Conditions: NASH - Nonalcoholic Steatohepatitis
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 128
Healthy volunteers: no

Brief summary:
This is a multi-center evaluation of efruxifermin (EFX) in a randomized, double-blind, placebo-controlled study in non-cirrhotic subjects with biopsy-proven F2 - F3 NASH.

Detailed description:

Arms:
arm 1: double-blind, once-weekly subcutaneous injection arm 2: double-blind, once-weekly subcutaneous injection arm 3: double-blind, once-weekly subcutaneous injection

Interventions: intervention 1: Efruxifermin intervention 2: Placebo
Intervention descriptions: intervention 1: subcutaneous injection intervention 2: subcutaneous injection

Protocol document:
Prot_000.pdf: 




Efr u xifer mi n  
Cli nical Trial Pr ot oc ol:  A K -U S -0 0 1 -0 1 0 2  
Pa ge 3 of 9 5  
A ker o T hera pe utics , I nc. 
C o nfi de ntial  
A me n d me nt 4, 1 8 A pr 2 0 2 2  
S Y N O P SI S  
N a me of S p o ns or C o m p a n y: A ker o T hera pe utics , I nc. 
N a me of Test Pr o d uct a n d D os a ge: E fr u xifer mi n ( E F X) 2 8 m g a n d 5 0 m g  
Title of St u d y:  
A P hase 2 b , Ra n d o mize d , D o u ble -Bli n d , Place b o -C o ntr olle d St u d y E val uati n g t he Safet y a n d Efficac y of 
Efr u xifer mi n  i n N o n -Cirr h otic S u bjects wit h N o nalc o h olic Steat o he patitis ( N A S H)  
I n vesti g at or a n d St u d y Ce nters:  
A p pr o xi matel y  5 5  ce nters i n N ort h A merica 
St u d y Peri o d: 
Parti ci pati o n will i ncl u de:  
•
Scree ni n g: 8 wee ks
•
Pri mar y E n d p oi nt  Treat me nt  D urati o n : 2 4 wee ks
•
L o n g -Ter m F oll o w -U p: U p  t o 9 6 wee ks
P h ase of De vel o p me nt: 
P hase 2 b  
O bjecti ves: 
T he pri mar y o bjecti ve of t his st u d y is: 
•
T o e val uate t he effect of E F X c o m pare d t o place b o o n fi br osis re gressi o n i n N A S H s u bjects
wit h sta ge 2 or 3 fi br osis .
T he sec o n dar y o bjecti ves of t his st u d y are: 
•
T o e val uate t he effect of E F X c o m pare d t o place b o o n ac hie vi n g  N A S H res ol uti o n  i n s u bjects
wit h sta ge 2 or 3 fi br osis .
•
T o e val uate t he effect of E F X c o m pare d t o place b o o n n o n -i n vasi ve mar kers of fi br osis.
•
T o e val uate t he effect of E F X c o m pare d t o place b o o n li p o pr otei ns.
•
T o e val uate t he effect of E F X c o m pare d t o place b o o n mar kers of gl yce mic c o ntr ol.
•
T o e val uate t he effect of E F X c o m pare d t o place b o o n  wei g ht c ha n ge.
•
T o assess t he s afet y , t olera bilit y, a n d i m m u n o ge nicit y of E F X .
E x pl orat or y o bj ecti ves are o utli ne d  i n t he pr ot oc ol  i n Secti o n  2. 3 . 
St u d y Desi g n: 
T his is a P hase 2 b , ra n d o mize d, d o u ble -bli n d , place b o -c o ntr olle d st u d y e val uati n g t he safet y a n d efficac y of 
E F X i n n o n -cirr h otic s u bjects wit h N A S H. S u bjects will be fi br osis sta ge 2 or 3 ( F 2 -3)  a n d d ose d wee kl y 
wit h E F X or place b o .  
S u bject s meeti n g t he st u d y’s eli gi bilit y  criteria will be ra n d o ml y assi g ne d i n a 1: 1: 1  rati o i nt o 3 treat me nt 
gr o u ps as s h o w n i n t he fi g ure bel o w. F oll o wi n g 2 4 wee ks of d osi n g, s u bjects will tra nsiti o n i nt o t he l o n g-
ter m safet y f oll o w-u p p orti o n of t he st u d y  a n d will be f oll o we d u ntil Wee k 9 6 . If a s u bject ref uses t o 
c o m plete  t he Wee k 2 4 li ver bi o ps y, t he s u bject will be disc o nti n ue d fr o m t he st u d y at Wee k 2 4.  O nl y a  3 0 -
D a y F oll o w -u p visit is re q uire d f oll o wi n g disc o nti n uati o n of st u d y dr u g.  After  all s u bjects ha ve c o m plete d at 
least 5 2 wee ks of treat me nt o n t heir ra n d o mize d d ose, all s u bjects ra n d o mize d t o recei ve E F X will r oll o ver 
i nt o a si n gle E F X d ose ar m  ( 2 8 m g or 5 0 m g). T he d ose will be selecte d base d o n  t he Wee k 2 4 a nal ysis a n d 
i n ali g n me nt wit h re g ulat or y a ut h orit y. 


Efr u xifer mi n  
Cli nical Trial Pr ot oc ol:  A K -U S -0 0 1 -0 1 0 2  
Pa ge 4 of 9 5   
 
 
 
A ker o T hera pe utics , I nc. 
C o nfi de ntial  
A me n d me nt 4, 1 8 A pr 2 0 2 2  
S u bjects o n place b o will re mai n i n t he sa me treat me nt gr o u p f or t he d urati o n of t he st u d y . After c o m pleti n g 
Wee k 9 6, s u bjects  o n place b o  will be offere d t he o pti o n t o recei ve E F X i n a r oll o ver st u d y.  
  
  
R a n d o miz ati o n:  
Ra n d o mizati o n will be stratifie d b y baseli ne t y pe-2 dia betes stat us a n d fi br osis sc ore . 
St u d y dr u g will be a d mi nistere d s u bc uta ne o usl y o nce wee kl y ( Q W).  
Eli gi ble s u bjects will be ra n d o mize d t o o ne of t hree treat me nt gr o u ps wit h a rati o  of  1: 1: 1  
Gr o u p A:  
Place b o  
Gr o u p B:  
2 8 m g E F X  
Gr o u p C:  
5 0 m g E F X   
N u m ber of S u bjects Pl a n ne d:  
A p pr o xi matel y 
 s u bjects  
T ar get P o p ul ati o n:  
Males a n d n o n -pre g na nt , n o n -lactati n g fe males bet wee n 1 8 – 7 5 years of a ge wit h bi o ps y pr o ve n F 2 - F 3 
N A S H.  
 
Di a g n osis a n d M ai n Criteri a f or I ncl usi o n:  
I ncl usi o n Criteria  
1.  Males a n d n o n -pre g na nt , n o n -lactati n g fe males bet wee n 1 8 - 7 5 years of a ge i ncl usi ve , at t he ti me  of t he 
scree ni n g visit. 
2.  Pre vi o us hist or y or prese nce of 2 o ut of 4 c o m p o ne nts of meta b olic s y n dr o me ( o besit y , d ysli pi de mia , 
ele vate d bl o o d press ure , ele vate d fasti n g gl uc ose) or t y pe 2 dia betes . 
3.  I niti al Scree ni n g Visit: After a si g ne d i nf or me d c o nse nt  a n d c o nfir mati o n of cli nical ris k pr ofile 
ass ociate d wit h N A S H , a scree ni n g la b pa nel a n d elast o gra p h y will be meas ure d f or all s u bjects d uri n g 
a n i nitial scree ni n g peri o d : 
a. 
Fi br o Sca n ®  me dia n li ver stiff ness 
  
b.  C A P 
 
N ote: All s u bjects m ust c o m plete a Fi br o Sca n ® e xa mi nati o n d uri n g t he scree ni n g peri o d.  
H o we ver, t he me dia n li ver stiff ness a n d C A P i ncl usi o n criteri o n  d o n ot a p pl y  t o s u bjects 


Efr u xifer mi n  
Cli nical Trial Pr ot oc ol:  A K -U S -0 0 1 -0 1 0 2  
Pa ge 5 of 9 5   
 
 
 
A ker o T hera pe utics , I nc. 
C o nfi de ntial  
A me n d me nt 4, 1 8 A pr 2 0 2 2  
wit h  an eli gi ble  hist orical li ver bi o ps y perf or me d ≤ 1 8 0 da y s pri or t o ra n d o mizati o n w hic h 
c o nfir m e d fi br osis 2- 3 a n d a N A S ≥ 4.  
 
If a hist orical val ue f or Fi br o Sca n® is a vaila ble i n t he past 3 m o nt hs pri or t o t he Scree ni n g 
Visit , t he n t he Fi br o Sca n® d oes n ot nee d t o be re peate d . 
 
c. 
A S T > 1 7 f or fe males a n d > 2 0 f or males ;  
N ote: T he A S T  i ncl usi o n criteri o n d oes n ot a p pl y t o s u bjects wit h an eli gi ble  hist orical 
li ver bi o ps y perf or me d ≤ 1 8 0 da y s pri or t o  ra n d o mizati o n w hic h c o nfir me d fi br osis 2- 3 
a n d a N A S ≥ 4 . 
d.  Esti mate d gl o mer ular filtrati o n rate (e G F R) ≥ 6 0 m L/ mi n , as calc ulate d b y t he C K D- E PI ; 
e. 
H b A 1c ≤ 9. 5 % ( or ser u m fr uct osa mi ne ≤ 3 8 1 µ m ol if H b A 1c is u na vaila ble ); 
f. 
I N R ≤ 1. 3, u nless d ue t o t hera pe utic a ntic oa g ulati o n;  
g.  Direct bilir u bi n ≤ U L N; 
h.  T otal bilir u bi n ≤ u p per li mit of n or mal ( U L N) , u nless d ue t o a n alter nate eti ol o g y s uc h as 
Gil bert ’s s y n dr o me or he m ol ytic a ne mia; 
i. 
Creati ni ne ki nase < 3 x U L N;  
j. 
Platelet c o u nt ≥ 1 4 0 ,0 0 0/ µ L;  
k.  T ri gl yceri de le vel ≤ 5 0 0 m g/ d L; 
l. 
A L T < 5 x U L N;  
m.  A S T <  5 x U L N;  
n.  A L P < 2 x U L N.  
N ote: S u bjects meeti n g all of t he a b o ve c o m p o ne nts will m o ve i nt o t he ne xt scree ni n g p hase. 
4.  D oc u me nte d hist orical sta bilit y ( 4 wee ks t o 6 m o nt hs pri or t o scree ni n g) of A L T a n d A S T le vels 
s h o wi n g n o w orse ni n g at scree ni n g base d o n t he f oll o wi n g:  
a. 
If t he hist orical a n d scree ni n g A L T a n d A S T val ues are b ot h ≤ 1. 5 × t he u p per li mit of 
n or mal ( U L N) , t here is n o li mit t o t he differe nce bet wee n t he val ues.  
b.  If at least 1 of t he hist orical val ues of A L T or A S T is > 1. 5 × U L N a n d s h o ws w orse ni n g at 
scree ni n g, t he differe nce of A L T a n d A S T val ues m ust be ≤ 5 0 %.  
 
N ote: S u bjects wit h o ut  hist orical A L T a n d A S T e val uati o ns ma y ha ve A L T a n d A S T re peate d 
( Pre-Baseli ne Visit) d uri n g t he scree ni n g peri o d at mi ni m u m  4 wee ks a part  t o c o nfir m a or b 
a b o ve; 
 
S u bjects w h o are i neli gi ble at t he scree ni n g or pr e-baseli ne visit ma y be re -scree ne d or ha ve a n 
assess me nt re peate d o nce if t here is reas o na ble belief t hat t he e xcl usi o nar y res ult was o btai ne d i n err or 
or is tra nsie nt u p o n a p pr o val of t he Me dical M o nit or . 
 
5.  M RI -P D F F 
 
N ote: All s u bjects m ust c o m plete a n M RI -P D F F e xa mi nati o n d uri n g t he scree ni n g peri o d.  H o we ver, t he 
M RI -P D F F  i ncl usi o n criteri o n d oes n ot a p pl y t o s u bjects wit h an eli gi ble  hist orical li ver bi o ps y 
perf or me d ≤ 1 8 0 da y s pri or t o  ra n d o mizati o n w hic h c o nfir m e d fi br osis 2- 3 a n d a N A S ≥ 4.  
 
6.  Bi o ps y -pr o ve n N A S H. M ust ha ve ha d a  li ver bi o ps y o btai ne d  ≤ 1 8 0 da ys pri or t o  ra n d o mizati o n wit h 
fi br osis sta ge 2 t o 3 a n d a n o n-alc o h olic fatt y li ver disease ( N A F L D) acti vit y sc ore ( N A S) of ≥ 4 wit h at 
least a sc ore of 1 i n eac h of t he f oll o wi n g N A S c o m p o ne nts:  
a. 
Steat osis (sc ore d 0 t o 3) , 
b.  Ball o o ni n g de ge nerati o n (sc ore d 0 t o 2) , a n d 
c. 
L o b ular i nfla m mati o n (sc ore d 0 t o 3)  
 


Efr u xifer mi n  
Cli nical Trial Pr ot oc ol:  A K -U S -0 0 1 -0 1 0 2  
Pa ge 6 of 9 5  
A ker o T hera pe utics , I nc. 
C o nfi de ntial  
A me n d me nt 4, 1 8 A pr 2 0 2 2  
7.
S u bjects  o n  Vita mi n  E  ≥ 4 0 0  I U/ da y, thiaz oli di ne di o nes  (i ncl u di n g, but  n ot  li mite d t o, pi o glitaz o ne, 
r osi glitaz o ne, an d  l o be glitaz o ne), G L P- 1 ag o nists , or S G L T 2  i n hi bit ors m ust  be  o n a sta ble d ose
( defi ned as n o si g nifica nt c ha n ge  in prescri pti o n  efficac y, i nitiati o n of  me dicati o n , or  me dicati o n 
disc o nti n uati o n)  f or at least 3 m o nt hs  pri or  to t he dia g n ostic  li ver bi o ps y t hr o u g h ra n d o mizati o n. A 
s witc h fr o m o n e dr u g  t o a n ot her i n t he sa me class s h o ul d be  disc usse d wit h  t he Me dical  M o nit or  t o 
c o nfir m eli gi bilit y.
8.
S u bjects  o n  a nti dia betic, wei g ht  loss , or  li pi d- mo dif yi n g me dicati o n(s)  m ust  be  o n sta ble d ose(s)  f or at 
least 3 m o nt hs  pri or  to t he dia g n ostic  li ver bi o ps y t hr o u gh ra n d o mizati o n;
9.  
Willi n g a nd a ble to gi ve  writte n i nf or med c o nse nt  pri or  t o a n y st u dy s pecific pr oce d ures  bei n g 
perf or me d .
1 0. Fe male  s u bjects of  c hil d beari n g  p ote ntial  (see defi niti o n  i n A p pe n di x D ) m ust  ha v e a ne gati ve 
pre g na nc y test at scree ni n g a nd Baseli ne / Da y 1 .
1 1. Mal e a n d fe male s u bjects of  c hil d beari n g  p ote ntial  wh o  e n ga ge i n heter ose x ual  interc o urs e m ust  agr ee t o 
use  pr ot oc ol  s pecified met h o d(s)  of  c o ntrace pti o n  as descri be d  i n A p pe n dix D.
E xcl usi o n Criteria : 
1.
Wei g ht l oss > 5 % i n t he 3 m o nt hs pri or t o scree ni n g u ntil ra n d o mizati o n or fr o m t he ti me of t he
dia g n ostic li ver bi o ps y u ntil  ra n d o mizati o n, w hic he ver is l o n ger .
2.
Prese nce of cirr h osis o n li ver bi o ps y (sta ge 4 fi br osis).
3.
T y pe 1 dia betes.
4.
U nc o ntr olle d T y pe 2  dia betes defi ne d as:
a.
I ns uli n d ose a dj ust me nt >3 5 % wit hi n 3 0 da ys pri or t o scree ni n g t hr o u g h ra n d o mizati o n,
b.
S y m pt o ms of t he f oll o wi n g wit hi n 3 m o nt hs pri or t o scree ni n g: ac utel y dec o m pe nsate d bl o o d
gl uc ose c o ntr ol ( e. g., t hirst, p ol y uria , wei g ht l oss) , or a hist or y of dia betic ket oaci d osis , or a hist or y
of h y per gl yce mic h y per os m olar state;
5.
H y p o gl yce mia u na ware ness , h os pitalizati o n d ue t o h y p o gl yce mia , or hist or y of se vere h y p o gl yce mia
(h y p o gl yce mia re q uiri n g o utsi de assista nce t o re gai n n or mal ne ur ol o gic stat us) wit hi n 3 m o nt hs pri or t o
scree ni n g.
6.
S u bjects wit h oste o p or osis , defi ne d as a T -sc ore of -2. 5 or l o wer at scree ni n g.
7.
P o orl y c o ntr olle d h y perte nsi o n ( s yst olic > 1 6 0  m m H g , or diast olic bl o o d press ure > 1 0 0  m m H g ).
8.
A n y pri or hist or y of dec o m pe nsate d li ver disease i ncl u di n g ascites , he patic e nce p hal o pat h y ( H E) , or
variceal blee di n g.
9.
Hist or y of pa ncreatitis .
N ote: S u bjects wit h a hist or y of gallst o ne pa ncreatitis  a n d s u bse q ue nt c h olec ystect o m y ma y be all o we d
t o partici pate u p o n a p pr o val b y  the Me dical M o nit or .
1 0. C hr o nic he patitis B vir us ( H B V) i nfecti o n  ( he patitis B s urface a nti ge n [ H Bs A g]) p ositi ve  or ac ute
he patitis A i nfecti o n ( he patitis A I g M a nti b o d y p ositi ve ).
1 1. C hr o nic he patitis C vir us ( H C V) i nfecti o n ( H C V a nti b o d y [ A b] a n d H C V  ri b o n ucleic aci d [ R N A]
p ositi ve). S u bjects c ure d of H C V i nfecti o n < 2 years pri or ( base d o n date of R N A p ol y merase c hai n
reacti o n [ P C R] ne gati ve c o nfir mati o n f oll o wi n g c o ncl usi o n of treatme nt) t o t he scree ni n g visit are n ot
eli gi ble.
1 2. Pri or  ( < 2 years pri or t o scree ni n g) or pla n ne d ( d uri n g t he st u d y peri o d) bariatric s ur ger y (e. g. ,
gastr o plast y , r o u x-e n-Y gastric b y pass) .  Sur ger y fail ure or re versal or re m o val of i ntra gastric ball o o n >
2 y ears pri or t o scree ni n g w o ul d be acce pta ble .
1 3. Ot her ca uses of li ver disease base d o n me dical hist or y a n d/ or ce ntralize d re vie w of li ver hist ol o g y ,
i ncl u di n g b ut n ot li mite d t o: alc o h olic li ver disease, a ut oi m m u ne dis or ders (e. g. , pri mar y biliar y
c h ola n gitis [ P B C], pri mar y scler osi n g c h ola n gitis [ P S C] , a ut oi m m u ne he patitis) , dr u g -i n d uce d
he pat ot o xicit y , Wils o n disease , cli nicall y si g nifica nt ir o n o verl oa d , or al p ha - 1-a ntitr ys pi n deficie nc y
re q uiri n g treat me nt.
1 4. Hist or y of li ver tra ns pla ntati o n.
1 5. C urre nt or pri or hist or y of he pat ocell ular carci n o ma ( H C C).
1 6. Hist or y of si g nifica nt alc o h ol c o ns u m pti o n f or a peri o d of m ore t ha n 3 c o nsec uti ve m o nt hs wit hi n 1 year
pri or t o scree ni n g;


Efr u xifer mi n  
Cli nical Trial Pr ot oc ol:  A K -U S -0 0 1 -0 1 0 2  
Pa ge 7 of 9 5   
 
 
 
A ker o T hera pe utics , I nc. 
C o nfi de ntial  
A me n d me nt 4, 1 8 A pr 2 0 2 2  
N ote: Si g nifica nt alc o h ol c o ns u m pti o n is defi ne d as a vera ge of > 2 0 g/ da y  i n fe male s u bjects a n d > 3 0 
g/ da y i n male s u bjects. 
1 7.  H u ma n i m m u n o deficie nc y vir us ( HI V) i nfecti o n.  
1 8.  U nc o ntr olle d car diac arr h yt h mia , or  c o nfir me d Q T i nter val c orrecte d usi n g Fri dericia’s f or m ula ( Q Tc F) 
> 4 5 0 msec f or males a n d > 4 7 0 msec f or fe males at t he scr ee ni n g electr ocar di o gra m ( E C G) assess me nt;  
1 9.  M y ocar dial i nfarcti o n , u nsta ble a n gi na , perc uta ne o us c or o nar y i nter ve nti o n , c or o nar y arter y b y pass 
graft , or str o ke wit hi n 3 m o nt hs pri or t o scree ni n g. 
2 0.  Life e x pecta nc y less t ha n 2 years.  
2 1.  Use of a n y i n vesti gati o nal  me dicati o n wit hi n 3 0 da ys or wit hi n 5 half -li ves pri or t o scree ni n g or 
c o nc urre nt partici pati o n i n a n ot her t hera pe utic cli nical st u d y . Partici pati o n i n a n e x peri me ntal vacci ne 
trial (e. g., C O VI D -1 9 or ot her) ma y be acce pta ble u p o n a p pr o val b y t he me dical m o nit or.  
2 2.  S u bjects wit h a hist or y of ( wit hi n  1 2 m o nt hs pri or t o scree ni n g) or c urre nt use of prescri pti o n dr u gs 
ass ociate d wit h li ver steat osis ( e. g., met h otre xate , a mi o dar o ne , hi g h -d ose est r o ge n, ta m o xife n, s yste mic 
ster oi ds, a na b olic ster oi ds , val pr oic aci d). S h ort c o urses of s yste mic c ortic oster oi ds (less t ha n t w o 
wee ks) a n d p h ysi ol o gical h or m o ne re place me nt t hera p y ma y be all o we d pri or t o scree ni n g if i n t he 
I n vesti gat or’s o pi ni o n t he y are n ot ass ociate d wit h li ver steat osis or cli nicall y rele va nt;  
2 3.  P ositi ve uri ne dr u g scree n f or a m p heta mi nes , c ocai ne or o piates (e. g. , her oi n , m or p hi ne) at scree ni n g. 
S u bjects o n sta ble met ha d o ne or b u pre n or p hi ne mai nte na nce treat me nt f or at least 6 m o nt hs pri or t o 
scree ni n g ma y be i ncl u de d i n t he st u d y. S u bjects wit h a p ositi ve uri ne dr u g scree n d ue t o prescri pti o n 
me dicati o n (e. g. , o piates , met h yl p he ni date) are eli gi ble if t he prescri pti o n a n d dia g n osis are re vie we d 
a n d a p pr o ve d b y t he I n vesti gat or.  
2 4.  U na ble t o safel y u n der g o a li ver bi o ps y. 
2 5.  S u bjects w h o ha ve c o ntrai n dicati o ns t o M R i ma gi n g (e. g. , u n ma na gea ble cla ustr o p h o bia , certai n metal 
i m pla nts, or u na ble t o fit wit hi n M R sca n ner d ue t o girt h).  
2 6.  Prese nce of a n y la b orat or y a b n or malit y or si g nifica nt s yste mic  or maj or ill nesses ( ot her t ha n li ver 
disease) t hat , i n t he o pi ni o n of t he I n vesti gat or, c o m pr o mise t he s u bject’s a bilit y t o safel y partici pate i n 
a n d c o m plete t he st u d y i ncl u di n g , b ut n ot li mite d t o :  
a. 
P ul m o nar y disease , heart fail ure , re nal fail ure, or ga n  tra ns pla ntati o n, seri o us ps yc hiatric disease, 
mali g na nc y , hist or y of s u bsta nce a b use a n d/ or a ps yc hiatric c o n diti o n re q uiri n g h os pitalizati o n 
a n d/ or e mer ge nc y r o o m visit wit hi n si x m o nt hs of scree ni n g.  
2 7.  U na vaila ble f or f oll o w -u p assess me nt or c o ncer n f or s u bject’s c o m plia nce wit h t he pr ot oc ol pr oce d ures . 
I n vesti g ati o n al Pr o d uct, D os a ge , a n d M o de of A d mi nistr ati o n:  
E F X is a n I g G 1 Fc-fi br o blast gr o wt h fact or 2 1 ( F G F 2 1) f usi o n pr otei n.   
 
E F X or Place b o will be pr o vi de d  as a fr oze n li q ui d f or m ulati o n a n d is a d mi nistere d s u bc uta ne o usl y i n t he 
a b d o me n  as f oll o ws: 
•  
Place b o Q W ( n = 4 0 ) 
•  
2 8 m g E F X  Q W ( n = 4 0 ) 
•  
5 0 m g E F X  Q W ( n = 4 0 ) 
 
Criteri a f or E v al u ati o n:  
S afet y:  
T he safet y of E F X  will be assesse d d uri n g t he st u d y t hr o u g h t he re p orti n g of a d verse e ve nts ( A Es) , cli nical 
la b orat or y tests, electr ocar di o gra m ( E C G) , B o ne Mi neral De nsit y ( B M D) , vital si g n assess me nts , b o d y 
wei g ht , a nti-dr u g a nti b o d y ( A D A) a n d ne utralizi n g a nti b o d y ( N A B) assess me nts, a n d c o nc o mita nt 
me dicati o n usa ge.  
A n e xter nal Data M o nit ori n g C o m mittee ( D M C) t hat c o nsists of t w o he pat ol o gists , o ne car di ol o gist , a n d a 
statisticia n will re vie w t he pr o gress of t he st u d y. T he D M C will c o n ve ne after 4 5 s u bjects (a p pr o xi matel y 1 5  
per treat me nt gr o u p) ha ve c o m plete d t he Wee k 1 2 assess me nts. T he D M C will recei ve all re p orts of seri o us 


Efr u xifer mi n  
Cli nical Trial Pr ot oc ol:  A K -U S -0 0 1 -0 1 0 2  
Pa ge 8 of 9 5   
 
 
 
A ker o T hera pe utics , I nc. 
C o nfi de ntial  
A me n d me nt 4, 1 8 A pr 2 0 2 2  
a d verse e ve nts ( S A Es) , p ote ntial dr u g -i n d uce d li ver i nj ur y ( DI LI) e ve nts f or e val uati o n a n d c o n ve ne as 
nee de d t o m o nit or f or safet y  a n d a d diti o nal meeti n gs will be sc he d ule d as re q uire d .   
 
T hr o u g h o ut t he st u d y , all treat me nt -e mer ge nt a d verse e ve nts ( T E A Es) , cli nical assess me nts , cli nical 
la b orat or y para meters , a n d p ote ntial DI LI  will be cl osel y m o nit ore d wit h s u bjects e nteri n g cl ose o bser vati o n , 
as re q uire d . 
 
P h ar m ac o ki netics:  
Bl o o d f or p har mac o ki netics ( P K) will be c ollecte d at s pecifie d ti me p oi nts after d osi n g as o utli ne d i n t he 
Sc he d ule of Assess me nts ( Sc he d ule of Assess me nts ) a n d will be use d t o esti mate stea d y state P K para meters 
(i.e., Tma x , Cma x , Ctr o u g h, A U C 0-t, t½ , C L/ F , Vz/ F) f oll o wi n g s u bc uta ne o us ( S C) a d mi nistrati o n of E F X . 
 
Effic ac y:   
T he pri mar y efficac y e n d p oi nt at Wee k 2 4  i ncl u des t he pr o p orti o n of s u bjects w h o ac hie ve i m pr o ve me nt i n 
li ver fi br osis, defi ne d as ≥ o ne sta ge  ( N A S H C R N fi br osis sc ore) a n d n o w orse ni n g of steat o he patitis 
( defi ne d as n o  i ncrease i n N A S f or ball o o ni n g , i nfla m mati o n, or steat osis ). 
 
S u bjects will be f oll o we d f or l o n g -ter m safet y a n d e x pl orat or y e val uati o n of cli nical o utc o mes f or 
a p pr o xi matel y 9 6 wee ks.    
 
Sec o n d ar y E n d p oi nts:  
•  
Pr o p orti o n  of s u bjects w h o ac hie ve res ol uti o n of steat o he patitis ( defi ne d as a N A S of 0 -1 f or 
i nfla m mati o n, 0 f or ball o o ni n g , a n d a n y val ue f or steat osis) a n d n o w orse ni n g of li ver fi br osis as 
deter mi ne d b y t he N A S H C R N criteria at Wee k 2 4  a n d Wee k 9 6.   
•  
P r o p orti o n of s u bjects w h o ac hie ve i m pr o ve me nt i n li ver fi br osis , defi ne d as ≥ o ne sta ge ( N A S H 
C R N fi br osis s c ore) a n d n o w orse ni n g of steat o he patitis ( defi ne d as n o i ncrease i n N A S f or 
ball o o ni n g , i nfla m mati o n, or steat osis) at Wee k 9 6 . 
•  
P r o p orti o n of s u bjects w h o ac hie ve i m pr o ve me nt i n li ver fi br osis , defi ne d as ≥ o ne sta ge ( N A S H 
C R N fi br osis sc ore) at Wee k 2 4 an d Wee k 9 6.  
•  
C ha n ge fr o m baseli ne i n he patic fat fracti o n meas ure d b y M RI -P D F F at Wee k 2 4  a n d Wee k 9 6 .  
•  
C ha n ge fr o m baseli ne of  li p o pr otei ns – tri gl yceri des, N o n -H D L - C, H D L -C a n d L D L -C.   
•  
C ha n ge fr o m baseli ne of mar kers of  gl yce mic c o ntr ol – H b A 1c , C-pe pti d e, A di p o necti n  a n d 
H O M A -I R. 
•  
C ha n ge fr o m baseli ne  i n n o n-i n vasi ve mar kers of fi br osis – E L F, Pr o -C 3 , C 3 M , NI S - 4 a n d li ver 
stiff ness assesse d b y tra nsie nt elast o gra p h y (Fi br o Sca n ® ). 
•  
C ha n ge fr o m baseli ne of b o d y wei g ht.  
 
Li ver bi o psies will be se nt t o a ce ntral la b orat or y a n d t he n rea d b y t w o i n de pe n de nt pat h ol o gists i n a bli n de d 
ma n ner. Wee k 2 4 a n d e n d  of treat me nt bi o psies will be c o m bi ne d wit h  baseli ne bi o psies  a n d rea d b y b ot h 
pat h ol o gists i n a bli n de d ma n ner  (b ut n ot paire d).  
 
E xter nal a dj u dicati o n c o m mittee s will  be esta blis he d t o a dj u dicate cases t hat meet pr ot oc ol -defi ne d criteria 
f or li ver-relate d e ve nts a n d f or car di o vasc ular -relate d e ve nts.   
 
T he D M C  will m o nit or st u d y pr o gress , trac ki n g t he act ual a n n ual e ve nt rate f or t he o utc o mes e n d p oi nt 
c o m pare d wit h t he ass u me d pre vale nce rate per year.  
 


Efr u xifer mi n  
Cli nical Trial Pr ot oc ol:  A K -U S -0 0 1 -0 1 0 2  
Pa ge 9 of 9 5   
 
 
 
A ker o T hera pe utics , I nc. 
C o nfi de ntial  
A me n d me nt 4, 1 8 A pr 2 0 2 2  
S a m ple Size C alc ul ati o n:  
T he pri mar y e n d p oi nt is t he perce nta ge of s u bjects wit h i m pr o ve me nt i n li ver fi br osis ≥ o ne sta ge a n d n o 
w orse n i n g of steat o he patitis at Wee k 2 4 . It is pre dicte d
 of s u bjects will  reac h t his e n d p oi nt f or t he 
place b o gr o u p , base d o n p u blis he d res ults. Base d o n  p hase 2a B A L A N C E D st u d y of E F X  it is esti mate d t hat 
a p pr o xi matel y 
s u bjects of eac h E F X  d ose gr o u p will reac h t his e n d p oi nt. Wit h t w o -si de d Pears o n c hi-
s q uare test f or pr o p orti o n differe nce, at a si g nifica nce le vel of 
 c o m plete d s u bjects per gr o u p will 
pr o vi de at least 
 p o wer. Fact ori n g i n  dr o p o ut s, t he st u d y pla ns t o ra n d o mize at least
 s u bjects i n t otal 
(  s u bjects per gr o u p). 
St atistic al Met h o ds:  
P o p ul ati o n:  
T he a nal ysis set f or t he n o n-hist ol o gical efficac y a nal yses will be t he F ull 
A nal ysis Set ( F A S), w hic h i ncl u des all s u bjects w h o were ra n d o mize d t o t he 
st u d y. T he a nal ysis set f or t he hist ol o gical efficac y a nal yses will be t he Li ver 
Bi o ps y  A nal ysis Set ( L B A S) w hic h will be a s u bset of t he F A S. T he L B A S will 
i ncl u de all F A S s u bjects w h o ha ve baseli ne a n d o n-st u d y li ver bi o ps y res ults. 
T he a nal ysis set f or safet y a nal yses will be t he Safet y Set w hic h i ncl u des all 
s u bjects w h o recei ve d at least o ne d ose of st u d y dr u g. 
Effic ac y A n al ysis:  
Pri m ar y Effic ac y A n al ysis: A C oc hra n -Ma ntel -Hae nszel ( C M H)  test will be 
use d t o c o m pare t he differe nces i n pr o p orti o n of s u bjects w h o ac hie ve a ≥ 1 -
sta ge i m pr o ve me nt i n fi br osis wit h o ut w orse ni n g of steat o he patitis at Wee k 2 4  
(bet wee n t he E F X ar m a n d t he place b o ar m , a dj usti n g f or stratificati o n fa ct ors. 
T he p oi nt esti mates a n d 
 c o nfi de nce i nter vals f or t he differe nces i n 
pr o p orti o ns will be calc ulate d .  
 
 
Sec o n d ar y Effic ac y A n al ysis: F or sec o n dar y e n d p oi nts , s uc h as res ol uti o n of 
steat o he patitis a n d n o w orse ni n g of li ver fi br osis, t he sa me stratifie d C M H test 
will be perf or me d t o c o m pare t he differe nces i n pr o p orti o ns bet wee n t he E F X 
ar m a n d t he place b o ar m . F or c o nti n u o us l y varia ble meas ures of  efficac y , 
a nal ysis of c o varia nce will be use d i nstea d.   
P h ar m ac o ki netic 
A n al ysis:  
Plas ma c o nce ntrati o ns of E F X  will be liste d a n d s u m marize d.  
 
Detaile d descri pti o n of data a nal ysis a n d statistical met h o ds t o be use d will be o utli ne d se paratel y i n a 
Statistical A nal ysis Pla n ( S A P).  
 
T his st u d y will be c o n d ucte d i n acc or da nce wit h t he g ui deli nes of G o o d Cli nical Practice 
( G C P) i ncl u di n g arc hi vi n g of esse ntial d oc u me nts. 
 
 


Efr u xifer mi n  
Cli nical Trial Pr ot oc ol:  A K -U S -0 0 1 -0 1 0 2  
Pa ge 1 0  of 9 5   
 
 
 
A ker o T hera pe utics , I nc. 
C o nfi de ntial  
A me n d me nt 4, 1 8 A pr 2 0 2 2  
T A B L E O F C O N T E N T S  
S T U D Y A C K N O W L E D G E M E N T  SI G N A T U R E P A G E  ........................................................ 2 
S Y N O P SI S  ................................................................................................................................. 3 
T A B L E O F C O N T E N T S  ......................................................................................................... 1 0 
LI S T O F T A B L E S  ................................................................................................................... 1 4 
LI S T O F A P P E N DI C E S  .......................................................................................................... 1 4 
LI S T O F A B B R E VI A TI O N S A N D D E FI NI TI O N S O F T E R M S  .......................................... 1 4 
1.  
B A C K G R O U N D A N D R A TI O N A L E  .......................................................................... 1 9 
1. 1.  
Bac k gr o u n d .................................................................................................................. 1 9  
1. 1. 1.  
F G F 2 1  .................................................................................................................... 1 9 
1. 2.  
Efr u xifer mi n Bac k gr o u n d ............................................................................................ 2 0  
1. 3.  
N o ncli nical P har mac ol o g y & T o xic ol o g y ................................................................... 2 1  
1. 4.  
Cli nical Trials of Efr u xifer mi n  .................................................................................... 2 3 
1. 4. 1.  
St u d y A K- U S - 0 0 1- 0 1 0 1 - P hase 2a , Ra n d o mize d, D o u ble-Bli n d , Place b o -
C o ntr olle d St u d y E val uati n g t he Safet y a n d Efficac y of E F X i n S u bjects 
wit h N o nalc o h olic Steat o he patitis ( N A S H) ........................................................... 2 3  
1. 4. 1. 1.  
S u bject Dis p ositi o n  .......................................................................................... 2 3 
1. 4. 1. 2.  
Safet y Res ults  ................................................................................................... 2 3 
1. 4. 1. 3.  
Efficac y Res ults  ............................................................................................... 2 4 
1. 4. 1. 4.  
C o ncl usi o n ....................................................................................................... 2 7  
1. 5.  
P har mac o ki netic Res ults  .............................................................................................. 2 8 
1. 6.  
Rati o nale f or t his St u d y  ............................................................................................... 2 8 
1. 7.  
Rati o nale f or Selecti o n of D ose  ................................................................................... 3 0 
1. 8.  
C o m plia nce .................................................................................................................. 3 1  
2.  
S T U D Y O BJ E C TI V E S  .................................................................................................. 3 2 
2. 1.  
Pri mar y O bjecti ves  ....................................................................................................... 3 2 
2. 2.  
Sec o n dar y O bjecti ves  ................................................................................................... 3 2 
2. 3.  
E x pl orat or y O bjecti ves  ................................................................................................ 3 2 
3.  
I N V E S TI G A TI O N A L P L A N ........................................................................................ 3 4 
3. 1.  
O verall St u d y Desi g n a n d Pla n .................................................................................... 3 4  
3. 2.  
St u d y D urati o n a n d N u m ber of Ce nters....................................................................... 3 5  
3. 3.  
Earl y Ter mi nati o n  ........................................................................................................ 3 5 
3. 4.  
3 0- Da y F oll o w- u p ........................................................................................................ 3 5  
3. 5.  
P ost St u d y Care  ............................................................................................................ 3 5 
4.  
S T U D Y P O P U L A TI O N S E L E C TI O N  .......................................................................... 3 6 


Efr u xifer mi n  
Cli nical Trial Pr ot oc ol:  A K -U S -0 0 1 -0 1 0 2  
Pa ge 1 1  of 9 5   
 
 
 
A ker o T hera pe utics , I nc. 
C o nfi de ntial  
A me n d me nt 4, 1 8 A pr 2 0 2 2  
4. 1.  
St u d y P o p ulati o n .......................................................................................................... 3 6  
4. 2.  
I ncl usi o n Criteria ......................................................................................................... 3 6 
4. 3.  
E xcl usi o n Criteria  ........................................................................................................ 3 8 
5.  
I N V E S TIG A TI O N A L M E DI CI N A L P R O D U C T S (I M P)  ............................................ 4 1 
5. 1.  
Ra n d o mizati o n , Bli n di n g a n d Treat me nt C o des .......................................................... 4 1 
5. 1. 1.  
Pr oce d ures f or Brea ki n g Treat me nt C o des  ............................................................ 4 1 
5. 2.  
I n vesti gati o nal Me dici nal Pr o d uct(s) ........................................................................... 4 1 
5. 2. 1.  
St ora ge a n d Ha n dli n g  ............................................................................................. 4 2 
5. 2. 2.  
D osa ge a n d A d mi nistrati o n.................................................................................... 4 2  
5. 3.  
Pri or a n d C o nc o mita nt Me dicati o ns ............................................................................ 4 3  
5. 4.  
I n vesti gati o nal Me dici nal Pr o d uct Acc o u nta bilit y ...................................................... 4 5 
5. 4. 1.  
I n vesti gati o nal Me dici nal Pr o d uct Ret ur n or Dis p osal .......................................... 4 5 
6.  
S T U D Y P R O C E D U R E S  ................................................................................................ 4 6 
6. 1.  
St u d y Pr o ce d ures i n Case of Crisis Sit uati o ns  ............................................................. 4 6 
6. 2.  
Scree ni n g a n d I nf or me d C o nse nt ................................................................................. 4 7  
6. 3.  
De m o gra p hics a n d Me dical Hist or y  ............................................................................ 4 7 
6. 4.  
P h ysical E xa mi nati o n ................................................................................................... 4 7 
6. 5.  
Vit al Si g ns, Wei g ht, Hi p a n d Waist Circ u mfere nce  .................................................... 4 8 
6. 6.  
1 2- Lea d Electr ocar di o gra p h y ....................................................................................... 4 8  
6. 7.  
Tra nsie nt Elast o gra p h y ( Fi br o Sca n ® ) .......................................................................... 4 9 
6. 8.  
Li ver Bi o ps y................................................................................................................. 4 9  
6. 9.  
M RI -P D F F  ................................................................................................................... 5 0 
6. 1 0.  D X A Sca n  .................................................................................................................... 5 0 
6. 1 1.  C hr o nic Li ver Disease Q uesti o n naire - N o nalc o h olic Steat o he patitis 
( C L D Q-N A S H)  ............................................................................................................ 5 1 
6. 1 2.  Lifest yle G ui da nce  ....................................................................................................... 5 1 
6. 1 3.  Cli nical La b orat or y Tests  ............................................................................................. 5 1 
6. 1 3. 1.  
La b orat or y Para meters  ........................................................................................... 5 1 
6. 1 4.  Sa m ple C ollecti o n , St ora ge, a n d S hi p pi n g .................................................................. 5 3 
6. 1 5.  P har mac o ki netic Assess me nts  ..................................................................................... 5 3 
6. 1 5. 1 
5 3  
6. 1 6.  A nti - Dr u g A nti b o d y a n d Ne utralizi n g A nti b o d y Sa m pli n g......................................... 5 3 
6. 1 7.  Bl o o d St ora ge............................................................................................................... 5 4  
6. 1 8.  Bi o mar kers  ................................................................................................................... 5 4 
6. 1 9.  S u bject Rete nti o n ......................................................................................................... 5 4  
6. 2 0.  Criteria f or Disc o nti n uati o n of St u d y Dr u g  ................................................................. 5 5 


Efr u xifer mi n  
Cli nical Trial Pr ot oc ol:  A K -U S -0 0 1 -0 1 0 2  
Pa ge 1 2  of 9 5   
 
 
 
A ker o T hera pe utics , I nc. 
C o nfi de ntial  
A me n d me nt 4, 1 8 A pr 2 0 2 2  
6. 2 1.  I nterr u pti o n of St u d y Dr u g ........................................................................................... 5 6 
6. 2 2.  A d verse E ve nts ............................................................................................................ 5 6  
6. 2 2. 1.  
Se verit y  .................................................................................................................. 5 7 
6. 2 2. 2.  
Relati o ns hi p  ........................................................................................................... 5 7 
6. 2 2. 3.  
St u d y St o p pi n g R ules ............................................................................................. 5 8  
6. 2 2. 4.  
O ver d ose ................................................................................................................ 5 8  
6. 2 2. 5.  
Seri o us A d verse E ve nts  ......................................................................................... 5 8 
6. 2 2. 5. 1.  
Defi niti o n  ......................................................................................................... 5 8 
6. 2 2. 6.  
Re p orti n g A d verse E ve nts ..................................................................................... 5 9  
6. 2 2. 6. 1.  
Re p orti n g Pr oce d ures f or N o n- Seri o us A d verse E ve nts  .................................. 5 9 
6. 2 2. 6. 2.  
Re p orti n g Pr oce d ures Seri o us A d verse E ve nts................................................ 5 9  
6. 2 3.  A d verse E ve nts of S pecial I nterest  .............................................................................. 6 1 
6. 2 4.  Cli nical La b orat or y A b n or malities a n d Ot her A b n or mal Assess me nts as 
A d verse E ve nts or Seri o us E ve nts ............................................................................... 6 2  
6. 2 5.  A dj u dicati o n C o m mittees  ............................................................................................ 6 3 
6. 2 5. 1.  
He patic E ve nts A dj u dicati o n C o m mittee  ............................................................... 6 3 
6. 2 5. 2.  
Car di o vasc ular E ve nts A dj u dicati o n C o m mittee  ................................................... 6 4 
6. 2 6.  O bser vati o n f or Dr u g I n d uce d Li ver I nj ur y ( DI LI)  ..................................................... 6 4 
6. 2 6. 1.  
S u bjects wit h N or mal Li ver Tra nsa mi nases a n d Bilir u bi n at Baseli ne  ................. 6 5 
6. 2 6. 2.  
S u bjects wit h Ele vati o ns i n Li ver Tra nsa mi nases or Bilir u bi n at Baseli ne  ........... 6 5 
6. 2 6. 3.  
Cl ose O bser vati o n f or S us pecte d Dr u g- I n d uce d Li ver I nj ur y ............................... 6 6 
6. 2 7.  Re m o val of S u bjects fr o m t he St u d y  ........................................................................... 6 7 
7.  
P L A N N E D S T A TI S TI C A L M E T H O D S  ....................................................................... 6 8 
7. 1.  
E n d p oi nts ..................................................................................................................... 6 8  
7. 1. 1.  
Efficac y E n d p oi nts ................................................................................................. 6 8  
7. 1. 1. 1.  
Pri mar y E n d p oi nt ............................................................................................. 6 8  
7. 1. 1. 2.  
Sec o n dar y E n d p oi nts ....................................................................................... 6 8  
7. 1. 1. 3.  
E x pl orat or y Efficac y  E n d p oi nts ....................................................................... 6 8  
7. 1. 2.  
Safet y E n d p oi nts .................................................................................................... 6 9  
7. 2.  
A nal ysis C o n ve nti o ns .................................................................................................. 7 0  
7. 3.  
A nal ysis Sets  ................................................................................................................ 7 0 


Efr u xifer mi n  
Cli nical Trial Pr ot oc ol:  A K -U S -0 0 1 -0 1 0 2  
Pa ge 1 3  of 9 5   
 
 
 
A ker o T hera pe utics , I nc. 
C o nfi de ntial  
A me n d me nt 4, 1 8 A pr 2 0 2 2  
7. 3. 1.  
F ull A nal ysis Set ( F A S)  ......................................................................................... 7 0 
7. 3. 2.  
Per Pr ot oc ol ( P P) Sets  ............................................................................................ 7 0 
7. 3. 3.  
Safet y Set  ............................................................................................................... 7 0 
7. 3. 3. 1.  
P har mac o ki netics Set  ....................................................................................... 7 0 
7. 3. 3. 2.  
Bi o ma r kers A nal ysis Set .................................................................................. 7 0 
7. 3. 3. 3.  
Li ver Bi o ps y A nal ysis Set ( L B A S) .................................................................. 7 1 
7. 3. 3. 4.  
M RI -P D F F A nal ysis Set  .................................................................................. 7 1 
7. 4.  
Data Ha n dli n g C o n ve nti o ns ......................................................................................... 7 1  
7. 5.  
Esti ma n ds ..................................................................................................................... 7 1  
7. 6.  
De m o gra p hic Data a n d Baseli ne C haracteristics  ......................................................... 7 2 
7. 7.  
Efficac y A nal ysis  ......................................................................................................... 7 2 
7. 7. 1.  
Pri mar y Efficac y A nal ysis ..................................................................................... 7 2  
7. 7. 2.  
Sec o n dar y Efficac y A nal ysis ................................................................................. 7 3  
7. 7. 3.  
E x pl orat or y Efficac y A nal ysis  ............................................................................... 7 3 
7. 8.  
Safet y A nal ysis  ............................................................................................................ 7 3 
7. 8. 1.  
E xte nt of E x p os ure ................................................................................................. 7 3  
7. 8. 2.  
A d verse E ve nts ...................................................................................................... 7 3  
7. 8. 3.  
La b orat or y E val uati o ns  .......................................................................................... 7 4 
7. 9.  
P har mac o ki netic A nal ysis  ............................................................................................ 7 4 
7. 1 0.  Bi o m ar ker A nal ysis  ..................................................................................................... 7 4 
7. 1 1.  I m m u n o ge nicit y A nal ysis ............................................................................................ 7 5 
7. 1 2.  Sa m ple Size  .................................................................................................................. 7 5 
7. 1 3.  Data M o nit ori n g C o m mittee  ........................................................................................ 7 5 
8.  
A D MI NI S T R A TI V E C O N SI D E R A TI O N S  .................................................................. 7 7 
8. 1.  
I n vesti gat or Res p o nsi bilities ........................................................................................ 7 7 
8. 1. 1.  
G o o d Cli nical Practice  ........................................................................................... 7 7 
8. 1. 2.  
I nstit uti o nal Re vie w B oar d (I R B)/I n de pe n de nt Et hics C o m mittee (I E C)/ 
Et hics C o m mittee ( E C) Re vie w a n d A p pr o val ...................................................... 7 7  
8. 1. 3.  
I nf or me d C o nse nt................................................................................................... 7 7 
8. 1. 4.  
C o nfi de ntialit y  ....................................................................................................... 7 8 
8. 1. 5.  
St u d y Files a n d Rete nti o n of Rec or ds .................................................................... 7 8  
8. 1. 6.  
Electr o nic Case Re p ort F or ms  ............................................................................... 7 9 
8. 1. 7.  
I ns pecti o ns ............................................................................................................. 8 0 
8. 1. 8.  
Pr ot oc ol C o m plia nce .............................................................................................. 8 0  
8. 2.  
S p o ns or Res p o nsi bilities .............................................................................................. 8 0  
8. 2. 1.  
Pr ot oc ol M o dificati o ns........................................................................................... 8 0  


