A Phase 2a, Double-Blind, Randomized, Placebo-Controlled, Multicenter Study to Assess the Safety of Engensis in Participants With Amyotrophic Lateral Sclerosis
Phase: PHASE2
Conditions: Amyotrophic Lateral Sclerosis
Sponsor: Helixmith Co., Ltd.



Heli x mit h C o., Lt d. 
C O N FI D E N TI A L  
Pr ot oc ol: V M A L S- 0 0 2- 2 
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 
Versi o n 3. 0 
6 
Fi nal : 2 0 Ja n uar y 2 0 2 1 
T a ble of C o nte nts  
SI G N A T U R E P A G E  ....................................................................................................................... 2 
Pr ot oc ol A me n d me nt S u m mar y of C ha n ges Ta bl e ......................................................................... 3 
1.  
P R O T O C O L S U M M A R Y  .......................................................................................... 1 2 
1. 1.  
S y n o psis ...................................................................................................................... 1 2  
1. 2.  
St u d y Sc he ma ............................................................................................................. 1 8  
1. 3.  
Sc he d ule of A cti vities ( S o A) ...................................................................................... 1 9  
2.  
I N T R O D U C TI O N ...................................................................................................... 2 4 
2. 1.  
St u d y Rati o nale ........................................................................................................... 2 4  
2. 2.  
Bac k gr o u n d ................................................................................................................. 2 5  
2. 2. 1.  
Pat h o p h ysi ol o g y of A m y otr o p hic Lateral Scler osis ................................................... 2 5  
2. 2. 2.  
C urre nt Treat me nt O pti o ns, Treat me nt A p pr o ac h es, a n d U n met Cli nical 
Nee d  ............................................................................................................................ 2 7 
2. 2. 3.  
He pat oc yte Gr o wt h Fac t or f or Treat me nt of A m y otr o p hic Lateral Scler osis ............ 2 7 
2. 2. 4.  
E n ge nsis a n d V M 2 0 2 .................................................................................................. 2 8  
2. 2. 5.  
N o ncli nical Data  ......................................................................................................... 2 9 
2. 2. 6.  
Cli nical Data  ............................................................................................................... 2 9 
2. 2. 6. 1.  
P hase 1/ 2 St u d y i n Partici pa nts wit h A m y otr o p hic Lateral Scler osis ........................ 3 0  
2. 2. 6. 2.  
Ot her E n ge nsis Cli nical St u dies  ................................................................................. 3 0 
2. 3.  
Be nefit/ Ris k Assess me nt  ............................................................................................ 3 1 
2. 3. 1.  
Ris k Assess me nt  ......................................................................................................... 3 1 
2. 3. 2.  
Be nefit Assess me nt  ..................................................................................................... 3 2 
2. 3. 3.  
O verall Be nefit / Ris k C o ncl usi o ns  ............................................................................ 3 2 
3.  
O BJ E C TI V E S A N D E N D P OI N T S  ............................................................................ 3 3 
4.  
S T U D Y D E SI G N  ....................................................................................................... 3 5 
4. 1.  
O verall Desi g n  ............................................................................................................ 3 5 
4. 1. 1.  
E n ge nsis a n d Place b o Tr eat me nt C ycles  .................................................................... 3 5 
4. 1. 1. 1.  
Treat me nt C ycle 1  ....................................................................................................... 3 6 
4. 1. 1. 2.  
Treat me nt C ycle 2  ....................................................................................................... 3 7 
4. 1. 1. 3.  
Treat me nt C ycle 3  ....................................................................................................... 3 7 
4. 2.  
Scie ntific Rati o nale f or St u d y Desi g n  ........................................................................ 3 8 
4. 3.  
J ustificati o n f or D ose .................................................................................................. 3 9 

Heli x mit h C o., Lt d. 
C O N FI D E N TI A L  
Pr ot oc ol: V M A L S- 0 0 2- 2 
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 
Versi o n 3. 0 
7 
Fi nal : 2 0 Ja n uar y 2 0 2 1 
4. 3. 1.  
S u p p ort fr o m N o ncli nical St u dies .............................................................................. 3 9  
4. 3. 2.  
S u p p ort fr o m Cli nical St u dies .................................................................................... 3 9  
4. 4.  
Ra n d o mizati o n ............................................................................................................ 4 1  
4. 5.  
E n d of St u d y Defi niti o n .............................................................................................. 4 1  
4. 6.  
St u d y C o m pleti o n ....................................................................................................... 4 1  
4. 7.  
C o m plete d Partici pa nts  ............................................................................................... 4 1 
5.  
S T U D Y P O P U L A TI O N  ............................................................................................. 4 2 
5. 1.  
I n cl usi o n Criteria  ........................................................................................................ 4 2 
5. 2.  
E xcl usi o n Criteria  ....................................................................................................... 4 2 
5. 3.  
N u m ber of Partici pa nts ............................................................................................... 4 3  
5. 4.  
E nr oll me nt, Ra n d o mizati o n, a n d Treat me nt Assi g n me nt ........................................... 4 3  
5. 4. 1.  
E nr oll me nt A dj u dicati o n Pr ocess ............................................................................... 4 3  
5. 4. 2.  
Ra n d o mizati o n a n d Treat me nt All ocati o n  .................................................................. 4 6 
5. 5.  
Partici pa nt I de ntificati o n  ............................................................................................ 4 6 
5. 6.  
Scree n Fail ures  ............................................................................................................ 4 6 
5. 7.  
Rescree ni n g  ................................................................................................................. 4 6 
5. 8.  
Lifest yle C o nsi derati o ns ............................................................................................. 4 6  
5. 8. 1.  
Meals a n d Dietar y Restri cti o ns  ................................................................................... 4 6 
5. 8. 2.  
Caffei ne, Al c o h ol, a n d T o bacc o ................................................................................. 4 7  
5. 8. 3.  
S u p ple me nts ................................................................................................................ 4 7  
5. 8. 4.  
Acti vit y  ....................................................................................................................... 4 7 
6.  
S T U D Y I N T E R V E N TI O N  ........................................................................................ 4 8 
6. 1.  
St u d y I nter v e nti o n(s) A d mi nistere d ........................................................................... 4 8  
6. 1. 1.  
E n ge nsis ...................................................................................................................... 4 8  
6. 1. 2.  
Place b o  ........................................................................................................................ 4 8 
6. 1. 3.  
S u m mar y of St u d y I nter ve nti o n C haracteristics  ......................................................... 4 9 
6. 2.  
Pre parati o n/ Ha n dli n g/ St ora ge/ Acc o u nta bilit y ............................................................ 4 9  
6. 2. 1.  
E n ge nsis Pre par ati o n .................................................................................................. 4 9  
6. 2. 2.  
St ora ge of E n ge nsis a n d Place b o ................................................................................ 4 9  
6. 2. 3.  
Pr o d uct Acc o u nta bilit y  ............................................................................................... 5 0 
6. 3.  
Meas ures t o Mi ni mize Bias  ........................................................................................ 5 0 
6. 3. 1.  
Ra n d o mizati o n ............................................................................................................ 5 0  

Heli x mit h C o., Lt d. 
C O N FI D E N TI A L  
Pr ot oc ol: V M A L S- 0 0 2- 2 
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 
Versi o n 3. 0 
8 
Fi nal : 2 0 Ja n uar y 2 0 2 1 
6. 3. 2.  
Bli n di n g ...................................................................................................................... 5 0  
6. 3. 3.  
Mai nte na nce of t he  Bli n d  ............................................................................................ 5 1 
6. 4.  
St u d y I nter v e nti o n C o m plia nce .................................................................................. 5 2  
6. 5.  
C o nc o mita nt T hera p y ................................................................................................. 5 2  
6. 6.  
D ose I nterr u pti o n  ........................................................................................................ 5 2 
6. 7.  
Pri or  a n d C o nc o mita nt Me dicati o ns, Treat me nts, a n d Pr oce d ures ............................. 5 2 
7.  
DI S C O N TI N U A TI O N O F S T U D Y I N T E R V E N TI O N A N D 
P A R TI CI P A N T WI T H D R A W A L  ............................................................................. 5 4 
7. 1.  
Disc o nti n uati o n of St u d y I nter ve nti o n........................................................................ 5 4  
7. 2.  
Partici pa nt Wit h dra w al/ Disc o nti n uati o n  .................................................................... 5 4 
7. 3.  
L ost t o F oll o w- u p ....................................................................................................... 5 5  
8.  
S T U D Y A S S E S S M E N T S A N D P R O C E D U R E S  ...................................................... 5 6 
8. 1.  
Scree ni n g ( D a ys - 3 0 t o - 1) .......................................................................................... 5 6 
8. 1. 1.  
Scree ni n g Pr oce d ures .................................................................................................. 5 6  
8. 1. 2.  
Re vise d El Esc orial/ Airlie H o use Criteria  .................................................................. 5 6 
8. 2.  
Safet y Assess me nts  ..................................................................................................... 5 7 
8. 2. 1.  
P h ysical E xa mi nati o ns ................................................................................................ 5 7  
8. 2. 2.  
Me dical Hist or y  .......................................................................................................... 5 7 
8. 2. 3.  
1 2- Lea d Electr ocar di o gr a ms  ....................................................................................... 5 8 
8. 2. 4.  
Vital Si g ns  .................................................................................................................. 5 8 
8. 2. 5.  
C oa g ulati o n Pr ofile ..................................................................................................... 5 8  
8. 2. 6.  
Cli nical La b orat or y Assess me nts  ............................................................................... 5 8 
8. 2. 6. 1.  
L ocal a n d Ce ntr al La b or at or y Assess me nts  ............................................................... 5 8 
8. 2. 7.  
Sl o w Vital Ca pacit y  .................................................................................................... 6 0 
8. 3.  
Ot her Assess me nts a n d Pr oce d ures  ............................................................................ 6 0 
8. 3. 1.  
Re vise d A m y otr o p hic Lateral Scler osis F u n cti o nal Rati n g........................................ 6 0  
8. 3. 2.  
Ha n d hel d D y na m o metr y ............................................................................................. 6 0  
8. 3. 3.  
Acc ur ate Test of Li m b Is o metric Stre n gt h  ................................................................. 6 1 
8. 3. 4.  
M uscle Bi o psies  .......................................................................................................... 6 1 
8. 3. 5.  
Q ualit y of Life Assess me nt, Patie nt Re p orte d O utc o mes, a n d Cli nical 
Re p orte d O utc o mes .................................................................................................... 6 1  
8. 3. 5. 1.  
A m y otr o p hic Later al Scler osis Assess me nt Q uesti o n naire ........................................ 6 1  
8. 3. 5. 2.  
Patie nt Gl o bal I m pr essi o n of C ha n ge ......................................................................... 6 1 

Heli x mit h C o., Lt d. 
C O N FI D E N TI A L  
Pr ot oc ol: V M A L S- 0 0 2- 2 
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 
Versi o n 3. 0 
9 
Fi nal : 2 0 Ja n uar y 2 0 2 1 
8. 3. 5. 3.  
Cli nical Gl o bal I m pr essi o n of C ha n ge ....................................................................... 6 2  
8. 4.  
Bl o o d Sa m ples St ore d f or F ut ure Ge netic T esti n g ..................................................... 6 2  
8. 5.  
A d verse E v e nts a n d Seri o us A d verse E v e nts ............................................................. 6 2  
8. 5. 1.  
Ti me Peri o d a n d Fr e q ue n c y f or C ollecti n g A E, T E A E, S A E, T E S A E 
I nf or mati o n ................................................................................................................. 6 2 
8. 5. 2.  
Met h o d of Detecti n g A Es, T E A Es, S A Es a n d T E S A Es ............................................ 6 3  
8. 5. 3.  
S A E Re p orti n g t o t he S p o ns or or Desi g nee ............................................................... 6 3  
8. 5. 4.  
A d verse E v e nts of S peci al I nt erest  ............................................................................. 6 3 
8. 5. 4. 1.  
A E SI C o nsi der e d Relate d t o A n gi o ge nesis ................................................................ 6 3  
8. 5. 4. 2.  
Ot her Me dical Pr o ble ms i n A L S Patie nts  ................................................................... 6 3 
8. 5. 4. 3.  
I njecti o n Site Reacti o ns  .............................................................................................. 6 4 
8. 5. 5.  
F oll o w- u p of A Es, T E A Es, S A Es, a n d A E SIs ........................................................... 6 4  
8. 5. 6.  
Re g ulat or y Re p orti n g Re q uire me nts f or S A Es ........................................................... 6 4  
8. 5. 7.  
S p o ns or’s Res p o nsi bilit y  ............................................................................................ 6 5 
8. 5. 8.  
Pre g na nc y a n d C o ntrace pti o n ..................................................................................... 6 5  
8. 5. 8. 1.  
Pre g na nc y T est ( W o me n of C hil d beari n g P ote ntial O nl y) a n d C o ntrace pti o n .......... 6 5  
8. 5. 8. 2.  
Pre g na nc y  ................................................................................................................... 6 5 
8. 5. 9.  
Disease -Rel ate d E ve nts a n d/ or Disease - R elate d O utc o mes N ot Q ualif yi n g as 
A Es or S A Es  ............................................................................................................... 6 6 
8. 6.  
St u d y C o m pleti o n ....................................................................................................... 6 6  
8. 6. 1.  
E n d of St u d y Defi niti o n .............................................................................................. 6 6  
8. 6. 2.  
C o m plete d Partici pa nts  ............................................................................................... 6 6 
9.  
S T A TI S TI C A L C O N SI D E R A TI O N S  ....................................................................... 6 7 
9. 1.  
Sa m ple Size Deter mi nati o n  ........................................................................................ 6 7 
9. 2.  
P o p ulati o n f or A nal ysis: Safet y P o p ulati o n ................................................................ 6 7  
9. 3.  
Statistical A nal yses  ..................................................................................................... 6 7 
9. 3. 1.  
Pri mar y E n d p oi nts ...................................................................................................... 6 7  
9. 3. 2.  
E x pl orat or y E n d p oi nts ................................................................................................ 6 7  
9. 4.  
Data Safet y M o nit ori n g B oar d .................................................................................... 6 8  
1 0.  
S U P P O R TI N G D O C U M E N T A TI O N A N D O P E R A TI O N A L 
C O N SI D E R A TI O N S  .................................................................................................. 6 9 
1 0. 1.  
A p pe n di x 1. Re g ulat or y, Et hical, a n d St u d y O versi g ht C o nsi derati o ns..................... 6 9  
1 0. 1. 1.  
Re g ulat or y a n d Et hical C o nsi derati o ns ...................................................................... 6 9  

Heli x mit h C o., Lt d. 
C O N FI D E N TI A L  
Pr ot oc ol: V M A L S- 0 0 2- 2 
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 
Versi o n 3. 0 
1 0 
Fi nal : 2 0 Ja n uar y 2 0 2 1 
1 0. 1. 1. 1.  
I nstit uti o nal Re vie w B oar d  ......................................................................................... 6 9 
1 0. 1. 1. 2.  
I nf or me d C o nse nt Pr ocess  .......................................................................................... 6 9 
1 0. 1. 1. 3.  
O bli gati o ns of t he S p o ns or a n d t he I n v esti gat or ......................................................... 7 0  
1 0. 1. 2.  
Fi na ncial Discl os ur e  ................................................................................................... 7 1 
1 0. 1. 2. 1.  
C o nflict of I nt erest P olic y  ........................................................................................... 7 1 
1 0. 1. 2. 2.  
Fi na ncial Discl os ur e  ................................................................................................... 7 1 
1 0. 1. 3.  
Partici pa nt Selecti o n a n d I nf or me d C o nse nt Pr ocess ................................................. 7 1  
1 0. 1. 4.  
Data Pr otecti o n a n d C o nfi de ntialit y ........................................................................... 7 2  
1 0. 1. 4. 1.  
C o nfi de ntialit y  ............................................................................................................ 7 2 
1 0. 1. 4. 2.  
Data  Pr otecti o n  ........................................................................................................... 7 2 
1 0. 1. 5.  
C o m mittee Str uct ure  ................................................................................................... 7 3 
1 0. 1. 5. 1.  
Data Safet y M o nit ori n g B oar d .................................................................................... 7 3  
1 0. 1. 5. 2.  
I nstit uti o nal Bi osafet y C o m mittee  .............................................................................. 7 4 
1 0. 1. 6.  
Data Q ualit y Ass ur a nce  .............................................................................................. 7 4 
1 0. 1. 6. 1.  
Cli nical M o nit ori n g  .................................................................................................... 7 4 
1 0. 1. 6. 2.  
Access t o St u d y D oc u me nts a n d St u d y M o nit ori n g ................................................... 7 4  
1 0. 1. 6. 3.  
Q ualit y Ass ura nce a n d Q ualit y C o ntr ol ...................................................................... 7 5  
1 0. 1. 6. 4.  
Data Q ualit y  Ass ura n ce  .............................................................................................. 7 6 
1 0. 1. 6. 5.  
Data C ollecti o n a n d Ma n a ge me nt  Res p o nsi bilities  .................................................... 7 6 
1 0. 1. 6. 6.  
Pr ot oc ol De viati o ns .................................................................................................... 7 7  
1 0. 1. 6. 7.  
S o urce D oc u m e nts ...................................................................................................... 7 7  
1 0. 1. 7.  
Data  Ma na ge m e nt  ....................................................................................................... 7 8 
1 0. 1. 8.  
Rec or d kee pi n g a n d Rete nti o n  ..................................................................................... 7 8 
1 0. 1. 9.  
St u d y a n d Site Start a n d Cl os ure ................................................................................ 7 9  
1 0. 1. 1 0.  
P u blicati o n P olic y  ....................................................................................................... 8 0 
1 0. 1. 1 1.  
I ns ura nce ..................................................................................................................... 8 0 
1 0. 2.  
A p pe n di x 2. A d vers e E v e nts: Defi niti o ns a n d Pr oce d ures f or Rec or di n g, 
E val uati n g, F oll o w- u p, a n d Re p orti n g ........................................................................ 8 1  
1 0. 2. 1.  
Defi niti o n of A E ......................................................................................................... 8 1  
1 0. 2. 2.  
Defi niti o n of T E A E  .................................................................................................... 8 2 
1 0. 2. 3.  
Defi niti o n of S A E ....................................................................................................... 8 2  
1 0. 2. 4.  
Defi niti o n of T E S A E .................................................................................................. 8 3  
1 0. 2. 5.  
Rec or di n g a n d F oll o w- U p of A E/ T E A E a n d/ or S A E/ T E S A E  ................................... 8 3 

Heli x mit h C o., Lt d. 
C O N FI D E N TI A L  
Pr ot oc ol: V M A L S- 0 0 2- 2 
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 
Versi o n 3. 0 
1 1 
Fi nal : 2 0 Ja n uar y 2 0 2 1 
1 0. 2. 6.  
Re p orti n g of S A Es/ T E S A Es ....................................................................................... 8 5  
1 0. 3.  
A p pe n di x 3. Gra di n g of I njecti o n Site Reacti o ns ....................................................... 8 6  
1 0. 4.  
A p pe n di x 4. List of A b br e viati o ns a n d Defi niti o ns .................................................... 8 7  
1 0. 4. 1.  
A b bre viati o ns .............................................................................................................. 8 7  
1 0. 4. 2.  
Defi niti o ns  .................................................................................................................. 8 9 
1 0. 5.  
A p pe n di x 5. St u d y Dr u g I njecti o n Sites ..................................................................... 9 1  
1 0. 6.  
A p pe n di x 6. Re vise d A m y otr o p hic Lateral Scler osis F u ncti o nal Rati n g Scale ......... 9 3  
1 0. 7.  
A p pe n di x 7. A m y otr o p hic Lateral Scler osis Assess me nt Q uesti o n naire ................... 9 4  
1 0. 8.  
A p pe n di x 8. Patie nt Gl o bal I m pressi o n of C ha n ge a n d Cli nical I m pressi o n 
of C ha n ge .................................................................................................................... 9 9  
1 0. 9.  
A p pe n di x 9. Pr ot oc ol A me n d me nt Hist or y .............................................................. 1 0 1  
1 1.  
R E F E R E N C E S  ......................................................................................................... 1 0 2 
 
