaloacetate transaminase (AST) 
SGPT 
serum glutamate pyruvate transaminase (ALT) 
SOC 
system organ class 
SUSAR 
suspected unexpected serious adverse reaction 
T1/2 
time to half plasma concentration (half-life) 
TBL 
Total bilirubin 
TEAEs 
treatment emergent adverse events 
TESAEs 
treatment-emergent serious AEs 
TK 
toxicokinetics 
Tmax 
time to maximum plasma concentration 
TSH 
thyroid stimulating hormone 


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ULN 
upper-limit of normal 
U.S. 
United States 
WBC 
white blood cell (count) 


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1.
BACKGROUND AND RATIONALE
1.1. 
Background 
Nonalcoholic steatohepatitis (NASH) is the most severe form of non-alcoholic fatty liver 
disease (NAFLD) and is characterized by the presence of an abnormal accumulation of fat in 
the liver, which in some individuals can progress to liver cell injury (hepatocellular 
ballooning), inflammation, and fibrosis. Lipotoxicity and oxidative stress are considered to 
be the drivers of disease progression, or the underlying cause of the disease. As NASH 
progresses, it can result in excessive deposition of extracellular collagen, or scarring of the 
liver (fibrosis) ultimately leading to liver cirrhosis. Later stages of NASH are associated with 
substantially increased risk of hepatocellular carcinoma and major adverse cardiac events 
(Ekstedt et al. 2015), underlining the healthcare burden presented by NASH in the absence of 
approved therapies.   
NASH is closely related to the epidemic of obesity and diabetes and is often viewed as the 
liver manifestation of the Metabolic Syndrome. It is heavily influenced by lifestyle (e.g., 
chronically excessive calorie intake, sedentary activity) and is distinct from other fatty liver 
diseases caused by viral infection, alcohol abuse, or medication side effects (The Nash 
Education Program 2019). NASH can potentially progress to advanced liver disease, 
cirrhosis, and hepatocellular carcinoma (The Nash Education Program 2019). The current 
prevalence of NASH in the United States (U.S.) population is estimated to be around 3 – 4%.  
Approximately 1 in 5 of the near 80 million patients with NAFLD in the U.S. (Ruhl & 
Everhart 2015) are projected to develop NASH (Younossi et al. 2016). This unfurling 
epidemic of liver disease warrants a major public health effort to control the burden of 
disease, in particular its many complications/ co-morbid conditions. 
1.1.1. 
FGF21 
Fibroblast growth factor 21 (FGF21) is a member of the endocrine FGF sub-family. It 
depends on a high affinity interaction with β-Klotho to enable formation of a co-receptor 
complex with fibroblast growth factor receptor (FGFR) to initiate intracellular signaling.  
FGF21 is a secreted polypeptide highly expressed in tissues relevant to metabolic function, 
including the liver, adipose tissue, and pancreas (Fon Tacer et al. 2010, Nishimura et al. 
2000). Studies have shown that FGF21 is a metabolic regulator of energy homeostasis, 
maintaining appropriate balance across glucose-lipid-protein utilization, and enhancing 
insulin sensitivity in the fed state (Kim et al. 2017, Gaich et al. 2013, Li et al. 2013, Talukdar 
et al. 2016). FGF21 directly modulates whole-body lipid metabolism to reduce hepatic lipid 
accumulation. FGF21 has been shown to reverse hepatic steatosis and to prevent diet-induced 
obesity in both rodents and nonhuman primates (Lin et al. 2013, Camporez et al. 2013, Mu et 
al. 2012, Xu et al. 2009, Coskun et al. 2008, Wu et al. 2017, Talukdar et al. 2016). Hence, 
FGF21 is a target for the development of novel biological drugs for metabolic diseases 
(Gimeno & Moller 2014, Chen et al. 2017). FGF21 forms a ligand co-receptor complex by 
anchoring to β-Klotho then interacts with one of three members of the FGFR family 
(specifically FGFR1c, 2c and 3c) to induce dimerization and autophosphorylation of FGFR. 
Activated FGFR initiates specific intracellular signaling cascades leading to the expression of 


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FGF21 autocrine biological functions (Li et al. 2013). Serum FGF21 levels are elevated in 
human subjects with diabetes, obesity, and NASH. This has been interpreted as evidence of 
FGF21 resistance (Li et al. 2013, Wu et al. 2017). 
In NASH, FGF21 appears to address both the underlying disease driver, i.e. excessive flux of 
calories and lipid into the liver, and the ensuing downstream sequelae of hepatocyte stress 
leading to hepatic inflammation and fibrosis.  FGF21 directly modulates whole body lipid 
metabolism to reduce hepatic lipid accumulation and has been shown to reverse hepatic 
steatosis and to prevent diet-induced obesity in both rodents and nonhuman primates (Lin et 
al. 2013, Camporez et al. 2013, Mu et al. 2012, Xu et al. 2009, Coskun et al. 2008, Wu et al. 
2017, Talukdar et al. 2016). 
Various in vitro and in vivo findings suggest potential beneficial effects of FGF21 agonism 
in NASH, including improvements in liver fat, inflammation, and fibrosis (Xu et al. 2009, 
Lee et al. 2016, Tanaka et al. 2015). Administration of native FGF21or long-acting FGF21 
analogues prevented an increase in liver fat and suppressed inflammation and fibrosis, as 
assessed by histology, in rodent models of liver disease (Tanaka et al. 2015, Fisher et al. 
2014, Bao et al. 2018). The models used a range of pathological insults, including excessive 
intake of fat and fructose, alcohol, diet deficient in methionine and choline, or chemical 
toxins (e.g., carbon tetrachloride, dimethyl nitrosamine; [Xu et al. 2016]). Increasing FGF21 
tone was effective in all the models, whereas loss of FGF21 function exacerbated 
development of liver pathology. 
Genetic and pharmacological studies provide further evidence that FGR21 agonism could 
have potentially beneficial effects on NASH.  FGF21 knockout (KO) mice are viable, fertile, 
and show no strong metabolic phenotypes when fed a normal chow diet. However, they 
become insulin resistant with hepatosteatosis and have significantly elevated plasma glucose 
and triglyceride levels when challenged with high-fat or ketogenic diets. In contrast, 
transgenic mice over-expressing FGF21 are lean and resistant to diet induced or 
age-associated obesity and insulin resistance. 
1.2. 
EFX Background 
EFX is a 92.0 kD E. coli-expressed human IgG1-Fc- Fc-FGF21 fusion protein—a long-acting 
FGF21 analogue. Each molecule contains one dimeric Fc portion and 2 modified FGF21 
proteins. EFX has 8 disulfide bonds, 6 intrachain, and 2 interchain as depicted in Figure 1. 
Two of the intrachain disulfide bonds are in the FGF21 protein between Cys318 and Cys336, 
one for each monomer unit. Additionally, 3 mutation sites, L98R (residue 341 in Fc-fusion), 
P171G (414 in Fc-fusion), and A180E (423 in Fc-fusion) have been introduced into the wild-
type human FGF21 sequence to decrease its susceptibility to in vivo proteolytic degradation 
and reduce aggregation while maintaining balanced FGF21 agonism across FGFR1c/2c/3c 
with selectivity over FGFR4. A schematic of the structure is shown in Figure 1. 


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Figure 1. 
EFX Schematic Structure with Disulfide Bonds and Chains 
 
1.3. 
Nonclinical Findings 
The intended clinical route of administration for EFX is via subcutaneous (SC) injection.  
EFX was studied in 4-week toxicology studies in rat and cynomolgus monkeys to support the 
original diabetes indication.  Subsequently, EFX was examined in 16-week toxicology 
studies in rat and cynomolgus monkeys to support this planned Phase 2 clinical study in 
NASH patients.  The results from the 16-week studies as well as previously conducted 
nonclinical studies are described in the Investigator’s Brochure (IB). 
1.3.1. 
Pharmacology 
In vitro characterization demonstrated that EFX bound to human, cynomolgus monkey, and 
mouse β-Klotho with EC50 values of 11 nM, 10 nM, and 0.8 nM, respectively. In cells 
transiently co-expressing β-Klotho and individual FGFR, EFX selectively activated 
c-isoforms of FGFR, FGFR1c, 2c and 3c, with balanced potency. The potency of EFX 
determined by measuring its ability to activate the β-Klotho dependent MAPK pathway was 
1.4 nM in human β-Klotho recombinant HEK 293 cells, and 0.44 nM in human primary 
adipocytes. EFX displayed cross species reactivity with comparable in vitro potency to 
activate receptor complex (FGFR1c/β-Klotho) from human, cynomolgus monkey, rat, and 
mice. In vivo, EFX is pharmacologically active in rodents and monkeys. Administration of 
EFX to obese and insulin resistant mouse and monkey models improved the metabolic state 
of these animals resulting in reduced plasma glucose, insulin, and triglyceride levels; 
improved lipoprotein profile; enhanced glucose tolerance; and significant weight loss. 


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Evaluation of cardiovascular, neurobehavioral, and respiratory function were incorporated 
into the 4-week repeated dose toxicity study with cynomolgus monkey treated with weekly 
doses of EFX of up to 100 mg/kg. No EFX-related effects on electrocardiograms (ECG) or 
pulse oximetry were observed, and no neurological abnormalities were observed at any dose 
in the treated monkeys. 
1.3.2. 
Pharmacokinetics 
The toxicokinetics (TK) of EFX was characterized in repeat-dose (weekly) SC toxicology 
studies conducted in Sprague Dawley rats and cynomolgus monkeys. EFX systemic exposure 
was approximately dose-proportional over the dose range of 1 - 100 mg/kg in rats and 
monkeys with no gender differences. Accumulation was less than 2-fold after once weekly 
doses of EFX for 16 weeks in rats and monkeys. The terminal half-life (t1/2,z) was 3-4 days in 
rats and monkeys.  
1.3.3. 
Toxicology 
1.3.3.1. 
Repeated-dose Toxicology Studies 
The toxicology studies conducted to support this Phase 2 clinical trial consisted of 16-week 
dosing in rats and cynomolgus monkeys. These studies were conducted in compliance with 
Good Laboratory Practice (GLP) and consistent with ICH M3(2) and ICH S6(R1). The 
summary findings are described below with further details provided in the current IB.   
1.3.3.1.1. 
4-Week Toxicity Studies Supporting Phase I 
In a 4-week SC injection study (Study 110993), EFX was administered at doses of 0, 1, 10, 
or 100 mg/kg to Sprague-Dawley rats. In this study, EFX-related pharmacologic effects 
observed included decreased body weight gain and mean body weight. Based on these 
results, the no-observed-adverse-effect-level (NOAEL) for this study was determined to be 
the highest dose evaluated: 100 mg/kg. 
In the 4-week subcutaneous injection study (Study 110988), EFX was administered at doses 
of 0, 1, 10 or 100 mg/kg to cynomolgus monkeys. Administration of EFX at 1, 10, or 100 
mg/kg SC was well tolerated. EFX related pharmacologic effects included decreased body 
weights, decreased insulin, and decreased glucose. Other EFX-related effects were limited to 
minimal increases of alanine aminotransferase (ALT) and aspartate aminotransferase (AST), 
decreased thymus weights and lymphoid cellularity in females at 100 mg/kg. Based on these 
results, the NOAEL for this study was determined to be 100 mg/kg SC. 
1.3.3.1.2. 
A 16-Week Subcutaneous Injection Toxicity Study of EFX in 
Sprague-Dawley Rats (Study 6700591) 
In this study, Sprague Dawley rats were treated weekly with EFX by SC injection at doses of 
0, 10, 30, or 100 mg/kg.   


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EFX related pharmacologic effects included decreased body weights, changes in food 
consumption, decreased triglyceride, protein, and albumin. Other EFX-related effects were 
limited to minimal increases of ALT without corroborative changes in microscopic 
appearance of liver, and decreased adipocyte cellularity in sternal and femoral bone marrow 
without discernible changes in peripheral blood cell populations.  Additionally, decreases in 
the bone resorption marker CTX were observed, suggesting a lower bone turnover.  
However, no treatment-related changes in the bone formation marker PINP were observed.  
These changes are considered to be associated with under-nutrition/negative caloric balance 
arising from the pharmacological effect of EFX.     
During the study, a dose-related increase in systemic exposure was evident across doses with 
serum concentrations of EFX at Day 1 and Day 57 being similar.  At the end of the study 
(Day 113), a decrease in EFX concentrations was observed for all doses.  The lower exposure 
based on Cmax values was most notable in the 10 and 100 mg/kg groups, with exposure at 
Day 113 up to 80% lower compared to Day 57 levels.  The AUC values showed a similar 
decline. The presence of anti-EFX antibodies was confirmed for 5 of the 26 animals (17.3%) 
in the 10 mg/kg group, 1 of the 26 animals (3.8%) in the 30 mg/kg group and 10 of the 26 
animals (36.5%) in the 100 mg/kg group.  However, the presence of ADAs could not be 
correlated with the lower exposure for all animals.   
Based on these results, the no-observed-adverse-effect level (NOAEL) was considered to be 
100 mg/kg for males and females.  The corresponding Cmax and AUC0-24hr values at Day 113 
were 17.5 μg/mL and 678 hr*μg/mL, respectively, for males and 120.0 μg/mL and 7650 
hr*μg/mL, respectively, for females.  Due to the variation in the Day 113 systemic exposures 
observed for male and female rats, the pharmacokinetic exposure values at Day 1 and Day 57 
were used to calculate the safety margins (Section 1.3.3.6) and appear more representative of 
the exposure over the course of the study.  The corresponding Cmax and AUC0-24hr values at 
Day 57 were 110 μg/mL and 7440 hr*μg/mL, respectively, for males and 311 μg/mL and 
16,900 hr*μg/mL, respectively, for females. 
1.3.3.1.3. 
A 16-Week Subcutaneous Injection Toxicity Study of EFX in 
Cynomolgus Monkeys (Study 6700592) 
Cynomolgus monkeys (n = 3/sex/group) were treated with EFX weekly by SC injection at 
doses of 0, 10, 30, or 100 mg/kg.  No EFX-related effects on ophthalmology, 
electrocardiology including heart rate, coagulation or urinalysis evaluation were observed 
during the study.   
EFX related effects included decreased body weights, minimal increases of ALT and AST, 
decreased thymus weights associated with decreased lymphoid cellularity, increased cortisol, 
decreased red blood cell, hemoglobin and hematocrit levels.  
At doses of ≥10 mg/kg reduced or a trend toward less bone growth was observed. The 
magnitude of reduction in measures of bone growth was comparable to the size of the deficit 
in body weight gain with EFX dose.  The deficit in bone growth was reflected in lower levels 
of the bone formation biomarker, PINP.  There were no changes in PINP levels in females at 


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10 mg/kg. Consistent with changes in bone morphology and strength arising mainly from 
reduced growth with EFX, levels of the bone resorption biomarker, CTX, were relatively 
stable in males and females during dosing. 
Minimal to moderate atrophy of the female genital duct (uterus, cervix and vagina) was 
commonly seen at ≥30 mg/kg and was associated with marked decreases in uterine weight.  
The reduced development of genital ducts may reflect a slightly delayed sexual maturation, 
secondary to the deficit in body weight gain. 
A single female in the 100 mg/kg group displayed symptoms associated with an immune 
mediated reaction, reddening of the skin (petechiae, hematoma, and/or purpura) that was 
diffuse on the extremities and upper body beginning at about Week 2 with recurring 
occurrences following each dose administration throughout the study.  Additionally, systemic 
exposure was transiently lower for this animal and body weight loss was greater than other 
females treated with 100 mg/kg.  At histopathological examination, this female presented a 
moderate chronically active crescentic glomerulonephritis associated with mild tubular 
hyaline casts.  These renal findings were associated with substantial proteinuria, hematuria 
and creatinuria; serum BUN or creatinine levels were not different from controls.  The 
occurrence of this histopathological finding has been reported for monkeys following 
injection of protein-based biologics that is generally immune mediated (Frazier & Obert 
2018).  Glomerulonephritis associated with the renal findings was considered adverse to the 
animal although these reactions have a limited prediction of the risk in humans (Vahle 2018, 
Kronenberg et al. 2017).   
Following SC administration, Tmax of EFX ranged between 8- and 48-hours post-dose on 
Days 1, 64 and 113.  The systemic exposure, as assessed by Cmax and AUC(0-t), increased in a 
near dose-proportional manner between 10 and 100 mg/kg.  AUC(0-t) values on Days 64 and 
113 indicated modest accumulation at all dose levels (1.1-1.8 fold) relative to the first dose 
(Day 1).  No differences in systemic exposure (Cmax and AUC(0-t)) were observed between 
males and females on Days 1, 64 and 113. 
Based on results available, the NOAEL was considered to be 30 mg/kg for males and 
females.  The combined Cmax/AUC0-24hr values at the end of the study (Day 113) at the 
NOAEL was 236 μg/mL and 17,400 hr*μg/mL, respectively.  
1.3.3.2. 
Genotoxicity (Mutagenicity) 
EFX is a recombinant protein made up entirely of naturally occurring amino acids and 
contains no inorganic or synthetic organic linkers or other non-protein portions. Thus, it is 
highly unlikely that EFX would react directly with deoxyribonucleic acid (DNA) or other 
chromosomal material. In accordance with ICH S6 (R1), no genotoxicity studies have been 
conducted or are planned with EFX. 


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1.3.3.3. 
Carcinogenicity 
No studies evaluating the carcinogenic potential of EFX have been conducted to date. 
However, studies were conducted to examine the potential of EFX to impact cell 
proliferation and mitogenicity.  In the 16-week repeat dose toxicology studies, no 
pre-neoplastic histopathology changes were observed in the rat. These data in conjunction 
with the lack of cellular proliferation described above suggests that EFX would not be 
associated with a risk for carcinogenicity.  
1.3.3.4. 
Developmental and Reproductive Toxicity 
No studies evaluating the developmental and reproductive toxicity of EFX have been 
conducted to date.  In the 16-week toxicity studies, no effects on male or female reproductive 
organs was observed in the rat.  In the monkey, minimal to moderate atrophy of the female 
genital tract (uterus, cervix and vagina) was seen at 30 and 100 mg/kg and were associated 
with marked decreases of uterus weight.  These findings in the female appear to be secondary 
to the negative caloric balance induced by EFX pharmacology (Cameron 1996, Adams et al. 
2013, Talukdar et al. 2016). 
1.3.3.5. 
Ongoing/Planned Toxicology Studies of EFX 
Chronic toxicity studies in rat and monkey and reproduction and developmental toxicity 
studies in the rat and rabbit are ongoing. . 
1.3.3.6. 
Margin of Safety for Clinical Dose of EFX 
In the 16-week toxicity study of EFX, rats and monkeys were dosed weekly by SC injections 
at doses of 10, 30, or 100 mg/kg. In both species, similar toxicity was observed with effects 
arising from the pharmacology of EFX. The NOAEL at the end of the 16-week study was 30 
mg/kg in monkeys and 100 mg/kg for rats. The AUC and maximum observed concentration 
(Cmax) at the NOAEL are shown in Table 1. The exposure margins were calculated using 
AUC0-t values for a period of 96 hours (AUC0-96h) in rats and monkeys compared to 168 
hours (AUC0-168h) in humans, and hence were not compared based on the same time period 
between species.  Based on the EFX PK profiles, this approach was considered acceptable as 
it provides more conservative estimates of exposure margins (i.e. lower calculated values) in 
terms of AUC0-t and supported the proposed clinical doses. 
 
 




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1.4.1.1. 
Subject Disposition 
Eligible subjects were to be enrolled into one of 7 dose cohorts.  For cohorts 1, 2, 3, 4, 5, and 
7, 8 subjects with T2D were to be randomized to receive EFX or placebo SC in a 3:1 ratio at 
dose levels of 2.1 mg, 7.0 mg, 21 mg, 70 mg, or 210 mg, respectively.  In cohort 6, 8 subjects 
with T2D were to receive EFX or placebo intravenous (IV) in a 3:1 ratio at a dose level of 70 
mg. 
A total of 42 subjects (25 men, 17 women; median age of 55) received a single dose of either 
placebo (11 subjects) or EFX (31 subjects) and completed the study. SC doses of 2.1 mg, 7.0 
mg, 21 mg, 70 mg, or 210 mg (6-7 subjects per dose level) were administered. In addition, 1 
subject received a 70 mg IV dose of EFX. 
1.4.1.2. 
Pharmacokinetic Results 
Median time to reach maximal serum EFX concentrations (tmax) ranged from 2 to 5 days 
following single doses of 2.1, 7, 21, 70, or 210 mg SC EFX. For the SC cohorts, mean EFX 
AUClast values increased 309-fold over the 100-fold dose range.  
The mean half-life ranged from 3.14 to 3.38 days after SC doses of 7 to 210 mg. The mean 
terminal half-life (t1/2,z) was 2.62 days after IV dosing. 
1.4.1.3. 
Pharmacodynamic Results 
A number of isolated differences were observed in the fasting metabolic parameters 
following single SC and IV doses of EFX.  After a single 7.0 mg SC dose, compared to 
placebo, fasting glucose increased as much as 40%, fasting insulin increased up to 60%, and 
fasting glucagon increased up to 60%.  At the 210 mg dose, significant decreases were seen 
with homeostasis model assessment (HOMA-B) (up to 40% decrease) and significant 
increases were seen in fasting glucagon (up to 70% increase) compared to placebo.  
Glucagon AUC0-4hr ratio to baseline increased compared to placebo at the 210 mg SC dose 
level after a mixed meal challenge.  Otherwise, single doses of EFX did not significantly 
affect metabolic parameters after a mixed meal challenge.  At the 210 mg SC dose, 
reductions were observed in total cholesterol (up to 20%) and low-density lipoprotein 
cholesterol (LDL-C) (up to 40%) compared to placebo.  At doses of 21 mg SC and higher, 
increases were observed in high-density lipoprotein cholesterol (HDL-C) (up to 50%) along 
with reductions in triglycerides (up to 50%) compared to placebo.  Increases of up to 50% 
were also noted in β-hydroxybutyrate with doses of 21 mg SC and higher compared to 
placebo.  Compared to placebo, up to 2% reductions in body weight were seen following 
administration of EFX at doses of 21 mg SC and higher. 
1.4.1.4. 
Safety Results 
A total of 42 subjects received a single dose of either placebo (11 subjects) or EFX 
(31 subjects).  Seven subjects (64%) receiving placebo and 17 subjects (55%) receiving EFX 
at any dose experienced ≥ 1 adverse event (AE) during the study.  AEs reported for ≥ 3 
subjects, by preferred term, were anemia (EFX: 3 [10%]; placebo: 1 [9%]); diarrhea (EFX: 3 


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[10%]; placebo: 1 [9%]); and increased appetite (EFX: 5 [16%]; placebo: 0 [0%]).  One 
subject in the 70 mg IV treatment group experienced a serious adverse event (SAE) of 
cholecystitis; the event was considered unrelated to investigational product.  The subject was 
hospitalized and underwent a cholecystectomy.  No other SAEs were reported during the 
study. No subjects withdrew from the study due to an AE and no subjects discontinued 
investigational product.  No subjects died during the study.  During the washout period, 4 
subjects (9%) reported AEs.  These included headache (3 subjects [6%]) and syncope (1 
subject [2%]).  There were no SAEs reported during the washout period. 
All AEs reported were either Grade 1 (mild) or Grade 2 (moderate) in severity with the 
exception of one Grade 3 (severe) event of syncope in the EFX 2.1 mg SC group and one 
Grade 3 event of cholecystitis in the EFX 70 mg IV group. Both events were considered 
unrelated to investigational product.  One subject (9%) in the placebo group and 8 subjects 
(26%) in the combined EFX treatment groups experienced treatment related AEs.  None of 
these were considered as serious.   Treatment-related AEs reported for ≥ 3 subjects, by 
preferred term, were diarrhea (EFX: 3 [10%]; placebo: 0 [0%]) and increased appetite (EFX: 
5 [16%]; placebo: 0 [0%]). During the washout period, 4 subjects (9%) reported AEs.  These 
included headache (3 subjects [6%]) and syncope (1 subject [2%]).  There were no SAEs 
reported during the washout period. There were no trends indicative of clinically important 
treatment-related laboratory abnormalities.  No clinically significant abnormalities in vital 
signs and ECGs were noted in subjects treated with EFX or placebo.  Anti-EFX binding, 
non-neutralizing antibodies in 4 subjects did not appear to affect the safety profile of EFX. 
Study 20100015 was closed prior to completing the enrollment of cohort 6 (70 mg IV) and 
initiating the enrollment of cohort 7 (420 mg SC).  Only the sentinel pair was dosed in 
cohort 6.  Upon review of the initial safety data from cohorts 5 and 6, which included the 
three events of Grade 2 diarrhea in the 210 mg SC group and the one event of Grade 3 
cholecystitis in the 70 mg IV group, the decision was made not to dose escalate to cohort 7, 
and no further subjects were enrolled into cohort 6.  
1.4.1.5. 
Conclusion 
Overall, EFX appeared to be well tolerated at doses up to 70 mg SC.  At doses up to 70 mg, 
subject incidences of overall AEs and treatment-related AEs did not differ notably between 
treatment groups, and no trends indicative of clinically important adverse effects of EFX on 
laboratory or other safety-related clinical parameters were apparent.   
At doses of 210 mg SC and 70 mg IV, dose stopping criteria were met by 3 subjects (Grade 2 
diarrhea) and 1 subject (Grade 3 cholecystitis), respectively.  The decision was made not to 
escalate to the planned 420 mg SC group and to discontinue enrollment in the 70 mg IV 
group.  Binding, non-neutralizing anti-EFX antibodies were detected in 4 subjects after 
treatment with EFX.  EFX-related effects on PD parameters were noted at doses higher than 
21 mg SC and included decreases in total cholesterol, LDL-C, and triglycerides, and 
increases for HDL-C.  Smaller changes were seen at the 7 mg SC dose.  Fasting glucose, 
HOMA-B, and glucagon also showed response to EFX administration.  Small reductions in 


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body weight were also noted with the 21 mg SC and higher doses.  EFX was absorbed into 
systemic circulation with a median tmax of 2 to 5 days following SC dosing.   
1.4.2. 
Study 20100018 - Phase 1b Multiple Ascending Dose Study in Diabetic 
Patients 
Study 20100018 was a Phase 1b multicenter, randomized, double-blind, placebo-controlled, 
ascending multiple-dose study in subjects with type 2 diabetes. Doses of 7 mg every 2 weeks 
(Q2W), 7 mg QW, 21 mg Q2W, 21 mg QW, 70 mg Q2W, 70 mg QW, 140 mg Q2W, and 
140 mg QW administered for 1 month were tested. The primary endpoints were subject 
incidence of TEAE, laboratory analyte markers of safety, vital signs, ECG, and subject 
incidence of anti-EFX antibodies. Secondary and exploratory endpoints included multiple 
metabolic PD and PK assessments. 
1.4.2.1. 
Subject Disposition 
Eligible subjects were to be enrolled into 1 of the 9 cohorts and randomized to receive EFX 
or placebo in a ratio of 3:1 (cohorts 1 to 8) or 1:1 (cohort 9).  The planned sample size was 
approximately 64 subjects in cohorts 1 to 8 (8 subjects in each cohort) and 60 subjects in 
cohort 9.  EFX or equivalent dose of placebo was administered SC Q2W or QW for 4 weeks.  
The planned dose escalation for AKR 001 in cohorts 1 through 8 was 7 mg Q2W, 7 mg QW, 
21 mg Q2W, 21 mg QW, 70 mg Q2W, 70 mg QW, 140 mg Q2W, and 140 mg QW, 
respectively.  Subjects in cohort 9 were to receive 70 mg EFX QW.   
A total of 86 patients were enrolled in 1 of 9 cohorts and randomized to receive EFX or 
placebo in a ratio of 3:1 (cohorts 1 to 8) or 1:1 (cohort 9).  Seventeen patients were 
withdrawn from the study during the washout period before receiving EFX.  The remaining 
69 subjects were randomized in cohorts 1 to 8 including 52 subjects in the EFX groups and 
17 subjects in the placebo group.  Of the 52 subjects in the EFX groups; 6 subjects each were 
in cohort 1 and cohorts 3 to 7, 7 subjects in cohort 2, and 9 subjects in cohort 8.  A total of 63 
subjects (91.3%) completed investigational product as per the dosing regimen for 4 weeks.  
Six subjects (8.7%) discontinued investigational product; 1 subject in EFX cohort 2, 4 
subjects in EFX cohort 8, and 1 subject in the placebo group.  All 6 subjects discontinued 
investigational product because of AEs.  A total of 63 subjects (92.8%) completed the study.  
Of the 5 subjects (7.2%) who discontinued the study; 2 subjects (2.9%) withdrew consent and 
1 (1.4%) subject each discontinued due to protocol specified criteria, sponsor decision, or 
loss of follow up.  All 5 subjects who discontinued the study were in EFX groups (1 subject 
in cohort 4, 4 subjects in cohort 8).  The study was terminated before enrollment of subjects 
into cohort 9 (70-mg EFX QW) upon review of the aggregate PD data from cohorts 1 to 8 
which confirmed the glucose lowering effect of EFX.  Therefore, cohort 9 was deemed 
unnecessary by the sponsor. 
1.4.2.2. 
Pharmacokinetic Results 
Based on linear regression analysis of dose-normalized log-transformed Cmax and AUCinf 
values, EFX exhibited linear PK after Q2W or QW SC administration across the dose range 