Efr u xifer mi n  
Cli nical Trial Pr ot oc ol:  A K -U S -0 0 1 -0 1 0 2  
Pa ge 1 4  of 9 5   
 
 
 
A ker o T hera pe utics , I nc. 
C o nfi de ntial  
A me n d me nt 4, 1 8 A pr 2 0 2 2  
8. 2. 2.  
St u d y Re p ort a n d P u blicati o ns ............................................................................... 8 0  
8. 3.  
J oi nt I n vesti gat or/ S p o ns or Res p o nsi bilities ................................................................. 8 1 
8. 3. 1.  
Pa y me nt Re p orti n g................................................................................................. 8 1  
8. 3. 2.  
Access t o I nf or mati o n f or A u diti n g or I ns pecti o ns ................................................ 8 1 
8. 3. 3.  
St u d y Disc o nti n uati o n ............................................................................................ 8 1  
9.  
R E F E R E N C E LI S T  ........................................................................................................ 8 2 
1 0.  
A P P E N DI C E S  ................................................................................................................ 8 5 
 
LI S T O F T A B L E S  
Ta ble 1.  
S u m mar y of Wee k 1 2 Efficac y E n d p oi nts ( F ull A nal ysis Set)  ........... 2 5 
Ta ble 2.  
S u m mar y of Hist ol o g y E n d p oi nts ( Li ver Bi o ps y A nal ysis Set) .......... 2 6  
Ta ble 3.  
Pr o hi bite d C o nc o mita nt Me dicati o ns  .................................................. 4 3 
Ta ble 4.  
C o n diti o nall y All o we d Me dicati o ns .................................................... 4 3  
Ta ble 5.  
Cli nical La b orat or y Assess me nts  ......................................................... 5 2 
Ta ble 6.  
A p pr oac h f or I nterc urre nt E ve nts f or t he Pri mar y E n d p oi nt  ............... 7 2 
LI S T O F FI G U R E S  
Fi g ure 1.  
Efr u xifer mi n Sc he matic Str uct ure wit h Dis ulfi de B o n ds a n d 
C o nstit ue nt P ol y pe pti de C hai ns  ........................................................... 2 1 
Fi g ure 2  
St u d y Sc he ma....................................................................................... 3 4  
 
LI S T O F A P P E N DI C E S  
A p pe n di x A.  
Sc he d ule of Assess me nts – Scree ni n g t o Wee k 2 4  .............................. 8 5 
A p pe n di x B.  
Sc he d ule of Assess me nts – L o n g- Ter m F oll o w -U p  ............................ 8 8 
A p pe n di x C.  
Pre g na nc y Preca uti o ns, Defi niti o n f or Fe male of C hil d beari n g 
P ote ntial, a n d C o ntrace pti ve Re q uire me nts .........................................9 2  
A p pe n di x D.  
West Ha ve n Criteria  .............................................................................9 5  
LI S T O F A B B R E VI A TI O N S A N D D E FI NI TI O N S O F T E R M S  
 
A D A  
a nti-dr u g a nti b o dies  
A E  
a d verse e ve nt  
A E SI  
a d verse e ve nt of s pecial i nterest  
A L P  
al kali ne p h os p hatase  
A L T  
ala ni ne a mi n otra nsferase ( S G P T)  


Efr u xifer mi n  
Cli nical Trial Pr ot oc ol:  A K -U S -0 0 1 -0 1 0 2  
Pa ge 1 5  of 9 5   
 
 
 
A ker o T hera pe utics , I nc. 
C o nfi de ntial  
A me n d me nt 4, 1 8 A pr 2 0 2 2  
A N C  
a bs ol ute ne utr o p hil c o u nt  
A N C O V A  
a nal ysis of c o varia nce  
a P T T 
acti vate d partial t hr o m b o plasti n ti me  
A S T  
as partate a mi n otra nsferase ( S G O T)  
A U C  
area u n der t he ti me -c o nce ntrati o n c ur ve  
B MI  
b o d y mass i n de x  
B S A P  
b o ne s pecific al kali ne p h os p hatase  
B U N  
bl o o d urea nitr o ge n  
C A P  
c o ntr olle d atte n uati o n para meter  
C F R  
C o de of Fe deral Re g ulati o ns  
CI  
c o nfi de nce i nter val  
C ma x  
ma xi m u m plas ma dr u g c o nce ntrati o n  
C mi n  
mi ni m u m plas ma dr u g c o nce ntrati o n  
C P  
C hil d -P u g h  
C R F  
case re p ort f or m  
C R N  
Cli nical Researc h Net w or k  
C R O  
Cli nical Researc h Or ga nizati o n  
C T C A E  
C o m m o n Ter mi n ol o g y Criteria f or A d verse E ve nts  
C V  
c oefficie nt of variati o n  
DI LI  
dr u g -i n d uce d li ver i nj ur y 
D N A  
de o x yri b o n ucleic aci d  
D X A  
D ual E ner g y X -ra y A bs or pti o metr y 
E C G  
electr ocar di o gra m  
e C R F  
electr o nic Case Re p ort F or m  
E D C  
Electr o nic Data Ca pt ure  
E F X  
efr u xifer mi n 
e G F R  
esti mate d G l o mer ular F iltrati o n R ate 
EI U  
E x p os ure i n Uter o  
E L F ™ 
E n ha nce d Li ver Fi br osis  Pa nel  


Efr u xifer mi n  
Cli nical Trial Pr ot oc ol:  A K -U S -0 0 1 -0 1 0 2  
Pa ge 1 6  of 9 5   
 
 
 
A ker o T hera pe utics , I nc. 
C o nfi de ntial  
A me n d me nt 4, 1 8 A pr 2 0 2 2  
E U  
E ur o pea n U ni o n  
F A S  
f ull a nal ysis set 
F D A  
F o o d a n d Dr u g A d mi nistrati o n  
F G F  
fi br o blast gr o wt h fact or 
F G F R  
fi br o blast gr o wt h fact or rece pt or 
F V B  
Frie n d Vir us B  
G C P  
G o o d Cli nical Practice  
G G T  
ga m ma gl uta m yl tra nsferase  
G L P  
G o o d La b orat or y Practice  
H b A 1c  
he m o gl o bi n A 1c  
H Bc A b  
t otal he patitis B c ore a nti b o d y  
H Bs A g  
he patitis B s urface a nti ge n  
H B V  
he patitis B vir us  
H C C  
he pat ocell ular carci n o ma  
Hct  
he mat ocrit  
H C V  
he patitis C vir us  
H D L  
hi g h -de nsit y li p o pr otei n  c h olester ol 
H g b  
he m o gl o bi n  
HI P A A  
Healt h I nf or mati o n P orta bilit y a n d Acc o u nta bilit y Act  
HI T E C H  
Healt h I nf or mati o n Tec h n ol o g y f or Ec o n o mic a n d Cli nical Healt h  
HI V  
h u ma n i m m u n o deficie nc y vir us  
H L G T  
hi g h -le vel gr o u p ter m 
H L T  
hi g h -le vel ter m 
H O M A  
h o me ostasis  m o del  assess me nt  of  i ns uli n  resista nce , ( H O M A-I R)  a n d 
beta cell f u ncti o n ( H O M A -B)  
I C F 
i nf or me d c o nse nt f or m 
I C H 
I nter nati o nal C ou ncil  f or Har m o nisati o n  
I E C 
I n de pe n de nt Et hics C o m mittee 
I g G 1 
h u ma n i m m u n o gl o b uli n G 1  


Efr u xifer mi n  
Cli nical Trial Pr ot oc ol:  A K -U S -0 0 1 -0 1 0 2  
Pa ge 1 7  of 9 5   
 
 
 
A ker o T hera pe utics , I nc. 
C o nfi de ntial  
A me n d me nt 4, 1 8 A pr 2 0 2 2  
I M P 
i n vesti gati o nal me dici nal pr o d uct 
I N D 
I n vesti gati o nal Ne w Dr u g  
I N R 
I nter nati o nal N or malize d Rati o 
I P 
i n vesti gati o nal pr o d uct 
I R B 
I nstit uti o nal Re vie w B oar d 
I R T 
i nteracti ve res p o nse tec h n ol o g y 
I T T 
i nte nt-t o-treat 
I V 
i ntra ve n o us 
K O  
k n oc k -o ut  
L B A S  
li ver bi o ps y a nal ysis set 
L D H  
lactate de h y dr o ge nase  
L D L  
l o w-de nsit y li p o pr otei n  c h olester ol 
L L T  
l o w-le vel ter m 
L O C F  
last o bser vati o n carrie d f or war d 
m A b  
m o n ocl o nal a nti b o d y  
Me d D R A  
Me dical Dicti o nar y f or Re g ulat or y Acti vities  
M E L D  
M o del f or E n d -Sta ge Li ver Disease  
M R E  
ma g netic res o na nce elast o gra p h y 
M RI  
ma g netic res o na nce i ma gi n g  
M RI -P D F F  
ma g netic res o na nce i ma gi n g –  pr ot o n de nsit y fat fracti o n  
N A F L D  
n o n -alc o h olic fatt y li ver disease  
N A  
N ort h A merica  
N A S  
n o n -alc o h olic fatt y li ver disease acti vit y sc ore  
N A S H  
n o nalc o h olic steat o he patitis  
N O A E L  
n o -o bser ve d -a d verse -effect-le vel 
P B C  
pri mar y biliar y c h ola n gitis  
P D  
p har mac o d y na mics  
PI  
pri nci pal i n vesti gat or  
P K  
p har mac o ki netics  


Efr u xifer mi n  
Cli nical Trial Pr ot oc ol:  A K -U S -0 0 1 -0 1 0 2  
Pa ge 1 8  of 9 5   
 
 
 
A ker o T hera pe utics , I nc. 
C o nfi de ntial  
A me n d me nt 4, 1 8 A pr 2 0 2 2  
P S C  
pri mar y scler osi n g c h ola n gitis  
P T  
preferre d ter m  
P T  
pr ot hr o m bi n ti me  
Q 2 W  
e ver y 2 wee ks  
Q W  
e ver y wee k 
R B C  
re d bl o o d cell (c o u nt) 
R N A  
ri b o n ucleic aci d 
S C  
s u bc uta ne o us 
S A E  
seri o us a d verse e ve nt 
S A P  
Statistical A nal ysis Pla n  
S D  
sta n dar d de viati o n 
S E  
sta n dar d err or  
S G O T  
ser u m gl uta mate o xal oacet ate tra nsa mi nase ( A S T) 
S G P T  
ser u m gl uta mate p yr u v ate tra nsa mi nase ( A L T) 
S O C  
s yste m or ga n class 
S U S A R  
s us pecte d u ne x pecte d seri o us a d verse reacti o n 
T 1/ 2 
ti me t o half plas ma c o nce ntrati o n ( half-life) 
T B L  
T otal bilir u bi n  
T E A Es  
treat me nt e mer ge nt a d verse e ve nts 
T E S A Es  
treat me nt-e mer ge nt seri o us A Es  
T K  
t o xic o ki netics 
T ma x  
ti me t o ma xi m u m plas ma c o nce ntrati o n 
T S H  
t h yr oi d sti m ulati n g h or m o ne 
U L N  
u p per -li mit of n or mal 
U .S . 
U nite d States  
W B C  
w hite bl o o d cell (c o u nt)  
 


Efr u xifer mi n  
Cli nical Trial Pr ot oc ol:  A K -U S -0 0 1 -0 1 0 2  
Pa ge 1 9  of 9 5  
A ker o T hera pe utics , I nc. 
C o nfi de ntial  
A me n d me nt 4, 1 8 A pr 2 0 2 2  
1.  
B A C K G R O U N D A N D R A TI O N A L E
1. 1.  
B ac k gr o u n d 
N o nalc o h olic steat o he patitis (N A S H ) is the m ost se vere f or m of n o n- alc o h olic  fatt y li ver 
di sease ( N A FL D)  a n d is c haracterize d b y the prese nce of  a n a b n or mal  acc u m ulati o n of  fat i n 
t he li ver, whic h  i n so me  i n di vi d uals ca n pro gress  t o li ver cell inj ur y ( he pat ocell ular 
bal l o o ni n g), i nfla m mati o n, an d ul ti matel y fi br osis. Li p ot o xicit y a n d o xi dati ve stress are 
c o nsi dere d  to  be t he dri vers of disease pr o gressi o n, or the u n derl yi n g  ca use of the d isease. As 
N A S H pr o gresses , it ca n res ult in  e xcessi ve de p ositi o n of e xtracell ular c olla ge n, or scarri n g 
of t he li ver (fi br osis) ulti matel y lea din g  t o li ver cirr h osis. Later  sta ges of N A S H a re 
ass ociate d  wit h s u bsta ntiall y i ncrease d ris k of he pat ocell ular  carci n o ma a n d  maj or a d verse 
car diac e ve nts ( E kste dt et al. 2 0 1 5), u n derli ni n g t he he alt hcare b ur de n prese nte d b y N A S H in 
t he a bse nce of  a p pro ve d  t hera pies.   
N A S H  is cl osel y relate d t o the epi de mic o f o be sit y a n d dia betes a n d  is ofte n vie we d as the 
li ver ma nifestati o n of t he m eta b olic s y n dro me . It is he a vil y i nfl ue nce d b y lifest yle (e. g., 
chr o nic all y e xcessi ve cal orie i nta ke , se de ntar y lifest yle) a n d is disti nct fr o m ot her fatt y li ver 
diseases ca use d  b y viral i nfecti o n, alc o h ol ab use, or  me dicati o n side effects ( E A S L e t al. 
2 0 1 6 ). N A S H ca n p ote ntiall y pr o gress t o a d va nce d li ver disease, c irr h osis, a n d he pat ocell ular 
carci n o ma ( T he Nas h E d ucati o n Pr o gra m 2 0 1 9 ). T he c urre nt pre vale nce of N A S H i n t he 
U nite d States (U. S.) p o p ul ati o n is esti mate d t o be ar o u n d 3 – 4 %.  A p pr o xi matel y 1 i n 5 of 
t he ne arl y 8 0  milli o n  patie nts  wit h N A FL D  i n t he U . S. (R u hl & E ver hart 2 0 1 5 ) are pr ojecte d  
t o de velo p N A S H ( Y o u n ossi et al. 2 0 1 6). T his e mer gi n g e pi demic li ver disease warra nt s a 
maj or  p u blic healt h  eff ort t o co ntr ol t he b ur de n of di sease, i n partic ular its si g nifica nt 
c o mplicati o ns  an d c o m or bi d c o n diti o ns. 
1. 1. 1.  
F G F 2 1 
Fi br o blast gr o wt h  fact or 2 1 (F G F 2 1) is  a me m ber of t he e n d ocri ne F G F su b- fa mil y. F G F 2 1 
f or ms a li ga n d/c o-rece pt or co m ple x b y first anc h ori n g t o β- Kl ot h o o n t he cell surface , t he n 
i nteracti n g wit h  o ne of t hree me m bers  of t he FG F R  famil y  (s pecificall y FG F R 1c , 2c an d 3c) 
t o i n d uce d i merizati o n a n d a ut o p h os p h or ylatio n of F G F R. Acti vate d F G F R init iates s pecific 
i ntracell ular si g nali n g casca des lea di n g to  the e x pressi o n  of F G F 2 1’ s paracri ne an d e n d ocri ne 
bi ol o gical fu ncti o ns ( Li et al. 2 0 1 3). F G F 2 1  is a secrete d p ol y pe pti de h i g hl y e x presse d in 
tiss ues rele va nt to  meta b olic f uncti o n , i ncl u di n g t he li ver, a di p ose tiss ue, a n d pa ncreas (F o n 
Tacer  et al. 2 0 1 0, Nis hi m ura et al. 2 0 0 0). Stu di es ha ve sh o w n t hat F G F 2 1 i s a meta b olic 
re g ulat or o f e ner g y h o me ostasis, mai ntai ni n g a p pr o priate bala nce acr oss gl uc ose-li pi d-
pr otei n  utilizati o n, a n d e n ha nci n g i ns uli n se nsiti vit y i n t he fe d state (Ki m et al. 2 0 1 7, Gaic h  
et al. 2 0 1 3, Li et al. 2 0 1 3, Tal u k dar et al. 2 0 1 6, Z ha o et al. 2 0 1 9). F G F 2 1 directly m o d ulates 
w h ole -b o d y li pid meta b olis m t o re d uce he pa tic li pi d acc u m ulati o n. F G F 2 1 has be e n s h o w n 
t o reverse  hepatic  steat osis an d  t o pre ve nt diet-i n d uce d o besit y in b ot h r o de nts an d n o n h u ma n 
pri mates  (Li n et al. 2 0 1 3, Ca m p orez et al. 2 0 1 3, M u et al. 2 0 1 2 , X u et al. 2 0 0 9 , C os k u n et al. 
2 0 0 8 , W u et al. 2 0 1 7 , Tal u k dar et al. 2 0 1 6). He nce, F G F 2 1  is a tar get f or t he de vel o p me nt of 
n o vel bi ol o gical dr u gs  f or meta b olic di seases (Gi me n o & M oller 2 0 1 4 , C he n et al. 2 0 1 7). 
S er u m FG F 2 1  le vels are  ele vate d in h u ma n s u bjects w it h dia betes, o besit y, NA S H  a n d ot her 


Efr u xifer mi n  
Cli nical Trial Pr ot oc ol:  A K -U S -0 0 1 -0 1 0 2  
Pa ge 2 0  of 9 5  
A ker o T hera pe utics , I nc. 
C o nfi de ntial  
A me n d me nt 4, 1 8 A pr 2 0 2 2  
meta b olic dis or ders.  As s uc h, raise d le vels reflect increase d  secreti o n of FG F 2 1  b y orga ns 
a n d cells u n der va ri o us ty pes of stress (e. g. n utrie nt stress, o xidati v e stress) a n d a p pears t o be 
a co m pe nsat or y pr otecti ve res p o nse. H i g her le vels of F G F 2 1 ha ve als o bee n i nter prete d  as 
e vi de nce of FG F 2 1  resista nce (Li  et al. 2 0 1 3, W u et al. 2 0 1 7). 
I n N A SH , F G F 2 1 a p pears to a d dress b ot h t he u n derl yi n g disease dr i ver, i.e. e xcessi ve fl u x of 
cal ories  a n d li pid  i nto  t he li ver, an d  th e e ns ui n g d ow nstrea m  se q uelae of hepat oc yte stress 
lea di n g t o he patic i nfla m mati o n an d  fi brosis.   FG F 2 1 directl y m o d ulates w h ole b o d y l i pi d 
met a b olis m t o re d uce he patic li pi d acc u m ulati o n an d has be e n s h o w n t o re verse h e patic 
steat osis a n d to  pre ve nt diet-i n d uce d o besit y in b ot h r o de nt s an d n o n h u m an pr i mates (Li n  et 
al. 2 0 1 3, Ca m p orez et al. 2 0 1 3, M u et al. 2 0 1 2, X u et al. 2 0 0 9, Cos k u n e t al. 2 0 0 8, W u et al. 
2 0 1 7, Tal u k dar et al. 2 0 1 6). 
Vari o us i n vitr o a n d i n vi v o fi n di n gs s u g gest p ote ntial be neficial effects of F G F 2 1 a g o nis m i n 
N A S H , incl u di n g  i m pr o ve me nts in  li ver fat, infla m mati o n , a n d fi br osis ( X u et al. 2 0 0 9,  Lee 
et al. 2 0 1 6 , Ta na ka et al. 2 0 1 5 , C ui et al. 2 0 2 0). Ad mi nistrati o n  of rec o m bi na nt h u ma n 
F G F 2 1  or lo n g-act i n g F G F 2 1 a nal o g ues pr e ve nte d a n i ncrease in li ver fat an d s u p presse d 
i nfla m mati o n an d  fi bro sis, as assesse d b y hist ol o g y, in  ro de nt  mo dels of  liver  disease 
( Ta na ka et al. 2 0 1 5, Fis her  et al. 2 0 14 , Ba o et al. 2 0 1 8 , O p o k u et al. 2 0 2 0). The m o dels us e d 
a ran ge  of pat h ol o gical i ns ults, i ncl u di n g e xcessi ve inta ke of fat an d fr uct ose, alc o h ol, diet 
de ficie nt i n met hi o ni ne an d  c h oli ne, or che mi cal to xi ns (e. g., car b o n tetrac hl ori de, di met h yl 
nitr osa mi ne;  [X u et al. 2 0 1 6]). I ncreasi n g FG F 2 1  t o ne was effecti ve i n all t he m o dels , 
w her eas los s of F G F 2 1 f u ncti o n e xacer bate d de vel o p me nt of l i ver pa t h ol o g y. 
Ge neti c an d  p har mac ol o gical stu dies  pr o vi de furt he r evi de nce that F G F 2 1-rece pt or a g o nis m 
c o ul d ha ve p ote ntiall y be neficial effects o n N A S H.  F G F 2 1 k n oc k o ut (K O) m ice are via ble, 
fertile, an d s h o w n o str o n g meta b olic p he n ot y pes w he n fe d a n or mal ch o w di et. Ho we ver , 
t he y bec o me i nsuli n  resista nt w it h he pat osteat osis an d ha ve si g nifica ntl y ele vate d plas ma 
gl uc ose an d tri gl yceri de le vels w he n c ha lle n ged wit h hi g h-fat or ke t o ge nic di ets. I n c o ntrast, 
tra ns ge nic mice o ver-e x pressi n g F G F 2 1 are lea n a n d resista nt to diet i n d uce d or 
a ge-ass ociate d  o besit y an d  ins uli n  resista nce.  
1. 2.  
E fr u xifer mi n  B ac k gr o u n d 
E F X  is a 9 2. 0 k D E. c oli -e x presse d  h u ma n I g G 1 Fc - F G F 2 1 f usi o n p ol y pe pti de —a lo n g-
acti n g F G F 2 1 a nal o g. Eac h m olec ule c o ntai ns o ne di meric F c d o mai n a n d 2 m o difie d F G F 2 1 
c hains. E F X  has 8 dis ulfi de b o n ds , 6 i ntra-c hai n, a n d 2 i nter- c hai n as de picte d  in Fi g ure 1 . 
T w o of t he intra c hai n dis ulfi de b o n ds are in t he F G F 2 1 p ol y pe pti de be t ween C ys 3 1 8 a n d 
C ys 3 3 6, o ne for eac h m on o mer. A d diti o nall y, t hree  m utati o n  sites, L 9 8 R (c orres p o n di n g 
resi d ue 3 4 1 i n Fc-F G F 2 1  f usi o n p ol y pe pti de), P 1 7 1 G (resi d ue 4 1 4) , a n d A 1 8 0 E (resi d ue 
4 2 3) ha ve b ee n i ntr o d uce d i nt o t he co nse ns us h u ma n F G F 2 1 se q ue nce t o decrease its
s usce pti bilit y t o i n vi v o pr ote ol ytic d e gradati o n, a n d t o re d uce ag gre gati o n w hile m ai ntai ni n g
bala nce d F G F 2 1 a g o nis m acr oss F G F R 1c/ 2c / 3c wit h  selecti vit y o ver FG F R 4.  A sc hematic of
t he str uct ure of EF X  is sh o w n i n Fi g ure 1.


Efr u xifer mi n  
Cli nical Trial Pr ot oc ol:  A K -U S -0 0 1 -0 1 0 2  
Pa ge 2 1  of 9 5   
 
 
 
A ker o T hera pe utics , I nc. 
C o nfi de ntial  
A me n d me nt 4, 1 8 A pr 2 0 2 2  
Fi g ure 1. 
Efr u xifer mi n  Sc he m atic Str uct ure wit h Dis ulfi de B o n ds a n d 
C o nstit ue nt P ol y pe pti de C h ai ns  
 
1. 3.  
N o ncli nic al P h ar m ac ol o g y & T o xic ol o g y 
I n vitr o c haracterizati o n of E F X  de m o nstrate d hi g h affi nit y bi n di n g ( < 1 0 n M) t o h u ma n, 
c y n o m ol g us m o n ke y, a n d m o use β- Kl ot h o. E F X  was de m o nstrate d t o acti vate c -is of or ms of 
F G F R: F G F R 1c , 2c a n d 3c, wit h bala nce d p ote nc y a n d hi g h selecti vit y o ver F G F R 4 usi n g a 
cell-li ne c o-e x pressi n g h u ma n β- Kl ot h o a n d eac h F G F R i n di vi d uall y (Sta nisla us et al. 2 0 1 7 ).   
I n vi v o, E F X  is p har mac ol o gicall y acti ve i n r o de nts a n d m o n ke ys. A d mi nistrati o n of E F X  t o 
o bese a n d  i ns uli n resista nt m o use a n d m o n ke y m o dels i m pr o ve d t he meta b olic stat us of t hese 
a ni mals res ulti n g i n re d uce d plas ma gl uc ose , i ns uli n, a n d tri gl yceri de le vels; i m pr o ve d 
li p o pr otei n pr ofile; e n ha nce d gl uc ose t olera nce; a n d si g nifica nt wei g ht l oss (Sta nisla us et al. 
2 0 1 7 ). 
E F X  has bee n e val uate d i n 1 6- a n d 2 6- wee k n o ncli nical t o xic ol o g y st u dies i n rats a n d 
m o n ke ys a d mi nistere d s u bc uta ne o us d oses of 0 ( ve hicle c o ntr ol), 1 0, 3 0, or 1 0 0 m g/ k g o nce 
wee kl y.  Effects o bser ve d i n t hese st u dies i n b ot h s pecies i ncl u de d decreases i n b o d y wei g ht 
gai n/ b o d y wei g ht, decreases i n lea n b o d y mass a n d b o d y fat , decrease d b o ne gr o wt h 
sec o n dar y t o effects o n b o d y wei g ht, a n d mi ni mal i ncreases i n A L T a n d or A S T wit h o ut 
c o nc o mita nt li ver pat h ol o g y.  I ncrease d a di p oc yte cell ularit y i n b o ne marr o w was o bser ve d 
i n rats.  T hese effects were c o nsiste nt wit h a n d attri b ute d t o t he k n o w n p har mac ol o gical 
effects of F G F 2 1 a nal o gs s uc h as E F X .  Decrease d re d cell mass (er yt hr oc ytes , he m o gl o bi n, 
a n d/ or he mat ocrit) , decrease d t h y mic l y m p h oi d cell ularit y , decrease s i n re pr o d ucti ve or ga n 
wei g hts i n b ot h se xes, a n d mi ni mal t o mil d atr o p h y of uter us , cer vi x, a n d va gi na i n m o n ke ys 
were attri b ute d t o stress a n d/ or re d uce d b o d y wei g ht/ gr o wt h.   E F X -relate d c ha n ges were 


Efr u xifer mi n  
Cli nical Trial Pr ot oc ol:  A K -U S -0 0 1 -0 1 0 2  
Pa ge 2 2  of 9 5   
 
 
 
A ker o T hera pe utics , I nc. 
C o nfi de ntial  
A me n d me nt 4, 1 8 A pr 2 0 2 2  
ge nerall y re versi ble or e x hi bite d a tre n d t o war ds re versi bilit y i n b ot h s pecies.  T he n o 
a d verse effect le vel ( N O A E L) i n b ot h rat st u dies was 1 0 0  m g/ k g; i n t he 2 6- wee k st u d y, 
ass ociate d C ma x  val ues at t he N O A E L were a p pr o xi matel y 9 t o 1 9- f ol d t he m o dele d Cma x  i n 
h u ma ns at 5 0 m g, a n d c orres p o n di n g A U C 0- 9 6 h val ues were a p pr o xi matel y 2 0 t o 4 1-f ol d 
hi g her t ha n t he m o dele d A U C 0- 1 6 8 h i n h u ma ns at 5 0 m g.  T he N O A E L i n t he 1 6-wee k 
m o n ke y st u d y was 3 0 m g/ k g/ d ose.  T he N O A E L i n t he 2 6- wee k m o n ke y st u d y was 3 0 m g/ k g 
i n fe males, a n d n ot i de ntifie d i n males d ue t o o verall i n hi biti o n of gr o wt h wit h res ulti n g 
deficit i n b o ne gr o wt h a n d c o ns oli dati o n.  I n t he 2 6- wee k m o n ke y st u d y, t he C ma x  val ue at t h e 
N O A E L w as 2 7-f ol d hi g her t ha n t he m o dele d C ma x  i n h u ma ns at 5 0 m g, a n d c orres p o n di n g 
A U C 0- 9 6 h val ues was 1 1- f ol d hi g her t ha n t he m o dele d A U C 0- 1 6 8 h i n h u ma ns at 5 0 m g.  T he 
e x p os ure m ulti ples base d o n A U C val ues are c o nsi dere d c o nser vati ve base d o n val ues 
calc ulate d t hr o u g h 9 6 h o urs p ost- d ose i n a ni mals c o m pare d t o m o dele d val ues t hr o u g h 1 6 8 
h o urs p ost- d ose i n h u ma ns.  
Ge n ot o xicit y or carci n o ge nicit y st u dies ha ve n ot bee n c o n d ucte d t o date wit h E F X . A 2- year 
rat carci n o ge nicit y st u dy will be c o n d ucte d i n parallel wit h t his pr o gra m.   H o we ver , st u dies 
ha ve bee n  c o n d ucte d t o e xa mi ne t he p ote ntial of EF X  t o i m pact cell pr oliferati o n a n d 
mit o ge nicit y.  Res ults of i n vitr o a n d s h ort -ter m i n viv o st u dies de m o nstrate d t hat E F X was 
n ot a direct- acti n g mit o ge n a n d was n ot ass ociate d wit h persiste nt cell pr oliferati o n i n li ver. 
M ore o ver, s tai ni n g of t he li ver wit h Ki 6 7, a mar ker of acti ve cell pr oliferati o n , s h o we d n o 
c ha n ges after 2 6 wee ks of re peat - d osi n g of rats o nce wee kl y at u p t o 1 0 0 m g / k g. I n a d diti o n, 
t here were n o pre- ne o plastic hist o pat h ol o g y c ha n ges o bser ve d i n rats or i n m o n ke ys 
a d mi nistere d wee kl y s u bc uta ne o us d oses u p t o 1 0 0 m g/ k g/ d ose f or 2 6 wee ks . T hese data 
s u g gest t hat E F X  w o ul d ha ve mi ni mal ris k f or carci n o ge nicit y. 
I n fertilit y a n d earl y e m br y o nic de vel o p me nt st u dies i n rats, E F X a d mi nistrati o n t o fe males 
pri or t o a n d d uri n g mati n g di d n ot i m pair fertilit y or n u m bers of e m br y os at d oses u p t o 
3 0 m g/ k g/ d ose, n or di d it i m pair fertilit y of males at d oses u p t o 1 0 0 m g/ k g/ d ose.  I n 
e m br y ofetal de vel o p me nt st u dies i n rats a n d ra b bits a d mi nistere d E F X e ver y 3 da ys d uri n g 
gestati o n , n o mater nal t o xicit y was o bser ve d u p t o 1 0 0 m g/ k g/ d ose a n d n o e m br y ofetal 
t o xicit y occ urre d at d oses u p t o 3 0 m g/ k g/ d ose.  E F X was n ot terat o ge nic i n rats or ra b bits.  
Please refer t o t he E F X I n vesti gat or’s Br oc h ure (I B) f or a d diti o nal det ails.  
 


Efr u xifer mi n  
Cli nical Trial Pr ot oc ol:  A K -U S -0 0 1 -0 1 0 2  
Pa ge 2 3  of 9 5   
 
 
 
A ker o T hera pe utics , I nc. 
C o nfi de ntial  
A me n d me nt 4, 1 8 A pr 2 0 2 2  
1. 4.  
Cli nic al Tri als of E fr u xifer mi n 
As of 0 1 Oct o ber 2 0 2 0, E F X  has bee n e val uate d i n P hase 1 si n gle- a n d m ulti ple -asce n di n g 
d ose st u dies u p t o 4- wee ks treat me nt d urati o n i n t y pe 2 dia betes ( T 2 D) s u bjects as well as 
o ne P hase 2a st u d y i n N A S H s u bjects. I n t he P hase 1a si n gle-asce n di n g d ose st u d y, t he 
hi g hest d ose teste d was 2 1 0 m g a d mi nistere d s u bc uta ne o usl y . In t he P hase 1 b m ulti ple-
asce n di n g d ose st u d y, t he hi g hest d ose teste d was 1 4 0 m g Q W S C . I n t he P hase 2a st u d y, 2 8, 
5 0, a n d 7 0 m g d oses were e val uate d at 1 6- wee ks of treat me nt. I n all st u dies, t he dr u g was 
ge nerall y well t olerate d. I nf or mati o n o n t he P hase 1 cli nical st u dies a n d a d diti o nal details o n 
t he P hase 2 cli nical st u d y are descri be d i n f urt her detail i n t he c urre nt E F X I B. 
1. 4. 1.  
St u d y A K -U S - 0 0 1- 0 1 0 1 - P h ase 2 a , R a n d o mize d , D o u ble -Bli n d , Pl ace b o -
C o ntr olle d St u d y E v al u ati n g t he S afet y a n d Effic ac y of E F X i n S u bjects wit h 
N o n alc o h olic Ste at o he p atitis ( N A S H)  
St u d y A K- U S - 0 0 1- 0 1 0 1 was a  P hase 2a , ra n d o mize d, d o u ble- bli n d, place b o-c o ntr olle d st u d y 
t o e val uate t he safet y a n d efficac y of E F X i n s u bjects wit h N A S H.  T he st u d y c o nsiste d of 
t he Mai n St u d y a n d a C o h ort C. All res ults i ncl u de d i n Secti o n 1. 4. 1 i ncl u des data fr o m t he 
Mai n St u d y o nl y.  
T he pri mar y e n d p o i nt was t o e val uate t he  a bs ol ute c ha n ge fr o m baseli ne i n he patic fat 
fracti o n assesse d b y Ma g netic Res o na nce I ma gi n g - Pr ot o n De nsit y Fat Fracti o n ( M RI -
P D F F) at Wee k 1 2 . Sec o n dar y a n d e x pl orat or y e n d p oi nts i ncl u de d e val uati o n of perce nt 
c ha n ge i n he patic f at fracti o n assesse d b y M RI -P D F F , hist ol o g y, re d ucti o ns i n A L T, a n d 
safet y a n d t olera bilit y. 
1. 4. 1. 1.  
S u bject Dis p ositi o n  
I n t he Mai n St u d y, eli gi ble s u bjects were ra n d o mize d t o recei ve 2 8, 5 0, or 7 0 m g E F X  or 
place b o i n a rati o of 1: 1: 1: 1.  T he pla n ne d sa m ple size was a p pr o xi matel y 8 0 s u bjects.  E F X  
or e q ui vale nt d ose of place b o was a d mi nistere d Q W f or 1 6 wee ks.   
A t otal of 8 0 s u bjects were e nr olle d wit h 7 9 s u bjects recei vi n g at least o ne d ose of st u d y 
dr u g.  A t otal of 6 6 s u bjects (8 2. 5 %) c o m plete d i n vesti gati o na l pr o d uct as per t he d osi n g 
re gi me n f or 1 6 wee ks.  T hirtee n  s u bjects (1 6. 3 %) disc o nti n ue d i n vesti gati o nal pr o d uct 
( 4 s u bjects i n 7 0 m g E F X , 4 s u bjects i n 5 0 m g E F X , 3 s u bjects i n 2 8 m g E F X  a n d 2 s u bjects 
i n t he place b o gr o u p). Se ve n  s u bjects disc o nti n ue d i n vesti gati o nal pr o d uct beca use of A Es 
a n d 7 s u bjects ( 9. 0 %) disc o nti n ue d t he st u d y d ue t o a d mi nistrati ve reas o ns .  A t otal of 6 6  
s u bjects ( 8 2. 5 %) c o m plete d t he st u d y.   
 
1. 4. 1. 2.  
S afet y Res ults  
O verall , 7 0 ( 8 8. 6 %) s u bjects e x perie nce d a n y treat me nt-e mer ge nt a d verse e ve nt ( T E A E): 1 8 
( 9 4. 7 %), 1 7 ( 8 9. 5 %), a n d 1 9 ( 9 5. 0 %) s u bjects i n t he 2 8, 5 0, a n d 7 0 m g E F X gr o u ps, 
res pecti vel y, a n d 1 6 ( 7 6. 2 %) s u bjects i n t he place b o gr o u p. T he m ost c o m m o n T E A Es b y 
preferre d ter m ( P T) were diarr hea ( 2 7 [ 3 4. 2 %] s u bjects) , na usea ( 2 6 [ 3 2. 9 %] s u bjects), 


Efr u xifer mi n  
Cli nical Trial Pr ot oc ol:  A K -U S -0 0 1 -0 1 0 2  
Pa ge 2 4  of 9 5  
A ker o T hera pe utics , I nc. 
C o nfi de ntial  
A me n d me nt 4, 1 8 A pr 2 0 2 2  
v o miti n g a n d i ncrease d a p petite ( 1 5 [ 1 9. 0 %] s u bjects eac h), fati g ue ( 1 3 [ 1 6. 5 %] s u bjects), 
a n d nas o p har y n gitis ( 1 1 [ 1 3. 9 %] s u bjects). 
T he maj orit y of s u bjects e x perie nce d a Gra de 1 or 2 T E A E wit h t he ma xi m u m T E A E 
se verit y bei n g Gra de 1 i n 1 8 ( 2 2. 8 %) s u bjects, Gra de 2 i n 4 6 ( 5 8. 2 %) s u bjects, a n d Gra de 3 
i n 5 ( 6. 3 %) s u bjects. O ne ( 1. 3 %) s u bject ( S u bject 1 0 1- 0 0 6 i n t he 7 0 m g E F X gr o u p) 
e x perie nce d a Gra de 4 T E S A E of pa ncreatitis ac ute a n d s u bse q ue ntl y , dia betic ket oaci d osis. 
T his s u bject was c o nsi dere d m or bi dl y o bese a n d ha d se vere i ns uli n resi sta nce as i n dicate d b y 
aca nt h osis ni grica ns a n d h y peri ns uli ne mia pri or t o starti n g t he st u d y.  
Fift y -t w o ( 6 5. 8 %) s u bjects e x perie nce d a st u d y dr u g-relate d T E A E: 1 3 ( 6 8. 4 %), 1 5 ( 7 8. 9 %), 
a n d 1 7 ( 8 5. 0 %) s u bjects i n t he 2 8, 5 0, a n d 7 0 m g E F X gr o u ps , res pecti vel y, a n d 7 ( 3 3. 3 %) 
s u bjects i n t he place b o gr o u p. T he maj orit y of st u d y dr u g-relate d T E A Es were Gra de 1 or 2.  
O ne ( 5. 0 %) s u bject e x perie nce d a T E S A E i n t he 7 0 m g E F X gr o u p. T here was o ne st u d y 
dr u g- relate d T E S A E a n d n o deat hs d ue t o T E A Es.  
O verall , 2 ( 2. 5 %) s u bjects e x perie nce d a n S A E: 1 ( 5. 3 %) s u bject i n t he 2 8 m g E F X gr o u p 
e x perie nce d a b d o mi nal pai n a n d p yre xia, w hic h was c o nsi dere d u nrelate d t o t he st u d y dr u g 
b ut relate d t o t he pre-treat me nt li ver bi o ps y pr oce d ure; 1 ( 5. 0 %) s u bject i n t he 7 0 m g E F X 
gr o u p e x perie nce d pa ncreatitis ac ute a n d s u bse q ue ntl y , dia betic ket oaci d osis.  T his s u bject 
was c o nsi dere d m or bi dl y o bese a n d ha d se vere i ns uli n resista nce as i n dicate d b y aca nt h osis 
ni grica ns a n d h y peri ns uli ne mia pri or t o starti n g t he st u d y. 
I n t he s u bjects recei vi n g at least o ne d ose of E F X, 4 1 of 5 7 i n di vi d uals ( 7 1. 9 %) were p ositi ve 
f or treat me nt-i n d uce d A D A, c o m pare d t o n o ne i n t he place b o gr o u p. W hile t he maj orit y of 
s u bjects de vel o pe d A D A d uri n g t he st u d y, i n di vi d ual data fr o m all s u bjects wit h treat me nt-
i n d uce d A D A i n dicate d t hat t he meas ure d a nti b o d y titers were l o w wit h a me dia n o bser ve d 
titer val ue at 2 0 wee ks of 1: 8. 6 7. I n a d diti o n, o nl y 4 s u bjects ( 7. 0 % of E F X-treate d s u bjects) 
de m o nstrate d e mer ge nce of fi br o blast gr o wt h fact or 2 1 ( F G F 2 1) cr oss- reactive a nti b o dies. 
O nl y 1 s u bject was p ositi ve f or ne utralizi n g a nti b o dies ( N A b) at a si n gle ti me p oi nt , a n d t his 
s u bject s u bse q ue ntl y teste d ne gati ve f or A D A. 
1. 4. 1. 3.  
Effic ac y Res ults  
All t hree  E F X  d ose gr o u ps met t he Pri mar y a n d Sec o n dar y E n d p oi nts de m o nstrati n g 
statisticall y si g nifica nt re d ucti o ns i n li ver fat a n d A L T  at Wee k 12 ( Ta bl e 1 ). T he E F X 
treat me nt gr o u ps dem o nstrate d  a statisticall y si g nifica nt re d ucti o n i n a bsol ute  cha n ge  fr o m 
Baseli ne  (re d ucti o n) in he patic fat fracti o n of 1 2. 3 %, 1 3. 4 % an d 1 4. 1 % in t he 2 8 , 5 0 a n d 7 0 
m g treat me nt gr o u ps res pecti vel y ( p < 0. 0 0 0 1 f or eac h). A m o n g s u bjects recei vi n g place b o, a  
0. 3 re d ucti o n ( p = 0. 3 8 2 8) w as o bs er ve d.  
All t hree  E F X  treat me nt gr o u ps  dem o nstrate d  a statisticall y si g nificant  relati ve re d ucti o n of  
he patic fat  fractio n  fr o m Baseli ne t o Wee k 1 2  of 6 3. 2 %, 7 0. 9 % an d 7 2. 3 % res pecti vel y f or 
s u bjects recei vi n g 2 8, 5 0 a n d 7 0 m g E F X (p < 0. 0 0 0 1 f or eac h d os e gr o u p vs. baseli ne), w hile  
a 0. 3 % red ucti o n was o b ser ve d f or pl ace b o s u bjects (p = 0. 9 4 9 4).  


Efr u xifer mi n  
Cli nical Trial Pr ot oc ol:  A K -U S -0 0 1 -0 1 0 2  
Pa ge 2 5  of 9 5   
 
 
 
A ker o T hera pe utics , I nc. 
C o nfi de ntial  
A me n d me nt 4, 1 8 A pr 2 0 2 2  
As detaile d i n (Ta ble 1 ), a lar ge pr o p orti o n of E F X treate d s u bjects were “res p o n ders” as 
defi ne d b y a ≥3 0 % re d ucti o n i n he patic fat fracti o n at Wee k 1 2. I n t he 2 8 m g, 5 0 m g, a n d 7 0 
m g E F X treat me nt gr o u ps , res pecti vel y, 8 4. 2 %, 8 5. 0 % a n d 7 5. 0 % of s u bjects were 
res p o n ders c o m pare d t o 9. 5 % i n t he place b o gr o u p ( p < 0. 0 0 0 1 or p < 0. 0 0 0 2 w he n c o m pare d 
t o place b o). 
 
At Wee k 1 2 , 1 1 ( 5 7. 9%) , 1 7 ( 8 5. 0 %), a n d 1 4 ( 70 . 0 %) s u bjects i n t he 2 8, 5 0, a n d 7 0 m g E F X 
gr o u ps, res pecti vel y, a n d 1  ( 4. 8 %)  s u bject  i n  t he  place b o  gr o u p ( w h o  ha d  a  wei g ht  l oss  of 
2 5 p o u n ds o ver 1 6 wee ks; 1 1 % wei g ht re d ucti o n) ha d a ≥5 0 % re d ucti o n i n he patic fat fracti o n . 
T here was a si g nifica nt differe nce ( p ≤0. 0 0 3 0 ) bet wee n eac h E F X treat me nt gr o u p a n d place b o  
i n t he n u m ber of s u bjects wit h a ≥5 0 % re d ucti o n i n he patic fat fracti o n f or t he F A S. 
W he n a nal yzi n g t he M RI -P D F F E val ua ble A nal ysis Set ( defi ne d as s u bjects w h o ha d baseli ne 
a n d  Wee k  1 2  he patic  fat  fracti o n assesse d  b y  M RI -P D F F )  at  Wee k  1 2,  1 6  ( 1 0 0. 0%) ,  1 7 
( 1 0 0. 0%) , a n d 1 5 ( 1 0 0. 0%) s u bjects i n t he 2 8, 5 0, a n d 7 0 m g E F X gr o u ps , res pecti vel y, a n d 
2 ( 1 0. 0 %)  s u bjects i n t he place b o gr o u p ha d a ≥3 0 % re d ucti o n. M ore o ver, 6 8. 8 %, 1 0 0. 0 %, a n d 
9 3. 3 % of s u bjects i n t he 2 8-, 5 0-, a n d 7 0- m g E F X gr o u ps e x perie nce d a ≥5 0 % re d ucti o n i n 
he patic fat fracti o n c o m pare d t o o nl y 5. 0 % i n t he place b o gr o u p. 
 
A statisticall y si g nifica nt re d ucti o n i n A L T L S mea n val ues fr o m Baseli ne t o Wee k 1 2 was 
als o o bser ve d i n E F X treate d s u bjects ( p < 0. 0 0 0 1 f or eac h d ose gr o u p vs. Baseli ne): 2 4. 5 U/ L, 
3 0. 5 U/ L a n d 3 2. 3 U/ L i n t he 2 8, 5 0 a n d 7 0 m g gr o u ps, res pecti vel y. 
T a ble 1. 
S u m m ar y of Wee k 1 2 Effic ac y E n d p oi nts ( F ull A n al ysis Set)  
Me as ure  
Pl ace b o  
( N = 2 1) 
E F X  ( o nce wee kl y d ose) 
2 8 m g  
( N = 1 9) 
5 0 m g  
( N = 2 0) 
7 0 m g  
( N = 2 0) 
A bs ol ute re d ucti o n i n he patic fat fracti o n a ( %) 
-0. 3  
-1 2. 3 * * *  
-1 3. 4 * * *  
-1 4. 1 * * *  
N or malizati o n ( < 5 %) of he patic fat fracti o n b ( %) 
5  
2 1  
4 5  
5 0 * *  
Relati ve re d ucti o n i n he patic fat fracti o na ( %) 
0  
-6 3 * * *  
-7 1 * * *  
-7 2 * * *  
≥3 0 % Relati ve re d ucti o n i n he patic fat fracti o n b ( %) 
1 0  
8 4 * * *  
8 5 * * *  
7 5 * * *  
≥5 0 % Relati ve re d ucti o n i n he patic fat fracti o n b ( %) 
5  
5 8 * *  
8 5 * * *  
7 0 * * *  
Re d ucti o n i n A L T a ( U/ L) 
-6  
-2 4 * * *  
-3 0 * * *  
-3 2 * * *  
a 
Least -s q uares mea n c ha n ge fr o m baseli ne 
b 
Least -s q uares mea n pr o p orti o n of s u bjects 
* *  
p < 0. 0 0 4 , vers us place b o  
* * *  
p < 0. 0 0 1 , vers us place b o  
 
S u bjects w h o ac hie ve d a ≥3 0 % re d ucti o n of he patic fat fracti o n  after 1 2 wee ks treat me nt , 
were eli gi ble  f or a bi o ps y after 1 6 wee ks treat me nt. T he li ver bi o ps y a nal ysis set i ncl u de d all 
res p o n ders w h o ha d Baseli ne a n d e n d-of treat me nt li ver bi o ps y res ults. Bi o psies were 
o btai ne d fr o m 2 , 1 3, 1 3 a n d 1 4 s u bjects res pecti vel y f or t he place b o, 2 8 m g , 5 0 m g, a n d 7 0 
m g t reat me nt gr o u ps. D ue t o C O VI D- 1 9 a n d ot her s u bject s pecific iss ues, bi o psies c o ul d n ot 
be o btai ne d fr o m 8 a d diti o nal bi o ps y- eli gi ble s u bjects , w h o were all i n E F X treat me nt 
gr o u ps.  