List of T a bles  
Ta ble  1: 
I njecti o n a n d D osi n g Sc h e d ule: Treat me nt C ycle 1: Da ys 0 a n d 1 4 .......................... 3 6 
Ta ble  2: 
I njecti o n a n d D osi n g Sc h e d ule: Treat me nt C ycle 2: Da ys 6 0 a n d 7 4 ........................ 3 7 
Ta ble  3: 
I njecti o n a n d D osi n g Sc h e d ule: Treat me nt C ycle 3: Da ys 1 2 0 a n d 1 3 4 .................... 3 8 
Ta ble  4: 
C o m p o ne nts of E n ge nsis ............................................................................................ 4 8  
Ta ble  5: 
C o m p o ne nts of t he Place b o ........................................................................................ 4 8  
Ta ble 6:  
I njecti o n Site Reactio n Gra di n g .................................................................................. 8 6  
List of Fi g ures  
Fi g ure 1:  
M olec ular Mec ha nis ms of M ot or Ne ur o n I nj ur y i n A L S ........................................... 2 6  
Fi g ure 2:  
V M 2 0 2 C o nstr uct ....................................................................................................... 2 9  
Fi g ure 3:  
Ra n d o mizati o n Pr ocess ............................................................................................... 4 5  
Fi g ure 4:  
E xa m ples of I njecti o n Sites f or U p p er Li m b I njecti o n Visit s (all i njecti o ns t o 
be c o n d ucte d bilat erall y) ............................................................................................. 9 1  
Fi g ure 5:  
E xa m ples of I njecti o n Sites f or L o w er Li m b I njecti o n Visits (all i njecti o ns t o 
be c o n d ucte d bilat erall y) ............................................................................................. 9 2  

Heli x mit h C o., Lt d. 
C O N FI D E N TI A L  
Pr ot oc ol: V M A L S- 0 0 2- 2 
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 
Versi o n 3. 0 
1 2 
Fi nal : 2 0 Ja n uar y 2 0 2 1 
1.  
P R O T O C O L S U M M A R Y  
T he f oll o wi n g secti o ns prese nt a n o v er vie w of t he st u d y, st u d y sc he ma, a n d Sc he d ule of 
A cti vities ( S o A). A list of a b bre vi ati o ns is prese nt e d i n Secti o n 1 0. 4 , A p pe n di x 4. 
1. 1.  
S y n o psis  
Pr ot oc ol Title:  
A P hase 2 a, D o u ble- Bli n d, Ra n d o mize d, Place b o - C o ntr olle d, M ultice nter 
St u d y t o Assess t he Safet y of E n ge nsis i n Partici pa nt s wit h A m y otr o p hic Lateral Scler osis 
S h ort Title:  P hase 2 a St u d y t o Assess t he Safet y of E n ge nsis i n A m y otr o p hic Lateral Scler osis 
R ati o n ale: 
T he p ur p ose of t his st u d y is t o e val uate t he safet y of i ntra m usc ular (I M) a d mi nistrati o n of 
E n ge nsis i n Partici pa nts wit h A m y otr o p hic Lateral Scler osis ( A L S) as c o m pare d t o Place b o . 
Safet y will be assesse d b y i nci de nces of treat me nt -e mer g e nt a d vers e e v e nts ( T E A Es) , treat me nt-
e mer ge nt seri o us a d vers e e ve nts (T E S A Es) , i njecti o n site reacti o ns (I S Rs) a n d ot her a d verse 
e ve nts of s peci al i nterest ( A E SI s), a n d t he cli nicall y si g nifica nt la b orat or y v al ues after i njecti o ns 
f or E n ge nsis c o m pare d t o Place b o. E x pl orat or y e n d p oi nts i ncl u de assess me nt of m uscle f u ncti o n 
usi n g t he Re vise d A m y otr o p hic Later al Scler osis F u ncti o nal Rati n g Scale ( A L S F R S- R) a n d 
A L S F R S -R s u bsc ores f or Fi ne a n d Gr oss M ot or F u ncti o n; m uscle stre n gt h b y q ua ntitati ve 
testi n g usi n g Ha n d hel d D y na m o metr y ( H H D) a n d t he Acc urate T est of Li m b Is o metri c Stre n gt h 
( A T LI S) w h ere a vaila ble ; q ualit y of life usi n g t he A L S Assess me nt Q uesti o n naire ( A L S A Q- 4 0); 
patie nt  gl o bal i m pressi o n of c ha n ge ( P GI C), a n d cli nical gl o bal i m pressi o n of c ha n ge ( C GI C); 
a n d e val uati o n of l u n g f u ncti o n usi n g Sl o w Vital Ca pacit y ( S V C). M uscle bi o psies will be 
perf or me d d uri n g t he st u d y f or f ut ure bi o mar ker a nal ys es. 
E n ge nsis c o ntai ns t he acti ve p har mace utical i n gre die nt V M 2 0 2, a n o vel ge n o mic c o m ple me ntar y 
de o x yri b o n ucleic aci d  ( c D N A) h y bri d h u ma n h e p at oc yte gr o wt h fact or ( H G F ) c o di n g se q ue nce 
( H G F- X 7) e x pressi n g t w o is of or ms of H G F, H G F7 2 8 a n d H G F 7 2 3, bei n g de vel o pe d f or treat me nt 
of A L S.  
D ata fr o m H eli x mit h’s first cli nical trial i n A L S, t he P hase 1/ 2 A L S st u d y (V M A L S - 0 0 1), w hic h 
i ncl u de d 1 8 Partici pa nts  w h o wer e f oll o we d f or 9 m o nt hs, s u g geste d t hat tar gete d deli ver y of 
H G F t o m ot or ne ur o ns vi a i ntra m usc ular (I M) i njectio ns of E n ge nsis was safe a n d w ell -t olerate d. 
Safet y assess me nts d uri n g t he st u d y i ncl u de d re p orts of 7 9 a d vers e e v e nts ( A E s) i n 1 7 
Partici pa nts ( 9 4. 4 %), i ncl u di n g 2 6 mil d i njecti o n site reacti o ns  ( Gra d e 1). Fi ve S A Es were 
re p orte d i n 3 Partici pa nts. O nl y i njecti o n site reacti o ns were c o nsi d ere d relate d t o st u d y 
treat me nt. F oll o wi n g i njecti o ns u ntil Da y 9 0, a platea u or a relati ve sl o wi n g i n decli ne of t he 
A L S F R S - R sc ores a n d m uscle stre n gt h was n ote d, s u g gesti n g a sl o wi n g of disease pr o gressi o n. 
After 9 0  da ys, t h e platea u was n o l o n ger o bser ve d i n t he A L S F R S- R,  wit h t he n ota ble e x ce pti o n 
of a tre n d t o w ar d better preser v ati o n of b ul bar a n d breat hi n g f u ncti o ns as m eas ure d b y t h e 
A L S F R S -R.  

Heli x mit h C o., Lt d. 
C O N FI D E N TI A L  
Pr ot oc ol: V M A L S- 0 0 2- 2 
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 
Versi o n 3. 0 
1 3 
Fi nal : 2 0 Ja n uar y 2 0 2 1 
Partici pa nts ra n d o ml y assi g ne d t o E n ge nsis will recei ve a t otal d ose of 1 9 2 m g V M 2 0 2 di vi de d 
i nt o 3 Treat me nt C ycle s of 6 4 m g V M 2 0 2 eac h. I n t his st u d y, t he per-i njecti o n a m o u nt ( 0. 2 5 m g) 
of E n ge nsis will be i de ntical t o t hat use d i n t he P hase 1/ 2 A L S st u d y a n d w as als o use d i n  t hree 
dia betic peri p heral ne u r o pat h y ( D P N) st u dies, b ut t he d osi n g sc he d ule will differ. I M i njecti o ns 
of E n ge nsis or Place b o t o m uscles i n ha n ds, u p per a n d l o wer ar ms, a n d le gs will be di vi de d i nt o 
t w o I njecti o n Visits sc he d ule d t w o wee ks a part d uri n g t hree Treat me nt C ycles: o n Da ys 0 a n d 
1 4 ( Treat me nt C ycl e 1), wit h retreat me nt o n D a ys 6 0 a n d 7 4 ( Treat me nt C ycle 2), a n d D a ys 1 2 0 
a n d 1 3 4 ( Treat me nt C ycl e 3). 
 
 

Heli x mit h C o., Lt d. 
C O N FI D E N TI A L  
Pr ot oc ol: V M A L S- 0 0 2- 2 
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 
Versi o n 3. 0 
1 5 
Fi nal : 2 0 Ja n uar y 2 0 2 1 
O bjecti ves  
E n d p oi nts  
•  C ha n ge fr o m Baseli ne ( Da y 0) i n t he 
Acc urate Test of Li m b Is o metric Stre n gt h 
( A T LI S) w h ere a vaila ble  at Da ys 3 0, 6 0, 
8 4, 1 2 0, 1 4 4, a n d 1 8 0 f or E n ge nsis 
c o m pare d t o Place b o  
•  T o e val uate Q u alit y of L ife i m pr o ve me nt 
f oll o wi n g E n ge nsis i njecti o ns i n A L S 
Partici pa nts c o m pare d t o Place b o  
•  C ha n ge fr o m Baseli ne ( Da y 0) i n Q ualit y 
of Life ( Q o L) usi n g t he A L S Assess me nt 
Q uesti o n naire ( A L S A Q; wit h 4 0 ite ms, 
A L S A Q - 4 0) o n D a ys 8 4 a n d 1 8 0 f or 
E n ge nsis c o m pare d t o Pl ace b o  
•  T o e val uate Patie nt a n d Cli nical Re p orte d 
O utc o me i m pr o ve me nt f oll o wi n g 
E n ge nsis i njecti o ns i n A L S Partici pa nts 
c o m pare d t o Place b o  
•  Patie nt Gl o bal I m pressi o n of C ha n ge 
( P GI C) a n d Cli nical Gl o bal I m pressi o n of 
C ha n ge ( C GI C) at D a ys  8 4 a n d 1 8 0 f or 
E n ge nsis c o m pare d t o Pl ace b o 
•  T o deter mi ne w h et her I M a d mi nistrati o n 
of E n ge nsis has effects o n res pirat or y 
f u ncti o n i n A L S Partici pa nts c o m pare d t o 
Place b o  
•  C ha n ge fr o m Baseli ne ( Da y 0) i n Sl o w 
Vital Ca pacit y ( S V C) o n Da ys 3 0, 6 0, 8 4, 
1 2 0, 1 4 4, a n d 1 8 0 f or E n ge nsis c o m pare d 
t o Place b o 
•  Ti me t o trac he ost o m y f or E n ge nsis 
c o m pare d t o Place b o  
•  T o deter mi ne w h et her I M a d mi nistrati o n 
of E n ge nsis has p ositi ve effects o n 
s ur vi val i n A L S Partici pa nts c o m pare d t o 
Place b o  
•  Ti me t o all-ca use m ortalit y  b y Da y 1 8 0 
f or E n ge nsis c o m pare d t o Place b o 
•  T o deter mi ne w h et her I M a d mi nistrati o n 
of E n ge nsis has p ositi ve effects o n m uscle 
atr o p h y i n A L S Partici pa nts c o m pare d t o 
Place b o  
•  C ha n ge fr o m Baseli ne ( Da y 0) i n 
bi o mar kers f or m uscle atr o p h y i n bi o psies 
c ollecte d bef ore a n d aft er i njecti o n s f or 
E n ge nsis c o m pare d t o Pl ace b o 
 
 

Heli x mit h C o., Lt d. 
C O N FI D E N TI A L  
Pr ot oc ol: V M A L S- 0 0 2- 2 
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 
Versi o n 3. 0 
1 6 
Fi nal : 2 0 Ja n uar y 2 0 2 1 
O ver all Desi g n  
V M A L S - 0 0 2- 0 2 is a P hase 2 a, d o u ble- bli n d, ra n d o mize d, p lace b o-c o ntr oll e d, multi ce nter st u d y 
desi g ne d t o assess t he saf et y of E n ge nsis (c o ntai ni n g t he acti ve p har mace utical i n gre die nt 
V M 2 0 2) i n Partici pa nt s wit h A L S. F oll o wi n g t he c o m pleti o n of t he i nf or me d c o nse nt pr ocess, 
Scree ni n g acti vities ( wit hi n 3 0 da ys pri or t o Da y 0 ) will deter mi ne w hic h P artici pa nts meet t he 
eli gi bilit y criteria a n d w h o will be e nr olle d a n d ra n d o ml y assi g ne d i n a d o u ble- bli n d fas hi o n i n a 
2: 1 rati o t o eit her E n ge nsis or Place b o , res p ecti vel y. 
D uri n g Scree ni n g, me di cal hist or y, fa milial ca ncer hist or y, de m o gra p hics, vital si g ns, wei g ht a n d 
hei g ht, c o m plete p h ysical e xa mi nati o n, t he A L S F R S- R, sl o w vital ca pacit y ( S V C), 1 2-lea d 
electr ocar di o gr a m ( E C G), la b orat or y ass ess me nts  (c oa g ulati o n pr ofile, s er u m c he mistr y, a n d 
he mat ol o g y), viral scr ee ni n g, a rec or d of all c o n c o mita nt me dicati o ns a n d pr oce d ures, a n d uri n e 
pre g na nc y t est f or f e males of c hil d beari n g p ote ntial will be c o n d ucte d. A d v erse e v e nt ( A E) 
assess me nt will start u p o n c o m pleti o n of t he c o ns e nt pr ocess at t he st art of Scree ni n g a n d 
treat me nt-e mer ge nt a d v erse e ve nt ( T E A E) assess me nt, i ncl u di n g i njecti o n site reacti o ns, will 
start after t h e first i njecti o n of E n ge nsis or Place b o ( Da y 0) a n d c o nti n ue t hr o u g h o ut t he st u d y. 
F oll o wi n g ra n d o mizati o n a n d pri or t o t he first I M i njecti o ns of E n ge nsis or Place b o o n Da y 0, 
vital si g ns  a n d wei g ht, a c o m plete p h ysical e x a mi nati o n, uri ne pre g n a nc y t est, S V C, c o nc o mita nt 
me dicati o ns a n d pr oce d ures, meas ur e me nt of m us cle stre n gt h b y H H D  a n d A T LI S  (at cli nical 
st u d y sites w here a v aila ble), A L S F R S- R, m uscle bi o ps y, a n d t he q ualit y of life assess me nt wit h 
t he A L S A Q- 4 0 will be c o m plete d. 
All Partici pa nt s will recei ve 0. 5-m L  ( 0. 2 5 m g) I M i njecti o ns ( 2 t o 2 0 i njecti o ns per m uscle , 
de pe n di n g o n t he a n at o mical l ocati o n of t he m uscl e) of E n ge nsis or Place b o i n tar get m uscle s at 
eac h of t w o d osi n g Visits d uri n g 3 Treat me nt C ycl es: Treat me nt C ycle 1 o n Da y s 0 a n d 1 4, 
Treat me nt C ycle  2 o n D a ys 6 0 a n d 7 4, a n d Treat me nt C ycle 3 o n Da ys 1 2 0 a n d 1 3 4. Vital si g n 
meas ure me nts will be perf or me d a t 2 h o urs after c o m pleti o n of I M i njecti o ns of E n ge nsis or 
Place b o o n Da ys 0, 1 4, 6 0 , 7 4, 1 2 0, a n d 1 3 4. 
Vital si g ns  will be rec or d e d at all St u d y Visits.  O n Da y 0, a bl o o d sa m ple will be c ollecte d f or 
f ut ure ge n etic testi n g. Muscle b i o psies will be c ollecte d o n  Da y 0 , 8 4 ( o pti o nal) , a n d 1 4 4. 
All Partici pa nt s will recei ve 2 5 6 I M i njecti o ns per Treat me nt C ycle ( 1 2 8 i njecti o ns o n eac h of 
2 d osi n g da ys) as a di vi d e d d ose t o m ulti ple i njecti o n sites i n eac h m uscle i de ntifie d i n t he u p per 
e xtre mities (ha n ds: first d orsal i nter osse o us, a b d u ct or p ollicis bre vis; ar ms: bice ps, delt oi d, 
e xte ns or car pi ra di alis, fle x or car pi ul naris, a n d fl e x or car pi ra dialis) a n d l o wer e xtre mities 
(le gs: q ua drice ps, g astr oc ne mi us, a n d ti bialis a nteri or). Eac h i njecti o n c o ntai ns 0. 2 5 m g 
E n ge nsis/ 0. 5 m L or 0. 5 m L of Place b o. Partici pa nts assi g ne d t o E n ge nsis will recei ve a t otal 
d ose of 1 9 2 m g ( 3 c y cles at 6 4 m g eac h) d uri n g t he st u d y. 
F oll o w- u p St u d y Visits will be c o n d ucte d o n D a ys 3 0, 8 4, 1 4 4, a n d 1 8 0 or earl y ter mi nati o n 
( E T). At t he D a y 1 8 0/ E T Visit, t he f oll o wi n g assess me nts will be c o n d ucte d: vital si g ns a n d 
wei g ht, c o m plete p h ysical e xa mi nati o n, 1 2-lea d E C G, uri ne pre g n a nc y test, A L S F R S - R, S V C, 
H H D  a n d A T LI S (at sites w here a vaila ble), A L S A Q - 4 0, P GI C, C GI C, c o nc o mita nt me dicati o ns, 
a n d T E A Es. Bl o o d will be dra w n f or ser u m c he mistr y a n d he mat ol o g y. 

Heli x mit h C o., Lt d. 
C O N FI D E N TI A L  
Pr ot oc ol: V M A L S- 0 0 2- 2 
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 
Versi o n 3. 0 
1 7 
Fi nal : 2 0 Ja n uar y 2 0 2 1 
St u d y a n d Tre at m e nt D ur ati o n:  
Scree ni n g will occ ur u p t o 3 0 da ys pri or t o Baseli ne  ( Da y 0) a n d Partici pa nts will be f oll o we d 
fr o m Da y 0, t he d a y of first St u d y I njecti o ns, t o D a y 1 8 0/ E T. 
Visit Fre q ue nc y:  
C o nse nte d Partici pa nt s will be see n a n d e v al uate d f or e nr oll me nt d uri n g Scree ni n g ( u p t o 
3 0 da ys pri or t o Baseli ne , Da y 0). T here are 1 0 Visit s d uri n g t he st u d y fr o m Da y 0 t o Da y 1 8 0 
f or St u d y I nj ecti o ns a n d f oll o w- u p. 
I nter ve nti o n Gr o u ps a n d D ur ati o n: 
T w o treat me nt gr o u ps of Partici pa nt s ( E n ge nsis or Place b o) will be i n t he st u d y f or 1 8 0 da ys. 
N u m ber of P artici p a nts ( N = 1 8): 
T he tar get sa m ple si ze is  1 8 Partici pa nt s w h o will be ra n d o mize d i n a 2: 1 rati o t o E n ge nsis or 
Place b o  ( 1 2: 6). 
D at a S afet y M o nit ori n g B o ar d: 
T he i n de pe n de nt D ata Safet y M o nit ori n g B oar d ( D S M B ) will peri o dicall y re vie w , first o n a 
li mite d set of n o nc o m par ati ve ( bli n de d) ta bles a n d/ or listi n gs of all data  a n d, if t here is a c o n cer n, 
a c o m par ati ve ( u n bli n de d) a nal ysis will be c o n d uct e d, i ncl u di n g re vie w of all re p orte d T E A Es 
a n d T E S A Es . T he D S M B  ma y perf or m m ulti ple n o nc o m parati ve a nal yses f or safet y. 
C o m parati ve i nf or mati o n will n ot be s hare d wit h t he S p o ns or or t he Pr oject Steeri n g C o m mittee, 
e xce pt i n t he e v e nt t hat t he D S M B rec o m me n ds a te m p ora r y s us pe nsi o n or ter mi nati o n of t he 
st u d y. 
 