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of 7-mg to 140-mg.  Median tmax values following Q2W or QW SC administration of 7-mg to 
140-mg ranged from 2 to 3.5 days for all cohorts.  There was minimal accumulation of EFX 
following 2 doses administered Q2W, with mean accumulation ratios ranging from 0.86 to 
1.94.  Following 4 doses administered QW, moderate accumulation was observed, with mean 
accumulation ratios ranging from 1.56 to 3.61. There was no discernible trend between dose 
and accumulation ratio.  For those subjects who developed anti-EFX antibodies, there was no 
detectable change in PK of EFX by comparison with ADA negative subjects in the respective 
dose groups. 
1.4.2.3. 
Pharmacodynamic Results 
Q2W Dosing Regimen: 
Fasting glucose increased over time as percent change compared with placebo in the 7-mg, 
21-mg, and 140-mg groups (up to 29%, 32%, and 53% increase, respectively).  Fasting 
insulin increased over time in the 7-mg group (up to 59% increase) and decreased over time 
in the 140-mg group (up to -41% decrease).  The percent change from baseline in 
homeostasis model assessment of insulin resistance (HOMA-IR) increased over time in the 
7-mg group (up to 75% increase) and decreased over time in the 140-mg group (up to -38% 
decrease).  Improvement in beta cell function was evident following 140mg doses, with 
HOMA-B decreasing by up to 50%.  Inconsistent with this, fasting C-peptide levels 
decreased by up to 36% in the 140-mg group.  Fasting glucagon increased by up to 36%, 
68%, and 31%, respectively in the 7 mg, 70 mg, and 140 mg groups. 
Following a mixed meal tolerance test on Day 18, compared with placebo, insulin and 
C-peptide AUC from 0 to 4 hours (AUC0-4hr) decreased by 27% and 18% respectively in the 
140-mg group. Glucagon AUC0-4hr increased 32% in the 70 mg group. 
Fasting total cholesterol increased by up to 25% over time in the 140 mg group.  HDL-C 
increased by up to 28% over time in the 21 mg and 70 mg groups, and by up to 40% in the 
140 mg group. Fasting triglyceride decreased by up to 43% and 56% respectively over time 
in the 70 mg and 140 mg groups. 
Fasting levels of β-hydroxybutyrate increased by 166% and 235% respectively in the 70-mg 
and 140-mg groups. 
Body weight appeared to decrease in a dose-responsive manner. 
QW Dosing Regimen:  
Fasting glucose decreased by up to 34% and 32% respectively compared with placebo, in the 
70-mg and 140-mg groups. Fasting insulin decreased by up to 54% and 51% respectively in 
the 70-mg and 140-mg groups. Consistent with this, fasting C-peptide decreased over time in 
the 21-mg, 70-mg, and 140-mg groups by up to 32%, 40% and 44% respectively. The 
improvements in insulin sensitivity underlying these changes were reflected by reductions of 
up to 63% and 60% in HOMA-IR respectively in the 70-mg and 140-mg groups. The 
improvement in insulin sensitivity occurred despite increases over time in fasting glucagon 


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for all the EFX groups: up to 55%, 50%, 38%, and 64% higher, respectively for 7-mg, 21-
mg, 70-mg, and 140-mg groups.  
Following a mixed meal tolerance test on Day 25, glucose AUC0-4hr was 29% and 30% lower 
in the 70-mg and 140-mg groups respectively. Insulin and C-peptide AUC0-4hr were –
respectively 28% and 20% lower in the 21-mg group, and 47% and 36% lower in the 140-mg 
group. Free fatty acids AUC0-4hr was decreased by 30% in the 70-mg group. Glucagon AUC0-
4hr was increased by 43% in the 7-mg group.   
Fasting total cholesterol decreased by up to 16% and 17% respectively in the 70-mg and 140-
mg groups.  Fasting LDL-C decreased by 33% over time in the 140-mg group. Fasting HDL-
C increased by up to 31%, 43%, 61%, and 48% respectively in the 7-mg, 21-mg, 70-mg, and 
140-mg groups. Fasting triglycerides decreased by up to 49%, 55%, 69%, and 65%
respectively in the 7-mg, 21-mg, 70-mg, and 140-mg groups.
Fasting levels of β-hydroxybutyrate increased by up to 271% in the 140-mg AKR-group.  
Body weight appeared to decrease in a dose-responsive manner. 
1.4.2.4. 
Safety Results Describing the Combined Q2W and QW Datasets 
A total of 69 subjects received at least a single dose of either EFX (52 subjects) or placebo 
(17 subjects) and were included in the safety analysis set.  Of these, 55 subjects (EFX group:  
43 [82.7%]; placebo group:  12 [70.6%]) had ≥ 1 AE during the study.   
Of the patients who received the 70 mg SC dose or less (the highest dose proposed in 
Protocol AK-US-001-0101), 3 AEs of Grade 3 or above were observed and considered not 
related to investigational product:  two instances of transient hyperglycemia in one subject 
(7 mg QW dose), and one instance of transient diarrhea (7 mg QW dose). 
Six subjects (8.7%) discontinued investigational product; one subject in cohort 2, four 
subjects in cohort 8, and one subject in the placebo group.  All six subjects discontinued 
investigational product because of AEs. Four of the patients who discontinued were in the 
140 mg QW group. The reasons for discontinuation by each of the four subjects dosed at 
140 mg QW were diarrhea; vomiting; tremor; and tremor/nausea, respectively. The 
remaining two discontinuations (one following treatment with 7mg QW; one on placebo) 
were attributed by the investigator to hyperglycemia and were considered unrelated to 
investigational product. Subjects were washed off anti-diabetic medications two weeks prior 
to the first dose and remained so until end of study.  A summary of the treatment-related AEs 
and withdrawals is provided in Table 2. 
There were no trends indicative of clinically important treatment-related laboratory 
abnormalities.  No trends in clinically significant abnormalities in vital signs and ECG were 
noted in subjects treated with EFX or placebo.  At the end of study visit (EOS), 7 subjects 
(13.5%) tested positive for anti-EFX binding, non-neutralizing antibodies dosing with EFX.  
Three of these 7 subjects returned for a follow-up antibody sample collected at least 2 
months after the End of Study (EOS) visit.  All 3 subjects tested negative for anti-EFX 
antibodies. 




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Following administration of a 210 mg dose, 3 of 6 subjects reported diarrhea and 4 of 
6 subjects reported increased appetite. Neither diarrhea nor increased appetite were reported 
for subjects receiving any other dose of EFX. No other AEs were reported by more than one 
subject. All AEs were reported as either mild or moderate, with the exception of two AEs 
graded as severe but considered unrelated to the investigational product by the investigators. 
One subject experienced a severe AE of vasovagal syncope secondary to blood draw 
following randomization to the 2.1mg cohort, but prior to receiving any investigational 
product. One subject who received EFX 70 mg IV had a severe AE of cholecystitis initially 
reported as abdominal pain beginning on Day 11. The subject thereafter reported having 
experienced intermittent abdominal pain for many years. Findings from a subsequent 
cholecystectomy were consistent with chronic cholecystitis.  
Seven subjects developed anti-EFX non-neutralizing antibodies post baseline.  Three of these 
7 subjects returned for a follow-up antibody sample collected at least 2 months after the EOS 
Visit, with all 3 subjects testing negative for anti-EFX antibodies.  EFX exhibited linear PK 
and increased dose-proportionally from 7-mg to 140-mg following Q2W or QW SC 
administration.  In general, minimal accumulation (< 2-fold) was observed after 2 SC doses 
administered Q2W, while moderate accumulation (approximately 2-fold) was observed after 
4 SC doses administered QW.  The presence of anti-EFX binding antibodies did not appear 
to affect PK of EFX.   
The extent of improvements in markers of insulin sensitivity elicited by Q2W dosing was 
less than for QW dosing. Likewise, the improvement in lipoprotein profile was greater for 
QW than Q2W and was evident at lower doses. In the context of NASH, greater insulin 
sensitivity would be expected to reduce flux of fatty acids from adipose tissue to liver, the 
major source of lipid entering the liver. At the same time, improved adipose insulin 
sensitivity is associated with greater uptake of plasma triglyceride whether of liver (VLDL) 
or dietary (chylomicron) origin. The substantial reductions in plasma triglyceride elicited by 
QW EFX are consistent with these effects, and potentially with reduced synthesis and 
secretion of VLDL by liver. Overall the improvements in metabolic status of the T2D 
subjects, particularly insulin sensitivity of adipose tissue, and in lipoprotein profile indicate 
potential for therapeutic benefit in NASH with QW dosing of EFX. 
1.5. 
Rationale for this Study 
Given FGF21’s well-documented beneficial effects on metabolic parameters, FGF21 has 
recently emerged as a promising drug candidate for metabolic diseases, including NASH. 
FGF21 has many of the key characteristics of an optimal NASH therapy as a result of its 
well-documented effects in improving insulin sensitivity and lipoprotein levels, reducing 
liver fat and inflammation, as well as inhibiting fibrosis.  In particular, EFX’s dual actions of 
addressing both the underlying NASH disease driver (i.e., increased liver fat and fat 
oxidation) and downstream NASH pathology (i.e. cellular stress, inflammation and fibrosis), 
is well suited to patients with F3 and F4 fibrosis, not just patients with early-stage disease. 


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Results from a Phase 2 trial of BMS-986036, an investigational PEGylated analog of FGF21, 
provide important validation for FGF21 agonism as a NASH therapy (Sanyal et al. 2019). In 
this study, 74 patients with biopsy-confirmed NASH (stages F1-F3) received 16 weeks of 
daily or weekly subcutaneous injections of BMS-986036 or placebo. The study achieved its 
primary endpoint of significant reduction in liver fat versus placebo, as measured non-
invasively by magnetic resonance imaging – proton density fat fraction (MRI-PDFF). 
Absolute fat levels in the daily and weekly dosing cohorts fell 6.8% and 5.2%, respectively, 
compared to 1.3% in the placebo group. These reductions translated into relative reductions 
of 38% and 26%, respectively, compared to 6% in the placebo group. Statistically significant 
improvements were also seen in prespecified exploratory endpoints including biomarkers of 
fibrosis, lipoprotein parameters and markers of liver injury. Positive changes in Pro-C3, a 
marker of liver fibrogenesis, and liver stiffness as measured by magnetic resonance 
elastography, or MRE, were also observed. The addition of Cohort C to the protocol will 
evaluate the effects of EFX on subjects with cirrhosis using non-invasive imaging and 
biomarkers of liver fibrosis. 
Results from a Phase 2 trial of NGM282, an FGF19 analog, provides additional clinical 
validation for FGF21 agonism (Harrison et al. 2019). FGF19 and FGF21 are both members 
of the endocrine subfamily of FGFs. Both have been shown to activate three FGF receptors 
(FGFR1c/2c/3c) expressed in liver cells (mainly 2c and 3c) and adipose cells (mainly 1c). 
FGF19 also activates a fourth receptor, known as FGFR4, which FGF21 does not activate.  
In a 12-week clinical trial in NASH patients, a 3 mg daily dose of NGM282 was shown to 
have a placebo-corrected absolute reduction in liver fat of 11.2% at 12 weeks, or a 67% 
relative reduction, as measured by MRI-PDFF. This magnitude of liver fat reduction is the 
largest observed to date in all NASH clinical trials.  
Preclinical data suggests that FGF21 agonism of FGFR1c substantially inhibits adipose tissue 
lipolysis. NGM313, which was developed to mimic FGF21’s effects on FGFR1c and 
βKlotho (but with no activity at FGFR2c and 3c), provides important clinical validation that 
agonism of FGFR1c substantially reduces liver fat in NASH patients. NGM313 was 
evaluated in a single-dose, open-label Phase 1b trial in 25 obese, insulin resistant subjects 
with NAFLD. Although it is an open label study, a 37% relative reduction of liver fat at 5 
weeks, along with a 48% reduction in fasting triglycerides at 4 weeks, suggests that agonism 
of FGFR1c will result in meaningful liver fat reduction in NASH patients (Shankar et al. 
2018). 
We hypothesize that EFX, by virtue of its balanced agonism across FGFR1c/2c/3c will act on 
both liver and adipose tissue to reduce liver fat substantially, in turn mitigating hepatocyte 
stress. By combining these metabolic improvements with the direct anti-inflammatory and 
antifibrotic effects evident with FGF21, EFX is expected to deliver clinically meaningful 
resolution of NASH. 
The dose and length of administration of the drug in study AK-US-001-0101 are supported 
by safety data from nonclinical studies and from prior Phase 1a/1b studies in T2D patients. 
The primary endpoint of the study will be the absolute change from baseline in hepatic fat 


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fraction assessed by MRI-PDFF at Week 12. Non-invasive imaging modalities that assess 
hepatic fat content are acceptable as study endpoints for early Phase 2 trials (Noncirrhotic 
Nonalcoholic Steatohepatitis With Liver Fibrosis: Developing Drugs for Treatment, 
Guidance for Industry, December 2018).  
The potential to observe early histologic changes at Week 12 is supported by the Phase 2 trial 
of NGM282.  Nineteen subjects with biopsy-confirmed NASH completed 12 weeks of 
treatment with paired biopsies. Histopathology of 13 (68%) of these biopsies revealed 
anti-fibrotic activity at Week 12, with biopsies from eight subjects (42%) showing a 
reduction of ≥ 1 fibrosis stage (Harrison et al. 2019). 
The current regulatory standard for assessing fibrosis referenced in the Guidance for Industry 
is liver biopsy. As such, improvement in liver fibrosis without worsening of NASH as 
assessed by liver biopsy will be evaluated in a subset of subjects who show a significant 
response to treatment (≥ 30% fat reduction by MRI-PDFF at Week 12). Liver biopsy is 
limited by cost, sampling error, and variability in subjective histopathological interpretation. 
Due to these limitations, the development and validation of noninvasive markers of liver 
injury has emerged as a clinical and research priority. A key exploratory objective of the 
study is to correlate these noninvasive markers with liver histology and determine their utility 
for monitoring and ultimately predicting histological responses that occur during the course 
of the study. 
Currently there are no approved drugs for the treatment of NASH, and there remains a clear 
unmet medical need to slow progression of, halt, or reverse NASH. As fibrosis is seen as the 
strongest predictor of adverse clinical outcomes in NASH, the Main Study will enroll 
biopsy-proven noncirrhotic NASH patients with (fibrosis stage 1 to 3 and a NAS of ≥ 4) and 
Cohort C will enroll patients with compensated cirrhosis with fibrosis stage 4. 
1.6. 
Rationale for Selection of Dose 
As described in Section 1.4.1 and Section 1.4.2, in the Phase 1a/1b studies, EFX appeared to 
be well tolerated at doses up to 70 mg SC. There were no patient deaths and no SAEs 
attributable to treatment with EFX. The most common AEs were gastrointestinal disorders, 
such as mild diarrhea and nausea.  
Exploratory analyses for Study 20100018 (Section 1.4.2) were conducted by Akero to 
demonstrate the dose-related change from baseline for lipoproteins and markers of insulin 
sensitivity, observed following administration of 21 mg and 70 mg QW doses of EFX, 
compared to placebo.  Significant improvements for each marker of insulin sensitivity were 
observed at the 70 mg QW dose, consistent with agonism of FGFR1c in adipose tissue.   
The analysis indicates maximal or near maximal effects were observed by the third dose of 
70 mg QW for lipoproteins, and by the fourth dose for markers of insulin sensitivity. 
Reductions in triglyceride and increases in HDL-C were significant at all time points from 
Day 4 through Day 57, while non-HDL-C was significantly lower from Day 15 through 
Day 57. Taken together with published clinical data for third-party FGF21 analogs, the 


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time-course and magnitude of changes in lipoproteins observed at the 70 mg QW dose 
suggest that EFX has the potential to rapidly and durably reduce liver fat in patients with 
NASH. Notably, EFX’s effects appear to be sustained for three weeks after the final dose, 
including significant increases of 39% in HDL-C and significant reductions of 28% and 67% 
in non-HDL-C and triglycerides, respectively, observed on Day 43. 
At 21 mg QW, there were also indications of improved sensitivity to insulin, with a 
significantly lower level of C-peptide observed after the fourth dose, and a trend toward 
lower levels of insulin and a lower calculated value of HOMA IR.  Although liver fat was not 
measured in Study 20100018, the magnitude and robustness of effects on lipoproteins at 
21 mg and 70 mg QW will likely translate into substantial reductions in liver fat with longer 
term treatment. 
Efficacy for the proposed Phase 2a study is predicted based on PK/PD modeling.  The doses 
to be tested are expected to mediate potentially beneficial changes in PD parameters 
including triglycerides and LDL.  PK/PD modeling suggests that the dose range selected will 
achieve approximately 45% to 90% of the maximum effect on triglycerides and LDL. 
EFX will be administered QW at doses ranging from 28 mg/day to 70 mg/day for up to 16 
weeks.  Subjects with advanced cirrhotic disease in Cohort C will receive 50 mg/day based 
on PK/PD modeling of data from the multiple ascending dose Study 20100018.  As presented 
in Section 1.3.3.6, a dose of 70 mg of EFX results in exposure margins ranging from 
approximately 2.9- to 37.5-fold based on Cmax and approximately 0.9- to 24-fold based on 
AUC0-t.  
At doses up to 70 mg, subject incidences of overall AEs and treatment-related AEs did not 
differ notably between treatment groups, and no trends were apparent indicative of clinically 
important adverse effects of EFX on laboratory or other safety-related clinical parameters.  
Of the patients who received the 70 mg SC dose or less (the highest dose proposed in this 
protocol), 3 AEs of Grade 3 or above were observed and considered not related to 
investigational product:  two instances of transient hyperglycemia in one subject (7 mg QW 
dose), and one instance of transient diarrhea (7 mg QW dose).  The withdrawals due to 
hyperglycemia are probably attributable to all subjects having been washed off all their anti-
diabetic medications for 14 days prior to first dose of EFX. Based on these results, the 
highest planned SC dose level to be tested is 70 mg SC QW.   
 
1.7. 
Compliance 
This study will be conducted in compliance with this protocol, Good Clinical Practice (GCP), 
and all applicable regulatory requirements. 
 


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2. 
STUDY OBJECTIVES 
2.1. 
Primary Objectives 
The primary objective of the Main Study is:  
 To evaluate the absolute change from baseline in hepatic fat fraction assessed by 
Magnetic Resonance Imaging - Proton Density Fat Fraction (MRI-PDFF) at Week 12  
The primary objective of Cohort C of this study is:  
 To assess the safety and tolerability of EFX in NASH subjects with compensated 
cirrhosis  
2.2. 
Secondary Objectives 
The secondary objectives of the Main Study are:  
 To evaluate percent change from baseline in hepatic fat fraction assessed by MRI-PDFF 
at Week 12 
 To evaluate the responder: subjects who achieved a clinically meaningful relative 
reduction of at least 30% in liver fat content as measured by MRI-PDFF at Week 12 
 To evaluate the responder based on NAFLD Activity Score (NAS) system: subjects who 
had a decrease of ≥ 2 points in NAS with at least a 1-point reduction in either lobular 
inflammation or hepatocellular ballooning and with no concurrent worsening of fibrosis 
stage 
 To evaluate the change from baseline in ALT at Week 12 
 To assess the safety and tolerability of EFX in subjects with NASH  
The secondary objectives of Cohort C of this study are:  
 To evaluate the change from baseline in liver stiffness as evaluated by FibroScan® at 
Week 16 
 To evaluate the change from baseline in non-invasive plasma (serum) fibrosis biomarkers 
including liver fibrosis by ELF™ Test score and pro-C3 levels 
  
2.3. 
Exploratory Objectives 
The exploratory objectives are:  
• Change from baseline in markers of liver injury and function including, aspartate 
aminotransferase (AST), alkaline phosphatase (ALP), gamma glutamyl transferase 
(GGT), bilirubin, International Normalized Ratio (INR), albumin, Model for End-Stage 
Liver Disease (MELD) score, and Child Pugh (CP) score 
• Change from baseline in body weight and waist-to-hip ratio 
• MRI-PDFF based quantitation of hepatic fat (Main Study Only) 


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• Changes from baseline in noninvasive plasma (or serum) biomarkers including liver 
fibrosis by Enhanced Liver Fibrosis (ELF™) Test score, and by pro-C3 levels (Main 
Study Only) 
• Change from baseline in bone mineral density of the lumbar spine, femoral neck, and 
total hip as measured by DXA 
• The proportion of subjects – whose fibrosis regresses by ≥ 1-stage according to the 
NASH CRN classification  
• The proportion of subjects who had no worsening in NAS with improvement in fibrosis 
stage 
• The proportion of subjects who had 2 points improvement in NAS with no worsening in 
fibrosis stage 
• The proportion of subjects who had ≥ 1 point improvement in NAS, fibrosis, steatosis 
lobular inflammation or hepatocellular ballooning 
• Changes from baseline in health-related quality of life (HRQoL) 
• Changes from baseline in lipoprotein profile and markers of lipid metabolism, insulin 
sensitivity and glycemic control 
• Change from baseline in body fat distribution as measured by DXA total body 
composition 
• Change from baseline in corrected T1 (cT1), an MRI-based metric of liver fibro-
inflammation at Week 12 (Main Study Only) 
• Plasma concentrations of EFX 
• To evaluate decompensated liver disease events including ascites, hepatic encephalopathy 
(HE), or variceal bleeding (Cohort C Only) 


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3.
INVESTIGATIONAL PLAN
3.1. 
Overall Study Design and Plan 
This is a Phase 2a, randomized, double-blind, placebo-controlled study evaluating the safety 
and efficacy of EFX in subjects with NASH.  
Main Study: Subjects meeting the study’s entry criteria will be randomly assigned in a 
1:1:1:1 ratio into 4 treatment groups as shown in Figure 2 below: 
Figure 2. 
Study Schema – Main Study 
Randomization will be stratified by baseline hepatic fat fraction (< 15% vs ≥ 15%) and F1 
fibrosis score. Study drug will be administered subcutaneously once weekly (QW) for a total 
of 16 weeks. After 16 weeks of treatment, a safety follow-up visit will occur at Week 20.  
Subjects with ≥ 30% relative fat reduction on MRI-PDFF at week 12 will be required to 
return between weeks 22 - 24 for a repeat liver biopsy and MRI-PDFF. 
Cohort C: Subjects meeting the study’s entry criteria will be randomly assigned in a 1:2 
ratio into 2 treatment groups as shown in Figure 3 below: 


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Figure 3. 
Study Schema – Cohort C 
 
 
Following 16 weeks of treatment, subjects will be given the option to collect an end of 
treatment biopsy. 
3.2. 
Study Duration and Number of Centers 
Main Study: Participation in the study can last up to 30 weeks, which includes 6 weeks for 
screening, 16 weeks on-treatment, 4 weeks of safety follow-up, and an additional 4 weeks for 
a repeat liver biopsy and MRI-PDFF in eligible subjects.   
Cohort C: Participation in the study can last up to 26 weeks, which includes 6 weeks for 
screening, 16 weeks on-treatment, and 4 weeks of safety follow-up.   
This study will be conducted at approximately 30 sites in the U.S. Additional sites may be 
added, depending on subject accrual rates. 
3.3. 
End of Study 
Main Study: The end of the study is considered to be the completion of the Safety Follow-
up Visit (Week 20) or the Repeat Biopsy (Week 22 - 24) for subjects who are eligible.   
Cohort C: The end of the study is considered to be the completion of the Safety Follow-up 
Visit (Week 20). 
3.4. 
Early Termination  
If a subject discontinues study drug, every attempt should be made to perform the Early 
Termination (ET) assessments and the Safety Follow-up assessments. The Safety Follow-up 
assessments should be completed 4 weeks after the last dose of study drug. 
Subjects with ongoing clinically significant clinical or laboratory findings will be followed 
until the finding is resolved or medically stable; reasonable attempts will be made to follow-
up with subjects. The subject’s participation will end once all study assessments and follow-
up has been completed. 


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The ET and Safety Follow-up assessments are outlined in the Schedule of Assessments 
(Appendix A and Appendix B).   
3.5. 
Post Study Care 
There is no offered post study care. 
 


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4. 
STUDY POPULATION SELECTION 
4.1. 
Study Population 
The Main Study will enroll approximately 80 subjects with biopsy-proven NASH.  F1 
fibrosis will comprise of approximately 35% of total subject population. 
Cohort C will enroll approximately 30 subjects with biopsy-proven NASH. All subjects in 
Cohort C will have F4 fibrosis. 
4.2. 
Inclusion Criteria 
Main Study: Subjects must meet all the following inclusion criteria to be eligible for study 
participation: 
1. Males and non-pregnant, non-lactating females between 18 - 80 years of age 
inclusive, based on the date of the screening visit. 
2. BMI > 25 kg/m2 (unless the subject has biopsy-proven NASH documented within the 
last 2 years). 
3. Must have confirmation of ≥ 10% liver fat content on MRI-PDFF at screening. 
4. Biopsy-proven NASH. Must have had a liver biopsy within 180 days of 
randomization with fibrosis stage 1 to 3 and a NAS of ≥ 4 with at least a score of 1 in 
each of the following NAS components: 
a. Steatosis (scored 0 to 3), 
b. Ballooning degeneration (scored 0 to 2), and 
c. Lobular inflammation (scored 0 to 3). 
5. Must have no evidence of worsening of ALT and AST (within 50%) measurements at 
the screening (-6 weeks) and pre-baseline (-2 weeks) visits. 
 