Efr u xifer mi n  
Cli nical Trial Pr ot oc ol:  A K -U S -0 0 1 -0 1 0 2  
Pa ge 2 6  of 9 5   
 
 
 
A ker o T hera pe utics , I nc. 
C o nfi de ntial  
A me n d me nt 4, 1 8 A pr 2 0 2 2  
A res p o n der base d o n N A S was defi ne d as a s u bject wit h a decrease of ≥2 p o i nts i n N A S 
wit h at least 1 -p oi nt re d ucti o n i n eit her l o b ular i nfla m mati o n or he pat ocell ular ball o o ni n g 
wit h n o c o nc urre nt w orse ni n g of fi br osis sta ge. I n eac h of t he 2 8 m g a n d 5 0 m g gr o u ps, 
7 6. 9 % of s u bjects were res p o n ders. I n t he 7 0 m g gr o u p, 7 8. 6 % of s u bjects were res p o n ders 
(Ta ble 2 ).  Of t he 4 0 E F X s u bjects i n t he Li ver Bi o ps y E val ua ble A nal ysis Set , 5 3. 8 %, 
7 6. 9 % a n d 3 5. 7 % i n t he 2 8 m g, 5 0 m g, a n d 7 0 m g E F X gr o u ps, res pecti vel y, ha d ≥1 sta ge 
i m pr o ve me nt i n fi br osis re gressi o n (Ta ble 2 ). Neit her of t he place b o res p o n ders ha d 
re gressi o n of fi br osis. 
Of t he sa me 4 0 E F X s u bjects , a t otal of 1 1 ( 2 7. 5 %) ac hie ve d ≥2 sta ge i m pr o ve me nt i n 
fi br osis re gressi o n. T his i ncl u de d 4 s u bjects ( 3 0. 8 %) i n t he 2 8 m g gr o u p, 5 s u bjects ( 3 8. 5 %) 
i n t he 5 0 m g gr o u p, a n d 2 s u bjects ( 1 4. 3 %) i n t he 7 0 m g gr o u p. 
Res ol uti o n of N A S H (s u bjects w h o ha d a sc ore of 0- 1 f or i nfla m mati o n a n d 0 f or ball o o ni n g) 
wit h o ut w or se ni n g of fi br osis sta ge was ac hie ve d b y 4 6. 2 %, 5 3. 8 %, a n d 4 2. 9 % res pecti vel y 
of t he 2 8-, 5 0 -, a n d 7 0- m g gr o u ps (Ta ble 2) . O ne of t w o place b o s u bjects met t his e n d p oi nt.  
O verall , of t he 4 0 E F X s u bjects, 1 9 ( 4 7. 5 %) e x perie nce d res ol uti o n of N A S H wit h o ut 
w orse ni n g of fi br osis sta g e. 
T he pr o p orti o n of  s u bjects w h o ac hie ve d N A S H res ol uti o n a n d i m pr o ve me nt i n fi br osis of 
≥1 sta ge was 3 0. 8 %, 3 8. 5 %, a n d 1 4. 3 % of s u bjects res pecti vel y i n t he 2 8-, 5 0-, a n d 7 0- m g 
E F X gr o u ps, res pecti vel y. Acr oss t he 4 0 E F X s u bjects, 1 1 ( 2 7. 5 %) ac hie ve d N A S H 
res ol uti o n a n d i m pr o ve me nt of ≥1 sta ge of fi br osis ( Ta ble 2). Neit her place b o s u bject met 
t his e n d p oi nt. 
O verall , 1 9 ( 4 7. 5 %) s u bjects ac hie ve d i m pr o ve me nt i n li ver fi br osis ≥1 sta ge a n d n o w orse ni n g 
of steat o he patitis. Si x ( 4 6. 2 %) , 8 ( 6 1. 5 %), a n d 5 ( 3 5. 7 %) s u bjects i n t he 2 8, 5 0, a n d 7 0 m g 
E F X gr o u ps , res pecti vel y, a n d 0 ( 0. 0 %) s u bjects i n t he place b o gr o u p ac hie ve d i m pr o ve me nt 
i n  li ver  fi br osis ≥1 sta ge  a n d  n o  w orse ni n g  of  steat o he patitis. Of  all  E F X -treate d  s u bjects, 
5 5. 0 % e x peri e nce d fi br osis i m pr o ve me nt of ≥1 sta ge. 
T a ble 2. 
S u m m ar y of Hist ol o g y  E n d p oi nts ( Li ver Bi o ps y  A n al ysis Set)  
Me as ure ( Me a n)  
Pl ace b o  
( N = 2) 
2 8 m g  
( N = 1 3) 
5 0 m g  
( N = 1 3) 
7 0 m g  
( N = 1 4) 
Li ver bi o ps y res p o n ders base d o n N A S s yste m , n ( %)  
1 ( 5 0) 
1 0 ( 7 6. 9)  
1 0 ( 7 6. 9)  
1 1 ( 7 8. 6)  
Fi br osis re gressi o n of ≥ 1 sta ge b y N A S H C R N 
Classificati o n , n ( %) 1  
0 ( 0) 
7 ( 5 3. 8)  
1 0 ( 7 6. 9)  
5 ( 3 5. 7)  
Fi br osis re gressi o n of ≥ 1 sta ge a n d n o w orse ni n g of 
steat o he patitis 
0 ( 0. 0)    
6 ( 4 6. 2)  
8 ( 6 1. 5)    
5 ( 3 5. 7)  
I m pr o ve me nt i n li ver fi br osis ≥2 sta ges  ( %)1 
0  ( 0) 
4 ( 3 0. 8)  
5 ( 3 8. 5)  
2 ( 1 4. 3)  
N A S H res ol uti o n a n d n o w ors e ni n g of fi br osis  sta ge ( %)1 
1 ( 5 0 . 0)*  
6 ( 4 6. 2)  
7 ( 5 3. 8)  
6 ( 4 2. 3)  
N A S H res ol uti o n A N D i m pr o ve me nt i n fi br osis sta ge ( %)1 
0  ( 0) 
4 ( 3 0. 8)  
5 ( 3 8. 5)  
2 ( 1 4. 3)  
1   
 Li ver Bi o ps y E val ua ble A nal ysis Set (all s u bjects w h o ha d Baseli ne a n d e n d - of-treat me nt li ver bi o ps y res ults) 
*   
A si n gle place b o res p o n der l ost 2 5 p o u n ds o ver 1 6 wee ks ( 1 1 % wei g ht re d ucti o n)  
T he o verall meta b olic effect of E F X was i m pressi ve , a n d healt h y li p o pr otei n pr ofiles were 
rest ore d i n s u bjects prese nti n g wit h d ysli pi de mia. Si g nifica nt c ha n ges at Wee k 1 6 were 


Efr u xifer mi n  
Cli nical Trial Pr ot oc ol:  A K -U S -0 0 1 -0 1 0 2  
Pa ge 2 7  of 9 5   
 
 
 
A ker o T hera pe utics , I nc. 
C o nfi de ntial  
A me n d me nt 4, 1 8 A pr 2 0 2 2  
o bser ve d acr oss all E F X gr o u ps i n H D L- C (i ncreases ra n gi n g fr o m 1 4. 0 3 t o 1 5. 8 0 m g/ d L), 
n o n H D L- C ( decreases ra n gi n g fr o m 2 3. 3 3 t o 3 1. 4 7 m g/ d L), a n d tri gl yceri des ( decreases 
ra n gi n g fr o m 7 1. 0 3 t o 8 9. 6 2 m g/ d L). M ost i m p orta ntl y, t here were n o i ncreases i n L D L-C 
acr oss E F X gr o u ps. A d diti o nall y, a si g nifica nt L D L -C re d u cti o n was n ote d i n t he 2 8 m g E F X 
gr o u p c o m pare d t o place b o. 
 
Cli nicall y mea ni n gf ul i m pr o ve me nts i n gl yce mic c o ntr ol a n d wei g ht l oss were re p orte d at all 
d oses, i ncl u di n g t he first re p ort of si g nifica nt wei g ht l oss i n 1 c o h ort. Si g nifica nt re d ucti o ns 
at Week 1 6 were o bser ve d i n H b A 1c f or t he 5 0 a n d 7 0 m g d ose gr o u ps (- 0. 3 9 % a n d - 0. 5 0 %, 
res pecti vel y). Cli nicall y mea ni n gf ul i m pr o ve me nts were als o o bser ve d f or i ns uli n resista nce 
as meas ure d b y H O M A -I R, a di p o necti n, a n d C-pe pti de. F or H O M A -I R, si g nifica nt 
re d ucti o ns i n t he 5 0 a n d 7 0 m g E F X gr o u ps were re p orte d ( 7. 6 7 5 a n d 8. 7 7 5, res pecti vel y), 
w hile a di p o necti n le vels i ncrease d si g nifica ntl y i n a d ose-relate d fas hi o n b y 2. 8 4 8 6 t o 5. 6 4 3 7 
m g/ d L acr oss all E F X gr o u ps. As e x pecte d wit h t he i m pr o ve d i ns uli n se nsiti vit y a n d 
gl yce mic c o ntr ol, C pe pti de le vels were si g nifica ntl y l o wer i n all E F X gr o u ps ( 1. 7 2 4 t o 2. 0 6 3 
µ g/ L). Lastl y , mea n wei g ht decreases were re p orte d i n all E F X gr o u ps , wit h a statisticall y 
si g nifica nt re d ucti o n of 2. 8 0 k g ( place b o-a dj uste d 3. 2 7 k g), i n t he 7 0 m g d ose gr o u p. 
T w o  ser u m  bi o mar kers  of  li ver  fi br osis  were  meas ure d: the  dia g n ostic  mar ker  E L F  Sc ore , 
w hic h is c o m prise d of H A , TI M P - 1 a n d a mi n o ter mi nal Pr o -C 3 ; a n d Pr o-C 3 , a mar ker of ne w 
c olla ge n s y nt hesis or fi br o ge nesis.  
T here was a si g nifica nt re d ucti o n fr o m baseli ne t o Wee k 1 2/ L O C F i n L S mea n E L F S c ore 
of  - 0. 7 0 2  ( p < 0. 0 0 0 1) ,  -0. 7 4 5  ( p < 0. 0 0 0 1) ,  -0. 4 3 5  ( p = 0. 0 0 8 9)  i n  t he  2 8 , 5 0, a n d  7 0 m g  E F X 
gr o u ps, res pecti vel y. W he n c o mpare d t o place b o , t he c ha n ge fr o m baseli ne i n E L F S c ore at 
Wee k  1 2/ L O C F was statisticall y si g nifica nt f or all 3 E F X gr o u ps ( p ≤0. 0 3 4 1).  
Pr o -C 3  le vels  decrease d  fr o m  baseli ne  after  1 6  wee ks  of  treat me nt  wit h  E F X ,  i n dicati n g 
re d uce d rates of s y nt hesis of c olla ge n i n t he li ver of N A S H s u bjects. Si g nifica nt re d ucti o ns 
fr o m  baseli ne  t o  Wee k  1 6/ L O C F  i n  L S  mea n  Pr o-C 3  val ues  of -6. 0 4  ( p < 0. 0 0 0 1) ,  - 4. 7 2 
( p < 0. 0 0 0 1), a n d - 5. 9 4 µ g/ L ( p < 0. 0 0 0 1) were o bser ve d i n t he 2 8, 5 0, a n d 7 0 m g E F X gr o u ps , 
res pecti vel y.  W he n  c o m pare d  t o  place b o, t he  c ha n ge  fr o m  baseli ne  i n  Pr o-C 3  at  Wee k 
1 6 / L O C F was statisticall y si g nifica nt f or all 3 E F X gr o u ps ( p ≤0. 0 0 3 8). 
1. 4. 1. 4.  
C o ncl usi o n  
T hese i m pr o ve me nts i n t he u n derl yi n g dri ver of N A S H , li p ot o xicit y, a n d i n d o w nstrea m 
pat h ol o gical se q uelae tra nslate d i nt o a p pr o xi matel y half of E F X treate d s u bjects ( wit h e n d of 
treat me nt li ver bi o psies) meeti n g t he re g ulat or y e n d p oi nts of i m pr o vi n g fi br osis b y ≥1 F-
sta ge a n d n o w orse ni n g of N A S H, or res ol vi n g N A S H a n d n o w orse ni n g of fi br osis after 1 6 
wee ks of treat me nt. 
E F X als o a meli orate d t w o c o m m o n c o m or bi dities of N A S H: i na de q uate gl yce mic c o ntr ol 
a n d d ysli pi de mia. Cli nicall y mea ni n gf ul re d ucti o ns i n H b A 1c were ac hie ve d at o p e xisti n g 
a nti dia betic me dicati o n a n d b y e n ha nci n g i ns uli n se nsiti vit y, w hile at t he sa me ti me re d uci n g 
b o d y wei g ht. T he ma g nit u de of i m pr o ve me nt i n li p o pr otei n pr ofile were s ufficie nt t o rest ore 


Efr u xifer mi n  
Cli nical Trial Pr ot oc ol:  A K -U S -0 0 1 -0 1 0 2  
Pa ge 2 8  of 9 5   
 
 
 
A ker o T hera pe utics , I nc. 
C o nfi de ntial  
A me n d me nt 4, 1 8 A pr 2 0 2 2  
a n or mal pr ofile a p ote ntiall y i m p orta nt effect gi ve n t he s usce pti bilit y of N A S H patie nts t o 
car di o va sc ular disease. 
E F X a p peare d t o be ge nerall y well t olerate d wit h a n acce pta ble safet y pr ofile.  
1. 5.  
P h ar m ac o ki netic Res ults  
I n t y pe- 2-dia betics , f oll o wi n g a si n gle d ose, t he me dia n ti me t o reac h Cma x  ra n ge d fr o m 2 t o 5 
da ys.  F oll o wi n g S C  d osi n g, mea n E F X area u n der t he dr u g c o nce ntrati o n vers us ti me c ur ve 
( A U C) val ues i ncrease d 3 0 9-f ol d o ver t he 1 0 0-f ol d d ose ra n ge. T he mea n E F X t 1/ 2 f or t he S C  
c o h orts was a p pr o xi matel y 3. 3 da ys. T he mea n t 1/ 2 ,z was a p pr o xi matel y 2. 6 2 da ys after 
i ntra ve n o us (I V) d osi n g. O verall, t he P K of E F X de m o nstrate d sli g htl y s u pra- pr o p orti o nal 
e x p os ure. 
 
I n t y pe- 2-dia betics , f oll o wi n g m ulti ple d oses, E F X e x hi bite d a p pr o xi matel y d ose 
pr o p orti o nal P K after Q 2 W or Q W S C  a d mi nistrat i o n of 7 m g t o 1 4 0 m g. T he me dia n T ma x  
val ues ra n ge d fr o m 2 t o 3. 5 da ys f or all c o h orts.  E F X C ma x  a n d A U C i ncrease d d ose-
pr o p orti o nall y fr o m 7 m g t o 1 4 0 m g after Q 2 W or Q W S C  a d mi nistrati o n. Mi ni mal 
acc u m ulati o n was o bser ve d f oll o wi n g Q 2 W d osi n g. F oll o wi n g Q W d osi n g, m o derate 
acc u m ulati o n was o bser ve d , wit h mea n acc u m ulati o n rati os ra n gi n g fr o m 1. 5 6 t o 3. 6 1. N o 
tre n d bet wee n d ose a n d acc u m ulati o n rati o was o bser ve d. 
 
I n N A S H s u bjects, E F X e x hi bite d a p pr o xi matel y d ose- pr o p orti o nal P K after Q W 
a d mi nistrati o n  of 2 8 t o 7 0 m g; n o nc o m part me ntal para meters f or N A S H s u bjects were 
esti mate d b y a p o p ulati o n P K m o del. Relati ve t o t y pe- 2- dia betics , N A S H s u bjects e x hi bite d 
a p pr o xi matel y 4- f ol d l o wer cleara nce yiel di n g a half-life of a p pr o xi matel y 9 da ys a n d a n 
acc u m ulati o n rati o of a p pr o xi matel y 4-f ol d. D ue t o t he a p pare nt decrease i n cleara nce , Cma x  
a n d A U C are si milarl y i ncrease d a p pr o xi matel y 4 -f ol d i n N A S H s u bjects relati ve t o t he t y pe-
2- dia betics.  
1. 6.  
R ati o n ale f or t his St u d y  
N A F L D is a gl o bal healt h b ur de n; al m ost 2 5 % of t he gl o bal p o p ulati o n is affecte d b y 
N A F L D a n d/ or its c o m plicati o ns.  It is t he m ost c o m m o n c hr o nic a n d pr o gressi ve li ver 
disease , es peciall y i n i n d ustrialize d c o u ntries ( Y o u n ossi et al. 2 0 1 6 ).  It is f orecast t hat b y 
2 0 3 0 t here will be m ore t ha n 8 milli o n patie nts wit h late-sta ge N A S H i n t he U. S. (Estes et al. 
2 0 1 8 ).  T he healt h b ur de n of N A S H e xte n ds be y o n d li ver relate d o utc o mes, i.e., cirr h osis , 
H C C , li ver fail ure, a n d li ver relate d m ortalit y ( D ulai et al. 2 0 1 7 , E kste dt et al. 2 0 1 5 , 
Ha gstr ö m et al. 2 0 1 7 ) t o greatl y i ncrease d ris k of car di o vasc ular disease a n d dia betic 
c o m plicati o ns ( Y o u n ossi et al. 2 0 1 6).  I n pre- cirr h otic N A S H , car di o vasc ular disease is t he 
lea di n g ca use of m or bi dit y a n d m ortalit y (C halasa ni et al. 2 0 1 8 ). Fi br osis of t he l i ver is t he 
critical fact or dri vi n g t he pr o gressi o n fr o m N A S H t o e n d -sta ge li ver disease (A n g ul o et al. 
2 0 1 5 ).   
 
E F X is a p ote nt a n d  l o n g-acti n g F G F 2 1 a nal o g hi g hl y e x presse d i n tiss ues rele va nt t o 
meta b olic f u ncti o n , i ncl u di n g t he li ver, a di p ose tiss ue , a n d pa ncreas ( F o n Tacer et al. 2 0 1 0 , 


Efr u xifer mi n  
Cli nical Trial Pr ot oc ol:  A K -U S -0 0 1 -0 1 0 2  
Pa ge 2 9  of 9 5   
 
 
 
A ker o T hera pe utics , I nc. 
C o nfi de ntial  
A me n d me nt 4, 1 8 A pr 2 0 2 2  
Nis hi m ura et al. 2 0 0 0 ). E F X has bee n e n gi neere d t o i ncrease h u ma n F G F 2 1’s half-life (t 1/ 2) 
( u p t o 3. 5 da ys) s ufficie ntl y t o e na ble o nce wee kl y ( Q W) d osi n g, w hile retai ni n g t he nati v e 
bi ol o gical acti vit y of F G F 2 1 ( Ka uf ma n et al. 2 0 2 0 ).  T hese u ni q ue pr o perties of E F X e na ble 
its p ote ntial t o a d dress t he c ore pr ocesses u n derl yi n g N A S H pat h o ge nesis: i m pr o vi n g e ner g y 
meta b olis m i n t he li ver , re d uci n g he pat oc yte stress, miti gati n g i nfla m ma ti o n, a n d res ol vi n g 
fi br osis (Lee et al. 2 0 1 6 , Ta na ka et al. 2 0 1 5 , X u et al. 2 0 0 9 ). 
 
Data fr o m t he Mai n St u d y of t he P hase 2a st u d y A K- U S - 0 0 1- 0 1 0 1 de m o nstrates t hat E F X 
a d mi nistere d i n d oses bet wee n 2 8 a n d 7 0 m g S C Q W f or 1 6 wee ks si g nifica ntl y i m pr o ve d 
he alt h of t he li ver wit h s u bsta ntial re d ucti o ns of fat a n d i n mar kers of li ver i nj ur y. T hese 
were ass ociate d wit h e nc o ura gi n g res ol uti o n of steat o he patitis a n d cr uciall y fi br osis after j ust 
1 6 wee ks of treat me nt. I n a d diti o n , E F X i m pr o ve d w h ole b o d y meta b olic stat us wit h better 
gl yce mic c o ntr ol a n d a meli orati o n of d ysli pi de mia, c o m bi ne d wit h a clear tre n d t o wei g ht 
l oss. T hese c ha n ges esta blis h a f o u n dati o n f or s ustai ne d i m pr o ve me nt i n li ver healt h a n d 
f urt her res ol uti o n of li ver i nj ur y a n d fi br osis be y o n d t hat o bser ve d after 1 6 wee ks of 
treat me nt.   
 
T his is a  P hase 2 b , ra n d o mize d, d o u ble-bli n d , place b o -c o ntr olle d st u d y e val uati n g t he safet y 
a n d efficac y of E F X  i n n o n-cirr h otic s u bjects wit h N A S H. S u bjects will be fi br osis sta ge 2 or 
3 ( F 2 - 3) a n d d ose d wee kl y wit h E F X  or place b o. F oll o wi n g t he 2 4-Wee k a nal ysis , selecti o n 
of t he 2 8 m g or 5 0 m g E F X  d ose will be base d o n ac hie vi n g t he efficac y e n d p oi nts a n d i n 
c o nsi derati o n of t he safet y a n d e x pl orat or y a nal ysis. S u bjects will be f oll o we d f or l o n g -ter m 
safet y u ntil Wee k 9 6. 
T he d ose a n d le n gt h of a d mi nistrati o n of t he dr u g i n A K -U S - 0 0 1- 0 1 0 2 are s u p p orte d b y 
safet y data fr o m n o ncli nical st u dies a n d fr o m t he safet y a n d efficac y data fr o m t he P hase 2a 
st u d y. 
N A S H wit h fi br osis is a c o n diti o n wit h a hi g h ris k of pr o gressi o n t o cirr h osis w hic h ma y lea d 
t o e n d-sta ge li ver disease a n d i ncrease t he ris k of H C C. T h us, re versi n g t he fi br otic pr ocess 
i n a d diti o n t o a meli orati n g t he meta b olic d ysf u ncti o n t hat dri ves N A S H pat h o ge nesis is 
para m o u nt t o i m pr o vi n g t he pr o g n osis of t his c o n diti o n. T he c urre nt g ol d sta n dar d f or 
assessi n g fi br osis is li ver bi o ps y. As s uc h , i m pr o ve me nt i n li ver fi br osis wit h o ut w orse ni n g 
of N A S H as assesse d b y li ver bi o ps y will be e val uate d as t he pri mar y efficac y para meter i n 
t his P hase  2 b st u d y. Efficac y will be deter mi ne d b y c ha n ges i n li ver hist ol o g y. I n a d diti o n, 
effect of E F X o n cli nical o utc o me e ve nts will be e val uate d base d o n a dj u dicate d he patic 
cli nical e ve nt rates t hat i ncl u de he patic dec o m pe nsati o n , li ver tra ns pla ntati o n, a n d all-ca use 
m ortalit y. D ue t o t he i ncrease d ris k of car di o vasc ular m or bi dit y a n d m ortalit y i n N A S H 
(A n g ul o et al. 2 0 1 5, E kste dt et al. 2 0 1 5, Tar g her et al. 2 0 1 6 ), t he i m pact of E F X  o n 
meta b olic para meters (e. g. , li pi ds a n d i ns uli n resista nce) will be m o nit ore d a n d 
car di o vasc ular e ve nts will be pr os pecti vel y rec or de d a n d a dj u dicate d.  
H o we ver , li ver bi o ps y has n u mer o us li mitati o ns i ncl u di n g its i n vasi ve ness a n d t he p ote ntial 
f or seri o us c o m plicati o ns, w hic h deter ma n y patie nts fr o m see ki n g e val uati o n f or N A F L D or 
e nr olli n g i n cli nical trials of n o vel t hera pies. Li ver bi o ps y is als o li mite d b y c ost, sa m pli n g 
err or , a n d varia bilit y i n hist o pat h ol o gical i nter pretati o n. D ue t o t hese li mitati o ns , t he 




Efr u xifer mi n  
Cli nical Trial Pr ot oc ol:  A K -U S -0 0 1 -0 1 0 2  
Pa ge 3 1  of 9 5   
 
 
 
A ker o T hera pe utics , I nc. 
C o nfi de ntial  
A me n d me nt 4, 1 8 A pr 2 0 2 2  
1. 8.  
C o m pli a nce  
T his st u d y will be c o n d ucte d i n c o m plia nce wit h t his pr ot oc ol, G o o d Cli nical Practice ( G C P) , 
a n d all a p plica ble re g ulat or y re q uire me nts.  
 






Efr u xifer mi n  
Cli nical Trial Pr ot oc ol:  A K -U S -0 0 1 -0 1 0 2  
Pa ge 3 4  of 9 5   
 
 
 
A ker o T hera pe utics , I nc. 
C o nfi de ntial  
A me n d me nt 4, 1 8 A pr 2 0 2 2  
3.  
I N V E S TI G A TI O N A L P L A N 
3. 1.  
O ver all St u d y Desi g n a n d Pl a n  
 
T his is a  P hase 2 b , ra n d o mize d, d o u ble-bli n d , place b o -c o ntr olle d st u d y e val uati n g t he safet y 
a n d efficac y of E F X  i n n o n-cirr h otic s u bjects wit h N A S H. S u bjects will be fi br osis sta ge 2 or 
3 ( F 2 - 3) a n d d ose d wee kl y wit h E F X  or place b o.   
S u bjects meeti n g t he st u d y’s eli gi bilit y criteria will be ra n d o ml y assi g ne d i n  a 1: 1: 1 rati o i nt o 
3 treat me nt gr o u ps as s h o w n i n Fi g ure 2  bel o w. F oll o wi n g 2 4 wee ks of d osi n g, s u bjects will 
tra nsiti o n i nt o t he l o n g-ter m safet y f oll o w- u p p orti o n of t he st u d y a n d will be f oll o we d u ntil 
Wee k 9 6 . If a s u bject ref uses t o c o m plete t he Wee k 2 4 li ver bi o ps y, t he s u bject will be 
disc o nti n ue d fr o m t he st u d y at Wee k 2 4. O nl y a 3 0- Da y F oll o w - u p visit is re q uire d f oll o wi n g 
disc o nti n uati o n of st u d y dr u g. After all s u bjects ha ve c o m plete d at least 5 2 wee ks of 
treat me nt o n t heir ra n d o mize d d ose, all s u bjects ra n d o mize d t o recei ve E F X  will  r oll o ver 
i nt o a si n gle E F X d ose ar m ( 2 8 m g or 5 0 m g). T he d ose will be selecte d base d o n t he Wee k 
2 4 a nal ysis a n d i n ali g n me nt wit h re g ulat or y a ut h orit y. 
S u bjects o n place b o will re mai n i n t he sa me treat me nt gr o u p f or t he d urati o n of t he st u d y. 
After c o m pleti n g Wee k 9 6, s u bjects o n place b o will be offere d t he o pti o n t o recei ve E F X i n a 
r oll o ver st u d y.  
Fi g ure 2. 
St u d y Sc he m a  
 
 
 
R a n d o miz ati o n:  
Ra n d o mizati o n will be stratifie d b y baseli ne t y pe-2 dia betes stat us  a n d fi br osis sc ore . St u d y 
dr u g will be a d mi nistere d s u bc uta ne o usl y o nce wee kl y ( Q W). Eli gi ble s u bjects will be 
ra n d o mize d t o o ne of t hree treat me nt gr o u ps wit h a rati o of 1: 1: 1 . 
Gr o u p A:  
Place b o  
Gr o u p B:   
2 8 m g E F X  
Gr o u p C:   
5 0 m g E F X  


Efr u xifer mi n  
Cli nical Trial Pr ot oc ol:  A K -U S -0 0 1 -0 1 0 2  
Pa ge 3 5  of 9 5  
A ker o T hera pe utics , I nc. 
C o nfi de ntial  
A me n d me nt 4, 1 8 A pr 2 0 2 2  
3. 2.  
St u d y  Dur ati o n  a nd N u m ber  of Ce nters 
Partici pa ti o n i n t he st u d y ca n last u p t o 1 0 8 wee ks, w hic h i ncl u des 8 w ee ks f or  scree ni n g, 
2 4 w ee ks to t he pri mar y e n d p oi nt , l o n g-ter m f oll o w-u p f or u p t o 9 6 w ee ks, a n d 3 0 da ys of 
f oll o w-u p. 
T his stu d y will be co n d ucte d at ap pr o xi matel y 5 5  sites i n N ort h  Americ a. A d diti o nal sites  
ma y be ad de d, de pe n di n g o n s u bject accr ual rates. 
3. 3.  
E arl y Ter mi n ati o n 
If di sc o nti n uati o n of st u d y dr u g occ urs, t he s u bject s h o ul d ret ur n t o t he cli nic wit hi n 5 da ys 
t o perf orm t he Earl y Ter mi nati o n ( ET ) assess me nts. 
S u bjects  wit h o n g oin g  cli nicall y si g nifica nt cli nical or  la b orat or y fi n di n gs will be f oll o wed  
u nt il t he fi n di n g is res ol ve d  or me dicall y sta ble; reas o na ble atte m pts will be  made  t o foll o w  
u p  wit h s u bjects. The s u bject’s partici pati o n  will e n d o nce all stu d y  assess me nts a n d t he 3 0-
Da y  Foll o w- u p v isit has bee n  c o m plete d. 
T he E T  assess me nts are o utli ne d  in  the Sc he d ul e of  Assess me nts (A p pe n di x A  - B ).  
3. 4.  
3 0- D a y F oll o w- u p  
T he 3 0- Da y F oll o w- u p visit s h o ul d be co m plete d 3 0 da ys foll o wi n g t he last d os e of st u d y 
dr u g recei ve d.  
T he 3 0- Da y F oll o w- u p  assess me nts are o utli ne d i n the Sc he d ule of  Assess me nts ( A p pe n di x 
A - B).   
3. 5.  
P os t Stu d y  Care  
S u bject s ra n d o mize d to t he place b o  treat me nt arm  w h o c o m plete Wee k  9 6 will be  offere d t he 
o pt i o n to recei ve E F X in a roll o ver st u d y. 




Efr u xifer mi n  
Cli nical Trial Pr ot oc ol:  A K -U S -0 0 1 -0 1 0 2  
Pa ge 3 7  of 9 5   
 
 
 
A ker o T hera pe utics , I nc. 
C o nfi de ntial  
A me n d me nt 4, 1 8 A pr 2 0 2 2  
m.  A S T <  5 x U L N;  
n.  A L P < 2 x U L N.  
 
N ote: S u bjects meeti n g  all of t he a b o ve c o m p o ne nts will m o ve i nt o t he ne xt scree ni n g 
p hase. 
 
4.  D oc u me nte d hist orical sta bilit y ( 4 wee ks t o 6 m o nt hs pri or t o scree ni n g) of A L T a n d 
A S T le vels s h o wi n g n o w orse ni n g at scree ni n g base d o n t he f oll o wi n g:  
a. If t he hist orical a n d scree ni n g A L T a n d A S T val ues are b ot h ≤ 1. 5 × t he u p per 
li mit of n or mal ( U L N), t here is n o li mit t o t he differe nce bet wee n t he val ues.  
b.  If at least 1 of t he hist orical val ues of A L T or A S T is > 1. 5 × U L N a n d s h o ws 
w orse ni n g at scree ni n g, t he differe nce of A L T a n d A S T val ues m ust be ≤ 5 0 %.  
 
N ote: S u bject s wit h o ut hist orical A L T a n d A S T e val uati o ns ma y ha ve A L T a n d A S T 
re peate d ( Pre-Baseli ne V isit) d uri n g t he scree ni n g peri o d at mi ni m u m  4 wee ks a part  
t o c o nfir m a or b a b o ve; 
 
S u bjects w h o are i neli gi ble at t he scree ni n g or pre -baseli ne visit ma y be re -scree ne d 
or ha ve a n assess me nt re peate d o nce if t here is reas o na ble belief t hat t he e xcl usi o nar y 
res ult was o btai ne d i n err or or is tra nsie nt u p o n a p pr o val of t he Me dical M o nit or. 
5.  M RI -P D F F 
 
N ote: All s u bjects m ust c o m plete a n M RI -P D F F e xa mi nati o n d uri n g t he scree ni n g 
peri o d. H o we ver, t he M RI -P D F F  i ncl usi o n criteri o n d oes n ot a p pl y t o s u bjects wit h 
an eli gi ble  hi st orical li ver bi o ps y perf or me d ≤ 1 8 0 da ys pri or t o  ra n d o mizati o n w hic h 
c o nfir m e d fi br osis 2- 3 a n d a N A S ≥ 4. 
 
6.  Bi o ps y- pr o ve n N A S H. M ust ha ve ha d a li ver bi o ps y o btai ne d ≤ 1 8 0 da ys pri or t o  
ra n d o mizati o n wit h fi br osis sta ge 2 t o 3 a n d a n o n-alc o h olic fatt y li ver disease 
( N A F L D) acti vit y sc ore ( N A S) of ≥ 4 wit h at least a sc ore of 1 i n eac h of t he 
f oll o wi n g N A S c o m p o ne nts: 
a. Steat osis (sc ore d 0 t o 3), 
b.  Ball o o ni n g de ge nerati o n (sc ore d 0 t o 2), a nd 
c. L o b ular i nfla m mati o n (sc ore d 0 t o 3)  
7.  S u bjects o n Vita mi n E ≥ 4 0 0 I U/ da y, t hiaz oli di ne di o nes (i ncl u di n g, b ut n ot li mite d t o , 
pi o glitaz o ne, r osi glitaz o ne, a n d l o be glitaz o ne), G L P - 1 a g o nists, or S G L T 2 i n hi bit ors 
m ust be o n a sta ble d ose ( defi ne d as n o si g ni fica nt c ha n ge i n prescri pti o n efficac y , 
i nitiati o n of me dicati o n , or me dicati o n disc o nti n uati o n) f or at least 3 m o nt hs pri or t o 
t he dia g n ostic li ver bi o ps y t hr o u g h ra n d o mizati o n. A s witc h fr o m o ne dr u g t o a n ot her 
i n t he sa me class s h o ul d be disc usse d wit h t he Me dical M o nit or t o c o nfir m eli gi bilit y .   
8.  S u bjects o n a nti dia betic , wei g ht l oss, or li pi d - m o dif yi n g me dicati o n(s) m ust be o n 
sta ble d ose(s) f or at least 3 m o nt hs pri or t o t he dia g n ostic li ver bi o ps y t hr o u g h 
ra n d o mizati o n. 


Efr u xifer mi n  
Cli nical Trial Pr ot oc ol:  A K -U S -0 0 1 -0 1 0 2  
Pa ge 3 8  of 9 5   
 
 
 
A ker o T hera pe utics , I nc. 
C o nfi de ntial  
A me n d me nt 4, 1 8 A pr 2 0 2 2  
9.  Willi n g a n d a bl e t o gi ve writte n i nf or me d c o nse nt pri or t o a n y st u d y s pecific 
pr oce d ures bei n g perf or me d . 
1 0.  Fe male s u bjects of c hil d beari n g p ote ntial (see defi niti o n i n  A p pe n di x D) m ust ha ve a 
ne gati ve pre g na nc y test at scree ni n g a n d Baseli ne/ Da y 1 . 
1 1.  Male a n d fe male s u bject s of c hild beari n g p ote ntial w h o e n ga ge i n heter ose x ual 
i nterc o urse m ust a gree t o use pr ot oc ol s pecifie d met h o d(s) of c o ntrace pti o n as 
descri be d i n A p pe n di x D. 
4. 3.  
E xcl usi o n Criteri a  
S u bject s meeti n g a n y of t he f oll o wi n g criteria are n ot eli gi ble f or st u d y partici pati o n: 
1.  Wei g ht l oss > 5 % i n t he 3 m o nt hs pri or t o scree ni n g u ntil ra n d o mizati o n or fr o m t he 
ti me of t he dia g n ostic li ver bi o ps y u ntil  ra n d o mizati o n, w hic he ver is l o n ger . 
2.  Prese nce of cirr h osis o n li ver bi o ps y (sta ge 4 fi br osis).  
3.  T y pe 1 dia betes. 
4.  U nc o ntr olle d T y pe 2 dia betes defi ne d as: 
a. I ns uli n d ose a dj ust me nt > 3 5 % wit hi n 3 0 da ys pri or t o scree ni n g t hr o u g h 
ra n d o mizati o n, 
b.  S y m pt o ms of t he f oll o wi n g wit hi n 3 m o nt hs pri or t o scree ni n g: ac utel y 
dec o m pe nsate d bl o o d gl uc ose c o ntr ol (e. g., t hirst, p ol y uria, wei g ht l oss) , or a 
hist or y of dia betic ket oaci d osis, or a hist or y of h y per gl yce mic h y per os m olar state 
5.  H y p o gl yce mia u na ware ness, h os pitalizati o n d ue t o h y p o gl yce mia, or hist or y of 
se vere h y p o gl yce mia (h y p o gl yce mia re q uiri n g o utsi de assista nce t o re gai n n o r mal 
ne ur ol o gic stat us) wit hi n 3 m o nt hs pri or t o scree ni n g.  
6.  S u bjects wit h oste o p or osis, defi ne d as a T -sc ore of - 2. 5 or l o wer at scree ni n g. 
7.  P o orl y c o ntr olle d h y perte nsi o n ( s yst olic bl o o d press ure > 1 6 0 m m H g , or diast olic 
bl o o d press ure > 1 0 0 m m H g ). 
8.  A n y p ri or hist or y of dec o m pe nsate d li ver disease i ncl u di n g ascites, he patic 
e nce p hal o pat h y ( H E), or variceal blee di n g.  
9.  Hist or y of pa ncreatitis .  
N ote: S u bjects wit h  a hist or y of gallst o ne pa ncreatitis  a n d s u bse q ue nt 
c h olec ystect o m y ma y be all o we d t o partici pate u p o n a p pr o val b y t he Me dical 
M o nit or. 
1 0.  C hr o nic he patitis B vir us ( H B V) i nfecti o n  ( he patitis B s urface a nti ge n [ H Bs A g]) 
p ositi ve  or ac ute he patitis A i nfecti o n ( he patitis A I g M a nti b o d y p ositi ve). 
1 1.  C hr o nic he patitis C vir us ( H C V) i nfecti o n ( H C V a nti b o d y [ A b] a n d H C V  ri b o n ucleic 
aci d [ R N A] p ositi ve). S u bjects c ure d of H C V i nfecti o n < 2 years pri or ( base d o n date 
of R N A p ol y merase c hai n reacti o n [ P C R] ne gati ve c o nfir mati o n f oll o wi n g 
c o ncl usi o n of treat me nt) t o t he scree ni n g visit are n ot eli gi ble.  
1 2.  Pri or  ( < 2 years pri or t o scree ni n g) or pla n ne d ( d uri n g t he st u d y peri o d) bariatric 
s ur ger y (e. g., gastr o plast y , r o u x-e n-Y gastric b y pass).  S ur ger y fail ure or re versal or 
re m o val of i ntra gastric ball o o n > 2 years pri or t o scree ni n g w o ul d be acce pta ble .   


Efr u xifer mi n  
Cli nical Trial Pr ot oc ol:  A K -U S -0 0 1 -0 1 0 2  
Pa ge 3 9  of 9 5   
 
 
 
A ker o T hera pe utics , I nc. 
C o nfi de ntial  
A me n d me nt 4, 1 8 A pr 2 0 2 2  
1 3.  Ot her ca uses of li ver disease base d o n me dical hist or y a n d/ or ce ntralize d re vie w of 
li ver hist ol o g y, i ncl u di n g b ut n ot li mite d t o: alc o h olic li ver disease, a ut oi m m u ne 
dis or ders (e. g., pri mar y biliar y c h ola n gitis [ P B C] , pri ma r y scler osi n g c h ola n gitis 
[ P S C], a ut oi m m u ne he patitis) , dr u g-i n d uce d he pat ot o xicit y, Wils o n disease , cli nicall y 
si g nifica nt ir o n o verl oa d, or al p ha- 1-a ntitr ys pi n deficie nc y re q uiri n g treat me nt.  
1 4.  Hist or y of li ver tra ns pla ntati o n. 
1 5.  C urre nt or pri or hist or y of he pat ocell ular carci n o ma ( H C C).  
1 6.  Hist or y of si g nifica nt alc o h ol c o ns u m pti o n f or a peri o d of m ore t ha n 3 c o nsec uti ve 
m o nt hs wit hi n 1 year pri or t o scree ni n g; 
N ote: Si g nifica nt alc o h ol c o ns u m pti o n is defi ne d as a vera ge of > 2 0 g/ da y i n fe male 
s u bjects a n d > 3 0 g/ da y i n male s u bjects. 
1 7.  H u ma n i m m u n o deficie nc y vir us ( HI V) i nfecti o n.  
1 8.  U nc o ntr olle d car diac arr h yt h mia, or c o nfir me d Q T i nter val c orrecte d usi n g 
Fri dericia’s f or m ula ( Q Tc F) > 4 5 0 msec f or males a n d > 4 7 0 msec f or fe males at t he 
scree ni n g electr ocardi o gra m ( E C G) assess me nt . 
1 9.  M y ocar dial i nfarcti o n , u nsta ble a n gi na, perc uta ne o us c or o nar y i nter ve nti o n, c or o nar y 
arter y b y pass graft, or str o ke wit hi n 3 m o nt hs pri or t o scree ni n g. 
2 0.  Life e x pecta nc y less t ha n 2 years.  
2 1.  Use of  a n y i n vesti gati o nal me dicati o n wit hi n 3 0 da ys or wit hi n 5 half- li ves pri or t o 
scree ni n g  or c o nc urre nt partici pati o n i n a n ot her t hera pe utic cli nical st u d y . 
Partici pati o n i n a n e x peri me ntal vacci ne trial (e. g., C O VI D - 1 9 or ot her) ma y be 
acce pta ble u p o n a p pr o val b y t he me dical m o nit or. 
2 2.  S u bjects wit h a hist or y of ( wit hi n 1 2 m o nt hs pri or t o scree ni n g) or c urre nt use of 
prescri pti o n dr u gs ass ociate d wit h li ver steat osis (e. g. met h otre xate , a mi o dar o ne, 
hi g h- d ose estr o ge n, ta m o xife n, s yste mic ster oi ds, a na b olic ster oi ds, val pr oic aci d). 
S h ort c o urses of s yste mic c ortic oster oi ds (less t ha n t w o wee ks) a n d p h ysi ol o gical 
h or m o ne re place me nt t hera p y ma y be all o we d pri or t o scree ni n g if i n t he 
I n vesti gat or’s o pi ni o n t he y are n ot ass ociate d wit h li ver steat osis or cli nicall y 
rele va nt. 
2 3.  P ositi ve uri ne dr u g scree n f or a m p heta mi nes , c ocai ne or o piates (e. g. , her oi n, 
m or p hi ne) at scree ni n g. S u bjects o n sta ble met ha d o ne or b u pre n or p hi ne mai nte na nce 
treat me nt f or at least 6 m o nt hs pri or t o scree ni n g ma y be i ncl u de d i n t he st u d y. 
S u bjects wit h a p ositi ve uri ne dr u g scree n d ue t o prescri pti o n me dicati o n (e. g., 
o pi ates, met h yl p he ni date) are eli gi ble if t he prescri pti o n a n d dia g n osis are re vie we d 
a n d a p pr o ve d b y t he I n vesti gat or.  
2 4.  U na ble t o safel y u n der g o a li ver bi o ps y. 
2 5.  S u bjects w h o ha ve c o n trai n dicati o ns t o M R i ma gi n g (e. g., u n ma na ge a ble 
cla ustr o p h o bia, certai n metal i m pla nts , or u na ble t o fit wit hi n M R sca n ner d ue t o 
girt h ). 
2 6.  Prese nce of a n y la b orat or y a b n or malit y or si g nifica nt s yste mic or maj or ill nesses 
( ot her t ha n li ver disease) t hat, i n t he o pi ni o n of t he I n vesti gat or, c o m pr o mise t he 
s u bject’s a bilit y t o safel y partici pate i n a n d c o m plete t he st u d y i ncl u di n g, b ut n ot 
li mite d t o:  


Efr u xifer mi n  
Cli nical Trial Pr ot oc ol:  A K -U S -0 0 1 -0 1 0 2  
Pa ge 4 0  of 9 5   
 
 
 
A ker o T hera pe utics , I nc. 
C o nfi de ntial  
A me n d me nt 4, 1 8 A pr 2 0 2 2  
a. P ul m o nar y disease , heart fail ure , re nal fail ure, or ga n tra ns pla ntati o n, seri o us 
ps yc hiatric disease , mali g na nc y, hist or y of s u bsta nce a b use a n d/ or a ps yc hiatric 
c o n diti o n re q uiri n g h os pitalizati o n a n d/ or e mer ge nc y r o o m visit wit hi n si x 
m o nt hs of scree ni n g . 
2 7.  U na vaila ble f or f oll o w -u p assess me nt or c o ncer n f or s u bject’s c o m plia nce wit h t he 
pr ot oc ol pr oce d ures.  
 


Efr u xifer mi n  
Cli nical Trial Pr ot oc ol:  A K -U S -0 0 1 -0 1 0 2  
Pa ge 4 1  of 9 5   
 
 
 
A ker o T hera pe utics , I nc. 
C o nfi de ntial  
A me n d me nt 4, 1 8 A pr 2 0 2 2  
5.  
I N V E S TI G A TI O N A L M E DI CI N A L P R O D U C T S (I M P) 
5. 1.  
R a n d o miz ati o n, Bli n di n g a n d Tre at me nt C o des  
A n I nteracti ve Res p o nse Tec h n ol o g y (IR T ) s yste m will be use d f or ce ntralize d 
ra n d o mizati o n a n d treat me nt assi g n me nt.  I n vesti gati ve site pers o n nel will o btai n t he 
treat me nt assi g n me nt fr o m t he I R T. S u bjects a n d all pers o n nel directl y i n v ol ve d i n t he 
c o n d uct of t he st u d y will be bli n de d t o treat me nt assi g n me nts. I n vesti gati o nal me dici nal 
pr o d ucts will be dis pe nse d i n a bli n de d fas hi o n t o t he s u bjects. 
5. 1. 1.  
Pr oce d ures  f or Bre a ki n g Tre at me nt C o des 
I n t he e ve nt of a me dical e mer ge nc y w here brea ki n g t he bli n d is re q uire d t o pr o vi de me dical 
care t o t he s u bject , t he In vesti gat or ma y o btai n treat me nt assi g n me nt directl y fr o m t he I R T 
f or t hat s u bject. W he n p ossi ble, A ker o rec o m me n ds b ut d oes n ot re q uire t hat t he I n vesti gat or 
c o ntact t he C R O  me dical m o nit or bef ore brea ki n g t he bli n d. Treat me nt assi g n me nt s h o ul d 
re mai n bli n de d u nless t hat k n o wle d ge is necessar y t o deter mi ne s u bject e mer ge nc y me dical 
care. T he rati o nale f or u n bli n di n g m ust be clearl y e x plai ne d i n s o urce d oc u me ntati o n a n d o n 
t he electr o nic case re p ort f or m (e C R F), al o n g wit h t he date o n w hic h t he treat me nt 
assi g n me nt was o btai ne d.  T he In vesti gat or is re q ueste d t o c o ntact t he C R O  me dical m o nit or 
pr o m ptl y i n cas e of a n y treat me nt u n bli n di n g, i nte nti o nal or acci de ntal. 
Bli n di n g of st u d y treat me nt is critical t o t he i nte grit y of t his cli nical trial a n d t heref ore , if a 
s u bject’s treat me nt assi g n me nt is discl ose d t o t he I n vesti gat or, re gar dless of reas o n, t he 
s u bject will ha ve st u d y treat me nt disc o nti n ue d. All s u bjects will be f oll o we d u ntil t heir 3 0-
Da y F oll o w- u p v isit u nless c o nse nt t o d o s o is s pecificall y wit h dra w n b y t he s u bject. 
T he C R O’s p har mac o vi gila nce a n d/ or desi g nee ma y i n de pe n de ntl y u n bli n d cases f or 
e x pedite d re p orti n g of s us pecte d u ne x pecte d seri o us a d verse reacti o ns ( S U S A Rs).  
5. 2.  
I n vesti g ati o n al Me dici n al Pr o d uct(s)  
 
E F X  is pr o vi de d i n 2 m L sterile vials fille d wit h a 1. 1 m L v ol u me at stre n gt hs of 2 8 or 
5 0 m g/ m L. E F X  will be prese nte d as a sterile , c ol orless t o sli g htl y yell o w a n d preser vati ve-
free fr oze n li q ui d.  
Place b o will be prese nte d i n a n i de ntical c o ntai ner a n d pac ka ge d t he sa me as E F X . 
After all s u bjects ha ve c o m plete d at least 5 2 wee ks of treat me nt o n t heir ra n d o mize d d ose, all 
s u bjects ran d o mize d t o recei ve E F X will r oll o ver i nt o a si n gle E F X d ose ar m ( 2 8 m g or 5 0 
m g). T he d ose will be selecte d base d o n t he Wee k 2 4 a nal ysis a n d i n ali g n me nt wit h 
re g ulat or y a ut h orit y.  
S u bjects o n place b o will re mai n i n t he sa me treat me nt gr o u p f or t he d urati o n of t he st u d y. 
After c o m pleti n g Wee k 9 6, s u bjects o n place b o will be offere d t he o pti o n t o recei ve E F X i n a 
r oll o ver st u d y. 