Heli x mit h C o., Lt d. 
C O N FI D E N TI A L  
Pr ot oc ol: V M A L S- 0 0 2- 2 
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 
Versi o n 3. 0 
2 1 
Fi nal : 2 0 Ja n uar y 2 0 2 1 
F O O T N O T E S F O R T H E S C H E D U L E O F A C TI VI TI E S  
N ote:  T he  Sc he d ule of Acti vities i ncl u des acti vities d uri n g Scree ni n g  a n d all St u d y Visits.  
Or der of Assess m e nts d uri n g Visits (if assess m e nt is t o b e perf or m e d): A Es/ T E A Es, vital si g ns  a n d wei g ht, A L S F R S-R, H H D, A T LI S, pre g na nc y test, c o m plete  
p h ysical e xa m, S V C, A L S A Q -4 0, ot her q uesti o n naires ( P GI C  a n d  C GI C) , bl o o d sa m ple c ollecti o n f or la b orat or y assess me nts, a n d m uscle bi o ps y  
a 
Da y 0 is t he Baseli ne Visit  
b 
T he Da y 1 4 Visit will be sc he d ule d 1 3 -1 5 da ys after t he Da y 0 Visit , the Da y 7 4 Visit will be sc he d ule d 1 3 -1 5 da ys after t he Da y 6 0 Visit , a n d t he Da y 1 3 4 Visit 
will be sc he d ule d 1 3 -1 5 da ys after t he Da y 1 2 0 Visit  
c 
M uscle  bi o psies will be c ollecte d as t he last pr oce d ure of t he Visit. It is c ollecte d p red ose o n Da y 0.  
d 
Da y 8 4 m uscle bi o ps y is o pti o nal . 
A b bre vi ati o ns : A Es = a d verse e ve nts; A E SI = a d verse e ve nts of s pecial i nterest; A L S F R S -R = Re vise d A m y otr o p hic Lateral Scler osis F u ncti o nal Rati n g Scale ; 
A L S A Q- 4 0 =  A m y o tr o p hic Lateral Scler osis Assess me nt Q uesti o n naire , 4 0 q uesti o ns; A T LI S = a cc urate test of li m b is o metric stre n gt h; C GI C = 
C li nical Gl o bal I m pressi o n of C ha n ge; D = da y; E T  = earl y ter mi nati o n or wit h dra wal;  H H D = Ha n d h el d D y na m o metr y ; P GI C = Patie nt Gl o bal 
I m pressi o n of C ha n ge; S V C  = Sl o w Vital Ca pacit y ; 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 d verse 
e ve nts 
1.  I nf or m e d C o nse nt pr ocess  is t o be c o m plete d at Scree ni n g pri or t o c o n d ucti n g a n y st u d y -s pecific pr oce d ures. 
2.  De m o gr a p hics a n d B aseli ne C h ar acteristics  will i nc l u de a ge, ge n der, race, a n d et h nicit y  a n d will be c ollecte d at Scree ni n g . 
3.  Me dic al Hist or y  a n d F a mili al C a ncer Hist or y : A me dical hist or y a n d fa milial ca ncer hist or y will be o btai ne d at Scree ni n g. T he I n vesti gat or will c o nfir m t he 
dia g n osis of A L S usi n g t he re vise d El Esc orial / Airlie H o use dia g n ostic criteria . Partici pa nt s will be c o nfir me d as ha vi n g cli nicall y defi nite A L S, cli nicall y 
pr o ba ble A L S, or cli nicall y pr o ba ble la b orat or y -s u p p orte d A L S ≤4 years . 
4.  Vit al Si g ns , Wei g ht , a n d Hei g ht: Vital si g ns  will be meas ure d at Scree ni n g , pre d ose , a n d 2 h o urs ( ± 1 h o ur) p ost -d ose at St u d y I njecti o n Visits d uri n g t he 
Treat me nt C ycle  1 ( Da ys 0 a n d 1 4), Treat me nt C ycle 2 ( Da ys 6 0 a n d 7 4), a n d Treat me nt C ycle 3 ( Da ys 1 2 0 a n d 1 3 4). Vital si g ns will als o be meas ure d at St u d y 
Visits o n Da ys 3 0 , 8 4 , 1 4 4 , a n d 1 8 0/ E T ( Da y 1 8 0 or Earl y Ter mi nati o n) . After t he Partici pa nt  has reste d i n t he seate d p ositi o n f or 5 mi n utes, vital si g ns will be 
c ollecte d, i ncl u di n g te m perat ur e, sitti n g bl o o d press ure, heart rate, res pirat or y rate, a n d o x y ge n sat urati o n o n r o o m air. T he met h o d of te m perat ure meas ure me nt 
s h o ul d be acc or di n g t o t he Site’s p olic y a n d s h o ul d be c o nsiste ntl y a p plie d . Wei g ht will be c ollecte d at Scree ni n g a n d pre d ose  at St u d y I njecti o n Visit s ( Da ys 0, 1 4, 
6 0, 7 4, 1 2 0, a n d 1 3 4) ; hei g ht will o nl y be meas ure d at Scree ni n g . 
5.  C o m plete P h ysic al E x a m i n ati o n will be perf or me d at Scree ni n g , pre d ose o n Da ys 0, 1 4, 6 0, 7 4, 1 2 0, a n d 1 3 4, a n d at St u d y Visits o n Da ys 3 0, 8 4, 1 4 4, a n d 
1 8 0/ E T. T he e xa mi nati o n will i ncl u de t he f oll o wi n g: hea d, e yes, ears, n ose, a n d t hr oat ( H E E N T); heart; l u n gs; a b d o me n; e xtre mities; l y m p h n o des; ne ur ol o gical; 
m usc ul o s keletal s yste m; a n d s ki n/i nte g u me ntar y s yste ms. A n y a b n or malities s h o ul d be cate g orize d as cli nicall y si g nifica nt ( C S) or n ot cli nicall y si g n ifica nt ( N C S), 
a n d t he a b n or malities  s h o ul d be rec or de d as a d verse e ve nts, e xce pt at Scree ni n g. 
6.  1 2 -Le a d Electr oc ar di o gr a m ( E C G) will be perf or me d at Scree ni n g, Da y 8 4 , a n d Da y 1 8 0/ E T. A n y cli nicall y si g nifica nt fi n di n gs at Scree ni n g will be rec or de d as 
part of t he me dical hist or y. Cli nicall y si g nifica nt a b n or malities are t o be rec or de d as a d verse e ve nts, e xce pt at Scr ee ni n g. T he E C G rec or di n g m ust be  st ore d wit h 
t he Partici pa nt’s rec or ds. 
7.  C o a g ul ati o n Pr ofile  will  be e val uate d at Scree ni n g a n d will  i ncl u de pr ot hr o m bi n ti me ( P T), partial pr ot hr o m bi n ti me ( P T T), a n d I nter nati o nal N or malize d Rati o 
(I N R). 

Heli x mit h C o., Lt d. 
C O N FI D E N TI A L  
Pr ot oc ol: V M A L S- 0 0 2- 2 
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 
Versi o n 3. 0 
2 2 
Fi nal : 2 0 Ja n uar y 2 0 2 1 
8.  Ser u m C he mistr y  a n d  He m at ol o g y: L a b orat or y assess me nts  will  be  e val uate d  at Scree ni n g  (t o esta blis h  eli gi bilit y ) a n d o n Da ys 6 0, 1 2 0, a n d 1 8 0/ E T . 
C he mistr y i ncl u des s o di u m, p otassi u m, c hl ori de, bicar b o nate, calci u m, i n or ga nic p h os p hate, ma g nesi u m, gl uc ose, a m ylase, li pase, creati ne ki nase, lactate 
de h y dr o ge nase, a n d : 
a. 
Ki d ne y f u ncti o n tests ( bl o o d urea nitr o ge n, creati ni ne)  
b.  Li ver f u ncti o n  tests (as partate a mi n otra nsferase [ A S T], ala ni ne a mi n otra nsferase [ A L T], al kali ne p h os p hatase, ga m ma-gl uta m yl tra ns pe pti dase [ G G T], 
t otal bilir u bi n, t otal pr otei n, a n d al b u mi n) 
He m at ol o g y i ncl u des platelet c o u nt, he m o gl o bi n, he mat ocrit, w hite bl o o d cell c o u nt, a n d ne utr o p hil c o u nt 
9.  Bl o o d S a m ple f or F ut ure Ge netic Testi n g : A bl o o d sa m ple will be c ollecte d at pre d ose  o n Da y 0  a n d  st ore d. 
1 0.  Vir al Scree ni n g  is to be c o n d ucte d at Scree ni n g a n d i ncl u des tests f or h u ma n i m m u n o deficie nc y vir us ( HI V), h u ma n T cell l y m p h otr o pic vir us ( H T L V)  I/II 
a nti b o d y wit h refle x c o nfir mat or y assa y , he patitis B vir us ( H B V: I g M H Bc A b, H Bs A b, a n d H Bs A g , a n d a q ua ntitati ve H B V if nee de d cli nicall y), a n d a nti-he patitis 
C vir us ( H C V) a nti b o dies  a n d a p ositi ve q ualitati ve P C R if nee de d cli nicall y . Testi n g will be perf or me d at a l ocal la b orat or y. All tests f or HI V, H T L V, H B V, a n d 
H C V  m ust be c o m plete d a n d ne gati ve pri or t o  ra n d o mizati o n. 
1 1.  Uri ne Pre g n a nc y Test:  Wo me n of c hil d beari n g p ote ntial m ust ha ve a ne gati ve uri ne pre g na nc y test at Scree ni n g, pre d ose  at St u d y I njecti o n Visit o n Da y 0 
a n d Da y 1 8 0/ E T. 
1 2.  Sl o w Vit al C a p acit y ( S V C ) will be meas ure d  at Scree ni n g, pre d ose  o n Da ys 0, 6 0, a n d 1 2 0, a n d at St u d y Visits o n Da ys 3 0,  8 4 , 1 4 4 , a n d 1 8 0/ E T . 
1 3.  C o nc o mit a nt Me dic ati o ns a n d Pr oce d ures: Rec or d all me dicati o ns or vacci nes, i ncl u di n g o ver -t he-c o u nter or prescri pti o n me dici nes, vita mi ns, her bal 
s u p ple me nts, a n d pr oce d ures t hat t he Partici pa nt  was recei vi n g d uri n g t he 3 0 da ys pri or t o c o m pleti o n of t he i nf or me d c o nse nt pr ocess at Scree ni n g, pre d ose  at 
St u d y I njecti o n Visits o n Da ys 0, 1 4, 6 0, 7 4, 1 2 0, a n d 1 3 4, a n d at St u d y Visits o n Da ys 3 0 , 8 4 , 1 4 4 , a n d 1 8 0/ E T. F or eac h me dicati o n, treat me nt, or pr oce d ure, t he 
f oll o wi n g i nf or mati o n will be c ollecte d: Me dicati o n tra de or ge neric na me, t y pe of pr oce d ure, i n dicati o n, start date, st o p date or o n g oi n g, d ose, u nits, fre q ue nc y, a n d 
r o ute. 
1 4.  R a n d o miz ati o n:  C o m pleti o n of Scree ni n g acti vities, ra n d o mizati o n, a n d first St u d y I njecti o ns ( Treat me nt C ycle 1, Da y 0) will occ ur o n t he sa me da y ( Da y 0) . 
1 5.  St u d y I njecti o ns:  I M i njecti o ns of E n ge nsis or Place b o will be  a d mi nistere d d uri n g Treat me nt C ycle 1 ( 1 st a n d 2 n d St u d y I njecti o ns o n Da ys 0 a n d 1 4), Treat me nt 
C yc le 2 ( 3r d a n d 4 t h St u d y I njecti o ns o n Da ys 6 0 a n d 7 4), a n d Treat me nt C ycle 3 ( 5 t h a n d 6 t h St u d y I njecti o ns o n Da ys 1 2 0 a n d 1 3 4) . 
1 6.  Re vise d A m y otr o p hic L ater al Scler osis F u ncti o n al R ati n g Sc ale ( A L S F R S -R) will be perf or me d at t he Cli nical Site at S cree ni n g, pre d ose  o n t he Da ys 0, 6 0, 
a n d 1 2 0, a n d o n Da ys  3 0 , 8 4 , 1 4 4 , a n d 1 8 0/ E T . 
1 7.  H a n d hel d  D y n a m o m etr y ( H H D)  will be meas ure d  at t he Cli nical Site  pre d ose  o n Da y s 0, 6 0, a n d 1 2 0 , a n d at Visits o n Da y s 3 0 , 8 4 , 1 4 4 , a n d 1 8 0/ E T. 
1 8.  A T LI S  will be meas ure d ( o nl y at sites t hat ha ve t he A T LI S e q ui p me nt) pre d ose  o n Da ys 0, 6 0, a n d 1 2 0, a n d at Visits o n Da ys 3 0 , 8 4 , 1 4 4 , a n d 1 8 0/ E T. 
1 9.  A m y otr o p hic L ater al Scler osis Assess m e nt Q uesti o n n air e , 4 0 q uesti o ns ( A L SA Q- 4 0)  will be meas ure d pre d ose  o n Da y 0 a n d at Visits o n  Da ys 8 4  a n d 1 8 0 / E T. 
2 0.  P atie nt Gl o b al I m pressi o n of C h a n ge ( P GI C)  a n d  Cli nic al Gl o b al I m pressi o n of C h a n ge  ( C GIC)  will be c o n d ucte d at Visits o n Da ys 8 4  a n d 1 8 0 / E T. 
2 1.  M uscle Bi o ps y : B i o psies of t he gastroc ne mi us  m uscle ar o u n d t he i njecti o n sites will be c ollecte d a n d st ore d at Da y 0 pre d ose , a n d Da ys 8 4 ( o pti o nal)  a n d 1 4 4 
(a p pr o xi matel y 1 0 da ys after t he sec o n d da y of i njecti o ns of Treat me nt C ycles 2 a n d 3). 

Heli x mit h C o., Lt d. 
C O N FI D E N TI A L  
Pr ot oc ol: V M A L S- 0 0 2- 2 
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 
Versi o n 3. 0 
2 3 
Fi nal : 2 0 Ja n uar y 2 0 2 1 
2 2.  A d verse E ve nts ( A Es) , Tre at m e nt -E m er ge nt A d verse E ve nts ( T E A Es), Seri o us A d ve rse E ve nts ( S A Es)  a n d Tre at m e nt -E m er ge nt Seri o us A d verse E ve nts 
( T E S A Es): A Es w ill be rec or de d after i nf or me d c o nse nt u ntil t he first i njecti o ns o n Da y 0. After t he start of t he 1st I njecti o ns o n Da y 0 t hr o u g h Da y 1 8 0, A Es will 
be rec or de d as treat me nt -e mer ge nt a d verse e ve nts ( T E A Es). Treat me nt -e mer ge nt seri o us a d verse e ve nts  ( T E S A E s) occ urri n g after ra n d o mizati o n a n d t hr o u g h o ut 
t he st u d y will be rec or de d. S A Es occ urri n g after t he c o m pleti o n of t he c o nse nt pr ocess a n d bef ore t he 1st I njecti o ns o n Da y 0 s h o ul d be rec or de d a n d re p orte d as 
S A Es o nl y if ass ociate d wit h a pr ot oc ol -s pecifie d pr oce d ure. All S A Es, a n d T E S A Es occ urri n g after t he ti me of t he 1st I njecti o ns t hr o u g h t he last St u d y Visit o n 
Da y 1 8 0 , s h o ul d be rec or de d a n d re p orte d t o t he S p o ns or/ desi g nee wit hi n 2 4 h o urs of a ware ness of t he S A E/ T E S A E b y t he  Site . 
2 3.  A d verse E ve nts of S peci al I nterest  ( A E SIs): All A E SIs will be c o nti n u o usl y m o nit ore d t hr o u g h o ut t he st u d y.  
2 4.  A E SI:  I njecti o n Site Re acti o ns (I S Rs) m ust be i nitiall y ass esse d i m me diatel y after all i njecti o ns at a n I njecti o n Visit . The I n vesti gat or or desi g nee will f oll o w u p 
wi t h t he Partici pa nt wit hi n 2 t o 3 da ys after St u d y I njecti o ns t o as k t he Partici pa nt a b o ut reacti o ns at a n y i njecti o n sites a n d, if a n y are n ote d, t he w orst reacti o n will 
be rec or de d as a T E A E a n d c o nsi dere d a n A E SI . 

Heli x mit h C o., Lt d. 
C O N FI D E N TI A L  
Pr ot oc ol: V M A L S- 0 0 2- 2 
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 
Versi o n 3. 0 
2 4 
Fi nal : 2 0 Ja n uar y 2 0 2 1 
2.  
I N T R O D U C TI O N 
E n ge nsis is a n o vel ge ne t hera p y bei n g de v el o pe d  f or treat me nt of A L S. T h e acti ve 
p har mace utical i n gre die nt of E n ge nsis is V M 2 0 2 ( d o na per mi n o ge ne s elt o plas mi d), a plas mi d 
de o x yri b o n ucleic aci d ( D N A) desi g ne d as a ge n e tra nsfer met h o d t o si m ulta ne o usl y e x press t w o 
is of or ms of h u ma n he pat oc yte gr o wt h fact or ( H G F), H G F7 2 8 a n d H G F 7 2 3, t hat are i de ntical t o 
wil d -t y pe h u ma n f or ms. 
He pat oc yte gr o wt h fact or is a p ote nt a n gi o ge nic a n d vasc ul o ge nic gr o wt h fact or sti m ulati n g t he 
gr o wt h of e n d ot helial cells a n d mi grati o n of vasc ular s m o ot h m uscle cells. As  a m ultif u ncti o nal 
mese nc h y me - d eri ve d c yt o ki ne, it has p ote nt a n gi o ge nic a n d a nti-a p o pt otic effects, i ncl u di n g t hat 
of t he l y m p hatic s yste m. I n a d diti o n, H G F u pre g ul ates t he e x pressi o n of vas c ular e n d ot helial 
gr o wt h fact or ( V E G F) a n d ot her fact ors a n d de m o nstrate s greater mit o ge ni c acti vit y t ha n t hat of 
V E G F al o ne i n h u ma n a ortic e n d ot helial cells i n vitr o . H G F is als o i m p orta nt i n t he 
pat h o p h ysi ol o g y of i ns uli n resista nce, as a ne ur otr o p hic fact or pr o m oti n g a x o nal gr o wt h a n d 
re ge nerati o n i n dia betics i n w ho m l oss of micr o vasc ulat ure ma y accelerate ne ur o nal l oss, m ore 
s o t ha n e x o ge n o us V E G F (see t he I n v esti gat or’s Br oc h ure [I B] f or m ore d etaile d i nf or mati o n). 
I n t his st u d y E n ge nsis will be a d mi nistere d b y I M i njecti o n, w hic h has disti nct a d va nta g es o ver 
alter nati ve deli ver y m o des of H G F or E n ge nsis.  I ntra ve n o us i nf usi o n is i m pe de d b y ra pi d 
clear a nce of H G F b y t he li ver a n d of E n ge nsis b y D Nases, res ulti n g i n l o w tiss ue le vels.   T he 
V M 2 0 2 plas mi d D N A e x presses H G F i n sit u, all o wi n g l ocal tar gete d d eli ver y. Plas mi d D N A 
als o has a l o were d ris k of ge n o mic i nte grati o n a n d of ge nerati n g i m m u ne res p o nses c o m pare d 
wit h viral deli ver y s yste ms.   I m p orta ntl y, certai n c o m p o ne nts of E n ge nsis, i ncl u di n g its u ni q ue 
plas mi d vect or p C K a n d pr o m oters a n d c o ntr ollers of ge ne tra ns cri pti o n t hat ma ke t he e x pressi o n 
fr o m s keletal m uscle m or e effi cie nt (see t he I B f or f ull descri pti o n), lea d t o e x pressi o n of H G F 
t hat is detecta ble f or u p t o 3 0 da ys after direct s keletal m uscle i njecti o n . 
2. 1.  
St u d y R ati o n ale 
V M A L S - 0 0 2- 2 is a well- c o ntr olle d st u d y t o e val u ate t he safet y of I M a d mi nistrati o n of E n ge nsis 
t o Partici pa nt s wit h A L S , as c o m par e d wit h Place b o . Partici pa nt s ra n d o ml y assi g ne d t o E n ge nsis 
will recei ve a t otal d ose of 1 9 2 m g V M 2 0 2 di vi de d i nt o 3 Treat me nt C ycle s of 6 4 m g V M 2 0 2 
eac h. A d osi n g sc h e d ule de vel o pe d fr o m t hose use d i n t he P hase 1/ 2 A L S st u d y a n d i n t hree 
dia betic peri p heral ne ur o pat h y ( D P N ) st u dies will be use d i n t his st u d y. T he  I M i njecti o ns t o 
eac h tar get m uscle gr o u p will be di vi de d i nt o t hree  I njecti o n Visits (e q ual hal ves), t w o wee ks 
a part o n Da ys 0 a n d 1 4, wit h retreat me nts at D a y s 6 0 a n d 7 4, a n d Da ys 1 2 0 a n d 1 3 4. E n ge nsis 
will be del i vere d i n a s ol uti o n of 0. 5 m g V M 2 0 2/ m L. See Secti o n 4. 3  f or detaile d i nf or mati o n 
s u p p orti n g t he selecti o n of d oses a n d d osi n g re gi me n f or t his st u d y. 
Res ults  fr o m a Phase 1/ 2 A L S st u d y s u g gest t hat tar gete d d eli ver y of H G F t o m ot or ne ur o ns via 
i ntra m usc ular i njecti o ns of E n ge nsis was  safe a n d well t olerate d, bas e d o n data fr o m 1 8 e nr olle d 
Partici pa nts w h o wer e f oll o we d t hr o u g h 9 0 da ys after t he first i njecti o n. 1 F oll o wi n g i njecti o ns 
u ntil Da y 9 0, a platea u or a relati ve sl o wi n g i n decli ne of t he A L S F R S- R sc ores a n d m uscle 
stre n gt h was n ote d, s u g g esti n g a sl o wi n g of disease pr o gressi o n. Aft er 9 0 da ys, t he platea u w as 
n o l o n ger o bser v e d i n t he A L S F R S- R, wit h t he n ota ble e xce pti o n of a tre n d t o war d better 