6. Screening laboratory parameters, as determined by the central laboratory: 
a. Estimated glomerular filtration rate (eGFR) ≥ 60 mL/min, as calculated by the 
Cockcroft-Gault equation;  
b. HbA1c ≤ 9.5% (or serum fructosamine ≤ 381 µmol if HbA1c measurement is 
unavailable); 
c. Hemoglobin ≥ 11 g/dL;  
d. International normalized ratio (INR) ≤ 1.3, unless due to therapeutic 
anticoagulation; 
e. Direct bilirubin ≤ 0.3 mg/dL; 
f. Total bilirubin ≤ 1.3 x upper limit of normal ULN, unless due to an alternate 
etiology such as Gilbert’s syndrome or hemolytic anemia; 
g. Creatinine kinase < 3 x ULN; 
h. Platelet count ≥ 150,000/µL; 
i. Serum triglyceride level ≤ 500 mg/dL; 
j. Alanine aminotransferase (ALT) < 5 x ULN;  


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k. Aspartate aminotransferase (AST) < 5 x ULN; 
l. AST >20u/L (only required for subjects without a historical biopsy in the last 2 
years confirming fibrosis 1-3 and a NAS ≥ 4); 
m. Alkaline phosphatase (ALP) < 2 x ULN; 
7. Subjects on Vitamin E ≥ 400 IU/day, thiazolidinediones (including, but not limited to, 
pioglitazone, rosiglitazone, and lobeglitazone), GLP1, or SGLT2 must be on a stable 
dose (defined as no changes in prescribed dose, new medications, or discontinuation) 
for at least 6 months prior to the diagnostic liver biopsy and screening. 
8. Subjects on antidiabetic, weight loss, or lipid-modifying medication(s) must be on 
stable dose(s) for at least 3 months prior to the diagnostic liver biopsy through 
randomization. 
9. Willing and able to give written informed consent prior to any study specific 
procedures being performed. 
10. Female subjects of childbearing potential (see definition in Appendix C) must have a 
negative pregnancy test at screening and Baseline/Day 1. 
11. Male subjects and female subjects of childbearing potential who engage in 
heterosexual intercourse must agree to use protocol specified method(s) of 
contraception as described in Appendix C. 
12. FibroScan® measurement > 7.0 kPa. 
Cohort C: Subjects must meet all the following inclusion criteria to be eligible for study 
participation: 
1. Males and non-pregnant, non-lactating females between 18 - 80 years of age 
inclusive, based on the date of the screening visit. 
2. Compensated cirrhosis (Fibrosis Stage 4) due to NASH documented by a local 
pathologist within 24 months of Screening with no evidence of competing etiology, 
and at least one co-existing or historic metabolic comorbidity. If a historical biopsy is 
not available within 24 months of Screening, the subject may undergo a liver biopsy 
to be assessed by the local or central reader and confirmed to have compensated 
cirrhosis (Fibrosis Stage 4). 
3. FibroScan® measurement > 13.1 kPa. 
4. Enhanced Liver Fibrosis (ELF) score of > 9.8. 
5. Must have no evidence of worsening of ALT and AST (within 50%) measurements at 
the screening (-6 weeks) and pre-baseline (-2 weeks) visits.   
a. A single retest of the pre-baseline labs is permitted only if there is reason to 
believe the initial value was erroneous due to a sample processing error or due to 
an extenuating circumstance. An average of the screening and pre-baseline value 
will be used and compared to the retest value. The retest value must have no 
evidence of worsening within 50% of the average of the screening and pre-
baseline value. 
6. Screening laboratory parameters, as determined by the central laboratory: 


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a. Estimated glomerular filtration rate (eGFR) ≥ 60 mL/min, as calculated by the 
Cockcroft-Gault equation;  
b. HbA1c ≤ 9.5% (or serum fructosamine ≤ 381 µmol if HbA1c measurement is 
unavailable); 
c. Hemoglobin ≥ 11 g/dL;  
d. International normalized ratio (INR) ≤ 1.3, unless due to therapeutic 
anticoagulation; 
e. Direct bilirubin ≤ 0.3 mg/dL; 
f. Total bilirubin ≤ 1.3 x upper limit of normal ULN, unless due to an alternate 
etiology such as Gilbert’s syndrome or hemolytic anemia; 
g. Creatinine kinase < 3 x ULN; 
h. Platelet count ≥ 125,000/µL; 
i. Serum triglyceride level ≤ 500 mg/dL; 
j. Alanine aminotransferase (ALT) < 5 x ULN;  
k. Aspartate aminotransferase (AST) < 5 x ULN; 
l. Alkaline phosphatase (ALP) < 2 x ULN; 
m. Albumin ≥ 3.5 g/dL. 
7. Subjects on Vitamin E ≥ 400 IU/day, thiazolidinediones (including, but not limited to, 
pioglitazone, rosiglitazone, and lobeglitazone), GLP1, or SGLT2 must be on a stable 
dose (defined as no changes in prescribed dose, new medications, or discontinuation) 
for at least 6 months prior to the screening visit. 
8. Subjects on antidiabetic, weight loss, or lipid-modifying medication(s) must be on 
stable dose(s) for at least 3 months prior to the screening visit. 
9. Willing and able to give written informed consent prior to any study specific 
procedures being performed; 
10. Female subjects of childbearing potential (see definition in Appendix C) must have a 
negative pregnancy test at screening and Baseline/Day 1; 
11. Male subjects and female subjects of childbearing potential who engage in 
heterosexual intercourse must agree to use protocol specified method(s) of 
contraception as described in Appendix C. 
4.3. 
Exclusion Criteria 
Main Study: Subjects meeting any of the following criteria are not eligible for study 
participation: 
1. Weight gain or loss >5% in the 3 months prior to randomization or > 10% in the 
6 months prior to screening. 
2. Type 1 and insulin dependent Type 2 diabetes. 
3. Presence of cirrhosis on liver biopsy (stage 4 fibrosis). 
4. Poorly controlled hypertension BP > 160/100. 
5. Prior history of decompensated liver disease including ascites, hepatic 
encephalopathy (HE), or variceal bleeding. 
6. Chronic hepatitis B virus (HBV) infection (hepatitis B surface antigen [HBsAg] 
positive). 


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7. Chronic hepatitis C virus (HCV) infection (HCV antibody [Ab] and HCV ribonucleic 
acid [RNA] positive). Subjects cured of HCV infection less than 2 years prior (based 
on date of RNA PCR negative confirmation following conclusion of treatment) to the 
screening visit are not eligible. 
8. Prior or planned (during the study period) bariatric surgery (e.g., gastroplasty, roux-
en-Y gastric bypass) surgery reversal or removal of intragastric balloon > 2 years 
prior to enrollment would be eligible. 
9. Other causes of liver disease based on medical history and/or centralized review of 
liver histology, including but not limited to: alcoholic liver disease, autoimmune 
disorders (e.g., primary biliary cholangitis [PBC], primary sclerosing cholangitis 
[PSC], autoimmune hepatitis), drug-induced hepatotoxicity, Wilson disease, clinically 
significant iron overload, or alpha-1-antitryspin deficiency requiring treatment. 
10. Subjects with osteoporosis, defined as a T-score of -2.5 or lower at screening. 
11. History of liver transplantation. 
12. Current or prior history of hepatocellular carcinoma (HCC). 
13. Alcohol intake above an average limit of 2 drinks per day for women and 3 drinks per 
day for men as assessed by the AUDIT-C questionnaire. 
14. Human immunodeficiency virus (HIV) infection. 
15. Unstable cardiovascular disease.   Any acute cardiovascular event in the six months 
prior to screening (ex: myocardial infarction, cerebral vascular accident, symptomatic 
rhythm disturbance (stable, controlled atrial fibrillation is allowed); or an emergency 
room visit or hospitalization for confirmed cardiovascular disease. 
16. Life expectancy less than 2 years. 
17. Subjects taking fibrates and peroxisome proliferator-activated receptor (PPAR) alpha 
agents (clofibrate, gemfibrozil, ciprofibrate, bezafibrate, or fenofibrate). 
18. Use of any investigational medication within 30 days or within 5 half-lives prior to 
screening. 
19. Subjects with a history of (12 months prior to screening) or current use of prescription 
drugs associated with liver steatosis (e.g. methotrexate, amiodarone, high-dose 
estrogen, tamoxifen, systemic steroids, anabolic steroids, valproic acid). Short courses 
of corticosteroids (less than two weeks) may be allowed prior to screening if in the 
investigator’s opinion they are not associated with liver steatosis or clinically 
relevant; 
20. Positive urine drug screen for amphetamines, cocaine or opiates (e.g., fentanyl, 
heroin, morphine) at screening. Subjects on stable methadone or buprenorphine 
maintenance treatment for at least 6 months prior to screening may be included in the 
study. Subjects with a positive urine drug screen due to prescription medication (e.g., 
opiates, methylphenidate) are eligible if the prescription and diagnosis are reviewed 
and approved by the investigator. 
21. Unable to safely undergo a liver biopsy. 
22. Subjects who have contraindications to MR imaging (e.g., unmanageable 
claustrophobia or metal implants). 
23. Concurrent participation in another therapeutic clinical study. 


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24. Presence of any laboratory abnormality or significant systemic or major illnesses 
(other than liver disease) that, in the opinion of the Investigator, compromise the 
subject’s ability to safely participate in and complete the study including:  
a. Pulmonary disease, renal failure, organ transplantation, serious psychiatric 
disease, malignancy, history of substance abuse and/or a psychiatric condition 
requiring hospitalization and/or emergency room visit within six months of 
screening. 
25. Unavailable for follow-up assessment or concern for subject’s compliance with the 
protocol procedures. 
Cohort C: Subjects meeting any of the following criteria are not eligible for study 
participation: 
1. Weight gain or loss >5% in the 3 months prior to randomization or > 10% in the 
6 months prior to screening. 
2. Type 1 and insulin dependent Type 2 diabetes. 
3. Prior history of decompensated liver disease including ascites, hepatic 
encephalopathy (HE), or variceal bleeding. 
4. Child-Pugh Score > 6 (Class B or C), as determined at screening, unless due to 
therapeutic anti-coagulation  
5. MELD score > 12, as determined at screening, unless due to therapeutic anti-
coagulation 
6. Poorly controlled hypertension BP > 160/100. 
7. Chronic hepatitis B virus (HBV) infection (hepatitis B surface antigen [HBsAg] 
positive). 
8. Chronic hepatitis C virus (HCV) infection (HCV antibody [Ab] and HCV ribonucleic 
acid [RNA] positive). Subjects cured of HCV infection less than 2 years prior (based 
on date of RNA PCR negative confirmation following conclusion of treatment) to the 
screening visit are not eligible. 
9. Prior or planned (during the study period) bariatric surgery (e.g., gastroplasty, roux-
en-Y gastric bypass) surgery reversal or removal of intragastric balloon > 2 years 
prior to enrollment would be eligible. 
10. Other causes of liver disease based on medical history and/or centralized review of 
liver histology, including but not limited to: alcoholic liver disease, autoimmune 
disorders (e.g., primary biliary cholangitis [PBC], primary sclerosing cholangitis 
[PSC], autoimmune hepatitis), drug-induced hepatotoxicity, Wilson disease, clinically 
significant iron overload, or alpha-1-antitryspin deficiency requiring treatment. 
11. Subjects with osteoporosis, defined as a T-score of -2.5 or lower at screening. 
12. History of liver transplantation. 
13. Current or prior history of hepatocellular carcinoma (HCC). 
14. Alcohol intake above an average limit of 2 drinks per day for women and 3 drinks per 
day for men as assessed by the AUDIT-C questionnaire. 
15. Human immunodeficiency virus (HIV) infection. 


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16. Unstable cardiovascular disease.   Any acute cardiovascular event in the six months 
prior to screening (ex: myocardial infarction, cerebral vascular accident, symptomatic 
rhythm disturbance (stable, controlled atrial fibrillation is allowed); or an emergency 
room visit or hospitalization for confirmed cardiovascular disease. 
17. Life expectancy less than 2 years. 
18. Subjects taking fibrates and peroxisome proliferator-activated receptor (PPAR) alpha 
agents (clofibrate, gemfibrozil, ciprofibrate, bezafibrate, or fenofibrate). 
19. Use of any investigational medication within 30 days or within 5 half-lives prior to 
screening.  
20. Subjects with a history of (12 months prior to screening) or current use of prescription 
drugs associated with liver steatosis (e.g. methotrexate, amiodarone, high-dose 
estrogen, tamoxifen, systemic steroids, anabolic steroids, valproic acid). Short courses 
of corticosteroids (less than two weeks) may be allowed prior to screening if in the 
investigator’s opinion they are not associated with liver steatosis or clinically 
relevant; 
21. Positive urine drug screen for amphetamines, cocaine or opiates (e.g., fentanyl, 
heroin, morphine) at screening. Subjects on stable methadone or buprenorphine 
maintenance treatment for at least 6 months prior to screening may be included in the 
study. Subjects with a positive urine drug screen due to prescription medication (e.g., 
opiates, methylphenidate) are eligible if the prescription and diagnosis are reviewed 
and approved by the investigator. 
22. Concurrent participation in another therapeutic clinical study. 
23. Presence of any laboratory abnormality or significant systemic or major illnesses 
(other than liver disease) that, in the opinion of the Investigator, compromise the 
subject’s ability to safely participate in and complete the study including:  
a. Pulmonary disease, renal failure, organ transplantation, serious psychiatric 
disease, malignancy, history of substance abuse and/or a psychiatric condition 
requiring hospitalization and/or emergency room visit within six months of 
screening. 
24. Unavailable for follow-up assessment or concern for subject’s compliance with the 
protocol procedures. 
25. History of significant pancreatic disorders (acute pancreatitis, chronic pancreatitis, 
hereditary pancreatitis, and pancreatic cancer). 
 


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5. 
INVESTIGATIONAL MEDICINAL PRODUCTS (IMP) 
5.1. 
Randomization, Blinding and Treatment Codes 
An Interactive Response Technology (IRT) will be used for centralized randomization and 
treatment assignment.  Randomization will be stratified by baseline hepatic fat fraction 
(< 15% vs ≥ 15%) and F1 fibrosis score in the Main Study.  
There will be no stratification for Cohort C. 
Investigative site personnel will obtain the treatment assignment from the IRT. 
Investigational medicinal product will be prepared by an unblinded, qualified health care 
professional (e.g., pharmacist or designee) at the investigative site who is not otherwise 
associated with the study.  Investigators, study site personnel, subjects and the Sponsor 
and/or designee will be blinded to treatment assignments. Investigational medicinal products 
will be dispensed in a blinded fashion to the subjects. 
5.1.1. 
Procedures for Breaking Treatment Codes 
In the event of a medical emergency where breaking the blind is required to provide medical 
care to the subject, the investigator may obtain treatment assignment directly from the IRT 
for that subject. Akero recommends but does not require that the investigator contact the 
Medpace medical monitor before breaking the blind. Treatment assignment should remain 
blinded unless that knowledge is necessary to determine subject emergency medical care. 
The rationale for unblinding must be clearly explained in source documentation and on the 
electronic case report form (eCRF), along with the date on which the treatment assignment 
was obtained. The investigator is requested to contact the Medpace medical monitor 
promptly in case of any treatment unblinding. 
Blinding of study treatment is critical to the integrity of this clinical trial and therefore, if a 
subject’s treatment assignment is disclosed to the investigator, the subject will have study 
treatment discontinued. All subjects will be followed until study completion unless consent 
to do so is specifically withdrawn by the subject. 
The CRO’s pharmacovigilance and/or designee may independently unblind cases for 
expedited reporting of suspected unexpected serious adverse reactions (SUSARs). 
5.2. 
Investigational Product(s) 
 
EFX is provided in 6 mL sterile vials filled with a 1.1 mL volume at a strength of 70 mg/mL. 
EFX will be presented as a sterile, colorless to slightly yellow and preservative-free frozen 
liquid.  
Placebo will be presented in identical containers and packaged the same as EFX. 


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For preparation of the 28 mg and 50 mg doses, diluent vials will be provided. Refer to the 
Pharmacy Manual for further instructions on EFX/placebo administration and use of the 
diluent vials. 
The Diluent will be presented as a sterile, clear, colorless refrigerated liquid in an identical 
vial as EFX. The 6 mL vials supplied will contain approximately 3.6 mL of diluent and each 
vial is intended for single use only. 
Investigational medicinal products are to be distributed to centers in the US are labeled to 
meet applicable requirements of the United States Food and Drug Administration (FDA). 
 
5.2.1. 
Storage and Handling 
EFX / Placebo will arrive frozen in secondary box packaging and should be immediately 
placed in a freezer maintained between -30°C to -70°C until planned use. The EFX / Placebo 
vials should be stored protected from light in a secure non-frost-free freezer prior to thawing 
and use. The set point for the freezer should be between -30°C to -70°C. The set point is a 
single temperature and should remain constant.  Do not refreeze EFX / Placebo after it has 
been thawed. 
 
Freezer Set Point (°C) for 
EFX / Placebo 
Acceptable Parameters: 
Acceptable 
Range: 
-30°C to -70°C 
-30°C (+ 10°C) to 
-70°C (+ 10°C) 
-20°C to -80°C 


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The Diluent vials are shipped in refrigerated containers maintained at a range of 2°C to 8°C 
and must not be frozen. The Diluent vials should be stored in a secure refrigerator that is 
maintained between 2°C to 8°C.  
All vials of IMP should be stored in a securely locked area, accessible only to authorized site 
personnel.  
Records of the actual storage conditions during the period of the study must be maintained 
(e.g., records of the date and time and initials of person checking, and the “working day” 
temperatures of the refrigerator and freezer used for storage of study supplies, continuous 
temperature recordings, or regularly maintained temperature alarm systems used in 
conjunction with temperature recording). 
Akero must be notified if any IMP undergoes temperature excursions or if the IMP is 
damaged. IMP supply should not be utilized unless Akero personnel have advised that it is 
acceptable to do so.  
5.2.2. 
Dosage and Administration 
Detailed information regarding the preparation and administration of EFX or Placebo for this 
study is contained in the EFX Pharmacy Manual.  Investigational medicinal product will be 
administered by subcutaneous injection once weekly as follows:   
 
Main Study: 
• Placebo QW for 16 weeks (n = 20) 
• 28 mg EFX QW for 16 weeks (n = 20) 
• 50 mg EFX QW for 16 weeks (n = 20) 
• 70 mg EFX QW for 16 weeks (n = 20) 
Cohort C: 
• Placebo QW for 16 weeks (n = 10) 
• 50 mg EFX QW for 16 weeks (n = 20) 
The IMP will be administered by a weekly 1.0 mL subcutaneous injection into the abdomen 
at the clinic by a qualified staff member.  The date and time of injection will be recorded.  If 
injection site reactions are observed, mitigation procedures should be put in place as per local 
standard of care.  Examples of mitigations include icing the injection site, rotating the 
quadrant of the abdomen in which the injection is administered, or providing antihistamine 
prior to injection. 
5.3. 
Prior and Concomitant Medications 
All concomitant medication will be recorded in the source documents and eCRFs. This 
includes concomitant medications taken within 30 days prior to screening and any taken 
during the study through end of the study. 


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Use of any investigational medication within 30 days or within 5 half-lives prior to screening 
and throughout the study is prohibited.  
Subjects with a history of (12 months prior to screening) or current use of prescription drugs 
associated with liver steatosis (e.g. methotrexate, amiodarone, high-dose estrogen, tamoxifen, 
systemic steroids, anabolic steroids, valproic acid) should be excluded.  Short courses of 
corticosteroids (less than two weeks) may be allowed prior to screening if in the 
investigator’s opinion they are not associated with liver steatosis or clinically relevant. 
As EFX is expected to improve insulin sensitivity, subjects on Sulfonylureas with unstable 
blood glucose levels should be reminded of the symptoms of hypo- and hyper-glycemia and 
how to correct them. 
Main Study: 
Subjects on Vitamin E ≥ 400 IU/day, thiazolidinediones (including, but not limited to, 
pioglitazone, rosiglitazone, and lobeglitazone), GLP1, or SGLT2 must be on a stable dose 
(defined as no changes in prescribed dose, new medications, or discontinuation) for at least 
6 months prior to the diagnostic liver biopsy and screening.  
Subjects who have insulin dependent Type 2 diabetes are excluded from the study. Subjects 
on other antidiabetic, weight loss, or lipid-modifying medication(s) must be on stable dose(s) 
for at least 3 months prior to the diagnostic liver biopsy through randomization. Dose 
adjustments for metformin are allowed in the 3 months prior to screening. If possible, the 
doses of these medications should remain stable through the end of treatment.  Fibrates and 
peroxisome proliferator-activated receptor (PPAR) alpha agents (clofibrate, gemfibrozil, 
ciprofibrate, bezafibrate, or fenofibrate) are prohibited from screening until the end of the 
study. 
Cohort C: 
Subjects on Vitamin E ≥ 400 IU/day, thiazolidinediones (including, but not limited to, 
pioglitazone, rosiglitazone, and lobeglitazone), GLP1, or SGLT2 must be on a stable dose 
(defined as no changes in prescribed dose, new medications, or discontinuation) for at least 
6 months prior to the screening visit.  
Subjects who have insulin dependent Type 2 diabetes are excluded from the study. Subjects 
on other antidiabetic, weight loss, or lipid-modifying medication(s) must be on stable dose(s) 
for at least 3 months prior to screening. Dose adjustments for metformin are allowed in the 
3 months prior to screening. If possible, the doses of these medications should remain stable 
through the end of treatment.  Fibrates and peroxisome proliferator-activated receptor 
(PPAR) alpha agents (clofibrate, gemfibrozil, ciprofibrate, bezafibrate, or fenofibrate) are 
prohibited from screening until the end of the study. 
 


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5.4. 
Investigational Medicinal Product Accountability 
The Sponsor or designee will supply the Investigational Medicinal Product (IMP).  The site 
will maintain the following records: receipt of shipments, dispensation to subjects, and return 
of partially used, or unused IMP. 
5.4.1. 
Investigational Medicinal Product Return or Disposal 
At the start of the study, the study monitor will evaluate the study center’s study drug 
disposal procedures and provide appropriate instruction for return or destruction of unused 
IMP supplies. If the site has an appropriate Standard Operating Procedure (SOP) for drug 
destruction, the site may destroy used (empty bottles) and unused IMP supplies performed in 
accordance with the site’s (hospital/pharmacy) SOP. If the site does not have acceptable 
procedures in place for drug destruction, arrangements will be made between the site and 
Akero (or Akero’s representative) for return of unused IMP supplies. A copy of the site’s 
SOP will be obtained for central files. Where possible, IMP will be destroyed at the site. 
Upon study completion, a copy of the Investigational Drug Accountability records must be 
filed at the site. Another copy will be returned to Akero. If IMP is destroyed on site, the 
Investigator must maintain accurate records for all IMP vials destroyed. Records must show 
the identification and quantity of each unit destroyed, the method of destruction, and person 
who disposed of the IMP. All IMP records must be maintained at the site and copies must be 
submitted to Akero at the end of the study. 
 


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6. 
STUDY PROCEDURES 
The following assessments will be conducted during screening and at selected time points 
specified in the Schedule of Assessments (Appendix A and Appendix B).  Additional 
procedures deemed necessary as part of standard of care may be performed at the discretion 
of the Investigator.  All missed visits and any performed procedures that are not protocol-
specified activities must be documented in the subject’s medical record and the appropriate 
eCRF.  
6.1. 
Screening and Informed Consent 
Before subjects commence any study-specific activities or procedures, the Sponsor requires a 
copy of the study site’s written institutional review board (IRB) approval of the protocol, 
informed consent form (ICF), and all other subject information and/or recruitment material, if 
applicable.  Each subject (or legally acceptable representative) must sign and date the ICF 
before participating in study-specific activities. 
After the ICF is signed, the subject enters the screening period.  Subjects will be screened 
within 6 weeks before randomization to determine eligibility for participation in the study. 
The screening period may be extended to 8 weeks to allow for pathology assessment of the 
liver biopsy.  Subjects who are ineligible at the screening visit may be re-screened if there is 
reasonable belief that the exclusionary result was obtained in error or is transient upon 
approval of the Medical Monitor.  Subjects who screen fail for the Main Study due to 
cirrhosis may apply any assessments from the original screening visit that are still within 
window for potential enrollment into Cohort C. 
After completing the screening period, the subject will be evaluated by the investigator to 
confirm eligibility. A subject is considered enrolled when the investigator decides that all of 
the eligibility criteria are met. The investigator will document this decision and date and time 
in the subject’s medical record and the eCRF.  Screen failure subjects will be entered into the 
eCRF. Investigators will maintain a screening log of all potential subjects that includes 
limited information about each subject, dates, and outcome of screening process (e.g., 
enrolled into study, reason for ineligibility, or withdrawal of consent). 
6.2. 
Demographics and Medical History 
Demographic data including sex, age, race, and ethnicity will be collected. 
The Investigator or designee will collect medical and surgical history that started prior to 
enrollment through the time of consent, including information on the subject’s concurrent 
medical conditions. All findings will be recorded on the medical history eCRF. 
6.3. 
Physical Examination 
The Investigator or designee will conduct a complete physical examination, or a symptom-
driven exam as outlined in the Schedule of Assessments. Physical exam findings prior to the 


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first dose of study drug will be recorded on the medical history eCRF page and clinically 
significant findings after the first dose of study drug will be recorded as AEs. 
At a minimum, the complete physical examination should include assessments of the head 
and neck, skin, nervous system, lungs, cardiovascular system, abdomen, thyroid, lymph 
nodes, and extremities.  
A symptom-driven physical examination will include assessment of any new subject 
complaints or changes from baseline. 
Physical assessments required to calculate Child-Pugh Score (CP Score) for Cirrhosis 
Mortality to be completed as part of the physical examination as indicated in the Schedule of 
Assessments. 
6.4. 
Vital Signs, Weight, Hip and Waist Circumference 
The following vital sign measurements will be performed as outlined in the schedule of 
assessments: systolic and diastolic blood pressure, pulse, respiration rate, oral temperature, 
height, weight, hip and waist circumference.   
The subject must be in seated or in a semi-recumbent position in a rested and calm state for at 
least 5 minutes before vital signs are collected.  The position selected for a subject should be 
the same throughout the study and documented on the vital signs eCRF.  Triplicate blood 
pressure (to be measured in same arm with at least two minutes rest between BP 
measurements) and heart rate to be collected at baseline and between 48-96 hours post-dose 
(to correspond to Cmax) at the timepoints indicated in the schedule of assessments. 
Height will be measured without shoes at screening.  
Weight will be obtained at screening and selected time points thereafter. On dosing days, 
weight will be collected pre-dose.  Weight should be obtained using a calibrated scale.  The 
subject should be weighed in consistent clothing.  
Waist circumference should be measured by placing the tape measure around the waist just 
above the top of the hip bone. Ensure it is snug against the skin, but not tight.  
Hip circumference should be measured by placing the tape measure around the widest part of 
the buttocks. Ensure the tape measure is parallel to the floor, and not slanted. 
Weight, waist and hip circumference should be obtained by the same study personnel 
between visits for each subject to minimize variability in the measurement. 
6.5. 
12-Lead Electrocardiography 
The subject must be in a seated, semi-recumbent, or supine position in a rested and calm state 
for at least 10 minutes before ECG assessment is conducted.  Each 12-lead ECG should be 
performed prior to blood draws, dosing (if applicable), or other invasive procedures.  Each 


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ECG must capture QRS, QT, QT interval corrected for heart rate (QTc), RR, and PR 
intervals and be documented on the ECG eCRF.   
The Investigator or designated study site physician will review, sign, and date all ECGs.  The 
original ECGs will be retained with the subject’s source documents.  At the request of the 
Sponsor, a copy of the original ECG will be made available to the Sponsor. 
6.6. 
FibroScan® 
FibroScan® examinations will be performed and median liver stiffness in kilopascals (kPa), 
interquartile range/median value (IQR/M), and success rate (number of valid shots/total 
number of shots) will be recorded. Where available, the median CAP and the interquartile 
range of CAP values will be recorded from FibroScan® examinations.  For the Main Study, a 
FibroScan® measurement of greater than 7.0 kPa is required to continue to progress the 
subject through the remaining screening assessments.   
At least 2-3 hours fasting is required prior to all elastography assessments. 
6.7. 
Liver Biopsy 
Main Study:  
A liver biopsy must be obtained at screening and between weeks 22-24 (for subjects with 
≥ 30% relative fat reduction on MRI-PDFF at Week 12) to provide the liver tissue for central 
reading. All reasonable attempts should be made to acquire a liver biopsy specimen of at 
least 2.0 cm in length. It is recommended that a 16-gauge needle is used to collect the tissue 
sample. 
A historical biopsy that meets eligibility criteria may be accepted as the screening biopsy if 
the sample is deemed acceptable for interpretation by the central reader. The historical 
sample must have been originally obtained within 180 days of the Randomization date and 
confirm the below criteria: 
• Subject was not previously treated for NASH/NAFLD with prohibited concomitant 
medications (including investigational products) within 6 months of historical biopsy. 
• Subject was not previously treated with an Investigational Product within 6 months 
prior to or at the time of historical biopsy. 
If the historical biopsy is not adequate for interpretation by the central reader, or was 
obtained more than 180 days prior to randomization, a fresh liver biopsy will be collected.  
Liver biopsies will be sent to a central laboratory and then read by a central reader. The 
central reader will read all screening biopsies for eligibility. 
Cohort C: 


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A historical biopsy performed within 24 months of the Screening Visit or for those subjects 
who undergo a liver biopsy for eligibility, the following is required for enrollment: 
• Biopsy must be consistent with NASH and cirrhosis as assessed by a local 
pathologist. 
• Subject was not previously treated for NASH/NAFLD (including investigational 
products unless documentation can be provided that the subject was randomized to 
placebo) between obtaining the historical biopsy and the Screening visit.   
Following 16 weeks of treatment, subjects will be given the option to collect an end of 
treatment biopsy.  Both the historical biopsy sample used to qualify the subject at screening 
as well as the end of treatment biopsy sample will be shipped for blinded pathology analysis 
by the central reader. 
 
All Subjects: 
If a liver biopsy is performed per standard of care outside of protocol mandated assessments, 
all possible attempts should be made to submit the biopsy specimen to the central reader for 
evaluation. 
If liver biopsy results are deemed unevaluable by the central reader, additional slides may be 
provided, or a repeat biopsy may be performed at the discretion of the Investigator.   
6.8. 
MRI-PDFF 
Main Study Only:  
The degree of steatosis will be measured by MRI-PDFF. Subjects who have 
contraindications to MR imaging (e.g., unmanageable claustrophobia or metal implants) 
should be excluded from the study.  
The MRI-PDFF images will be analyzed by a central reader. Please refer to the Imaging 
Manual for MRI-PDFF imaging guidelines. At least 4 hours fasting is required prior to all 
MR assessments. 
Corrected T1 (cT1) will also be collected at the same time as MRI-PDFF, under the same 
conditions, where available. 
6.9. 
DXA Scan 
A DXA scan will be performed to confirm eligibility and again after treatment has been 
discontinued.  DXA scan should include lumbar spine, femoral neck, and total hip with 
subjects in the standard (supine) position. 