Efr u xifer mi n  
Cli nical Trial Pr ot oc ol:  A K -U S -0 0 1 -0 1 0 2  
Pa ge 4 2  of 9 5   
 
 
 
A ker o T hera pe utics , I nc. 
C o nfi de ntial  
A me n d me nt 4, 1 8 A pr 2 0 2 2  
Refer t o t he P har mac y Ma n ual f or f urt her i nstr ucti o ns o n E F X / place b o a d mi nistrati o n. 
I n vesti gati o nal me dici nal pr o d ucts are t o be distri b ute d t o ce nters i n t he U S a n d ot her 
partici pati n g c o u ntries s hall be la bele d t o meet a p plica ble re q uire me nts of t he U nite d States 
F o o d a n d Dr u g A d mi nistrati o n ( F D A), E ur o pea n U ni o n ( E U) G ui deli ne t o G o o d 
Ma n ufact uri n g Practice – A n ne x 1 3 (I n vesti gati o nal Me dici nal Pr o d ucts) , a n d/ or ot her l ocal 
re g ulati o ns. 
 
5. 2. 1.  
St or a ge a n d H a n dli n g  
E F X  / p lace b o v ials will arri ve fr oze n i n i n di vi d ual cart o ns  a n d m ust re mai n i n t heir 
i n di vi d ual cart o ns a n d be i m me diatel y place d i n a freezer mai ntai ne d at ≤ - 2 0° C u ntil 
pla n ne d use. T he E F X  / place b o vials s h o ul d be st ore d pr otecte d fr o m li g ht i n a sec ure n o n-
fr ost-free freezer pri or t o t ha wi n g a n d use. T he set p oi nt f or t he freezer s h o ul d be ≤ - 2 0° C. 
T he set  p oi nt is a  si n gle te m perat ure a n d s h o ul d re mai n c o nsta nt.  D o n ot refreeze E F X  / 
p lace b o after it has bee n t ha we d. 
All vials of I M P m ust be st ore d i n a sec urel y l oc ke d area , accessi ble o nl y t o a ut h orize d site .  
C o nsi derati o n s h o ul d be gi ve n t o ha n dli n g, pre parati o n, a n d dis p osal t hr o u g h meas ures t hat 
mi ni mize dr u g c o ntact wit h t he b o d y. A p pr o priate preca uti o ns s h o ul d be f oll o we d t o a v oi d 
e x p os ure w he n ha n dli n g. 
Rec or ds of t he act ual st ora ge c o n diti o ns d uri n g t he peri o d of t he st u d y m ust be mai ntai ne d 
(e. g., rec or ds of t he date a n d ti me a n d i nitials of pers o n c hec ki n g, a n d t he “ w or ki n g da y” 
te m perat ures of t he refri gerat or a n d freezer use d f or st ora ge of st u d y s u p plies, c o nti n u o us 
te m perat ure rec or di n gs, or re g ularl y mai ntai ne d te m perat ure alar m s yste ms use d i n 
c o nj u ncti o n wit h te m perat ure rec or di n g).  
T he C R O  m ust be n otifie d if a n y I MP u n der g oes te m perat ure e xc ursi o ns or if t he I M P is 
da ma ge d. I m pacte d I M P s u p pl y s h o ul d be q uara nti ne d a n d s h o ul d n ot be utilize d u ntil a n d 
u nless A ker o pers o n nel ha v e a d vise d t hat it is acce pta ble t o d o s o.  
5. 2. 2.  
D os a ge a n d A d mi nistr ati o n 
Detaile d i nf or mati o n re gar di n g t he pre parati o n a n d a d mi nistrati o n of E F X  or place b o f or t his 
st u d y is c o ntai ne d i n t he E F X  P har mac y Ma n ual.   I n vesti gati o nal me dici nal pr o d uct will be 
a d mi nistere d b y s u bc uta ne o us i njecti o n o nce wee kl y as f oll o ws:   
 
•  Place b o Q W ( n  = 4 0) 
•  2 8 m g E F X  Q W ( n  = 4 0) 
•  5 0 m g E F X  Q W ( n  = 4 0) 
T he I M P will be a d mi nistere d b y a wee kl y 1. 0 m L s u bc uta ne o us i njecti o n i nt o t he a b d o me n 
b y a q ualifie d staff me m ber at t he cli nic or utilizi n g i n -h o me n ursi n g .  T he date a n d ti me of 
i njecti o n will be rec or de d.  If i njecti o n site reacti o ns are o bser ve d, miti gati o n pr oce d ures 
s h o ul d be p ut i n place as per l ocal sta n dar d of care.  E xa m ples of miti gati o ns i ncl u de ici n g 


Efr u xifer mi n  
Cli nical Trial Pr ot oc ol:  A K -U S -0 0 1 -0 1 0 2  
Pa ge 4 3  of 9 5   
 
 
 
A ker o T hera pe utics , I nc. 
C o nfi de ntial  
A me n d me nt 4, 1 8 A pr 2 0 2 2  
t he i njecti o n site, r otati n g t he q ua dra nt of t he a b d o me n i n w hic h t he i njecti o n is a d mi nistere d, 
or pr o vi di n g a nti hista mi ne pri or t o i njecti o n.    
If s u bjects are u na ble t o atte n d st u d y visits a n d/ or st u d y ce nters are u na ble t o acc o m m o date 
o n- site visits d ue t o pa n de mics, nat ural disasters , or ot her maj or disr u pti o ns pr oce d ures will 
be p ut i n place t o all o w f or direct -t o-s u bject dr u g s hi p me nts f or utilizati o n of i n -h o me 
n ursi n g, as necessar y. 
5. 3.  
Pri or a n d C o nc o mit a nt Me dic ati o ns 
All c o nc o mita nt me dicati o n s will be rec or de d i n t he s o urce d oc u me nts a n d e C R Fs. T his 
i ncl u des c o nc o mita nt me dicati o ns ta ke n wit hi n 3 0 da ys pri or t o scree ni n g a n d a n y ta ke n 
d uri n g t he st u d y t hr o u g h e n d of t he st u d y. 
Use of a n y i n vesti gati o nal me dicati o n wit hi n 3 0 da ys or wit hi n 5 half- li ves pri or t o scree ni n g 
a n d t hr o u g h o ut t he st u d y is pr o hi bite d.  
S u bjects wit h a hist or y of ( wit hi n 1 2 m o nt hs pri or t o scree ni n g) or c urre nt use of prescri pti o n 
dr u gs ass ociate d wit h li ver steat osis (e. g. met h otre xate , a mi o dar o ne, hi g h- d ose estr o ge n, 
ta m o xife n, s yste mic ster oi ds, a na b olic ster oi ds , val pr oic aci d)  s h o ul d be e xcl u de d.   
E xa m ples of re prese ntati ve me dicati o ns t hat are pr o hi bite d or w hic h s h o ul d be use d wit h 
ca uti o n are liste d bel o w i n Ta ble 3  a n d Ta ble 4 . 
T a ble 3. 
Pr o hi bite d C o nc o mit a nt Me dic ati o ns  
Dr u g Cl ass  
A ge nts Dis all o we d  
G ui d a nce  
Select c hr o nic 
i m m u n os u p pressa nts 
 
C hr o nic s yste mic a c ortic oster oi ds  
S h ort c o urses of s yste mic 
c ortic oster oi ds (less t ha n t w o wee ks) 
ma y be all o we d pri or t o scree ni n g if i n 
t he In vesti gat or’s o pi ni o n t he y are n ot 
ass ociate d wit h li ver steat osis n or 
cli nicall y rele va nt.  
Prescri pti o n dr u gs 
ass ociate d wit h li ver 
steat osis 
Met h otre xate , a mi o dar o ne, hi g h- d ose 
estr o ge n, ta m o xife n, a na b olic ster oi ds , 
val pr oic aci d  
Pr o hi bite d fr o m wit hi n 1 2 m o nt hs pri or 
t o scree ni n g u ntil t he e n d of t he st u d y. 
a 
I ntra-artic ular , t o pical, nasal , e pi d ural, o p ht hal mic  or i n hale d r o utes are all o we d. C hr o nic s yste mic use of 
c ortic oster oi ds e q ui vale nt t o pre d nis o ne > 1 0 m g/ da y f or > 2 wee ks is n ot all o we d.  
T a ble 4. 
C o n diti o n all y  All o we d  Me dic ati o ns  
Dr u g Cl ass  
C o n diti o n all y All o we d Me dic ati o ns   
G ui d a nce  
A nti o xi da nts  
Vita mi n E a 
D oses > 4 0 0 I U/ da y m ust be sta ble f or at 
least 3 m o nt hs pri or t o t he dia g n ostic 
li ver bi o ps y. 
A nti -H y per gl yce mic 
T hera p y  
T hiaz oli di ne di o nes (i ncl u di n g , b ut n ot 
li mite d t o, pi o glitaz o ne , r osi glitaz o ne, 
M ust be o n a sta ble d ose f or at least 3 
m o nt hs pri or t o t he dia g n ostic li ver 


Efr u xifer mi n  
Cli nical Trial Pr ot oc ol:  A K -U S -0 0 1 -0 1 0 2  
Pa ge 4 4  of 9 5   
 
 
 
A ker o T hera pe utics , I nc. 
C o nfi de ntial  
A me n d me nt 4, 1 8 A pr 2 0 2 2  
Dr u g Cl ass  
C o n diti o n all y All o we d Me dic ati o ns   
G ui d a nce  
a n d l o be glitaz o ne) , G L P -1  a g o nists , or 
S G L T 2  i n hi bit orsa 
 
 
 
I ns uli n 
 
 
 
 
 
 
 
 
 
Metf or mi n  
 
 
 
 
 
 
 
S ulf o n yl ureas  or ot her a nti dia betic 
me dicati o n(s)  
 
 
 
 
 
 
 
 
 
Ot her wei g ht l oss , or li pi d -m o dif yi n g 
me dicati o n(s)  
 
bi o ps y  t hr o u g h ra n d o mizati o n. If 
p ossi ble , t he d ose of t his me dicati o n 
s h o ul d re mai n sta ble t hr o u g h t he e n d of 
treat me nt. 
 
M ust be o n a sta ble d ose(s) f or at least 3 
m o nt hs pri or t o t he dia g n ostic li ver 
bi o ps y t hr o u g h ra n d o mizati o n. If 
p ossi ble , t he d ose of t his me dicati o n 
s h o ul d re mai n sta ble t hr o u g h t he e n d of 
treat me nt. E F X is e x pecte d t o i m pr o ve 
i ns uli n se nsiti vit y, s u bjects o n i ns uli n 
wit h varia ble  bl o o d gl uc ose le vels 
s h o ul d be re mi n de d of t he s y m pt o ms of 
h y p o - a n d h y per -gl yce mia a n d h o w t o 
c orrect t he m . 
 
D ose a dj ust me nts ( b ut n ot i nitiati o n or 
disc o nti n uati o n) f or metf or mi n are 
all o we d i n t he 3 m o nt hs pri or t o 
dia g n ostic li ver bi o ps y . If p ossi ble, t he 
d ose of t his me dicati o n s h o ul d re mai n 
sta ble after war ds t hr o u g h t he e n d of 
treat me nt. 
 
 
M ust be o n a sta ble  d ose(s) f or at least 3 
m o nt hs pri or t o t he dia g n ostic li ver 
bi o ps y  t hr o u g h ra n d o mizati o n. If 
p ossi ble , t he d ose of t his me dicati o n 
s h o ul d re mai n sta ble t hr o u g h t he e n d of 
treat me nt.  E F X  is e x pecte d t o i m pr o ve 
i ns uli n se nsiti vit y, s u bjects o n 
S ulf o n yl urea s or ot her a nti dia betic 
me dicati o ns wit h varia ble  bl o o d gl uc ose 
le vels s h o ul d be re mi n de d of t he 
s y m pt o ms of h y p o- a n d h y per-gl yce mia 
a n d h o w t o c orrect t he m.  
 
M ust be o n a sta ble d ose(s) f or at least 3 
m o nt hs pri or t o t he dia g n ostic li ver 
bi o ps y  t hr o u g h ra n d o mizati o n . If 
p ossi ble , t he d ose of t his me dicati o n 
s h o ul d re mai n sta ble t hr o u g h t he e n d of 
treat me nt. 
 
a 
A sta ble d ose is defi ne d as n o c ha n ges i n prescri be d d ose , ne w me dicati o ns , or disc o nti n uati o n  
 


Efr u xifer mi n  
Cli nical Trial Pr ot oc ol:  A K -U S -0 0 1 -0 1 0 2  
Pa ge 4 5  of 9 5   
 
 
 
A ker o T hera pe utics , I nc. 
C o nfi de ntial  
A me n d me nt 4, 1 8 A pr 2 0 2 2  
5. 4.  
I n vesti g ati o n al Me dici n al Pr o d uct Acc o u nt a bilit y  
T he S p o ns or or desi g nee will s u p pl y t he I n vesti gati o nal Me dici nal Pr o d uct (I M P).  T he site 
will mai ntai n t he f oll o wi n g rec or ds: te m perat ure e xc ursi o ns, recei pt of s hi p me nts, 
dis pe nsati o n t o s u bjects, a n d ret ur n  (a n d if a p plica ble, destr ucti o n) of partiall y use d, or 
u n use d I M P. 
5. 4. 1.  
I n vesti g ati o n al Me dici n al Pr o d uct Ret ur n or Dis p os al 
At t he start of t he st u d y , t he st u d y m o nit or will e val uate t he st u d y ce nter’s st u d y dr u g 
dis p osal pr oce d ures a n d pr o vi de a p pr o priate i nstr ucti o n f or ret ur n or destr ucti o n of u n use d 
I M P s u p plies. If t he site has a n a p pr o priate Sta n dar d O perati n g Pr oce d ure ( S O P) f or dr u g 
destr ucti o n , t he site ma y destr o y use d a n d u n use d I M P s u p plies perf or me d i n acc or da nce 
wit h t he site’s ( h os pital/ p har mac y) S O P. If t he site d oes n ot ha ve acce pta ble pr oce d ures i n 
place f or dr u g destr ucti o n , arra n ge me nts will be ma de bet wee n t he site a n d A ker o ( or 
A ker o ’s re prese ntati ve) f or ret ur n of u n use d I M P s u p plies. A c o p y of t he site’s S O P will be 
o btai ne d f or ce ntral files. W here p ossi ble , I M P will be destr o ye d at t he site. U p o n st u d y 
c o m pleti o n , a c o p y of t he I n vesti gati o nal Dr u g Acc o u nta bilit y rec or ds m ust be file d at t he 
site. A n ot her c o p y will be ret ur ne d t o A ker o. If I M P is destr o ye d o n site, t he I n vesti gat or 
m ust mai ntai n acc urate rec or ds f or  all I M P destr o ye d. Rec or ds m ust s h o w t he i de ntificati o n 
a n d q ua ntit y of eac h u nit destr o ye d, t he met h o d of destr ucti o n, a n d pers o n w h o dis p ose d of 
t he I M P. All I M P rec or ds m ust be mai ntai ne d at t he site a n d c o pies m ust be s u b mitte d t o 
A ker o d uri n g a n d at t he c o ncl usi o n of t he st u d y. 


Efr u xifer mi n  
Cli nical Trial Pr ot oc ol:  A K -U S -0 0 1 -0 1 0 2  
Pa ge 4 6  of 9 5  
A ker o T hera pe utics , I nc. 
C o nfi de ntial  
A me n d me nt 4, 1 8 A pr 2 0 2 2  
6.  
S T U D Y P R O C E D U R E S
T he f oll o wi n g assess me nts will be c o n d ucte d d uri n g scree ni n g a n d at selecte d ti me p oi nts 
s pecifie d i n t he Sc he d ule of Assess me nt s (A p pe n di x A - B ).  A d diti o nal pr oce d ures dee me d 
necessar y  as part of sta n dar d of care ma y  be perf or me d at t he discreti o n of t he I n vesti gat or.   
All m issed visits an d a n y pe rf or med pr oce d ures that are n ot p r ot oc ol-s pecifie d acti vities m ust 
be d oc u me nte d i n t he s u bject’s me dical recor d a n d t he ap pr o priate eC R F.  
6. 1.  
St u d y  Proce d ures  in C ase  of Crisis Sit u ati o ns 
A d diti o nal preca uti o ns  ca n be i m ple me nte d i n case of crisis sit uati o ns (e. g. C O VI D - 1 9 
pa n de m ic, political strife , nat ural disaster) t o pr otect s u bject safet y, partic ularl y i n t he e ve nt 
t hat a s u bject is u nable  to  p h ysicall y c o me t o t he site f or a n onsite  visit a n d/ or t o be di s pe nse d 
I n vesti gati o nal Me dici nal  Pr o d uct (I MP) . In vesti gati o nal st u d y  sites m ust c o m pl y  wit h l ocal 
p u blic he alth r ules an d te m p orar y meas ures ma y be im pl eme nte d  im me diatel y  t o co m pl y  
wit h  l ocal aut h orit y’s  re q uire me nts/restricti o ns. T he  Re g ulat ory  Age nc y/I R B/ E Cs  will be 
n otifie d  i n p arallel of t hese  meas ures , as ap pr o priate. T hese a d diti o nal pr eca uti o ns re main i n 
effect o nl y  unt il t he l ocal g o ver n me nt, healt h a uth orities  an d/ or ot he r re g ulat or y b o dies lift 
t he ba n o n a n y l oc k d o w n/ is olati o n re q uire me nts/ g ui deli nes. 
Base d  o n assess me nt of ris k, an d  t o e ns ure  su bject safet y  an d  mi nimize  ris ks t o trial i nte grit y, 
t he sp o ns or de ter mi ne d t hat t he foll o wi n g o pt i o nal off-site st u d y proce d ures ca n  be 
perf or me d i n case a st u d y partici pa nt ca n n ot atte n d a n o n-site visit d uri n g  a crisis sit uati o n 
(e. g. C O VID - 1 9 pa n de mic, p olitical strife, nat ural disaster): 
•
Safet y assess m e nt via p h o ne or vi de o call , i ncl u di n g t he s u bject or pr o x y a ns weri n g
q uesti o ns a b o ut h o w t he y are feeli n g
•
S u bject’s tra vel t o a l ocal la b (if p ossi ble) f or c ollecti o n of bl o o d a n d uri ne sa m ples
a n d ot her assess me nts , wit h res ults se nt t o t he i n vesti gat or
•
Deli ver y of t he st u d y tr eat me nt t o s u bject
•
Visit t o s u bject’s h o me (e. g. m o bile healt h n ursi n g)
I n t he e ve nt of a crisis sit uati o n, t hese o pti o ns a p pl y t o all o n-site st u d y visits e xce pt f or t he 
scree ni n g visit a n d baseli ne/ra n d o mizati o n visit, w hic h m ust be perf or me d o n- site.    
T hese s ol uti o ns ca n be a p plie d de pe n di n g o n t he i n vesti gat or’s j u d g me nt of eac h case a n d t he 
s u bject’s a gree me nt. T he alter nati ve s ol uti o ns ca n be i m ple me nte d i n res p o nse t o a crisis 
pri or t o t he n otificati o n or s u b missi o n t o a n d a p pr o val of re g ulat or y  a ge ncies a n d et hics 
c o m mittees. 
Bef ore i m ple me nti n g a n y of t hese o pti o ns f or a s u bject, t he site will c o ntact t he s u bject t o 
c hec k w het her he/s he a grees wit h t he off -site pr oce d ures a n d t his will be d oc u me nte d i n t he 
s u bject’s s o urce.  


Efr u xifer mi n  
Cli nical Trial Pr ot oc ol:  A K -U S -0 0 1 -0 1 0 2  
Pa ge 4 7  of 9 5   
 
 
 
A ker o T hera pe utics , I nc. 
C o nfi de ntial  
A me n d me nt 4, 1 8 A pr 2 0 2 2  
T he s u bject will be  i n vite d t o atte n d a n o n-site visit t o c o m plete t he st u d y pr oce d ures as per 
pr ot oc ol, as s o o n as t he sit uati o n all o ws. 
6. 2.  
Scree ni n g a n d I nf or me d C o nse nt  
Bef ore s u bjects c o m me nce a n y st u d y-s pecific acti vities or pr oce d ures, t he S p o ns or re q uires a 
c o p y of t he s t u d y site’s writte n Instit uti o nal R e vie w B oar d (I R B) /I n de pe n de nt Et hics 
C o m mittee (I E C)/ Et hics C o m mittee ( E C) a p pr o val of t he pr ot oc ol, i nf or me d c o nse nt f or m 
(I C F), a n d all ot her s u bject i nf or mati o n a n d/ or recr uit me nt material, if a p plica ble. Eac h 
s u bject ( or le gall y acce pta ble re prese ntati ve) m ust si g n a n d date t he I C F bef ore partici pati n g 
i n st u d y-s pecific acti vities. 
 
After t he I C F is si g ne d , t he s u bject e nters t he scree ni n g peri o d.  Su bjects will be scree ne d u p 
t o 8 wee ks bef ore ra n d o mizati o n t o deter mi ne eli gi bilit y f or partici pati o n i n t he st u d y. T he 
scree ni n g peri o d ma y be e xte n de d u n der s pecial circ u msta nces wit h t he e x plicit a p pr o val of 
t he C R O Me dical M o nit or. S u bjects w h o are i neli gi ble at t he scree ni n g visit ma y be re -
scree ne d or ha ve a n assess me nt re peate d o nce  if t here is reas o na ble belief t hat t he 
e xcl usi o nar y res ult was o btai ne d i n err or or is tra nsie nt u p o n a p pr o val of t he Me dical 
M o nit or.   
After c o m pleti n g t he scree ni n g peri o d , t he s u bject will be e val uate d b y t he I n vesti gat or t o 
c o nfir m eli gi bilit y. A s u bject is c o nsi dere d eli gi ble f or ra n d o mizati o n  w he n t he In vesti gat or 
deci des t hat all of t he eli gi bilit y criteria are met. T he In vesti gat or will d oc u me nt t his decisi o n 
a n d date a n d ti me i n t he s u bject’s me dical rec or d. Scree n fail ure s u bjects will be e ntere d i nt o 
t he e C R F. I n vesti gat ors will mai ntai n a scree ni n g l o g of all p ote ntial s u bjects t hat i ncl u des 
li mite d i nf or mati o n a b o ut eac h s u bject, dates , a n d o utc o me of scree ni n g pr ocess (e. g. , 
ra n d o mize d i nt o st u d y, reas o n f or i neli gi bilit y, or wit h dra wal of c o nse nt). 
6. 3.  
De m o gr a p hics a n d Me dic al Hist or y  
De m o gra p hic data i ncl u di n g se x, a ge, race, a n d et h nicit y will be c ollecte d.  
T he I n vesti gat or or desi g nee will c ollect me dical a n d s ur gical hist or y t hat starte d pri or t o t he 
ti me of c o nse nt, i ncl u di n g i nf or mati o n o n t he s u bject’s c o nc urre nt me dical c o n diti o ns.  All 
fi n di n gs will be rec or de d o n t he me dical hist or y e C R F. 
6. 4.  
P h ysic al E x a mi n ati o n  
T he I n vesti gat or or desi g nee will  c o n d uct a c o m plete p h ysical e xa mi nati o n , or a s y m pt o m-
dri ve n e xa m as o utli ne d i n t he Sc he d ule of A ssess me nts. Cli nicall y rele va nt p h ysical e xa m 
fi n di n gs pri or t o t he first d ose of st u d y dr u g will be rec or de d o n t he me dical hist or y e C R F 
pa ge a n d cli nicall y  si g nifica nt fi n di n gs after t he first d ose of st u d y dr u g will be rec or de d as 
A Es . 


Efr u xifer mi n  
Cli nical Trial Pr ot oc ol:  A K -U S -0 0 1 -0 1 0 2  
Pa ge 4 8  of 9 5   
 
 
 
A ker o T hera pe utics , I nc. 
C o nfi de ntial  
A me n d me nt 4, 1 8 A pr 2 0 2 2  
At a mi ni m u m , t he c o m plete p h ysical e xa mi nati o n s h o ul d i ncl u de assess me nts of t he hea d 
a n d nec k, s ki n, ner v o us s yste m, l u n gs, car di o vasc ular s yste m , a b d o me n, t h yr oi d, l y m p h 
n o des, a n d e xtre mitie s.  
A s y m pt o m- dri ve n p h ysical e xa mi nati o n will i ncl u de assess me nt of a n y ne w s u bject 
c o m plai nts or c ha n ges fr o m baseli ne.  
P h ysical assess me nts re q uire d t o calc ulate C hil d - P u g h Sc ore ( C P Sc ore) are t o be c o m plete d 
as part of t he p h ysical e xa mi nati o n as i n dicate d i n t he Sc he d ule of Assess me nts.  
6. 5.  
Vit al Si g ns , Wei g ht, Hi p a n d W aist Circ u mfere nce  
T he f oll o wi n g vital si g n meas ure me nts will be perf or me d  as o utli ne d i n t he sc he d ule of 
assess me nts: s yst olic a n d diast olic bl o o d press ure, p ulse, res pirati o n rate, te m perat ure, 
hei g ht, wei g ht , hi p a n d waist circ u mfere nce .   
T he s u bject m ust be i n seate d or i n a se mi -rec u m be nt p ositi o n i n a reste d a n d cal m state f or at 
least 5 mi n utes bef ore vital si g ns are c ollec te d. T he p ositi o n selecte d f or a s u bject s h o ul d be 
t he sa me t hr o u g h o ut t he st u d y a n d d oc u me nte d o n t he vital si g ns e C R F. Tri plicate bl o o d 
press ure  (t o be meas ure d i n sa me ar m wit h at least t w o mi n utes rest bet wee n B P 
meas ure me nts)  a n d heart rate t o be c ollecte d at baseli ne  a n d at t he ti me p oi nts i n dicate d i n t he 
sc he d ule of assess me nts. 
Hei g ht will be meas ure d wit h o ut s h oes at scree ni n g.  
Wei g ht will be o btai ne d at scree ni n g a n d selecte d ti me p oi nts t hereafter. O n d osi n g da ys, 
wei g ht will be c ollecte d pre - d ose. Wei g ht s h o ul d be o btai ne d usi n g a cali brate d scale.  T he 
s u bject s h o ul d be wei g he d i n c o nsiste nt cl ot hi n g.  
Waist circ u mfere nce s h o ul d be meas ure d b y placi n g t he ta pe meas ure ar o u n d t he waist j ust 
a b o ve t he t o p of t he hi p b o ne. E ns ure it is s n u g a gai nst t he s ki n, b ut n ot ti g ht.  
Hi p circ u mfere nce s h o ul d be meas ure d b y placi n g t he ta pe meas ure ar o u n d t he wi dest part of 
t he b utt oc ks. E ns ure t he ta pe meas ure is parallel t o t he fl o or, a n d n ot sla nte d. 
Wei g ht, waist , a n d hi p circ u mfere nce s h o ul d be o btai ne d b y t he sa me st u d y pers o n nel as 
m uc h as p ossi ble acr oss visits f or eac h s u bject t o mi ni mize varia bilit y i n t he meas ure me nt.  
6. 6.  
1 2- Le a d Electr oc ar di o gr a p h y  
T he s u bject m ust be i n a seate d , se mi-rec u m be nt, or s u pi ne p ositi o n i n a reste d a n d cal m state 
f or at least 1 0 mi n utes bef ore E C G assess me nt is c o n d ucte d.  Eac h 1 2-lea d E C G s h o ul d be 
perf or me d pri or t o bl o o d dra ws, d osi n g (if a p plica ble), or ot her i n vasi ve pr oce d ures.  Eac h 
E C G m ust ca pt ure Q R S , Q T , Q T i nter val c orrecte d f or heart rate ( Q Tc F), R R , a n d P R 
i nter vals a n d be d oc u me nte d o n t he E C G e C R F.   


Efr u xifer mi n  
Cli nical Trial Pr ot oc ol:  A K -U S -0 0 1 -0 1 0 2  
Pa ge 4 9  of 9 5   
 
 
 
A ker o T hera pe utics , I nc. 
C o nfi de ntial  
A me n d me nt 4, 1 8 A pr 2 0 2 2  
T he I n vesti gat or or desi g nate d st u d y site p h ysicia n will re vie w , si g n, a n d date all E C Gs.   T he 
ori gi nal E C Gs will be retai ne d wit h t he s u bject’s s o urce d oc u me nts.  At t he re q uest of t he 
S p o ns or, a c o p y of t he ori gi nal E C G will be ma de a vaila ble t o t he S p o ns or. 
6. 7.  
Tr a nsie nt El ast o gr a p h y ( Fi br o Sc a n ® ) 
Tra nsie nt elast o gra p h y  will be perf or me d usi n g Fi br o Sca n ®  a n d me dia n li ver stiff ness i n 
kil o pascals ( k Pa) , i nter q uartile ra n ge/ me dia n val ue (I Q R/ M), a n d s uccess rate ( n u m ber of 
vali d s h ots/t otal n u m ber of s h ots) will be rec or de d. T he me dia n c o ntr olle d atte n uati o n 
para meter ( C A P ) a n d t he i nter q uartile ra n ge of C A P val ues will be rec or de d fr o m 
Fi br o Sca n ®  e xa mi nat i o ns.  
At least 2- 3 h o urs fasti n g is re q uire d pri or t o all elast o gra p h y assess me nts.  
 
Scree ni n g:  All s u bjects m uc h c o m plete a  Fi br o Sca n ® e xa mi nati o n d uri n g t he scree ni n g 
peri o d. H o we ver, t he me dia n li ver stiff ness  a n d C A P  i ncl usi o n criteri o n d o n ot a p pl y t o 
s u bjects wit h an eli gi ble  hist orical  li ver bi o ps y perf or me d ≤ 1 8 0 da ys pri or t o ra n d o mizati o n 
w hic h c o nfir m e d fi br osis 2- 3 a n d a N A S ≥ 4.  
 
If a hist orical val ue f or li ver stiff ness base d o n tra nsie nt elast o gra p h y is a vaila ble i n t he past 3 
m o nt hs pri or t o t he Scree ni n g Visit, t he n t he Fi br o Sca n® e xa mi nati o n  d oes n ot nee d t o be 
re peate d. T he res ults of s uc h a pre vi o us sca n are t o be rec or de d i n t he e C R F. 
6. 8.  
Li ver Bi o ps y 
All reas o na ble atte m pts s h o ul d be ma de t o ac q uire a nee dle c ore li ver bi o ps y s peci me n of at 
It is rec o m me n de d t hat a 
 nee dle 
is use d t o c ollect t he tiss ue sa m ple. It is rec o m me n de d t hat t he s u bject s h o ul d re mai n u n der 
o bser vati o n c o nsiste nt wit h t he sta n dar d of care of t hat i nstit uti o n after t he bi o ps y pr oce d ure.  
A li ver bi o ps y m ust be o btai ne d at scree ni n g t o pr o vi de t he li ver tiss ue f or ce ntral rea di n g. A 
hist orical bi o ps y t hat meets eli gi bilit y criteria ma y be acce pte d as t he scree ni n g bi o ps y if t he 
sa m ple is dee me d acce pta ble f or i nter pretati o n b y t he ce ntral rea ders. T he hist orical sa m ple 
m ust ha ve bee n ori gi nall y o btai ne d ≤ 1 8 0 da ys pri or t o  t he Ra n d o mizati o n date a n d s h o ul d 
ali g n wit h Secti o n 5. 3  Pri or a n d C o nc o mita nt Me dicati o n g ui da nce.  
If t he li ver bi o ps y fra g me nt is t o o s mall or of ba d q ualit y a n d precl u des a n a de quate rea d  
fr o m t he ce ntral rea der, t he site ma y be re q ueste d t o pr o vi de ot her a vaila ble sli des or pre pare  
ne w sli des  fr o m a n a vaila ble bl oc k of tiss ue.   
Li ver bi o psies will be se nt t o a ce ntral la b orat or y  a n d sca n ne d o n a vali date d i ma gi n g sca n ner 
a n d t he n rea d b y t w o, i n de pe n de nt, trai ne d pat h ol o gists. B ot h  pat h ol o gists will rea d t he sa me 
sli des fr o m all scree ni n g bi o psies f or eli gi bilit y.   O n  treat me nt bi o psies will be rea d wit h 
scree ni n g bi o psies i n a ra n d o m, bli n de d fas hi o n (i.e. n ot paire d) b y b ot h pat h ol o gists . If 
si g nifica nt sc ori n g differe nces e xist bet wee n t he t w o pat h ol o gists f or t he efficac y a nal yses , 
a n a dj u dicati o n meeti n g will occ ur t o o btai n c o nse ns us.  T he pr ocess f or sc ori n g of bi o psies 


Efr u xifer mi n  
Cli nical Trial Pr ot oc ol:  A K -U S -0 0 1 -0 1 0 2  
Pa ge 5 0  of 9 5   
 
 
 
A ker o T hera pe utics , I nc. 
C o nfi de ntial  
A me n d me nt 4, 1 8 A pr 2 0 2 2  
a n d mi ni mizati o n of i nter - a n d i ntra-o bser ver disc or da nce will be f urt her o utli ne d i n t he 
Bi o ps y Ma na ge me nt Pla n.  
If a li ver bi o ps y is perf or me d per sta n dar d of care o utsi de of pr ot oc ol ma n date d assess me nts, 
all p ossi ble atte m pts s h o ul d be ma de t o s u b mit t he  bi o ps y s peci me n t o t he ce ntral rea der f or 
e val uati o n. 
If li ver bi o ps y res ults are dee me d u ne val ua ble b y t he ce ntral rea der, a d diti o nal sli des ma y be 
pr o vi de d, or a re peat bi o ps y ma y be perf or me d at t he discreti o n of t he I n vesti gat or.  
If a s u bject ref uses t o c o m plete t he Wee k 2 4 li ver bi o ps y, t he s u bject will be disc o nti n ue d 
fr o m t he st u d y at Wee k 2 4 . O nl y a 3 0- Da y Foll o w - u p visit is re q uire d f oll o wi n g 
disc o nti n uati o n of st u d y dr u g.  
6. 9.  
M RI -P D F F  
T he de gree of steat osis will be meas ure d b y M RI - P D F F. S u bjects w h o ha ve 
c o ntrai n dicati o ns t o M R i ma gi n g as o utli ne d i n t he e xcl usi o n criteria s h o ul d be e xcl u de d 
fr o m t he st u d y. At least 4 h o urs fasti n g is re q uire d pri or t o all M R assess me nts.  
T he M RI -P D F F i ma ges will be a nal yze d b y a bli n de d ce ntral rea der. Please refer t o t he 
I ma gi n g Ma n ual f or M RI- P D F F i ma gi n g g ui deli nes.  
Scree ni n g:  All s u bjects m ust c o m plete a n M RI - P D F F e xa mi nati o n d uri n g t he scree ni n g 
peri o d. H o we ver, t he M RI -P D F F  i ncl usi o n criteri o n d oes n ot a p pl y t o s u bjects wit h a n 
eli gi ble hist orical li ver bi o ps y perf or me d ≤ 1 8 0 da y s pri or t o  ra n d o mizati o n w hic h  c o nfir me d 
fi br osis 2- 3 a n d a N A S ≥ 4. 
Rescree ni n g:  If a s u bject is rescree ne d wit h Me dical M o nit or a p pr o val, q ualif yi n g M RI-
P D F F res ults fr o m t he s u bject’s i nitial scree ni n g d o n ot nee d t o be res u b mitte d f or a nal ysis t o 
t he bli n de d ce ntral rea der if t he sca n is o btai ne d ≤ 4 m o nt hs pri or t o ra n d o mizati o n. 
6. 1 0.  D X A Sc a n  
A D X A sca n s h o ul d i ncl u de l u m bar s pi ne, fe m oral nec k, a n d t otal hi p wit h s u bjects i n t he 
sta n dar d (s u pi ne) p ositi o n. 
Rescree ni n g : If a s u bject is rescree ne d wit h Me dical M o nit or a p pr o val, q ualif yi n g D X A 
sca n res ults fr o m t he s u bject’s i nitial scree ni n g d o n ot nee d t o be res u b mitte d f or a nal ysis t o 
t he bli n de d ce ntral rea der if t he sca n is o btai ne d ≤ 6 m o nt hs pri or t o ra n d o mizati o n. 
Please refer t o t he I ma gi n g Ma n ual f or D X A i ma gi n g g ui deli nes. 


Efr u xifer mi n  
Cli nical Trial Pr ot oc ol:  A K -U S -0 0 1 -0 1 0 2  
Pa ge 5 1  of 9 5  
A ker o T hera pe utics , I nc. 
C o nfi de ntial  
A me n d me nt 4, 1 8 A pr 2 0 2 2  
6. 1 1.  C hr o nic Li ver Dise as e Q uesti o n n aire - N o n alc o h olic Ste at o he p atitis  
( C L D Q-N A S H ) 
T he  C LD Q -N A S H  as ks q ue sti o ns relate d t o li ver disease a n d s pecifically  N A S H , to  meas ure 
healt h  relate d q ualit y of life i n s u bjects wit h c hr o nic li ver  disease. It is rec o m me n ded t hat the 
q uesti o n naire be c o m plete d pri or t o a n y st u d y pr oce d ures b ei n g perf or me d an d pri or t o the 
s u bject seei n g a healt h care pr o vi der.  If the baseli ne q uesti o n nair e is misse d  at Baseli ne/ Da y  
1, t he q ues tio n naire sh o ul d n ot be collecte d at the re mai ni n g ti me p oi nts.   
6. 1 2.  L ifest yle G ui d a nce  
A ll su bjects  will recei ve co u nseli n g r e gar di n g lifest yle incl u di n g the mai nte na nce of a 
healt h y d iet an d p h ys ical acti vit y at the  Scree ni n g  visit .  At eac h s u bse q ue nt vi sit, su bjects 
will  be as ke d if there has bee n  a si g nifica nt c ha n ge i n diet or p h ys ical acti vit y. C ha n ges will 
be d oc u me nte d i n t he eC R F. 
6. 1 3.  C li nic al L a b or at or y Tests 
6. 1 3. 1.  
L a b or at or y P ar a meters 
Bl o o d  sa mples will  be c ollecte d  acc or di n g to  the Sc he d ule of  Assess me nts ( A p pe n di x A - B ) 
a n d bel o w. Sa m ples w ill be se nt to t he ce ntral la b orat or y f or a nal ysis an d re p orti n g.  Sa m ples 
ma y be anal yze d f or t he tests o u tli ne d i n t his p r ot oc ol an d f or a n y a d diti o nal tests ne cessar y 
t o e ns ure s u bject safet y. T hese ma y i ncl u de, b ut are n ot li mite d  to, i n vesti gati o n of 
u ne x pect e d res ults a n d i nc urre d sa m ple rea nal ysis.  
At  visits w here in dicate d, s a m ples s h o ul d be collecte d i n t he m or ni n g f oll o wi n g a n o ver ni g ht 
fast of at least 8 or 1 2 h o urs. 
S u bject s will be i n a seate d, se mi-rec u m be nt, or su pi ne p os iti o n d uri n g bl o o d c ollecti o n. 
Cli nical la b orat or y  tests will i ncl u de t he f oll o wi n g:  


Efr u xifer mi n  
Cli nical Trial Pr ot oc ol:  A K -U S -0 0 1 -0 1 0 2  
Pa ge 5 2  of 9 5   
 
 
 
A ker o T hera pe utics , I nc. 
C o nfi de ntial  
A me n d me nt 4, 1 8 A pr 2 0 2 2  
T a ble 5. 
Cli nic al L a b or at or y Assess me nts  
C he mistr y  
He m at ol o g y/ C o a g ul ati o n  Uri ne/ Miscell a ne o us  
Bi o m ar kers  
S o di u m  
P otassi u m  
C hl ori de  
Bicar b o nate  
Calci u m  
Ma g nesi u m  
P h os p h or us  
Gl uc ose b 
B U N  
Creati ni ne  
T otal pr otei n  
Al b u mi n  
Uric aci d  
L D H  
T otal ( T B L) a n d 
direct bilir u bi n  
Al kali ne p h os p hatase 
( A L P) 
A L T ( S G P T)  
A S T ( S G O T)  
G G T  
C K 
hs C R P 
A m ylase  
Li pase c 
3 H y dr o x y b ut yrate  
H b A 1c  
 
Li p o pr otei ns  
L p (a)  
N M R Li p o Pr ofile b 
(i ncl u des T otal 
C h olester ol , H D L - C, 
L D L - C, L D L - P, 
Tri gl yceri des)  
 
 
He m at ol o g y  
R B C c o u nt  
He m o gl o bi n ( H g b) 
He mat ocrit ( Hct)  
Platelet c o u nt  
 
W B C c o u nt wit h 
differe ntial: ne utr o p hils , 
l y m p h oc ytes, m o n oc ytes , 
e osi n o p hils, a n d bas o p hils  
 
A N C  
 
C o a g ul ati o n  
P T  
a P T T 
I N R 
P AI - 1 
Fi bri n o ge n  
 
Ge netic S u bst u d y  
 
 
Uri ne  
Dr u g scree ni n g: 
a m p heta mi nes , 
c ocai ne a n d o piates 
(i.e., her oi n , 
m or p hi ne)  
 
Miscell a ne o us  
Scree ni n g Ser ol o g y 
Tests  
H Bs A g  
H Bc A b  
H B V D N A  
He p A I g M  
A nti -H C V a nti b o d y  
H C V R N A  
HI V  
 
E n d o ge n o us F G F 2 1 b 
 
 
Pre g na nc y test a 
 
P har mac o ki netics 
( P K) 
 
A nti E F X  a nti b o d y 
( A D A) 
Ne utralizi n g A nti E F X  
a nti b o d y ( N A B)  
Fi br osis Bi o m ar kers  
E L F  
Pr o- C 3 
C 3 M 
NI S - 4d 
 
B o ne Bi o m ar kers  
P 1 N P  
C T X- 1 b 
 
Li pi d Met a b olis m  
Bi o m ar kers  
A p o B & A p o C 3  
 
I ns uli n Se nsiti vit y & 
Gl yce mic C o ntr ol  
Bi o m ar kers  
I ns uli n 
A di p o necti n  
C- Pe pti de  
H O M A -I Rb 
 
 
 
A D A  = a nti-dr u g a nti b o dies; A L T = ala ni ne a mi n otra nsferase; A N C  = a bs ol ute ne utr o p hil c o u nt; A p o  = A p oli p o pr otei n; 
A S T = as partate a mi n otra nsferase; a P T T  = acti vate d partial t hr o m b o plasti n ti me; B U N  = bl o o d urea nitr o ge n; E L F  = 
E n ha nce d Li ver Fi br osis pa nel; G G T  = ga m ma -gl uta m yl tra nsferase; H b A 1c  = Gl ycate d He m o gl o bi n A 1c; H Bc A b  = t otal 
he patitis B c ore a nti b o d y; H Bs A g  = he patitis B s urface a nti ge n; H B V D N A  = he patitis B vir us de o x yri b o n ucleic aci d; H C V  
= he patitis C vir us; H D L - C = hi g h d e nsit y li p o pr otei n c h olester ol; HI V  = h u ma n i m m u n o deficie nc y vir us; H O M A -I R = 
H o me ostatic M o del  Assess me nt of I ns uli n Resista nce; hs C R P  = hi g h se nsiti vit y C -Reacti ve Pr otei n; I N R  = I nter nati o nal 
N or malize d Rati o; L D H  = lactate de h y dr o ge nase; L D L- C = lo w de nsit y li p o pr otei n c h olester ol; L D L -P = l o w de nsit y 
li p o pr otei n particle; L p = Li p o pr otei n ; L & H MW = l o w a n d hi g h m olec ular wei g ht; N M R = n uclear ma g netic res o na nce; 
P AI - 1 = Plas mi n o ge n Acti vat or I n hi bit or -1; Pr o - C 3 = N-ter mi nal T y pe III C olla ge n Pr o pe pti de; P T = pr ot hr o m bi n ti me; 




Efr u xifer mi n  
Cli nical Trial Pr ot oc ol:  A K -U S -0 0 1 -0 1 0 2  
Pa ge 5 4  of 9 5   
 
 
 
A ker o T hera pe utics , I nc. 
C o nfi de ntial  
A me n d me nt 4, 1 8 A pr 2 0 2 2  
a n d ne gati ve, will be c o m m u nicate d t o t he sites. M ore  fre q ue nt testi n g (e. g., e ver y m o nt h) or 
testi ng f or a l o n ger peri o d of ti me ma y be re q ueste d i n t he e ve nt of safet y-relate d c o ncer ns. 
F oll o w- u p testi n g is n ot re q uire d  w here it is esta blis he d t hat t he s u bject di d n ot recei ve E F X . 
6. 1 7.  Bl o o d St or a ge 
A p orti o n of t he bl o o d sa m ples dra w n at st u d y visits will be fr oze n a n d st ore d.  T he st ore d 
sa m ples ma y be use d f or f ut ure cli nical la b orat or y testi n g t o pr o vi de a d diti o nal cli nical data.  
N o h u ma n ge netic testi n g will be perf or me d wit h o ut e x presse d c o nse nt of st u d y s u bjects.  At 
t he c o ncl usi o n of t he st u d y, t hese sa m ples ma y be retai ne d i n st ora ge b y A ker o f or a peri o d 
of u p t o 1 5 years  or per l ocal g ui deli nes. 
6. 1 8.  Bi o m ar kers 
T he bi ol o gical s peci me ns c ollecte d i n t his st u d y will be use d t o e val uate t he ass ociati o n of 
e x pl orat or y s yste mic bi o mar kers wit h st u d y dr u g res p o nse, i ncl u di n g efficac y a n d/ or A Es 
a n d t o i ncrease k n o wle d ge a n d u n dersta n di n g of t he bi ol o g y of h o w E F X  affects s u bjects 
wit h N A S H . Bi ol o gical s peci me ns ma y  als o be use d t o i ncrease t he k n o wle d ge of diseases 
s uc h as N A F L D, li ver fi br osis, i nfla m mat or y diseases, b o ne t ur n o ver , a n d/ or t he vali dati o n of 
a c o m pa ni o n dia g n ostic if a p plica ble. T he s pecific a nal yses will i ncl u de , b ut will n ot be 
li mite d t o, t he bi o mar kers a n d assa ys descri be d i n Ta ble 5 .  As bi o mar ker scie nce is a ra pi dl y 
e v ol vi n g area of i n vesti gati o n, a n d A Es i n partic ular are diffic ult t o pre dict , it is n ot p ossi ble 
t o s pecif y pr os pecti vel y all tests t hat will be perf or me d o n t he s peci me ns pr o vi de d. T he 
testi n g o utli ne d is base d u p o n t he c urre nt state of scie ntific k n o wle d ge a n d ma y be m o difie d 
d uri n g or after t he e n d of t he st u d y t o re m o ve tests n o l o n ger i n dicate d a n d/ or t o a d d ne w 
tests base d u p o n t he ne west tec h n ol o gies. 
Sa m ples will be destr o ye d n o later t ha n 1 5 years after t he e n d of t he st u d y. T he s peci me n 
st ora ge peri o d will be i n acc or da nce wit h t he I R B/I E C/ E C a p pr o ve d I C F a n d a p plica ble laws 
(e. g., healt h a ut h orit y re q uire me nts).  
6. 1 9.  S u bject Rete nti o n  
Gi ve n t he b ur de n of st u d y assess me nts, l o n g st u d y d urati o n, a n d p ote ntial c o m mercial 
a vaila bilit y of treat me nts f or s u bjects wit h N A S H , mai ntai ni n g s u bject rete nti o n i n a l o n g-
ter m, place b o -c o ntr olle d cli nical o utc o mes st u d y c o ul d be c halle n gi n g. T he o bjecti ve of t he 
s u bject rete nti o n pla n is t o descri be t he acti vities a n d tactics t hat ca n be i m ple me nte d wit h 
t he g oal of retai ni n g s u bjects o n treat me nt a n d i n f oll o w- u p t hr o u g h t he cli nical o utc o mes 
p orti o n of t he st u d y. T o ac hie ve t his o bjecti ve, t he f oll o wi n g t y pes of a p pr oac hes ma y be 
a p plie d: 
Site S u p p ort a n d T actics  
O ur ai m will be t o pr o vi de t he sites wit h t he s u p p ort a n d t o ols t o e nc o ura ge be ha vi ors t hat 
o pti mize s u bject e n ga ge me nt , rete nti o n a n d c o m plia nce:  


Efr u xifer mi n  
Cli nical Trial Pr ot oc ol:  A K -U S -0 0 1 -0 1 0 2  
Pa ge 5 5  of 9 5   
 
 
 
A ker o T hera pe utics , I nc. 
C o nfi de ntial  
A me n d me nt 4, 1 8 A pr 2 0 2 2  
•  C R O staff a n d A ker o staff will mai ntai n re g ular c o ntact (i.e. tele p h o ne calls or i n- pers o n 
as a vaila ble) wit h t he sites t o s pecificall y disc uss rete nti o n a n d c o m plia nce at t hat site a n d 
t o e xc ha n ge a n d s hare e x perie nce a n d best practices. 
•  Site ne wsletters e m p hasizi n g rete nti o n tactics a n d metrics will be e m pl o ye d. Rete nti o n 
Trai ni n g We bi nars will be hel d t o rei nf orce pr o gress a n d s hare i deas acr oss sites.  
•  Site s u p p ort materials will be pr o vi de d t o m oti vate a n d assist sites i n e n ga gi n g i n s u bject 
rete nti o n acti vities. 
•  C R O staff a n d A ker o staff will c o nti n ue  t o rei nf orce ke y be ha vi ors wit h site staff s uc h as: 
e nc o ura gi n g staff t o c o nti n ue b uil di n g s u bject relati o ns hi p , c o n d ucti n g re g ular c hec k -i n 
p h o ne calls or vi de o- ca pa ble tele healt h e n ga ge me nts , office visit re mi n der p h o ne calls 
a n d e ns uri n g t he Pri nci pal I n vesti gat or is prese nt at st u d y visits, tal ki n g directl y t o t he 
s u bject a n d re-e nf orci n g t he i m p orta nce of t heir st u d y partici pati o n.  
•  Pr o vi de s u p p ort t o mi ni mize l ost t o f oll o w- u p t hr o u g h use of a t hir d- part y i n vesti gati ve 
ser vice t o searc h f or s u bject locati o n a n d c o ntact i nf or mati o n , vital stat us researc h , a n d 
deat h certificate retrie vals.  
Details of t he materials a n d t o ols t o be utilize d are o utli ne d i n t he S u bject Recr uit me nt & 
Rete nti o n Pla n.  
6. 2 0.  Criteri a f or Disc o nti n u ati o n of St u d y Dr u g  
St u d y dr u g m us t be disc o nti n ue d i n t he f oll o wi n g i nsta nces: 
 
•  Li ver -relate d cli nical e ve nt t hat warra nts disc o nti n uati o n as deter mi ne d b y t he He patic 
E ve nts A dj u dicati o n C o m mittee.  
•  S u bject de vel o ps a n S A E c o nsisti n g of a seri o us h y perse nsiti vit y reacti o n t o st u d y dr u g. 
•  S u bject e x perie nces diarr hea t hat meets t he criteria i n Secti o n 6. 2 4  f or disc o nti n uati o n.   
•  S u bject e x perie nces a Gra de I V C o m m o n Ter mi n ol o g y Criteria f or A d verse E ve nts 
(C T C A E ) or meets t he criteria f or Dr u g I n d uce d Li ver I nj ur y descri be d i n  Secti o n 6. 2 6 . 
 T he Data M o nit ori n g C o m mittee ( D M C ) s h o ul d perf or m a ca usalit y assess me nt. T he 
st u d y dr u g ma y be restarte d if t he D M C c o ncl u des t hat t he A E or la b orat or y 
a b n or malities were n ot  relate d t o st u d y dr u g, t he A E has res ol ve d, la b orat or y 
a b n or malities ha ve ret ur ne d t o baseli ne, a n d t he s u bject is a me na ble t o cl ose cli nical 
f oll o w- u p. 
 If, after re-c halle n ge, a s u bject has a sec o n d A E or rec urre nt ele vati o ns (e ve n mil d or 
mi ni mal) of t o tal bilir u bi n, A L T , or A S T as defi n e d i n Secti o n 6. 2 6. 3 , st u d y dr u g 
s h o ul d be disc o nti n ue d per ma ne ntl y. 