Heli x mit h C o., Lt d. 
C O N FI D E N TI A L  
Pr ot oc ol: V M A L S- 0 0 2- 2 
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 
Versi o n 3. 0 
2 7 
Fi nal : 2 0 Ja n uar y 2 0 2 1 
t he u pre g ulati o n of cas pases c o ul d p ote ntiall y i m pr o ve s ur vi val a n d q u alit y of Life ( Q o L) of 
A L S patie nts.  
2. 2. 2.  
C urre nt Tre at m e nt O pti o ns , Tre at me nt A p pr o ac hes,  a n d U n met Cli nic al Nee d  
Ril ute k ( ori gi nall y ma n ufact ure d b y Sa n ofi A ve ntis a n d a p pr o ve d as a n or p ha n dr u g o n 
Dece m b er 1 2, 1 9 9 5 [ N D A 0 2 0 5 9 9]) is n o w a v aila ble i n ge neric f or m as ril uz ole. T he  be n efit of 
ril uz ole lies i n e xte n di n g earl y s ur vi val a n d/ or ti me t o trac he ost o m y, b ut wit h o ut statisticall y 
si g nifica nt differ e nce i n m uscle stre n gt h or ne ur ol o gical f u ncti o n. 3 1  
E dara v o n e was a p pr o ve d b y t he F o o d a n d Dr u g A d mi nistrati o n ( F D A ) o n Ma y 5, 2 0 1 7 f or 
patie nts wit h A L S . T he  dr u g is a d mi nistere d b y I V i nf usi o n a n d belie ve d t o re d uce o xi d ati ve 
stress. E dara v o n e was a p pr o ve d base d o n t h e res ults of a P hase  3 cli nical tri al i n Ja pa n a n d S o ut h 
K orea i n w hic h 1 3 7 A L S patie nts were gi v e n eit her e dara v o ne or p l ace b o. T he gr o u p gi ve n 
e dara v o n e e x p erie n ce d a 3 3 % re d ucti o n i n t he decli ne of t heir p h ysical a bilities c o m pare d wit h  
t he p lace b o gr o u p. Statistical si g nifica nce was o nl y reac h e d i n Partici pa nts dia g n ose d less t ha n 
t w o years earlier a n d wit h ra pi d pr o gressi o n of s y m pt o ms, h o we v er; 2 ot her P hase  3 st u dies 
faile d t o s h o w a n y cli nical be nefit of e dara v o ne, a n d s ur vi val was n ot de m o nstrate d t o be 
pr ol o n ge d wit h its use.  Neit her r il uz ole n or e dara v o ne pre ve nt or c orrect t h e u n derl yi n g ca us es of 
A L S . Clearl y, a t her a p y t hat c o ul d i m pe de or re verse ne ur o d e ge nerati o n is nee de d f or patie nts 
wit h A L S . E n ge nsis pr o d uces H G F, w hic h  acts as a ne ur otr o p hic fact or t hat ai ds i n t he 
de vel o p me nt a n d r e ge ner ati o n of peri p heral ner v es ; it acti vate d Sc h wa n n  cells t o bec o me 
re pair-t y p e cells a n d en h a nce d t he re m yeli nati o n pr ocess, c o ns e q ue ntl y lea di n g t o t he pr o per 
re ge nerati o n of i nj ure d p eri p her al ner ves  i n a ni mal m o dels (see t he I B f or m ore i nf or mati o n). 
Treat me nt a p pr oac h es base d o n a nat o mic deli ver y strate gies ha ve als o bee n pr o p ose d f or 
treatme nt of A L S or ot her ne ur o de g e nerati ve diseases.
3 2 ,3 3 F or e x a m ple, base d o n o bser vati o ns 
of retr o gr a de n e ural tr a ns p ort of bi ot hera pe utics f oll o wi n g I M i njecti o n i n a ni mal m o dels, a 
deli ver y a p pr o ac h of I M i njecti o ns of ste m cells has bee n a p plie d i n cli nical trials of vari o us 
a d ult ste m cells p o p ulati o ns, all wit h a li mite d n u m ber of i njecti o ns a n d fe w m uscle 
tar gets.3 4 ,3 5 ,3 6 A m uc h br oa der a nat o mic deli ver y strate g y is bei n g use d i n t he prese nt st u d y. 
2. 2. 3.  
He p at oc yte Gr o wt h F act or f or Tre at me nt of A m y otr o p hic L ater al Scler osis  
He pat oc yte gr o wt h fact or ( H G F) is a m ulti -f u ncti o nal mese nc h y me- deri ve d c yt o ki ne. It is a 
rec o g nize d p ote nt a n gi o g e nic gr o wt h fact or a n d a nti-a p o pt osis a ge nt, sti m ulati n g t he gr o wt h of 
e n d ot helial cells  a n d t he mi grati o n of vasc ular s m o ot h m uscle cells.3 7 ,3 8 ,3 9 ,4 0 H G F sti m ulates 
D N A, R N A , a n d pr otei n s y nt hesis b y e n d ot helial cells i n a d ose- de p e n de nt ma n ner, u pre g ulates 
V E G F e x pressi o n, a n d e x hi bits  greater mit o ge nic acti vit y t ha n t hat of V E G F al o ne i n h u ma n 
a ortic e n d ot helial cells i n vitr o.4 1 ,4 2 ,4 3 
Alt h o u g h lar gel y t h o u g ht of as a n a n gi o g e nic a g e nt, H G F has b ee n rece ntl y i de ntifie d as a 
ne ur otr o p hic f act or. 4 4 ,4 5 ,4 6 ,4 7 ,4 8 ,4 9 ,5 0   H G F  a n d its c o g n ate rece pt or (t he c-M et rece pt or ) are 
e x presse d i n t he p eri p her al ner v o us s yste m as w ell as i n vari o us re gi o ns of t he brai n a n d s pi nal 
c or d. S u n et al. ( 2 0 0 2) f o u n d t hat l ocal s ustai ne d H G F pr o d u cti o n i n ne ural tiss ue i n S O DG 9 3 A  
mice  (tra ns ge ni c A L S m o del) alle viated t he s y m pt o ms of A L S b y direct ne ur otr o p hic acti vities 
o n m ot o r ne ur o ns a n d i n direct acti vities o n glial cells. 4 7 T he y f o u n d t hat H G F was 
ne ur o pr otecti ve. S O D mice tra nsf ecte d wit h a si n gle c o p y of t he H G F g e ne ( G 9 3 A/ H G F) 

Heli x mit h C o., Lt d. 
C O N FI D E N TI A L  
Pr ot oc ol: V M A L S- 0 0 2- 2 
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 
Versi o n 3. 0 
2 8 
Fi nal : 2 0 Ja n uar y 2 0 2 1 
retai ne d a si g nifica ntl y lar ger n u m ber of s pi nal m ot o r ne ur o ns wit h a healt hier m or p h ol o g y t ha n 
S O D mice wit h o ut t he H G F ge n e ( G 9 3 A si n gle tra ns ge nic). 
G 9 3 A/ H G F mice als o e x perie nce d i m pr o ve d m ot or perf or ma nce, si g nifica ntl y dela ye d o nset i n 
paral ysis , a n d s ur vi ve d l o n ger t ha n G 9 3 A mice. Researc hers als o f o u n d i n direct e vi de n ce t hat 
H G F s u p pr esses micr o gli osis a n d astr oc yt osis, b ot h of w hic h c o ntri b ute t o m ot or ne ur o n 
de ge ner ati o n b y pr o d uci n g c yt ot o xic c yt o ki nes a n d e ve nt ual glial scar f or m ati o n .5 1 ,5 2 
It has b ee n d e m o nstrate d t hat H G F ca n pr o m ote ne ur o ge nesis, a n gi o ge n esis, a n d s y na pt o ge nesis 
a n d t hat it ca n i n hi bit fi br otic c ha n ges i n isc he mic re gi o ns better t ha n glial cell li ne -deri ve d  
ne ur otr o p hic f act or ( G D N F). 5 3 
H G F ma y als o ha ve pr ot ecti ve effects  a gai nst e xcit ot o xic i nj uries , beca use it has bee n s h o w n t o 
atte n uate a x o n al de ge n er ati o n b y re d uci n g e x cit ot o xicit y t hr o u g h m o d ulati o n of t he e x pressi o n 
of t he scaff ol di n g pr otei n of t he N- met h yl- D- as partate (N M D A ) rece pt or at t he s y na pse.5 4 ,5 5 
Fi nall y, H G F m a y sta ve off cell deat h a n d halt t he casca d e of n ei g h b ori n g cell da ma ge b y 
i n hi biti n g cas pase si g nali n g directl y i n m ot or ne ur o ns a n d i n directl y b y its effects o n 
astr oc ytes. 5 6 I n A L S patie nts, c hr o nic, s u blet hal acti vati o n of cas pas e a p pears t o me diate cell 
d ysf u ncti o n, w hic h prece des cell deat h .5 7 ,5 8 Cell d ysf u ncti o n of s u bsta ntial ma g nit u de, occ urri n g 
bef ore cell deat h, mi g ht res ult i n s y m pt o matic disease . Gi ve n t hat cas pases ma y be acti ve i n 
i n di vi d ual ne ur o ns f or a l o n g peri o d ( p ote ntiall y w ee ks t o m o nt hs), i n hi biti o n of cas pas e i n t hese 
circ u msta nces c o ul d re d u ce cell d ysf u ncti o n a n d d ela y cell deat h. 5 4 T heref ore, t he ne ur otr o p hic 
acti o n of H G F o n m ot o r ne ur o ns is, at least i n part, pr o m ote d b y pre ve nti n g cas p ase -me diate d 
cell deat h si g nals.  
H G F o vere x pr essi o n als o atte n uates m o n oc yte c he m oattracta nt pr otei n -1 ( M C P - 1) i n d ucti o n i n 
astr oc ytes, w hic h res ults i n a re d ucti o n i n micr o glial acc u m ulati o n, a h all mar k i nfla m mat or y 
pr ocess i n A L S. 5 9  
T he c halle n g e ass ociat e d wit h deli veri n g a tar g ete d s ustai ne d d ose of e x o g e n o us H G F is i n 
o verc o mi n g t he i nsta bilit y of H G F i n bl o o d circ ul ati o n a n d its ra pi d cleara nce b y t he li ver; H G F 
has a n i n vi v o half -life of less t ha n 1 5 mi n utes.6 0 ,6 1 
O ne a p pr o ac h t o i ncr easi n g H G F a v aila ble t o ne ur o ns is t o de vel o p a ge ne tra nsfer strate g y t hat 
w o ul d all o w f or persiste nt e x pressi o n of H G F pr ot ei n i n vi v o. Alt h o u g h plas mi d D N A is o ne of 
t he least effi cie nt ge ne tr a nsfer s yste ms c urre ntl y i n use, t he fact t hat it is ass ociate d wit h li mite d 
persiste nce a n d n o pr o pe nsit y f or ge n o mic i nte grati o n ( partic ularl y i n s ke letal m uscle tiss ue) 
ma kes it a n attracti ve o pti o n f or l ocal tar g ete d deli ver y . 
2. 2. 4.  
E n ge nsis  a n d V M 2 0 2 
T he i n vesti gati o nal a ge nt (st u d y dr u g) bei n g st u die d i n t his pr ot oc ol is E n ge nsis, w hic h c o ntai ns 
t he acti ve p har mace utical i n gre die nt V M 2 0 2. V M 2 0 2 is a plas mi d D N A t hat c o ntai ns t he n o vel 
ge n o mic c o m ple me ntar y D N A  (c D N A) h y bri d h u ma n H G F c o di n g se q ue n ce ( H G F-X 7) 
e x pressi n g t w o is of or ms of H G F, H G F 7 2 8 a n d H G F 7 2 3 (Fi g ure 2 ). 

Heli x mit h C o., Lt d. 
C O N FI D E N TI A L  
Pr ot oc ol: V M A L S- 0 0 2- 2 
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 
Versi o n 3. 0 
3 4 
Fi nal : 2 0 Ja n uar y 2 0 2 1 
O bjecti ves  
E n d p oi nts  
•  T o e val uate Q u alit y of L ife i m pr o ve me nt 
f oll o wi n g E n ge nsis i njecti o ns i n A L S 
Partici pa nts c o m pare d t o Place b o  
•  C ha n ge fr o m Baseli ne ( Da y 0) i n Q ualit y 
of Life ( Q o L) usi n g t he A L S Assess me nt 
Q uesti o n naire ( A L S A Q; wit h 4 0 ite ms, 
A L S A Q - 4 0) o n D a ys 8 4 a n d 1 8 0 f or 
E n ge nsis c o m pare d t o Pl ace b o  
•  T o e val uate Patie nt a n d Cli nical Re p orte d 
O utc o me i m pr o ve me nt f oll o wi n g 
E n ge nsis i njecti o ns i n A L S Partici pa nts 
c o m pare d t o Place b o  
•  Patie nt Gl o bal I m pressi o n of C ha n ge 
( P GI C) a n d Cli nical Gl o bal I m pressi o n of 
C ha n ge ( C GI C) at D a ys  8 4 a n d 1 8 0 f or 
E n ge nsis c o m pare d t o Pl ace b o 
•  T o deter mi ne w h et her I M a d mi nistrati o n 
of E n ge nsis has effects o n res pirat or y 
f u ncti o n i n A L S Partici pa nts c o m pare d t o 
Place b o  
•  C ha n ge fr o m Baseli ne ( Da y 0) i n Sl o w 
Vital Ca pacit y ( S V C) o n Da ys 3 0, 6 0, 8 4, 
1 2 0, 1 4 4, a n d 1 8 0 f or E n ge nsis c o m pare d 
t o Place b o 
•  Ti me t o trac he ost o m y f or E n ge nsis 
c o m pare d t o Place b o  
•  T o deter mi ne w h et her I M a d mi nistrati o n 
of E n ge nsis has p ositi ve effects o n 
s ur vi val i n A L S Partici pa nts c o m pare d t o 
Place b o  
•  Ti me t o all -ca use m ortalit y  b y Da y 1 8 0 
f or E n ge nsis c o m pare d t o Place b o 
•  T o deter mi ne w h et her I M a d mi nistrati o n 
of E n ge nsis has p ositi ve effects o n m uscle 
atr o p h y i n A L S Partici pa nts c o m pare d t o 
Place b o  
•  C ha n ge fr o m Baseli ne ( Da y 0) i n 
bi o mar kers f or m uscle atr o p h y i n bi o psies 
c ollecte d bef ore a n d aft er i njecti o n s f or 
E n ge nsis c o m pare d t o Pl ace b o 