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Total body composition may also be collected at the DXA timepoints, where available, to 
determine body fat distribution. 
Refer to the DXA manual for more information. 
6.10. Health Related Quality of Life Questionnaires 
It is recommended that the questionnaires be completed prior to any study procedures being 
performed and prior to the subject seeing a health care provider.  If the baseline 
questionnaires are missed at Day 1, questionnaires should not be collected at the remaining 
timepoints.   
6.10.1. 
Short Form 36 Health Survey (SF-36) 
The SF-36 asks 36 questions to measure functional health and well-being from the subject’s 
point of view. It consists of eight health domains: physical functioning, role-physical, bodily 
pain, general health, vitality, social functioning, role-emotional, and mental health. These 
health domain scales contribute to the physical health and mental health summary measures. 
6.10.2. 
Chronic Liver Disease Questionnaire-Nonalcoholic Fatty Liver Disease 
(CLDQ-NAFLD) 
The CLDQ-NAFLD asks questions related to liver disease and specifically NAFLD, to 
measure health related quality of life in subjects with chronic liver disease. 
6.10.3. 
Work Productivity and Activity Impairment (WPAI) 
The WPAI questionnaire asks questions regarding the effect of NASH on a person’s ability 
to work and perform regular activities.  
6.11. Alcohol Use Disorders Identification Test (AUDIT-C) 
The Alcohol Use Disorders Identification Test (AUDIT-C) is a 3-item screening tool 
developed by the World Health Organization (WHO) to assess alcohol consumption, 
drinking behaviors, and alcohol-related problems. Subjects should be encouraged to answer 
the AUDIT-C questions in terms of standard drinks. A chart illustrating the approximate 
number of standard drinks in different alcohol beverages is included for reference. 
6.12. Lifestyle Modification  
Lifestyle modifications such as weight loss via diet and increased exercise can be effective in 
the treatment of NASH. All subjects will receive counseling regarding lifestyle modifications 
including the maintenance of a healthy diet and participation in regular exercise at the 
Baseline visit.  At each subsequent visit, subjects will be asked if there has been a significant 
change in diet, or physical activity. Changes will be documented in the eCRF. 


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6.13. Clinical Laboratory Tests 
6.13.1. 
Laboratory Parameters 
Blood samples will be collected according to the Schedule of Assessments (Appendix A and 
Appendix B) and below.  Samples will be sent to the central laboratory for analysis and 
reporting.  Samples may be analyzed for the tests outlined in this protocol and for any 
additional tests necessary to ensure subject safety.  These may include, but are not limited to, 
investigation of unexpected results and incurred sample reanalysis. 
At visits where CTX-1 or lipids are collected, the samples should be collected in the morning 
following an overnight fast of at least 8 hours. 
Subjects will be in a seated, semi-recumbent, or supine position during blood collection. 
Clinical laboratory tests will include the following:  


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Table 3. 
Clinical Laboratory Assessments 
Chemistry 
Hematology/Coagulation Urine/Miscellaneous 
Biomarkers 
Sodium 
Potassium 
Chloride 
Bicarbonate 
Calcium 
Magnesium 
Phosphorus 
Glucoseb 
BUN 
Creatinine 
Total protein 
Albumin 
Uric acid 
LDH 
Total (TBL) and 
direct bilirubin 
Alkaline phosphatase 
(ALP) 
ALT (SGPT) 
AST (SGOT) 
GGT 
CK 
hsCRP 
Amylase 
Lipasec 
 
Lipoproteins  
Total Cholesterol 
HDL-Cb 
LDL-Cb 
Triglycerides 
Free Fatty Acidsb 
Hematology 
RBC count 
Hemoglobin (Hgb) 
Hematocrit (Hct) 
Platelet count 
 
WBC count with 
differential: neutrophils, 
lymphocytes, monocytes, 
eosinophils, and basophils 
 
ANC 
 
Coagulation 
PT 
aPTT 
INR 
PAI-1 
Fibrinogen 
Urine 
Drug screening: 
amphetamines, 
cocaine and opiates 
(i.e., fentanyl, heroin, 
morphine) 
 
Miscellaneous 
Screening Serology 
Tests 
HBsAg 
HBcAb 
HBV DNA 
Anti-HCV antibody 
HCV RNA 
HIV 
 
Endogenous FGF21b 
 
Saliva Cortisol 
 
Pregnancy testa 
 
Pharmacokinetics 
(PK) 
 
Anti EFX antibody 
(ADA) 
Neutralizing Anti EFX 
antibody (NAB) 
Fibrosis Biomarkers 
ELF 
Pro-C3 
 
Bone Biomarkers 
Osteocalcin 
P1NP 
CTX-1b 
BSAP 
Parathyroid hormone 
(PTH) 
Vitamin D 
 
Lipid Metabolism 
Biomarkers 
Lp (a) 
ApoB, ApoC2 & Apo 
C3 
3 Hydroxy-butyrate 
Bile acids 
 
Insulin Sensitivity & 
Glycemic Control 
Biomarkers 
Insulin 
Glucagon 
Adiponectin  
C-Peptide 
HOMA-IR 
HbA1c  
 
 
ADA = anti-drug antibodies; ALT = alanine aminotransferase; ANC = absolute neutrophil count; Apo = 
Apolipoprotein; AST = aspartate aminotransferase; aPTT = activated partial thromboplastin time; BSAP= bone 
specific alkaline phosphatase; BUN = blood urea nitrogen; ELF = Enhanced Liver Fibrosis panel; GGT = 
gamma-glutamyl transferase; HbA1c = Glycated Hemoglobin A1c; HBcAb = total hepatitis B core antibody; 
HBsAg = hepatitis B surface antigen; HBV DNA = hepatitis B virus deoxyribonucleic acid; HCV = hepatitis C 
virus; HDL-C = high density lipoprotein cholesterol; HIV = human immunodeficiency virus; HOMA-IR = 
Homeostatic Model Assessment of Insulin Resistance; hsCRP = high sensitivity C-Reactive Protein; INR 
= International Normalized Ratio; LDH = lactate dehydrogenase; LDL-C = low density lipoprotein cholesterol; 
Lp = Lipoprotein; L&HMW = low and high molecular weight; PAI-1 = Plasminogen Activator Inhibitor-1; Pro-
C3 = N-terminal Type III Collagen Propeptide; PT =prothrombin time; RBC = red blood cell; RNA = 
ribonucleic acid; TBL, total bilirubin; WBC = white blood cell 
a For female subjects of childbearing potential only. Serum pregnancy test at screening and urine pregnancy test 
at other time points. 
b Samples to be collected in the morning following an overnight fast of at least 8 hours. 
c Reflex lipase testing is performed in subjects with total amylase > 1.5 ULN. 


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6.14. Sample Collection, Storage, and Shipping 
Blood and urine samples from screening through ET or end of study visits will be collected 
and submitted to the central laboratory for analysis.  Validated assays will be used for 
analysis when appropriate. 
6.15. Pharmacokinetic Assessments 
Pharmacokinetic samples will be collected at time points specified in the Schedule of 
Assessments (Appendix A and Appendix B).   
6.16. Anti-Drug Antibody and Neutralizing Antibody Sampling 
Samples will be obtained for detection of anti-drug antibodies (ADA) against EFX as 
outlined in the Schedule of Assessments (Appendix A and Appendix B). 
In the event of a positive anti-EFX antibody detection, a neutralizing ADA assay will be run 
for the sample timepoint with the positive result. 
Subjects who test positive for binding antibodies to EFX at the final scheduled study visit 
will be required to return for additional follow-up testing. This testing is to occur once the 
site has been notified of the positive result and approximately every 3 months until: (1) 
antibodies are no longer detectable or (2) the subject has been followed for a period of at 
least 6 months (± 2 weeks) after administration of EFX. All follow-up results, both positive 
and negative, will be communicated to the sites. More frequent testing (e.g., every month) or 
testing for a longer period of time may be requested in the event of safety-related concerns. 
Follow-up testing is not required where it is established that the subject did not receive EFX. 
6.17. Blood Storage 
A portion of the blood samples drawn at study visits will be frozen and stored.  The stored 
samples may be used for future clinical laboratory testing to provide additional clinical data.  
No human genetic testing will be performed without expressed consent of study subjects.  At 
the conclusion of the study, these samples may be retained in storage by Akero for a period 
of up to 15 years. 
6.18. Biomarkers 
The biological specimens collected in this study will be used to evaluate the association of 
exploratory systemic biomarkers with study drug response, including efficacy and/or AEs 
and to increase knowledge and understanding of the biology of how EFX affects subjects 
with NASH. Biological specimens may also be used to increase the knowledge of diseases 
such as NAFLD, liver fibrosis, inflammatory diseases, bone turnover, and/or the validation of 
a companion diagnostic if applicable. The specific analyses will include, but will not be 
limited to, the biomarkers and assays described in Table 3.  As biomarker science is a rapidly 
evolving area of investigation, and AEs in particular are difficult to predict, it is not possible 
to specify prospectively all tests that will be performed on the specimens provided. The 


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testing outlined is based upon the current state of scientific knowledge and may be modified 
during or after the end of the study to remove tests no longer indicated and/or to add new 
tests based upon the newest technologies. 
Samples will be destroyed no later than 15 years after the end of the study. The specimen 
storage period will be in accordance with the IRB/independent ethics committee (IEC)/ethics 
committee (EC) approved ICF and applicable laws (e.g., health authority requirements). 
6.19. Criteria for Discontinuation of Study Drug 
Study drug must be discontinued in the following instances: 
 
• Liver transplantation  
• Subject develops an SAE consisting of a serious hypersensitivity reaction to study drug 
• Subject experiences diarrhea that meets the criteria in Section 6.23 for discontinuation.   
• Subject experiences a Grade IV Common Terminology Criteria for Adverse Events 
(CTCAE) or meets the criteria for Drug Induced Liver Injury described in Section 6.24. 
 The Data Monitoring Committee (DMC) should perform a causality assessment. The 
study drug may be restarted if the DMC concludes that the AE or laboratory 
abnormalities were not related to study drug, the AE has resolved, laboratory 
abnormalities have returned to baseline, and the subject is amenable to close clinical 
follow-up. 
 If, after re-challenge, a subject has a second serious AE or recurrent elevations (even 
mild or minimal) of total bilirubin, ALT, or AST as defined in Section 6.24.3, study 
drug should be discontinued permanently. 
• Intercurrent illness that would, in the judgment of the Investigator, affect assessments of 
clinical status to a significant degree. Following resolution of intercurrent illness, the 
subject may resume study dosing at the discretion of the Investigator, in consultation with 
the Medical Monitor 
• Unacceptable toxicity or toxicity that, in the judgment of the Investigator, compromises 
the ability to continue study-specific procedures or is considered to not be in the subject’s 
best interest 
• Subject or Investigator request to discontinue for any reason 
• Significant subject noncompliance 
• Significant protocol violation that impacts subject safety 


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•
Pregnancy during the study; refer to Appendix C.
•
Discontinuation of the study at the request of Akero, a regulatory agency, or an 
IRB/IEC/EC.
Cohort C 
In addition to the above criteria, study drug must be discontinued in the following instances 
in Cohort C:  
•
Development of any decompensation events including ascites, hepatic encephalopathy
(HE), or variceal bleeding
•
Progression to Child Pugh Class C
6.20. Interruption of Study Drug 
If dosing is interrupted (i.e., as a result of an AE), every attempt should be made to keep the 
subject in the study and continue to perform the required study-related procedures. 
Discussion with the Medical Monitor is recommended. If this is not possible or acceptable to 
the subject or Investigator, the subject may be withdrawn from the study. 
6.21. Adverse Events 
An AE is any unfavorable and unintended sign (including an abnormal laboratory finding), 
symptom, or disease temporally associated with the use of a study drug, whether or not 
related to the study drug.  AEs may also include pre- or post-treatment complications that 
occur as a result of protocol specified procedures, lack of efficacy, overdose, drug 
abuse/misuse reports, or occupational exposure. Pre-existing events that increase in severity 
or change in nature during or as a consequence of participation in the clinical study will also 
be considered AEs.  AEs that occur after the first dose of EFX or during the study treatment 
and safety follow up periods will be documented on the AE eCRF.  The Investigator will 
assess the AE severity and relationship of the AE to study drug.  The Investigator will treat 
the subject as medically required.  
Laboratory values that are outside the laboratory reference range should be reported as AEs 
only if considered clinically significant by the Investigator. 
From the time of obtaining informed consent until 30 days after the last administration of 
study drug, all SAEs and non-serious AEs related to protocol-mandated procedures will be 
recorded on the SAE/AE eCRF.  All other untoward medical occurrences observed during 
screening, including exacerbation or changes in medical history, will be captured on the 
medical history eCRF.  Details on recording and reporting AEs are provided below. 
Clinical judgment of the Investigator should be used to determine whether a subject is to be 
withdrawn due to an AE.  In the event the subject requests to withdraw from study-related 


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treatment or the study due to an AE, the subject should be followed for the safety follow up 
period as outlined in the Schedule of Assessments.  
All subjects experiencing AEs, including clinically significant abnormal laboratory values, 
whether or not associated with use of the study drug, must be monitored until the condition 
returns to normal, returns to the subject’s baseline, until the Investigator determines the AE 
has reached a stable outcome and is no longer clinically significant, or the subject is 
considered lost to follow up. 
6.21.1. 
Severity 
All AEs, both serious and non-serious, will be assessed for severity using the 
Common Terminology Criteria for Adverse Events (CTCAE) Version 5.0.  The CTCAE 
scale includes unique clinical descriptions of AEs that are categorized by anatomy and/or 
pathophysiology and is provided in the Site Operations Manual.   
The CTCAE scale displays Grades 1 through 5 with unique clinical descriptions of severity 
for each AE (including abnormal laboratory values) based on this general guideline provided 
in the CTCAE scale.  For any AEs not covered by CTCAE the conventional definition of 
severity will be used.  
 Grade 1 (Mild) AE: minor; no specific medical intervention; marginal clinical relevance  
 Grade 2 (Moderate) AE: minimal intervention; local intervention; noninvasive 
intervention 
 Grade 3 (Severe) AE: significant symptoms requiring hospitalization or invasive 
intervention;  
 Grade 4 (Life-threatening or disabling) AE: Complicated by acute, life-threatening 
complications; need for intensive care or emergent invasive procedure 
 Grade 5 Fatal AE 
6.21.2. 
Relationship 
The Investigator or qualified sub-Investigator is responsible for assessing the relationship to 
study drug using clinical judgment and the following considerations: 
 Not related: all AEs should be considered related unless the AE is clearly unrelated to 
study drug or clearly due to the subject’s underlying disease.  For a SAE, an alternative 
causality must be provided (e.g., preexisting condition, underlying disease, intercurrent 
illness, or concomitant medication). 
 Related: There is reasonable possibility that the event may have been caused by the study 
drug. 
Ineffective treatment should not be reported as an AE.  
The relationship to study-related procedures (e.g., invasive procedures such as venipuncture 
or biopsy) should be assessed using the following considerations: 


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 Not related: Evidence exists that the AE has an etiology other than the study procedure. 
 Related: The AE occurred as a result of study procedures. 
6.21.3. 
Overdose 
An overdose is any dose of study drug given to a subject that exceeds the protocol specified 
dose by 10% or more.  In the event of an overdose-associated AE, appropriate supportive 
therapy should be initiated according to the subject’s signs and symptoms. 
Any overdose, with or without associated AEs, will be promptly reported to the Sponsor and 
recorded as non-compliance on the eCRF.  AEs associated with overdose should be reported 
on relevant AE/SAE sections in the eCRF. 
6.21.4. 
Serious Adverse Events 
6.21.4.1. 
Definition 
A SAE is defined by federal regulation as any AE occurring at any dose that results in any of 
the following outcomes: death, life-threatening AE, hospitalization or prolongation of 
existing hospitalization, a persistent or significant incapacity or substantial disruption of the 
ability to conduct normal life functions, or a congenital anomaly/birth defect. 
Important medical events that may not result in death, be life threatening, or require 
hospitalization may be considered an SAE when, based upon appropriate medical judgment, 
they may jeopardize the subject, and may require medical or surgical intervention to prevent 
one of the outcomes listed in this definition.  Examples of such medical events include 
allergic bronchospasm requiring intensive treatment in an emergency room or at home, blood 
dyscrasias or convulsions that do not result in inpatient hospitalization, or the development of 
drug dependency or drug abuse. 
A life-threatening AE is one that, in the view of the Investigator, places the subject at 
immediate risk of death from the reaction as it occurred. 
An unexpected AE is any event for which the specificity or severity is not consistent with the 
AE profile in the current EFX IB. 
All SAEs, regardless of cause(s) or relationship to study drug, must be reported immediately 
to the study Sponsor and/or designee. 
6.21.5. 
Reporting Adverse Events 
6.21.5.1. 
Reporting Procedures for Non-Serious Adverse Events 
The Investigator is responsible for ensuring that all AEs observed by the Investigator or 
designee or reported by the subject are reported using the AE eCRF.  
The Investigator will assign the following AE attributes: 


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 AE diagnosis or syndrome(s), if known (if not known, signs or symptoms) 
 Dates of onset and resolution (if resolved) 
 Severity  
 Relatedness to study drug or study-related procedures  
 Action taken 
Follow-up of non-serious AEs will continue through the last day on the study and/or until a 
definitive outcome (e.g., resolved, resolved with sequelae, lost to follow-up) is achieved. 
When a subject is withdrawn from the study because of a non-serious AE, the Sponsor and/or 
designee must be notified by e-mail or phone within 48 hours. 
6.21.5.2. 
Reporting Procedures Serious Adverse Events 
The Investigator is responsible for ensuring that all SAEs observed by the Investigator or 
reported by the subject are promptly assessed and reported.  The Investigator must assess 
whether the SAE is related to study drug or any study-related procedure.  
The procedures for reporting SAEs are as follows: 
Initial Reports 
 All SAEs occurring after the first dose of EFX or during the study treatment and 
safety follow up periods must be reported to Medpace Clinical Safety within 24 hours 
of the knowledge of the occurrence. After the protocol-specified reporting window, 
any SAE that the investigator considers related to study must be reported to Medpace 
Clinical Safety or the Sponsor/designee. 
 
 To report the SAE, complete the SAE form electronically in the electronic data 
capture (EDC) system for the study. When the form is completed, Medpace Safety 
personnel will be notified electronically by the EDC system and will retrieve the 
form. If the event meets serious criteria and it is not possible to access the EDC 
system, send an email to Medpace Safety at
 or call the Medpace SAE hotline (phone number 
listed below), and fax/email the completed paper SAE form to Medpace (contact 
information listed below) within 24 hours of awareness. When the EDC system 
becomes available, the SAE information must be entered within 24 hours of the 
system becoming available. 
 
Follow-Up Reports 
 The investigator must continue to follow the subject until the SAE has subsided or 
until the condition becomes chronic in nature, stabilizes (in the case of persistent 
impairment) or the subject dies. 
 
 Within 24 hours of receipt of follow-up information, the investigator must update the 
SAE form electronically in the EDC system for the study, and submit any supporting 
documentation (e.g., subject discharge summary or autopsy reports) to Medpace 




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applicable regulations.  The Sponsor or its designee will report SAEs and/or SUSARs as 
required to regulatory authorities and Investigators in compliance with all reporting 
requirements according to local regulations and Good Clinical Practice (GCP). 
The Investigator will notify the appropriate IRB of SAEs occurring at the study site and other 
AE reports received from the Sponsor, in accordance with local procedures and statutes.  The 
Investigator or designee at each study site is responsible for submitting Investigational New 
Drug (IND) safety reports (initial and follow-up) and other safety information (e.g., revised 
Investigator’s Brochure) to the IRB and for retaining a copy in the study files. 
6.22. Adverse Events of Special Interest 
The Investigator will monitor each subject for clinical and laboratory-evidence for predefined 
AEs of special interest (AESIs) throughout the subject’s participation in this study.  The 
Investigator should treat the AESI according to local standard of care.  The following 
conditions will be monitored as AESIs during this study: 
• Injection site reactions 
• Diarrhea 
• Hypoglycemia 
In addition, drug-induced liver injury will be monitored and managed according to Section 
6.24. 
During the course of the study, additional AESIs may be identified by the Sponsor.  The 
Investigator will assess and record in detail any additional information for AESIs on the AE 
eCRF form.  
6.23. Clinical Laboratory Abnormalities and Other Abnormal Assessments as 
Adverse Events or Serious Events 
Laboratory abnormalities are usually not recorded as AEs or SAEs, however, laboratory 
abnormalities (e.g., clinical chemistry, hematology, urinalysis) independent of the underlying 
medical condition that require medical or surgical intervention or lead to investigational 
medicinal product interruption or discontinuation must be recorded as an AE, as well as an 
SAE, if applicable. In addition, laboratory or other abnormal assessments (e.g., 
electrocardiogram, X-rays, vital signs) that are associated with signs and/or symptoms must 
be recorded as an AE or SAE if they meet the definition of an AE (or SAE) as described in 
Section 6.21. If the laboratory abnormality is part of a syndrome, record the syndrome or 
diagnosis (e.g., anemia) not the laboratory result (i.e., decreased hemoglobin). 
Severity should be recorded and graded according to the CTCAE Version 5.0. For AEs 
associated with laboratory abnormalities, the event should be graded based on the clinical 
severity in the context of the underlying conditions; this may or may not be in agreement 
with the grading of the laboratory abnormality. 


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Toxicity Management 
Any questions regarding toxicity management should be directed to the Medical Monitor. 
Grade 1 and 2 Laboratory Abnormality or Clinical Event 
Continue investigational medicinal product at the discretion of the Investigator. 
 
Grade 3 Laboratory Abnormality or Clinical Event 
• For Grade 3 clinically significant laboratory abnormality or clinical event, 
investigational medicinal product may be continued if the event is considered to be 
unrelated to investigational medicinal product. 
 
• For a Grade 3 clinical event, or clinically significant laboratory abnormality 
confirmed by repeat testing, that is considered to be related to investigational 
medicinal product, investigational medicinal product should be withheld until the 
toxicity returns to ≤ Grade 2. 
 
• If a laboratory abnormality recurs to ≥ Grade 3 following re-challenge with 
investigational medicinal product and is considered related to investigational 
medicinal product, then investigational medicinal product should be permanently 
discontinued, and the subject managed according to local practice. Recurrence of 
laboratory abnormalities considered unrelated to investigational medicinal product 
may not require permanent discontinuation. 
 
Grade 4 Laboratory Abnormality or Clinical Event 
• For a Grade 4 clinical event or clinically significant Grade 4 laboratory abnormality 
confirmed by repeat testing, the DMC should perform a causality assessment. The 
study drug may be restarted if the DMC concludes that the AE or laboratory 
abnormalities were not related to study drug, the AE has resolved, laboratory 
abnormalities have returned to baseline, and the subject is amenable to close clinical 
follow-up. 
• If a laboratory abnormality recurs to ≥ Grade 4 following re-challenge with 
investigational medicinal product and is considered related to investigational 
medicinal product, then investigational medicinal product should be permanently 
discontinued, and the subject managed according to local practice. Recurrence of 
laboratory abnormalities considered unrelated to investigational medicinal product 
may not require permanent discontinuation. 
• If, after re-challenge, a subject has a second serious AE or recurrent elevations (even 
mild or minimal) of total bilirubin, ALT, or AST as defined in Section 6.19, study 
drug should be discontinued permanently. 


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6.24. Observation for Drug Induced Liver Injury (DILI) 
Throughout the study, all TEAEs, clinical assessments, and clinical laboratory parameters will 
be closely monitored against the criteria for drug-induced liver injury as detailed in this 
protocol. 
6.24.1. 
Subjects with Normal Liver Transaminases and Bilirubin at Baseline 
Drug-induced liver injury monitoring in subjects with normal liver transaminases and bilirubin 
at baseline should be performed throughout the study according to the procedures summarized 
below.  
• If subjects with normal baseline liver indices develop elevations of >5 × ULN during the 
study, repeat testing should be performed within 2 - 5 days from receipt of results. For 
Cohort C subjects, repeat testing should be performed within 48 to 72 hours from receipt 
of results. 
o If there are persistent elevations (ALT > 5 × ULN or TBL > 2 × ULN) upon repeat 
testing, close observation (testing and physical examination 2 to 3 times per week) 
should be implemented. An important purpose of the close observation is to gather 
additional clinical information to seek other possible causes of the observed liver test 
abnormalities, such as one of the following: acute viral hepatitis, alcoholic and 
autoimmune hepatitis, hepatobiliary disorders, cardiovascular causes, or concomitant 
treatments. Discontinuation of study drug should be considered. 
• Study drug should be discontinued, and the subject should be followed until resolution of 
signs or symptoms, in the following situations:  
o ALT >8 × ULN 
o ALT >5 × ULN and (TBL >2 × ULN) 
o ALT >5 × ULN with the appearance of fatigue, nausea, vomiting, right upper quadrant 
pain or tenderness, fever, rash, and/or eosinophilia (> 5%) 
For any subjects who present with a constellation of syndromes indicative of liver disease as 
per the Investigator’s overall assessment (i.e., fatigue, nausea, vomiting, right upper quadrant 
pain or tenderness, fever, rash, and/or eosinophilia [> 5%]), perform liver function tests to 
determine if liver disease is worsening. 
Re-initiation of study drug may be considered after consultation with the Medical Monitor. 
6.24.2. 
Subjects with Elevations in Liver Transaminases or Bilirubin at Baseline 
Drug-induced liver injury monitoring in subjects with elevations in liver transaminases or 
bilirubin at baseline should be performed throughout the study according to the procedures 
summarized below. 
• If subjects with abnormal baseline liver indices develop elevations of ALT >3 × baseline 
or 300 U/L (whichever occurs first) during the study, repeat testing should be performed 
within 2 - 5 days. 


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o If there are persistent elevations (ALT >3 × baseline, or 300 U/L) upon repeat testing, 
then close observation (testing and physical examination 2 to 3 times per week) should 
be implemented and discontinuation of study drug should be considered. 
• Discontinue the study drug if any of the following occur:  
o ALT increases to >5 × baseline measurements or 400 U/L (whichever occurs first). 
o ALT increase >3 × baseline measurements or 300 U/L (whichever occurs first) AND 
the increase is accompanied by a concomitant increase in TBL to > 2 × ULN. 
o ALT increase >3 × baseline measurements or 300 U/L (whichever occurs first) with 
the appearance of fatigue, nausea, vomiting, right upper quadrant pain or tenderness, 
fever, rash, and/or eosinophilia (> 5%) 
For any subjects who present with a constellation of syndromes indicative of liver disease as 
per the Investigator’s overall assessment (i.e., fatigue, nausea, vomiting, right upper quadrant 
pain or tenderness, fever, rash, and/or eosinophilia [> 5%]), perform liver function tests to 
determine if liver disease is worsening. 
Re-initiation of study drug may be considered after consultation with the Medical Monitor. 
6.24.3. 
Close Observation for Suspected Drug-Induced Liver Injury  
For all subjects, close observation for suspected drug-induced liver injury includes the 
following within 72 hours of suspected drug-induced liver injury: 
• Repeating liver enzyme (ALT, AST, and alkaline phosphatase) and serum bilirubin tests 2 
or 3 times weekly.  
• The frequency of repeat testing can decrease to once a week or less if abnormalities 
stabilize or the study drug has been discontinued and the subject is asymptomatic. 
• Obtaining a more detailed history of symptoms and prior or concurrent diseases. 
• Obtaining a history of concomitant drug use (including nonprescription medications and 
herbal and dietary supplement preparations), alcohol use, recreational drug use, and special 
diets. 
• Ruling out acute viral hepatitis types A, B, C, D, and E; autoimmune or alcoholic hepatitis; 
hypoxic/ischemic hepatopathy; and biliary tract disease. 
• Obtaining a history of exposure to environmental chemical agents. 
• Obtaining additional tests to evaluate liver function, as appropriate (e.g., INR, direct 
bilirubin). 
• Considering gastroenterology or hepatology consultations. 
• If biochemistries stabilize and the subject is asymptomatic, monitor liver biochemistries 
once a week until they return to baseline. 
• Subjects who live far from study sites can be evaluated locally for history, physical exam, 
and laboratories, provided results can be communicated promptly to the site investigator. 


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6.25. Removal of Subjects from the Study 
The Investigator may withdraw a subject from the study for any of the following reasons: 
 Withdrawal of consent 
 Non-compliance as determined by the Investigator 
 At the discretion of the Investigator and/or study Medical Monitor and/or the DMC if it is 
in the best interest of the subject 
 Lost to follow-up 
At any time, the Investigator can remove a subject from the study drug and/or the study if 
deemed necessary for subject safety.  The Sponsor also reserves the right to terminate the 
study at any time.  All data normally collected at completion of the study must be collected at 
the time of the subject’s early termination or termination of the study.  
The Investigator will discuss with the subject or legally acceptable representative(s) the most 
appropriate way to withdraw to ensure the subject’s health.  Should a subject (or a legally 
acceptable representative) request or decide to withdraw consent, all efforts will be made to 
complete and report the observations as thoroughly as possible up to the date of withdrawal. 