Efr u xifer mi n  
Cli nical Trial Pr ot oc ol:  A K -U S -0 0 1 -0 1 0 2  
Pa ge 5 6  of 9 5  
A ker o T hera pe utics , I nc. 
C o nfi de ntial  
A me n d me nt 4, 1 8 A pr 2 0 2 2  
•
U nacce pta ble t o xicit y or t o xicit y t hat , i n t he j u d g me nt of t he I n vesti gat or or t he S p o ns or,
c o m pr o mises t he a bilit y t o c o nti n ue st u d y- s pecific proce d ures or is c o nsi dere d t o n ot be
i n t he s u bject’s best i nterest.
•
Si g nifica nt s u bject n o nc o m plia nce  i ncl u di n g ref usal t o c o m plete t he Wee k 2 4 li ver
bi o ps y.
•
Si g nifica nt pr ot oc ol vi olati o n t hat i m pacts s u bject safet y .
•
Pre g na nc y d uri n g t he st u d y; refer t o A p pe n di x D .
•
Disc o nti n uati o n of t he st u d y at t he re q uest of A ker o, a re g ulat or y a ge nc y , or a n
I R B/I E C/ E C.
6. 2 1.  I nterr u pti o n of St u d y Dr u g 
If d osi n g is i nterr u pte d (i.e., as a res ult of a n A E  or i nterc urre nt ill ness t hat w o ul d affect 
assess me nts of cli nical stat us  t o a si g nifica nt de gree), e ver y atte m pt s h o ul d be ma de t o kee p 
t he s u bject i n t he st u d y a n d c o nti n ue t o perf or m t he re q uire d st u d y-relate d pr oce d ures. 
Disc ussi o n wit h t he Me dical M o nit or is rec o m me n de d. If t his is n ot p ossi ble or acce pta ble t o 
t he s u bject or I n vesti gat or, t he s u bject ma y be wit h dra w n fr o m t he st u d y.   
6. 2 2.  A d verse E ve nts  
A n A E is a n y u nfa v ora ble a n d u ni nte n de d si g n (i ncl u di n g a n a b n or mal la b orat or y fi n di n g), 
s y m pt o m, or disease te m p orall y ass ociate d wit h t he use of a  st u d y dr u g, w het her or n ot 
relate d t o t he st u d y dr u g. A Es ma y als o i ncl u de pre- or p ost-treat me nt c o m plicati o ns t hat 
occ ur as a res ult of pr ot oc ol s pecifie d pr oce d ures , lac k of efficac y, o ver d ose, dr u g 
a b use/ mis use re p orts , or occ u pati o nal e x p os ure. Pre-e xisti n g e ve nts t hat i ncrease i n se verit y 
or c ha n ge i n nat ure d uri n g or as a c o nse q ue nce of partici pati o n i n t he cli nical st u d y will als o 
be c o nsi dere d A Es. A Es t hat occ ur after t he first d ose of E F X  or d uri n g t he st u d y treat me nt 
a n d safet y f oll o w u p peri o ds will be d oc u me nte d o n t he  A E eC R F. T he I n vesti gat or will 
assess t he A E se verit y a n d relati o ns hi p of t he A E t o st u d y dr u g. T he I n vesti gat or will treat 
t he s u bject as me dicall y re q uire d.  
La b orat or y val ues t hat are o utsi de t he la b orat or y refere nce ra n ge of n or mal s h o ul d be 
re p orte d as A Es o nl y if c o nsi dere d cli nicall y si g nifica nt b y t he I n vesti gat or. 
Fr o m t he ti me of o btai ni n g i nf or me d c o nse nt u ntil 3 0 da ys after t he last a d mi nistrati o n of 
st u d y dr u g, all S A Es a n d n o n-seri o us A Es relate d t o pr ot oc ol-ma n date d pr oce d ures will be 
rec or de d o n t he S A E/ A E e C R F. All ot her u nt o war d me dical occ urre nces o bser ve d d uri n g 
scree ni n g, i ncl u di n g e xacer bati o n or c ha n ges i n me dical hist or y, will be ca pt ure d o n t he 
me dic al hist or y e C R F. Details o n rec or di n g a n d re p orti n g A Es are pr o vi de d bel o w. 
C li nical j u d g me nt of t he I n vesti gat or s h o ul d be use d t o deter mi ne w het her a s u bject is t o be 
wit h dra w n d ue t o a n A E. I n t he e ve nt t he s u bject re q uests t o wit h dra w fr o m st u d y-related 


Efr u xifer mi n  
Cli nical Trial Pr ot oc ol:  A K -U S -0 0 1 -0 1 0 2  
Pa ge 5 7  of 9 5   
 
 
 
A ker o T hera pe utics , I nc. 
C o nfi de ntial  
A me n d me nt 4, 1 8 A pr 2 0 2 2  
treat me nt or t he st u d y d ue t o a n A E, t he s u bject s h o ul d be f oll o we d f or t he safet y f oll o w u p 
peri o d as o utli ne d i n t he Sc he d ule of Assess me nts .  
All s u bjects e x perie nci n g A Es, i ncl u di n g cli nicall y si g nifica nt a b n or mal la b orat or y val ues, 
w het her or n ot ass ociate d wit h use of t he st u d y dr u g, m ust be m o nit ore d u ntil t he c o n diti o n 
ret ur ns t o n or mal, ret ur ns t o t he s u bject’s baseli ne, u ntil t he I n vesti gat or deter mi nes t he A E 
has reac he d a sta ble o utc o me a n d is n o l o n ger cli nicall y si g nifica nt , or t he s u bject is 
c o nsi dere d l ost t o f oll o w u p. 
6. 2 2. 1.  
Se verit y  
All A Es , b ot h seri o us a n d n o n-seri o us, will be assesse d f or se verit y usi n g t he 
C o m m o n Ter mi n ol o g y Criteria f or A d verse E ve nts ( C T C A E ) Versi o n 5. 0. T he C T C A E scale 
i ncl u des u ni q ue cli nical descri pti o ns of A Es t hat are cate g orize d b y a nat o m y a n d/ or 
pat h o p h ysi ol o g y a n d is pr o vi de d i n t he Site O perati o ns Ma n ual.   
T he C T C A E scale dis pla ys Gra des 1 t hr o u g h 5 wit h u ni q ue cli nical descri pti o ns of se verit y 
f or eac h A E (i ncl u di n g a b n or mal la b orat or y val ues) base d o n t his ge neral g ui deli ne pr o vi de d 
i n t he C T C A E scale.  F or a n y A Es n ot c o vere d b y C T C A E t he c o n ve nti o nal defi niti o n of 
se verit y will be use d.  
 Gra de 1 ( Mil d) A E: mi n or; n o s pecific me dical i nter ve nti o n; mar gi nal cli nical rele va nce  
 Gra de 2 ( M o derate) A E: mi ni mal i nter ve nti o n; l ocal i nter ve nti o n; n o n -i n vasi ve 
i nter ve nti o n 
 Gra de 3 ( Se vere) A E: si g nifica nt s y m pt o ms  re q uiri n g h os pitalizati o n or i n vasi ve 
i nter ve nti o n  
 Gra de 4 ( Life -t hreate ni n g or disa bli n g) A E: C o m plicate d b y ac ute, life-t hreate ni n g 
c o m plicati o ns; nee d f or i nte nsi ve care or e mer ge nt i n vasi ve pr oce d ure 
 Gra de 5 A E: Fatal  
6. 2 2. 2.  
Rel ati o ns hi p  
T he I n vesti gat or or q ualifie d s u b-I n vesti gat or is res p o nsi ble f or assessi n g t he relati o ns hi p t o 
st u d y dr u g usi n g cli nical j u d g me nt a n d t he f oll o wi n g c o nsi derati o ns: 
 N ot relate d: all A Es s h o ul d be c o nsi dere d relate d u nless t he A E is clearl y u nrelate d t o 
st u d y dr u g or clearl y  d ue t o t he s u bject’s u n derl yi n g disease.  F or a S A E , a n alter nati ve 
ca usalit y m ust be pr o vi de d ( e. g., pree xisti n g c o n diti o n, u n derl yi n g disease, i nterc urre nt 
ill ness, or c o nc o mita nt me dicati o n).  
 Relate d: T here is reas o na ble p ossi bilit y t hat t he e ve nt ma y ha ve bee n ca use d b y t he st u d y 
dr u g. 
I neffecti ve treat me nt s h o ul d n ot be re p orte d as a n A E.  
T he relati o ns hi p t o st u d y- relate d pr oce d ures (e. g., i n vasi ve pr oce d ures s uc h as ve ni p u nct ure 
or bi o ps y) s h o ul d be assesse d usi n g t he f oll o wi n g c o nsi derati o ns: 


Efr u xifer mi n  
Cli nical Trial Pr ot oc ol:  A K -U S -0 0 1 -0 1 0 2  
Pa ge 5 8  of 9 5   
 
 
 
A ker o T hera pe utics , I nc. 
C o nfi de ntial  
A me n d me nt 4, 1 8 A pr 2 0 2 2  
 N ot r elate d: E vi de nce e xists t hat t he A E has a n eti ol o g y ot her t ha n t he st u d y pr oce d ure. 
 Relate d: T he A E occ urre d as a res ult of st u d y pr oce d ures . 
6. 2 2. 3.  
St u d y  St o p pi n g R ules   
T he D M C will be c o n ve ne d base d o n e mer gi n g safet y data if a n y of t he f oll o wi n g occ ur: 
•  O ne or m ore s u bjects de vel o p t he sa me treat me nt -e mer ge nt gra de 5 a d verse e ve nt or la b 
a b n or malit y (c o nfir me d b y re peat testi n g) dee me d relate d t o E F X . 
•  T w o or m ore s u bjects de vel o p t he sa me treat me nt -e mer ge nt gra de 4 or hi g her a d verse 
e ve nt or la b a b n or mali t y (c o nfir me d b y re peat testi n g) dee me d relate d t o t he sa me d ose 
le vel of E F X . 
•  T hree or m ore s u bjects de vel o p t he sa me treat me nt -e mer ge nt gra de 3 or hi g her a d verse 
e ve nt or la b a b n or malit y (c o nfir me d b y re peat testi n g) dee me d relate d t o t he sa me d ose 
le vel of E F X . 
T he D M C will assess t he ca usalit y a n d cli nical rele va nce of t he a d verse e ve nts or la b 
a b n or malities a n d rec o m me n d t o eit her halt st u d y d osi n g f or all s u bjects, pa use 
ra n d o mizati o n, or ta ke n o acti o n. If ra n d o mizati o n or d osi n g is pa use d, it ma y be res u me d 
( wit h or wit h o ut m o dificati o ns) o nl y after f urt her re vie w of all a vaila ble safet y data a n d 
a gree me nt b y t he a p pr o priate re g ulat or y a ge ncies.      
6. 2 2. 4.  
O ver d ose  
A n o ver d ose is a n y d ose of st u d y dr u g gi ve n t o a s u bject t hat e xcee ds t he pr ot oc ol s pecifie d 
d ose b y 1 0 % or m ore.  I n t he e ve nt of a n o ver d ose- ass ociate d A E , a p pr o priate s u p p orti ve 
t hera p y s h o ul d be i nitiate d acc or di n g t o t he s u bject’s si g ns a n d s y m pt o ms. 
A n y o ver d ose, wit h or wit h o ut ass ociate d A Es , will be pr o m ptl y re p orte d t o t he S p o ns or a n d 
rec or de d as n o n-c o m plia nce o n t he e C R F. A Es ass ociate d wit h o ver d ose s h o ul d be re p orte d 
o n rele va nt A E/ S A E secti o ns i n t he e C R F.  
6. 2 2. 5.  
Seri o us A d verse E ve nts  
6. 2 2. 5. 1.  
Defi niti o n  
A S A E is defi ne d b y fe deral re g ulati o n as a n y A E occ urri n g at a n y d ose t hat res ults i n a n y of 
t he f oll o wi n g o utc o mes: deat h, life-t hreate ni n g A E, i n- patie nt h os pitalizati o n or pr ol o n gati o n 
of e xisti n g h os pitalizati o n , a persiste nt or si g nifica nt i nca pacit y or s u bsta ntial disr u pti o n of 
t he a bilit y t o c o n d uct n or mal life f u ncti o ns, or a c o n ge nital a n o mal y/ birt h defect.  
I m p orta nt me dical e ve nts t hat ma y n ot res ult i n deat h, be l ife t hreate ni n g, or re q uire 
h os pitalizati o n ma y be c o nsi dere d a n S A E w he n, base d u p o n a p pr o priate me dical j u d g me nt , 
t he y ma y je o par dize t he s u bject, a n d ma y re q uire me dical or s ur gical i nter ve nti o n t o pre ve nt 
o ne of t he o utc o mes liste d i n t his defi niti o n.  E xa m ples of s uc h me dical e ve nts i ncl u de 


Efr u xifer mi n  
Cli nical Trial Pr ot oc ol:  A K -U S -0 0 1 -0 1 0 2  
Pa ge 5 9  of 9 5   
 
 
 
A ker o T hera pe utics , I nc. 
C o nfi de ntial  
A me n d me nt 4, 1 8 A pr 2 0 2 2  
aller gic br o nc h os pas m re q uiri n g i nte nsi ve treat me nt i n a n e mer ge nc y r o o m or at h o me, bl o o d 
d yscrasias or c o n v ulsi o ns t hat d o n ot res ult i n i n patie nt h os pitalizati o n, or t he de vel o p me nt of 
dr u g de pe n de nc y or dr u g a b use. 
A life -t hreate ni n g A E is o ne t hat, i n t he vie w of t he I n vesti gat or, places t he s u bject at 
i m me diate ris k of deat h fr o m t he reacti o n as it occ urre d. 
A n u ne x pecte d A E is a n y e ve nt f or w hic h t he s pecificit y or se verit y is n ot c o nsiste nt wit h t he 
A E pr ofile i n t he c urre nt E F X  I B. 
All S A Es , re gar dless of ca use(s) or relati o ns hi p t o st u d y dr u g, m ust be re p orte d i m me diatel y 
t o t he st u d y S p o ns or a n d/ or desi g nee. 
6. 2 2. 6.  
Re p orti n g A d verse E ve nts  
6. 2 2. 6. 1.  
Re p orti n g Pr oce d ures f or N o n -Seri o us A d verse E ve nts  
T he I n vesti gat or is res p o nsi ble f or e ns uri n g t hat all A Es o bser ve d b y t he I n vesti gat or or 
desi g nee or  re p orte d b y t he s u bject are re p orte d usi n g t he A E e C R F.  
T he I n vesti g at or will assi g n t he f oll o wi n g A E attri b utes:  
 A E dia g n osis or s y n dr o me(s), if k n o w n (if n ot k n o w n, si g ns or s y m pt o ms) 
 Dates of o nset a n d res ol uti o n (if res ol ve d) 
 Se verit y  
 Relate d ness t o st u d y dr u g or st u d y- relate d pr oce d ures  
 Acti o n ta ke n  wit h st u d y treat me nt  
F oll o w- u p of n o n-seri o us A Es will c o nti n ue t hr o u g h t he last da y o n t he st u d y partici pati o n 
a n d/ or u ntil a defi niti ve o utc o me (e. g., res ol ve d, res ol ve d wit h se q uelae, l ost t o f oll o w- u p) is 
ac hie ve d. 
W he n a s u bject  is wit h dra w n fr o m t he st u d y beca use of a n o n-seri o us A E, t he S p o ns or a n d/ or 
desi g nee m ust be n otifie d b y e- mail or p h o ne wit hi n 4 8 h o urs. 
6. 2 2. 6. 2.  
Re p orti n g Pr oce d ures f or Seri o us A d verse E ve nts  
T he I n vesti gat or is res p o nsi ble f or e ns uri n g t hat all S A Es o bser ve d b y t he I n vesti gat or or 
re p orte d b y t he s u bject are pr o m ptl y assesse d a n d re p orte d.  T he I n vesti gat or m ust assess 
w het her t he S A E is relate d t o st u d y dr u g or a n y st u d y-relate d pr oce d ure.  
T he pr oce d ures f or re p orti n g S A Es are as f oll o ws:  
I nitial Re p orts 
 All S A Es occ urri n g after t he I C F has bee n si g ne d  or d uri n g t he st u d y treat me nt a n d 
safet y f oll o w u p peri o ds m ust be re p orte d t o La bc or p Cli nical Safet y wit hi n 2 4 h o urs 
of t he k n o wle d ge of t h e occ urre nce. After t he pr ot oc ol -s pecifie d re p orti n g wi n d o w, 


Efr u xifer mi n  
Cli nical Trial Pr ot oc ol:  A K -U S -0 0 1 -0 1 0 2  
Pa ge 6 0  of 9 5   
 
 
 
A ker o T hera pe utics , I nc. 
C o nfi de ntial  
A me n d me nt 4, 1 8 A pr 2 0 2 2  
a n y S A E t hat t he I n vesti gat or c o nsi ders relate d t o st u d y m ust be re p orte d t o La bc or p 
Cli nical Safet y or t he S p o ns or/ desi g nee.  
 
 T o re p ort t he S A E , c o m plete t he S A E f or m , i n dicati n g S A E criteria has bee n met, 
electr o nicall y i n t he electr o nic data ca pt ure ( E D C) s yste m f or t he st u d y. If t he e ve nt 
meets seri o us criteria a n d it is n ot p ossi ble t o access t he E D C s yste m , fa x/e mail t he 
c o m plete d pa per S A E f or m t o La bc or p Safet y at S A EI nta ke @ La bc or p.c o m or 1- 8 8 8-
8 8 7- 8 0 9 7 wit hi n 2 4 h o urs of a ware ness.  
N O T E: a n y re p orts fa xe d t o 1- 8 8 8- 8 8 7 - 8 0 9 7 will be r o ute d t o S A EI nta ke @ La bc or p.c o m. 
W he n t he E D C s yste m bec o mes a vaila ble , t he S A E i nf or mati o n m ust be e ntere d wit hi n 
2 4 h o urs. 
 
F oll o w- U p Re p orts 
 T he I n vesti gat or m ust c o nti n ue t o f oll o w t he s u bject u ntil t he S A E has s u bsi de d or 
u ntil t he c o n diti o n bec o mes c hr o nic i n nat ure , sta bilizes (i n t he case of persiste nt 
i m pair me nt) or t he s u bject dies. 
 
 Wit hi n 2 4 h o urs of recei pt of f oll o w - u p i nf or mati o n, t he I n vesti gat or m ust u p date t he 
S A E electr o nicall y i n t he E D C s yste m f or t he st u d y , a n d s u b mit a n y s u p p orti n g 
d oc u me ntati o n (e. g., s u bject disc har ge s u m mar y or a ut o ps y re p orts) t o La bc or p 
Cli nical Safet y via fa x or e -mail. If it is n ot p ossi ble t o access t he E D C s yste m , refer 
t o t he pr oce d ures o utli ne d a b o ve f or i nitial re p orti n g of S A Es.  
 
 T he S p o ns or or/ or desi g nee ma y re q uest a d diti o nal i nf or mati o n fr o m t he I n vesti gat or 
t o e ns ure t he ti mel y c o m pleti o n of acc urate safet y re p orts. 
T he I n vesti gat or m ust ta ke all t hera pe uti c meas ures necessar y f or res ol uti o n of t he S A E.  
A n y me dicati o ns or t hera pies necessar y f or treat me nt of t he S A E m ust be rec or de d i n t he A E 
f or m a n d t he c o nc o mita nt me dicati o n e C R F. 
F oll o w- u p of S A Es will c o nti n ue t hr o u g h t he last da y o n t he st u d y a n d/ or u ntil a defi niti ve 
o utc o me (e . g., res ol ve d, res ol ve d wit h se q uelae, l ost t o f oll o w- u p, fatal) is ac hie ve d. 
 
If a s u bject bec o mes pre g na nt d uri n g t he st u d y or wit hi n t he safet y f oll o w u p peri o d defi ne d 
i n t he pr ot oc ol, t he I n vesti gat or is t o st o p d osi n g wit h st u d y dr u g(s) i m me diatel y a n d t he 
s u bject s h o ul d be wit h dra w n fr o m t he st u d y treat me nt. Earl y ter mi nati o n pr oce d ures a n d 
safet y f oll o w- u p s h o ul d be i m ple me nte d at t hat ti me.   
 
A pre g na nc y is n ot c o nsi dere d t o be a n A E or S A E; h o we ver, it m ust be re p orte d t o La bc or p 
Cli nical Safet y wit hi n 2 4 h o urs of k n o wle d ge of t he e ve nt. La bc or p Cli nical Safet y will t he n 
pr o vi de t he In vesti gat or/site t he E x p os ure I n Uter o ( EI U) f or m f or c o m pleti o n. T he 
In vesti gat or/site m ust c o m plete t he EI U f or m a n d  fa x/e mail it bac k t o La bc or p  Cli nical 
Safet y.  
 


Efr u xifer mi n  
Cli nical Trial Pr ot oc ol:  A K -U S -0 0 1 -0 1 0 2  
Pa ge 6 1  of 9 5   
 
 
 
A ker o T hera pe utics , I nc. 
C o nfi de ntial  
A me n d me nt 4, 1 8 A pr 2 0 2 2  
If t he fe male part ner of a male s u bject bec o mes pre g na nt w hile t he s u bject is recei vi n g st u d y 
dr u g or wit hi n t he safet y f oll o w u p peri o d defi ne d i n t he pr ot oc ol, t he I n vesti gat or s h o ul d 
n otif y La bc or p  Cli nic al Safet y as descri be d a b o ve.  
 
T he pre g na nc y s h o ul d be f oll o we d u ntil t he o utc o me of t he pre g na nc y, w he ne ver p ossi ble.  
O nce t he o utc o me of t he pre g na nc y is k n o w n, t he f oll o w- u p EI U f or m s h o ul d be c o m plete d 
a n d fa xe d/e maile d t o La bc or p Cli nical Safet y. If  t he o utc o me of t he pre g na nc y meets t he 
criteria f or i m me diate classificati o n as a n S A E (i.e. , p ost part u m c o m plicati o n , s p o nta ne o us 
a b orti o n, still birt h, ne o natal deat h, or c o n ge nital a n o mal y) , t he I n vesti gat or s h o ul d f oll o w t he 
pr oce d ures f or re p orti n g a n S A E.  
 
S afet y C o nt act I nf or m ati o n:  
La bc or p Cli nical Safet y  
Facsi mile: U nite d States 1- 8 8 8- 8 8 7- 8 0 9 7 ( Gl o bal fa x n u m bers l ocate d i n St u d y Bi n der) 
E- mail: S A EI nta ke @ La bc or p.c o m 
S o me S A Es will q ualif y f or re p orti n g t o t he F o o d a n d Dr u g A d mi nistrati o n ( F D A) as 
a p plica ble via t he Me d Watc h/ CI O M S re p orti n g s yste m i n acc or da nce wit h F D A a n d ot her 
a p plica ble re g ulati o ns.  T he S p o ns or or its desi g nee will re p ort S A Es a n d/ or S U S A Rs as 
re quire d t o re g ulat or y a ut h orities  a n d I n vesti gat ors i n c o m plia nce wit h all re p orti n g 
re q uire me nts acc or di n g t o l ocal re g ulati o ns a n d G o o d Cli nical Practice ( G C P). 
De pe n di n g o n rele va nt l ocal le gislati o n or re g ulati o ns, i ncl u di n g t he a p plica ble U S F D A 
C o de of Fe deral Re g ulati o ns , t he E U Cli nical Trials Directi ve ( 2 0 0 1/ 2 0/ E C) a n d rele va nt 
u p dates, a n d ot her c o u ntr y- s pecific le gislati o n or re g ulati o ns, A ker o ma y be re q uire d t o 
e x pe dite t o w orl d wi de re g ulat or y a ge ncies re p orts of S A Es, seri o us a d verse dr u g reactio ns 
( S A D Rs), or S U S A Rs. I n acc or da nce wit h t he E U Cli nical Trials Directi ve ( 2 0 0 1/ 2 0/ E C) , 
A ker o or a s pecifie d desi g nee will n otif y w orl d wi de re g ulat or y a ge ncies a n d t he rele va nt 
I R B/I E C/ E C i n c o ncer ne d Me m ber States of a p plica ble S U S A Rs as o utli ne d i n c urre nt 
re g ulati o ns. 
T he I n vesti gat or will n otif y t he a p pr o priate I R B/I E C/ E C of S A Es occ urri n g at t he st u d y site 
a n d ot her A E re p orts recei ve d fr o m t he S p o ns or, i n acc or da nce wit h l ocal pr oce d ures a n d 
stat utes.  T he I n vesti gat or or desi g nee at eac h st u d y site is res p o nsi ble f or s u b mitti n g 
I n vesti gati o nal Ne w Dr u g (I N D) safet y re p orts (i nitial a n d f oll o w- u p) a n d ot her safet y 
i nf or mati o n (e. g., re vise d I n vesti gat or’s Br oc h ure) t o t he I R B/I E C/ E C a n d f or retai ni n g a 
c o p y i n t he st u d y files. 
6. 2 3.  A d verse E ve nts of S peci al I nterest  
T he I n vesti gat or will m o nit or eac h s u bject f or cli nical a n d la b orat or y-e vi de nce f or pre defi ne d 
A Es  of s pecial i nterest ( A E SIs ) t hr o u g h o ut t he s u bject’s partici pati o n i n t his st u d y. T he 
I n vesti gat or s h o ul d treat t he A E SI acc or di n g t o l ocal sta n dar d of care.  T he f oll o wi n g 
c o n diti o ns will be m o nit ore d as A E SIs d uri n g t his st u d y: 
•  I njecti o n Site R eacti o ns 


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Cli nical Trial Pr ot oc ol:  A K -U S -0 0 1 -0 1 0 2  
Pa ge 6 2  of 9 5   
 
 
 
A ker o T hera pe utics , I nc. 
C o nfi de ntial  
A me n d me nt 4, 1 8 A pr 2 0 2 2  
•  Diarr hea  
•  H y p o gl yce mia 
•  Ne ur ol o gical a n d Ps yc hiatric E ve nts 
•  Dr u g-i n d uce d li ver i nj ur y 
Dr u g-i n d uce d li ver i nj ur y will be m o nit ore d a n d ma na ge d a cc or di n g t o Secti o n 6. 2 6 . 
D uri n g t he c o urse of t he st u d y, a d diti o nal A E SIs ma y be i de ntifie d b y t he S p o ns or.  T he 
I n vesti gat or will assess a n d rec or d i n detail a n y a d diti o nal i nf or mati o n f or A E SIs o n t he A E 
e C R F f or m .  
S u bjects w h o e x perie nce gastr oi ntesti nal a d verse e ve nts w hile o n st u d y s h o ul d be ma na ge d 
acc or di n g t o l ocal sta n dar d of care i ncl u di n g c o nc o mita nt me dicati o ns t o ma na ge s y m pt o ms. 
6. 2 4.  Cli nic al L a b or at or y A b n or m alities a n d Ot her A b n or m al Assess me nts as 
A d verse E ve nts or Seri o us E ve nts  
La b orat or y a b n or malities are us uall y n ot rec or de d as A Es or S A Es , h o we ver, la b orat or y 
a b n or malities (e. g. , cli nical c he mistr y , he mat ol o g y , uri nal ysis) i n de pe n de nt of t he u n derl yi n g 
me dical c o n diti o n t hat re q uire me dical or s ur gical  i nter ve nti o n or lea d t o i n vesti gati o nal 
me dici nal pr o d uct i nterr u pti o n or disc o nti n uati o n m ust be rec or de d as a n A E, as well as a n 
S A E , if a p plica ble. I n a d diti o n, la b orat or y or ot her a b n or mal assess me nts (e. g., 
electr ocar di o gra m , X-ra ys, vital si g ns) t ha t are ass ociate d wit h si g ns a n d/ or s y m pt o ms m ust 
be rec or de d as a n A E or S A E if t he y meet t he defi niti o n of a n A E ( or S A E) as descri be d i n 
Secti o n 6. 2 2 . If t he la b orat or y a b n or malit y is part of a s y n dr o me, rec or d t he s y n dr o me or 
dia g n osis (e. g. , a ne mia) n ot t he la b orat or y res ult (i.e., decrease d he m o gl o bi n). 
Se verit y s h o ul d be rec or de d a n d gra de d acc or di n g t o t he C T C A E Versi o n 5. 0. F or A Es  
ass ociate d wit h la b orat or y a b n or malities, t he e ve nt s h o ul d be gra de d base d o n t he cli nical 
se verit y i n t he c o nte xt of t he u n derl yi n g c o n diti o ns; t his ma y or ma y n ot be i n a gree me nt 
wit h t he gra di n g of t he la b orat or y a b n or malit y.  
 
T o xicit y M a n a ge me nt 
A n y q uesti o ns re gar di n g t o xicit y ma na ge me nt s h o ul d be directe d t o t he Me dical M o nit or. 
Gr a de 1 a n d 2 L a b or at or y A b n or m alit y or Cli nic al E ve nt 
C o nti n ue i n vesti gati o nal me dici nal pr o d uct at t he discreti o n of t he I n vesti gat or.  
 
Gr a de 3 L a b or at or y A b n or m alit y or Cli nic al E ve nt  
•  F o r Gra de 3 cli nicall y si g nifica nt la b orat or y a b n or malit y or cli nical e ve nt, 
i n vesti gati o nal me dici nal pr o d uct ma y be c o nti n ue d if t he e ve nt is c o nsi dere d t o be 
u nrelate d t o i n vesti gati o nal me dici nal pr o d uct.  
 


Efr u xifer mi n  
Cli nical Trial Pr ot oc ol:  A K -U S -0 0 1 -0 1 0 2  
Pa ge 6 3  of 9 5   
 
 
 
A ker o T hera pe utics , I nc. 
C o nfi de ntial  
A me n d me nt 4, 1 8 A pr 2 0 2 2  
•  F or a Gra de 3 cli nical e ve nt , or cli nicall y si g nifica nt la b orat or y a b n or malit y 
c o nfir me d b y re peat testi n g , t hat is c o nsi dere d t o be relate d t o i n vesti gati o nal 
me dici nal pr o d uct, i n vesti gati o nal me dici nal pr o d uct s h o ul d be wit h hel d u ntil t he 
t o xicit y ret ur ns t o ≤ Gra de 2. 
 
•  If a la b orat or y a b n or malit y rec urs t o ≥ Gra de 3 f oll o wi n g re-c halle n ge wit h 
i n vesti gati o nal me dici nal pr o d uct a n d is c o nsi dere d relate d t o i n vesti gati o nal 
me dici nal pr o d uct, t he n i n vesti gati o nal me dici nal pr o d uct s h o ul d be per ma ne ntl y 
disc o nti n ue d, a n d t he s u bject ma na ge d acc or di n g t o l ocal practice. Rec urre nce of 
la b orat or y a b n or malities c o nsi dere d u nrelate d t o i n vesti gati o nal me dici nal pr o d uct 
ma y n ot re q uire per ma ne nt disc o nti n uati o n. 
 
Gr a de 4 L a b or at or y A b n or m alit y or Cli nic al E ve nt 
•  F or a Gra de 4 cli nical e ve nt or cli nicall y si g nifi ca nt Gra de 4 la b orat or y a b n or malit y 
c o nfir me d b y re peat testi n g , t he D M C s h o ul d perf or m a ca usalit y assess me nt. T he 
i n vesti gati o nal me dici nal pr o d uct ma y be restarte d if t he D M C c o ncl u des t hat t he A E 
or la b orat or y a b n or malities were n ot relate d t o st u d y dr u g, t he A E has res ol ve d, 
la b orat or y a b n or malities ha ve ret ur ne d t o baseli ne, a n d t he s u bject is a me na ble t o 
cl ose cli nical f oll o w - u p. 
•  If a la b orat or y a b n or malit y rec urs t o ≥ Gra de 4 f oll o wi n g re-c halle n ge wit h 
i n vesti gati o nal me dici nal pr o d uct a n d is c o nsi dere d relate d t o i n vesti gati o nal 
me dici nal pr o d uct, t he n i n vesti gati o nal me dici nal pr o d uct s h o ul d be per ma ne ntl y 
disc o nti n ue d, a n d t he s u bject ma na ge d acc or di n g t o l ocal practice. Rec urre nce of 
la b orat or y a b n or malities c o nsi dere d u nrelate d t o i n vesti gati o nal me dici nal pr o d uct 
ma y n ot re q uire per ma ne nt disc o nti n uati o n. 
•  If, after re-c halle n ge, a s u bject has a sec o n d seri o us A E or rec urre nt ele vati o ns (e v e n 
mil d or mi ni mal) of t otal bilir u bi n , A L T , or A S T as defi ne d i n  Secti o n 6. 2 0, 
i n vesti gati o nal me dici nal pr o d uct s h o ul d be disc o nti n ue d per ma ne ntl y. 
6. 2 5.  
A dj u dic ati o n C o m mittee s 
E xter nal a dj u dicati o n c o m mittee s will  be esta blis he d t o a dj u dicate cases t hat meet pr ot oc ol -
defi ne d criteria f or li ver-relate d e ve nts, a n d f or car di o vasc ular-relate d e ve nts.     
6. 2 5. 1.  
He p atic E ve nts A dj u dic ati o n C o m mittee  
A ke y o bjecti ve of t his st u d y is t o pre ve nt pr o gressi o n t o cirr h osis a n d ass ociate d 
c o m plicati o ns. C li nical e ve nts t hat c o nstit ute t he cli nical o utc o mes e n d p oi nt i ncl u de: 
1)  Pr o gressi o n t o cirr h osis as defi ne d b y a li ver bi o ps y s h o wi n g F 4 fi br osis acc or di n g t o t he 
N A S H C R N classificati o n , as assesse d b y t he ce ntral rea der.  
2)  E ve nts of he patic dec o m pe nsati o n i ncl u di n g: 


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Pa ge 6 4  of 9 5   
 
 
 
A ker o T hera pe utics , I nc. 
C o nfi de ntial  
A me n d me nt 4, 1 8 A pr 2 0 2 2  
a) Cli nicall y a p pare nt ascites re q uiri n g treat me nt  
b)  H E of Gra de 2 or a b o ve (acc or di n g t o t he West Ha ve n criteria defi ne d i n A p pe n di x 
E ) re q uiri n g treat me nt 
c) P ortal h y perte nsi o n-relate d u p per gastr oi ntesti nal blee di n g i de ntifie d b y e n d osc o p y 
a n d re q uiri n g h os pitalizati o n, i ncl u di n g e ve nts of blee di n g fr o m es o p ha geal varices, 
gastric varices , a n d p ortal h y perte nsi ve gastr o pat h y 
3)  Li ver tra ns pla ntati o n or q ualificati o n f or li ver tra ns pla ntati o n , defi ne d as M E L D sc ore 
≥ 1 5 ( u nless d ue t o t hera pe utic a ntic oa g ulati o n) o n at least 2 c o nsec uti ve occasi o ns at 
least 4 wee ks a part 
4)  All -ca use m ortalit y 
Eac h of t he cli nical e ve nts (e xce pt hist ol o gic pr o gressi o n t o cirr h osis , all-ca use m ortalit y a n d 
li ver tra ns pla ntati o n) will re q uire c o nfir mati o n b y a He patic E ve nts A dj u dicati o n C o m mittee. 
All deat hs will be re vie we d b y t his c o m mittee t o deter mi ne if t he y are li ver-relate d.  
If t here is cli nical e vi dence t hat a s u bject has pr o gresse d t o cirr h osis (e. g. , base d o n t he 
prese nce of ne w es o p ha geal varices , c ha n ges i n bi o mar kers [i ncl u di n g , b ut n ot li mite d t o , 
l o w ser u m al b u mi n, hi g h ser u m bilir u bi n , a l o w platelet c o u nt , pr ol o n ge d I N R, or ele vate d 
li ver stiff ness], or de vel o p me nt of ot her cli nical si g ns or s y m pt o ms of cirr h osis) , t he s u bject 
s h o ul d u n der g o re peat li ver bi o ps y f or c o nfir mati o n of pr o gressi o n t o cirr h osis ( F 4 fi br osis as 
assesse d b y t he ce ntral rea der acc or di n g t o t he N A S H C R N classificati o n) at t he discreti o n of 
t he pri nci pal i n vesti gat or ( PI). 
O nce t he cli nical e ve nt (e xce pt hist ol o gical pr o gressi o n t o cirr h osis , all-ca use m ortalit y a n d 
li ver tra ns pla ntati o n) is c o nfir me d b y t he He patic E ve nts A dj u dicati o n C o m mittee, t he 
s u bject will disc o nti n ue fr o m t he st u d y . S u bjects w h o e x perie nce hist ol o gical pr o gressi o n t o 
cirr h osis , all-ca use m ortalit y a n d li ver tra ns pla ntati o n  will be disc o nti n ue d fr o m t he st u d y, 
b ut d o n ot re q uire c o nfir mati o n fr o m t he a dj u dicati o n c o m mittee pri or t o disc o nti n uati o n. 
6. 2 5. 2.  
C ar di o v asc ul ar E ve nts A dj u dic ati o n C o m mittee  
Car di o vasc ular e ve nts i ncl u di n g car di o vasc ular deat h , m y ocar dial i nfarcti o n , str o ke, 
h os pitalizati o n f or u nsta ble a n gi na, h os pitalizati o n f or car diac fail ure , a n d ur ge nt or 
e mer ge nc y visits f or ur ge nt heart fail ure will be a dj u dicate d b y a n i n de pe n de nt 
Car di o vasc ular E ve nts A dj u dicati o n C o m mittee. All deat hs will be re vie we d b y t his 
c o m mittee t o deter mi ne if t he y are car di o vasc ular-relate d. S u bjects e x perie nci n g a 
car di o vasc u lar e ve nt will be all o we d t o c o nti n ue i n t he st u d y at t he discreti o n of t he PI.  
6. 2 6.  O bser v ati o n f or Dr u g I n d uce d Li ver I nj ur y ( DI LI)  
T hr o u g h o ut t he st u d y , all T E A Es , cli nical assess me nts , a n d cli nical la b orat or y para meters , a n d 
t he  criteria  f or p ote ntial dr u g- i n d uce d  li ver  i nj ur y will  be  cl osel y  m o nit ore d  wit h  s u bjects 
e nteri n g cl ose o bser vati o n as detaile d i n t his pr ot oc ol. 


Efr u xifer mi n  
Cli nical Trial Pr ot oc ol:  A K -U S -0 0 1 -0 1 0 2  
Pa ge 6 5  of 9 5   
 
 
 
A ker o T hera pe utics , I nc. 
C o nfi de ntial  
A me n d me nt 4, 1 8 A pr 2 0 2 2  
6. 2 6. 1.  
S u bject s wit h N or m al Li ver Tr a ns a mi n ases a n d Bilir u bi n at B aseli ne 
Dr u g -i n d uce d li ver i nj ur y m o nit ori n g i n s u bjects wit h n or mal li ver tra nsa mi nases a n d bilir u bi n 
at baseli ne s h o ul d be perf or me d t hr o u g h o ut t he st u d y acc or di n g t o t he pr oce d ures s u m marize d 
bel o w.  
•  If s u bjects wit h n or mal baseli ne li ver i n dices de vel o p ele vati o ns i n A L T of > 5 ×  U L N  
d uri n g t he st u d y, re peat testi n g s h o ul d be perf or me d wit hi n 2 - 5 da ys fr o m recei pt of 
res ults.  
o  If t here are persiste nt ele vati o ns ( A L T > 5 ×  U L N  or T B L >  2 ×  U L N ) u p o n re peat 
testi n g, cl ose o bser vati o n (testi n g a n d p h ysical e xa mi nati o n 2 t o 3 ti mes per wee k) 
s h o ul d be i m ple me nte d. A n i m p orta nt p ur p ose of t he cl ose o bser vati o n is t o gat her 
a d diti o nal cli nical i nf or mati o n t o see k ot her p ossi ble ca uses of t he o bser ve d li ver test 
a b n or malities, s uc h as o ne of t he f oll o wi n g: ac ute viral he patitis, alc o h olic a n d 
a ut oi m m u ne he patitis, he pat o biliar y dis or ders , car di o vasc ular ca uses , or c o nc o mita nt 
treat me nts. Disc o nti n uati o n of i n vesti gati o nal me dici nal pr o d uct s h o ul d be 
c o nsi dere d. 
•  St u d y dr u g s h o ul d be disc o nti n ue d , a n d t he s u bject s h o ul d be f oll o we d u ntil res ol uti o n of 
si g ns or s y m pt o ms, i n t he f oll o wi n g sit uati o ns:  
o  A L T > 8 ×  U L N  
o  A L T > 5 ×  U L N a n d ( T B L > 2 ×  U L N ) 
o  A L T > 5 ×  U L N wit h t he a p peara nce of fati g ue , na usea , v o miti n g , ri g ht u p per q ua dra nt 
pai n  or  te n der ness , fe ver, ras h, a n d/ or  e osi n o p hilia ( > 5 %) as  assesse d  b y  t he  PI  t o 
i n dicate he patic i nj ur y 
F or a n y s u bjects w h o prese nt wit h a c o nstellati o n of s y n dr o mes i n dicati ve of li ver disease as 
per t he I n vesti gat or’s o verall assess me nt (i .e., fati g ue, na usea , v o miti n g, ri g ht u p per q ua dra nt 
pai n or te n der ness , fe ver, ras h, a n d/ or e osi n o p hilia [ > 5 %]) , perf or m li ver f u ncti o n tests t o 
deter mi ne if li ver disease is w orse ni n g.  
Re -i nitiati o n of i n vesti gati o nal me dici nal pr o d uct ma y be c o nsi dere d after c o ns ultati o n wit h 
t he Me dical M o nit or a n d D M C assess me nt . 
6. 2 6. 2.  
S u bject s wit h E le v ati o ns i n L i ver T r a ns a mi n ases or B ilir u bi n at B aseli ne  
Dr u g -i n d uce d li ver i nj ur y m o nit ori n g i n s u bjects wit h ele vati o ns i n li ver tra nsa mi nases or 
bilir u bi n at baseli ne s h o ul d be perf or me d t hr o u g h o ut t he st u d y acc or di n g t o t he pr oce d ures 
s u m marize d bel o w. 
•  If s u bjects wit h a b n or mal baseli ne li ver i n dices de vel o p ele vati o ns of A L T >3 ×  baseli ne  
or ≥3 0 0 U/ L ( w hic he ver occ urs first)  d uri n g t he st u d y , re peat testi n g s h o ul d be perf or me d 
wit hi n 2 - 5 da ys . 


Efr u xifer mi n  
Cli nical Trial Pr ot oc ol:  A K -U S -0 0 1 -0 1 0 2  
Pa ge 6 6  of 9 5   
 
 
 
A ker o T hera pe utics , I nc. 
C o nfi de ntial  
A me n d me nt 4, 1 8 A pr 2 0 2 2  
o  If t here are persiste nt ele vati o ns ( A L T >3 ×  baseli ne , or ≥3 0 0 U/ L ) u p o n re peat testi n g, 
t he n cl ose o bser vati o n (testi n g a n d p h ysical e xa mi nati o n 2 t o 3 ti mes per wee k) s h o ul d 
be i m ple me nte d a n d disc o nti n uati o n of st u d y dr u g s h o ul d be c o nsi dere d. 
•  Disc o nti n ue t he st u d y dr u g if a n y of t he f oll o wi n g occ ur:  
o  A L T i ncreases t o > 5 ×  baseli ne meas ure me nts  or ≥4 0 0 U/ L ( w hic he ver occ urs first) . 
o  A L T i ncrease > 3 ×  baseli ne meas ure me nts or ≥3 0 0 U/ L ( w hic he ver occ urs first) A N D 
t he i ncrease is acc o m pa nie d b y a c o nc o mita nt i ncrease i n T B L t o > 2 ×  U L N . 
o  A L T i ncrease > 3 ×  baseli ne meas ure me nts or ≥3 0 0 U/ L ( w hi c he ver occ urs first) wit h 
t he a p peara nce of fati g ue, na usea , v o miti n g, ri g ht u p per q ua dra nt pai n or te n der ness, 
fe ver, ras h, a n d/ or e osi n o p hilia ( > 5 %)  
F or a n y s u bjects w h o prese nt wit h a c o nstellati o n of s y n dr o mes i n dicati ve of li ver disease as 
per t he I n vesti gat or’s o verall assess me nt (i .e., fati g ue, na usea , v o miti n g, ri g ht u p per q ua dra nt 
pai n or te n der ness , fe ver, ras h, a n d/ or e osi n o p hilia [ > 5 %]) , perf or m li ver f u ncti o n tests t o 
deter mi ne if li ver disease is w orse ni n g.  
Re -i nitiati o n of i n vesti gati o nal me dici nal pr o d uct ma y be c o nsi dere d after c o ns ultati o n wit h 
t he C R O Me dical M o nit or  a n d D M C assess me nt . 
6. 2 6. 3.  
C l ose O bser v ati o n f or S us pecte d D r u g-In d uce d L i ver Inj ur y  
F or all s u bjects, cl ose o bser vati o n f or s us pecte d dr u g -i n d uce d li ver i nj ur y i ncl u des t he 
f oll o wi n g wit hi n 7 2 h o urs of s us pecte d dr u g-i n d uce d li ver i nj ur y: 
•  Re peati n g li ver e nz y me ( A L T , A S T , a n d al kali ne p h os p hatase) a n d ser u m bilir u bi n tests 2  
or 3 ti mes wee kl y.  
•  T he  fre q ue nc y  of  re peat  testi n g  ca n  decrease  t o  o nce  a  wee k  or  less  if  a b n or malities 
sta bilize or t he st u d y dr u g has bee n disc o nti n ue d a n d t he s u bject is as y m pt o matic. 
•  O btai ni n g a m ore detaile d hist or y of s y m pt o ms a n d pri or or c o nc urre nt diseases.  
•  O btai ni n g a hist or y of c o nc o mita nt dr u g use (i ncl u di n g n o n prescri pti o n me dicati o ns a n d 
her bal a n d dietar y s u p ple me nt pre parati o ns) , alc o h ol use , recreati o nal dr u g use, a n d s pecial 
diets.  
•  R uli n g o ut ac ute viral he patitis t y pes A , B, C, D, a n d E; a ut oi m m u ne or alc o h olic he patitis; 
h y p o xic/isc he mic he pat o pat h y; a n d biliar y tract disease.  
•  O btai ni n g a hist or y of e x p os ure t o e n vir o n me ntal c he mical a ge nts. 
•  O btai ni n g  a d diti o nal  tests  t o  e val uate  li ver  f u ncti o n , as  a p pr o priate  ( e. g., I N R, direct 
b ilir u bi n). 
•  C o nsi deri n g gastr oe nter ol o g y or he pat ol o g y c o ns ultati o ns. 
•  S u bjects w h o li ve far fr o m st u d y sites ca n be e val uate d l ocall y f or hist or y , p h ysical e xa m , 
a n d la b orat ories, pr o vi de d res ults ca n be c o m m u nicate d pr o m ptl y t o t he site I n vesti gat or. 