Heli x mit h C o., Lt d. 
C O N FI D E N TI A L  
Pr ot oc ol: V M A L S- 0 0 2- 2 
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 
Versi o n 3. 0 
3 5 
Fi nal : 2 0 Ja n uar y 2 0 2 1 
4.  
S T U D Y D E SI G N  
4. 1.  
O ver all  Desi g n  
V M A L S - 0 0 2- 2 is a P has e 2a, d o u ble- bli n d, ra n d o mize d, place b o -c o ntr olle d, m ultice nter  st u d y 
desi g ne d t o assess t he saf et y of I M a d mi nistrati o n of E n ge nsis i n Partici pa nt s wit h A L S  as 
c o m pare d t o Place b o . St u d y Partici pa nt s will be ra n d o mize d i n a 2: 1 rati o t o E n ge nsis or Place b o 
(c o ntr ol gr o u p). T h e st u d y will i ncl u de o nl y patie nts wit h li m b o nset of A L S. 
Scree ni n g.  Scree ni n g acti vities ( see S o A, Secti o n 1. 3 ) i ncl u de assess me nt s t o deter mi ne st u d y 
eli gi bilit y, assess me nts t o esta blis h Baseli ne  res ults f or use i n a nal ysis of e n d p oi nts, a n d Baseli ne  
safet y assess me nts. All S cree ni n g  acti vities will  occ ur wit hi n t he 3 0 da ys pri or t o Da y 0. 
R a n d o miz ati o n. Partici pa nt s w h o meet t he eli gi bilit y criteria will be ra n d o ml y assi g ne d i n a 2 : 1 
rati o t o o ne of t he t w o treat me nt ar ms, E n ge nsis or Place b o . Ra n d o mize d treat me nt assi g n me nt 
will occ ur t hr o u g h t he E DC ra n d o mizati o n m o d ule i n a d o u ble- bli n de d fas hi o n. Bli n di n g will be 
ac hie ve d b y h a vi n g t he st u d y me dicati o n ( E n ge nsis a n d Place b o ) pre pare d b y t he u n bli n de d 
P har macist  or dele g ate d staff . 
Tre at me nt Peri o d.  Partici pa nts will u n der g o t hree Treat me nt C ycles of St u d y I njecti o ns 
( En ge nsis or Place b o) at 6 0 - da y i nter vals ( o n Da ys 0 a n d 1 4, Da ys 6 0 a n d 7 4, a n d Da ys 1 2 0 a n d 
1 3 4), wit h f oll o w- u p Visit s at Da ys 3 0, 8 4, 1 4 4, a n d 1 8 0/ E T. 
4. 1. 1.  
E n ge nsis a n d Pl ace b o Tre at me nt C ycles  
E n ge nsis is deli vere d i n 0. 5 m L I M i njecti o ns of a s ol uti o n of 0. 5 m g/ m L V M 2 0 2. Eli gi ble 
Partici pa nts will recei ve 3 Treat me nt C ycles  of eit her E n ge nsis or Place b o at 6 0- da y i nter v als. 
D uri n g eac h  Treat me nt C ycle , E n ge nsis ( 6 4 m g) will be a d mi nister e d o ver t he c o urse of t w o 
d osi n g Visit s: Da ys 0 a n d 1 4, Da ys 6 0 a n d 7 4, a n d Da ys 1 2 0 a n d 1 3 4, as prese nte d i n det ail i n 
Ta ble  1, Ta ble  2, a n d Ta ble  3 f or t he First, Sec o n d, a n d T hir d Treat me nt C ycles, res pecti vel y. 
All Partici pa nt s will recei ve 2 5 6 i njecti o ns of E n ge nsis I M p er Treat me nt C ycle ( 1 2 8 i njecti o ns 
o n eac h d osi n g da y) as a di vi de d d ose i n t he u p per e xtre mit ies (a b d uct or p ollicis bre vis, first 
d orsal i nter osse o us, bice ps, delt oi d, e xte ns or car pi ra dialis, fle x or car pi ul n aris, a n d fle x or car pi 
ra dialis) a n d l o wer e xtr e mities ( q ua drice ps, gastr oc ne mi us, a n d ti bialis a nteri or). E ac h i njecti o n 
c o ntai ns 0. 2 5 m g/ 0. 5 m L V M 2 0 2 or 0. 5 m L of Place b o . Partici pa nts ra n d o ml y assi g ne d t o 
E n ge nsis will recei ve a t otal d ose of 1 9 2 m g of E n ge nsis ( 3 c ycles at 6 4 m g eac h) d uri n g t he 
st u d y. 
I m me diat el y bef or e t he first da y of i njecti o ns of t h e First, Sec o n d, a n d Thir d Treat me nt C ycles  
( Da ys 0, 6 0, a n d 1 2 0, res pecti vel y) assess me nts  will be c o n d ucte d i n t he f oll o wi n g or der: 
1.  
Rec or di n g of T E A Es  
2.  
Rec or di n g of c o n c o mita nt me dicati o ns/ pr oce d ures 
3.  
V ital si g ns a n d wei g ht 
4.  
A L S F R S - R 
5.  
H H D  

Heli x mit h C o., Lt d. 
C O N FI D E N TI A L  
Pr ot oc ol: V M A L S- 0 0 2- 2 
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 
Versi o n 3. 0 
3 6 
Fi nal : 2 0 Ja n uar y 2 0 2 1 
6.  
A T LI S  
7.  
Pre g na nc y test ( Da y 0 o nl y) 
8.  
C o m plete p h ysical e xa mi nati o n  
9.  
S V C ( pre d ose Da y 0, 6 0, a n d 1 2 0) 
1 0.  A L S A Q - 4 0 ( pr e d ose o n Da y 0) 
1 1.  Bl o o d dra w f or ser u m c h e mistr y, a n d he mat ol o g y ( pre d ose o n Da ys 6 0 a n d 1 2 0) 
1 2.  M uscle bi o ps y ( pre d ose o n Da y 0) 
A s u m mar y of t he sc h e d ule of e val uati o ns a n d Visit s d uri n g t he st u d y ca n be f o u n d i n t he S o A . 
4. 1. 1. 1.  
Tre at m e nt C ycle 1 
Partici pa nts will recei ve E n ge nsis or P lace b o b y I M i njecti o ns t o t he ri g ht a n d left si des of t he 
s pecifie d m uscles o n D a ys 0 a n d 1 4 as s h o w n i n Ta ble  1. 
T a ble 1: 
I njecti o n a n d D osi n g Sc he d ule: Tre at me nt C ycl e 1: D a ys 0 a n d 1 4 
A n at o mic T ar get Are a  
N u m ber  of I njecti o ns ( E n ge nsis or Pl ace b o)  a n d D ose  
per  Tre at m e nt C ycle  
Tre at m e nt C ycle  1: D a y 0 
Tre at m e nt C ycle  1: D a y 1 4 
T ot al per 
Tre at m e nt 
C ycle  
Ri g ht  
Left  
Ri g ht  
Left  
 
N u m ber of I njecti o ns ( E n ge nsis or Pl ace b o)  
1 i njecti o n = 0. 5 m L  
H a n d s 
 
A b d uct or p ollicis bre vis  
2 i njecti o ns  
2 i njecti o ns  
2 i njecti o ns  
2 i njecti o ns  
8 i njecti o ns  
First d orsal i nter osse o us  
2 i njecti o ns 
2 i njecti o ns  
2 i njecti o ns  
2 i njecti o ns  
8 i njecti o ns  
U p per Ar ms  
 
Bice ps  
8 i njecti o ns  
8 i njecti o ns  
8 i njecti o ns  
8 i njecti o ns  
3 2  i njecti o ns 
Delt oi d  
8 i njecti o ns  
8 i njecti o ns  
8 i njecti o ns  
8 i njecti o ns  
3 2  i njecti o ns 
L o wer Ar ms  
 
E xte ns or car pi ra dialis 
2 i njecti o ns  
2 i njecti o ns  
2 i njecti o ns  
2 i njecti o ns  
8 i njecti o ns  
Fle x or car pi ul naris  
2 i njecti o ns  
2 i njecti o ns  
2 i njecti o ns  
2 i njecti o ns  
8 i njecti o ns  
Fle x or car pi ra dialis  
2 i njecti o ns  
2 i njecti o ns  
2 i njecti o ns  
2 i njecti o ns  
8 i njecti o ns 
Le gs  
 
Q ua drice ps  
2 0 i njecti o ns  
2 0 i njecti o ns  
2 0 i njecti o ns  
2 0 i njecti o ns  
8 0 i njecti o ns  
Gastr oc ne mi us  
1 2 i njecti o ns  
1 2 i njecti o ns  
1 2 i njecti o ns  
1 2 i njecti o ns  
4 8 i njecti o ns  
Ti bialis a nteri or  
6 i njecti o ns  
6 i njecti o ns  
6 i njecti o ns  
6 i njecti o ns 
2 4 i njecti o ns  
T ot al N u m ber of 
E n ge nsis or Pl ace b o 
I njecti o ns 
6 4 i njecti o ns  
6 4 i njecti o ns  
6 4  i njecti o ns 
6 4  i njecti o ns 
2 5 6  i njecti o ns 
E n ge nsis  D ose per 
Tre at m e nt D a y / C ycle 
3 2 m g  
3 2 m g  
6 4 m g  

Heli x mit h C o., Lt d. 
C O N FI D E N TI A L  
Pr ot oc ol: V M A L S- 0 0 2- 2 
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 
Versi o n 3. 0 
3 7 
Fi nal : 2 0 Ja n uar y 2 0 2 1 
4. 1. 1. 2.  
Tre at m e nt C ycle  2 
Partici pa nts will recei ve E n ge nsis or Place b o b y I M i njecti o ns t o t he ri g ht a n d left si des of t he 
s pecifie d m uscles o n D a ys 6 0 a n d 7 4 as s h o w n i n Ta ble  2. 
T a ble 2: 
I njecti o n a n d D osi n g Sc he d ule: Tre at me nt C ycl e 2: D a ys 6 0 a n d 7 4 
A n at o mic T ar get Are a  
N u m ber  of I njecti o ns ( E n ge nsis or Pl ace b o) a n d D ose  
per  Tre at m e nt C ycle  
Tre at m e nt C ycle  2: D a y 6 0 
Tre at m e nt C ycle  2: D a y 7 4 
T ot al per 
Tre at m e nt 
C ycle  
Ri g ht  
Left  
Ri g ht  
Left  
 
N u m ber of I njecti o ns ( E n ge nsis or Pl ace b o)  
1 i njecti o n = 0. 5 m L  
H a n d s 
 
A b d uct or p ollicis bre vis  
2 i njecti o ns  
2 i njecti o ns  
2 i njecti o ns  
2 i njecti o ns  
8 i njecti o ns  
First d orsal i nter osse o us  
2 i njecti o ns 
2 i njecti o ns  
2 i njecti o ns  
2 i njecti o ns  
8 i njecti o ns  
U p per Ar ms  
 
Bice ps  
8 i njecti o ns  
8 i njecti o ns  
8 i njecti o ns  
8 i njecti o ns  
3 2 i njecti o ns  
Delt oi d  
8 i njecti o ns  
8 i njecti o ns  
8 i njecti o ns  
8 i njecti o ns  
3 2 i njecti o ns  
L o wer Ar ms  
 
E xte ns or car pi ra dialis 
2 i njecti o ns  
2 i njecti o ns  
2 i njecti o ns  
2 i njecti o ns  
8 i njecti o ns  
Fle x or car pi ul naris  
2 i njecti o ns  
2 i njecti o ns  
2 i njecti o ns  
2 i njecti o ns  
8 i njecti o ns  
Fle x or car pi ra dialis  
2 i njecti o ns  
2 i njecti o ns  
2 i njecti o ns  
2 i njecti o ns  
8 i njecti o ns 
Le gs  
 
Q ua drice ps  
2 0 i njecti o ns  
2 0 i njecti o ns  
2 0 i njecti o ns  
2 0 i njecti o ns  
8 0 i njecti o ns  
Gastr oc ne mi us  
1 2 i njecti o ns  
1 2 i njecti o ns  
1 2 i njecti o ns  
1 2 i njecti o ns  
4 8 i njecti o ns  
Ti bialis a nteri or  
6 i njecti o ns  
6 i njecti o ns  
6 i njecti o ns  
6 i njecti o ns 
2 4 i njecti o ns  
T ot al N u m ber of 
E n ge nsis or Pl ace b o 
I njecti o ns 
6 4 i njecti o ns  
6 4 i njecti o ns  
6 4  i njecti o ns 
6 4  i njecti o ns 
2 5 6  i njecti o ns 
E n ge nsis D ose per 
Tre at m e nt D a y / C ycle 
3 2 m g  
3 2 m g  
6 4 m g  
 
4. 1. 1. 3.  
Tre at m e nt C ycle  3 
Partici pa nts will recei ve E n ge nsis or Place b o b y I M i njecti o ns t o t he ri g ht a n d left si des of t he 
s pecifie d m uscles o n D a ys 1 2 0 a n d 1 3 4 as s h o w n i n Ta ble  3. 

Heli x mit h C o., Lt d. 
C O N FI D E N TI A L  
Pr ot oc ol: V M A L S- 0 0 2- 2 
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 
Versi o n 3. 0 
3 8 
Fi nal : 2 0 Ja n uar y 2 0 2 1 
T a ble 3: 
I njecti o n a n d D osi n g Sc he d ule: Tre at me nt C ycl e 3: D a ys 1 2 0 a n d 1 3 4 
A n at o mic T ar get Are a  
N u m ber  of I njecti o ns ( E n ge nsis or Pl ace b o) a n d D ose  
per  Tre at m e nt C ycle  
Tre at m e nt C ycle  3: D a y 1 2 0 
Tre at m e nt C ycle  3: D a y 1 3 4  
T ot al per 
Tre at m e nt 
C ycle  
Ri g ht  
Left  
Ri g ht  
Left  
 
N u m ber of I njecti o ns ( E n ge nsis or Pl ace b o)  
1 i njecti o n = 0. 5 m L  
H a n d s 
 
A b d uct or p ollicis bre vis  
2 i njecti o ns  
2 i njecti o ns  
2 i njecti o ns  
2 i njecti o ns  
8 i njecti o ns  
First d orsal i nter osse o us 
2 i njecti o ns  
2 i njecti o ns  
2 i njecti o ns  
2 i njecti o ns  
8 i njecti o ns  
U p per Ar ms  
 
Bice ps  
8 i njecti o ns  
8 i njecti o ns  
8 i njecti o ns  
8 i njecti o ns  
3 2 i njecti o ns  
Delt oi d  
8 i njecti o ns  
8 i njecti o ns  
8 i njecti o ns  
8 i njecti o ns  
3 2 i njecti o ns  
L o wer Ar ms  
 
E xte ns or car pi ra dialis  
2 i njecti o ns  
2 i njecti o ns  
2 i njecti o ns  
2 i njecti o ns  
8 i njecti o ns  
Fle x or car pi ul naris  
2 i njecti o ns  
2 i njecti o ns  
2 i njecti o ns  
2 i njecti o ns  
8 i njecti o ns  
Fle x or car pi ra dialis  
2 i njecti o ns  
2 i njecti o ns  
2 i njecti o ns  
2 i njecti o ns 
8 i njecti o ns  
Le gs  
 
Q ua drice ps  
2 0 i njecti o ns  
2 0 i njecti o ns  
2 0 i njecti o ns  
2 0 i njecti o ns  
8 0 i njecti o ns  
Gastr oc ne mi us  
1 2 i njecti o ns  
1 2 i njecti o ns  
1 2 i njecti o ns  
1 2 i njecti o ns  
4 8 i njecti o ns  
Ti bialis a nteri or  
6 i njecti o ns  
6 i njecti o ns  
6 i njecti o ns 
6 i njecti o ns  
2 4 i njecti o ns  
T ot al N u m ber of 
E n ge nsis or Pl ace b o 
I njecti o ns 
6 4 i njecti o ns  
6 4 i njecti o ns  
6 4  i njecti o ns 
6 4  i njecti o ns 
2 5 6  i njecti o ns 
E n ge nsis D ose per 
Tre at m e nt D a y/ C ycle  
3 2 m g  
3 2 m g  
6 4 m g  
4. 2.  
Scie ntific R ati o n ale f or St u d y Desi g n  
V M A L S - 0 0 2- 2 is desi g n e d as a w ell-c o ntr olle d P hase 2a st u d y i n A L S Partici pa nts, as it is a 
d o u ble- bli n d, ra n d o mize d, place b o- c o ntr olle d, a n d m ultice nter st u d y t hat is s ufficie ntl y size d i n 
n u m bers of Partici pa nts t o e val uate t he s afet y  of E n ge nsis i n Partici pa nt s wit h A L S.  
4. 3.  
P artici p a nt I n p ut i nt o Desi g n  
Partici pa nt i n p ut i nt o t he  desi g n of t his st u d y was c ollecte d via patie nt i nter vie ws. Pri or t o 
fi nalizati o n of t his pr ot oc ol, A L S patie nts re vie we d a n d pr o vi de d direct i n p ut t o t he desi g n of t he 
cli nical trial fr o m a p atie nt’s pers pecti ve. I n p ut i ncl u de d ra n d o mizati o n rati o, i njecti o n 
met h o d ol o g y, a n d or der of assess me nts d uri n g visits. L o gistical i n p ut was als o recei ve d a n d 
i m ple me nte d t o acc o m m o date f or p ote ntial i nc o n ve nie nce a n d disc omf ort f or  Partici pa nts . 

Heli x mit h C o., Lt d. 
C O N FI D E N TI A L  
Pr ot oc ol: V M A L S- 0 0 2- 2 
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 
Versi o n 3. 0 
3 9 
Fi nal : 2 0 Ja n uar y 2 0 2 1 
4. 4.  
J ustific ati o n f or D ose 
P har mac o ki netic st u dies i n a ni mals a n d h u ma ns b ot h i n dicate t hat V M 2 0 2 ( E n ge nsis) has ver y 
li mite d s yste mic distri b uti o n. T he plas mi d D N A pr o d uct is ta ke n u p i nt o m uscle cells wit hi n a 
ra di us of a b o ut 1 c m of eac h I M i njecti o n site. O nl y a s mall fracti o n of V M 2 0 2 D N A is 
detecta ble i n t he s yste mi c circ ulati o n f oll o wi n g I M i njecti o n. V M 2 0 2’s s h ort circ ulat or y h alf is 
2 t o 5 mi n utes c o nse q ue nt t o ra pi d cleara nce b y circ ulati n g D Nases a n d ra pi d u pta ke b y t he li ver 
(ref ere n ce I n v esti gat or’s Br oc h ure). T h e e x pressi o n of h u ma n H G F after i ntracell ular V M 2 0 2 
u pta ke c o nti n ues f or a b o ut 2 t o 3 wee ks f oll o wi n g i njecti o n (i bi d.). As H G F pr otei n ca n bi n d t o 
he para n s ulf ate, w hic h is a b u n da nt i n t he e xtracell ular matri x ( E C M), l o n ger- ter m rete nti o n of 
H G F pr ot ei n res ults fr o m e ntra p me nt wit hi n t he E C M. M ost H G F release d i nt o circ ulati o n, 
i ncl u di n g fr o m t he E C M, is q uic kl y de gra de d. T h e re peat e d i njecti o n of E n ge nsis i n st u d y 
V M A L S - 0 0 2- 2, wit h 6 tr eat me nt da ys o ver 1 9 wee ks, is t h us e x pecte d t o pr o vi de e n ha n ce d H G F 
e x pressi o n f or a p pr o xi matel y 5 t o 6 m o nt hs. 
I n a d diti o n, t he fa v or a ble safet y pr ofile of E n ge nsis fr o m 1 0 cli nical st u dies wit h o ver 5 0 0 t otal 
Partici pa nts w h o ha ve r ecei ve d t he dr u g i n dicates t hat t he mi ni mal safet y ris k of 3 c ycles of 
treat me nt wit h E n ge nsis o ver a 1 9-wee k p eri o d is j ustifie d f or Partici pa nts wit h a life -t hreate ni n g 
ill ness w h o ma y recei v e a p ote ntial be nefit fr o m i ncreas e d ne ur o m us c ular acti vit y a n d great er 
a bilit y t o e xert self -c o ntr ol of v ol u ntar y m uscle m o ve me nts d uri n g t heir partici pati o n i n st u d y 
V M A L S - 0 0 2- 2. 
4. 4. 1.  
S u p p ort fr o m N o ncli nic al St u dies  
Pre vi o us n o ncli nical G L P safet y st u dies i n rats a n d ra b bits i ncl u de d si n gle a n d re peat i njecti o ns 
of V M 2 0 2 (si n gle i njecti o n da y i n a rat st u d y; 4 i njecti o n da ys i n a re p eate d - d ose rat st u d y; 
5 i njecti o n da ys i n a re p eate d- d ose r a b bit st u d y). N o treat me nt-relate d s afet y e ve nts were 
o bser ve d i n a n y of t he st u dies, s o t he n o o bser ve d a d verse effect le v el ( N O A E L) d ose w as 
c o nsi dere d t o be e q ual t o or hi g her t ha n t he hi g hest d oses teste d i n eac h m o del s yste m.  
I n t he si n gle- d ose r at st u d y, t he ma xi m u m d ose a d mi nistere d was 1 2. 8 ti mes t he d ose per 
i njecti o n da y of 3 2 m g a n d 2. 1 ti mes t he t otal c u m ulati ve d ose of 1 9 2 m g t o be a d mi nistere d i n 
t his st u d y, ass u mi n g a h uma n wei g ht of 6 0 k g. I n t he re peate d- d os e ra b bit st u d y – i n w hic h 
ra b bits were i njecte d o n Da ys 0, 7, 1 4, 2 1, a n d 2 8 – t he t otal c u m ulati ve d ose i n t he hi g h- d ose 
gr o u p was 1. 9 ti mes t he t otal c u m ulati ve d ose t o be a d mi nistere d i n t his st u d y. I n t he re p eate d 
d ose rat st u d y – i n w hic h rats wer e i njecte d o n Wee ks 0, 4, 8, a n d 1 2 – t he t otal c u m ulati ve d ose 
i n t he hi g h- d ose gr o u p w as 4. 3 ti mes t he t otal c u m ulati ve d ose t o be a d mi nistere d i n t his st u d y. 
T hese calc ulati o ns i n dicate t hat t he si n gle dail y d ose a n d t otal h u ma n d ose of E n ge nsis t o be 
use d i n st u d y V M A L S- 0 0 2- 2 is wit hi n t he N O A E L esta blis he d i n t hese G L P st u dies.  
4. 4. 2.  
S u p p ort fr o m Cli nic al St u dies  
Pre vi o us cli nical st u dies ha ve use d a v ariet y of d oses a n d ti mi n g peri o ds f or a d mi nistrati o n of 
E n ge nsis ( V M 2 0 2). T he d ose-res p o ns e f or E n g e nsis was e val uate d i n t w o pai nf ul D P N st u dies. 
I n st u d y V M D N- 0 0 1 ( P h ase 1/ 2 o pe n-la b el d ose-escalati o n st u d y i n 1 2 D P N s u bjects), 
Partici pa nts recei ve d t otal d oses of 4, 8, or 1 6 m g E n ge nsis a d mi nistere d i nt o t he calf m uscle of 
o ne le g. Half of eac h d os e was a d mi nistere d at Da y 0 a n d t he ot her half was a d mi nistere d at 
Da y  1 4. N o d ose-li miti n g t o xicities, n o S A Es, a n d n o u ne x pecte d A Es were o bser ve d. O n e 

