A Phase 2b, Randomized, Double-Blind, Placebo-Controlled Study Evaluating the Safety and Efficacy of Efruxifermin in Non-Cirrhotic Subjects With Nonalcoholic Steatohepatitis (NASH)
Phase: PHASE2
Conditions: NASH - Nonalcoholic Steatohepatitis
Sponsor: Akero Therapeutics, Inc



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 

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 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: 

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 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