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7. 
PLANNED STATISTICAL METHODS 
7.1. 
Endpoints 
7.1.1. 
Efficacy Endpoints 
7.1.1.1. 
Primary Endpoint 
The primary endpoint (Main Study Only) is the absolute change from baseline in hepatic fat 
fraction measured by MRI-PDFF at Week 12  
 
7.1.1.2. 
Secondary Efficacy Endpoints 
Main Study: The secondary endpoints are: 
• Absolute change from baseline in hepatic fat fraction measured by MRI-PDFF at Week 
22 - 24  
• Percent change from baseline in hepatic fat fraction measured by MRI-PDFF at Weeks 
12 and 22 - 24 
• Responder: subjects who achieved a clinically meaningful relative reduction of at least 
30% in liver fat content as measured by MRI-PDFF at Week 12 
• Responder based on NAFLD Activity Score (NAS) system: subjects who had a decrease 
of ≥ 2 points in NAS with at least a 1-point reduction in either lobular inflammation or 
hepatocellular ballooning and with no concurrent worsening of fibrosis stage 
• Change from baseline in ALT at Weeks 12, 16 and 20 
Cohort C: The secondary endpoints are: 
• Change from baseline in liver stiffness as evaluated by FibroScan® at Week 16 
• Changes from baseline in non-invasive biomarkers including Pro-C3 at Weeks 12, 16 and 
20, and liver fibrosis by ELF™ Test score at Weeks 6 and 16 
7.1.1.3. 
Exploratory Efficacy Endpoints 
The exploratory endpoints are: 
 
• Change from baseline in markers of liver injury and function including AST, ALP, GGT, 
bilirubin, INR, albumin, MELD score, and CP score at Weeks 12, 16 and 20 
• Change from baseline in body weight and waist-to-hip ratio at Weeks 12, 16 and 20 
• MRI-PDFF based quantitation of hepatic fat (Main Study only) 


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• Changes from baseline in non-invasive biomarkers including Pro-C3 at Weeks 12, 16 and 
20, and liver fibrosis by ELF™ Test score at Weeks 6 and 12 (Main Study Only)  
• Change from baseline in bone mineral density of the lumbar spine, femoral neck, and 
total hip as measured by DXA at Week 16 
• The proportion of subjects at Week 22 - 24 (Main Study) and Week 16 (Cohort C) whose 
fibrosis regresses by ≥ 1-stage according to the NASH CRN classification  
• The proportion of subjects at Week 22 - 24 (Main Study) and Week 16 (Cohort C) who 
had no worsening in NAS with improvement in fibrosis stage  
• The proportion of subjects at Week 22 - 24 (Main Study) and Week 16 (Cohort C) who 
had 2 points improvement in NAS with no worsening in fibrosis stage  
• The proportion of subjects at Week 22 - 24 (Main Study) and Week 16 (Cohort C) who 
had ≥ 1point improvement in NAS, fibrosis, steatosis lobular inflammation or 
hepatocellular ballooning  
• Changes from baseline in HRQoL (SF-36, CLDQ-NAFLD, WPAI) at Weeks 12 and 16 
• Change from baseline in lipoprotein profile and markers of lipid metabolism, insulin 
sensitivity and glycemic control at Weeks 12, 16 and 20 
• Change from baseline in body fat distribution as measured by DXA total body 
composition at Week 16 
• Changes from baseline in corrected T1 (cT1), an MRI-based metric of fibro-inflammation 
at Weeks 12 and 22 - 24 (Main Study only) 
• Plasma concentrations of EFX 
• The incidence of the decompensated liver disease events including ascites, hepatic 
encephalopathy (HE), or variceal bleeding (Cohort C Only) 
7.1.2. 
Safety Endpoints 
The safety endpoint is safety and tolerability of EFX in subjects with NASH. 
Safety analyses include: summaries of extent of exposure, AEs, laboratory evaluations, ECG, 
and vital sign assessments, body weight, anti-drug antibody (ADA) and neutralizing antibody 
(NAB) assessments, and concomitant medication usage. 


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7.2. 
Analysis Conventions 
All individual subject data will be listed as measured. All statistical summaries and analyses 
will be performed using Statistical Analysis System (SAS®) software (SAS Institute, Cary, 
North Carolina, USA). 
7.3. 
Analysis Sets 
7.3.1. 
Efficacy 
The primary analysis set for efficacy analyses will be the Full Analysis Set (FAS) which 
includes all subjects who were randomized into the study. 
 
Subjects who receive a dose of study drug other than that to which they were randomized for 
the entire duration of treatment will be analyzed according to treatment group to which they 
were randomized. 
 
7.3.2. 
Safety 
The primary analysis set for safety analyses will be the Safety Set which includes all subjects 
who received at least one dose of study drug. Subjects who received a dose of study drug 
other than that to which they were randomized for the entire duration of treatment will be 
analyzed according to the dose of study drug received. 
All data collected during treatment plus 30 days after last dose of study drug will be included 
in the safety summaries. 
7.3.2.1. 
Pharmacokinetics 
The PK analysis set will include all randomized subjects who took at least one dose of study 
drug and for whom concentration data of EFX is available.  
7.3.2.2. 
Biomarkers 
The Biomarker Analysis Set will include data from subjects in the Safety Analysis Set who 
have the necessary baseline and on-study measurements to provide interpretable results for 
the specific parameters of interest. 
7.4. 
Data Handling Conventions 
Missing data can have an impact on the interpretation of the trial data. In general, values for 
missing data will not be imputed. 
Where appropriate, safety data for subjects that did not complete the study will be included in 
summary statistics. For example, if a subject received study drug, the subject will be included 
in a summary of AEs according to the treatment received; otherwise, if the subject is not 
dosed then they will be excluded from the summary. If safety laboratory results for a subject 


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are missing for any reason at a time point, the subject will be excluded from the calculation 
of summary statistics for that time point. If the subject is missing a pre-dose value, then the 
subject will be excluded from the calculation of summary statistics for the pre-dose value and 
the change from pre-dose values. 
Values for missing safety laboratory data will not be imputed; however, a missing baseline 
result will be replaced with a screening result, if available. If no pre-treatment laboratory 
value is available, the baseline value will be assumed to be normal (i.e., no grade [Grade 0]) 
for the summary of graded laboratory abnormalities.   
Values for missing vital signs data will not be imputed; however, a missing baseline result 
will be replaced with a screening result, if available. 
Further details of data handling conventions and transformation will be provided in the SAP. 
7.5. 
Demographic Data and Baseline Characteristics 
Demographic and baseline measurements will be summarized using standard descriptive 
methods.  
Demographic summaries will include T2D status, sex, race/ethnicity, and age. 
Baseline data will include a summary of body weight, height, BMI, waist-to-hip ratio, 
randomization stratification groups, and other disease characteristic variables. 
7.6. 
Efficacy Analysis 
7.6.1. 
Primary Efficacy Analysis 
The primary efficacy variable will be the absolute change from baseline hepatic fat fraction 
measured by MRI-PDFF at Week 12. Summary statistics (number of subjects, mean, 
standard deviation, median, minimum, and maximum) at all visits and change from baseline 
will be provided. The primary efficacy analysis will be analyzed with an analysis of 
covariance (ANCOVA) model with treatment group and F1 fibrosis score as factors and 
baseline hepatic fat fraction measured by MRI-PDFF as a covariate. For any subjects in the 
full analysis set (FAS) with a missing primary efficacy value, the primary efficacy variable 
will be imputed with multiple imputation method. The specification of the multiple 
imputation method will be provided in the SAP. The treatment effect of each active dose 
comparing with placebo will be estimated from the ANCOVA model. LS means, one-sided, 
97.5% confidence intervals and one-sided p-values will be calculated. In order to control the 
Type I error rate inflation caused by multiplicity issues, a step-down fixed hypothesis testing 
sequence will be used. That is, only high dose is proved to be significantly better than 
placebo will the next low dose be compared.  
7.6.2. 
Secondary Efficacy Analysis 
Main Study:  


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For the continuous secondary efficacy variables related to hepatic fat fraction, like percent 
change from baseline in fat fraction measured by MRI-PDFF at week 12, the same 
ANCOVA model used for primary efficacy variable will be used. For the other continuous 
secondary efficacy variables, the ANCOVA model with treatment group, baseline hepatic fat 
fraction (< 15% vs ≥ 15%), and F1 fibrosis score as factors will be used. Normality will be 
tested for the model residuals. For certain efficacy variables, logarithmic transformation may 
be performed prior to fitting the ANCOVA model.  
For the responder(s) based on MRI-PDFF, logistic regression will be used for the analyses. 
The analyses will include the treatment group and F1 fibrosis score as factors and baseline 
hepatic fat fraction measured by MRI-PDFF as a covariate. The missing value will be 
imputed as a non-responder. 
For the responder(s) based on the NAS system, Fisher’s exact test will be used for the 
analyses. Odds ratios, 95% confidence intervals and p-values will be provided. The missing 
value will be imputed as a non-responder. 
Cohort C:  
Summary statistics (number of subjects, mean, standard deviation, median, minimum, and 
maximum) at all visits and change from baseline will be provided. The efficacy variables will 
be analyzed with an ANCOVA model with treatment group as a factor and baseline value as 
a covariate. The effect of Type 2 diabetes status will be explored. Normality will be tested for 
the model residuals. 
7.6.3. 
Exploratory Efficacy Analysis 
The same efficacy analyses used for the secondary efficacy variables will be used for the 
exploratory efficacy variables. 
7.7. 
Safety Analysis 
All safety data collected on or after the date that study drugs were first dispensed up to the 
date of last dose of study drugs plus 30 days will be summarized by treatment group. Data for 
the follow-up period will be included in data listings.  
7.7.1. 
Extent of Exposure 
Data of a subject’s extent of exposure to study drug will be generated from the study drugs 
administration eCRF data. Exposure data will be summarized by treatment group.  
7.7.2. 
Adverse Events 
Clinical and laboratory AEs will be coded using the Medical Dictionary for Regulatory 
Activities (MedDRA). System Organ Class (SOC), High-Level Group Term (HLGT), 
High-Level Term (HLT), Preferred Term (PT), and Lower-Level Term (LLT) will be 
attached to the clinical database. AE severity will be graded using the CTCAE. 


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Events will be summarized on the basis of the date of onset for the event. A TEAE will be 
defined as one or both of the following: 
 
• Any AEs with an onset date on or after the study drugs start date and no later than 
30 days after permanent discontinuation of study drugs 
• Any AEs leading to premature discontinuation of study drugs 
Summaries (number and percentage of subjects) of TEAEs and SAEs by SOC and PT will be 
provided by treatment group. Treatment-emergent AEs will also be summarized by 
relationship to study drugs and severity. In addition, TEAEs leading to premature 
discontinuation of study drugs and study, and SAEs leading to death will be summarized and 
listed. 
All AEs collected during the course of the study will be presented in data listings with a field 
for treatment-emergent event (Yes/No). 
7.7.3. 
Laboratory Evaluations 
Selected laboratory data will be summarized (n, mean, SD, median, minimum, and 
maximum) by treatment group and study visit along with the corresponding change from 
baseline values. 
Graded laboratory abnormalities will be defined using the grading scheme in the CTCAE. 
Grading of laboratory abnormalities for analysis purposes will be defined in the Statistical 
Analysis Plan. 
The incidence of treatment-emergent laboratory abnormalities, defined as values that 
increase at least one toxicity grade from baseline at any time post baseline up to and 
including the date of last dose of study drugs plus 30 days, will be summarized by treatment 
group. If baseline data are missing, then any graded abnormality (i.e., at least a Grade 1) will 
be considered treatment-emergent. 
7.8. 
Pharmacokinetic Analysis 
Plasma concentrations of EFX will be listed and summarized pre-dose and between 48-96 
hours post-dose at the timepoints listed in the Schedule of Assessments. Noncompartmental 
parameters will be listed and summarized descriptively. 
7.9. 
Biomarker Analysis 
Descriptive statistics of biomarker change from baseline will be provided at each sampling 
time by treatment. Point estimates and 95% confidence intervals may be calculated. 


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Exploratory analyses may also be performed to evaluate the association of individual 
exploratory biomarkers or combination of biomarkers with clinical measurements and other 
risk factors.  
Additional exploratory analyses that could enhance the understanding of the biological 
effects and the mechanism of action of EFX may be added in the Biomarker Analysis Plan if 
necessary. 
7.10. 
Sample Size 
Main Study:  
Due to the exploratory nature of this study, no formal power calculations were used to 
determine sample size. The number of subjects was chosen based on clinical experience with 
other similar proof of concept studies. 
With the following assumptions, the power for N = 20 subjects with active treatment is 
approximately 91% to detect: 
• a true, baseline-adjusted, mean decrease from baseline in MRI-PDFF-estimated 
hepatic fat of 5% compared to placebo, 
• with a one-sided t-test for decrease from placebo, 
• a 5% significance level, 
• 20 subjects receiving placebo, and 
• a standard deviation estimated as 5.2% (Sanyal et al. 2019). 
Cohort C:  
Since the primary objective is to assess the safety and tolerability of EFX in NASH subjects 
with compensated cirrhosis, the sample size is determined based on clinical considerations, 
and the treatment comparisons of efficacy measurements are not powered. 
7.11. 
Data Monitoring Committee 
An external DMC that consists of two hepatologists, one cardiologist and a statistician will 
review the progress of the study. The DMC will convene after 20 subjects (approximately 5 
per treatment group) have completed the Week 4 assessments in the Main Study. The DMC 
will convene again after 10 subjects have completed the Week 4 assessments in Cohort C. 
The DMC will receive all reports of SAEs including potential DILI and liver decompensation 
events and convene as needed to monitor for safety. The DMC will provide 
recommendations to Akero whether the nature, frequency, and severity of adverse effects 
associated with study treatment warrant the early termination of the study in the best interests 
of the participants, whether the study should continue as planned, or the study should 
continue with modifications. The DMC may also provide recommendations as needed 
regarding study design. 


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The DMC’s specific activities will be defined by a mutually agreed charter, which will define 
the DMC’s membership, conduct, and meeting schedule.  
While the DMC will be asked to advise Akero regarding future conduct of the study, 
including possible early study termination, Akero retains final decision-making authority on 
all aspects of the study. 
7.11.1. 
Stopping Rules 
The DMC will be convened based on emerging safety data if any of the following occur: 
• One or more subjects develop the same treatment-emergent grade 5 adverse event or 
lab abnormality (confirmed by repeat testing) deemed related to EFX. 
• Two or more subjects develop the same treatment-emergent grade 4 or higher adverse 
event or lab abnormality (confirmed by repeat testing) deemed related to the same 
dose level of EFX. 
• Three or more subjects develop the same treatment-emergent grade 3 or higher 
adverse event or lab abnormality (confirmed by repeat testing) deemed related to the 
same dose level of EFX. 
The DMC will assess the causality and clinical relevance of the adverse events or lab 
abnormalities and recommend to either halt study dosing for all subjects, pause enrollment, 
or take no action. If enrollment or dosing is paused, it may be resumed (with or without 
modifications) only after further review of all available safety data and agreement by the 
appropriate regulatory agencies.      
7.12. 
Adjudication Committee 
An external adjudication committee may be established to adjudicate cases that meet 
protocol-defined criteria for hepatic decompensation events and possible cases of drug-
induced liver injury following DMC review and escalation.   
 


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8. 
ADMINISTRATIVE CONSIDERATIONS 
8.1. 
Investigator Responsibilities 
8.1.1. 
Good Clinical Practice 
The Investigator will ensure that this study is conducted in accordance with the principles of 
the Declaration of Helsinki, International Council for Harmonisation (ICH) guidelines, or 
with the laws and regulations of the country in which the research is conducted, whichever 
affords the greater protection to the study subject. These standards are consistent with the 
European Union Clinical Trials Directive 2001/20/EC and Good Clinical Practice 
Directive 2005/28/EC. 
 
The Investigator will ensure adherence to the basic principles of Good Clinical Practice, as 
outlined in 21 Code of Federal Regulations (CFR) 312, subpart D, “Responsibilities of 
Sponsors and Investigators,” 21 CFR, part 50, 1998, and 21 CFR, part 56, 1998. 
 
The Investigator and all applicable subinvestigators will comply with 21 CFR, Part 54, 1998, 
providing documentation of their financial interest or arrangements with Akero, or 
proprietary interests in the investigational drug under study. This documentation must be 
provided prior to the Investigator’s (and any subinvestigator’s) participation in the study. The 
Investigator and subinvestigator agree to notify Akero of any change in reportable interests 
during the study and for 1 year following completion of the study. Study completion is 
defined as the date when the last subject completes the protocol-defined activities. 
8.1.2. 
Institutional Review Board (IRB)/Independent Ethics Committee (IEC)/ 
Ethics Committee (EC) Review and Approval 
Before initiating a trial, the Investigator (or Sponsor as appropriate according to local 
regulations) will submit this protocol, ICF, and any accompanying material to be provided to 
the subject (such as advertisements, subject information sheets, or descriptions of the study 
used to obtain informed consent) to an IRB/IEC/EC. The Investigator will not begin any 
study subject activities until approval from the IRB/IEC/EC has been documented and 
provided as a letter to the Investigator. 
Before implementation, the investigator will submit to and receive documented approval 
from the IRB/IEC/EC any modifications made to the protocol or any accompanying material 
to be provided to the subject after initial IRB/IEC/EC approval, with the exception of those 
necessary to reduce immediate risk to study subjects. 
8.1.3. 
Informed Consent 
Eligible subjects may only be included in the study after providing (witnessed, where 
required by law or regulation), IRB/IEC-approved informed consent, or, if applicable after 
such consent has been provided by a legally acceptable representative(s) of the subject. 
Informed consent must be obtained before conducting any study-specific procedures (e.g., all 


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of the procedures described in the protocol). The process of obtaining informed consent must 
be documented in the subject source documents. 
The investigator must use the most current IRB/IEC/EC-approved consent form for 
documenting written informed consent.  
8.1.4. 
Confidentiality 
The investigator will ensure that subjects’ anonymity will be strictly maintained and that 
their identities are protected from unauthorized parties. Only partial date of birth (as 
applicable in certain countries), another unique identifier (as allowed by local law), and an 
identification code will be recorded on any form or biological sample submitted to the 
Sponsor, IRB/IEC/EC, or laboratory. Laboratory specimens must be labeled in such a way as 
to protect subject identity while allowing the results to be recorded to the proper subject. 
Refer to specific laboratory instructions. The investigator will keep a screening log showing 
codes, names, and addresses for all subjects screened and for all subjects enrolled in the trial. 
Subject data will be processed in accordance with all applicable regulations. 
The investigator agrees that all information received from Akero, including but not limited to 
the IB, this protocol, eCRFs, the IMP, and any other study information, remain the sole and 
exclusive property of Akero during the conduct of the study and thereafter. This information 
is not to be disclosed to any third party (except employees or agents directly involved in the 
conduct of the study or as required by law) without prior written consent from Akero. The 
investigator further agrees to take all reasonable precautions to prevent the disclosure by any 
employee or agent of the study site to any third party or otherwise into the public domain. 
8.1.5. 
Study Files and Retention of Records 
The investigator must maintain adequate and accurate records to enable the conduct of the 
study to be fully documented and the study data to be subsequently verified. These 
documents should be classified into at least the following two categories: (1) Investigator’s 
study file, and (2) subject clinical source documents. 
The investigator’s study file will contain the protocol/amendments, CRF and query forms, 
IRB/IEC/EC and governmental approval with correspondence, informed consent, drug 
records, staff curriculum vitae and authorization forms, and other appropriate documents and 
correspondence. 
The Investigator must maintain source documents for each subject in the study, consisting of 
case and visit notes (hospital or clinic medical records) containing demographic and medical 
information, laboratory data, electrocardiograms, and the results of any other tests or 
assessments. All information on CRFs must be traceable to these source documents in the 
subject's file. Data not requiring a separate written record will be defined before study start 
and will be recorded directly on the CRFs. The Investigator must also keep the original 
informed consent form signed by the subject (a signed copy is given to the subject). 


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The Investigator must give the monitor access to all relevant source documents to confirm 
their consistency with the data capture and/or data entry. Akero monitoring standards require 
full verification for the presence of informed consent, adherence to the inclusion/exclusion 
criteria, documentation of SAEs, and of data that will be used for all primary variables. 
Additional checks of the consistency of the source data with the CRFs are performed 
according to the study-specific monitoring plan. No information in source documents about 
the identity of the subjects will be disclosed. 
All clinical study documents must be retained by the investigator until at least 2 years or 
according to local laws, whichever is longer, after the last approval of a marketing 
application in an ICH region (i.e., United States, Europe, or Japan) and until there are no 
pending or planned marketing applications in an ICH region; or, if no application is filed or if 
the application is not approved for such indication, until 2 years after the investigation is 
discontinued and regulatory authorities have been notified. Investigators may be required to 
retain documents longer if specified by regulatory requirements, by local regulations, or by 
an agreement with Akero. The investigator must notify Akero before destroying any clinical 
study records. 
Should the investigator wish to assign the study records to another party or move them to 
another location, Akero must be notified in advance. 
If the investigator cannot provide for this archiving requirement at the study site for any or all 
of the documents, special arrangements must be made between the investigator and Akero to 
store these records securely away from the site so that they can be returned sealed to the 
investigator in case of an inspection. When source documents are required for the continued 
care of the subject, appropriate copies should be made for storage away from the site. 
8.1.6. 
Electronic Case Report Forms 
Designated investigator staff will enter the data required by the protocol into the eCRF using 
fully validated secure web-enabled software that conforms to US CFR 21 Part 11 
requirements. Designated investigator site staff will not be given access to the system until 
they have been trained. Subsequent to data entry, a study monitor will perform source data 
verification within the EDC system. Original entries as well as any changes to data fields will 
be stored in the audit trail of the system. 
Automatic validation procedures within the system check for data discrepancies during and 
after data entry and, by generating appropriate error messages, allow the data to be confirmed 
or corrected online by the designated investigator site staff. The Investigator must certify that 
the data entered into the electronic Case Report Forms are complete and accurate.  
At the conclusion of the trial, Akero will provide the site with a read-only archive copy of the 
data entered by that site. This archive must be stored in accordance with the records retention 
requirements outlined in Section 8.1.5.  


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8.1.7. 
Inspections 
The investigator will make available all source documents and other records for this trial to 
Akero’s appointed study monitors, to IRB/IEC/EC, or to regulatory authority or health 
authority inspectors. 
8.1.8. 
Protocol Compliance 
The investigator is responsible for ensuring the study is conducted in accordance with the 
procedures and evaluations described in this protocol. 
8.2. 
Sponsor Responsibilities 
8.2.1. 
Protocol Modifications 
Protocol modifications, except those intended to reduce immediate risk to study subjects, 
may be made only by Akero. The investigator must submit all protocol modifications to the 
IRB/IEC/EC in accordance with local requirements and receive documented IRB/IEC/EC 
approval before modifications can be implemented. 
8.2.2. 
Study Report and Publications 
A clinical study report (CSR) will be prepared and provided to the regulatory agencies. 
Akero will ensure that the report meets the standards set out in the ICH Guideline for 
Structure and Content of Clinical Study Reports (ICH E3). Note that an abbreviated report 
may be prepared in certain cases.  
Investigators in this study may communicate, orally present, or publish in scientific journals 
or other scholarly media only after the following conditions have been met: the results of the 
study in their entirety have been publicly disclosed by or with the consent of Akero in an 
abstract, manuscript, or presentation form or the study has been completed at all study sites 
for at least 18 months. 
The investigator will submit to Akero any proposed publication or presentation along with 
the respective scientific journal or presentation forum at least 60 days before submission of 
the publication or presentation.  
No such communication, presentation, or publication will include Akero’s confidential 
information (see Section 8.1.4). 
The investigator will comply with Akero’s request to delete references to its confidential 
information (other than the study results) in any paper or presentation and agrees to withhold 
publication or presentation for an additional 60 days in order to obtain patent protection if 
deemed necessary. 


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8.3. 
Joint Investigator/Sponsor Responsibilities 
8.3.1. 
Payment Reporting 
Investigators and their study staff may be asked to provide services performed under this 
protocol (e.g., attendance at Investigator's Meetings). If required under the applicable 
statutory and regulatory requirements, Akero will capture and disclose to Federal and State 
agencies any expenses paid or reimbursed for such services, including any clinical trial 
payments, meal, travel expenses or reimbursements, consulting fees, and any other transfer of 
value. 
8.3.2. 
Access to Information for Auditing or Inspections 
Representatives of regulatory authorities or of Akero may conduct inspections or audits of 
the clinical study. If the investigator is notified of an inspection by a regulatory authority the 
investigator agrees to notify the Akero medical monitor immediately. The investigator agrees 
to provide to representatives of a regulatory agency or Akero access to records, facilities, and 
personnel for the effective conduct of any inspection or audit. 
8.3.3. 
Study Discontinuation 
Both the sponsor and the investigator reserve the right to terminate the study at any time. 
Should this be necessary, both parties will arrange discontinuation procedures and notify the 
appropriate regulatory authorities, IRBs, IECs, and ECs. In terminating the study, Akero and 
the investigator will assure that adequate consideration is given to the protection of the 
subjects’ interests. 
 


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9. 
REFERENCE LIST 
Adams AC, Halstead CA, Hansen BC, et al. LY2405319, an Engineered FGF21 Variant, 
Improves the Metabolic Status of Diabetic Monkeys. PLoS One. 2013; 8(6): e65763. doi: 
10.1371/journal.pone.0065763. 
Bao L, Yin J, Gao W, et al. A long-acting FGF21 alleviates hepatic steatosis and 
inflammation in a mouse model of non-alcoholic steatohepatitis partly through an FGF21-
adiponectin-IL17A pathway. Br J Pharmacol. 2018; 175: 3379-3393. 
Cameron JL. Nutritional determinants of puberty. Nutr Rev. 1996; 54(2 Pt 2): S17-22. 
Camporez JP, Jornayvaz FR, Petersen MC, et al. Cellular mechanisms by which FGF21 
improves insulin sensitivity in male mice. Endocrinology. 2013; 154: 3099–3109. 
Chen MS, Chang JC, Zavala-Solorio J, et al. FGF21 mimetic antibody stimulates UCP1-
independent brown fat thermogenesis via FGFR1/bKlotho complex in non-adipocytes. Mol. 
Metab. 2017; 6: 1454-1467. 
Coskun T, Bina HA, Schneider MA, et al. Fibroblast growth factor 21 corrects obesity in 
mice. Endocrinology. 2008; 149: 6018–6027. 
Ekstedt M, Hagström H, Nasr P, et al. Fibrosis stage is the strongest predictor for disease-
specific mortality in NAFLD after up to 33 years of follow-up. Hepatology. 2015; 61: 1547-
54. 
Fisher FM, Chui PC, Nasser IA, et al. Fibroblast growth factor 21 limits lipotoxicity by 
promoting hepatic fatty acid activation in mice on methionine and choline-deficient diets. 
Gastroenterology. 2014; 147: 1073-83. 
 
Fon Tacer K, Bookout AL, Ding X, et al.  Research resource: Comprehensive expression 
atlas of the fibroblast growth factor system in adult mouse.  Mol Endocrinol.  2010; 24: 
2050-2064. 
 
Frazier KS, Obert LA. Drug-Induced Glomerulonephritis: The Spectre of Biotherapeutic and 
Antisense Oligonucleotide Immune Activation in the Kidney. Toxicol Pathol. 2018; 
46(8):904-17. 
Gaich G, Chien JY, Fu H, et al. The effects of LY2405319, and FGF21 analog, in obese 
human subjects with type 2 diabetes. Cell Metab. 2013; 18(3):333-340. 
Gimeno RE, Moller DE. FGF21-based pharmacotherapy: Potential utility for metabolic 
disorders. Trends Endocrinol. Metabol. 2014; 25: 303-311. 
Harrison SA, Rossi SJ, Paredes AH, Trotter JF, Bashir MR, Guy CD, et al. NGM282 
Improves Liver Fibrosis and Histology in 12 Weeks in Patients with Nonalcoholic 
Steatohepatitis. Hepatology. 2019. doi: 10.1002/hep.30590. 