Heli x mit h C o., Lt d. 
C O N FI D E N TI A L  
Pr ot oc ol: V M A L S- 0 0 2- 2 
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 
Versi o n 3. 0 
4 0 
Fi nal : 2 0 Ja n uar y 2 0 2 1 
s u bject e x peri e nce d a mi n or i njecti o n site reacti o n (I S R) of tra nsie nt er yt he ma t hat res ol ve d 
wit h o ut treat me nt. Re d ucti o ns i n D P N pai n were o bser ve d i n 9 of t he 1 2 s u bjects at 3 m o nt hs 
after i njecti o n a n d i n 1 0 of t he 1 2 s u bjects at 6 a n d 1 2 m o nt hs after i njecti o n. 
I n st u d y V M D N- 0 0 2 ( P h ase 2 d o u ble- bli n d place b o-c o ntr olle d st u d y i n 1 0 3 s u bjects), 
Partici pa nts recei ve d t otal d oses of 1 6 m g or 3 2 m g E n ge nsis or Place b o i n di vi de d d oses o n 
Da ys 0 a n d 1 4. D oses were a d mi nistere d t o b ot h le gs (t otal of 8 m g or 1 6 m g per le g). Safet y a n d 
efficac y w ere f oll o we d f or 9 m o nt hs. All S A Es occ urri n g i n 1 0 s u bjects w ere cl assifie d as 
u nrelate d t o st u d y dr u g. T he effi cac y d ata s h o w e d t hat 1 6 m g was t he o pti mal d ose wit h 
si g nifica nt a nal gesia lasti n g f or u p t o 9 m o nt hs f oll o wi n g t he treat me nts o n Da ys 0 a n d 1 4. 
P hase 3 D P N st u dies wit h E n ge nsis d o u ble d t he treat me nt da ys a n d d o u ble d t he t otal d ose of 
E n ge nsis wit h o ut a si g nifica nt i ncrease i n A Es. D oses of 1 6 m g of E n ge nsis were a d mi nistere d 
as di vi de d d oses at Da ys 0 a n d 1 4 ( 4 m g per le g p er da y), wit h a sec o n d treat me nt of 1 6 m g 
V M 2 0 2 at 3 m o nt hs a d mi nistere d as di vi de d d oses at Da ys 9 0 a n d 1 0 4, f or a fi nal t otal d ose of 
3 2 m g E n ge nsis a d mi nistere d per s u bject. All d oses i n D P N st u dies ha ve bee n a d mi nistere d t o 
t he gastr oc ne mi us m uscl es, as ner v es a n d m uscles i n t he l o wer li m bs are t y picall y m ost affect e d 
b y D P N pai n i n earlier st a ges of t he disease.  
I n t he i nitial V M A L S- 0 0 1 st u d y i n A L S s u bjects ( Secti o n 2. 2. 6. 1 ), d oses w ere a d mi nistere d t o 
m ulti ple m uscle gr o u ps i n b ot h t he l o wer a n d u p p er b o d y. F or c o n ve ni e nce, d oses were 
a d mi nistere d bilaterall y t o t he l o wer li m bs o n Da y 0, f oll o we d b y d oses t o t he u p per li m bs o n 
Da y 7, or vice- vers a i n t w o se par ate gr o u ps of P artici pa nts. T he sa me series of i njecti o ns were 
re peat e d at Da ys 1 4 a n d 2 1. He nce, a t otal of 2 5 6 i njecti o ns were a d mi nistere d o ver 4 visits 
d uri n g t w o Treat me nt C y cles ( 6 4 i njecti o ns, eit her 1 3 or 1 9 m g t otal d ose per d osi n g da y, 
de pe n di n g o n w het her u p per or l o wer li m b m uscles were i njecte d; d osi n g o n Da ys 0, 7, 1 4, a n d 
3 0) wit h a n o ver all t otal d ose of 6 4 m g per Partici pa nt. T h us, t he t otal d ose i n st u d y 
V M A L S - 0 0 1 was d o u ble t he t otal d ose i n t he P hase 3 D P N st u dies, alt h o u g h t he d ose per 
i n di vi d ual i njecti o n ( 0. 2 5 m g a d mi nistere d i n 0. 5 m L of s ol uti o n) has re mai ne d c o nsta nt si nce 
t he earlier d ose-r a n gi n g st u dies i n D P N s u bjects. All partici pa nts t olerate d 6 4 m g of V M 2 0 2 well 
wit h n o S A Es relate d t o t he dr u g. 
I n t his V M A L S- 0 0 2- 2 st u d y, t he t otal n u m ber of i njecti o n da ys was  i ncreas e d fr o m 4 da ys t o 
6 da ys wit h b ot h u p per a n d l o wer li m bs bei n g i njecte d o n eac h d osi n g da y. T heref ore, a t otal of 
7 6 8 i njecti o ns is bei n g a d mi nistere d o ver 6 visits ( 1 2 8 i njecti o ns, 3 2 m g t otal d ose per d osi n g 
da y; Da ys 0, 1 4, 6 0, 7 4, 1 2 0, a n d 1 3 4) f or a n o verall t otal d ose of 1 9 2 m g E n ge nsis per 
Partici pa nt. T he d ose of E n ge nsis per i n di vi d ual i njecti o n a n d t he n u m ber of m uscle gr o u ps 
i njecte d is u nc ha n ge d fr o m t he earlier A L S st u d y. He nce t h e d osi n g re gi me n per i njecte d m uscl e 
re mai ns t he sa me o n eac h treat me nt da y as i n t he pre vi o us A L S st u d y, b ut treat me nt da ys ha v e 
bee n s prea d o ut o ver a l o n ger peri o d of ti me a n d t he o verall n u m ber of treat me nt da ys has bee n 
i ncreas e d b y 5 0 %. T his gra d ual es calati o n of d osi n g is c o nsiste nt wit h t he safet y pr ofile of 
E n ge nsis b ot h i n a ni mals a n d i n h u ma ns, a n d wit h t he e xte n de d, c hr o nic de bilitati n g disease 
pr ocess of A L S. 
M ost i m p orta ntl y, a fa v ora ble saf et y pr ofile f or E n ge nsis has bee n d e m o nstrate d i n o ver 
5 0 0 reci pie nts. Gi ve n t he life-t hreat e ni n g nat ure of A L S, 3 a d mi nistrati o ns of E n ge nsis, eac h 
se parat e d b y t w o m o nt hs o ver a 6- m o nt h peri o d, are j ustifie d f or partici p a nts wit h s uc h a 
ne gati ve pr o g n osis a n d pr of o u n dl y u n met nee d. 

Heli x mit h C o., Lt d. 
C O N FI D E N TI A L  
Pr ot oc ol: V M A L S- 0 0 2- 2 
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 
Versi o n 3. 0 
4 1 
Fi nal : 2 0 Ja n uar y 2 0 2 1 
4. 5.  
R a n d o miz ati o n 
Partici pa nts  s h o ul d be ra n d o mize d as cl ose as possi ble t o t he ti me of t he first St u d y I njecti o ns . 
Ra n d o mizati o n will be c o n d ucte d via a n E D C ra n d o mizati o n m o d ule i n a 2: 1 rati o t o recei ve 
eit her E n ge nsis or Place b o .  
4. 6.  
E n d of St u d y Defi niti o n  
T he e n d of t he st u d y is d efi ne d as t he d ate o n w hi c h t he last Partici pa nt  i n t he st u d y c o m pletes 
t he Da y 1 8 0 Visit or is ter mi nate d or disc o nti n ue d earl y fr o m t he st u d y (earl y ter mi nati o n). 
4. 7.  
St u d y C o m pleti o n  
T he st u d y will be c o nsi dere d c o m plet e u p o n S p o ns or a p pr o val of t h e cli nical st u d y re p ort. 
4. 8.  
C o m plete d P artici p a nt s 
A Partici pa nt  is c o nsi der e d t o ha ve c o m plet e d t he st u d y if t he Partici pa nt  c o m pletes t he Da y 1 8 0 
Visit.  

Heli x mit h C o., Lt d. 
C O N FI D E N TI A L  
Pr ot oc ol: V M A L S- 0 0 2- 2 
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 
Versi o n 3. 0 
4 2 
Fi nal : 2 0 Ja n uar y 2 0 2 1 
5.  
S T U D Y P O P U L A TI O N  
Partici pa n ts meeti n g t he eli gi bilit y criteria will be e nr olle d a n d ra n d o mize d . 
5. 1.  
I ncl usi o n Criteri a 
1.  
Male or fe m ale Partici pa nt s age ≥ 1 8 years, b ut ≤ 8 0 years , at ti me of c o m pleti o n of t he 
i nf or me d c o nse nt pr o cess 
2.  
C li nicall y defi nite or pr o ba ble A m y otr o p hic Lat eral Scler osis  (A L S ) or 
la b orat or y-s u p p orte d pr o ba ble A L S as defi ne d i n t he re vise d El Esc orial/ Airlie H o use 
dia g n ostic criteria  
3.  
T he site of o nset of A L S s y m pt o ms is a li m b a n d e x perie nci n g s y m pt o ms of l o wer 
m ot or d ysf u ncti o n (e. g., wea k ness, atr o p h y, cra m ps, p o or circ ulati o n, etc.) wit h u p per 
m ot or ne ur o n s y m pt o ms (e. g., bris k refle xes, s p asticit y) 
4.  
O nset of A L S  s y m pt o ms ≤ 4 years  
5.  
Sl o w Vital Ca pacit y ( S V C) ≥ 5 0 % of pre dict e d val ue at Scree ni n g  
6.  
N ot ta ki n g ril uz ole, or o n a sta ble d ose ( d efi ne d as n o n ote d t o xicities) f or at least 
3 0 da ys pri or t o S cree ni n g  a n d t hr o u g h o ut t he st u d y 
7.  
N ot ta ki n g e dara v o n e or o n a mai nte na nce c ycl e f or at least 3 0 da ys 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  
8.  
F or f e males of c hil d beari n g p ote ntial, a ne gati ve uri ne pre g n a nc y test at Scree ni n g a n d 
o n Da y 0 
9.  
Male Partici pa nts a n d t heir fe male p art ners m ust a gree t o use d o u ble- barrier 
c o ntrace pti o n d uri n g t he st u d y or pr o vi de pr o of of p ost me n o pa usal state ( mi ni m u m 
1 year) or s ur gical sterilit y  
1 0.  Male Partici pa nt s m ust n ot d o nate s per m d uri n g t he st u d y 
1 1.  Fe male Partici pa nt s m ust be n o n pre g na nt, n o nlact ati n g, a n d eit her p ost me n o pa usal f or 
at least 1 year, or s ur gicall y sterile f or at least 3 m o nt hs, or a gree t o use d o u ble-barri er 
c o ntrace pti o n fr o m 2 8 da ys pri or t o ra n d o mizati o n ( Da y 0) a n d/ or t heir last c o nfir me d 
me nstr ual peri o d pri or t o st u d y ra n d o mizati o n ( w hic he ver is l o n ger) u ntil t he e n d of t he 
st u d y 
1 2.  Ca pa ble of c o m pl yi n g a n d willi n g t o c o m pl y wit h t he re q uire m e nts a n d restricti o ns i n 
t he i nf or me d c o nse nt f or m a n d t his pr ot oc ol 
1 3.  Willi n g t o f or g o ne w e x p eri me ntal  A L S treat me nts f or at least 6 m o nt hs f oll o wi n g 
ra n d o mizati o n 
5. 2.  
E xcl usi o n Criteri a   
1.  
Pr o gressi ve or de g e ner ati ve ne ur ol o gical dis or d er s uc h as Alz hei mer’s disease, 
Par ki ns o n’s disease, vas c ular de me ntia, m ulti ple scler osis, a n d ot her n e ur ol o gical or 
vasc ular dis or d ers f elt b y t he I n v esti gat or t o precl u de partici pati o n  
2.  
Re q uires trac h e ot o m y ve ntilati o n or n o ni n vasi ve ve ntilati o n relate d t o b ul bar f u ncti o n 

Heli x mit h C o., Lt d. 
C O N FI D E N TI A L  
Pr ot oc ol: V M A L S- 0 0 2- 2 
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 
Versi o n 3. 0 
4 3 
Fi nal : 2 0 Ja n uar y 2 0 2 1 
3.  
E vi de nce b y p h ysical e xa mi nati o n , hist or y, or la b orat or y e v al uati o n of si g nifica nt 
c o nc o mita nt disease wit h a life e x pecta nc y of < 6 m o nt hs at Scree ni n g  
4.  
I N R val ues > 2. 0 
5.  
P latelet c o u nt < 1 0 0, 0 0 0/ µ L 
6.  
I nfla m mat or y dis or der of t he bl o o d vessels (i nfla m mat or y a n gi o pat h y or v asc ulitis , 
s uc h as B uer ger’s diseas e) 
7.  
Acti ve infecti o n  ( chr o nic i nfecti o n or se vere acti v e i nfecti o n t hat ma y c o m pr o mise t he 
Partici pa nt ’s well bei n g or partici pati o n i n t he st u d y i n t he I n v esti gat or’s j u d g me nt) 
8.  
C hr o nic i nfla m mat or y disease (e. g., Cr o h n’s disease, r he u mat oi d art hritis)  
9.  
P ositi ve h u ma n i m m u n o deficie nc y vir us ( HI V ) or h u ma n T-cell l y m p h otr o pic vir us 
(H T L V ) I/II test at Scr ee ni n g  
1 0.  Acti ve ac ut e or c hr o nic h e patitis B  
1 1.  A cti ve he patitis C  
1 2.  I m m u n os u p pr essi o n d ue t o u n derl yi n g disease (e. g., r he u mat oi d art hritis, s yste mic 
l u p us er yt he mat os us), or t o c urre ntl y recei vi n g i m m u n os u p pressi ve dr u gs (e. g., 
c he m ot hera p y, c ortic oster oi ds) , or t o ra diati o n t hera p y 
1 3.  Str o ke or m y ocar dial i nf arcti o n wit hi n 3 m o nt hs pri or t o Scree ni n g  
1 4.  Acti ve dee p v ei n t hr o m b osis 
1 5.  Rece nt hist or y ( < 3 y ears) or pres e nce of ca n cer e xce pt basal cell carci n o ma or 
s q ua m o us cell car ci n o ma of t he s ki n t hat was e xcise d a n d has s h o w n n o e vi de nce of 
rec urre nce f or at least 1 y ear  
1 6.  Maj or ps yc hiatric dis or d er dia g n ose d i n t he p ast 6 m o nt hs t hat has  n ot bee n sta bilize d 
or i n t he I n vesti gat or’s o pi ni o n w o ul d n ot all o w t he patie nt t o partici pate i n t he 
sc he d ule d pr o ce d ur es  
1 7.  Use of a n i n vesti gati o nal dr u g f or t he treat me nt of A L S i n t he past 3 0 da ys or 5 half-
li ves (if a vaila ble), w hic h e ver is l o n ger, or pre vi o us partici pati o n i n a cli nical st u d y 
wit h E n ge nsis 
1 8.  S te m cell a d mi nistrati o n  f or i n vesti gati o nal treat m e nt of A L S  or ot her c o n diti o ns i n t he 
6 m o nt hs pri or t o Scree ni n g 
5. 3.  
N u m ber of P artici p a nts  
T he tar get sa m ple si ze is 1 8 Partici pa nt s w h o will be ra n d o mize d i n a 2: 1 rati o t o E n ge nsis or 
Place b o ( 1 2: 6).  
5. 4.  
E nr oll m e nt, R a n d o miz ati o n, a n d Tre at me nt Assi g n me nt  
5. 4. 1.  
E nr oll m e nt A dj u dic ati o n Pr ocess  
All Scree ni n g  i nf or mati o n f or eac h Partici pa nt  pri or t o ra n do mizati o n will be se nt t o a n 
A dj u dicati o n C o m mittee (Fi g ure 3 ). T he A dj u dicati o n C o m mittee is c o m p ose d of t he S p o ns or 
Me dical Direct or, Me dical M o nit or,  a n d Cli nical O perati o ns pers o n nel. T h e A dj u dicati o n 

Heli x mit h C o., Lt d. 
C O N FI D E N TI A L  
Pr ot oc ol: V M A L S- 0 0 2- 2 
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 
Versi o n 3. 0 
4 4 
Fi nal : 2 0 Ja n uar y 2 0 2 1 
C o m mittee re vie ws t he r ele va nt cli nical i nf or m ati o n of eac h Partici pa nt  o n a ti mel y basis t o 
e ns ure strict a d h ere n ce t o t he I n cl usi o n/ E xcl usi o n Criteria . T he C o m mittee eit her c o nfir ms t he 
eli gi bilit y f or ra n d o mizati o n of a n i n di vi d ual Partici pa nt or  c o nfers wit h t he I n v esti gat or 
re gar di n g t he stat us of a Partici pa nt  as a scree n fail ure.  
 