Efr u xifer mi n  
Cli nical Trial Pr ot oc ol:  A K -U S -0 0 1 -0 1 0 2  
Pa ge 6 7  of 9 5   
 
 
 
A ker o T hera pe utics , I nc. 
C o nfi de ntial  
A me n d me nt 4, 1 8 A pr 2 0 2 2  
6. 2 7.  Re m o v al of S u bject s fr o m t he S t u d y 
T he I n vesti gat or ma y wit h dra w a s u bject fr o m t he st u d y f or a n y of t he f oll o wi n g reas o ns: 
 Wit h dra wal of c o nse nt  
 N o n -c o m plia nce as deter mi ne d b y t he I n vesti gat or or S p o ns or 
 At t he discreti o n of t he I n vesti gat or a n d/ or st u d y Me dical M o nit or  a n d/ or t he D M C if it is 
i n t he best i nterest of t he s u bject 
 L ost t o f oll o w - u p 
At a n y ti me , t he I n vesti gat or ca n re m o ve a s u bject fr o m st u d y treat me nt a n d/ or t he st u d y if 
dee me d necessar y f or s u bject safet y. T he S p o ns or als o reser ves t he ri g ht t o ter mi nate t he 
st u d y at a n y ti me.  All data n or mall y c ollecte d at c o m pleti o n of t he st u d y m ust be c ollecte d at 
t he ti me of t he s u bject’s earl y ter mi nati o n or ter mi nati o n of t he st u d y .  
T he I n vesti gat or will disc uss wit h t he s u bject or le gall y acce pta ble re prese ntati ve(s) t he m ost 
a p pr o priate wa y t o wit h dra w t o e ns ure t he s u bject’s healt h.  S h o ul d a s u bject ( or a le gall y 
acce pta ble re prese ntati ve) re q uest or deci de t o wit h dra w c o nse nt , all eff orts will be ma de t o 
c o m plete a n d re p ort t he o bser vati o ns as t h or o u g hl y as p ossi ble u p t o t he date of wit h dra wal. 


Efr u xifer mi n  
Cli nical Trial Pr ot oc ol:  A K -U S -0 0 1 -0 1 0 2  
Pa ge 6 8  of 9 5   
 
 
 
A ker o T hera pe utics , I nc. 
C o nfi de ntial  
A me n d me nt 4, 1 8 A pr 2 0 2 2  
7.  
P L A N N E D S T A TI S TI C A L M E T H O D S  
7. 1.  
E n d p oi nts  
Details will be pr o vi de d i n t he statistical a nal ysis pla n ( S A P). 
7. 1. 1.  
Effic ac y E n d p oi nts  
7. 1. 1. 1.  
Pri m ar y E n d p oi nt  
T he pri mar y e n d p oi nt is: 
•  Pr o p orti o n of s u bjects w h o ac hie ve i m pr o ve me nt i n li ver fi br osis, defi ne d as ≥ o ne 
sta ge ( N A S H C R N fi br osis sc ore) a n d n o w orse ni n g of steat o he patitis ( defi ne d as n o 
i ncrease i n N A S f or ball o o ni n g, i nfla m mati o n, or steat osis)  at Wee k 2 4.   
7. 1. 1. 2.  
Sec o n d ar y E n d p oi nts  
T he sec o n dar y e n d p oi nts are: 
•  Pr o p orti o n of s u bjects w h o ac hie ve res ol uti o n of steat o he patitis ( defi ne d as a N A S of 0 - 1 
f or i nfla m mati o n, 0 f or ball o o ni n g , a n d a n y val ue f or steat osis) a n d n o w orse ni n g of li ver 
fi br osis as deter mi ne d b y t he N A S H C R N criteria at Wee k 2 4 a n d Wee k 9 6. 
•  Pr o p orti o n of s u bjects w h o ac hie ve i m pr o ve me nt i n li ver fi br osis, defi ne d as ≥ o ne sta ge 
( N A S H C R N fi br osis sc ore) a n d n o w orse ni n g of steat o he patitis ( defi ne d as n o i ncrease 
i n N A S f or ball o o ni n g, i nfla m mati o n, or steat osis) at Wee k 9 6 . 
•  Pr o p orti o n of s u bjects w h o ac hie ve i m pr o ve me nt i n li ver fi br osis, defi ne d as ≥ o ne sta ge 
( N A S H C R N fi br osis sc ore) at Wee k 2 4 a n d Wee k 9 6. 
•  C ha n ge fr o m baseli ne i n he patic fat frac ti o n meas ure d b y M RI-P D F F at Wee k 2 4  a n d 
Wee k 9 6. 
•  C ha n ge fr o m baseli ne of  li p o pr otei ns – tri gl yceri des, N o n -H D L - C, H D L -C a n d L D L -C.   
•  C ha n ge fr o m baseli ne of mar kers of  gl yce mic c o ntr ol – H b A 1c , C- pe pti de, A di p o necti n 
a n d H O M A-I R. 
•  C ha n ge fr o m baseli ne i n no n-i n vasi ve mar kers of fi br osis – E L F , Pr o -C 3 , C 3 M , NI S - 4 
a n d li ver stiff ness assesse d b y tra nsie nt elast o gra p h y ( Fi br o Sca n ®). 
•  C ha n ge fr o m baseli ne of b o d y wei g ht. 
7. 1. 1. 3.  
E x pl or at or y Effic ac y  E n d p oi nts   
T he e x pl orat or y e n d p oi nts are: 
 




Efr u xifer mi n  
Cli nical Trial Pr ot oc ol:  A K -U S -0 0 1 -0 1 0 2  
Pa ge 7 0  of 9 5   
 
 
 
A ker o T hera pe utics , I nc. 
C o nfi de ntial  
A me n d me nt 4, 1 8 A pr 2 0 2 2  
Safet y a nal yses i ncl u de: s u m maries of e xte nt of e x p os ure , A Es , cli nical la b orat or y tests, 
e n d o ge n o us F G F 2 1 , E C G , B M D , vital si g n assess me nts , b o d y wei g ht, a nti- dr u g a nti b o d y 
( A D A) a n d ne utralizi n g a nti b o d y ( N A B) assess me nts , a n d c o nc o mita nt me dicati o n usa ge.  
7. 2.  
A n al ysis C o n ve nti o ns 
All i n di vi d ual s u bject data will be liste d as meas ure d. All statistical s u m maries a n d a nal yses 
will be perf or me d usi n g Statistical A nal ysis S yste m ( S A S ® ) s oft ware ( S A S I nstit ute, Car y , 
N ort h  Car oli na , U S A).  
7. 3.  
A n al ysis Sets  
T he st u d y a nal ysis sets are detaile d bel o w.  
7. 3. 1.  
F ull A n al ysis Set ( F A S)  
T he pri mar y a nal ysis set f or n o n- hist ol o gical efficac y a nal yses will be t he F ull A nal ysis Set 
( F A S) w hic h will i ncl u de all s u bjects w h o were ra n d o mize d i nt o t he st u d y. 
 
S u bjects w h o recei ve a d ose of st u d y dr u g ot her t ha n t hat t o w hic h t he y were ra n d o mize d f or 
t he e ntire d urati o n of treat me nt will be a nal yze d acc or di n g t o treat me nt gr o u p t o w hic h t he y 
were ra n d o mize d . 
 
7. 3. 2.  
Per Pr ot oc ol ( P P) Sets  
T he Per Pr ot oc ol ( P P) Sets will be a  s u bset of t he F A S a n d will i ncl u de s u bjects w h o fi nis h 
sc he d ule d visits wit h a p plica ble assess me nts  a n d d o n ot ha ve maj or pr ot oc ol de viati o ns. 
 
7. 3. 3.  
S afet y  Set  
All s u bjects w h o recei ve at least o ne d ose of st u d y dr u g will be i ncl u de d i n t he Safet y Set. 
All safet y e n d p oi nts will be s u m marize d usi n g t he Safet y Set a n d will be base d o n act ual 
treat me nt recei ve d if t his differs fr o m t he ra n d o mize d treat me nt . 
7. 3. 3. 1.  
P h ar m ac o ki netics  Set  
T he P K a nal ysis set will i ncl u de all ra n d o mize d s u bjects w h o t o o k at least o ne d ose of st u d y 
dr u g a n d f or w h o m c o nce ntrati o n data of E F X  is a vaila ble.  
7. 3. 3. 2.  
Bi o m ar kers  A n al ysis Set  
T he Bi o mar ker A nal ysis Set will i ncl u de data fr o m s u bjects i n t he Safet y A nal ysis Set w h o 
ha ve t he necessar y baseli ne a n d o n -st u d y meas ure me nts t o pr o vi de i nter preta ble res ults f or 
t he s pecific para meters of i nterest. 


Efr u xifer mi n  
Cli nical Trial Pr ot oc ol:  A K -U S -0 0 1 -0 1 0 2  
Pa ge 7 1  of 9 5   
 
 
 
A ker o T hera pe utics , I nc. 
C o nfi de ntial  
A me n d me nt 4, 1 8 A pr 2 0 2 2  
7. 3. 3. 3.  
Li ver Bi o ps y  A n al ysis Set  ( L B A S) 
T he pri mar y a nal ysis set f or hist ol o g ical efficac y a nal yses will be t he Li ver Bi o ps y A nal ysis 
Set  ( L B A S), w hic h  will be a s u bset of t he F A S. It will i ncl u de all F A S s u bjects w h o ha ve t he 
baseli ne a n d o n -st u d y li ver bi o ps y res ults. 
 
7. 3. 3. 4.  
M RI -P D F F A n al ysis Set  
T he M RI -P D F F A nal ysis Set will be a s u bset of t he F A S. It will i ncl u de all F A S s u bjects 
w h o ha ve baseli ne a n d o n- st u d y meas ure me nts assesse d b y M RI-P D F F . 
 
7. 4.  
D at a H a n dli n g C o n ve nti o ns 
Missi n g data ca n ha ve a n i m pact o n t he i nter pretati o n of t he trial data. I n ge neral , val ues f or 
missi n g data will n ot be i m p ute d  u nless s pecifie d . 
W here a p pr o priate, safet y data f or s u bjects t hat di d n ot c o m plete t he st u d y will be i ncl u de d i n 
s u m mar y statistics. F or e xa m ple, if a s u bject recei ve d st u d y dr u g, t he s u bject will be i ncl u de d 
in a s u m mar y of A Es acc or di n g t o t he treat me nt recei ve d; ot her wise , if t he s u bject is n ot 
d ose d t he n t he y will be e xcl u de d fr o m t he s u m mar y. If safet y la b orat or y res ults f or a s u bject 
are missi n g f or a n y reas o n at a ti me p oi nt, t he s u bject will be e xcl u de d fr o m t he calc ulati o n 
of s u m mar y statistics f or t hat ti me p oi nt. If t he s u bject is missi n g a baseli ne  val ue, t he n t he 
s u bject will be e xcl u de d fr o m t he calc ulati o n of s u m mar y statistics f or t he baseli ne  val ue a n d 
t he c ha n ge fr o m baseli ne  val ues.  
Val ues f or missi n g safet y la b orat or y data will n ot be i m p ute d; h o we ver, a missi n g baseli ne 
res ult will be re place d wit h a scree ni n g res ult , if a vaila ble. If n o pre-treat me nt la b orat or y 
val ue is a vaila ble , t he baseli ne val ue will be ass u me d t o be n or mal (i.e., n o gra de [ Gra de  0]) 
f or t he s u m mar y of gra de d la b orat or y a b n or malities.   
Val ues f or missi n g vital si g ns data will n ot be i m p ute d; h o we ver , a missi n g baseli ne res ult 
will be re place d wit h a scree ni n g res ult , if a vaila ble. 
F urt her details of data ha n dli n g c o n ve nti o ns a n d tra nsf or mati o n will be pr o vi de d i n t he S A P. 
7. 5.  
E sti m a n ds 
I n li ne wit h I C H E 9 ( R 1) a d de n d u m, 5 attri b utes (treat me nt , p o p ulati o n, e n d p oi nt, 
i nterc urre nt e ve nts, a n d p o p ulati o n -le vel s u m mar y) ha ve bee n s pecifie d t o tra nslate t he 
pri mar y a n d ke y sec o n dar y efficac y o bjecti ves i nt o treat me nt effects t hat are t o be esti mate d 
(esti ma n ds). 
T he treat me nt c o n diti o ns of i nterest are E F X 2 8  m g a d mi nistere d wee kl y , a n d E F X 5 0  m g 
a d mi nistere d wee kl y , a n d are c o m pare d wit h matc hi n g place b o a d mi nistere d wee kl y . 
T he treat me nt effect is assesse d b y t he pr i mar y hist ol o gical e n d p oi nt of i m pr o ve me nt i n li ver 
fi br osis a n d n o w orse ni n g of steat o he patitis.  


Efr u xifer mi n  
Cli nical Trial Pr ot oc ol:  A K -U S -0 0 1 -0 1 0 2  
Pa ge 7 2  of 9 5   
 
 
 
A ker o T hera p e utics , I nc. 
C o nfi de ntial  
A me n d me nt 4 , 1 8 A pr 2 0 2 2  
T he p o p ulati o n of s u bjects tar gete d is a d ults wit h N A S H wit h li ver fi br osis as defi ne d b y t he 
i ncl usi o n/e xcl usi o n criteria. 
I nterc urre nt e v e nts are ha n dle d t hr o u g h a c o m p osite strate g y (s ee  Ta bl e 6 ). 
T he p o p ulati o n -le vel s u m mar y of t he treat me nt effect will be q ua ntifie d b y c o m pari n g 
o bser ve d res p o n der pr o p orti o ns s u p p orte d b y t he ris k rati o of i n vesti gati o nal pr o d uct 
c o m pare d  t o place b o ( E F X 2 8 m g vers us  place b o or  E F X 5 0  m g vers us  place b o) calc ulate d 
fr o m t he o d ds rati o o btai ne d t hr o u gh C oc hra n -Ma ntel -Hae ns zel ( C M H) test detaile d i n t he 
Statistical A nal ysis Pla n.  
T a ble 6 . 
A p pr o ac h f or Interc urre nt E ve nts f or t he P ri m ar y E n d p oi nt  
I nterc urre nt E ve nt  
St at us   
Start of a d diti o nal t hera p y wit h 
p ote ntial t o i m pact N A S H 
c o n diti o n (i.e. resc ue me dicati o n)  
S u bject defi ne d as a n o n -res p o n der (e ve n if a p ost-treat me nt 
bi o ps y is a vaila ble)  
 
M E L D sc ore ≥1 5  
S u bject defi ne d as a n o n -res p o n der (e ve n if a p ost -treat me nt 
bi o ps y is a vaila ble)   
He p atic dec o m pe nsati o n e v e nt  
U nsc h e d ule d bi o ps y s h o wi n g 
pr o gressi o n t o F 4  
S u bject will be c o u nte d as a n o n -res p o n der  
Bariatric s ur ger y  
S u bject defi ne d as a n o n -res p o n der 
T he esti ma n ds attri b utes f or all sec o n d ar y hist ol o gical e n d p oi nts are d efi ne d i n t he sa me 
ma n ner as f or t he pri mar y e n d p oi nt descri be d a b o ve.  
 
7. 6.  
De m o gr a p hic D at a a n d B aseli ne C h ar acteristics  
De m o gra p hic a n d baseli n e meas ur e me nts will be s u m marize d usi n g sta n dar d descri pti ve 
met h o ds.  
De m o gr a p hic s u m mari es will i ncl u de T 2 D  stat us, se x, race/et h nicit y, a n d a ge.  
Baseli ne data will i ncl u de a s u m mar y of b o d y wei g ht , hei g ht , B MI , waist -t o-hi p rati o , 
ra n d o mizati o n stratificati o n gr o u ps, a n d ot her dise ase c haracteristic vari a bles.  
7. 7.  
Effic ac y A n al ysis  
7. 7. 1.  
Pri m ar y Effic ac y A n al ysis  
T he pri mar y effic ac y a n al ysis will be c o n d ucte d w he n all t he pla n ne d s u bjects c o m plete t he 
2 4 -Wee k visit . A C M H t est  will be use d t o c o m pare t he differe n ces i n pr o p orti o ns of s u bjects  
 
 


Efr u xifer mi n  
Cli nical Trial Pr ot oc ol:  A K -U S -0 0 1 -0 1 0 2  
Pa ge 7 3  of 9 5   
 
 
 
A ker o T hera pe utics , I nc. 
C o nfi de ntial  
A me n d me nt 4, 1 8 A pr 2 0 2 2  
w h o ac hie ve a ≥ 1-sta ge i m pr o ve me nt i n fi br osis wit h o ut w orse ni n g of steat o he patitis 
bet wee n t he E F X ar ms a n d t he place b o ar m, a dj usti n g f or stratificati o n fact ors . T he a nal ysis 
will be perf or me d usi n g t he L B A S . T he p oi nt esti mates a n d  
c o nfi de nce i ntervals f or t he 
differe nces i n pr o p orti o ns will be calc ulate d .   
T he Pri mar y efficac y e n d p oi nt will be teste d at T y pe I err or rate of 
, t w o-si de d wit h o ut 
a dj ust me nt f or m ulti plicit y .  
7. 7. 2.  
Sec o n d ar y Effic ac y A n al ysis  
F or t he sec o n dar y e n d p oi nts, a C M H test  wi ll be perf or me d t o c o m pare t he differe nces i n 
pr o p orti o ns bet wee n t he E F X ar m  a n d t he place b o ar m a dj usti n g f or stratificati o n fact ors .   
A n a nal ysis of c o varia nce ( A N C O V A) m o del c o ntr olli n g f or stratificati o n fact ors will be 
use d t o e val uate t he c ha n ges fr o m baseli ne t o Wee k 2 4 i n he patic fat fracti o n a n d li ver 
stiff ness bet wee n eit her E F X ar m a n d t he place b o ar m i n t he Wee k 2 4 a nal ysis.  
A mi xe d -m o del re peate d -meas ures ( M M R M) will be use d t o e val uate t he c ha n ges fr o m 
b aseli ne i n he patic fat fracti o n, tri gl yceri des, N o n -H D L - C, H D L - C, L D L - C, H b A 1c , C-
pe pti de, H O M A -I R, n o n-i n vasi ve fi br osis mar kers, li ver stiff ness, a n d b o d y wei g ht bet wee n 
t he E F X  ar m a n d t he place b o ar m at sc he d ule d visits , c o ntr olli n g f or stratificati o n fact ors.    
S u m maries a n d will be prese nte d f or c ha n ges fr o m baseli ne i n tri gl yceri des, N o n -H D L - C, 
H D L - C, L D L - C, H b A 1c , C- pe pti de, H O M A -I R, a n d b o d y wei g ht at t he c ollecti o n ti me p oi nts 
defi ne d i n t he Sc he d ule of Assess me nts  b y treat me nt ar m.  
7. 7. 3.  
E x pl or at or y Ef fic ac y A n al ysis 
 
T he sa me efficac y a nal yses use d f or t he sec o n dar y efficac y varia bles will be use d f or t he 
e x pl orat or y efficac y varia bles.   
7. 8.  
S afet y A n al ysis 
All safet y data c ollecte d o n or after t he date t hat st u d y dr u g is first dis pe nse d u p t o t he date of 
last d ose of st u d y dr u gs pl us 3 0 da ys will be s u m marize d b y treat me nt gr o u p. Data f or t he 
f oll o w- u p peri o d will be i ncl u de d i n data listi n gs.  
7. 8. 1.  
E xte nt of E x p os ure 
Data of a s u bject’s e xte nt of e x p os ure t o st u d y dr u g will be ge nerate d fr o m t he st u d y dr u gs 
a d mi nistrati o n e C R F data. E x p os ure data will be s u m marize d b y treat me nt gr o u p.  
 
7. 8. 2.  
A d verse E ve nts  
Cli nical a n d la b orat or y A Es will be c o de d usi n g t he Me dical Dicti o nar y f or Re g ulat or y 
Acti vities ( Me d D R A). S yste m Or ga n Class ( S O C) , Hi g h -Le vel Gr o u p Ter m ( H L G T) , 


Efr u xifer mi n  
Cli nical Trial Pr ot oc ol:  A K -U S -0 0 1 -0 1 0 2  
Pa ge 7 4  of 9 5   
 
 
 
A ker o T hera pe utics , I nc. 
C o nfi de ntial  
A me n d me nt 4, 1 8 A pr 2 0 2 2  
Hi g h -Le vel Ter m ( H L T) , Preferre d Ter m ( P T) , a n d L o wer-Le vel Ter m ( L L T) will be 
attac he d t o t he cli nical data base.  A E se verit y will be gra de d usi n g t he C T C A E. 
 
E v e nts will be s u m marize d o n t he basis of t he date of o nset f or t he e ve nt. A T E A E will be 
defi ne d as o ne  or b ot h of t he f oll o wi n g: 
 
•  A n y A Es wit h a n o nset date o n or after t he st u d y dr u g start date a n d n o later t ha n 3 0 da ys 
after per ma ne nt disc o nti n uati o n of st u d y dr u g 
•  A n y A Es lea di n g t o pre mat ure disc o nti n uati o n of st u d y dr u g 
S u m maries ( n u m ber a n d perce nta ge of s u bjects) of T E A Es a n d S A Es b y S O C a n d P T will be 
pr o vi de d b y treat me nt gr o u p. Treat me nt- e mer ge nt A Es will als o be s u m marize d b y 
relati o ns hi p t o st u d y dr u gs a n d se verit y. I n a d diti o n, T E A Es lea di n g t o pre mat ure 
disc o nti n uati o n of st u d y dr u gs a n d st u d y, a n d S A Es lea di n g t o deat h will be s u m marize d a n d 
liste d. 
All A Es c ollecte d d uri n g t he c o urse of t he st u d y will be prese nte d i n data listi n gs wit h a fiel d  
f or treat me nt-e mer ge nt e ve nt ( Yes/ N o).  
7. 8. 3.  
L a b or at or y E v al u ati o ns 
Selecte d la b orat or y data will be s u m marize d ( n , mea n , S D , me dia n , mi ni m u m , a n d 
ma xi m u m) b y treat me nt gr o u p a n d st u d y visit al o n g wit h t he c orres p o n di n g c ha n ge fr o m 
baseli ne val ues.  
Gra de d la b orat or y a b n or malities will be defi ne d usi n g t he gra di n g sc he me i n t he C T C A E.  
Gra di n g of la b orat or y a b n or malities f or a nal ysis p ur p oses will be defi ne d i n t he Statistical 
A nal ysis Pla n. 
T he i nci de nce of treat me nt -e mer ge nt la b orat or y a b n or malities , defi ne d as val ues t hat 
i ncrease at least o ne t o xicit y gra de fr o m baseli ne at a n y ti me p ost baseli ne u p t o a n d 
i ncl u di n g t he date of last d ose of st u d y dr u gs pl us 3 0 da ys, will be s u m marize d b y treat me nt 
gr o u p. If baseli ne data are missi n g , t he n a n y gra de d a b n or malit y (i.e., at least a Gra de 1) will 
be c o nsi dere d treat me nt -e mer ge nt. 
7. 9.  
P h ar m ac o ki netic A n al ysis  
Plas ma c o nce ntrati o n s of E F X  will be liste d a n d s u m marize d  pre- d ose at t he ti me p oi nts liste d 
i n t he Sc he d ule of Assess me nts. N o nc o m part me ntal para meters will be liste d a n d 
s u m marize d descri pti vel y. 
7. 1 0.  
Bi o m ar ker A n al ysis  
Descri pti ve statistics of bi o mar ker c ha n ge fr o m baseli ne will be pr o vi de d at eac h sa m pli n g 
ti me b y treat me nt. P oi nt esti mates a n d  
 c o nfi de nce i nter vals ma y be calc ulate d. 




Efr u xifer mi n  
Cli nical Trial Pr ot oc ol:  A K -U S -0 0 1 -0 1 0 2  
Pa ge 7 6  of 9 5  
A ker o T hera pe utics , I nc. 
C o nfi de ntial  
A me n d me nt 4, 1 8 A pr 2 0 2 2  
D ue t o t he c halle n ge of rec o g nizi n g a n d dia g n osi n g DI LI i n s u bjects wit h pre-e xist i n g 
he patic d ysf u ncti o n, t he D M C  will re vie w pote ntial cases  of DI LI (refe r t o Secti o n  6. 2 6 ). 
S u bjects w ill be cate g orize d as th ose f or w h o m D I LI or w orse ni n g of he patic f u ncti o n 
attri b uta ble t o st u d y dr u g co ul d be excl u de d (e. g., a clear, alter nati ve ex pl a nati o n exists); 
t h ose for w h o m D I LI or w orse ni n g of he patic fu ncti o n attri b uta ble t o st u d y dr u g c o ul d n ot be 
e xcl u de d (e. g., n o c lear, alter nati ve ex pla nati o n  exists); a n d  t h ose wit h i ns ufficie nt data t o 
ma ke a deter mi nati o n. S u bjects ex perie nci n g D I LI wi ll be all o we d t o c o nti n ue in t he st u d y 
acc or di n g  t o t he f oll o w- u p pr oce d ures o ut li ne d i n Secti o n 6. 2 6.  
T he D M C’s s pecific acti vities will  be defi ne d  b y a m ut uall y a gree d c harter, whic h  will defi ne 
t he D M C’s  me m bers hi p , c o n d uct, a n d meeti n g sc he d ule.  
W hile t he D M C w ill be as ke d t o a d vise A ker o re gar di n g f ut ure co n d uct o f the st u d y, 
i ncl u di n g p ossi ble  earl y st u d y ter mi nati o n, Aker o  retai ns fi nal decisi o n-ma ki n g a ut h orit y o n 
all as pects of the st u d y.  


Efr u xifer mi n  
Cli nical Trial Pr ot oc ol:  A K -U S -0 0 1 -0 1 0 2  
Pa ge 7 7  of 9 5   
 
 
 
A ker o T hera pe utics , I nc. 
C o nfi de ntial  
A me n d me nt 4, 1 8 A pr 2 0 2 2  
8.  
A D MI NI S T R A TI V E C O N SI D E R A TI O N S  
8. 1.  
I n vesti g at or Res p o nsi bilities 
8. 1. 1.  
G o o d Cli nic al Pr actice  
T he I n vesti gat or will e ns ure t hat t his st u d y is c o n d ucte d i n acc or da nce wit h t he pri nci ples of 
t he Declarati o n of Helsi n ki, I nter nati o nal C o u ncil f or Har m o nisati o n (I C H) g ui deli nes , or 
wit h t he la ws a n d re g ulati o ns of t he c o u ntr y i n w hic h t he researc h is c o n d ucte d, w hic he ver 
aff or ds t he greater pr otecti o n t o t he st u d y s u bject. T hese sta n dar ds are c o nsiste nt wit h t he 
E ur o pea n U ni o n Cli nical Trials Directi ve 2 0 0 1/ 2 0/ E C a n d G o o d Cli nical Pract ice 
Directi ve  2 0 0 5/ 2 8/ E C. 
 
T he I n vesti gat or will e ns ure a d here nce t o t he basic pri nci ples of G o o d Cli nical Practice , as 
o utli ne d i n 2 1 C o de of Fe deral Re g ulati o ns ( C F R) 3 1 2, s u b part D, “ Res p o nsi bilities of 
S p o ns ors a n d I n vesti gat ors,” 2 1 C F R , part 5 0, 1 9 9 8, a n d 2 1 C F R , part 5 6, 1 9 9 8. 
 
T he I n vesti gat or a n d all a p plica ble s u bi n vesti gat ors will c o m pl y wit h 2 1 C F R , Part  5 4, 1 9 9 8, 
pr o vi di n g d oc u me ntati o n of t heir fi na ncial i nterest or arra n ge me nts wit h A ker o , or 
pr o prietar y i nterests i n t he i n vesti gati o nal me dic i nal pr o d uct u n der st u d y. T his 
d oc u me ntati o n m ust be pr o vi de d pri or t o t he I n vesti gat or’s (a n d a n y s u bi n vesti gat or’s) 
partici pati o n i n t he st u d y. T he I n vesti gat or a n d s u bi n vesti gat or a gree t o n otif y A ker o of a n y 
c ha n ge i n re p orta ble i nterests d uri n g t he st u d y a n d f or 1 year f oll o wi n g c o m pleti o n of t he 
st u d y. St u d y c o m pleti o n is defi ne d as t he date w he n t he last s u bject c o m pletes t he pr ot oc ol-
defi ne d acti vities.  
8. 1. 2.  
I nstit uti o n al Re vie w B o ar d (I R B)/I n de pe n de nt Et hics C o m mittee (I E C)/ 
Et hics C o m mittee ( E C) Re vie w  a n d A p pr o v al  
Bef ore i nitiati n g a trial , the I n vesti gat or ( or S p o ns or as a p pr o priate acc or di n g t o l ocal 
re g ulati o ns) will s u b mit t his pr ot oc ol, I C F, a n d a n y acc o m pa n yi n g material t o be pr o vi de d t o 
t he s u bject (s uc h as a d vertise me nts, s u bject i nf or mati o n s heets, or descri pti o ns of t he st u d y 
use d t o o btai n i nf or me d c o nse nt) t o a n I R B/I E C/ E C. T he I n vesti gat or will n ot be gi n a n y 
st u d y s u bject acti vities until a p pr o val fr o m t he I R B/I E C/ E C has bee n d oc u me nte d a n d 
pr o vi de d as a letter t o t he I n vesti gat or. 
Bef ore i m ple me ntati o n , t he I n vesti gat or will s u b mit t o a n d recei ve d oc u me nte d a p pr o val 
fr o m t he I R B/I E C/ E C a n y m o dificati o ns ma de t o t he pr ot oc ol or a n y acc o m pa n yi n g material 
t o be pr o vi de d t o t he s u bject after i nitial I R B/I E C/ E C a p pr o val, wit h t he e xce pti o n of t h ose 
necessar y t o re d uce i m me diate ris k t o st u d y s u bjects.  
8. 1. 3.  
I nf or me d C o nse nt 
Eli gi ble s u bjects ma y o nl y be i ncl u de d i n t he st u d y after pr o vi di n g ( wit n esse d, w here 
re q uire d b y la w or re g ulati o n), I R B/I E C-a p pr o ve d i nf or me d c o nse nt, or, if a p plica ble after 
s uc h c o nse nt has bee n pr o vi de d b y a le gall y acce pta ble re prese ntati ve(s) of t he s u bject. 


Efr u xifer mi n  
Cli nical Trial Pr ot oc ol:  A K -U S -0 0 1 -0 1 0 2  
Pa ge 7 8  of 9 5   
 
 
 
A ker o T hera pe utics , I nc. 
C o nfi de ntial  
A me n d me nt 4, 1 8 A pr 2 0 2 2  
I nf or me d c o nse nt m ust be o btai ne d bef ore c o n d ucti n g a n y st u d y-specific pr oce d ures (e. g. , all 
of t he pr oce d ures descri be d i n t he pr ot oc ol). T he pr ocess of o btai ni n g i nf or me d c o nse nt m ust 
be d oc u me nte d i n t he s u bject s o urce d oc u me nts. 
T he In vesti gat or m ust use t he m ost c urre nt I R B/I E C/ E C -a p pr o ve d c o nse nt f or m f or 
d oc u me nti n g writte n i nf or me d c o nse nt.  
8. 1. 4.  
C o nfi de nti alit y  
T he I n vesti gat or will e ns ure  t hat s u bjects’ a n o n y mit y will be strictl y mai ntai ne d a n d t hat 
t heir i de ntities are pr otecte d fr o m u na ut h orize d parties. O nl y partial date of birt h (as 
a p plica ble i n certai n c o u nt ries), a n ot her u ni q ue i de ntifier (as all o we d b y l ocal la w), a n d a n 
i de ntificati o n c o de will be rec or de d o n a n y f or m or bi ol o gical sa m ple s u b mitte d t o t he 
S p o ns or, I R B/I E C/ E C, or la b orat or y. La b orat or y s peci me ns m ust be la bele d i n s uc h a wa y as 
t o pr otect su bject i de ntit y w hile all o wi n g t he res ults t o be rec or de d t o t he pr o per s u bject. 
Refer t o s pecific la b orat or y i nstr ucti o ns . T he In vesti gat or will  kee p a scree ni n g l o g s h o wi n g 
st u d y s u bject I Ds, na mes , a n d a d dresses f or all s u bjects scree ne d a n d f or all s u bjects 
ra n d o mize d i n t he trial. S u bject data will be pr ocesse d i n acc or da nce wit h all a p plica ble 
re g ulati o ns. 
T he In vesti gat or a grees t hat all i nf or mati o n recei ve d fr o m A ker o , i ncl u di n g b ut n ot li mite d t o 
t he I B, t his pr ot oc ol, e C R Fs, t he I M P, a n d a n y ot her st u d y i nf or mati o n, re mai n t he s ole a n d 
e xcl usi ve pr o pert y of A ker o d uri n g t he c o n d uct of t he st u d y a n d t hereafter. T his i nf or mati o n 
is n ot t o be discl ose d t o a n y t hir d part y (e xce pt e m pl o yees or a ge nts directl y i n v ol ve d i n t he 
c o n d uct of t he  st u d y or as re q uire d b y la w) wit h o ut pri or writte n c o nse nt fr o m A ker o. T he 
In vesti gat or f urt her a grees t o ta ke all reas o na ble preca uti o ns t o pre ve nt t he discl os ure b y a n y 
e m pl o yee or a ge nt of t he st u d y site t o a n y t hir d part y or ot her wise i nt o t he p u blic d o mai n. 
8. 1. 5.  
St u d y Files a n d Rete nti o n of Rec or ds  
T he In vesti gat or m ust mai ntai n a de q uate a n d acc urate rec or ds t o e na ble t he c o n d uct of t he 
st u d y t o be f ull y d oc u me nte d a n d t he st u d y data t o be s u bse q ue ntl y verifie d. T hese 
d oc u me nts s h o ul d be classifie d i nt o at least t he f oll o wi n g t w o cate g ories: ( 1) I n vesti gat or’s 
st u d y file, a n d ( 2) s u bject cli nical s o urce d oc u me nts. 
T he In vesti gat or’s st u d y file will c o ntai n t he pr ot oc ol/a me n d me nts , C R F a n d q uer y f or ms, 
I R B/I E C/ E C a n d g o ver n me ntal a p pr o val wit h c orres p o n de nce, i nf or me d c o nse nt, dr u g 
rec or ds, staff c urric ul u m vitae a n d a ut h orizati o n f or ms, a n d ot her a p pr o priate d oc u me nts a n d 
c orres p o n de nce. 
T he I n vesti gat or m ust mai ntai n s o urce d oc u me nts f or eac h s u bject i n t he st u d y, c o nsisti n g of 
case a n d visit n otes ( h os pital or cli nic me dical rec or ds) c o ntai ni n g de m o gra p hic a n d me dical 
i nf or mati o n, la b orat or y data, electr ocar di o gra ms , a n d t he res ults of a n y ot her tests or 
assess me nts. All i nf or mati o n o n C R Fs m ust be tracea ble t o t h ese s o urce d oc u me nts i n t he 
s u bject's file. Data n ot re q uiri n g a se parate writte n rec or d will be defi ne d bef ore st u d y start 


Efr u xifer mi n  
Cli nical Trial Pr ot oc ol:  A K -U S -0 0 1 -0 1 0 2  
Pa ge 7 9  of 9 5   
 
 
 
A ker o T hera pe utics , I nc. 
C o nfi de ntial  
A me n d me nt 4, 1 8 A pr 2 0 2 2  
a n d will be rec or de d directl y o n t he C R Fs. T he I n vesti gat or m ust als o kee p t he ori gi nal 
i nf or me d c o nse nt f or m si g ne d b y t he s u bject (a si g ne d c o p y is gi ve n t o t he s u bject). 
T he In vesti gat or m ust gi ve t he m o nit or access t o all rele va nt s o urce d oc u me nts t o c o nfir m 
t heir c o nsiste nc y wit h t he data ca pt ure a n d/ or data e ntr y. A ker o m o nit ori n g sta n dar ds re q uire 
f ull verificati o n f or t he presence of i nf or me d c o nse nt, a d here nce t o t he i ncl usi o n/e xcl usi o n 
criteria, d oc u me ntati o n of S A Es , a n d of data t hat will be use d f or all pri mar y varia bles. 
A d diti o nal c hec ks of t he c o nsiste nc y of t he s o urce data wit h t he C R Fs are perf or me d 
acc or di n g t o t he st u d y-s pecific m o nit ori n g pla n. N o i nf or mati o n i n s o urce d oc u me nts a b o ut 
t he i de ntit y of t he s u bjects will be discl ose d. 
All cli nical st u d y d oc u me nts m ust be retai ne d b y t he I n vesti gat or u ntil at least 2  years or f or 
a peri o d acc or di n g t o l ocal la ws, w hic he ver is l o n ger , after t he last a p pr o val of a mar keti n g 
a p plicati o n i n a n I C H re gi o n ( i.e., U nite d States , E ur o pe, or Ja pa n) a n d u ntil t here are n o 
pe n di n g or pla n ne d mar keti n g a p plicati o ns i n a n I C H re gi o n; or, if n o a p plicati o n is file d or if 
t he a pplicati o n is n ot a p pr o ve d f or s uc h i n dicati o n, u ntil 2  years after t he i n vesti gati o n is 
disc o nti n ue d a n d re g ulat or y a ut h orities ha ve bee n n otifie d. I n vesti gat ors ma y be re q uire d t o 
retai n d oc u me nts l o n ger if s pecifie d b y re g ulat or y re q uire me nts, b y l ocal r e g ulati o ns, or b y 
a n a gree me nt wit h A ker o. T he I n vesti gat or m ust n otif y A ker o bef ore destr o yi n g a n y cli nical 
st u d y rec or ds. 
S h o ul d t he I n vesti gat or wis h t o assi g n t he st u d y rec or ds t o a n ot her part y or m o ve t he m t o 
a n ot her l ocati o n , A ker o m ust be n otifie d i n a d va nce. 
If t he I n vesti gat or ca n n ot pr o vi de f or t his arc hi vi n g re q uire me nt at t he st u d y site f or a n y or 
all of t he d oc u me nts , s pecial arra n ge me nts m ust be ma de bet wee n t he In vesti gat or a n d A ker o 
t o st ore t hese rec or ds sec urel y a wa y fr o m t he site s o t hat t he y ca n be ret ur ne d seale d t o t he 
I n vesti gat or i n case of a n i ns pecti o n. W he n s o urce d oc u me nts are re q uire d f or t he c o nti n ue d 
care of t he s u bject , a p pr o priate c o pies s h o ul d be ma de f or st ora ge a wa y fr o m t he site. 
8. 1. 6.  
Electr o nic C ase Re p ort F or ms  
Desi g nate d I nvesti gat or -staff will e nter t he data re q uire d b y t he pr ot oc ol i nt o t he e C R F usi n g 
f ull y vali date d sec ure we b-e na ble d s oft ware t hat c o nf or ms t o U S C F R 2 1 Part 1 1 
re q uire me nts. Desi g nate d i n vesti gat or site staff will n ot be gi ve n access t o t he s yste m u ntil 
t he y ha ve bee n trai ne d. S u bse q ue nt t o data e ntr y, a st u d y m o nit or will perf or m s o urce data 
verificati o n wit hi n t he E D C s yste m. Ori gi nal e ntries as well as a n y c ha n ges t o data fiel ds will 
be st ore d i n t he a u dit trail of t he s yste m.  
A ut o matic vali dati o n pr oce d ures wit hi n t he s yste m c hec k f or data discre pa ncies d uri n g a n d 
after data e ntr y a n d , b y ge nerati n g a p pr o priate err or messa ges, all o w t he data t o be c o nfir me d 
or c orrecte d o nli ne b y t he desi g nate d I n vesti gat or- site staff. T he I n vesti gat or m ust certif y t hat 
t he data e ntere d i nt o t he electr o nic Case Re p ort F or ms are c o m plete a n d acc urate.  


Efr u xifer mi n  
Cli nical Trial Pr ot oc ol:  A K -U S -0 0 1 -0 1 0 2  
Pa ge 8 0  of 9 5   
 
 
 
A ker o T hera pe utics , I nc. 
C o nfi de ntial  
A me n d me nt 4, 1 8 A pr 2 0 2 2  
At t he c o ncl usi o n of t he trial, A ker o will pr o vi de t he site wit h a rea d - o nl y arc hi ve c o p y of t he 
data e ntere d b y t hat site. T his arc hi ve m ust be st ore d i n acc or da nce wit h t he rec or ds rete nti o n 
re q uire me nts o utli ne d i n Secti o n  8. 1. 5 .  
8. 1. 7.  
I ns pecti o ns 
T he In vesti gat or will ma ke a vaila ble all s o urce d oc u me nts a n d ot her rec or ds f or t his trial t o 
A ker o’s a p p oi nte d st u d y m o nit ors, t o I R B/I E C/ E C, or t o re g ulat or y a ut h orit y or healt h 
a ut h orit y i ns pect ors. 
8. 1. 8.  
Pr ot oc ol C o m pli a nce  
T he I n vesti gat or is res p o nsi ble f or e ns uri n g t he st u d y is c o n d ucte d i n acc or da nce wit h t he 
pr oce d ures a n d e val uati o ns descri be d i n t his pr ot oc ol. 
8. 2.  
S p o ns or Res p o nsi bilities  
8. 2. 1.  
Pr ot oc ol M o dific ati o ns  
Pr ot oc ol m o dificati o ns , e xce pt t h ose i nte n de d t o re d uce i m me diate ris k t o st u d y s u bjects, 
ma y be ma de o nl y b y A ker o. T he I n vesti gat or m ust s u b mit all pr ot oc ol m o dif icati o ns t o t he 
I R B/I E C/ E C i n acc or da nce wit h l ocal re q uire me nts a n d recei ve d oc u me nte d I R B/I E C/ E C 
a p pr o val bef ore m o dificati o ns ca n be i m ple me nte d. 
8. 2. 2.  
St u d y Re p ort a n d P u blic ati o ns  
A cli nical st u d y re p ort ( C S R) will be pre pare d a n d pr o vi de d t o t he re g ulat or y a ge ncies. 
A ker o will e ns ure t hat t he re p ort meets t he sta n dar ds set o ut i n t he I C H G ui deli ne f or 
Str uct ure a n d C o nte nt of Cli nical St u d y Re p orts (I C H  E 3). N ote t hat a n a b bre viate d re p ort 
ma y be pre pare d i n certai n cases.  
I n vesti gat ors i n t his st u d y ma y c o m m u nicate, orall y prese nt , or p u blis h i n scie ntific j o ur nals 
or ot her sc h olarl y me dia o nl y after t he f oll o wi n g c o n diti o ns ha ve bee n met: t he res ults of t he 
st u d y i n t heir e ntiret y ha ve bee n p u blicl y discl ose d b y or wit h t he c o nse nt of A ker o i n a n 
a bstract , ma n uscri pt , or prese ntati o n f or m or t he st u d y has bee n c o m plete d at all st u d y sites 
f or at least 1 8 m o nt hs. 
T he I n vesti gat or will s u b mit t o A ker o a n y pr o p ose d p u blicati o n or prese ntati o n al o n g wit h 
t he res pecti ve scie ntific j o ur nal or prese ntati o n f or u m at least 6 0 da ys bef ore s u b missi o n of 
t he p u blicati o n or prese ntati o n.  
N o s uc h c o m m u nicati o n, prese ntati o n , or p u blicati o n will i ncl u de A ker o’s c o nfi de ntial 
i nf or mati o n (see Secti o n  8. 1. 4 ). 
T he In vesti gat or will c o m pl y wit h A ker o’s re q uest t o delete refere nces t o its c o nfi de ntial 
i nf or mati o n ( ot her t ha n t he st u d y res ults) i n a n y pa per or prese ntati o n a n d a grees t o wit h h ol d 


Efr u xifer mi n  
Cli nical Trial Pr ot oc ol:  A K -U S -0 0 1 -0 1 0 2  
Pa ge 8 1  of 9 5   
 
 
 
A ker o T hera pe utics , I nc. 
C o nfi de ntial  
A me n d me nt 4, 1 8 A pr 2 0 2 2  
p u b licati o n or prese ntati o n f or a n a d diti o nal 6 0 da ys i n or der t o o btai n pate nt pr otecti o n if 
dee me d necessar y.  
8. 3.  
J oi nt I n vesti g at or/ S p o ns or Res p o nsi bilities 
8. 3. 1.  
P a y me nt Re p orti n g  
I n vesti gat ors a n d t heir st u d y staff ma y be as ke d t o pr o vi de ser vices perf or me d u n der t his 
pr ot oc ol ( e. g., atte n da nce at I n vesti gat or's Meeti n gs). If re q uire d u n der t he a p plica ble 
stat ut or y a n d re g ulat or y re q uire me nts, A ker o will ca pt ure a n d discl ose t o Fe deral a n d State 
a ge ncies a n y e x pe nses pai d or rei m b urse d f or s uc h ser vices , i ncl u di n g a n y cli nical trial 
pa y me nts, meal , tra vel e x pe nses or rei m b urse me nts, c o ns ulti n g fees, a n d a n y ot her tra nsfer of 
val ue. 
8. 3. 2.  
Access t o I nf or m ati o n f or A u diti n g or I ns pecti o ns  
Re prese ntati ves of re g ulat or y a ut h orities or of A ker o ma y c o n d uct i ns pecti o ns or a u dits of 
t he cli nical st u d y. If t he I n vesti gat or is n otifie d of a n i ns pecti o n b y a re g ulat or y a ut h orit y t he 
In vesti gat or a grees t o n otif y t he A ker o me dical m o nit or i m me diatel y. T he In vesti gat or a grees 
t o pr o vi de t o re prese ntati ves of a re g ulat or y a ge nc y or A ker o access t o rec or ds, facilities, a n d 
pers o n nel f or t he effecti ve c o n d uct of a n y i ns pecti o n or a u dit. 
8. 3. 3.  
St u d y Disc o nti n u ati o n  
B ot h t he s p o ns or a n d t he I n vesti gat or reser ve t he ri g ht t o ter mi nate t he st u d y at a n y ti me. 
S h o ul d t his be necessar y, b ot h parties will arra n ge disc o nti n uati o n pr oce d ures a n d n otif y t he 
a p pr o priate re g ulat or y a ut h orities , I R Bs, I E Cs, a n d E Cs. I n ter mi nati n g t he st u d y, A ker o a n d 
t he I n vesti gat or will ass ure t hat a de q uate c o nsi derati o n is gi ve n t o t he pr otecti o n of t he 
s ubjects’ i nterests.  
 