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Kim AM, Somayaji VR, Dong JQ, et al. Once-weekly administration of a long-acting 
fibroblast growth factor 21 analogue modulates lipids, bone turnover markers, blood pressure 
and body weight differently in obese people with hypertriglyceridaemia and in non-human 
primates. Diabetes Obes Metab. 2017; 19(12):1762-1772. 
Kronenberg S, Husar E, Schubert C, et al. Comparative assessment of immune complex-
mediated hypersensitivity reactions with biotherapeutics in the non-human primate: Critical 
parameters, safety and lessons for future studies. Regul Toxicol Pharmacol. 2017; 88:125-37. 
Lee JH, Kang YE, Chang JY, et al. An engineered FGF21 variant, LY2405319, can prevent 
non-alcoholic steatohepatitis by enhancing hepatic mitochondrial function. Am J Transl Res. 
2016; 8: 4750-4763. 
Li H, Zhang J, Jia W. Fibroblast growth factor 21: a novel metabolic regulator from 
pharmacology to physiology. Front Med. 2013; 7: 25–30. 
Lin Z, Tian H, Lam KS, et al. Adiponectin mediates the metabolic effects of FGF21 on 
glucose homeostasis and insulin sensitivity in mice. Cell Metab. 2013; 17: 779–789. 
Mu J, Pinkstaff J, Li Z, et al. FGF21 analogs of sustained action enabled by orthogonal 
biosynthesis demonstrate enhanced antidiabetic pharmacology in rodents. Diabetes. 2012; 
61: 505–512. 
Nicoles A, Guillet S, Tomlinson E, et al. A mouse model of hepatocellular carcinoma ectopic 
expression of fibroblast growth factor 19 in skeletal muscle of transgenic mice. Amer. J of 
Pathology. 2002; 160: 2295-2307. 
Nishimura T, Nakatake Y, Konishi M, Itoh N.  Identification of a novel FGF, FGF-21, 
preferentially expressed in the liver.  Biochim Biophys Acta.  2000; 1492: 203-206. 
Ruhl CE, Everhart JE. Fatty liver indices in the multiethnic United States National Health 
and Nutrition Examination Survey. Aliment Pharmacol. Ther. 2015; 41: 65–76 . 
 
Sanyal A, Charles ED, Neuschwander-Tetri BA, Loomba R, Harrison SA, Abdelmalek MF, 
et al. Pegbelfermin (BMS-986036), a PEGylated fibroblast growth factor 21 analogue, in 
patients with non-alcoholic steatohepatitis: a randomised, double-blind, placebo-controlled, 
phase 2a trial. Lancet. 2019; 392(10165) :2705-2717. 
 
Shankar S, Bashir MR, Baxter BA, Phung V, Yan AZ, Rossi SJ, et al. NGM313, a Novel 
Once-Monthly Activator of bKlotho -FGFR1c, Significantly Reduces Hepatic Steatosis and 
Key Biomarkers of Non-alcoholic Steatohepatitis: Results of a Randomized, Active-
Controlled Clamp Study in Obese Insulin-Resistant Patients with NAFLD. Poster presented 
at American Association for the Study of Liver Diseases, 2018. 
Talukdar S, Zhou Y, Li D, et al. A long-acting FGF21 molecule, PF-05231023, decreases 
body weight and improves lipid profile in non-human primates and type 2 diabetic subjects. 
Cell Metab. 2016; 23: 427-440.  


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Tanaka N, Takahashi S, Zhang Y, et al. Role of fibroblast growth factor 21 in the early stage 
of NASH induced by methionine- and choline-deficient diet. Biochim. Biophysica. Acta. 
2015; 1852: 1242-1252. 
 
The NASH Education Program. https://www.the-nash-education-program.com/.  Accessed 
February 25, 2019. 
Vahle J. Immunogenicity and immune complex disease in preclinical safety studies. Toxicol 
Pathol. 2018; 46(8):1013-19. 
Wu G, Li H, Fang Q, et al. Complementary role of fibroblast growth factor 21 and 
cytokeratin 18 in monitoring the different stages of nonalcoholic fatty liver disease. Sci. Rep. 
2017; 7: 5095. 
Xu J, Lloyd DJ, Hale C, et al. Fibroblast growth factor 21 reverses hepatic steatosis, 
increases energy expenditure, and improves insulin sensitivity in diet-induced obese mice. 
Diabetes. 2009; 58: 250–259.  
Xu J, Zhang Y, Liu Y, et al. Fibroblast growth factor 21 attenuates hepatic fibrogenesis 
through TGF-β/smad2/3 and NF-κB signaling pathways. Toxicol Appl. Pharmacol. 2016; 
290: 43-53. 
Younossi ZM, Koenig AB, Abdelatif D, et al. Global epidemiology of nonalcoholic fatty 
liver disease- meta-analytic assessment of prevalence, incidence, and outcomes. Hepatology. 
2016; 64: 73–84. 


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10. 
APPENDICES 
Appendix A. 
Schedule of Assessments- Main Study 
Assessmentsa 
Screening 
(- 6 wks) 
Pre-
Baselinel 
(-2 wks) 
Baseline 
Day 1 
On-Treatment Visitsa 
ET 
Week 
20 
Safety 
follow
-upbb 
Repeat 
Biopsy 
Week 
22-24o 
Week  
1 
Wks  
2 and 
3 
Week 
4 
48-
96hrs 
post-
dose 
Wks 
5, 6 
and 7 
Week 
8 
48-
96hrs 
post-
dose 
Wks 9, 
10, 11, 
13, 14, 
15 
Week 
12 
Week 
16 
 
Clinical Assessments 
Written Informed Consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Eligibility 
X 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical History 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Physical Examinationb 
X 
 
X 
X 
 
X 
 
 
X 
 
 
X 
X 
X 
X 
 
Vital Signsc  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Weightw 
X 
X 
X 
X 
X 
X 
 
X 
X 
 
X 
X 
X 
X 
X 
 
Triplicate BP/HRd 
 
 
X 
 
 
 
X 
 
 
X 
 
 
 
 
 
 
Height 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Hip and Waist 
Circumferencew  
X 
 
X 
X 
 
X 
 
 
X 
 
 
X 
X 
X 
X 
 
12-lead ECG 
X 
 
X 
 
 
 
 
 
 
 
 
 
X 
X 
 
 
FibroScan® 
Xr 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Liver Biopsy 
Xe 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
MRI-PDFFs 
Xf 
 
 
 
 
 
 
Xf 
 
 
 
Xf 
 
Xp 
 
X 
DXA Scant 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
 
 
AUDIT-C Questionnaire 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
On-Study Questionnairesg 
 
 
X 
X 
 
X 
 
 
X 
 
 
X 
X 
Xp 
 
 
Lifestyle Modificationu 
X 
 
X 
X 
X 
X 
 
X 
X 
 
X 
X 
X 
 
 
 
Administer Study Drugy 
 
 
X 
X 
X 
X 
 
X 
X 
 
X 
X 
 
 
 
 
Concomitant Medications 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Adverse Events 
Xh 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 


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Amendment 6, 08Oct2020 
Assessmentsa 
Screening 
(- 6 wks) 
Pre-
Baselinel 
(-2 wks) 
Baseline 
Day 1 
On-Treatment Visitsa 
ET 
Week 
20 
Safety 
follow
-upbb 
Repeat 
Biopsy 
Week 
22-24o 
Week  
1 
Wks  
2 and 
3 
Week 
4 
48-
96hrs 
post-
dose 
Wks 
5, 6 
and 7 
Week 
8 
48-
96hrs 
post-
dose 
Wks 9, 
10, 11, 
13, 14, 
15 
Week 
12 
Week 
16 
 
 
Laboratory Assessments 
Chemistry, Hematology, 
Lipids, Coagulationi 
X 
Xx 
X 
X 
Xz 
X 
 
Xz 
X 
 
Xz 
X 
X 
X 
X 
 
Serum Storage Sampleq 
 
 
X 
X 
 
X 
 
 
X 
 
 
X 
X 
X 
X 
 
Urine drug screeni 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Serologiesi 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Endogenous FGF21v 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Enhanced Liver Fibrosis 
(ELF™) 
X 
 
 
 
 
 
 
Xf 
 
 
 
Xf 
 
X 
 
 
Biomarkersi 
Xaa 
 
X 
X 
 
X 
 
 
X 
 
 
X 
X 
X 
X 
 
PKj 
 
 
X 
X 
 
X 
X 
 
X 
X 
 
X 
X 
X 
X 
X 
ADA and NABk 
 
 
X 
 
 
X 
 
 
X 
 
 
 
X 
X 
X 
X 
Saliva cortisol testingm 
 
 
X 
X 
 
X 
X 
 
X 
X 
 
X 
X 
X 
X 
 
Pregnancy testingn 
X 
 
X 
 
 
X 
 
 
X 
 
 
X 
X 
X 
X 
 
ADA = anti-drug antibodies; AUDIT-C = alcohol use disorders identification test; BP = blood pressure; DXA = Dual Energy X-ray Absorptiometry; 
ECG = electrocardiogram; HR = heart rate; PK = pharmacokinetic; MRI-PDFF = magnetic resonance imaging – proton density fat fraction; NAB = neutralizing 
antibody 
a 
All visits after Baseline (Day 1) can be performed within the following window: ± 3 days for weekly visits 1 - 20.  Other windows are indicated below. 
b 
Complete PE including assessment at Screening, Baseline and Weeks 12 and 16, symptom driven at weeks 1, 4, 8, 20, or ET.  CP Score assessments should 
be completed as part of the physical exam at Baseline, Week 12, Week 16, ET and Week 20. 
c 
Vitals to include systolic and diastolic BP, pulse, respiration rate, and oral temperature (at Screening and Baseline only) will be collected at each visit.   
d 
Triplicate BP/HR at Baseline and at 48 - 96 hours post-dose on Weeks 4 and 8 to correspond to Cmax. BP/HR to be measured in same arm with at least two 
minutes rest between measurements. 
e 
Liver biopsy obtained within 180 days of randomization to confirm eligibility. 
f 
MRI-PDFF and ELF™ will be performed during screening, at Weeks 6 and 12 ± 5 days. Corrected T1 will be collected, where available. 
g 
If the Baseline questionnaires are missed at Day 1, questionnaires should not be collected at the remaining timepoints.  The following questionnaires will be 
administered: HRQoL include:  SF-36, CLDQ-NAFLD, WPAI.  It is recommended that the questionnaires be completed prior to any study procedures being 
performed and prior to the subject seeing a health care provider. 
h 
AE reporting during screening is limited to SAEs and AEs related to study procedures. 
i 
Refer to Table 3. At visits where CTX-1 or lipids are collected, the samples to be collected in the morning following an overnight fast of at least 8 hours. 


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j 
PK sampling will be obtained pre-dose at all timepoints listed and at 48-96 hours post-dose on weeks 4 and 8 to correspond to Cmax. 
k 
Samples will be obtained for detection of ADA against EFX and if required a neutralizing ADA assay will be run on the same sample.  
l 
Pre-baseline labs should be collected 4 weeks post-Screening.  
m Saliva cortisol testing will be obtained pre-dose at all timepoints listed and at 48 - 96 hours post-dose on Weeks 4 and 8 to correspond to Cmax. 
n 
For female subjects of childbearing potential only. Serum pregnancy test at screening and urine pregnancy test at other time points.  
o 
Subjects with ≥ 30% relative fat reduction on MRI-PDFF at Week 12 will be required to return at Week 22 - 24 for a repeat liver biopsy and MRI-PDFF.  
The biopsy and MRI-PDFF should be collected within 5 working days of one another.  The window for this visit is – 6 weeks.   
p 
At the discretion of the Investigator. 
q 
Serum storage samples banked for possible additional clinical testing. 
r 
At least 2-3 hours fasting is required prior to all elastography assessments. 
s 
At least 4 hours fasting is required prior to all MR assessments. 
t 
DXA scan should include lumbar spine, femoral neck, and total hip with Subjects in the standard (supine) position.  Total body composition may also be 
collected at the DXA timepoints, where available, to determine body fat distribution. 
u 
All subjects will receive counseling regarding lifestyle modifications including the maintenance of a healthy diet and participation in regular exercise at the 
Baseline Visit.  At each subsequent visit, subjects will be asked if there has been a significant change in diet, or physical activity.  
v 
Endogenous FGF21 serum sample to be collected in the morning following an overnight fast of at least 8 hours. 
w 
Weight, waist and hip circumference should be obtained by the same study personnel between visits for each subject to minimize variability in the 
measurement. On dosing days, weight will be collected pre-dose.  Weight should be obtained using a calibrated scale.  The subject should be weighed in 
consistent clothing. 
x 
Only confirmatory ALT/AST to be collected at the Pre-Baseline Visit to confirm eligibility.  Pre-Baseline labs may not be repeated if inclusion criteria is not 
met. 
y 
Administration of study drug should occur following all other study procedures and sample collection for that visit. 
z 
Glucose only to be measured.  Sample should be collected at the end of the study visit. 
aa HbA1c only to be measured. 
bb The Safety Follow-up visit should be performed 4 weeks following the last dose of study drug.  For subjects who complete the study, this will be Week 20.  
Subjects who terminate the study early should have this visit 4 weeks following the last dose of study drug received. 
 
 


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Amendment 6, 08Oct2020 
Appendix B. 
Schedule of Assessments- Cohort C 
Assessmentsa 
Screening 
(- 6 wks) 
Pre-
Baselinel 
(-2 wks) 
Baseline 
Day 1 
On-Treatment Visitsa 
ET 
Week 20 
Safety 
follow-upz 
Week  
1 
Wks  
2 and 
3 
Week 
4 
48-
96hrs 
post-
dose 
Wks 
5, 6 
and 7 
Week 
8 
48-
96hrs 
post-
dose 
Wks 9, 
10, 11, 
13, 14, 
15 
Week 
12 
Week 
16 
 
Clinical Assessments 
Written Informed Consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Eligibility 
X 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Medical History 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Physical Examinationb 
X 
 
X 
X 
 
X 
 
 
X 
 
 
X 
X 
X 
X 
Vital Signsc  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Weightw 
X 
X 
X 
X 
X 
X 
 
X 
X 
 
X 
X 
X 
X 
X 
Triplicate BP/HRd 
 
 
X 
 
 
 
X 
 
 
X 
 
 
 
 
 
Height 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Hip and Waist 
Circumferenceu  
X 
 
X 
X 
 
X 
 
 
X 
 
 
X 
X 
X 
X 
12-lead ECG 
X 
 
X 
 
 
 
 
 
 
 
 
 
X 
X 
 
FibroScan® 
Xq 
 
 
 
 
 
 
 
 
 
 
 
Xq 
 
 
Liver Biopsy 
Xe 
 
 
 
 
 
 
 
 
 
 
 
Xaa 
 
 
DXA Scanr 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
 
AUDIT-C Questionnaire 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
On-Study Questionnairesg 
 
 
X 
X 
 
X 
 
 
X 
 
 
X 
X 
Xo 
 
Lifestyle Modifications 
X 
 
X 
X 
X 
X 
 
X 
X 
 
X 
X 
X 
 
 
Administer Study Drugw 
 
 
X 
X 
X 
X 
 
X 
X 
 
X 
X 
 
 
 
Concomitant Medications 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Adverse Events 
Xh 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Laboratory Assessments 
Chemistry, Hematology, 
Lipids, Coagulationi 
X 
Xv 
X 
X 
Xx 
X 
 
Xx 
X 
 
Xx 
X 
X 
X 
X 
Serum Storage Samplep 
 
 
X 
X 
 
X 
 
 
X 
 
 
X 
X 
X 
X 


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Amendment 6, 08Oct2020 
Assessmentsa 
Screening 
(- 6 wks) 
Pre-
Baselinel 
(-2 wks) 
Baseline 
Day 1 
On-Treatment Visitsa 
ET 
Week 20 
Safety 
follow-upz 
Week  
1 
Wks  
2 and 
3 
Week 
4 
48-
96hrs 
post-
dose 
Wks 
5, 6 
and 7 
Week 
8 
48-
96hrs 
post-
dose 
Wks 9, 
10, 11, 
13, 14, 
15 
Week 
12 
Week 
16 
Urine drug screeni 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Serologiesi 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Endogenous FGF21t 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Enhanced Liver Fibrosis 
(ELF™) 
X 
 
 
 
 
 
 
Xf 
 
 
 
 
X 
X 
 
Biomarkersi 
Xy 
 
X 
X 
 
X 
 
 
X 
 
 
X 
X 
X 
X 
PKj 
 
 
X 
X 
 
X 
X 
 
X 
X 
 
X 
X 
X 
X 
ADA and NABk 
 
 
X 
 
 
X 
 
 
X 
 
 
 
X 
X 
X 
Saliva cortisol testingm 
 
 
X 
X 
 
X 
X 
 
X 
X 
 
X 
X 
X 
X 
Pregnancy testingn 
X 
 
X 
 
 
X 
 
 
X 
 
 
X 
X 
X 
X 
ADA = anti-drug antibodies; AUDIT-C = alcohol use disorders identification test; BP = blood pressure; DXA = Dual Energy X-ray Absorptiometry; 
ECG = electrocardiogram; HR = heart rate; PK = pharmacokinetic; NAB = neutralizing antibody 
a 
All visits after Baseline (Day 1) can be performed within the following window: ± 3 days for weekly visits 1 - 20.  Other windows are indicated below. 
b 
Complete PE including assessment at Screening, Baseline and Weeks 12 and 16, symptom driven at weeks 1, 4, 8, 20, or ET.  CP Score assessments should 
be completed as part of the physical exam at Screening, Baseline, Week 12, Week 16, ET and Week 20. 
c 
Vitals to include systolic and diastolic BP, pulse, respiration rate, and oral temperature (at Screening and Baseline only) will be collected at each visit.   
d 
Triplicate BP/HR at Baseline and at 48 - 96 hours post-dose on Weeks 4 and 8 to correspond to Cmax. BP/HR to be measured in same arm with at least two 
minutes rest between measurements. 
e 
Historical liver biopsy obtained within 24 months of screening required to confirm eligibility.  If a historical biopsy is not available within 24 months of 
Screening, the subject may undergo a liver biopsy to confirm eligibility. 
f 
ELF™ will be performed during screening, at Weeks 6 and 16 ± 5 days.  
g 
If the Baseline questionnaires are missed at Day 1, questionnaires should not be collected at the remaining timepoints.  The following questionnaires will be 
administered: HRQoL include:  SF-36, CLDQ-NAFLD, WPAI.  It is recommended that the questionnaires be completed prior to any study procedures being 
performed and prior to the subject seeing a health care provider. 
h 
AE reporting during screening is limited to SAEs and AEs related to study procedures. 
i 
Refer to Table 3. At visits where CTX-1 or lipids are collected, the samples to be collected in the morning following an overnight fast of at least 8 hours. 
j 
PK sampling will be obtained pre-dose at all timepoints listed and at 48-96 hours post-dose on weeks 4 and 8 to correspond to Cmax. 
k 
Samples will be obtained for detection of ADA against EFX and if required a neutralizing ADA assay will be run on the same sample.  
l 
Pre-baseline labs should be collected 4 weeks post-Screening.  
m Saliva cortisol testing will be obtained pre-dose at all timepoints listed and at 48 - 96 hours post-dose on Weeks 4 and 8 to correspond to Cmax. 
n 
For female subjects of childbearing potential only. Serum pregnancy test at screening and urine pregnancy test at other time points.  
o 
At the discretion of the Investigator. 


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p 
Serum storage samples banked for possible additional clinical testing. 
q 
At least 2-3 hours fasting is required prior to all elastography assessments. 
r 
DXA scan should include lumbar spine, femoral neck, and total hip with Subjects in the standard (supine) position.  Total body composition may also be 
collected at the DXA timepoints, where available, to determine body fat distribution. 
s 
All subjects will receive counseling regarding lifestyle modifications including the maintenance of a healthy diet and participation in regular exercise at the 
Baseline Visit.  At each subsequent visit, subjects will be asked if there has been a significant change in diet, or physical activity.  
t 
Endogenous FGF21 serum sample to be collected in the morning following an overnight fast of at least 8 hours. 
u 
Weight, waist and hip circumference should be obtained by the same study personnel between visits for each subject to minimize variability in the 
measurement. On dosing days, weight will be collected pre-dose.  Weight should be obtained using a calibrated scale.  The subject should be weighed in 
consistent clothing. 
v 
Only confirmatory ALT/AST to be collected at the Pre-Baseline Visit to confirm eligibility.  Pre-Baseline labs may not be repeated if inclusion criteria is not 
met. 
w 
Administration of study drug should occur following all other study procedures and sample collection for that visit. 
x 
Glucose only to be measured.  Sample should be collected at the end of the study visit. 
y 
HbA1c only to be measured. 
z 
The Safety Follow-up visit should be performed 4 weeks following the last dose of study drug.  For subjects who complete the study, this will be Week 20.  
Subjects who terminate the study early should have this visit 4 weeks following the last dose of study drug received. 
aa Subjects will be given the option to collect an end of treatment biopsy.  Biopsy should be taken within 2-4 weeks of last dose of EFX. 


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Appendix C. 
Pregnancy Precautions, Definition for Female of Childbearing 
Potential, and Contraceptive Requirements 
1) Definitions 
a) Definition of Childbearing Potential 
For the purposes of this study, a female born subject is considered of childbearing potential 
following the initiation of puberty (Tanner stage 2) until becoming post-menopausal, unless 
permanently sterile or with medically documented ovarian failure.  
Women are considered to be in a postmenopausal state when they are > 54 years of age with 
cessation of previously occurring menses for > 12 months without an alternative cause. In 
addition, women of any age with amenorrhea of > 12 months may also be considered 
postmenopausal if their follicle stimulating hormone (FSH) level is in the postmenopausal range 
and they are not using hormonal contraception or hormonal replacement therapy. 
Permanent sterilization includes hysterectomy, bilateral oophorectomy, or bilateral 
salpingectomy in a female subject of any age. 
b) Definition of Male Fertility 
For the purposes of this study, a male born subject is considered of fertile after the initiation of 
puberty unless permanently sterile by bilateral orchidectomy or medical documentation. 
2) Contraception Requirements for Female Subjects 
a) Study Drug Effects on Pregnancy and Hormonal Contraception 
No formal studies have been conducted to evaluate the reproductive toxicity of EFX; therefore, 
the reproductive toxicity of EFX in humans is unknown.  
EFX has not yet been studied in pregnant women.  
Please refer to the latest version of the Investigator’s Brochure for additional information. 
b) Contraception Requirements for Female Subjects of Childbearing Potential 
The inclusion of female subjects of childbearing potential requires the use of highly effective 
contraceptive measures. They must have a negative serum pregnancy test at screening and a 
negative pregnancy test on the Baseline/Day 1 visit prior to enrollment. Pregnancy tests will be 
performed at monthly intervals thereafter. Female subjects must agree to one of the following 
from screening until the Week 20 Safety Follow-up Visit. 
• Complete abstinence from intercourse of reproductive potential. Abstinence is an acceptable 
method of contraception only when it is in line with the subject’s preferred and usual 
lifestyle. 


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Or 
• Consistent and correct use of 1 of the following methods of birth control listed below. 
 Intrauterine device (IUD) with a failure rate of < 1% per year 
 Intrauterine hormone-releasing system (IUS) with a failure rate of < 1% per year 
 Tubal sterilization 
 Essure® micro-insert system (provided confirmation of success 3 months after procedure) 
 Vasectomy in the male partner (provided that the partner is the sole sexual partner and 
had confirmation of surgical success 3 months after procedure) 
Should female subjects wish to use a hormonally based method, use of a male condom by the 
female subject's male partner is required. Subjects who utilize a hormonal contraceptive as one 
of their birth control methods must have used the same method for at least three months prior to 
study dosing. Hormonally-based contraceptives permitted for use in this protocol are as follows: 
 Oral contraceptives (either combined or progesterone only) 
 Injectable progesterone 
 Implants of levonorgestrel 
 Transdermal contraceptive patch 
 Contraceptive vaginal ring 
Not all of these methods may be approved in each of the countries where the study is being 
conducted: please refer to local product information. Additional local regulatory requirements 
may apply. 
Female subjects must also refrain from egg donation and in vitro fertilization during treatment 
and until at least 90 days after the last dose of study drug. 
3) Contraception Requirements for Male Subjects 
It is theoretically possible that a relevant systemic concentration may be achieved in a female 
partner from exposure of the male subject’s seminal fluid. Therefore, male subjects with female 
partners of childbearing potential must use condoms during treatment until 90 days after the last 
dose of study drug. Female partners of male study subjects are asked to select one of the above 
methods. 
Male subjects must also refrain from sperm donation during treatment and until at least 90 days 
after the last dose of study drug. 


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4) Unacceptable Birth Control Methods 
Birth control methods that are unacceptable include periodic abstinence (e.g., calendar, 
ovulation, symptothermal, post-ovulation methods), withdrawal (coitus interruptus), spermicides 
only, and lactational amenorrhea method (LAM). Female condom and male condom should not 
be used together. 
5) Procedures to be Followed in the Event of Pregnancy 
Subjects will be instructed to notify the investigator if they become pregnant at any time during 
the study, or if they become pregnant within 90 days of last study drug dose. Subjects who 
become pregnant or who suspect that they are pregnant during the study must report the 
information to the investigator and discontinue study drug immediately. Subjects whose partner 
has become pregnant or suspects she is pregnant during the study must report the information to 
the investigator. Instructions for reporting pregnancy, partner pregnancy, and pregnancy outcome 
are outlined in Section 6.21.5.2. 
 

SAP_001.pdf: 
 
 
 
 
 
 
STATISTICAL ANALYSIS PLAN 
Protocol Title: 
A PHASE 2A, RANDOMIZED, DOUBLE-BLIND, 
PLACEBO-CONTROLLED STUDY EVALUATING THE 
SAFETY AND EFFICACY OF AKR-001 IN SUBJECTS 
WITH NONALCOHOLIC STEATOHEPATITIS (NASH) 
 
Protocol Number: 
AK-US-001-0101 
Protocol Version/Date: 
Version 1.0 / 26 March 2019 
Version 2.0 / 10 April 2019 
Amendment 1 / 05 June 2019 
Amendment 2 / 13 September 2019 
Amendment 3 / 02 October 2019 
Amendment 4 / 08 January 2020 
 
Investigational Product: AKR-001 
 
 
Sponsor: 
Akero Therapeutics, Inc 
 
 
 
 
SAP Version/Date: 
Version 2.0 / 04 March 2020 
 
CONFIDENTIAL 
Information contained in this SAP is proprietary and confidential in nature and may not be used, 
divulged, published, or otherwise disclosed to others except to the extent necessary to obtain 
approval of the Institutional Review Board or as required by law.  Persons to whom this 
information is disclosed should be informed that this information is confidential and may not be 
further disclosed without the express permission of Akero Therapeutics, Inc. 
 
 




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VERSION HISTORY 
Version 
Version Date 
Description 
1.0 
24 January 2020 
Original signed version 
2.0 
04 March 2020 
Additional baseline lab parameters to 
3.3.4; 
MELD score derivation description to 
3.4.3.1; 
An additional histology exploratory 
endpoint to 2.3.3 and 3.4.3.5: ≥ 2 point 
decrease in NAS score with 0-1 point 
inflammation, 0 point ballooning, without 
worsening of fibrosis;  
An additional exploratory endpoint to 
3.4.3.7: non-HDL cholesterol; and 
Additional exploratory endpoint to 2.3.3 
and 3.4.3.9 for MRI-PDFF responders. 
 