Heli x mit h C o., Lt d. 
C O N FI D E N TI A L  
Pr ot oc ol: V M A L S- 0 0 2- 2 
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 
Versi o n 3. 0 
4 5 
Fi nal : 2 0 Ja n uar y 2 0 2 1 
Fi g ure 3:  
R a n d o miz ati o n Pr ocess 
 
 

Heli x mit h C o., Lt d. 
C O N FI D E N TI A L   
Pr ot oc ol: V M A L S- 0 0 2- 2 
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 
Versi o n 3. 0 
4 6 
Fi nal : 2 0 Ja n uar y 2 0 2 1 
5. 4. 2.  
R a n d o miz ati o n a n d Tre at me nt All oc ati o n 
O nce a Partici pa nt  is dee me d t o meet all I ncl usi o n/ E xcl usi o n Criteria, bli n de d ran d o mizati o n 
will be c o n d ucte d via a n E D C ra n d o mizati o n m o d ule i n a 2: 1 rati o t o recei ve eit her E n g e nsis or 
Place b o. T he u n bli n de d P har macist or dele g ate d staff will pre pare t he E n g e nsis or Place b o 
i njecti o ns f or t hat Partici pa nt  pri or t o First I njecti o ns b y t he I n v esti gat or or q ualifie d desi g nee o n 
Da y 0. 
5. 5.  
P artici p a nt I de nt ific ati o n 
T o mai ntai n c o nfi de ntialit y, t he na me of t he Partici pa nt  s h o ul d n ot be rec or de d o n a n y st u d y 
d oc u me nt ot her t ha n t he i nf or me d c o ns e nt f or m. All Partici pa nt s w h o si g n t he i nf or me d c o ns e nt 
f or m will be assi g ne d a u ni q ue i de ntifier i n t he f oll o wi n g f or mat: X X-Y Y Y w here X X is t he 
2- di git Site n u m ber a n d Y Y Y is t he 3- di git se q ue ntial I D n u m ber starti n g wit h 0 0 1 f or t he first 
Partici pa nt  c o nse nte d at t hat Site. F or e xa m ple, t h e first Partici pa nt  c o nse nt e d at Site 1 1 will be 
assi g ne d 1 1- 0 0 1. I D n u m bers f or s cree n fail ures will n ot be re use d. If a scree n fail ure is later 
rec o nse nt e d f or r escr ee ni n g, a ne w I D n u m ber will be assi g ne d. 
5. 6.  
Scree n F ail ures  
A c o nse nte d Partici p a nt  w h o d oes n ot meet all eli gi bilit y criteria will i m me diatel y cease f urt her 
st u d y-relate d testi n g; t he cessati o n will be c o m m u nicate d t o t he S p o ns or or desi g nee wit hi n 
2 4 h o urs. 
A mi ni mal a m o u nt of scree n fail ur e i nf or mati o n is re q uire d t o e ns ure tra ns p are nt re p orti n g of 
scree n fail ures t o meet t he C o ns oli date d Sta n dar ds of Re p orti n g Trials ( C O N S O R T) p u blis hi n g 
re q uire me nts a n d t o res p o n d t o q ueries fr o m re g ulat or y a ut h orities. Mi ni mal i nf or mati o n 
i ncl u des eli gi bilit y criteria, de m o gra p hic d ata, scree n fail ure d etails, a n d ot h er perti ne nt 
materials.  
5. 7.  
Rescree ni n g  
Partici pa nts w h o pr o vi de d i nf or me d c o nse nt b ut faile d t o meet all eli gi bilit y criteria ma y b e 
rescr ee ne d o n ce wit h S p o ns or writte n per missi o n via t he a dj u dicati o n pr ocess. A n y scree n fail ure 
ma y o nl y be rec o ns e nte d a n d rescree n e d o nce. 
T he f oll o wi n g Scree ni n g assess me nts, if c o m plete d d uri n g t he first Scree ni n g a n d f o u n d t o meet 
eli gi bilit y criteria, ma y n ot nee d t o be re p eate d w he n t he Partici pa nt  ret ur ns f or res cree ni n g: 
•  Viral Scree ni n g if perf or me d wit hi n 3 m o nt hs of si g ni n g t he ne w i nf or me d  c o nse nt 
All ot her Scree ni n g assess me nts will nee d t o be re peate d.  
5. 8.  
Lifest yle C o nsi der ati o ns  
5. 8. 1.  
Me als a n d Diet ar y Rest ricti o ns  
T here are n o meal or diet ar y restri cti o ns f or t his st u d y. 

Heli x mit h C o., Lt d. 
C O N FI D E N TI A L   
Pr ot oc ol: V M A L S- 0 0 2- 2 
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 
Versi o n 3. 0 
4 7 
Fi nal : 2 0 Ja n uar y 2 0 2 1 
5. 8. 2.  
C affei ne, Alc o h ol, a n d T o b acc o 
T here are n o caffei ne, t o bacc o, or al c o h ol restricti o ns f or t his st u d y.  
5. 8. 3.  
S u p ple m e nts  
T here are n o restricti o ns o n her bal me dici nes or dietar y s u p ple me nts or c ha n ges i n t heir use 
d uri n g t he st u d y. T he use of a n y s u p ple me nts d uri n g t he st u d y will be rec or de d o n t he 
Partici pa nt’s me dical r ec or d a n d t he electr o nic cas e re p ort f or m (e C R F) as c o nc o mita nt 
me dicati o ns.  
5. 8. 4.  
Acti vit y  
T here are n o restricti o ns o n acti vit y. Partici pa nts s h o ul d be a d vise d t o c o nti n ue t heir n or mal 
acti vit y le vel d uri n g t he st u d y. 

Heli x mit h C o., Lt d. 
C O N FI D E N TI A L   
Pr ot oc ol: V M A L S- 0 0 2- 2 
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 
Versi o n 3. 0 
4 8 
Fi nal : 2 0 Ja n uar y 2 0 2 1 
6.  
S T U D Y I N T E R V E N TI O N  
6. 1.  
St u d y I nter ve nti o n(s) A d mi nistere d 
Refer t o t he St u d y Dr u g I njecti o n G ui deli nes f or a d mi nistrati o n of E n ge nsis or Place b o. 
6. 1. 1.  
E n ge nsis  
E n ge nsis c o ntai ns t he acti ve p har mace utical i n gre die nt V M 2 0 2, a plas mi d D N A c o ntai ni n g a 
n o vel ge n o mic c D N A h y bri d h u ma n H G F c o di n g se q ue nce, H G F - X 7, t hat e x presses t w o 
is of or ms of H G F, H G F7 2 8 a n d H G F 7 2 3. T he plas mi d has 7, 3 7 7 base pairs wit h a h u ma n 
c yt o me gal o vir us ( H C M V) e n ha n cer / pr o m oter, a gr o wt h h or m o ne p ol ya de n ylati o n ter mi nat or 
se q ue nce, C ol El ori gi nat or, a n d t he ka n a m yci n resista nce ge ne o n a p C K b ac k b o ne. 
T he c o m p o ne nts of E n g e nsis are pr o vi de d i n Ta bl e  4.  
T a ble 4: 
C o m p o ne nts of E n ge nsis  
C o m p o ne nt  
F u ncti o n  
C o m p ositi o n 
V M 2 0 2 
Acti ve p har mace utical i n gre die nt 
2. 5 m g 
S ucr ose 
S us pe nsi o n me di u m  
5 5 m g ( 1. 1 %) a 
S o di u m C hl ori de 
S us pe nsi o n me di u m  
4 5 m g ( 0. 9 %) a 
Sterile Water f or I njecti o n  
S us pe nsi o n me di u m  
5 m L 
a C o nce ntrati o n after rec o nstit uti o n i n 5 m L water f or i njecti o n.  
6. 1. 2.  
Pl ace b o  
Place b o  will be sterile E n ge nsis ve hicle. T he c o m p o ne nts of t he Place b o are pr o vi de d i n Ta ble  5. 
T he Place b o is  s u p plie d i n a sterile glass vial i n li q ui d f or m. Eac h vial is o nl y t o be use d f or o n e 
Partici pa nt. Vis uall y, t he Place b o is i n disti n g uis ha ble fr o m rec o nstit ute d E n ge nsis. T he 
Partici pa nt , I n vesti gat or, a n d st u d y n urse will n ot be a ble t o disti n g uis h Place b o fr o m E n g e nsis. 
T a ble 5: 
C o m p o ne nts of t he Pl ace b o  
C o m p o ne nt  
F u ncti o n  
C o m p ositi o n 
S ucr ose 
S us pe nsi o n me di u m  
5 5 m g ( 1. 1 %)  
S o di u m C hl ori de 
S us pe nsi o n me di u m  
4 5 m g ( 0. 9 %)  
Sterile Water f or I njecti o n  
S us pe nsi o n me di u m  
5 m L 

Heli x mit h C o., Lt d. 
C O N FI D E N TI A L   
Pr ot oc ol: V M A L S- 0 0 2- 2 
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 
Versi o n 3. 0 
5 1 
Fi nal : 2 0 Ja n uar y 2 0 2 1 
T he u n bli n de d p har mac y staff ar e res p o nsi ble f or recei vi n g, st ori n g, pre p ari n g, a n d dis pe nsi n g 
st u d y dr u g per t he Phar m ac y M a n ual. A n I n vesti g at or ma y be u n bli n de d t o t he treat me nt 
assi g n me nt f or a Partici p a nt  wit h a n S A E w he n t h e treat me nt decisi o n re q uires k n o wle d ge of t he 
treat me nt assi g n me nt.  
T o a v oi d p ote ntial bias, I n vesti gat ors a n d st u d y staff are e x p ecte d t o refrai n fr o m s hari n g safet y 
a n d treat me nt o utc o mes wit h ot her partici pati n g Sites.  
T he D S M B, i n de pe n de nt of t he S p o ns or, ma y re vi e w i n di vi d ual u n bli n de d Partici pa nt  narrati ves 
i n t he case of a n S A E or m ulti ple S A Es f or w hic h t he D S M B C hair re q uests u n bli n di n g, b ut will 
n ot ha ve access t o u n bli n de d ta bles a n d listi n gs u nless re q ueste d b y t he D S M B C hair w he n 
assessi n g a p ote ntial saf et y si g nal. W hile t he st u d y is o n g oi n g a n d pri or t o data base l oc k, t h e 
datasets will re mai n bli n de d wit h n o preli mi nar y s u m mar y of t he st u d y b y t he i n di vi d ual 
treat me nt ar ms e x ce pt w he n re q uest e d b y t he D S M B C hair. T he D S M B c harter will s pecif y its 
c o m p ositi o n, fre q ue nc y of meeti n gs, g ui deli nes f or n o nc o m parati ve or c o m parati ve dat a re vie w, 
a n d ra n ge of rec o m me n d ati o ns t hat ma y be pr o vi d e d as a se p arat e d oc u me nt acc o m pa n yi n g t he 
pr ot oc ol. 
6. 3. 3.  
M ai nte n a nce of t he  Bli n d  
O nce t he Partici p a nt  has bee n a dj u dicate d a n d d ee me d eli gi ble f or p ote ntial ra n d o mizati o n, t he 
dr u g de p ot will pre par e a n d s hi p b ot h E n ge nsis a n d Place b o vials t o t he Site p har mac y. T he 
p har mac y will kee p b ot h E n ge nsis a n d Place b o vials a n d t he d ose pre p arati o n w or ks heet i n a 
sec ure l o cati o n wit h access li mite d t o u n bli n de d p har mac y p ers o n nel res p o nsi ble f or pre p ari n g 
t he s yri n ges wit h assi g ne d st u d y treat me nt. T he I n vesti gat or or desi g nee will ra n d o mize t he 
Partici pa nt  usi n g t he E D C ra n d o mizati o n m o d ule o n Da y 0 after c o nfir mi n g eli gi bilit y criteria.  
T he u n bli n de d P har macist or dele gate d staff will recei ve a n otificati o n fr o m t he E D C 
ra n d o mizati o n m o d ule i n dicati n g i nt o w hic h ar m t he partici pa nt has b ee n ra n d o mize d.  T he 
u n bli n de d P har macist or dele gate d staff will pre p are E n ge nsis or Place b o p er t he P har mac y 
Ma n ual.  
Bli n di n g will be ac hie ve d b y ha vi n g st u d y dr u g s yri n ges pre pare d b y t he p har mac y staff a n d 
e ns uri n g t hat t he st u d y dr u g vials are ne v er left i n a l ocati o n w here t he y c o ul d be see n b y bli n de d 
st u d y staff (e. g., st u d y c o or di nat or, st u d y n urse, I n vesti gat or). T he E n g e nsis a n d Place b o vials 
are r ea dil y disti n g uis ha ble fr o m eac h ot her, e ve n fr o m a dista nce. H o we ver, beca use 
rec o nstit ute d E n ge nsis is i n disti n g uis ha ble fr o m Place b o, s yri n g es c o ntai ni n g E n ge nsis are 
i n disti n g uis ha ble fr o m s yri n ges c o ntai ni n g Place b o. 
T he p har mac y staff a n d s elect i n di vi d uals s uc h as t he U n bli n de d C R A will be t he o nl y o nes t hat 
will be u n bli n de d t o t he treat me nt assi g n me nts. T he Partici pa nt  a n d st u d y pers o n nel, i ncl u di n g 
st u d y c o or di nat ors, st u d y n urses, la b orat or y tec h ni cia ns, I n vesti gat ors, a n d bli n de d C R As, will 
re mai n bli n de d u ntil all data has bee n e ntere d i nt o t he data base a n d t he dat a base is l oc ke d. 

Heli x mit h C o., Lt d. 
C O N FI D E N TI A L   
Pr ot oc ol: V M A L S- 0 0 2- 2 
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 
Versi o n 3. 0 
5 2 
Fi nal : 2 0 Ja n uar y 2 0 2 1 
I N C A S E O F E M E R G E N C Y (i.e., S E RI O U S A D V E R S E E V E N T [ S A E]) A N D O N L Y W H E N 
T HI S I N F O R M A TI O N I N F L U E N C E S T H E P A R TI CI P A N T' S M E DI C A L M A N A G E M E N T, 
t he I n v esti gat or ma y c o nt act t he M e dical M o nit or t o re q uest u n bli n di n g of t he treat me nt 
assi g n me nt. T he date a n d reas o n  f or u n bli n di n g will be d oc u me nte d i n t he electr o nic data ca pt ure 
( E D C) s yste m. 
6. 4.  
St u d y I nter ve nti o n C o m pli a nce  
All Site pers o n nel i n v ol ve d wit h t he recei pt, st ora ge, pre parati o n, a d mi nistrati o n, a n d destr ucti o n 
of st u d y dr u g are re q uir e d t o d oc u me nt t heir u n dersta n di n g of t he St u d y Dr u g I njecti o n 
G ui deli nes. Refer t o t he I njecti o n G ui deli nes. 
All st u d y dr u g will be a d mi nistere d u n der t he s u p er visi o n of t he I n vesti gat or. 
C o m plia nce wit h st u d y dr u g a d mi nistrati o n i nstr ucti o ns will be assesse d t hr o u g h t he re vie w of 
acc o u nta bilit y a n d pr e par ati o n l o gs as well as t he rec o nciliati o n of use d a n d u n use d vials, vials 
destr o ye d, a n d vials r et ur ne d t o t he S p o ns or. 
6. 5.  
C o nc o mit a nt T her a p y  
Sta n dar d of care f or A L S  is prese nte d i n t he A merica n Aca de m y of N e ur ol o g y ( A A N) g ui deli ne 
re gar di n g ma n a ge me nt a n d care of t he patie nt wit h A L S. 6 4 Rec o m me n dati o ns are prese nte d f or 
m ulti disci pli nar y care, s y m pt o m ma na ge me nt, a n d t he treat me nt of c o g niti ve/ be ha vi oral 
i m pair me nt. 
6. 6.  
D ose I nterr u pti o n 
N o i nte nti o nal m o dificati o ns of t he n u m ber or c o n ce ntrati o n of d oses will be per mitte d. A n 
u ni nte nti o nal i nterr u pti o n of t he n u m ber of i njecti o ns ( 1 2 8 per St u d y I njecti o n Visit) is o nl y 
all o we d if t he Partici pa nt  e x perie n ces a n A E rel ate d t o st u d y dr u g a d mi nistrati o n or ot her healt h-
relate d e v e nts (e. g., ill ness) d uri n g t he st u d y. If t he f ull set of st u d y i njecti o ns ca n n ot be 
a d mi nistere d d uri n g t he n or mal St u d y I njecti o n Visit, t he Partici pa nt s h o ul d be sc he d ule d t o 
recei v e t he r e mai ni n g i njecti o ns wit hi n 4 8 h o urs. If t his is n ot p ossi ble, t he n t he re mai n der of t he 
i njecti o ns f or t hat visit will n ot be a d mi nistere d.  
6. 7.  
P ri or a n d C o nc o mit a nt Me dic ati o ns, Tre at me nts, a n d Pr oce d ures  
Me dicati o ns a n d treat me nts ta ke n wit hi n 3 0 da ys pri or t o Da y 0 will be rec or de d o n t he 
Me dicati o n a n d Hist or y e C R F at t he Da y 0 Visit. A n y me dicati o n or vacci ne, i ncl u di n g 
o ver-t he- c o u nter or pres cri pti o n me dici nes, vita mi ns, her bal s u p ple me nts, a n d t o pical a nest hetics 
f or p ost-i njecti o n pai n a n d pr oce d ur es t hat t he Partici pa nt  is recei vi n g at t he ti me of e nr oll me nt 
or recei ves d uri n g t he st u d y m ust be rec or d e d o n t he C o nc o mita nt Me dicati o ns or C o nc o mita nt 
Pr oce d ures e C R F. F or eac h me dicati o n or treat me nt, t he f oll o wi n g i nf or mati o n will be c ollecte d: 
•  Me dicati o n tra de or ge neric na me, o r pr oce d ure  
•  I n dicati o n f or w hic h t h e me dicati o n/ pr oce d ure w as gi ve n 

Heli x mit h C o., Lt d. 
C O N FI D E N TI A L   
Pr ot oc ol: V M A L S- 0 0 2- 2 
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 
Versi o n 3. 0 
5 3 
Fi nal : 2 0 Ja n uar y 2 0 2 1 
•  D ose/stre n gt h, r o ute, a n d fre q ue n c y of a d mi nistrati o n 
•  Date starte d a n d date st o p pe d ( or c o nti n uati o n at st u d y e xit) 
•  Reas o n f or use 
T he me dical m o nit or will be c o ntact e d if t here are a n y q u esti o ns re gar di n g c o nc o mita nt or pri or 
t hera p y. 

Heli x mit h C o., Lt d. 
C O N FI D E N TI A L   
Pr ot oc ol: V M A L S- 0 0 2- 2 
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 
Versi o n 3. 0 
5 4 
Fi nal : 2 0 Ja n uar y 2 0 2 1 
7.  
DI S C O N TI N U A TI O N O F S T U D Y I N T E R V E N TI O N A N D 
P A R TI CI P A N T WI T H D R A W A L  
7. 1.  
Disc o nti n u ati o n of St u d y I nter ve nti o n  
I n rar e i nsta nces, it ma y be necessar y t o disc o nti n ue st u d y dr u g f or a Partici pa nt. If st u d y dr u g is 
disc o nti n ue d, t he Partici pa nt  will  re mai n i n t he st u d y t o be e val uate d f or safet y if t he Partici pa nt  
a grees t o c o nti n ue partici pati n g i n t he st u d y. See Secti o n 1. 3  ( S o A) f or a n y f urt her ass ess me nts 
t hat nee d t o be c o m plete d. 
7. 2.  
P artici p a nt  Wit h dr a w al/ Disc o nti n u ati o n 
A n y Partici pa nt  ma y v ol u ntaril y disc o nti n ue t he st u d y at a n y ti me wit h o ut prej u dice. T h e 
I n v esti gat or ma y disc o nti n ue a Partici pa nt  fr o m t he st u d y at a n y ti me if, i n t he I n vesti gat or’s 
j u d g me nt, t he Partici pa nt’s healt h or safet y w o ul d be c o m pr o mise d b y re m ai ni n g i n t he st u d y. 
S pecific  reas o ns f or st u d y disc o nti n uati o n i ncl u de t he f oll o wi n g: 
•  Partici pa nt  decisi o n  
•  I n v esti gat or’s decisi o n 
•  A d verse e ve nt  
•  
I ns ufficie nt c o m plia n ce wit h st u d y re q uire me nts 
•  L ost t o f oll o w- u p 
•  Ot her  
T he  s pecific reas o ns f or Partici pa nt  disc o nti n uati o n will be rec or de d. 
T he f oll o wi n g assess me nts will be perf or me d  at a n Earl y Ter mi nati o n ( E T) V isit, if p ossi ble, f or 
Partici pa nt s w h o disc o nti n ue pri or t o t he Da y 1 8 0 Visit . 
•  C o m plete P h ysical e xa m i nati o n 
•  Vital si g ns, wei g ht 
•  1 2- lea d EC G 
•  Ser u m che mistr y  a n d he mat ol o g y 
•  Uri ne pre g n a nc y test  
•  S V C  
•  C o nc o mita nt me dicati o ns  
•  M uscle stre n gt h b y H H D  
•  A T LI S ( w here a v aila ble)  
•  A L S F R S - R 
•  A L S A Q - 4 0 
•  P GI C  a n d C GI C  
•  I njecti o n site reacti o n ass ess me nt  if disc o nti n ue d pri or t o Da y 1 4 4 
•  Treat me nt -e mer ge nt ad v erse ev e nts  

Heli x mit h C o., Lt d. 
C O N FI D E N TI A L   
Pr ot oc ol: V M A L S- 0 0 2- 2 
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 
Versi o n 3. 0 
5 5 
Fi nal : 2 0 Ja n uar y 2 0 2 1 
7. 3.  
L ost t o F oll o w- u p 
A Partici pa nt  will be c o nsi dere d l ost t o f oll o w - u p if he or s he re peate dl y fails t o ret ur n f or 
sc he d ule d Visit s a n d is u na ble t o be c o ntacte d b y t he Site b y Da y 1 8 0 ( + 7 da ys). 
T he f oll o wi n g acti o ns m ust be ta ke n a n d rec or d e d if a Partici pa nt  fails t o ret ur n t o t he cli nic f or a 
re q uire d st u d y Visit : 
•  T he site m ust atte m pt t o c o ntact t he Partici pa nt  a n d resc he d ul e t he misse d Visit  as 
s o o n as p ossi ble. T he site m ust  c o u nsel t he Partici pa nt  o n t he i m p orta nce of 
mai ntai ni n g t he assi g ne d Visit  sc he d ule an d ascert ai n w het her or n ot t he Partici pa nt  
wis hes t o a n d/ or s h o ul d c o nti n ue i n t he st u d y. 
•  If n o res p o ns e is o btai ne d fr o m t he Partici pa nt, t h e I n vesti gat or is e n c o ura ge d t o 
c o ntact o ne of t h e Partici pa nt’s relati ves or his/ her ge neral practiti o ner .  
•  Bef ore a Partici pa nt  is dee me d l ost t o f oll o w u p, t he I n vesti gat or or d esi g nee m ust 
ma ke e ver y eff ort t o re g ai n c o ntact wit h t he Partici pa nt , i ncl u di n g at least t hree 
tele p h o ne calls a n d, fi nall y, a certifie d letter t o t he Partici pa nt ’s last k n o w n maili n g 
a d dress . T hes e c o ntact atte m pts s h o ul d be d oc u me nte d i n t he s o urce rec or ds. 
•  S h o ul d t he Partici pa nt  c o nti n ue t o be u nreac ha ble, t he Partici pa nt will be c o nsi dere d 
l ost t o f oll o w- u p.  