Efr u xifer mi n  
Cli nical Trial Pr ot oc ol:  A K -U S -0 0 1 -0 1 0 2  
Pa ge 8 2  of 9 5  
A ker o T hera pe utics , I nc. 
C o nfi de ntial  
A me n d me nt 4, 1 8 A pr 2 0 2 2  
9.
R E F E R E N C E LI S T
A n g ul o P, Klei ner D E , Da m -Larse n S , et al. Li ver fi br osis , b ut n o ot her hist ol o gic feat ures , is 
ass ociate wit h l o n g -ter m o utc o mes i n patie nts wit h n o nalc o h olic fatt y li ver disease. 
Gastr oe nter ol o g y. 2 0 1 5; 1 4 9: 3 8 9- 3 9 7. 
Ba o L , Yi n J , Ga o W , et al. A l o n g-acti n g F G F 2 1 alle viates he patic steat osis a n d 
i nfla m mati o n i n a m o use m o del of n o n-alc o h olic st eat o he patitis partl y t hr o u g h a n F G F 2 1-
a di p o necti n-I L 1 7 A pat h wa y. Br J P har mac ol. 2 0 1 8; 1 7 5: 3 3 7 9- 3 3 9 3. 
Ca m p orez J P , J or na y vaz F R, Peterse n M C , et al. Cell ular mec ha nis ms b y w hic h F G F 2 1 
i m pr o ves i ns uli n se nsiti vit y i n male mice. E n d ocri n ol o g y. 2 0 1 3; 1 5 4: 3 0 9 9 – 3 1 0 9. 
C halasa ni N , Y o u n ossi Z, La vi ne J F , et al.  T he dia g n osis a n d ma na ge me nt of n o nalc o h olic 
fatt y li ver disease: Practice g ui da nce fr o m t he A merica n Ass ociati o n f or t he st u d y of li ver 
diseases. He pat ol o g y. 2 0 1 8; 6 7( 1): 3 2 8- 3 5 7. 
C he n M S, C ha n g J C, Za va la-S ol ori o J , et al. F G F 2 1 mi metic a nti b o d y sti m ulates U C P 1 -
i n de pe n de nt br o w n fat t her m o ge nesis via F G F R 1/ b Kl ot h o c o m ple x i n n o n-a di p oc ytes. M ol. 
Meta b. 2 0 1 7; 6: 1 4 5 4- 1 4 6 7. 
C os k u n T, Bi na H A , Sc h nei der M A , et al. Fi br o blast gr o wt h fact or 2 1 c orrects o besit y i n 
mice. E n d ocri n ol o g y. 2 0 0 8; 1 4 9: 6 0 1 8 – 6 0 2 7. 
C ui A , Li J , Ji S, Ma F , Wa n g G, X ue Y , et al. T he effects of B 1 3 4 4 , a n o vel fi br o blast 
gr o wt h fact or 2 1 a nal o g, o n n o nalc o h olic steat o he patitis i n n o n h u ma n pri mates. Dia betes. 
2 0 2 0. 
D ulai P S , Si n g h S, Patel J , et al. I ncrease d ris k of m ortalit y b y fi br osis sta ge i n n o nalc o h olic 
fatt y li ver disease: S yste mic re vie w a n d meta-a nal ysis. He pat ol o g y. 2 0 1 7; 6 5( 5): 1 5 5 7- 1 5 6 5. 
E kste dt M, Ha gstr ö m H , Nasr P , et al. Fi br osis sta ge is t he str o n gest pre dict or f or disease -
s pecific m ortalit y i n N A F L D after u p t o 3 3 years of f oll o w- u p. He pat ol o g y. 2 0 1 5; 6 1: 1 5 4 7-
5 4. 
Estes C , A nstee Q M , Arias -L oste M T et al. M o deli n g N A F L D disease b u r de n i n C hi na, 
Fra nce ,Ger ma n y , Ital y, Ja pa n, S pai n , U nite d Ki n g d o m, a n d U nite d States f or t he peri o d 
2 0 1 6- 2 0 3 0. J. He pat ol. 2 0 1 8; 6 9; 8 9 6 – 9 0 4. 
E ur o pea n Ass ociati o n f or t he St u d y of t he Li ver ( E A S L), E ur o pea n Ass ociati o n f or t he St u d y 
of Dia betes ( E A S D) , E ur o pea n Ass ociati o n f or t he St u d y of O besit y ( E A S O). E A S L- E A S D -
E A S O Cli nical practice g ui deli nes f or t he ma na ge me nt of n o n -alc o h olic fatt y li ver disease. J. 
He pat ol, 2 0 1 6; 6 4( 6): 1 3 8 8- 1 4 0 2. 
Fis her F M , C h ui P C, Nasser I A , et al. Fi br o blast gr o wt h fact or 2 1 li m its li p ot o xicit y b y 
pr o m oti n g he patic fatt y aci d acti vati o n i n mice o n met hi o ni ne a n d c h oli ne- deficie nt diets. 
Gastr oe nter ol o g y. 2 0 1 4; 1 4 7: 1 0 7 3- 8 3.  


Efr u xifer mi n  
Cli nical Trial Pr ot oc ol:  A K -U S -0 0 1 -0 1 0 2  
Pa ge 8 3  of 9 5  
A ker o T hera pe utics , I nc. 
C o nfi de ntial  
A me n d me nt 4, 1 8 A pr 2 0 2 2  
F o n  Tacer K, B o o k o ut A L, Di n g X, e t al.  Researc h res o urce:  C o m pre he ns i ve e x pressi o n 
atlas of t he fi br o blast gr o wt h fact or s yste m i n ad ult m o use.   M ol E n d ocri n ol.  2 0 1 0; 2 4: 
2 0 5 0- 2 0 6 4. 
Gaic h  G , C hie n J Y, Fu  H, et al. T he effects of L Y 2 4 0 5 3 1 9, a n d F G F 2 1 a nal o g, i n o bese 
h u ma n s u bjects w ith t y pe 2 dia betes. Cell M etab. 2 0 1 3; 1 8( 3): 3 3 3- 3 4 0. 
Gi m e n o R E, Mol ler DE.  F GF 2 1- base d  p har mac ot hera p y: P ote ntial utilit y for meta b olic  
dis or ders. Tre n ds E n d ocri n ol. Meta b ol. 2 0 1 4; 2 5: 3 0 3- 3 1 1. 
Ha gstr ö m H , Nasr P, Es kte dt M , et al. Fi br osis sta ge b ut n ot N A S H  pre dicts m ortalit y an d  
ti me t o deve l o p me nt of se vere li ver disease i n bio ps y - pr o ven N A F L D. J. He pat ol o g y. 2 0 1 7; 
6 7: 1 2 6 5- 1 2 7 3. 
Ka uf ma n A, A b u qa y yas L, De n ne y W S, T ill ma n EJ, R ol p h T. A K R- 0 0 1, a n d Fc-F G F 2 1  
a nal o g, sh o we d  s ustai ne d p har mac o d y na mic effects o n i ns uli n se nsiti vit y a n d li pi d 
met a b olis m i n t y pe 2 dia betes pa tie nts. Cell R e p orts M e dici ne. 2 0 2 0; 1: 1 0 0 0 5 7. 
Ki m  A M, S o ma yaji V R, D o n g J Q, e t al. Once - wee kl y a d mi nistrati o n of a l o n g-acti n g 
fi br o blast gr o wt h fact or 2 1 a nal o g ue m o d ulates li pi ds, b o ne tur n o ver m ar kers, bl o o d press ure 
a n d b o d y we i g ht di ffere ntl y i n o bese pe o ple w ith h y pertri gl yceri dae mia an d i n n o n- h u ma n 
pri mates.  Dia betes O bes Meta b. 2 0 1 7; 1 9( 1 2): 1 7 6 2- 1 7 7 2. 
Lee J H , Ka n g Y E, C ha n g J Y, et al. A n  e n gi neere d F G F 2 1 varia nt, L Y 2 4 0 5 3 1 9, ca n pre ve nt 
n o n-alc o h olic steat o he patitis b y e n ha nci n g he patic m it oc h o n drial fu ncti o n. A m  J Tra nsl Res. 
2 0 1 6; 8: 4 7 5 0- 4 7 6 3. 
Li  H, Z ha n g J, Jia W. Fi br o blast gr o wt h fact or 2 1: a n o vel meta b olic  re g ulat or fr o m 
p har mac ol o g y t o p h ysi ol o g y. F r o nt M ed. 2 0 1 3; 7: 2 5 – 3 0. 
Li n  Z, Tia n H, La m K S, et al. Adi p o necti n  me diat es t he meta b olic effects of  FG F 2 1  o n 
gl uc ose h o me ostasis a n d i ns uli n se nsiti vit y i n mice . Cell Meta b. 2 0 1 3; 1 7: 7 7 9 – 7 8 9. 
M u J, P i n kstaff J, Li Z, et al. F G F 2 1 a nal o gs of s ustai ne d acti o n e na ble d b y ort h o g o nal 
bi os y nt hesis de m o nstrate en ha nce d a nti dia betic p har mac ol o g y i n r o de nts. D ia betes. 2 0 1 2; 
6 1: 5 0 5 – 5 1 2. 
T he Nas h E d ucati o n Pr o gra m. 2 0 1 9. Retrie ve d A pril 2 2, 2 0 2 2, fr o m htt ps:// w w w.t he- n as h-
e d ucati o n- pr o gra m.c o m/  
Nis hi m ura  T, Na kata ke Y, K o nis hi M , It o h N.  I de ntificati o n of a n o ve l F G F, F G F - 2 1, 
prefere ntiall y e x presse d i n t he li ver.  Bi oc hi m B i o p h ys A cta.  2 0 0 0; 1 4 9 2: 2 0 3- 2 0 6. 
O p o k u Y. K, Li u  Z, Afrifa J, Ku mi  A. K, Li u H, Gharte y -K w a nsa h G, K ora nte n g H, et al.  
Fi br o blast Gr o wt h  Fact or- 2 1 A meli orates H e patic E nce p hal o pat h y b y Acti vati n g t he S T A T 3-
S O C S 2  Pat h wa y t o I n hibit Acti vate d  He patic  Stellate Cells.  E X C LI: 1 9: 5 6 7- 5 8 1, 2 0 2 0. 


Efr u xifer mi n  
Cli nical Trial Pr ot oc ol:  A K -U S -0 0 1 -0 1 0 2  
Pa ge 8 4  of 9 5   
 
 
 
A ker o T hera pe utics , I nc. 
C o nfi de ntial  
A me n d me nt 4, 1 8 A pr 2 0 2 2  
R u hl C E , E ver hart J E. Fatt y li ver i n dices i n t he m ultiet h nic U nite d States Nati o nal Healt h 
a n d N utriti o n E xa mi nati o n S ur ve y. Ali me nt P har mac ol. T her. 2 0 1 5; 4 1: 6 5 – 7 6. 
Sta nisla us S , Hec ht R , Yie J , Ha ger T , Hall M , S pa hr C , et al. A N o vel Fc- F G F 2 1 Wit h 
I m pr o ve d Resista nce t o Pr ote ol ysis, I ncrease d Affi nit y T o war d b-Kl ot h o, a n d E n ha nce d 
Efficac y i n Mice a n d C y n o m ol g us M o n ke ys. E n d ocri n ol o g y 1 5 8: 1 3 1 4 – 1 3 2 7, 2 0 1 7. 
Tal u k dar S, Z h o u Y, Li D , et al. A l o n g-acti n g F G F 2 1 m olec ule, P F - 0 5 2 3 1 0 2 3, decreases 
b o d y wei g ht a n d i m pr o ves li pi d pr ofile i n n o n- h u ma n pri mates a n d t y pe 2 di a betic s u bjects. 
Cell Meta b . 2 0 1 6; 2 3: 4 2 7- 4 4 0.  
Ta na ka N , Ta ka has hi S , Z ha n g Y, et al. R ole of fi br o blast gr o wt h fact or 2 1 i n t he earl y sta ge 
of N A S H i n d uce d b y met hi o ni ne- a n d c h oli ne- deficie nt diet. Bi oc hi m. Bi o p h ysica. Acta. 
2 0 1 5; 1 8 5 2: 1 2 4 2 - 1 2 5 2. 
T he  N A S H E d ucati o n Pr o gra m. htt ps:// w w w.t he -nas h -e d ucati o n-pr o gra m.c o m/.  Accesse d 
Fe br uar y 2 5, 2 0 1 9. 
 
Tar g her G, B yr ne C. D, L o nar d o A, Z o p pi ni G, Bar b ui C.  N o n- alc o h olic fatt y li ver disease 
a n d ris k i nci de nt car di o vasc ular disease: A meta -a nal ysis.  J o ur nal of He pat ol o g y. V ol 6 5: 
5 8 9- 6 0 0. 2 0 1 6. 
W u G, Li H , Fa n g Q, et al. C o m ple me ntar y r ole of fi br o blast gr o wt h fact or 2 1 a n d 
c yt o kerati n 1 8 i n m o nit ori n g t he differe nt sta ges of n o nalc o h olic fatt y li ver disease . Sci. Re p. 
2 0 1 7; 7: 5 0 9 5. 
X u J , Ll o y d DJ, Hale C , et al. Fi br o blast gr o wt h fact or 2 1 re verses he patic steat osis , 
i ncreases e ner g y e x pe n dit ure, a n d i m pr o ves i ns uli n se nsiti vit y i n diet-i n d uce d o bese mice. 
Dia betes . 2 0 0 9; 5 8: 2 5 0 – 2 5 9.  
X u J , Z ha n g Y, Li u Y , et al. Fi br o blast gr o wt h fact or 2 1 atte n uates he patic fi br o ge nesis 
t hr o u g h T G F- β/s ma d 2/ 3 a n d N F- κ B si g nali n g pat h wa ys. T o xic ol A p pl. P har mac ol. 2 0 1 6; 
2 9 0: 4 3- 5 3. 
Y o u n ossi Z M, K oe ni g A B, A b delatif D , et al. Gl o bal e pi de mi ol o g y of n o nalc o h olic fatt y 
li ver disease- meta -a nal ytic assess me nt of pre vale nce , i nci de nce, a n d o utc o mes. He pat ol o g y. 
2 0 1 6; 6 4: 7 3 – 8 4. 
Z ha o L, Ni u J , Li n H , Z ha o J, Li u Y , S o n g Z, Xia n g C, et al.  Paracri ne -e n d ocri ne F G F 
c hi meras as p ote nt t hera pe utics f or meta b olic diseases.  E Bi o Me dici ne. 2 0 1 9; 4 8: 4 6 2- 4 7 7 .   


Efr u xifer mi n  
Cli nical Trial Pr ot oc ol:  A K -U S -0 0 1 -0 1 0 2  
Pa ge 8 5  of 9 5   
 
 
 
A ker o T hera pe utics , I nc. 
C o nfi de ntial  
 
A me n d me nt 4, 1 8 A pr 2 0 2 2  
1 0.  
A P P E N DI C E S  
A p pe n di x A. 
Sc he d ule of Assess me nts – Scree ni n g  t o Wee k 2 4 
 
Assess me nts  a 
S cree ni n g t 
(- 8 w ks)  
Pre - Baseli ne  b 
(- 4 w ks)  
B aseli ne  / 
D a y 1 
W eek 1  
W eeks  
2  &  3  
Wee k 
4  
Wee k 
8  
Wee k 
1 2  
W eek 
1 6  
Wee k 
2 0  
W eeks 5 , 6 , 7 , 
9, 1 0 , 1 1 , 1 3 , 
1 4 , 1 5 , 1 7 , 1 8 , 
1 9 , 2 1 , 2 2 , 2 3  c 
W eek 
2 4  
 
E arl y Ter m 
& 3 0 -D a y 
F oll o w -U p  r 
 
Cli nic al Assess me nts  
Writte n I nf or me d C o nse nt  
X 
 
 
 
 
 
 
 
 
 
 
 
 
Eli gi bilit y  
X 
X 
X 
 
 
 
 
 
 
 
 
 
 
Me dical Hist or y  
X 
 
 
 
 
 
 
 
 
 
 
 
 
P h ysical E xa mi nati o n  d 
X 
 
X 
X 
 
X 
X 
X 
X 
X 
 
X 
X 
C hil d -P u g h Sc ore d 
 
 
X 
 
 
 
 
X 
 
 
 
X 
X 
Vital Si g ns  e  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
X 
Wei g ht 
f 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
X 
Hei g ht 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Hi p a n d Waist 
Circ u mfere nce f  
X 
 
X 
 
 
 
 
X 
 
 
 
X 
X 
1 2- lea d E C G 
X 
 
X 
 
 
 
 
 
 
 
 
X 
X 
Fi br o Sca n ® g  
X  
 
 
 
 
 
 
 
 
 
 
X 
X 
M RI -P D F F  
X 
 
 
 
 
 
 
 
 
 
 
X 
X s 
D X A  
X 
 
 
 
 
 
 
 
 
 
 
 
 
Li ver Bi o ps y  a 
X  
 
 
 
 
 
 
 
 
 
 
X 
X s 
C L D Q -N A S H  h 
 
 
X  
 
 
 
 
X 
 
 
 
X 
 




Efr u xifer mi n  
Cli nical Trial Pr ot oc ol:  A K -U S -0 0 1 -0 1 0 2  
Pa ge 8 7  of 9 5   
 
 
 
A ker o T hera pe utics , I nc. 
C o nfi de ntial  
 
A me n d me nt 4, 1 8 A pr 2 0 2 2  
c 
S u bjects will ha ve t he o pti o n t o c o n d uct visit usi n g i n -h o me n ursi n g.  
d  
C o m plete P E i ncl u di n g assess me nt at Scree ni n g , Baseli ne a n d Wee ks 1 2 & 2 4 , ot her wise s y m pt o m-dri ve n.  C hil d -P u g h ( C P) Sc ore assess me nts s h o ul d be 
c o m plete d as part of t he p h ysical e xa m at Baseli ne , Wee k 1 2 , Wee k 2 4 , a n d E T & 3 0 -Da y F oll o w -u p.   
e 
Vitals t o i ncl u de s yst olic a n d diast olic B P , p ulse , res pirati o n rate will be c ollecte d at eac h visit.  T e m perat ure will als o be c ollecte d at Scree ni n g a n d Baseli ne 
o nl y . Tri plicate bl o o d press ure (t o be meas ure d i n sa me ar m wit h at least t w o mi n utes rest bet wee n B P meas ure me nts) a n d heart rate t o be c ollecte d at 
B aseli ne, Wee k 1 2  & Wee k 2 4 a n d si n gle meas ure me nts t o be c ollecte d at all ot her visits.  
f 
Wei g ht , waist a n d hi p c irc u mfere nce s h o ul d be o btai ne d b y t he sa me st u d y pers o n nel as m uc h as p ossi ble acr oss visits f or eac h s u bject t o mi ni mize 
varia bilit y i n t he meas ure me nt. O n i n cli nic d osi n g da ys , wei g ht will be c ollecte d pre -d ose . Wei g ht s h o ul d be o btai ne d usi n g a cali brate d scale.  T he s u bject 
s h o ul d be wei g he d i n c o nsiste nt cl ot hi n g. 
g  
At least 2 -3 h o urs fasti n g is re q uire d pri or t o all elast o gra p h y assess me nts.  
h  
If t he C L D Q -N A S H  is misse d at Baseli ne/ Da y 1 , q uesti o n naire s h o ul d n ot be c ollecte d at t he re mai ni n g ti me p oi nts.  It is rec o m me n de d t hat t he 
q uesti o n naire be c o m plete d pri or t o a n y st u d y pr oce d ures bei n g perf or me d a n d pri or t o t he s u bject seei n g a healt h care pr o vi d er. 
i 
All s u bjects will recei ve c o u nseli n g re gar di n g lifest yle m o dificati o ns i ncl u di n g t he mai nte na nce of a healt h y diet a n d partici pati o n i n re g ular e xercise at t he 
Scree ni n g  Visit.  At eac h s u bse q ue nt visit , s u bjects will be as ke d if t here has bee n a si g nifica nt c ha n ge i n diet, or p h ysical acti vit y.  
j 
A d mi nistrati o n of st u d y dr u g s h o ul d occ ur f oll o wi n g all  ot her st u d y pr oce d ures a n d sa m ple c ollecti o n f or t hat visit.   
k  
A E re p orti n g d uri n g scree ni n g is li mite d t o S A Es a n d A Es relate d t o st u d y pr oce d ures.  
l 
Refer t o Ta ble of Cli nical La b orat or y Assess me nts. Sa m ples t o be c ollecte d i n t he m or ni n g f oll o wi n g a n o ve r ni g ht fast of at least 8  or 1 2  h o urs  w here 
i n dicate d. 
m  O nl y c o nfir mat or y A L T/ A S T t o be c ollecte d at t he Pre -Baseli ne Visit t o c o nfir m eli gi bilit y if re q uire d.  
n  
Ser u m  & plas ma  st ora ge sa m ples ba n ke d f or p ossi ble a d diti o nal cli nical testi n g. 
o  
P K sa m pli n g will be o btai ne d pre-d ose .     
p  
Sa m ples will be o btai ne d f or detecti o n of A D A a gai nst E F X  a n d if re q uire d a ne utralizi n g A D A assa y will be r u n o n t he sa me sa m ple . 
q  
F or fe male s u bjects of c hil d beari n g p ote ntial o nl y. Ser u m pre g na nc y test at scree ni n g  a n d uri ne pre g na nc y test at ot her ti me p oi nts . 
r 
Earl y Ter mi nati o n visit s h o ul d occ ur wit hi n 5 da ys of disc o nti n uati o n of st u d y dr u g.  T he 3 0 -Da y F oll o w -U p visit s h o ul d occ ur 3 0 da ys f oll o wi n g t he last 
d ose of st u d y dr u g recei ve d . 
s 
Li ver Bi o ps y t o be o btai ne d  at Earl y Ter mi nati o n o nl y if t he s u bject recei ve d at least 1 6 wee ks of E F X/ Place b o . M RI t o be o btai ne d ± 5 da ys fr o m t he li ver 
bi o ps y.  
t 
T he scree ni n g peri o d ma y be e xte n de d b y 2 wee ks  u n der s pecial circ u msta nces wit h t he e x plicit a p pr o val of t he C R O Me dica l M o nit or. 
 
 
 
 


Efr u xifer mi n  
Cli nical Trial Pr ot oc ol:  A K -U S -0 0 1 -0 1 0 2  
Pa ge 8 8  of 9 5   
 
 
 
A ker o T hera pe utics , I nc. 
C o nfi de ntial  
 
A me n d me nt 4, 1 8 A pr 2 0 2 2  
A p pe n di x B.  
Sc he d ule of Assess me nts – L o n g - Ter m F oll o w-U p  
 
Assess me nts  a 
W eeks 2 8 , 3 6 , 4 4 , 5 2  
Wee k 3 2 , 4 0  
4 8  
Wee ks 5 6 , 6 4 , 8 0 , 
8 8  
Wee k 7 2  
Wee ks 9 6   
E arl y Ter m & 3 0 -
D a y F oll o w -U p  l 
 
Cli nic al Assess me nts  
P h ysical E xa mi nati o n   
X 
X 
X b 
X 
X 
X  
X 
C hil d P u g h Sc ore b 
 
 
X 
 
 
X 
X 
Vital Si g ns  c 
X 
X 
X 
X 
X 
X 
X 
Wei g ht 
d 
X 
X 
X 
X 
X 
X 
X 
Hi p a n d Waist Circ u mfere nce  d  
X 
X 
X 
X 
X 
X 
X 
1 2- lea d E C G 
 
 
X 
 
 
X 
X 
Fi br o Sca n ® e  
 
 
X 
 
 
X  
 
M RI -P D F F  
 
 
 
 
 
X m  
X o 
D X A  
 
 
X p 
 
 
X  
 
Li ver Bi o ps y   
 
 
 
 
 
X m 
X o 
C L D Q -N A S H f 
X 
 
X 
 
 
X  
 
Lifest yle G ui da nce g 
X 
X 
X 
X 
X 
X 
 
A d mi nister St u d y Dr u g  h 
X  
X 
X 
X 
X 
X  
 
C o nc o mita nt Me dicati o ns  
X 
X 
X 
X 
X 
X 
X 
A d verse E ve nts  
X 
X 
X 
X 
X 
X 
X 
 
L a b or at or y Assess me nts  
C he mistr y , He mat ol o g y, Li pi ds , 
C oa g ulati o n i 
X 
X 
X 
X 
X 
X 
X 
Ser u m & Plas ma  St ora ge Sa m ple s j 
X 
X 
X 
X 
X 
X 
X 


Efr u xifer mi n  
Cli nical Trial Pr ot oc ol:  A K -U S -0 0 1 -0 1 0 2  
Pa ge 8 9  of 9 5   
 
 
 
A ker o T hera pe utics , I nc. 
C o nfi de ntial  
 
A me n d me nt 4, 1 8 A pr 2 0 2 2  
Assess me nts  a 
W eeks 2 8 , 3 6 , 4 4 , 5 2  
Wee k 3 2 , 4 0  
4 8  
Wee ks 5 6 , 6 4 , 8 0 , 
8 8  
Wee k 7 2  
Wee ks 9 6   
E arl y Ter m & 3 0 -
D a y F oll o w -U p  l 
Fi br osis Bi o mar kers i 
 
 
X 
 
X 
X  
X 
Ot her Bi o mar kers i 
 
X 
X 
 
X 
X  
X 
P K 
 
X 
X 
X 
X 
X 
X 
A D A a n d N A B  n 
 
X 
X 
X 
X 
X  
X 
E n d o ge n o us F G F 2 1  
 
X 
X 
X 
X 
X  
X 
Pre g na nc y testi n g  k 
X 
X 
X 
X 
X 
X 
X 
A D A = a nti -dr u g a nti b o dies; B P = bl o o d press ure; E C G  = electr ocar di o gra m; H R = heart rate; P E = P h ysical E xa mi nati o n; P K = p har mac o ki netic; N A B = 
ne utralizi n g a nti b o d y  
a 
I n-cli nic visits will be c o n d ucte d e ver y 4 wee ks  ± 5 da ys fr o m Wee k 2 8  t o Wee k 5 6 a n d t he n e ver y 8 wee ks  ± 7 da ys  fr o m Wee k 6 4  t o Wee k 9 6 .  
b  
C o m plete P E i ncl u di n g assess me nt at Wee k 4 8 , ot her wise s y m pt o m -dri ve n.  C hil d -P u g h ( C P) Sc ore assess me nts s h o ul d be c o m plete d as part of t he p h ysical 
e xa m at W ee k 4 8 , Wee k 9 6 , a n d E T & 3 0-Da y F oll o w -u p.  
c 
Vitals t o i ncl u de s yst olic a n d diast olic B P , p ulse , res pirati o n rate will be c ollecte d at eac h visit.  Tri plicate bl o o d press ure (t o be meas ure d i n sa me ar m wit h 
at least t w o mi n utes rest bet wee n B P meas ure me nts) a n d heart rate t o be c ollecte d at Wee k 4 8  a n d Wee k 9 6 . Si n gle meas ure me nts t o be c ollecte d at all ot her 
visits.  
d  
Wei g ht , waist a n d hi p circ u mfere nce s h o ul d be o btai ne d b y t he sa me st u d y pers o n nel as m uc h as p ossi ble acr oss visits f or eac h s u bject t o mi ni mize 
varia bilit y i n t he meas ure me nt. O n d osi n g da ys , wei g ht will be c ollecte d pre -d ose.  Wei g ht s h o ul d be o btai ne d usi n g a cali brate d scale.  T he s u b ject s h o ul d 
be wei g he d i n c o nsiste nt cl ot hi n g.  
e 
At least 2 -3 h o urs fasti n g is re q uire d pri or t o all elast o gra p h y assess me nts.  
f 
If t he C L D Q -N A S H  is misse d at Baseli ne/ Da y 1 , q uesti o n naire s h o ul d n ot be c ollecte d at t he re mai ni n g ti me p oi nts. It is rec o m me n de d t hat t he q uesti o n naire 
be c o m plete d pri or t o a n y st u d y pr oce d ures bei n g perf or me d a n d pri or t o t he s u bject seei n g a healt h care pr o vi der . 
g  
At eac h visit , s u bjects will be as ke d if t here has bee n a si g nifica nt c ha n ge i n diet, or p h ysical acti vit y.  
h  
A d mi nistr ati o n of st u d y dr u g s h o ul d occ ur f oll o wi n g all ot her st u d y pr oce d ures a n d sa m ple c ollecti o n f or t hat visit. Be gi n ni n g at  Wee k 2 5 , wee kl y 
a d mi nistrati o n of st u d y dr u g is re q uire d eit her o n site or utilizi n g i n -h o me n ursi n g  f or t he f oll o wi n g visits: Wee ks 2 5 -2 7, 2 9 -3 1, 3 3 -3 5, 3 7 -3 9, 4 1 -4 3, 4 5 -4 7, 
4 9 -5 1, 5 3 -5 5, 5 7 -6 3, 6 5 -7 1, 7 3 -7 9, 8 1 -8 7 , a n d 8 9-9 5 . A d mi nistrati o n of last d ose of st u d y dr u g will occ ur at Wee k 9 5 . 
i 
Refer t o Ta ble of Cli nical La b orat or y Assess me nts. Sa m ples t o be c ollecte d i n t he m or ni n g f oll o wi n g a n o ver ni g ht fast of at least 8  or 1 2  h o urs w here 
i n dicate d. 
j 
Ser u m  & plas ma  st ora ge sa m ples ba n ke d f or p ossi ble a d diti o nal cli nical testi n g. 
k  
F or fe male s u bjects of c hil d beari n g p ote ntial o nl y. U ri ne pre g na nc y test at all ti me p oi nts. 
l 
Earl y Ter mi nati o n visit s h o ul d occ ur wit hi n 5 da ys of disc o nti n uati o n of st u d y dr u g.  T he 3 0 -Da y F oll o w -U p visit s h o ul d occ ur 3 0 da ys f oll o wi n g t he last 
d ose of st u d y dr u g recei ve d . 
m  A d diti o nal bi o ps y re q uire d at Wee k 9 6 . T he li ver bi o ps y s h o ul d be o btai ne d  ( –) 8 wee ks t o ( +) 4 wee ks fr o m t he sc he d ule d visit date. M RI -P D F F  t o be 
o btai ne d ± 5 da ys fr o m t he li ver bi o ps y.  
n  
Sa m ples will be o btai ne d f or detecti o n of A D A a gai nst E F X  a n d if re q uire d a ne utralizi n g A D A assa y will be r u n o n t he sa me sa m ple . 


Efr u xifer mi n  
Cli nical Trial Pr ot oc ol:  A K -U S -0 0 1 -0 1 0 2  
Pa ge 9 0  of 9 5   
 
 
 
A ker o T hera pe utics , I nc. 
C o nfi de ntial  
 
A me n d me nt 4, 1 8 A pr 2 0 2 2  
o  
Li ver Bi o ps y ma y be re q uire d f or a dj u dicati o n of pre -s pecifie d li ver-relate d o utc o mes or t o be o btai ne d at Earl y Ter mi nati o n o nl y if t he pre vi o us li ver 
bi o ps y was o btai ne d ≥ 1 2 m o nt h s pri or. M RI -P D F F t o be perf or me d if a li ver bi o ps y is o btai ne d, ± 5 da ys fr o m t he li ver bi o ps y . 
p  
D X A  t o be o btai ne d ± 1 0  da ys  o f t he Wee k 4 8 Visit. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Efr u xifer mi n  
Cli nical Trial Pr ot oc ol:  A K -U S -0 0 1 -0 1 0 2  
Pa ge 9 1  of 9 5   
 
 
 
A ker o T hera pe utics , I nc. 
C o nfi de ntial  
 
A me n d me nt 4, 1 8 A pr 2 0 2 2  
A p pe n di x C  
 


Efr u xifer mi n  
Cli nical Trial Pr ot oc ol:  A K -U S -0 0 1 -0 1 0 2  
Pa ge 9 2  of 9 5   
 
 
 
A ker o T hera pe ut ics, I nc. 
C o nfi de ntial  
  
 
A me n d me nt 4, 1 8 A pr 2 0 2 2  
A p pe n di x D 
Pre g n a nc y Prec a uti o ns , Defi niti o n f or Fe m ale of C hil d be ari n g 
P ote nti al , a n d C o ntr ace pti ve Re q uire me nts  
1)  Defi niti o ns  
a)  Defi niti o n of C hil d be ari n g P ote nti al  
F or t he p ur p oses of t his st u d y, a fe male b or n s u bject is c o nsi dere d of c hil d beari n g p ote ntial 
f oll o wi n g t he i nitiati o n of p u bert y ( Ta n ner sta ge 2) u ntil bec o mi n g p ost- me n o pa usal, u nless 
per ma ne ntl y sterile or wit h me dicall y d oc u me nte d o varia n fail ure.  
W o me n are c o nsi dere d t o be i n a p ost me n o pa usal state w he n t he y are > 5 4 years of a ge wit h 
cessati o n of pre vi o usl y occ urri n g me nses f or > 1 2 m o nt hs wit h o ut a n alter nati ve ca use. I n 
a d diti o n, w o me n of a n y a ge wit h a me n orr hea of > 1 2 m o nt hs ma y als o be c o nsi dere d 
p ost me n o pa usal if t heir f ollicle sti m ulati n g h or m o ne ( F S H) le vel is i n t he p ost me n o pa usal ra n ge 
a n d t he y are n ot usi n g h or m o nal c o ntrace pti o n or h or m o nal re place me nt t hera p y. 
A n y testi n g (e. g., of F S H le vels t o c o nfir m p ost me n o pa usal stat us) is n ot ma n date d b y t he 
pr ot oc ol a s a st u d y pr oce d ure. It is t he res p o nsi bilit y of t he I n vesti gat or t o c o nfir m 
p ost me n o pa usal stat us.  
Per ma ne nt sterilizati o n i ncl u des h ysterect o m y , bilateral o o p h orect o m y , or bilateral 
sal pi n gect o m y i n a fe male s u bject of a n y a ge. 
b)  Defi niti o n of M ale Fertilit y 
F or t he p ur p oses of t his st u d y, a male b or n s u bject is c o nsi dere d of fertile after t he i nitiati o n of 
p u bert y u nless per ma ne ntl y sterile b y bilateral orc hi dect o m y or me dical d oc u me ntati o n.  
2)  C o ntr ace pti o n Re q uire me nts f or Fe m ale S u bjects  
a)  St u d y Dr u g Effects o n Pre g n a nc y a n d H or m o n al C o ntr ace pti o n 
N o f or mal st u dies ha ve bee n c o n d ucte d t o e val uate t he re pr o d ucti ve t o xicit y of E F X ; t heref ore, 
t he re pr o d ucti ve t o xicit y of E F X  i n h u ma ns is u n k n o w n.  
E F X  has n ot yet bee n st u die d i n pre g na nt w o me n.  
Please refer t o t he latest versi o n of t he I n vesti gat or’s Br oc h ure f or a d diti o nal i nf or mati o n. 
b)  C o ntr ace pti o n Re q uire me nts f or Fe m ale S u bjects of C hil d be ari n g P ote nti al  
T he i ncl usi o n of fe male s u bjects of c hil d beari n g p ote ntial re q uires t he use of hi g hl y effecti ve 
c o ntrace pti ve meas ures. T he y m ust ha ve a ne gati ve ser u m pre g na nc y test at scree ni n g a n d a 
ne gati ve pre g na nc y test o n t he Baseli ne/ Da y 1 visit pri or t o ra n d o mizati o n. Pre g na nc y tests will 
be perf or me d per Sc he d ule of Assess me nts. Fe male s u bjects m ust a gree t o o ne of t he f oll o wi n g 
fr o m scree ni n g u ntil t he 3 0-Da y  F oll o w- u p Visit. 


Efr u xifer mi n  
Cli nical Trial Pr ot oc ol:  A K -U S -0 0 1 -0 1 0 2  
Pa ge 9 3  of 9 5   
 
 
 
A ker o T hera pe ut ics, I nc. 
C o nfi de ntial  
  
 
A me n d me nt 4, 1 8 A pr 2 0 2 2  
•  C o m plete a bsti ne nce fr o m i nterc o urse of re pr o d ucti ve p ote ntial. A bsti ne nce is a n acce pta ble 
met h o d of c o ntrace pti o n o nl y w he n it is i n li ne wit h t he s u bject’s preferre d a n d us ual 
lifest yle. 
Or  
•  C o nsiste nt a n d c orrect use of 1 of t he f oll o wi n g met h o ds of birt h c o ntr ol liste d bel o w.  
 I ntra uteri ne de vice (I U D) wit h a fail ure rate of < 1 % per year 
 I ntra uteri ne h or m o ne-releasi n g s yste m (I U S) wit h a fail ure rate of < 1 % per year 
 T u bal sterilizati o n 
 Ess ure ®  micr o -i nsert s yste m ( pr o vi de d c o nfir mati o n of s uccess 3 m o nt hs after pr oce d ure) 
 Vasect o m y i n t he male part ner ( pr o vi de d t hat t he part ner is t he s ole se x ual part ner a n d 
ha d c o nfir mati o n of s ur gical s uccess 3 m o nt hs after pr oce d ure) 
S h o ul d fe male s u bjects wis h t o use a h or m o nall y base d met h o d, use of a male c o n d o m b y t he 
fe male s u bject's male part ner is re q uire d. S u bjects w h o utilize a h or m o nal c o ntrace pti ve as o ne 
of t heir birt h c o ntr ol met h o ds m ust ha ve use d t he sa me met h o d f or at leas t t hree m o nt hs pri or t o 
st u d y d osi n g. H or m o nall y-base d c o ntrace pti ves per mitte d f or use i n t his pr ot oc ol are as f oll o w s: 
 Oral c o ntrace pti ves (eit her c o m bi ne d or pr o gester o ne o nl y) 
 I njecta ble pr o gester o ne 
 I m pla nts of le v o n or gestrel 
 Tra ns der mal c o ntrace pti ve patc h  
 C o ntrace pti ve va gi nal ri n g  
N ot all of t hese met h o ds  m a y be a p pr o ve d i n eac h of t he c o u ntries w here t he st u d y is bei n g 
c o n d ucte d: please refer t o l ocal pr o d uct i nf or mati o n. A d diti o nal l ocal re g ulat or y  re q uire me nts 
m a y a p pl y. 
Fe male s u bje cts m ust als o refrai n fr o m e g g d o nati o n a n d i n vitr o fertilizati o n d uri n g treat me nt 
a n d u ntil at least 9 0 da y s after t he last d ose of st u d y dr u g. 
3)  C o ntr ace pti o n Re q uire me nts f or M ale S u bjects  
It is t he oreticall y p ossi ble t hat a rele va nt s yste mic c o nce ntrati o n ma y be ac hie ve d i n a fe male 
part ner fr o m e x p os ure of t he male s u bject’s se mi nal fl ui d. T he ref ore, male s u bjects wit h fe male 
part ners of c hil d beari n g p ote ntial m ust use c o n d o ms d uri n g treat me nt u ntil 9 0 da y s after t he last 


Efr u xifer mi n  
Cli nical Trial Pr ot oc ol:  A K -U S -0 0 1 -0 1 0 2  
Pa ge 9 4  of 9 5   
 
 
 
A ker o T hera pe ut ics, I nc. 
C o nfi de ntial  
  
 
A me n d me nt 4, 1 8 A pr 2 0 2 2  
d ose of st u d y dr u g. Fe male part ners of male st u d y  s u bjects are as ke d t o select o ne of t he a b o ve 
met h o ds. 
Male s u bjects m ust als o refrai n fr o m s per m d o nati o n d uri n g treat me nt a n d u ntil at least 9 0  da ys 
after t he  last d ose of st u d y dr u g. 
4)  U n acce pt a ble Birt h C o ntr ol Met h o ds  
Birt h  c o ntr ol met h o ds t hat are u nacce pta ble i ncl u de peri o dic a bsti ne nce ( e. g., cale n dar , 
o v ulati o n, s y m pt ot her mal, p ost-o v ulati o n met h o ds) , wit h dra wal (c oit us i nterr u pt us) , s per mici des 
o nl y, a n d lactati o nal a me n orr hea met h o d ( L A M). Fe male c o n d o m a n d male c o n d o m s h o ul d n ot 
be use d t o get her.  
5)  Pr oce d ures t o be F oll o we d i n t he E ve nt of Pre g n a nc y  
S u bjects will be i nstr ucte d t o n otif y t he I n vesti gat or if t he y bec o me pre g na nt at a n y ti me d uri n g 
t he st u d y, or if t he y bec o me pre g na nt wit hi n 9 0 da ys of last st u d y dr u g d ose. S u bjects w h o 
bec o me pre g na nt or w h o s us pect t hat t he y are pre g na nt d uri n g t he st u d y m ust re p ort t he 
i nf or mati o n t o t he I n vesti gat or a n d disc o nti n ue st u d y dr u g i m me diatel y. S u bjects w h ose part ner 
has bec o me pre g na nt or s us pects s he is pre g na nt d uri n g t he st u d y m ust re p ort t he i nf or mati o n t o 
t he In vesti gat or. I nstr ucti o ns f or re p orti n g pre g na nc y , part ner pre g na nc y , a n d pre g na nc y 
o utc o me are o utli ne d i n Secti o n  6. 2 2. 6. 2 . 
 
 


Efr u xifer mi n  
Cli nical Trial Pr ot oc ol:  A K -U S -0 0 1 -0 1 0 2  
Pa ge 9 5  of 9 5   
 
 
 
A ker o T hera pe ut ics, I nc. 
C o nfi de ntial  
  
 
A me n d me nt 4, 1 8 A pr 2 0 2 2  
A p pe n di x E. 
West H a ve n Criteri a  
htt p:// w w w. m dcalc.c o m/ he patic-e nce p hal o pat h y- gra des- sta ges/  
Gr a de of He p atic 
E nce p h al o p at h y  
Descri pti o n  
S u g geste d O per ati ve Criteri a  
Gra de I  
•  
Tri vial lac k of a ware ness 
•  
E u p h oria or a n xiet y  
•  
S h orte ne d atte nti o n s pa n  
•  
I m pair me nt of a d diti o n or s u btracti o n 
•  
Altere d slee p r h yt h m  
Des pite orie nte d i n ti me a n d s pace (see 
bel o w) , t he s u bject a p pears t o ha ve s o me 
c o g niti ve/ be ha vi oral deca y wit h res pect t o 
his or he r sta n dar d o n cli nical e xa mi nati o n or 
t o t he care gi vers 
Gra de II  
•  
Let har g y or a pat h y  
•  
Dis orie ntati o n f or ti me  
•  
O b vi o us pers o nalit y c ha n ge  
•  
I na p pr o priate be ha vi or 
•  
D ys pra xia  
•  
Asteri xis  
Dis orie nte d f or ti me (at least t hree of t he 
f oll o wi n gs are wr o n g: da y of t he m o nt h, da y 
of t he wee k , m o nt h , seas o n, or year) ± t he 
ot her me nti o ne d s y m pt o ms  
Gra de III  
•  
S o m n ole nce t o se mi  st u p or 
•  
Res p o nsi ve t o sti m uli  
•  
C o nf use d  
•  
Gr oss dis orie ntati o n  
•  
Bizarre be ha vi or  
Dis orie nte d als o f or s pace (at least t hree of 
t he f oll o wi n g wr o n gl y re p orte d: c o u ntr y, 
state [ or re gi o n], cit y, or place) ± t he ot her 
me nti o ne d s y m pt o ms  
Gra de I V  
•  
C o ma  
D oes n ot res p o n d e ve n t o pai nf ul sti m uli  
S o urce: Vistr u p H , A M o di o P , Bajaj J , C or d o ba J , Fere nci P , M ulle n K D et al. He patic e nce p hal o pat h y i n c hr o nic 
li ver disease: 2 0 1 4 Practice G ui deli ne b y t he A merica n Ass ociati o n f or t he St u d y of Li ver Diseases a n d t he 
E ur o pea n Ass ociati o n f or t he St u d y of t he Li ver. He pat ol o g y. 2 0 1 4; 6 0( 2): 7 1 5 – 3 5  

SAP_001.pdf: 


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Table of Contents 
Statistical Analysis Plan ................................................................................ 1 
Table of Contents ........................................................................................ 2 
Reviewers .................................................................................................. 6 
Glossary of Abbreviations ............................................................................. 7 
1. 
Source Documents .............................................................................. 9 
2. 
 9 
 
 
 
 
 
 
 
 
 
Overall Study Design....................................................................... 10 
 
 
3. 
Efficacy and Safety Variables .............................................................. 12 
 
Primary Efficacy Endpoint ................................................................ 12 
 
Secondary Efficacy Endpoints ........................................................... 12 
 
Exploratory Efficacy Endpoints .......................................................... 12 
 
Estimands ..................................................................................... 13 
 
Safety Variables ............................................................................. 14 
4. 
Pharmacokinetic/Pharmacodynamic variables ........................................ 16 
5. 
Analysis populations .......................................................................... 16 
 
All Randomized Subjects .................................................................. 16 
 
Liver Biopsy Analysis Set ................................................................. 16 
 
Full Analysis Set ............................................................................. 16 
 
Modified Full Analysis Set ................................................................. 16 
 
Safety Set ..................................................................................... 17 
 
Pharmacokinetics Set ...................................................................... 17 
 
Biomarkers Analysis Set .................................................................. 17 
 
MRI-PDFF Analysis Set .................................................................... 17 
 
Per Protocol Set ............................................................................. 17 


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5.9.1 
Important Protocol Deviations Leading to Exclusion from the PPS 
Analysis ............................................................................................. 17 
 Special Subpopulations .................................................................... 19 
6. 
Data Handling ................................................................................... 22 
 
Time points and Visit Windows .......................................................... 22 
 
Handling of Dropouts, Missing Data, and Outliers ................................. 26 
7. 
Statistical Methods ............................................................................ 27 
 
General Principles ........................................................................... 27 
7.1.1 
Definition of Baseline ................................................................. 28 
 
Subject Disposition and Data Sets Analyzed ........................................ 28 
 
Protocol Deviations ......................................................................... 29 
 
Demographics and Other Baseline Characteristics ................................ 29 
7.4.1 
Medical History ......................................................................... 31 
7.4.2 
Previous and Concomitant Medications ......................................... 31 
 
Measurements of study drug Compliance ............................................ 31 
 
Efficacy ......................................................................................... 32 
7.6.1 
Primary Efficacy Analysis ............................................................ 32 
7.6.2 
Secondary Efficacy Analysis ........................................................ 33 
7.6.2.1 
Proportion of subjects who achieve resolution of steatohepatitis and no worsening of 
liver fibrosis at Week 24 and Week 96 ........................................................................................... 33 
7.6.2.2 
Proportion of subjects who achieve improvement in liver fibrosis (≥ one stage) and no 
worsening of steatohepatitis at Week 96 ....................................................................................... 33 
7.6.2.3 
Proportion of subjects who achieve improvement in liver fibrosis (≥ one stage) at 
Week 24 and Week 96 .................................................................................................................... 34 
7.6.2.4 
Change from baseline in hepatic fat fraction measured by MRI-PDFF at Week 24 and 
Week 96 34 
7.6.2.5 
Change from baseline of lipoproteins and markers of lipid metabolism ....................... 35 
7.6.2.6 
Change from baseline of glycemic control biomarkers .................................................. 35 
7.6.2.7 
Change from baseline of serum fibrosis biomarkers ...................................................... 35 
7.6.2.8 
Change from baseline in liver stiffness and controlled attenuation parameter (CAP) as 
evaluated by FibroScan ................................................................................................................... 35 
7.6.2.9 
Change from baseline of body weight ............................................................................ 36 


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7.6.3 
Exploratory Analysis .................................................................. 36 
7.6.3.1 
Proportion of subjects who achieve resolution of steatohepatitis AND improvement in 
liver fibrosis (≥ one stage) at Week 24 and Week 96 ................................................................... 36 
7.6.3.2 
Liver histology as measured by the fibrosis stage and NAFLD Activity Score ................. 37 
7.6.3.3 
Proportion of subjects who achieve improvement in liver fibrosis (≥ two stages) and 
no worsening of steatohepatitis at Week 24 and Week 96 ............................................................ 37 
7.6.3.4 
Clinical outcomes of event-free survival ......................................................................... 38 
7.6.3.5 
Proportion of subjects with adjudicated cardiovascular endpoints ............................... 38 
7.6.3.6 
Changes from baseline in bone biomarkers ................................................................... 38 
7.6.3.7 
Changes in cardiovascular and metabolic risk factors .................................................... 39 
7.6.3.8 
Non-invasive measures of fibrosis can predict histological regression and/or 
progression of fibrosis and clinical complications of cirrhosis........................................................ 39 
7.6.3.9 
Change from baseline in markers of liver injury and function ........................................ 39 
7.6.3.10 
MRI-PDFF based quantitation of hepatic fat............................................................... 40 
7.6.3.11 
Change from baseline in waist-to-hip ratio ................................................................ 40 
7.6.3.12 
Changes from baseline in health-related quality of life (CLDQ-NASH) ....................... 40 
7.6.4 
Sensitivity Analysis .................................................................... 41 
7.6.5 
Subgroup Analysis ..................................................................... 41 
 
Safety .......................................................................................... 43 
7.7.1 
Extent of Exposure .................................................................... 43 
7.7.2 
Adverse Events ......................................................................... 44 
7.7.3 
Laboratory Evaluations ............................................................... 46 
7.7.4 
Vital Signs ............................................................................... 50 
7.7.5 
Electrocardiograms .................................................................... 50 
7.7.6 
Other safety assessments ........................................................... 51 
7.7.6.1 
Physical examination....................................................................................................... 51 
7.7.6.2 
DXA scan measurements ................................................................................................ 51 
7.7.6.3 
Anti-drug antibody and neutralizing antibody ................................................................ 51 
 
Pharmacokinetic Analysis ................................................................. 52 
 
Interim Analysis ............................................................................. 52 
8. 
Changes in Planned Analysis ............................................................... 52 
9. 
Data Issues ...................................................................................... 52 


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10. 
References ....................................................................................... 53 
11. 
Appendices ...................................................................................... 54 
 Appendix 1: Document History ......................................................... 54 
 Appendix 2: Schedule of Assessments – Screening to Week 24 .............. 56 
 Appendix 3: Schedule of Assessments – Long-Term Follow-Up ............... 59 
 
List of Tables 
Table 1 Approach for Intercurrent Events for the Primary Endpoint at Week 24 .. 14 
Table 2 Data Review to Identify Important Protocol Deviations ........................ 18 
Table 3 Summary of Outcome Variables and Analysis Sets .............................. 19 
Table 4 Summary of Subgroup Analysis ....................................................... 42 
Table 5 Clinical Laboratory Assessments ...................................................... 47 
Table 6 Laboratory Toxicity Grade Criteria of Selected Clinical Laboratory 
Assessments ................................................................................ 48 
 
 
 










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2.1.3 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 Overall Study Design 
 
 
 
 
 


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3. Efficacy and Safety Variables 
 Primary Efficacy Endpoint 
The primary endpoint is: 
• 
Proportion of subjects who achieve improvement in liver fibrosis, defined as 
≥ one stage (NASH CRN fibrosis score) and no worsening of steatohepatitis 
(defined as no increase in NAS for ballooning, inflammation, or steatosis) at 
Week 24. 
 Secondary Efficacy Endpoints 
The secondary endpoints are: 
• 
Proportion of subjects who achieve resolution of steatohepatitis (defined as a 
NAS of 0-1 for inflammation, 0 for ballooning, and any value for steatosis) 
and no worsening of liver fibrosis as determined by the NASH CRN criteria at 
Week 24 and Week 96. 
• 
Proportion of subjects who achieve improvement in liver fibrosis by ≥ one 
stage (NASH CRN fibrosis score) and no worsening of steatohepatitis (defined 
as no increase in NAS for ballooning, inflammation, or steatosis) at Week 96. 
• 
Proportion of subjects who achieve improvement in liver fibrosis by ≥ one 
stage (NASH CRN fibrosis score) at Week 24 and Week 96. 
• 
Change from baseline in hepatic fat fraction measured by MRI-PDFF at Week 
24 and Week 96. 
• 
Change from baseline of lipoproteins – Lp (a), total cholesterol, triglycerides, 
Non-HDL-C, HDL-C, LDL-C, and LDL-P and in markers of lipid metabolism 
(ApoB and ApoC-III). 
• 
Change from baseline of markers of glycemic control – HbA1c, C-peptide, 
Adiponectin and HOMA-IR. 
• 
Change from baseline in non-invasive markers of fibrosis – ELF, Pro-C3, C3M, 
NIS-4 and liver stiffness assessed by transient elastography (FibroScan®). 
• 
Change from baseline of body weight. 
 Exploratory Efficacy Endpoints 
The exploratory endpoints are: 
• 
 
 
 
 


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• 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 Estimands 
In line with ICH E9 (R1) addendum, five attributes (treatment, population, 
endpoint, intercurrent events, and population-level summary) have been specified 
to translate the primary efficacy objective into treatment effect that is to be 
estimated (estimand). 
The treatment conditions of interest are EFX 28 mg administered weekly, and EFX 
50 mg administered weekly, and are compared with matching placebo administered 
weekly in addition to standard of care. 