 
 
 
 


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TABLE OF CONTENTS 
1 
Introduction ......................................................................................................................... 9 
2 
Study Overview ................................................................................................................... 9 
2.1 
Study Objectives .......................................................................................................... 9 
2.1.1 
Primary Objective ................................................................................................. 9 
2.1.2 
Secondary Objectives ........................................................................................... 9 
2.1.3 
Exploratory Objectives .......................................................................................... 9 
2.2 
Study Design ..............................................................................................................10 
2.2.1 
Overview ..............................................................................................................10 
2.2.2 
Sample Size Determination ..................................................................................11 
2.3 
Study Endpoints ..........................................................................................................12 
2.3.1 
Primary Efficacy Endpoints ..................................................................................12 
2.3.2 
Secondary Efficacy Endpoints .............................................................................12 
2.3.3 
Exploratory Efficacy Endpoints ............................................................................12 
2.3.4 
Safety Endpoints ..................................................................................................13 
3 
Statistical Methodology ......................................................................................................13 
3.1 
General Considerations ..............................................................................................13 
3.1.1 
Analysis Day ........................................................................................................13 
3.1.2 
Analysis Visits ......................................................................................................13 
3.1.3 
Definition of Baseline ...........................................................................................15 
3.1.4 
Summary Statistics ..............................................................................................15 
3.1.5 
Hypothesis Testing ..............................................................................................15 
3.1.6 
Handling of Dropouts and Missing Data ...............................................................15 
3.2 
Analysis Populations ...................................................................................................16 
3.2.1 
Full Analysis Set (FAS) ........................................................................................16 
3.2.2 
Safety Set ............................................................................................................16 
3.2.3 
PK Analysis Set ...................................................................................................16 
3.2.4 
Biomarker Analysis Set ........................................................................................16 
3.2.5 
Per Protocol Analysis Set (PPAS) ........................................................................16 
3.2.6 
MRI-PDFF Evaluable Analysis Set .......................................................................16 
3.2.7 
Liver Biopsy Evaluable Analysis Set ....................................................................17 
3.2.8 
Stratification .........................................................................................................17 
3.3 
Subject Data and Study Conduct ................................................................................17 
3.3.1 
Subject Disposition ..............................................................................................17 
3.3.2 
Protocol Deviations ..............................................................................................17 
3.3.3 
Analysis Populations ............................................................................................17 
3.3.4 
Demographic and Baseline Characteristics ..........................................................17 
3.3.5 
Medical History ....................................................................................................18 
3.3.6 
Concomitant Medications .....................................................................................18 
3.3.7 
Study Drug Exposure and Compliance ................................................................19 


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3.4 
Efficacy Assessment ...................................................................................................19 
3.4.1 
Primary Efficacy Endpoint ....................................................................................19 
3.4.2 
Secondary Efficacy Endpoints .............................................................................21 
3.4.3 
Exploratory Efficacy Endpoints ............................................................................23 
3.4.4 
Subgroups ...........................................................................................................27 
3.5 
Safety Assessment .....................................................................................................27 
3.5.1 
Adverse Events ....................................................................................................27 
3.5.2 
Clinical Laboratory Tests .....................................................................................28 
3.5.3 
Vital Signs ............................................................................................................30 
3.5.4 
12-Lead Electrocardiograms ................................................................................30 
3.5.5 
Other Safety Assessments ...................................................................................30 
3.6 
Pharmacokinetic (PK) Assessment .............................................................................30 
3.7 
Bone Biomarker Assessment ......................................................................................30 
4 
Data Monitoring Committee (DMC) ....................................................................................31 
5 
Interim Analysis .................................................................................................................31 
6 
Changes from Protocol-Specified Statistical Analyses .......................................................31 
7 
Programming Specifications ..............................................................................................31 
Appendix A:  References ..........................................................................................................32 
 
 
 


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Statistical Analysis Plan 
AK-US-001-0101 
 
Version 2.0, 04 March 2020 
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LIST OF ABBREVIATIONS 
Abbreviation 
Definition 
ADA 
Anti-drug Antibodies 
AE 
Adverse Event 
AESI 
Adverse Event of Special Interest 
ALP 
Alkaline Phosphatase 
ALT 
Alanine Aminotransferase 
ANCOVA 
Analysis of Covariance 
AST 
Aspartate Aminotransferase 
ATC 
Anatomical Therapeutic Chemical 
BLQ 
Below Limit of Quantification 
BMI 
Body Mass Index 
BSAP 
Bone Specific Alkaline Phosphatase 
CLDQ-NAFLD 
Chronic Liver Disease Questionnaire-Nonalcoholic Fatty 
Liver Disease 
CP 
Child Pugh 
CRN 
Clinical Research Network 
CRF 
Case Report Form 
CSR 
Clinical Study Report 
cT1 
Corrected T1 
CTCAE 
Common Terminology Criteria for Adverse Events 
DILI 
Drug-Induced Liver Injury 
DMC 
Data Monitoring Committee 
DXA 
Dual Energy X-ray Absorptiometry 
eDISH 
Evaluation of Drug-Induced Serious Hepatotoxicity 
ECG 
Electrocardiogram 
ELF™ 
Enhanced Liver Fibrosis Panel 
EOT 
End of Treatment 
FAS 
Full Analysis Set 
GGT 
Gamma Glutamyl Transferase 
HRQoL 
Health-Related Quality of Life 
INR 
International Normalized Ratio 
LLOQ 
Low Limit of Quantification 
MedDRA 
Medical Dictionary for Regulatory Activities 
MELD 
Model for End-Stage Liver Disease 
MMRM 
Mixed-Model Repeated-Measures 
MRI-PDFF 
Magnetic Resonance Imaging - Proton Density Fat Fraction 
NAB 
Neutralizing Antibody 
NAFLD 
Nonalcoholic Fatty Liver Disease 
NAS 
NAFLD Activity Score 
NASH 
Nonalcoholic Steatohepatitis 
PK 
Pharmacokinetics 
PPAS 
Per Protocol Analysis Set 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SF-36 
Short Form 36 Health Survey 
SOC 
System Organ Class 
TB 
Total Bilirubin 


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Abbreviation 
Definition 
TEAE 
Treatment-Emergent Adverse Event 
TESAE 
Treatment-Emergent Serious Adverse Event 
TFLs 
Tables, Figures, and Listings 
WHO 
World Health Organization 
WPAI 
Work Productivity and Activity Impairment 
 
 


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1 INTRODUCTION 
The purpose of this Statistical Analysis Plan (SAP) is to provide a description of the statistical 
methods to be implemented for the analysis of the Main Study data from 
Akero Therapeutics, Inc. Protocol AK-US-001-0101.  A separate SAP will be provided for the 
analysis of Cohort C data from Akero Therapeutics, Inc. Protocol AK-US-001-0101.  The SAP 
will be finalized prior to unblinding of the database.  Any deviations from the SAP after database 
unblinding will be documented in the final Clinical Study Report (CSR). 
2 STUDY OVERVIEW 
2.1 Study Objectives 
2.1.1 Primary Objective 
The primary objective of this study is: 
• 
To evaluate absolute change from baseline in hepatic fat fraction assessed by Magnetic 
Resonance Imaging - Proton Density Fat Fraction (MRI-PDFF) at Week 12 
2.1.2 Secondary Objectives 
The secondary objectives of this study are: 
• 
To evaluate percent change from baseline in hepatic fat fraction assessed by MRI-PDFF 
at Week 12 
• 
To evaluate the responder: subjects who achieved a clinically meaningful relative 
reduction of at least 30% in liver fat content as measured by MRI-PDFF at Week 12 
• 
To evaluate the responder based on Nonalcoholic Fatty Liver Disease (NAFLD) Activity 
Score system (NAS): subjects who had a decrease of ≥ 2 points in NAS with at least a 
1- point reduction in either lobular inflammation or hepatocellular ballooning and with no 
concurrent worsening of fibrosis stage  
• 
To evaluate the change from baseline in alanine aminotransferase (ALT) at Week 12 
• 
To assess the safety and tolerability of AKR-001 in subjects with NASH  
2.1.3 Exploratory Objectives 
The exploratory objectives of this study are: 
• 
Change from baseline in markers of liver injury and function including aspartate 
aminotransferase (AST), alkaline phosphatase (ALP), gamma glutamyl transferase 
(GGT), bilirubin, International Normalized Ratio (INR), albumin, Model for End-Stage 
Liver Disease (MELD) score, and Child Pugh (CP) score 
• 
Change from baseline in body weight and waist-to-hip ratio 
• 
MRI-PDFF based quantitation of hepatic fat 
• 
Changes from baseline in noninvasive plasma (or serum) biomarkers including liver 
fibrosis by Enhanced Liver Fibrosis (ELF™) Test score, and by pro-C3 levels 


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• 
Change from baseline in bone mineral density of the lumbar spine, femoral neck, and 
total hip as measured by Dual Energy X-ray Absorptiometry (DXA) 
• 
The proportion of subjects at Week 22 - 24 whose fibrosis regresses by ≥ 1-stage 
according to the NASH Clinical Research Network (CRN) classification 
• 
The proportion of subjects who had no worsening in NAS with improvement in fibrosis 
stage 
• 
The proportion of subjects who had 2 points improvement in NAS with no worsening in 
fibrosis stage 
• 
The proportion of subjects who had ≥ 1 point improvement in NAS, fibrosis, steatosis 
lobular inflammation or hepatocellular ballooning 
• 
Changes from baseline in health-related quality of life (HRQoL) 
• 
Changes from baseline in lipoprotein profile and markers of lipid metabolism, insulin 
sensitivity and glycemic control 
• 
Change from baseline in body fat distribution as measured by DXA total body 
composition 
• 
Change from baseline in corrected T1 (cT1), an MRI-based metric of liver fibro-
inflammation at Week 12 
• 
Plasma concentrations of AKR-001 
2.2 Study Design 
2.2.1 Overview 
This is a Phase 2a, randomized, double-blind, placebo-controlled study evaluating the safety 
and efficacy of AKR-001 in subjects with NASH. 
This study will enroll approximately 80 subjects with biopsy proven F1 - F3 NASH.  F1 fibrosis 
will comprise approximately 35% of total subject population.  Subjects meeting the study’s entry 
criteria will be randomly assigned in 1:1:1:1 ratio into 4 treatment groups as shown in the figure 
below: 


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Randomization will be stratified by baseline hepatic fat fraction (< 15% vs ≥ 15%) and F1 
fibrosis score.  Study drug will be administered subcutaneously once weekly (QW) for a total of 
16 weeks.  After 16 weeks of treatment, a safety follow-up visit will occur at Week 20.  Subjects 
with ≥ 30% relative fat reduction on MRI-PDFF at Week 12 will be required to return between 
Weeks 22 - 24 for a repeat liver biopsy and MRI-PDFF. 
This study will be conducted at approximately 30 sites in the U.S.  Additional sites may be 
added, depending on subject accrual rates. 
2.2.2 Sample Size Determination 
Due to the exploratory nature of this study, no formal power calculations were used to determine 
sample size.  The number of subjects was chosen based on clinical experience with other 
similar proof of concept studies. 
With the following assumptions, the power for N = 20 subjects with active treatment is 
approximately 91% to detect: 
• 
A true, baseline-adjusted, mean decrease from baseline in MRI-PDFF-estimated hepatic 
fat of 5% compared to placebo, 
• 
With a one-sided t-test for decrease from placebo, 
• 
A 5% significance level, 
• 
20 subjects receiving placebo, and 
• 
A standard deviation estimated as 5.2% (Sanyal et al. 2019). 


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2.3 Study Endpoints 
2.3.1 Primary Efficacy Endpoints 
The primary endpoint is the absolute change from baseline in hepatic fat fraction measured by 
MRI-PDFF at Week 12.   
2.3.2 Secondary Efficacy Endpoints 
The secondary endpoints are: 
• 
Absolute change from baseline in hepatic fat fraction measured by MRI-PDFF at 
Week 22 - 24 
• 
Percent change from baseline in hepatic fat fraction measured by MRI-PDFF at 
Weeks 12 and 22 - 24 
• 
Responder: subjects who achieved a clinically meaningful relative reduction of at least 
30% in liver fat content as measured by MRI-PDFF at Week 12 
• 
Responder based on NAS system: subjects who had a decrease of ≥ 2 points in NAS 
with at least a 1-point reduction in either lobular inflammation or hepatocellular 
ballooning and with no concurrent worsening of fibrosis stage  
• 
Change from baseline in ALT at Weeks 12, 16 and 20 
2.3.3 Exploratory Efficacy Endpoints 
The exploratory endpoints are: 
• 
Change from baseline in markers of liver injury and function including AST, ALP, GGT, 
bilirubin, INR, albumin, MELD score, and CP score at Weeks 12, 16 and 20 
• 
Change from baseline in body weight and waist-to-hip ratio at Weeks 12, 16 and 20 
• 
MRI-PDFF based quantitation of hepatic fat 
• 
Changes from baseline in noninvasive biomarkers including Pro-C3 at 
Weeks 12, 16 and 20, and liver fibrosis by ELF™ Test score at Weeks 6 and 12 
• 
Change from baseline in bone mineral density of the lumbar spine, femoral neck, and 
total hip as measured by DXA at Week 16 
• 
The proportion of subjects at Week 22 - 24 whose fibrosis regresses by ≥ 1-stage 
according to the NASH CRN classification 
• 
The proportion of subjects at Week 22 - 24 who had no worsening in NAS with 
improvement in fibrosis stage 
• 
The proportion of subjects at Week 22 - 24 who had 2 points improvement in NAS with 
no worsening in fibrosis stage  
• 
The proportion of subjects at Week 22 - 24 who had ≥ 1 point improvement in NAS, 
fibrosis, steatosis lobular inflammation or hepatocellular ballooning 
• 
The proportion of subjects at Week 22 - 24 who had ≥ 2 point decrease in NAS score 
with 0-1 point inflammation, 0 point ballooning, without worsening of fibrosis 


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• 
Changes from baseline in HRQoL (SF-36, CLDQ-NAFLD, WPAI) at Weeks 12 and 16 
• 
Changes from baseline in lipoprotein profile and markers of lipid metabolism, insulin 
sensitivity and glycemic control at Weeks 12, 16 and 20 
• 
Change from baseline in body fat distribution as measured by DXA total body 
composition at Week 16 
• 
Change from baseline in cT1, an MRI-based metric of liver fibro-inflammation at 
Weeks 12 and 22 - 24 
• 
Plasma concentrations of AKR-001 
• 
The proportion of subjects who achieved a relative reduction of at least 50% in liver fat 
content as measured by MRI-PDFF at Week 12 
• 
The proportion of subjects who achieved a relative reduction of at least 70% in liver fat 
content as measured by MRI-PDFF at Week 12 
• 
The proportion of normalized subjects whose liver fat content as measured by MRI-
PDFF ≤ 5% at Week 12 
2.3.4 Safety Endpoints 
The safety endpoint is safety and tolerability of AKR-001 in subjects with NASH. 
Safety analyses include: summaries of extent of exposure, adverse events (AEs), laboratory 
evaluations, electrocardiogram (ECG), vital sign assessments, body weight, anti-drug antibody 
(ADA) and neutralizing antibody (NAB) assessments, and concomitant medication usage. 
3 STATISTICAL METHODOLOGY 
3.1 General Considerations 
3.1.1 Analysis Day 
Analysis day will be calculated from the date of first dose of study drug.  The day of the first 
dose of study drug will be Day 1, and the day immediately before Day 1 will be Day -1.  There 
will be no Day 0, in alignment with international data standards for clinical trials.  Analysis day 
will be calculated as (date of clinical event – date of first dose of study drug) + 1 if the date of 
the event is on or after the date of first dose and as (date of clinical event – date of first dose of 
study drug) if the date of event is before the date of first dose. 
3.1.2 Analysis Visits 
Scheduled visits will be assigned to analysis visits as recorded on the Case Report Form (CRF).  
Unscheduled and early termination visits for the MRI-PDFF, cT1, ELF™ and pro-C3 will be 
assigned to analysis visits according to the following visit windows: 
Analysis Visit 
Target Analysis Day Low Analysis Day 
High Analysis Day 
Week 6 
43 
22 
64 
Week 12 
85 
65 
127 
Note: if the unscheduled collection or early term collection is >21 days after the last dose 
of study drug, it will not be used in analyses. 


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For ALT, markers of liver injury and function, waist-to-hip ratio, biomarkers and HRQoL, 
unscheduled and early termination visits will be assigned to analysis visits according to the 
following visit windows: 
Analysis Visit 
Target Analysis Day Low Analysis Day 
High Analysis Day 
Week 1 
8 
2 
15 
Week 4 
29 
16 
43 
Week 8 
57 
44 
71 
Week 12 
85 
72 
99 
Week 16 
113 
100 
127 
Week 20 Safety 
follow-up 
141 
128 
EOS 
Note: if the unscheduled collection or early term collection is >14 days after the last dose 
of study drug, it will not be used in analyses. 
For body weight, unscheduled and early termination visits will be assigned to analysis visits 
according to the following visit windows: 
Analysis Visit 
Target Analysis Day Low Analysis Day 
High Analysis Day 
Week 1 
8 
2 
11 
Week 2 
15 
12 
18 
Week 3 
22 
19 
25 
Week 4 
29 
26 
32 
Week 5 
36 
33 
39 
Week 6 
43 
40 
46 
Week 7 
50 
47 
53 
Week 8 
57 
54 
60 
Week 9 
64 
61 
67 
Week 10 
71 
68 
74 
Week 11 
78 
75 
81 
Week 12 
85 
82 
88 
Week 13 
92 
89 
95 
Week 14 
99 
96 
102 
Week 15 
106 
103 
109 
Week 16 
113 
110 
127 
Week 20 Safety 
follow-up 
141 
128 
EOS 
The efficacy assessments from two biopsies (Screening and Repeat Biopsy Weeks 22 - 24) and 
the safety assessments from two DXA Scans (Screening and Week 16) will be considered for 
the analysis regardless of when the second assessment or biopsy takes place.  Unscheduled 
visits after the first dose of study drug and early termination visits will be assigned as post-
baseline. 
For PK concentration summaries, a concentration that is intended as predose will be excluded 
from analysis if it is >24 hours before a dose or after the current dose.  Beyond this rule, PK 
concentrations must be within the visit window to be included in summary statistics of PK.  
Within an analysis visit window, the measurement from the scheduled visits will be used if 
available.  If no scheduled visit occurs, the measurement from the visit closest to the defined 
target analysis day within the window will be used.  If there is more than one measurement with 


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equal distance to the defined target analysis day, the latter will be used.  If no visits occur within 
a visit window, the measurement for this visit will be treated as missing. 
3.1.3 Definition of Baseline  
For all variables except lipids and liver enzymes variables, pre-dose measurements on Baseline 
visit (Day 1) will be considered the baseline values.  If the measurement at this visit is not 
available, the last measurement prior to the first dose of study drug may be used as the 
baseline value unless it is stated otherwise.  The scheduled baseline visit for MRI-PDFF, 
FibroScan, liver biopsy, DXA scan, cT1, ELF™ and pro-C3 is Screening.  Baseline lipid 
variables including Total Cholesterol, HDL-C, LDL-C, Triglycerides, non-HDL cholesterol will be 
the average of Screening and Baseline visit (Day 1) values.  Baseline liver enzymes variables 
including ALT and AST will be the average of Pre-Baseline and Baseline visit (Day 1) values.  If 
one is missing for lipids and liver enzymes variables, the available one will be used.   
3.1.4 Summary Statistics 
Categorical data will generally be summarized with counts and percentages of subjects.  The 
denominator used for the percentage calculation will be clearly defined.  Continuous data will 
generally be summarized with descriptive statistics including n (number of non-missing values), 
mean, median, standard deviation, minimum, and maximum.  For certain continuous data, it will 
be summarized with descriptive statistics including n (number of non-missing values), arithmetic 
mean, arithmetic standard deviation, geometric mean, geometric coefficient of variation, 
median, minimum, and maximum.  PK concentrations will be summarized with the set of 
continuous parameters including geometric mean and will add the statistic of number of 
samples below the limit of quantification (nblq). 
All individual subject data will be listed as measured. 
3.1.5 Hypothesis Testing 
The statistical hypotheses will be tested at the 2-sided, 0.05 significance for the parameters with 
neutral direction other than specified.  Fixed hypothesis testing sequence will be used to control 
the multiplicity for each active dose to be compared with placebo. 
3.1.6  Handling of Dropouts and Missing Data 
Missing data can have an impact on the interpretation of the trial data.  In general, values for 
missing data will not be imputed. 
Where appropriate, safety data for subjects that did not complete the study will be included in 
summary statistics.  For example, if a subject received study drug, the subject will be included in 
a summary of AEs according to the treatment received; otherwise, if the subject is not dosed 
then they will be excluded from the summary.  If safety laboratory results for a subject are 
missing for any reason at a time point, the subject will be excluded from the calculation of 
summary statistics for that time point.  If the subject is missing a pre-dose value, then the 
subject will be excluded from the calculation of summary statistics for the pre-dose value and 
the change from pre-dose values. 
Values for missing safety laboratory data will not be imputed; however, a missing baseline result 
will be replaced with a screening result, if available.  If no pre-treatment laboratory value is 
available, the baseline value will be assumed to be normal (i.e., no grade [Grade 0]) for the 
summary of graded laboratory abnormalities. 


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Values for missing vital signs data will not be imputed; however, a missing baseline result will be 
replaced with a screening result, if available. 
Below limit of quantification (BLQ) PK concentration at pre-dose at Baseline will be imputed as 
zero and the other pre-dose BLQ PK concentrations will be imputed as half of the low limit of 
quantification (0.5*LLOQ).   
3.2 Analysis Populations 
3.2.1 Full Analysis Set (FAS) 
The FAS will include all subjects who were randomized into the study.  The FAS will be the 
primary analysis set for efficacy analyses. 
Subjects who receive a dose of study drug other than that to which they were randomized for 
the entire duration of treatment will be analyzed according to treatment group to which they 
were randomized. 
3.2.2 Safety Set 
The Safety Set will include all subjects who received at least one dose of study drug.  The 
Safety Set will be the primary analysis set for safety analyses.   
Subjects who received a dose of study drug other than that to which they were randomized for 
the entire duration of treatment will be analyzed according to the dose of study drug received.  
All data collected during treatment plus 30 days after last dose of study drug will be included in 
the safety summaries. 
3.2.3 PK Analysis Set 
The PK Analysis Set will include all randomized subjects who took at least one dose of study 
drug and for whom concentration data of AKR-001 is available. 
3.2.4 Biomarker Analysis Set 
The Biomarker Analysis Set will include data from subjects in the Safety Set who have the 
necessary baseline and on-study measurements to provide interpretable results for the specific 
parameters of interest. 
3.2.5 Per Protocol Analysis Set (PPAS) 
The PPAS is defined as any subject who is randomized, receives at least one dose of study 
drug, and has Baseline and Week 12 hepatic fat fraction assessed by MRI-PDFF without any 
major protocol deviations.  A full detail of inclusions and exclusions from PPAS will be in the 
classifications specifications and finalized before unblinding. 
3.2.6 MRI-PDFF Evaluable Analysis Set 
MRI-PDFF Evaluable Analysis Set will be a subset of the FAS. It will include all FAS subjects 
who have Baseline and Week 12 hepatic fat fraction assessed by MRI-PDFF.  It will be the 
analysis population for the responders based on MRI-PDFF. 


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3.2.7 Liver Biopsy Evaluable Analysis Set 
Liver Biopsy Evaluable Analysis Set will be a subset of the FAS. It will include all FAS subjects 
who have Baseline and Week 22 - 24 liver biopsy results.  It will be the analysis population for 
the responders based on NAS system and fibrosis stage. 
3.2.8 Stratification 
For statistical analysis, the factors on which randomization has been stratified will be used.  
Preservation of the initial randomization in analysis is important in preventing bias and in 
providing a secure foundation for statistical tests (ICH E9). 
3.3 Subject Data and Study Conduct 
3.3.1 Subject Disposition 
Counts and percentages of subjects who were screened (signed informed consent), 
discontinued early during screening (screen failures), and randomized will be summarized in 
total based on all screened subjects.  Reasons for early discontinuation will also be 
summarized. 
Counts and percentages of subjects in each of the following disposition categories will be 
presented by treatment and in total based on all randomized subjects: 
• 
Subjects who were randomized 
• 
Subjects who started study drug 
• 
Subjects who completed the 12-week treatment 
• 
Subjects who completed the 16-week treatment 
• 
Subjects who withdrew from the 16-week treatment 
• 
Subjects who completed the study 
• 
Subjects who withdrew from the study 
For randomized subjects who withdraw from the treatment and withdraw from the study, the 
primary reason for the withdrawal will be summarized.  
3.3.2 Protocol Deviations 
Protocol deviations will be defined in the Protocol Deviation Plan.  Counts and percentages of 
subjects with CSR reportable protocol deviations by deviation category will be summarized by 
treatment and in total based on all randomized subjects. 
3.3.3 Analysis Populations 
Counts and percentages of subjects in each analysis population will be summarized by 
treatment and in total based on all randomized subjects. 
3.3.4 Demographic and Baseline Characteristics 
The following demographic and baseline characteristics will be summarized: 
• 
Age (years) and age categories (<45 years, ≥45 to <65 years, ≥65 years) 
• 
Sex 


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• 
Race 
• 
Ethnicity 
• 
Height (cm) at Screening 
• 
Weight (kg) at Baseline 
• 
Body mass index (BMI) (kg/m2) at Baseline and BMI categories at Baseline (<30 kg/m2, 
≥30 kg/m2) 
• 
Waist circumference (cm) at Baseline 
• 
Hip circumference (cm) at Baseline 
• 
Waist-to-hip ratio at Baseline 
• 
Type 2 diabetes status at Screening 
• 
Fibrosis stage at Screening 
• 
Biopsy diagnosis at Screening 
• 
NAS and NAS components at Screening 
• 
Hepatic fat fraction (%) by MRI-PDFF at Screening  
• 
Stratification groups at Baseline: F1 fibrosis score (F1, F2-3) and hepatic fat fraction 
categories (< 15%, ≥ 15%) 
• 
Alanine aminotransferase (U/L) and Aspartate Aminotransferase (U/L) at Baseline 
• 
Triglyceride (mg/dL), Total Cholesterol (mg/dL), LDL-C (mg/dL), HDL-C (mg/dL), and 
non-HDL-C (mg/dL) at Baseline 
• 
Hemoglobin A1c (%) at Baseline 
• 
Endogenous FGF21 at Baseline 
• 
Bone Mineral Density at Baseline  
• 
Body Fat Distribution at Baseline  
Demographic and baseline characteristics will be summarized with descriptive statistics or 
counts and percentages of subjects as appropriate by treatment and in total for all randomized 
subjects and each defined analysis population if the analysis population composition is different 
than all randomized subjects. 
3.3.5 Medical History 
Medical history will be coded to system organ class (SOC) and preferred term using the Medical 
Dictionary for Regulatory Activities (MedDRA) version 22.0 or the latest version.  Counts and 
percentages of subjects with medical history by SOC and preferred term will be summarized by 
treatment and in total based on all randomized subjects. 
3.3.6 Concomitant Medications 
Concomitant medications will be coded to anatomical therapeutic chemical (ATC) class and 
preferred term using the World Health Organization (WHO) Drug Dictionary version 2019G B3 
or the latest version.  For summary purposes, medications will be considered prior medications 
if they stopped prior to the first dose of study drug and concomitant medications if they were 
taken at any time on or after the first dose of study drug (i.e. started prior to the first dose of 
study drug and were ongoing or started after the first dose of study drug). 
Counts and percentages of subjects taking concomitant medications by ATC class and 
preferred term will be summarized by treatment and in total based on the Safety Set.  The use 
of any prior medication or concomitant medication will be listed for all randomized subjects. 