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(ADA) and neutralizing antibody (NAb) assessments, and concomitant medication 
usage. 
• 
Adverse events (AEs) and serious adverse events (SAEs): 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. 
The Investigator will assign the following AE attributes: 
o AE diagnosis or syndrome(s) (if not known, signs or symptoms)  
o Dates of onset and resolution (if resolved) 
o Seriousness 
o Severity 
o Relatedness to study drug or study-related procedures  
o Action taken with study treatment 
• 
Adverse events of special interest (AESIs): The following conditions. 
assessed by clinical and laboratory evidence, will be monitored as AESIs 
during this study: 
o Injection Site Reactions 
o Diarrhea 
o Hypoglycemia 
o Neurological and Psychiatric Events 
o Adjudicated DILI Events 
Suspected DILI events will be assessed and adjudicated by the Data Monitoring 
Committee (DMC). 
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. 
• 
Overdose: Any overdose, with or without associated AEs, will be recorded as 
non-compliance on the eCRF.  


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4. Pharmacokinetic/Pharmacodynamic variables 
Pharmacokinetic samples to assess plasma EFX concentrations will be collected at 
specified time points as defined in the Schedule of Assessments. 
No pharmacodynamic endpoint is identified in protocol. 
5. Analysis populations 
The study analysis sets are detailed below.  
 All Randomized Subjects 
All subjects randomized will be included in the All Randomized Subjects set. 
 Liver Biopsy Analysis Set 
The primary analysis set for histological analyses will be the Liver Biopsy Analysis 
Set (LBAS) which will be a subset of the Full Analysis Set (FAS). It will include all 
FAS subjects who have baseline and on-study liver biopsy results corresponding to 
the appropriate time point. 
Note: Week 24 and Week 96 LBAS populations may be distinct analysis 
populations. 
 Full Analysis Set 
The analysis set for non-histological efficacy analyses will be the FAS which will 
include 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 the 
treatment group to which they were randomized. 
 Modified Full Analysis Set 
The analysis set for additional supplementary efficacy analyses will be the MFAS 
which will include all subjects who were randomized into the study and received at 
least one dose of study drug. 
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 the 
treatment group to which they were randomized. 


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 Safety Set 
The analysis set for safety analyses will be the Safety Set which includes all 
subjects who received at least one dose of study drug. 
All subjects who receive at least one dose of study drug will be included in the 
Safety Set. All safety endpoints will be summarized using the Safety Set and will be 
based on the actual treatment received if this differs from the randomized 
treatment. Some endpoints may be analyzed in additional populations or 
subgroups. 
 Pharmacokinetics Set 
The Pharmacokinetics (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. 
 Biomarkers Analysis Set 
The Biomarkers 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 biomarkers or parameters of interest. 
 MRI-PDFF Analysis Set 
The MRI-PDFF Analysis Set will be a subset of the FAS. It will include all FAS 
subjects who have baseline and on-study measurements assessed by MRI-PDFF. 
 Per Protocol Set 
The Per Protocol Set (PPS) will be a subset of the LBAS and will include subjects 
who finish at least 16 weeks of dosing, are evaluated for NASH CRN fibrosis stage 
and NAS at Week 24 (or early termination after 22 weeks on treatment) and do not 
have important protocol deviations.  
Protocol deviations are defined as any change, divergence, or departure from the 
study design or procedures defined in the study protocol. Important protocol 
deviations are a subset of protocol deviations and may significantly impact the 
correctness, accuracy, and/or reliability of the study data, or that may significantly 
affect a subject’s rights, safety, or well-being. Section 5.9.1 details the deviations 
that will be considered as basis to exclude subjects from PPS. 
5.9.1 Important Protocol Deviations Leading to Exclusion from the PPS Analysis 
The occurrence of any deviation listed in Table 2 might have an important influence 
on the primary efficacy endpoint and will be reviewed to determine subjects 












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Markers of glycemic control, bone biomarkers and lipid metabolism biomarkers: 
Analysis Visit 
Target Analysis 
Day 
Low Analysis Day 
High Analysis Day 
Week 4 
29 
16 
57 
Week 12 
85 
58 
127 
Week 24 
169 
128 
197 
Week 32 
225 
198 
253 
Week 40 
281 
254 
309 
Week 48 
337 
310 
421 
Week 72 
505 
422 
589 
Week 96 
673 
590 
EOS 
Serum fibrosis biomarkers: 
Analysis Visit 
Target Analysis 
Day 
Low Analysis Day 
High Analysis Day 
Week 12 
85 
44 
127 
Week 24 
169 
128 
253 
Week 48 
337 
254 
421 
Week 72 
505 
422 
589 
Week 96 
673 
590 
EOS 
Body weight: 
Analysis Visit 
Target Analysis 
Day 
Low Analysis Day 
High Analysis Day 
Week 1 
8 
5 
11 
Week 2 
15 
12 
18 
Week 3 
22 
19 
25 
Week 4 
29 
26 
43 
Week 8 
57 
44 
71 
Week 12 
85 
72 
99 
Week 16 
113 
100 
127 
Week 20 
141 
128 
155 
Week 24 
169 
156 
183 
Week 28 
197 
184 
211 
Week 32 
225 
212 
239 
Week 36 
253 
240 
267 
Week 40 
281 
268 
295 
Week 44 
309 
296 
323 
Week 48 
337 
324 
351 
Week 52 
365 
352 
379 
Week 56 
393 
380 
421 
Week 64 
449 
422 
477 
Week 72 
505 
478 
533 
Week 80 
561 
534 
589 


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Analysis Visit 
Target Analysis 
Day 
Low Analysis Day 
High Analysis Day 
Week 88 
617 
590 
645 
Week 96  
673 
646 
EOS 
FibroScan examination: 
Analysis Visit 
Target Analysis 
Day 
Low Analysis Day 
High Analysis Day 
Week 24 
169 
86 
253 
Week 48 
337 
254 
505 
Week 96 
673 
506 
EOS 
CP score assessment: 
Analysis Visit 
Target Analysis 
Day 
Low Analysis Day 
High Analysis Day 
Week 12 
85 
44 
127 
Week 24 
169 
128 
253 
Week 48 
337 
254 
505 
Week 96 
673 
506 
EOS 
MRI-PDFF based quantitation of hepatic fat: 
Analysis Visit 
Target Analysis 
Day 
Low Analysis Day 
High Analysis Day 
Week 24 
169 
86 
421 
Week 96 
673 
422 
EOS 
DXA scan measurement: 
Analysis Visit 
Target Analysis 
Day 
Low Analysis Day 
High Analysis Day 
Week 48 
337 
170 
505 
Week 96 
673 
506 
EOS 
Waist-to-hip ratio: 
Analysis Visit 
Target Analysis 
Day 
Low Analysis Day 
High Analysis Day 
Week 12 
85 
44 
127 
Week 24 
169 
128 
183 
Week 28 
197 
184 
211 
Week 32 
225 
212 
239 
Week 36 
253 
240 
267 
Week 40 
281 
268 
295 
Week 44 
309 
296 
323 
Week 48 
337 
324 
351 


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Analysis Visit 
Target Analysis 
Day 
Low Analysis Day 
High Analysis Day 
Week 52 
365 
352 
379 
Week 56 
393 
380 
421 
Week 64 
449 
422 
477 
Week 72 
505 
478 
533 
Week 80 
561 
534 
589 
Week 88 
617 
590 
645 
Week 96  
673 
646 
EOS 
Health-related quality of life (CLDQ-NASH): 
Analysis Visit 
Target Analysis 
Day 
Low Analysis Day 
High Analysis Day 
Week 12 
85 
44 
127 
Week 24 
169 
128 
183 
Week 28 
197 
184 
225 
Week 36 
253 
226 
281 
Week 44 
309 
282 
323 
Week 48 
337 
324 
351 
Week 52 
365 
352 
519 
Week 96 
673 
520 
EOS 
Liver histology: 
Analysis Visit 
Target Analysis 
Day 
Low Analysis Day 
High Analysis Day 
Week 24 
169 
113 
421 
Week 96 
673 
422 
EOS 
ADA and NAb: 
Analysis Visit 
Target Analysis 
Day 
Low Analysis Day 
High Analysis Day 
Week 8 
57 
30 
85 
Week 16 
113 
86 
141 
Week 24 
169 
142 
197 
Week 32 
225 
198 
253 
Week 40 
281 
254 
309 
Week 48 
337 
310 
365 
Week 56 
393 
366 
421 
Week 64 
449 
422 
477 
Week 72 
505 
478 
533 
Week 80 
561 
534 
589 
Week 88 
617 
590 
645 
Week 96  
673 
646 
EOS 


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Within an analysis visit window, the measurement from the scheduled visit will be 
used if available. If multiple scheduled visits occur within a single visit window, then 
the visit closest to the target day of the visit window will be used in the analysis. If 
there is a tie, the later visit will be used in the analysis.  
If no scheduled visit occurs, the measurement from the unscheduled visit closest to 
the defined target analysis day within the window will be used. If there is more 
than one measurement with 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. 
 Handling of Dropouts, Missing Data, and Outliers 
Subjects in the FAS with missing liver biopsy data will be considered as non-
responder in the analyses of histological endpoints on the FAS. With these 
exceptions, values for missing data will not be imputed unless specified. The same 
handling of missing liver biopsy data will also be applied for the MFAS, which is a 
subset of the FAS.  
Where appropriate, safety data for subjects who 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. 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. 
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). 
No rules for outlier detection are planned. 






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Counts and percentages of subjects who were screened (i.e. signed informed 
consent), discontinued early during screening (screen failures), and randomized will 
be summarized in total based on all screened subjects. Reasons for screen failures 
will also be summarized. In addition, the number of screening failures which were 
noted to have a COVID-19 as a contributory factor will 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 treatment 
• 
Subjects who withdrew from the 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 discontinuation/withdrawal will be summarized. In 
addition, early discontinuation from the treatment contributed by COVID-19 and 
early discontinuation from the study contributed by COVID-19 will be summarized. 
A summary of subject enrollment by stratification factor will also be provided by 
treatment group and in total for All Randomized Subjects. 
Counts and percentages of subjects in each analysis population will be summarized 
by treatment and in total based on All Randomized Subjects. 
 Protocol Deviations 
All protocol deviations and COVID-19 related protocol deviations will be listed. 
All important protocol deviations leading to exclusion from the PPS (see Section 
5.9.1) will be listed and summarized by treatment group for All Randomized Subjects. 
 Demographics and Other Baseline Characteristics 
Demographic and baseline measurements will be listed and summarized by 
treatment group and in all EFX subjects and total for All Randomized Subjects. 
The following demographic and baseline characteristics will be summarized: 
• 
Age (years)  
• 
Age categories (<65 years, ≥65 years, ≥75 years) 


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• 
Sex 
• 
Race 
• 
Ethnicity 
• 
Height (cm) at Screening 
• 
Weight (kg) at Baseline 
• 
Body mass index (BMI) (kg/m2) at Baseline 
• 
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 
• 
T2D status at Screening 
• 
Fibrosis stage at Screening 
• 
Statin use at baseline 
• 
Vitamin E/ Thiazolidinedione use at baseline 
• 
NAS and NAS components at Screening 
• 
Median Liver Stiffness Measurement (LSM) in kiloPascals (kPa) as Evaluated 
by FibroScan at Screening   
• 
Median Controlled Attenuation Parameter (CAP) at Screening 
• 
ALT (U/L) and AST (U/L) at Baseline 
• 
ALT and AST categories at Baseline (≤ULN, >ULN) 
• 
Systolic blood pressure at baseline, Diastolic blood pressure at baseline, and 
Systolic blood pressure category at baseline (<130mmHg, >=130mmHg) 
• 
Fasting values of Triglyceride (mg/dL), Total Cholesterol (mg/dL), LDL-C 
(mg/dL), HDL-C (mg/dL), and non-HDL-C (mg/dL) at Baseline 
• 
Endogenous FGF21 at Baseline 
• 
Serum fibrosis biomarkers: ELF score, Pro-C3 (µg/mL), C3M, Pro-C3/C3M, 
NIS-4 at Baseline 
• 
Pro-C3 categories at Baseline (<14 µg/mL, ≥14 µg/mL) 
• 
Liver Injury Biomarkers: MELD score and CP score at Baseline 
• 
Bone Biomarkers: P1NP and CTX-1 at Baseline 


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• 
Insulin Sensitivity and Glycemic Control Biomarkers: Hemoglobin A1c (%), 
Fasting values of Insulin, Blood Glucose, Adiponectin, and HOMA-IR at 
Baseline 
Other baseline measurements, such as safety laboratory, ADA, vital signs, and ECG, 
will be summarized by treatment group with the post-baseline measurements. 
7.4.1 Medical History 
Medical history will be coded using the Medical Dictionary for Regulatory Activities 
(MedDRA) Version 23.1 (or a later version if updated during the study). All medical 
history will be listed, and the number and percentage of subjects with any medical 
history will be summarized for All Randomized Subjects by treatment group and in 
total by system organ class (SOC) and preferred term (PT).  
7.4.2 Previous and Concomitant Medications 
Medications received prior to or concomitantly with study drug will be coded by 
Fortrea using the WHODrug Dictionary Version Sep 2020 Global Dictionary Version 
B3 (or a later version if updated during the study) preferred terms and Anatomical 
Therapeutic Chemical (ATC) Classification codes.  
For summary purposes, medications will be considered prior medications if they 
stopped prior to the first dose of study drug and concomitant medications of the 
randomized treatment period 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) and started prior to the 30-Day follow-up 
visit of the randomized treatment period.  
If a medication cannot be classified as “prior” or “concomitant” after applying 
imputation rules for missing/incomplete dates, it will be classified as concomitant. 
The use of any prior medication or concomitant medication will be listed for All 
Randomized Subjects. Counts and percentages of subjects taking concomitant 
medications by therapeutic class (ATC-Level 2), chemical subgroup (ATC-Level 4), 
and generic term will be summarized by treatment and in total based on the Safety 
Set. 
 Measurements of study drug Compliance 
Subjects who receive less than 80% of planned 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 
for the Safety Set. 


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 Efficacy 
Efficacy analysis will be performed by treatment group. In addition, all EFX subjects 
will be combined as “All EFX” group in all histology analyses and for other efficacy 
parameters as appropriate.  
Note that for analyses using an MMRM model, the model will first use an 
unstructured covariance matrix. In the event that there are convergence issues, an 
autoregressive heterogeneous (ARH(1)) covariance structure will be used, followed 
by autoregressive structure (AR(1)) if convergence issues still exist.  
In addition, for analyses using the CMH test, it is noted that the CMH test statistic is 
not defined in the event there are no responses in one treatment arm and that 
there may be issues with numerical stability of the estimated odds ratio (and 
related statistics, e.g. p-values) in the event of few responses within a treatment 
arm. Therefore, the nominal p-value and corresponding population level summaries 
will be generated using Fisher’s Exact Test on the 2x2 contingency table of an 
individual active treatment arm (EFX 28mg or EFX 50mg) and Placebo, and the 
response variable (histology response or non-response) for a given endpoint in the 
event that there are no responses in a treatment arm for a given population. The 
analysis with all EFX subjects in a given analysis population will also be generated 
in this case. Further, in the event of insufficient responses (e.g. less than 
approximately 3 responses in a given arm) to assess numerical stability of the CMH 
odds ratio estimate, the Fisher’s Exact Test odds ratio estimate and p-value may 
also be summarized in order to assess the impact of limited responses on the 
stability of the CMH test.   
7.6.1 Primary Efficacy Analysis 
The primary efficacy analysis will be conducted when all the planned subjects 
complete the 24-Week visit. A CMH test will be used to compare the differences in 
proportions of subjects who achieve a ≥ 1-stage improvement in fibrosis compared 
to baseline without worsening of steatohepatitis between the EFX arms and the 
placebo arm, adjusting for stratification factors. The analysis will be performed 
using the LBAS. The point estimates and 95% confidence intervals (CIs) for the 
differences in proportions will be calculated. The 95% CI will be constructed using 
the Miettinen and Nurminen method. In addition, the odds ratio and risk ratio point 
estimate and 95% CI will be summarized for each EFX arm compared to placebo. 
The Primary efficacy endpoint will be tested at Type I error rate of 0.05, two-sided 
without adjustment for multiplicity for the comparisons between EFX arms and the 
placebo arm. P-values will be presented. 


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The same analysis will be repeated on the PPS and FAS. For any subjects in the FAS 
with a missing efficacy value, the efficacy variable will be considered as non-
responder. 
7.6.2 Secondary Efficacy Analysis 
7.6.2.1 Proportion of subjects who achieve resolution of steatohepatitis and no 
worsening of liver fibrosis at Week 24 and Week 96 
A CMH test will be used to compare the differences in proportions of subjects who 
achieve resolution of steatohepatitis and no worsening of liver fibrosis at Week 24 
and Week 96 between the EFX arms and the placebo arm, adjusting for 
stratification factors. The analysis will be performed using the LBAS. The point 
estimates and 95% CIs for the differences in proportions, and p-values will be 
calculated. The 95% CI will be constructed using the Miettinen and Nurminen 
method. In addition, the odds ratio and risk ratio point estimate and 95% CI will be 
summarized for each EFX arm compared to placebo. 
The same analysis will be repeated on the PPS and FAS for Week 24 and repeated 
on the FAS, Week 24 LBAS, and MFAS for Week 96. For any subjects with a missing 
efficacy value, the efficacy variable will be considered as non-responder. 
A descriptive summary will present the shift from Week 24 response to Week 96 
response for the Week 24 LBAS, subjects with a Week 24 biopsy but missing Week 
96 biopsy will be summarized in the missing category in this summary. In addition, 
a descriptive summary will present the number of subjects with steatohepatitis 
resolution at Week 24 (with no improvement in fibrosis) and the number of subjects 
with fibrosis improvement (>= 1 stage) with no worsening of steatohepatitis at 
Week 96.  
7.6.2.2 Proportion of subjects who achieve improvement in liver fibrosis (≥ one 
stage) and no worsening of steatohepatitis at Week 96 
A CMH test will be used to compare the differences in proportions of subjects who 
achieve improvement in liver fibrosis (≥ one stage) and no worsening of 
steatohepatitis at Week 96 between the EFX arms and the placebo arm, adjusting 
for stratification factors. The analysis will be performed using the LBAS. The point 
estimates and 95% CIs for the differences in proportions, and p-values will be 
calculated. The 95% CI will be constructed using the Miettinen and Nurminen 
method. In addition, the odds ratio and risk ratio point estimate and 95% CI will be 
summarized for each EFX arm compared to placebo. 


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The same analysis will be repeated on the FAS, Week 24 LBAS, and MFAS at Week 
96. For any subjects with a missing efficacy value, the efficacy variable will be 
considered as non-responder. 
A descriptive summary will present the shift from Week 24 response to Week 96 
response for the Week 24 LBAS, subjects with a Week 24 biopsy but missing Week 
96 biopsy will be summarized in the missing category in this summary. In addition, 
a descriptive summary will present the number of subjects with one stage fibrosis 
improvement at Week 24 with no worsening of steatohepatitis that shift to >= 2 
stage improvement in fibrosis at Week 96. 
7.6.2.3 Proportion of subjects who achieve improvement in liver fibrosis (≥ one 
stage) at Week 24 and Week 96 
A CMH test will be used to compare the differences in proportions of subjects who 
achieve improvement in liver fibrosis (≥ one stage) at Week 24 and Week 96 
between the EFX arms and the placebo arm, adjusting for stratification factors. The 
analysis will be performed using the LBAS. The point estimates and 95% CIs for the 
differences in proportions, and p-values will be calculated. The 95% CI will be 
constructed using the Miettinen and Nurminen method. In addition, the odds ratio 
and risk ratio point estimate and 95% CI will be summarized for each EFX arm 
compared to placebo. 
The same analysis will be repeated on the PPS and FAS for Week 24 and repeated 
on the FAS, MFAS, and Week 24 LBAS for Week 96. For any subjects in the FAS 
with a missing efficacy value, the efficacy variable will be considered as non-
responder.   
A descriptive summary will present the shift from Week 24 response to Week 96 
response for the Week 24 LBAS, subjects with a Week 24 biopsy but missing Week 
96 biopsy will be summarized in the missing category in this summary.  
7.6.2.4 Change from baseline in hepatic fat fraction measured by MRI-PDFF at 
Week 24 and Week 96 
An analysis of covariance (ANCOVA) model with baseline covariate will be used to 
evaluate the changes and percent changes from baseline in hepatic fat fraction 
between the EFX arms and the placebo arm at Week 24, controlling for stratification 
factors. A mixed-model repeated-measures (MMRM) with baseline covariate will be 
used to evaluate the changes and percent changes from baseline in hepatic fat 
fraction between the EFX arms and the placebo arm at Week 24 , Week 48, and 
Week 96, controlling for stratification factors. Least square (LS) means, 95% CIs, 
and p-values will be presented. The analysis will be performed using the MRI-PDFF 
Analysis Set. 


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7.6.2.5 Change from baseline of lipoproteins and markers of lipid metabolism 
An MMRM model with baseline covariate will be used to evaluate the changes and 
percent changes from baseline in lipoproteins (Lp (a), total cholesterol, 
triglycerides, Non-HDL-C, HDL-C, LDL-C, and LDL-P) and markers of lipid 
metabolism (ApoB and ApoC-III) between the EFX arms and the placebo arm at 
scheduled visits, controlling for stratification factors. Least square (LS) means, 95% 
CIs, and p-values will be presented. The analysis will be performed using the FAS. 
Non-HDL cholesterol will be calculated as Total Cholesterol - HDL-C. 
Summaries and boxplots will be presented for actual values and changes from 
baseline in Lp (a), total cholesterol, triglycerides, Non-HDL-C, HDL-C, LDL-C, LDL-P, 
and ApoB and ApoC-III at the collection time points defined in the Schedule of 
Assessments by treatment group. 
7.6.2.6 Change from baseline of glycemic control biomarkers 
An MMRM model with baseline covariate will be used to evaluate the changes and 
percent changes from baseline in HbA1c, C-peptide, Adiponectin, and HOMA-IR 
between the EFX arms and the placebo arm at scheduled visits, controlling for 
stratification factors. LS means, 95% CIs, and p-values will be presented. The 
analysis will be performed using the Biomarkers Analysis Set. 
Summaries and boxplots will be presented for actual values and changes from 
baseline in HbA1c, C-peptide, Adiponectin, and HOMA-IR at the collection time 
points defined in the Schedule of Assessments by treatment group. 
7.6.2.7 Change from baseline of serum fibrosis biomarkers 
An MMRM model with baseline covariate will be used to evaluate the changes and 
percent changes from baseline in ELF, Pro-C3, C3M, and NIS-4 between the EFX 
arms and the placebo arm at scheduled visits, controlling for stratification factors. 
LS means, 95% CIs, and p-values will be presented. The analysis will be performed 
using the Biomarkers Analysis Set and LBAS. 
Summaries and boxplots will be presented for actual values and changes from 
baseline in ELF, Pro-C3, C3M, and NIS-4 at the collection time points defined in the 
Schedule of Assessments by treatment group. 
7.6.2.8 Change from baseline in liver stiffness and controlled attenuation parameter 
(CAP) as evaluated by FibroScan 
An ANCOVA model with baseline covariate will be used to evaluate the changes and 
percent changes from baseline in liver stiffness (kPa) and CAP (dB/m) between the 
EFX arms and the placebo arm at Week 24, controlling for stratification factors. An 


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MMRM model with baseline covariate will be used to evaluate the changes and 
percent changes from baseline in liver stiffness and CAP between the EFX arms and 
the placebo arm at Weeks 24, 48, and 96, controlling for stratification factors. LS 
means, 95% CIs, and p-values will be presented. The analysis will be performed 
using the FAS and LBAS. 
Summaries and boxplots will be presented for actual values and changes from 
baseline in liver stiffness at the collection time points defined in the Schedule of 
Assessments by treatment group. 
In addition, the proportion of patients with interquartile range (IQR)/Median ratio 
<30% for liver stiffness and IQR <40dB/m for CAP, will be summarized by visit.  
7.6.2.9 Change from baseline of body weight 
An MMRM model with baseline covariate will be used to evaluate the changes and 
percent changes from baseline in body weight between the EFX arms and the 
placebo arm at scheduled visits, controlling for stratification factors. LS means, 
95% CIs, and p-values will be presented. The analysis will be performed using the 
FAS. 
Summaries and boxplots will be presented for actual values and changes from 
baseline in body weight at the collection time points defined in the Schedule of 
Assessments by treatment group. 
7.6.3 Exploratory Analysis 
The same efficacy analyses used for the secondary efficacy variables will be used 
for the exploratory efficacy variables. 
7.6.3.1 Proportion of subjects who achieve resolution of steatohepatitis AND 
improvement in liver fibrosis (≥ one stage) at Week 24 and Week 96 
A CMH test will be used to compare the differences in proportions of subjects who 
achieve resolution of steatohepatitis AND improvement in liver fibrosis (≥ one 
stage) at Week 24 and Week 96 between the EFX arms and the placebo arm, 
adjusting for stratification factors. The analysis will be performed using the LBAS. 
The point estimates and 95% CIs for the differences in proportions, and p-values 
will be calculated. The 95% CI will be constructed using the Miettinen and 
Nurminen method. In addition, the odds ratio and risk ratio point estimate and 95% 
CI will be summarized for each EFX arm compared to placebo. 
The same analysis will be repeated on the PPS for Week 24. The analysis will be 
repeated using the MFAS, Week 24 LBAS, and Week 96 LBAS at Week 96. 


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A descriptive summary will present the shift from Week 24 response to Week 96 
response for the Week 24 LBAS, subjects with a Week 24 biopsy but missing Week 
96 biopsy will be summarized in the missing category in this summary. 
7.6.3.2 Liver histology as measured by the fibrosis stage and NAFLD Activity Score 
The analysis of fibrosis stage and NAS will be performed using the LBAS and PPS. 
Fibrosis stage at baseline and post-baseline time points, change from baseline, and 
shift from baseline frequencies will be summarized by treatment group. In the 
calculation of change and shift from baseline, fibrosis stage 1A, 1B, and 1C will be 
considered as stage 1.  
In addition, a descriptive summary will present the change from baseline in fibrosis 
at Week 24 and the change from baseline in fibrosis at week 96, irrespective of 
change in steatohepatitis.  
NAS and components at baseline and post-baseline time points and the change 
from baseline frequencies together with mean (SD) and median will be summarized 
by treatment. Shift from baseline frequencies will be presented for the individual 
components of NAS as well. 
7.6.3.3 Proportion of subjects who achieve improvement in liver fibrosis (≥ two 
stages) and no worsening of steatohepatitis at Week 24 and Week 96 
A CMH test will be used to compare the differences in proportions of subjects who 
achieve improvement in liver fibrosis (≥ two stages) and no worsening of 
steatohepatitis at Week 24 and Week 96 between the EFX arms and the placebo 
arm, adjusting for stratification factors. The analysis will be performed using the 
LBAS. The point estimates and 95% CIs for the differences in proportions, and p-
values will be calculated. The 95% CI will be constructed using the Miettinen and 
Nurminen method. In addition, the same test will be performed to compare the 
difference in proportions of subjects who achieve two stage improvement in liver 
fibrosis at Week 24 and Week 96 between the EFX arms and the placebo arm. In 
addition, the odds ratio and risk ratio point estimate and 95% CI will be 
summarized for each EFX arm compared to placebo. 
The same analysis will be repeated on the PPS for Week 24. The analysis will be 
repeated using the MFAS, Week 24 LBAS, and Week 96 LBAS at Week 96.  
A descriptive summary will present the shift from Week 24 response to Week 96 
response for the Week 24 LBAS, subjects with a Week 24 biopsy but missing Week 
96 biopsy will be summarized in the missing category in this summary. 


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7.6.3.4 Clinical outcomes of event-free survival  
EFS will be assessed by time to the first clinical event including progression to 
cirrhosis as determined by central pathology, adjudicated liver decompensation 
events, liver transplantation and all-cause mortality using the FAS. For subjects 
without any clinical event at the analysis cutoff date, EFS will be censored on the 
date of last assessment. The number and percentage of subjects with clinical event 
and subjects censored at the time of analysis will be presented. The 50th percentile 
of Kaplan-Meier estimates will be used to estimate the median duration of EFS 
(months). A two-sided 95% CI will be provided for this estimate. The 25th and 75th 
percentiles, and the range (minimum, maximum) will be presented as well. The 
range will be determined including censored observations. 
In the event that the median EFS is not reached, the pointwise confidence interval 
for the survival probability at clinically relevant timepoints may be presented.  
7.6.3.5 Proportion of subjects with adjudicated cardiovascular endpoints 
The analysis of proportion of subjects with adjudicated cardiovascular endpoints, 
including cardiovascular death, nonfatal myocardial infarction, nonfatal stroke, 
hospitalization for unstable angina, hospitalization for cardiac failure, and urgent or 
emergency visits for heart failure at Week 48, Week 96, and end of study will be 
performed using the FAS. A CMH test will be used to compare the differences in 
proportions of subjects with adjudicated cardiovascular endpoints between the EFX 
arms and the placebo arm, adjusting for stratification factors. The point estimates 
and 95% CIs for the differences in proportions, and p-values will be calculated. The 
95% CI will be constructed using the Miettinen and Nurminen method. In addition, 
the odds ratio and risk ratio point estimate and 95% CI will be summarized for each 
EFX arm compared to placebo. 
7.6.3.6 Changes from baseline in bone biomarkers 
The analysis of changes from baseline in bone biomarkers will be performed using 
the Biomarkers Analysis Set. An MMRM model with baseline covariate will be used 
to evaluate the changes and percent changes from baseline in P1NP and CTX-1 
between the EFX arms and the placebo arm at scheduled visits, controlling for 
stratification factors. LS means, 95% CIs, and p-values will be presented. 
Summaries and boxplots will be presented for actual values and changes from 
baseline in P1NP and CTX-1 at the collection time points defined in the Schedule of 
Assessments by treatment group. 


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7.6.3.7 Changes in cardiovascular and metabolic risk factors 
The analysis of changes in cardiovascular and metabolic risk factors will be 
performed using the Safety Set. Descriptive summaries and boxplots of BMI and 
blood pressure will be presented by treatment group and visit. 
An MMRM model with baseline covariate will be used to evaluate the changes from 
baseline in blood pressure between the EFX arms and the placebo arm at scheduled 
visits, controlling for stratification factors. Least square (LS) means, 95% CIs, and 
p-values will be presented. The analysis will be performed using the Safety Set. 
A CMH test will be used to compare the differences in proportions of subjects with 
new onset of T2D between the EFX arms and the placebo arm, adjusting for 
stratification factors. The new onset of T2D is defined as a single HbA1C value of 
6.5% or higher when baseline HbA1c <6.5%. The analysis will be performed using 
the Safety Set. 
7.6.3.8 Non-invasive measures of fibrosis can predict histological regression and/or 
progression of fibrosis and clinical complications of cirrhosis 
Correlation models will be fitted to explore the correlation coefficient between non-
invasive measures of fibrosis and histological fibrosis (CRN fibrosis stage of liver 
biopsy) and clinical complications of cirrhosis (MELD score and CP score). Non-
invasive measures of fibrosis include serum biomarkers (ELF and Pro-C3) and 
imaging (liver stiffness by FibroScan). In addition, correlation between the imaging 
marker for hepatic fat (MRI-PDFF) and histological fibrosis and NASH resolution will 
also be explored. The analysis will be performed using the LBAS.  
7.6.3.9 Change from baseline in markers of liver injury and function 
The analysis of markers of liver injury and function, including ALT, AST, ALP, GGT, 
bilirubin, INR, albumin, uric acid, platelets, MELD score, and CP score will be 
performed using the FAS and LBAS. Summaries of actual values and changes from 
baseline will be presented by treatment group and visit. 
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 


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Ascites  
No ascites 
Mild to moderate 
(diuretic 
responsive/controlled) 
Severe (diuretic 
refractory/poorly 
controlled) 
Encephalopathy  No Encephalopathy  
Grade 1-2  
Grade 3-4 
Class A = 5-6 points 
Class B = 7-9 points 
Class C = 10-15 points 
An MMRM model with baseline covariate will be used to evaluate the changes and 
percent changes from baseline in markers of liver injury and function between the 
EFX arms and the placebo arm at scheduled visits, controlling for stratification 
factors. LS means, 95% CIs, and p-values will be presented. 
Summaries and boxplots will be presented for actual values and changes from 
baseline in ALT, AST, ALP, GGT, bilirubin, INR, albumin, uric acid, MELD score, and 
CP score at the collection time points defined in the Schedule of Assessments by 
treatment group. 
7.6.3.10 
MRI-PDFF based quantitation of hepatic fat 
The analysis of MRI-PDFF based quantitation of hepatic fat will be performed using 
the MRI-PDFF Analysis Set. Summaries of actual values and absolute and percent 
changes from baseline will be presented by treatment group and visit. A CMH test 
will be used to compare the differences in proportions of subjects with relative 
reduction ≥30% and ≥50% in hepatic fat and with liver fat content ≤5% at Week 
24 and Week 96 between the EFX arms and the placebo arm, adjusting for 
stratification factors. The point estimates and 95% CIs for the differences in 
proportions, and p-values will be calculated. The 95% CI will be constructed using 
the Miettinen and Nurminen method.  
7.6.3.11 
Change from baseline in waist-to-hip ratio 
The analysis of change from baseline in waist-to-hip ratio will be performed using 
the FAS and PPS. Summaries of actual values and changes from baseline will be 
presented by treatment group and visit. An MMRM model with baseline covariate 
will be used to evaluate the changes from baseline in waist-to-hip ratio between the 
EFX arms and the placebo arm at scheduled visits, controlling for stratification 
factors. LS means, 95% CIs, and p-values will be presented. 
7.6.3.12 
Changes from baseline in health-related quality of life (CLDQ-NASH) 
The analysis of changes from baseline in CLDQ-NASH will be performed using the 
FAS and PPS. Summaries of CLDQ-NASH total score and domain scores will be 
presented by treatment group and visit. An MMRM model with baseline covariate 


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will be used to evaluate the changes from baseline in total score between the EFX 
arms and the placebo arm at scheduled visits, controlling for stratification factors. 
LS means, 95% CIs, and p-values will be presented. 
7.6.4 Sensitivity Analysis  
Analyses of the primary efficacy endpoint (improvement in liver fibrosis and no 
worsening of steatohepatitis at Week 24) in the PPS and FAS will be performed as a 
sensitivity analysis. Analyses of secondary endpoints of resolution of steatohepatitis 
and no worsening of liver fibrosis at Week 24 and improvement in liver fibrosis at 
Week 24 will also be presented for the PPS and FAS.  
In addition, tipping point analysis will be performed to evaluate various deviations 
from the assumption of non-response for the primary efficacy endpoint in the FAS. 
For subjects with missing liver biopsy data at Week 24, responder status will be 
imputed in an increasing manner by subject level for each treatment group. 
Specifically, for each subject, a responder/non-responder status will be imputed 
with the scenario where all subjects being non-responders up to the scenario where 
all subjects are responders. This will include all possible scenarios of responder 
status for all missing data, including scenarios where subjects on EFX groups have 
worse outcomes than subjects on placebo (see table below). For each scenario, an 
analysis similar to the primary analysis will be performed. 
“Response” 
in Missing 
in Placebo 
Group 
“Response” in Missing in EFX Group 
0 
1 
2 
… 
m-2 
m-1 
m [1] 
0 
p=0.xxx 
p=0.xxx 
p=0.xxx 
p=0.xxx 
p=0.xxx 
p=0.xxx 
p=0.xxx 
1 
p=0.xxx 
p=0.xxx 
p=0.xxx 
p=0.xxx 
p=0.xxx 
p=0.xxx 
p=0.xxx 
2 
p=0.xxx 
p=0.xxx 
p=0.xxx 
p=0.xxx 
p=0.xxx 
p=0.xxx 
p=0.xxx 
… 
p=0.xxx 
p=0.xxx 
p=0.xxx 
p=0.xxx 
p=0.xxx 
p=0.xxx 
p=0.xxx 
n-2 
p=0.xxx 
p=0.xxx 
p=0.xxx 
p=0.xxx 
p=0.xxx 
p=0.xxx 
p=0.xxx 
n-1 
p=0.xxx 
p=0.xxx 
p=0.xxx 
p=0.xxx 
p=0.xxx 
p=0.xxx 
p=0.xxx 
n [2] 
p=0.xxx 
p=0.xxx 
p=0.xxx 
p=0.xxx 
p=0.xxx 
p=0.xxx 
p=0.xxx 
[1] m = total number of subjects with missing data at Week 24 in EFX group 
[2] n = total number of subjects with missing data at Week 24 in Placebo group 
7.6.5 Subgroup Analysis 
Subgroup analysis will be performed for the efficacy endpoints (see Table 4). The 
group variables are as follows: 






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(date of last dose of study drug - date of first dose of study drug + 7) / 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 to ≤20 weeks 
• 
>20 to ≤24 weeks 
• 
>24 to ≤52 weeks 
• 
>52 weeks to ≤72 weeks 
• 
>72 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: 1-10, 11-
20, 21-30, 31-40, 41-50, 51-60, 61-70, 71-80, 81-90, and >90. 
7.7.2 Adverse Events 
Clinical and laboratory AEs will be coded using the MedDRA Version 23.1 (or a later 
version if updated during the study). SOC, High-Level Group Term (HLGT), High-
Level Term (HLT), PT, and Lower-Level Term (LLT) will be attached to the clinical 
database. AE severity will be graded using the National Cancer Institute-Common 
Terminology Criteria for Adverse Events (NCI-CTCAE, version 5.0). The relationship 
between an AE and study drug will be assessed (Related/ Not related) and also the 
relationship to study procedures. 
AEs will be classified as either pre-treatment AEs or TEAEs as follows: 
• 
pre-treatment AEs are events that start prior to the date of first dose of study 
drug. 
• 
TEAEs are events with start date on or after the date of first dose of study 
drug and up to 30 days after date of last dose of study drug.  
Any AEs leading to premature discontinuation of study drug will be summarized 
separately. 


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An overview table will summarize the number and percentage of subjects with at 
least one of the following AEs, where subjects with more than one event in a 
particular category are counted only once in that category: 
• 
Any TEAEs;  
• 
Any TEAEs by maximum severity grade (a subject will be counted in only one 
category); 
• 
Study drug-related TEAEs (overall and by maximum severity);  
• 
Study procedure related TEAEs (overall and by maximum severity); 
• 
Any TEAEs of special interest (overall, injection site reaction, diarrhea, 
hypoglycemia, neurological or psychiatric event, or DILI) 
• 
Any TEAEs of decompensated liver disease events including ascites, hepatic 
encephalopathy (HE), or variceal bleeding; 
• 
Any SAEs;  
• 
Any treatment-emergent SAEs (TESAEs); 
• 
Any TEAEs leading to premature discontinuation of study drug; 
• 
Any TEAEs leading to premature discontinuation of study from the end of 
study eCRF; 
• 
Any TEAE leading to death. 
Summaries (number and percentage of subjects) will be presented by SOC and PT 
for each of the categories in the overview (with the exception of Any TEAEs leading 
to premature discontinuation of study). Common TEAEs (PTs with an incidence 
≥15% in any treatment group) will be presented by SOC and PT as well. 
Summaries will also be presented by SOC, PT and maximum severity grade for 
TEAEs, study drug-related TEAEs, and study procedure related TEAEs. In these 
summaries, subjects with more than one AE within a particular SOC are counted 
only once for that SOC. Similarly, subjects with more than one AE within a 
particular PT are counted only once for that PT. For summaries by maximum 
severity grade, subjects with multiple AEs within a particular SOC or PT will be 
counted under the category of their most severe AE within that SOC or PT. 
All AEs collected during the course of the study will be presented in data listings 
with fields for treatment-emergent event (Yes / No), Start and end dates, Outcome 
(Fatal / Not resolved or Not recovered / Recovered or resolved / Recovered or 
resolved with sequelae [describe sequelae] / Unknown), Relationship to study 
treatment (Related / Not related), Relationship to study procedures (Related 
[specify procedure] / Not related), Toxicity Grade (CTCAE v 5.0), Action taken with 
the study drug (Dose not changed/ Drug interrupted/ Drug withdrawn/ Not 


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applicable), Any other action (Yes [specify]/ No), Event of clinical interest (DILI/ 
Injection site reaction/ Diarrhea/ Hypoglycemia/ Neurological or Psychiatric event).  
In addition, corresponding listings of SAEs and additional SAE details, AESIs and 
separate listing details of DILI and injection site reactions, decompensated liver 
disease events, TEAEs leading to discontinuation of study drug, and AEs leading to 
death will be produced. 
7.7.3 Laboratory Evaluations 
Safety laboratory tests of chemistry, hematology/coagulation, and endogenous 
FGF21 (Table 5) received from central laboratory will be summarized (n, mean, SD, 
median, minimum, and maximum) by treatment group and study visit along with 
the corresponding change from baseline values. Data for all laboratory tests, 
including urine/miscellaneous, unscheduled local laboratory tests recorded to the 
eCRF, and any additional analytes will be listed. 








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of normal (ULN) or below the lower limit of normal (LLN) using the maximum 
increase and/or decrease observed throughout the course of treatment and 
including the 30-day follow-up visit. Scheduled and unscheduled assessments will 
be included in this analysis. 
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. 
7.7.4 Vital Signs 
The following vital signs will be collected from subjects in seated or semi-recumbent 
position. 
• 
systolic and diastolic blood pressure (mmHg); 
• 
heart rate (bpm); 
• 
respiration rate (breaths/min); 
• 
oral/ intra-aural body temperature (°C). 
Descriptive summaries by treatment and visit will be presented for the mean of 
triplicate measures (rounded to the nearest integer) at Baseline, Week 12 Week 24, 
Week 48, and Week 96, and for single measurements collected at all other visits. 
The summary at each visit will pool assessments in seated or semi-recumbent 
positions. Vital signs data and changes from baseline will be summarized by visit 
using standard descriptive statistics for the Safety population. Baseline for each 
vital sign is the pre-dose measurement on Baseline visit (Day 1) with exceptions as 
defined in Section 7.1.1. For post-baseline, only data from scheduled visits will be 
included in the summary tables.  
7.7.5 Electrocardiograms 
The following quantitative ECG measurements will be recorded on the eCRF: 
• 
heart rate (bpm) 
• 
QRS (msec); 
• 
RR (msec); 
• 
PR (msec); 
• 
QT (msec); 
• 
Fridericia corrected QT (QTcF) interval (msec).  


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An overall Investigator assessment of ECG will be provided (categories “normal”, 
“abnormal, not clinically significant” and “abnormal, clinically significant”). 
The ECG measurements and changes from baseline in ECG will be listed and 
summarized by treatment group and visit using standard descriptive statistics for 
the Safety Set.  
The Investigator assessment will be listed and the number and percentage of 
subjects within each assessment category will be tabulated by treatment group and 
visit for the Safety Set.  
Baseline for each ECG measurement is the pre-dose measurement on Baseline visit 
(Day 1) with exceptions as defined in Section 7.1.1. For post-baseline, only data 
from scheduled visits will be included in the by visit summary tables. 
The number and percentage of subjects with absolute QTcF interval values in the 
pre-specified categories (>450, >480, and >500 msec), and QTcF interval change 
(>30 and >60 msec) will be summarized. The summary of maximum post-baseline 
QTcF will include scheduled and unscheduled visits. 
7.7.6 Other safety assessments 
7.7.6.1 Physical examination 
Clinically relevant physical exam findings prior to the first dose of study drug will be 
recorded on the medical history eCRF and clinically significant findings after the first 
dose of study drug will be recorded as AEs. 
7.7.6.2 DXA scan measurements 
DXA scan measurements will include bone mineral density of the lumbar spine and 
femoral neck. An MMRM model with baseline covariate will be used to evaluate the 
changes from baseline in DXA scan measurements between the EFX arms and the 
placebo arm at Week 48 and Week 96, controlling for stratification factors. Least 
square (LS) means, 95% CIs, and p-values will be presented. The analysis will be 
performed using the Safety Set.  
Summaries and boxplots will be presented for actual values and changes from 
baseline in DXA scan measurements at the collection time points defined in the 
Schedule of Assessments by treatment group. 
7.7.6.3 Anti-drug antibody and neutralizing antibody 
The incidence of pre-existing, treatment-emergent positive ADA, positive ADA at 
any time point, negative ADA at all time points, and NAb, if any, will be 
summarized by treatment and period.  


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Pre-existing ADA is defined as positive ADA result at or before dosing. Treatment-
emergent positive ADA is defined as negative result at or before dosing and positive 
result post dose. Titers will also be summarized descriptively for positive ADAs. 
 Pharmacokinetic Analysis 
Plasma EFX concentrations will be listed and summarized at the time points listed in 
the Schedule of Assessments for the PK Set. Summary statistics for plasma EFX 
include geometric mean and geometric CV. 
 Interim Analysis 
Throughout the study, all TEAEs, clinical assessments, clinical laboratory 
parameters, and the criteria for DILI will be closely monitored with subjects 
entering close observation, as required. 
An external DMC that consists of two hepatologists, one cardiologist, one 
endocrinologist, and a statistician will review the progress of the study. The DMC 
will convene after 45 subjects (approximately 15 per treatment group) have 
completed the Week 12 assessments. The DMC will receive all reports of SAEs and 
convene as needed to monitor for safety and additional meetings will be scheduled 
as required. 
Week 24 analysis will be conducted when all the planned subjects have completed 
the 24-week visit. The analysis will be performed by the unblinded DMC supporting 
team at Fortrea and the analysis results will be reviewed by the unblinded team at 
Akero Therapeutics. Treatment assignment should remain blinded until after the 
database lock. Akero unblinded team will be prevented from being involved in day-
to-day administration of study conduct after they are unblinded. 
All Subjects will remain in the same treatment group for the duration of the study. 
8. Changes in Planned Analysis 
Not applicable. 
Note that while Protocol Amendment 4 indicated that all EFX-treated subjects would 
switch to a single dose of EFX, after further consultation with regulatory bodies, all 
subjects were maintained on the as randomized EFX dose until Week 96.  
9. Data Issues 
This section is not required at this time, but will be populated if applicable in a 
future approved version of this document. 


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10. References 
1 
European Medicines Agency. ICH E9 (R1) addendum on estimands and 
sensitivity analysis in clinical trials to the guideline on statistical principles for 
clinical trials. Available at 
https://www.ema.europa.eu/en/documents/scientific-guideline/ich-e9-r1-
addendum-estimands-sensitivity-analysis-clinical-trials-guideline-statistical-
principles_en.pdf 
 
 
 


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11. Appendices 
 Appendix 1: 
Document History 
Document Version, Status, 
Date 
Summary/Reason for Changes 
Version 1, Final, 27 Jul 2021 
Not applicable; the first version 
Version 2, Final, 19 Aug 2022 
 
 
 
 
 
 
 
 
 
 
 
 
 
   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Version 3, Final,  
07 Feb 2024 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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