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3.3.7 Study Drug Exposure and Compliance 
Weeks of exposure to study drug will be calculated as: 
(date of last dose of study drug - date of first dose of study drug + 1) / 7 
Weeks of exposure to study drug will be summarized by treatment based on the Safety Set with 
descriptive statistics and with counts and percentages of subjects with exposure in the following 
categories: 
• 
>0 to ≤4 weeks 
• 
>4 to ≤8 weeks 
• 
>8 to ≤12 weeks  
• 
>12 to ≤16 weeks 
• 
>16 weeks 
The total number of injections administered will be calculated for each subject. A contingency 
table will be provided to display the number and percentage of subjects in each treatment group 
with the following number of injections: 1-3, 4-6, 7-9, 10-12, 13-15, >=16. 
Subjects that miss 2 or more doses of study drug over the course of study participation are 
considered noncompliant. The frequency and percentage of subjects who are compliant and 
noncompliant will be summarized by treatment group. 
3.4 Efficacy Assessment 
Efficacy data will be summarized and analyzed by randomized treatment based on the FAS 
unless otherwise specified. 
3.4.1 Primary Efficacy Endpoint 
The primary efficacy endpoint will be the absolute change from baseline hepatic fat fraction 
measured by MRI-PDFF at Week 12. 
Absolute change in fat fraction by MRI-PDFF = Week 12 - Baseline 
MRI-PDFF will be performed at Screening, Week 6 and Week 12, and a repeat MRI-PDFF in 
eligible subjects will be performed at Week 22 - 24.  Summary statistics at all visits for the 
values, change from baseline and percent change from baseline will be provided. 
3.4.1.1 
Primary Analysis 
The primary efficacy analysis will be analyzed with an analysis of covariance (ANCOVA) model 
with treatment group and F1 fibrosis score (F1 vs F2-3) as factors and baseline hepatic fat 
fraction measured by MRI-PDFF as a covariate.  The SAS sample code is listed: 
***********************************************************************  
  TREATMENT: 0 (Placebo), 1 (AKR-001 28 mg), 2 (AKR-001 50 mg), or 
             3 (AKR-001 70 mg) 
  FSCORE: Fibrosis score (F1 vs F2-3) 
  BASE: Baseline fat fraction by MRI-PDFF 
  CHG: Change from baseline to Week 12 in fat fraction by MRI-PDFF 
**********************************************************************;  
proc glm;  


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  class TREATMENT FSCORE;  
  model CHG = TREATMENT FSCORE BASE / p;  
  lsmeans TREATMENT / stderr pdiff cl;  
  estimate "AKR-001 70 mg : Placebo" TREATMENT -1 0 0 1;  
  estimate "AKR-001 50 mg : Placebo" TREATMENT -1 0 1 0; 
  estimate "AKR-001 28 mg : Placebo" TREATMENT -1 1 0 0;  
run; 
For any subjects in the FAS with a missing primary efficacy value, the primary efficacy variable 
will be imputed with multiple imputation method. 
The treatment effect of each active dose comparing with placebo will be estimated from the 
ANCOVA model.  LS means, one-sided, 97.5% confidence intervals and one-sided p-values will 
be calculated.  Normality will be tested for the model residuals by the Shapiro-Wilk normality 
test. 
In order to control the Type I error rate inflation caused by multiplicity issues, a step-down fixed 
hypothesis testing sequence will be used, following the order of AKR-001 70 mg vs. Placebo, 
AKR-001 50 mg vs. Placebo, and then AKR-001 28 mg vs. Placebo.  That is, only if the higher 
dose is proved to be significantly better than placebo will the next low dose be compared. 
Multiple Imputation Method: 
Missing primary efficacy endpoint will be handled using the MAR multiple imputation method. 
The multiple imputation procedure will be conducted by two parts: PROC MI and PROC 
MIANALYZE. 
• 
Multiple imputation will be used to impute missing data and will be implemented using SAS® 
PROC MI:  Missing data may be the result of missing hepatic fat fraction (%) assessed by MRI-
PDFF at Week 12 or the result of subjects discontinuing treatment prior to Week 12.  Missing at 
random (MAR) will be assumed.  The imputation model will include the subject demographics 
(age [<median, ≥median], race [white, non-white], baseline weight [<median, ≥median]), F1 
fibrosis score [F1, F2-3], and baseline and Week 6 hepatic fat fraction assessed by MRI-PDFF.  
Missing data will be imputed 100 times to generate 100 complete data sets.  The seed will be 
98765.  The fully conditional specification method will be used.  The 100 complete data sets 
will then be analyzed using the same analysis method as the one used to analyze the primary 
endpoint. 
• 
The results from the 100 fitted models will be combined using SAS® PROC MIANALYZE:  The 
estimate of the treatment difference and standard error from the analysis will be analyzed by 
PROC MIANALYZE to obtain the overall estimate of treatment difference, as well as the 
confidence interval and p-value for the hypothesis testing. 
• 
If the model fails to converge, exclusion of subject demographics will be considered. 
3.4.1.2 
Secondary Analysis 
The absolute change from baseline in hepatic fat fraction measured by MRI-PDFF will be 
analyzed using a mixed-model repeated-measures (MMRM) on the FAS.  No imputation will be 
performed.  The factors in the model will be F1 fibrosis score, treatment group, baseline value, 
visit, and the treatment group by visit interactions. An unstructured covariance matrix will be 
used.  The SAS sample code is listed: 


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***********************************************************************  
  USUBJID: Unique subject identifier 
  TREATMENT: 0 (Placebo), 1 (AKR-001 28 mg), 2 (AKR-001 50 mg), or 
             3 (AKR-001 70 mg) 
  FSCORE: Fibrosis score (F1 vs F2-3) 
  BASE: Baseline fat fraction by MRI-PDFF 
  VISIT: Week 6, Week 12 
  CHG: Change from baseline to Week 12 in fat fraction by MRI-PDFF 
**********************************************************************;  
proc mixed;   
  class USUBJID FSCORE TREATMENT VISIT;   
  model CHG = FSCORE TREATMENT BASE VISIT TREATMENT*VISIT;   
  Repeated VISIT / TYPE=UN sub=USUBJID;   
  lsmeans VISIT*TREATMENT / cl pdiff slice=VISIT;   
run;   
3.4.1.3 
Sensitivity Analyses 
• 
Robustness of the results to departure from the MAR assumption will be explored in the 
FAS using tipping-point analysis approach: this sensitivity analysis assumes the “missing 
not at random (MNAR)” mechanism for dropouts in the active treatment group and the 
“missing at random (MAR)” mechanism for dropouts in the placebo group in this study. It 
also assumes that dropouts from the active treatment group at a given post-baseline visit 
would have, on average, their unobserved fat fraction worse by δ compared to the fat 
fraction imputed by a Multiple Imputation (MI) approach based on the MAR method. 
• 
Estimations will be performed using the multiple imputation approach as described 
above. In each treatment group, a penalty δ will be added to the imputed values (δ = 
0 corresponds to the MAR assumption) in the multiple imputation step. 
• 
To investigate how the conclusions for the endpoint depend on the adopted values δ, 
the testing will be repeated over a range of plausible values for each treatment 
groups.  Results will then be summarized using contour plot. 
The smallest value of δ_treatment while δ_placebo = 0 which will statistically reverse the 
conclusion for the primary endpoint will be assessed and interpreted from its clinical 
plausibility. 
• 
The primary analysis will be repeated on the PPAS.  No imputation will be performed.   
• 
The treatment group-by-baseline MRI-PDFF interaction will be added in the ANCOVA 
model of the primary analysis to check the homogeneity of regression slopes 
assumption. 
3.4.2 Secondary Efficacy Endpoints 
3.4.2.1 
Absolute change from baseline in fat fraction measured by MRI-PDFF at Week 22 - 24 
This analysis is defined for subjects with ≥ 30% relative fat reduction on MRI-PDFF at Week 12 
and required to return between Weeks 22 - 24.  ANCOVA model with treatment group, F1 
fibrosis score (F1 vs F2-3) as factors and baseline hepatic fat fraction as a covariate will be 
performed on the FAS.  LS means, 95% confidence intervals and p-values will be presented.  
The same MI method will be used for the missing value at Week 22 - 24.  The analysis will be 


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repeated on the observed data only including subjects with non-missing baseline and 
Weeks 22 - 24 fat fraction. 
3.4.2.2 
Percent change from baseline in fat fraction measured by MRI-PDFF at Weeks 12 and 22 - 24 
Percent (relative) change in fat fraction by MRI-PDFF = 100 x (Week 12 - Baseline) / Baseline 
For the percent change from baseline to Week 12, the same ANCOVA model used for primary 
efficacy endpoint will be performed on the FAS with the same multiple imputation method, and 
repeated on the PPAS without imputation, as well as the same MMRM model on the FAS.  The 
same statistics will be presented as for the primary model.  Normality will be tested for the 
model residuals by the Shapiro-Wilk normality test.  The homogeneity of regression slopes 
assumption will be checked.  For the percent change from baseline to Week 22 - 24, the 
analysis is defined for subjects with ≥ 30% relative fat reduction on MRI-PDFF at Week 12 and 
required to return between Weeks 22 - 24.  The same MI method will be used for the missing 
value at Week 22 - 24.  The analysis will be repeated on the observed data only including 
subjects with non-missing baseline and Weeks 22 - 24 fat fraction. 
3.4.2.3 
Responder based on MRI-PDFF: subjects who achieved a clinically meaningful relative reduction 
of at least 30% in liver fat content as measured by MRI-PDFF at Week 12 
That is the percent change from baseline to Week 12 ≤ -30% in hepatic fat fraction.  The 
number and percentage of responders will be provided by treatment group and by stratification 
group.  Logistic regression will be used for the analyses based on FAS with missing values 
imputed as non-responders and repeated on MRI-PDFF Evaluable Analysis Set without 
imputation.  The analyses will include the treatment group and F1 fibrosis score (F1 vs F2-3) as 
factors and baseline hepatic fat fraction measured by MRI-PDFF as a covariate.  The odds ratio, 
95% confidence interval, and p-value from the logistic regression will be provided.  The SAS 
sample code is listed: 
***********************************************************************  
  TREATMENT: 0 (Placebo), 1 (AKR-001 28 mg), 2 (AKR-001 50 mg), or 
             3 (AKR-001 70 mg) 
  FSCORE: Fibrosis score (F1 vs F2-3) 
  BASE: Baseline fat fraction by MRI-PDFF 
  RESPONSE: 0 (Non-responder), 1 (Responder) 
**********************************************************************;  
proc logistic;   
  class TREATMENT FSCORE;   
  model RESPONSE (event='1') = TREATMENT FSCORE BASE / link=logit  
        clodds=wald orpvalue;   
  oddsratio TREATMENT /diff=ref;  
run;  
3.4.2.4 
Change from baseline in ALT at Weeks 12, 16 and 20 
ALT will be measured at Screening, Pre-Baseline, Baseline (Day 1), Week 1, Week 4, Week 8, 
Week 12, Week 16 and Week 20 Safety follow-up.  Values and changes from baseline in ALT 
will be summarized descriptively.  ANCOVA model with treatment group, baseline hepatic fat 
fraction (< 15% vs ≥ 15%), and F1 fibrosis score (F1 vs F2-3) as factors and baseline value as a 
covariate will be performed on the FAS with the same multiple imputation method in Section 
3.4.1.1, and repeated on the PPAS without imputation, as well as the same MMRM model on 
the FAS in Section 3.4.1.2.  LS means, 95% confidence intervals and p-values will be 


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presented.  Normality will be tested for the model residuals by the Shapiro-Wilk normality test.  
The homogeneity of regression slopes assumption will be checked. 
3.4.2.5 
Responder based on NAS system: subjects who had a decrease of ≥ 2 points in NAS with at least 
a 1-point reduction in either lobular inflammation or hepatocellular ballooning and with no 
concurrent worsening of fibrosis stage 
The responders are defined for subjects with ≥ 30% relative fat reduction on MRI-PDFF at 
Week 12 and required to return between Weeks 22 - 24.  The number and percentage of 
responders will be provided by treatment group.  Fisher’s exact test will be used for the analysis 
using FAS with missing values imputed as non-responders and repeated on Liver Biopsy 
Evaluable Analysis Set without imputation.  Odds ratios (vs Placebo), 95% confidence intervals 
and p-values will be provided.   
3.4.3 Exploratory Efficacy Endpoints  
The exploratory efficacy endpoints are defined in Section 2.3.3.  Descriptive statistics at each 
scheduled visit on the values and changes from baseline of the exploratory efficacy endpoints 
will be summarized.  For certain efficacy endpoints, logarithmic transformation may be 
performed prior to fitting the ANCOVA model.  Since these endpoints are for exploratory 
purposes, no adjustments for multiplicity will be made. 
3.4.3.1 
Markers of liver injury and function 
Markers of liver injury and function including AST, ALP, GGT, bilirubin, INR, albumin, MELD 
score, and CP score will be measured at Screening, Pre-Baseline, Baseline (Day 1), Week 1, 
Week 4, Week 8, Week 12, Week 16 and Week 20 Safety follow-up.   
MELD score will be calculated as below: 
• 
Candidates who are at least 12 years old receive an initial MELD (i) score equal to: 
0.957 x Loge(creatinine mg/dL) + 0. 378 x Loge (bilirubin mg/dL) + 1.120 x Loge (INR) + 
0.643 
• 
Multiply the score by 10 and round to the nearest whole number. Laboratory values less 
than 1.0 are set to 1.0 for the purposes of the MELD score calculation. 
• 
For candidates with an initial MELD score greater than 11, the MELD score is then re-
calculated as follows:  
MELD = MELD(i) + 1.32*(137-Na) – [0.033*MELD(i)*(137-Na)], where Sodium values 
less than 125 mmol/L will be set to 125, and values greater than 137 mmol/L will be set 
to 137. 
CP score will be calculated as below, ranging from 5-15: 
 
1 point  
2 point 
3 point 
Bilirubin (Total)  
<2 mg/dL (<34.2 µmol/L) 
2-3 mg/dL (34.2-51.3 µmol/L) 
>3 mg/dL (>51.3 µmol/L) 
Albumin 
>3.5 g/dL (>35 g/L) 
2.8-3.5 g/dL (28-35 g/L) 
<2.8 g/dL (<28 g/L) 
INR  
<1.7  
1.7-2.2  
>2.2 
Ascites  
Absent  
Slight 
Moderate 
Encephalopathy 
No Encephalopathy 
Grade 1-2 
Grade 3-4  
Class A = 5-6 points 
Class B = 7-9 points 
Class C = 10-15 points  


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ANCOVA model with treatment group, baseline hepatic fat fraction (< 15% vs ≥ 15%), and F1 
fibrosis score (F1 vs F2-3) as factors and baseline value as a covariate will be used for 
analyzing the change from baseline to Week 12, the change from baseline to Week 16, and the 
change from baseline to Week 20.  LS means, 95% confidence intervals and p-values will be 
presented.  The missing value will be imputed by last-observed-carried-forward (LOCF) method. 
3.4.3.2 
Body weight and waist-to-hip ratio 
Body weight, waist circumference and hip circumference will be measured at all visits.   
ANCOVA model with treatment group, baseline hepatic fat fraction (< 15% vs ≥ 15%), and F1 
fibrosis score (F1 vs F2-3) as factors and baseline value as a covariate will be used for 
analyzing the change from baseline to Week 12, the change from baseline to Week 16, and the 
change from baseline to Week 20.  LS means, 95% confidence intervals and two-sided p-values 
will be presented for body weight, and LS means, 95% confidence intervals and p-values will be 
presented for the other parameters.  The missing value will be imputed by LOCF method. 
3.4.3.3 
Biomarkers 
ELF™ will be performed at Screening, Week 6 and Week 12.  Fibrosis biomarker pro-C3, lipid 
metabolism biomarker and insulin sensitivity & glycemic control biomarker will be measured at 
Baseline (Day 1), Week 1, Week 4, Week 8, Week 12, Week 16 and Week 20 Safety follow-up. 
ANCOVA model with treatment group, baseline hepatic fat fraction (< 15% vs ≥ 15%), and F1 
fibrosis score (F1 vs F2-3) as factors and baseline value as a covariate will be used for 
analyzing the change from baseline to Week 6 and the change from baseline to Week 12 for the 
ELF™ test score.  For other biomarkers, the same ANCOVA model will be used for analyzing 
the change from baseline to Week 12, the change from baseline to Week 16, and the change 
from baseline to Week 20.  LS means, 95% confidence intervals and p-values will be presented.  
The missing value will be imputed by LOCF method. 
Additional exploratory analyses that could enhance the understanding of the biological effects 
and the mechanism of action of AKR-001 may be added in the Biomarker Analysis Plan if 
necessary. 
3.4.3.4 
DXA scan measurements 
DXA scans measurements including bone mineral density of the lumbar spine, femoral neck, 
total hip and body fat distribution will be performed at Baseline (Day 1) and Week 16.   
An analysis will be performed on the change from baseline to Week 16 in DXA Scan 
measurements using ANCOVA model with treatment group, baseline hepatic fat fraction (< 15% 
vs ≥ 15%), and F1 fibrosis score (F1 vs F2-3) as factors and baseline value as a covariate.  LS 
means, 95% confidence intervals and two-sided p-values will be presented.  The missing value 
will be imputed by LOCF method. 
3.4.3.5 
Liver fibrosis responders 
• 
The proportion of subjects at Week 22 - 24 whose fibrosis regresses by ≥ 1-stage according to the 
NASH CRN classification; 
• 
The proportion of subjects at Week 22 - 24 who had no worsening in NAS with improvement in 
fibrosis stage;  


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• 
The proportion of subjects at Week 22 - 24 who had 2 points improvement in NAS with no 
worsening in fibrosis stage;  
• 
The proportion of subjects at Week 22 - 24 who had ≥ 1 point improvement in NAS, fibrosis, 
steatosis lobular inflammation or hepatocellular ballooning; and 
• 
The proportion of subjects at Week 22 - 24 who had ≥ 2 point decrease in NAS score with 0-1 point 
inflammation, 0 point ballooning, without worsening of fibrosis. 
The responders are defined as subjects with a ≥ 30% relative fat reduction on MRI-PDFF at 
Week 12 and required to return between Weeks 22 - 24.  Liver biopsy will be obtained at 
Screening and Week 22 - 24.  The number and percentage of the responders will be provided 
by treatment group.  Fisher’s exact test will be used for the analyses on the Liver Biopsy 
Evaluable Analysis Set.  Odds ratios, 95% confidence intervals and p-values will be provided.   
3.4.3.6 
HRQoL 
HRQoL including Short Form 36 Health Survey (SF-36), Chronic Liver Disease Questionnaire-
Nonalcoholic Fatty Liver Disease (CLDQ-NAFLD) and Work Productivity and Activity 
Impairment (WPAI) will be collected at Baseline (Day 1), Week 1, Week 4, Week 8, Week 12 
and Week 16.   
ANCOVA model with treatment group, baseline hepatic fat fraction (< 15% vs ≥ 15%), and F1 
fibrosis score (F1 vs F2-3) as factors and baseline value as a covariate will be used for 
analyzing the change from baseline to Week 12 and the change from baseline to Week 16.  LS 
means, 95% confidence intervals and p-values will be presented.  The missing value will be 
imputed by LOCF method. 
SF-36: The SF-36 asks 36 questions to measure functional health and well-being from the 
subject’s point of view.  It consists of eight health domains in the table below.  These health 
domain scales contribute to the physical health and mental health summary measures.   
The scores are weighted sums of the questions in each domain. All the raw scores will be 
transformed to scores ranging from 0 - 100.  Higher scores represent better health.  Physical 
Component Summary (PCS) is calculated by positively weighting the four subscales in the 
physical domain (PF, RP, BP and GH) and the remaining psychological domain subscales 
negatively.  In contrast, the Mental Component Summary (MCS) is calculated by positively 
weighting the four mental domain subscales (VT, SF, RE and MH), and negatively weighting the 
four physical domain subscales. 
Domains 
Number of Items 
Items 
Physical functioning (PF) 
10 
3, 4, 5, 6, 7, 8, 9, 10, 11, 12 
Role-physical (RP) 
4 
13, 14, 15, 16 
Bodily pain (BP) 
2 
21, 22 
General health (GH) 
5 
1, 33, 34, 35, 36 
Vitality (VT) 
4 
23, 27, 29, 31 
Social functioning (SF) 
2 
20, 32 
Role-emotional (RE) 
3 
17, 18, 19 
Mental health (MH) 
5 
24, 25, 26, 28, 30 
CLDQ-NAFLD: The CLDQ-NAFLD asks questions related to liver disease and specifically 
NAFLD, to measure health related quality of life in subjects with chronic liver disease.   
The questionnaire has 36 items grouped into six domains: Abdominal Symptoms, Activity, 
Emotional, Fatigue, Systemic Symptoms, and Worry.  Items are scored by a 7-point rating scale 
from 1 (all of the time) to 7 (none of the time).  The higher item values indicate better health.  


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The domain score will be calculated as dividing the sum of the domain’s items by the number of 
items within that domain.  The total score will be calculated as an average of the six domain 
scores.   
Domains 
Number of Items 
Items 
Abdominal Symptoms (AS) 
3 
1, 5, 17 
Fatigue (FA) 
6 
2, 4, 8, 11, 13, 35 
Systemic Symptoms (SS) 
6 
3, 6, 21, 23, 27, 36 
Activity (AC) 
5 
7, 9, 14, 30, 31 
Emotional Function (EF) 
9 
10, 12, 15, 16, 19, 20, 24, 26, 34 
Worry (WO) 
7 
18, 22, 25, 28, 29, 32, 33 
WPAI: The questionnaire asks questions regarding the effect of NASH on a person’s ability to 
work and perform regular activities. 
The WPAI consists of six questions: 1 = currently employed; 2 = hours missed due to specified 
problem; 3 = hours missed other reasons; 4 = hours actually worked; 5 = degree problem 
affected productivity while working; 6 = degree problem affected regular activities.  WPAI 
outcomes are expressed as impairment percentages, with higher numbers indicating greater 
impairment and less productivity.  Four main outcomes can be generated and expressed in 
percentages by multiplying the following scores by 100: 
• 
Percent work time missed due to problem:  Q2 / (Q2 + Q4) 
• 
Percent impairment while working due to problem:  Q5 / 10 
• 
Percent overall work impairment due to problem:   
Q2 / (Q2 + Q4) + [(1 - (Q2 / (Q2 + Q4))) x (Q5 / 10)] 
For those who missed work and did not actually work in the past seven days, the percent 
overall work impairment due to problem will be equal to the percent work time missed 
due to problem. 
• 
Percent activity impairment due to problem:  Q6 / 10 
3.4.3.7 
Lipoprotein profile and free fatty acids 
Lipoprotein profile including Total Cholesterol, HDL-C, LDL-C, Triglycerides, and free fatty acids 
will be measured at Screening, Baseline (Day 1), Week 1, Week 4, Week 8, Week 12, Week 16 
and Week 20 Safety follow-up.   
Non-HDL cholesterol will be calculated as Total Cholesterol - HDL-C. 
ANCOVA model with treatment group, baseline hepatic fat fraction (< 15% vs ≥ 15%), and F1 
fibrosis score (F1 vs F2-3) as factors and baseline value as a covariate will be used for 
analyzing the change from baseline to Week 12, the change from baseline to Week 16, and the 
change from baseline to Week 20.  LS means, 95% confidence intervals and p-values will be 
presented.  The missing value will be imputed by LOCF method. 
3.4.3.8 
cT1 
cT1, an MRI-based metric of liver fibro-inflammation, will be performed at Screening, Week 6, 
Week 12 and Week 22 - 24, where available.   
ANCOVA model with treatment group, baseline hepatic fat fraction (< 15% vs ≥ 15%), and F1 
fibrosis score (F1 vs F2-3) as factors and baseline value as a covariate will be used for 
analyzing the change from baseline to Week 12 and the observed change from baseline to 
Week 22 - 24.  LS means, 95% confidence intervals and p-values will be presented.  The 
missing value will be imputed by LOCF method for the change from baseline to Week 12.  No 


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imputation will be performed for the analysis of the observed change from baseline to 
Week 22 - 24.  Only subjects with non-missing baseline and Week 22 - 24 cT1 will be included.  
The analysis will be performed if data is available. 
3.4.3.9 
MRI-PDFF responders 
• 
The proportion of subjects who achieved a relative reduction of at least 50% in liver fat content as 
measured by MRI-PDFF at Week 12; 
• 
The proportion of subjects who achieved a relative reduction of at least 70% in liver fat content as 
measured by MRI-PDFF at Week 12; and 
• 
The proportion of normalized subjects whose liver fat content as measured by MRI-PDFF ≤ 5% at 
Week 12. 
The number and percentage of responders will be provided by treatment group and by 
stratification group.  Logistic regression will be used for the analyses based on FAS with missing 
values imputed as non-responders and repeated on MRI-PDFF Evaluable Analysis Set without 
imputation.  The analyses will include the treatment group and F1 fibrosis score (F1 vs F2-3) as 
factors and baseline hepatic fat fraction measured by MRI-PDFF as a covariate.  The odds ratio, 
95% confidence interval, and p-value from the logistic regression will be provided.   
3.4.4 Subgroups 
Subgroup analyses will be performed for the primary efficacy endpoint.  The group variables 
include baseline hepatic fat fraction, F1 fibrosis score, Type 2 diabetes status and baseline 
Endogenous FGF21.  
3.5 Safety Assessment 
The safety of AKR-001 will be assessed during the study through the reporting of AEs, clinical 
laboratory tests, ECG, vital sign assessments, body weight, ADA and NAB assessments, and 
concomitant medication usage.  
All safety data collected on or after the date that study drugs were first dispensed up to the date 
of last dose of study drugs plus 30 days will be summarized by treatment group.  Data for the 
follow-up period will be included in data listings. 
Safety data will be summarized by actual treatment received (and in total for selected analyses) 
based on the Safety Set unless otherwise specified. 
3.5.1 Adverse Events 
All AEs will be coded to system organ class and preferred term using MedDRA version 22.0 or 
the latest version. 
Treatment-emergent adverse events (TEAEs) are defined as one or both of the following: 
• 
Any AEs with an onset date/time on or after the study drugs start date/time and no later 
than 30 days after permanent discontinuation of study drugs 
• 
Any AEs leading to premature discontinuation of study drugs.   
Injection site reactions, diarrhea, hypoglycemia and drug-induced liver injuries (DILI) will be 
monitored as AEs of special interests (AESIs) during this study.  During the course of the study, 
additional AESIs may be identified by the Sponsor. 






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For the other parameters, the incidence of abnormalities (as defined by normal ranges) prior to 
the first dose of study drug and after the first dose of study drug will be summarized with counts 
and percentages of subjects. 
The incidence of treatment-emergent laboratory abnormalities, defined as values that increase 
at least one toxicity grade from baseline at any time post baseline up to and including the date 
of last dose of study drugs plus 30 days, will be summarized with counts and percentages of 
subjects by treatment group.  If baseline data are missing, then any graded abnormality (i.e., at 
least a Grade 1) will be considered treatment-emergent.  If no pre-treatment laboratory value is 
available, the baseline value will be assumed to be normal (i.e., no grade [Grade 0]) for the 
summary of graded laboratory abnormalities. 
Evaluation of drug-induced serious hepatotoxicity (eDISH) plot will be provided to display peak 
serum ALT and Total Bilirubin (TB) levels for each subject.  The peak serum AST versus TB 
levels for each subject will also be provided. 
3.5.3 Vital Signs 
Height will be measured without shoes at Screening.  Other vital signs (body weight, BMI, 
systolic and diastolic blood pressure, pulse, respiration rate and oral temperature) will be 
measured at each visit.  Triplicate blood pressure and heart rate will be measured at Baseline 
(Day 1) and at 48 - 96 hours post-dose on Weeks 4 and Week 8.  
Values and changes from baseline to each visit and timepoint for vital signs will be summarized 
descriptively.  Triplicate measurements will be averaged prior to summary. 
3.5.4 12-Lead Electrocardiograms 
12-lead ECG will be measured at Screening, Baseline (Day 1) and Week 16. 
Values and changes from baseline of ECG parameters (heart rate, PR interval, QRS Interval, 
QT interval, QTcB interval, QTcF interval and RR interval) and overall interpretation will be 
summarized by visit.  The number and percentage of subjects with absolute QTc interval values 
in the pre-specified categories (>450, >480, and >500 msec), and QTc interval change (>30 and 
>60 msec) will be summarized.  
3.5.5 Other Safety Assessments 
ADA, NAB and other safety data will be listed. 
3.6 Pharmacokinetic (PK) Assessment 
PK sampling will be obtained pre-dose at Baseline (Day 1), Week 1, Week 4, Week 8, Week 12, 
Week 16, Week 20 Safety follow-up and Repeat Biopsy Week 22 - 24, and at 48-96 hours post-
dose on Week 4 and Week 8. 
Plasma AKR-001 concentrations will be listed and summarized by treatment group, visit, and 
time point for the PK Analysis Set. 
3.7 Bone Biomarker Assessment 
Bone biomarkers samples (Osteocalcin, P1NP, CTX-1, BSAP, PTH, and Vitamin D) will be 
collected at Baseline (Day 1), Week 1, Week 4, Week 8, Week 12, Week 16 and Week 20 
Safety follow-up. 


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Values of bone biomarkers and changes from baseline to each visit will be summarized 
descriptively on Biomarker Analysis Set. 
4 DATA MONITORING COMMITTEE (DMC) 
An external DMC that consists of two hepatologists, one cardiologist and a statistician will 
review the progress of the study.  The DMC will convene after 20 subjects (approximately 5 per 
treatment group) have completed the Week 4 assessments.  The DMC will receive all reports of 
SAEs including potential DILI and liver decompensation events and convene as needed to 
monitor for safety.  The DMC will provide recommendations to Akero whether the nature, 
frequency, and severity of adverse effects associated with study treatment warrant the early 
termination of the study in the best interests of the participants, whether the study should 
continue as planned, or the study should continue with modifications.  The DMC may also 
provide recommendations as needed regarding study design. 
The DMC’s specific activities will be defined by a mutually agreed charter, which will define the 
DMC’s membership, conduct, and meeting schedule. 
While the DMC will be asked to advise Akero regarding future conduct of the study, including 
possible early study termination based on the stopping rules from the protocol, Akero retains 
final decision-making authority on all aspects of the study.   
5 INTERIM ANALYSIS 
No formal interim analysis is planned.  However, a primary efficacy analysis is planned after all 
subjects complete Week 12 study visit, prior to the final analyses.   
An unblinded biostatistician will be involved and send the unblinded tables to the pre-specified 
personnel only.  The unblinded individual Week 12 MRI-PDFF results will be only available for 
the unblinded personnel or team.  The individual treatments and individual Week 12 MRI-PDFF 
results must remain blinded to the study team until DBL and full study unblinding. 
The unblinded tables will be unblinded at the treatment group level, and be limited to topline 
results for efficacy and safety (i.e. primary efficacy, MRI-PDFF responders, ALT, selected 
TEAE).  Statistics that could potentially unblind at the individual level will be removed.  All the 
details will be defined in the unblinding plan. 
6 CHANGES FROM PROTOCOL-SPECIFIED STATISTICAL ANALYSES 
Additional exploratory endpoints: non-HDL cholesterol, liver fibrosis responder (≥ 2 point 
decrease in NAS score with 0-1 point inflammation, 0 point ballooning, without worsening of 
fibrosis); and MRI-PDFF responders. 
7 PROGRAMMING SPECIFICATIONS 
Analyses will be performed using SAS® version 9.4 or higher.  All available data will be 
presented in subject data listings which will be sorted by subject and visit date as applicable.  
Detailed Programming Specifications will be provided in a separate document. 
 
 


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APPENDIX A:  REFERENCES 
Sanyal A, Charles ED, Neuschwander-Tetri BA, Loomba R, Harrison SA, Abdelmalek MF, et al. 
Pegbelfermin (BMS-986036), a PEGylated fibroblast growth factor 21 analogue, in patients with 
non-alcoholic steatohepatitis: a randomised, double-blind, placebo-controlled, phase 2a trial. 
Lancet. 2019; 392(10165) :2705-2717.