Heli x mit h C o., Lt d. 
C O N FI D E N TI A L   
Pr ot oc ol: V M A L S- 0 0 2- 2 
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 
Versi o n 3. 0 
5 6 
Fi nal : 2 0 Ja n uar y 2 0 2 1 
8.  
S T U D Y A S S E S S M E N T S A N D P R O C E D U R E S  
All s t u d y pr oce d ures a n d assess me nts t o get her wit h t heir ti mi n g are s u m marize d i n Secti o n 1. 3  
( S o A). 
Pr ot oc ol wai vers or e xe m pti o ns are n ot all o we d. A d here n ce t o t he pr ot o c ol re q uire me nts is 
esse ntial. 
8. 1.  
Scree ni n g ( D a ys - 3 0 t o - 1) 
8. 1. 1.  
Scree ni n g Pr oce d ures  
D uri n g Scree ni n g, a n d pri or t o ra n d o mizati o n, Partici pa nt eli gi bilit y will be assesse d, a n d t he 
f oll o wi n g Scree ni n g pr oce d ures will be c o n d u cte d: 
•  
I nf or me d c o ns e nt pri or t o a n y st u d y- relate d pr oce d ures 
•  
E val uati o n of e li gi bilit y criteria 
•  
Dia g n osis c o nfir me d f or cli nicall y defi nite or pr o b a ble A L S or la b orat or y s u p p orte d 
pr o ba ble A L S as d efi ne d i n t he re vise d El Esc ori al/ Airlie H o use dia g n ostic criteria  
•  
De m o gra p hics, b aseli ne c haracteristics, a n d me dical h ist or y 
•  
C o nc o mita nt m e dicati o ns  a n d pr oce d ures 
•  
A L S F R S - R 
•  
S V C  
•  
Vital si g ns, wei g ht, a n d hei g ht 
•  
C o m plete p h ysical exa m i nati o n 
•  
1 2- Lea d E C G 
•  
Ser u m c he mistr y a n d he mat ol o g y, a n d c oa g ulati o n pr ofile 
•  
Uri ne P re g na n c y Test (f or w o me n of c hil d beari n g p ote ntial o nl y) 
•  
Viral Scree ni n g – HI V, A nti - H u ma n T- Cell L y m p h otr o pic Vir us ( H T L V) I/II a nti b o d y 
wit h refle x c o nfir mat or y assa y , He p atitis B c ore a nti b o d y (I g M H Bc A b), a nti b o d y t o 
He patitis B a nti ge n ( H Bs A b), He p atitis B s urface  a nti ge n ( H Bs A g) i n a d diti o n t o a 
q ua ntitati ve  H B V viral l oa d if nee d e d cli nicall y, a n d He patitis C a nti b o dies ( A nti- H C V)  
a n d a p ositi ve q ualitati ve P C R t o assess H C V viral l oa d  
8. 1. 2.  
Re vise d  El Esc ori al/ Airlie H o use Criteri a  
Acc or di n g t o t he Re vise d El Esc orial/ Airlie H o use g ui deli nes ,6 5 defi niti o ns f or A L S are as 
f oll o ws:  
•  Cli nic all y defi nite A L S  is defi ne d b y cli nical or electr o p h ysi ol o gical e vi de nce b y t he 
prese nce of l o wer m ot or ne ur o n ( L M N) as well as u p per m ot or ne ur o n ( U M N) si g ns i n 

Heli x mit h C o., Lt d. 
C O N FI D E N TI A L   
Pr ot oc ol: V M A L S- 0 0 2- 2 
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 
Versi o n 3. 0 
5 7 
Fi nal : 2 0 Ja n uar y 2 0 2 1 
t he b ul bar re gi o n a n d at l east 2 s pi nal re gi o ns or t he prese n ce of L M N a n d U M N si g ns i n 
3 s pi nal re gi o ns. 
•  Cli nic all y pr o b a ble A L S  is defi ne d o n cli nical or electr o p h ysi ol o gical e vi de nce b y L M N 
a n d U M N si g ns i n at least 2 re gi o ns wit h s o me U M N si g ns necessaril y r ostral t o (a b o ve) 
t he L M N si g ns. 
•  Pr o b a ble A L S – L a b or at or y S u p p orte d , w hic h is defi ne d w he n cli nical si g ns of U M N 
a n d L M N d ysf u ncti o n ar e f o u n d i n o nl y 1 re gi o n b ut electr o p h ysi ol o gical si g ns of L M N 
l oss are o bser v e d i n ≥2 r e gi o ns. 
8. 2.  
S afet y Assess m e nts  
8. 2. 1.  
P h ysic al E x a mi n ati o ns 
A c o m plete p h ysical e x a mi nati o n ( P E) will be perf or me d at t he Scree ni n g , pre d ose o n D a ys 0, 
1 4, 6 0, 7 4, 1 2 0, a n d 1 3 4, a n d o n Da ys 3 0, 8 4, 1 4 4, a n d Da y 1 8 0/ E T . T he c o m plete P E will 
i ncl u de t he f oll o wi n g: a n e xa mi nati o n of t he s ki n/i nte g u me ntar y s yste ms, g e neral a p peara n ce, 
hea d, nec k (i ncl u di n g t h yr oi d), e yes, ears, n ose, t hr oat, l y m p h n o des, c hest (l u n gs), heart, 
a b d o me n, m usc ul os kelet al s yste m, ne ur ol o gical s yste m, a n d a n y a d diti o nal assess me nts nee de d 
t o esta blis h Baseli ne  stat us or e val uate s y m pt o ms or A Es. Hei g ht will be rec or de d o nl y d uri n g 
Scree ni n g . A n y a b n or malities s h o ul d be cate g orize d as cli nicall y si g nifica nt ( C S) or n ot 
cli nicall y si g nifica nt ( N C S), a n d t he a b n or malities rec or d e d . 
T he I n vesti gat or or q u alifie d me dical pers o n nel w h o r o uti nel y perf or m t hes e e val uati o ns i n 
patie nts wit h A L S will c o n d uct t he e xa mi nati o n, deter mi ne fi n di n gs, a n d assess a n y 
a b n or malities as t o cli nical si g nifica nce. 
8. 2. 2.  
Me dic al Hist or y  
A detaile d descri pti o n of t he Partici pa nt ’s c urre nt disease stat us, past me dical c o n diti o ns 
(i ncl u di n g ca ncer), s o cial hist or y, a n d me dicati o n a n d treat me nt hist or y will be rec or de d at t he 
Scree ni n g Visit . 
T he I n vesti gat or will c o nfir m t he dia g n osis of A L S usi n g t he re vise d El Esc orial / Airlie H o use 
dia g n ostic criteria . 
S ocial hist or y i ncl u des  fa milial, occ u pati o nal, a n d recreati o nal as p ects of t h e Partici pa nt's 
pers o nal life t hat ha v e t h e p ote ntial t o be cli nicall y si g nifica n t, i ncl u di n g caffei n e, nic oti ne, 
alc o h ol, a n d illicit dr u g use. 
Me dicati o n a n d treat me nt hist or y will als o be c ollecte d at S cree ni n g, incl u d i n g ril uz ole a n d 
e dara v o n e. 
Ca ncer h ist or y will  be c ollecte d f or t he 3 y ears pri or t o S cree nin g. Fa milial ca ncer hist or y will 
als o be c ollecte d.  

Heli x mit h C o., Lt d. 
C O N FI D E N TI A L   
Pr ot oc ol: V M A L S- 0 0 2- 2 
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 
Versi o n 3. 0 
5 8 
Fi nal : 2 0 Ja n uar y 2 0 2 1 
A n y u nt o war d me dical e ve nts t hat occ ur fr o m t he ti me of c o nse nt a n d d uri n g t he Scree ni n g  
peri o d ( pri or t o st u d y dr u g a d mi nistrati o n) will be ca pt ure d as A Es i n t he el ectr o nic case re p ort 
f or m (e C R F). A c ha n g e i n me dical stat us or me dical hist or y fr o m ti me of si g ni n g of i nf or me d 
c o nse nt t hr o u g h first d os e of st u d y dr u g is t o be re p orte d as a n A E or S A E ( o nl y if ass ociate d 
wit h a st u d y s pecific pr o ce d ure) as a p pr o priate.  
8. 2. 3.  
1 2- Le a d Electr oc a r di o gr a ms  
1 2- Lea d E C Gs will be perf or me d d uri n g Scree ni n g, Da y 8 4, a n d D a y  1 8 0/ E T. A n y cli nicall y 
si g nifica nt a b n or malities are t o be rec or de d. T h e E C G rec or di n g will be pri nte d o ut a n d st ore d 
wit h t he Partici pa nt ’s rec or ds. 
8. 2. 4.  
Vit al Si g ns  
Vital si g ns will be meas ure d at Scr ee ni n g a n d all s u bse q ue nt st u d y visits, i ncl u di n g pre - a n d 
p ost- d ose at St u d y I njecti o n Visits d uri n g Treat me nt C ycle 1 ( Da ys 0 a n d 1 4), Treat me nt C ycl e 2 
( Da ys 6 0 a n d 7 4 ), a n d Tr eat me nt C ycle 3 ( D a ys 1 2 0 a n d 1 3 4), a n d at all ot her St u d y Visits 
( Da ys 3 0, 8 4, 1 4 4, a n d 1 8 0/ E T). Wei g ht will be c ollecte d pre d os e at St u d y I njecti o n Visits. After 
resti n g i n t he seate d p ositi o n f or 5 mi n utes, vital si g ns will be rec or d e d  i ncl u di n g te m perat ure, 
sitti n g bl o o d press ure, heart rate, res pirat or y rate, a n d o x y ge n sat urati o n o n r o o m air. T he met h o d 
of te m perat ur e meas ure m e nt s h o ul d be acc or di n g t o t he Site ’s p olic y a n d s h o ul d be c o nsiste ntl y 
a p plie d. 
8. 2. 5.  
C o a g ul ati o n Pr ofile 
Bl o o d sa m ples f or meas ure me nt of c o a g ulati o n pr ofile para m eters ( P T, P T T, a n d I N R) will be 
c ollecte d at Scr ee ni n g. 
8. 2. 6.  
Cli nic al L a b or at or y Assess me nts 
T he I n vesti gat or m ust re vie w t he la b orat or y re p ort, d oc u me nt t his re vie w, a n d rec or d a n y 
cli nicall y rele va nt c ha n g es occ urri n g d uri n g t he st u d y. T he la b orat or y re p orts m ust be file d wit h 
t he s o urce d o c u me nts. Cli nic all y si g nifica nt a b n or mal la b orat or y fi n di n gs are t h ose t hat are n ot 
ass ociate d wit h t he u n derl yi n g disease, u nless j u d ge d b y t he I n vesti gat or t o be m ore se v ere t ha n 
e x pecte d f or t he Partici p a nt ’s c o n diti o n. 
All pr ot oc ol-re q uir e d la b orat or y assess me nts m us t be perf or me d i n acc or d a nce wit h t he 
la b orat or y ma n u al a n d t h e S o A. 
8. 2. 6. 1.  
L oc al a n d Ce ntr al L a b or at or y Ass ess me nts 
T he la b orat or y assess me nts f or safet y a n d esta blis hi n g eli gi bilit y will be perf or me d at l ocal 
la b orat ories at t he ti me p oi nts n ote d i n Secti o n 1. 3  ( S o A). T he Scree ni n g L ocal la b orat or y res ults 
fr o m Scree ni n g will be e ntere d i nt o t he E D C s yste m  b y t he sites. All assess me nts  fr o m Da y 0 t o 
1 8 0 / E T will be perf or me d b y t he ce ntral la b orat or y; t h ose f or Scree ni n g will be d o ne b y a l ocal 
la b orat or y. 
T he I n vesti gat or m ust re vie w t he la b orat or y re p ort, d oc u me nt t his re vie w, a n d rec or d a n y 
cli nicall y rele va nt c ha n g es occ urri n g d uri n g t he st u d y. T he la b orat or y re p orts m ust be file d wit h 

Heli x mit h C o., Lt d. 
C O N FI D E N TI A L   
Pr ot oc ol: V M A L S- 0 0 2- 2 
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 
Versi o n 3. 0 
5 9 
Fi nal : 2 0 Ja n uar y 2 0 2 1 
t he s o urce d o c u me nts a n d u pl oa de d i nt o t he E D C. Cli nicall y si g nifica nt a b n or mal la b orat or y 
fi n di n gs are t h ose t hat ar e n ot ass ociate d wit h t he u n derl yi n g disease, u nless j u d ge d b y t he 
I n v esti gat or t o be m ore s e vere t h a n e x pecte d f or t he Partici pa nt’s c o n diti o n. 
All pr ot oc ol-re q uir e d la b orat or y assess me nts m ust be perf or me d i n acc or d a nce wit h t he 
la b orat or y ma n u al a n d t h e S o A. 
8. 2. 6. 1. 1.  He m at ol o g y 
•  W hite bl o o d cell c o u nt 
•  Ne utr o p hil (i ncl u di n g cal c ulate d a bs ol ute ne utr o p hil c o u nt) 
•  He m o gl o bi n 
•  He mat ocrit  
•  Platelet  c o u nt 
8. 2. 6. 1. 2.  Ki d ne y F u ncti o n Tests  
•  Bl o o d urea nitr o ge n ( B U N) 
•  Creati ni ne  
8. 2. 6. 1. 3.  Li ver F u ncti o n Tests  
•  As partate a mi n otra nsferase  ( A S T) 
•  Ala ni ne a mi n otra nsf eras e  ( A L T) 
•  Al kali ne  p h os p hatase 
•  Ga m ma - gl uta m yl tra ns pe pti dase ( G G T) 
•  T otal  bilir u bi n  
•  T otal  pr otei n 
•  Al b u mi n  
8. 2. 6. 1. 4.  Cli nic al C he mistr y  
•  Electr ol ytes (s o di u m, p otassi u m, c hl ori de, bicar b o nate, cal ci u m, i n or ga nic p h os p hate, 
ma g nesi u m) 
•  Gl uc ose (r a n d o m c ollecti o n, i.e., n ot necessaril y fasti n g) 
•  A m ylase  
•  Li pase  
•  Lactate  d e h y dr o ge n ase 
•  Creati ne  ki nase 

Heli x mit h C o., Lt d. 
C O N FI D E N TI A L   
Pr ot oc ol: V M A L S- 0 0 2- 2 
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 
Versi o n 3. 0 
6 0 
Fi nal : 2 0 Ja n uar y 2 0 2 1 
8. 2. 6. 1. 5.  A d diti o n al Tests  
•  Uri ne pre g n a nc y  t est 
8. 2. 6. 1. 6.  Vir al  Scree ni n g  
•  HI V  
•  H T L V  I/II a nti b o d y wit h refle x c o nfir mat or y assa y 
•  H Bc A b  (I g M) 
•  H Bs A b  
•  H Bs A g  
•  H B V viral l oa d (if nee de d cli nicall y)  
•  A nti -H C V  a nti b o dies a n d a p ositi ve q ualitati ve P C R t o assess H C V viral  l oa d 
8. 2. 7.  
Sl o w Vit al C a p acit y  
Sl o w vital ca pacit y is a p ul m o nar y f u ncti o n test t hat q ua ntifies t he v ol u me of air t hat ca n be 
sl o wl y e x hale d aft er sl o w ma xi m u m i n halati o n. S V C will be deter mi ne d at Scree ni n g, pre d ose 
o n Da ys 6 0 a n d 1 2 0, a n d o n Da ys 3 0, 8 4, 1 4 4, a n d 1 8 0 / E T.  
8. 3.  
Ot her Assess m e nts a n d Pr oce d ures  
8. 3. 1.  
Re vise d A m y otr o p hic L ater al Scler osis F u ncti o n al R ati n g  
T he re vise d A m y otr o p hi c Later al Scler osis F u n cti o nal Rati n g Scale ( A L S F R S -R) is a vali date d 
rati n g scale f or meas uri n g t he gl o bal f u ncti o n of p atie nts wit h A L S. It pr o vi des a healt h 
pr ofessi o nal- g e ner ate d esti mate of t he patie nt’s de gree of f u ncti o nal i m pair me nt, w hic h ca n b e 
e val uate d seriall y t o o bjecti vel y assess a n y res p o nse t o treat me nt or pr o gressi o n of disease. T he 
A L S F R S - R i ncl u des t wel ve q uesti o ns t hat as k t he p h ysicia n t o rate his/ her i m pressi o n of t he 
patie nt’s le vel of f u n cti o nal i m pair me nt i n perf or mi n g o ne of t wel ve c o m m o n tas ks, e. g., 
cli m bi n g stairs . Eac h tas k is rate d o n a fi ve - p oi nt scale fr o m 0 (ca n't d o) t o 4 ( n or mal a bilit y). 
I n di vid ual ite m sc or es ar e s u m me d t o pr o d uce a re p orte d sc ore of b et wee n 0 = w orst a n d 4 8 = b est . 
T he A L S F R S - R will be c o n d ucte d at Scree ni n g, pre d ose o n Da ys 0, 6 0, a n d 1 2 0, a n d o n 
Da y s 3 0, 8 4, 1 4 4, a n d 1 8 0/ E T. Details a b o ut t he s cale ca n be f o u n d i n Secti o n  1 0. 6 , A p pe n di x 6. 
8. 3. 2.  
H a n d hel d D y n a m o m etr y  
M uscle stre n gt h will be meas ure d q u a ntitati vel y b y Ha n d hel d D y na m o metr y ( H H D ) a n d t he 
c ha n ge fr o m baseli ne i n H H D f oll o wi n g E n ge nsis i njecti o ns as c o m pare d t o Place b o. H H D is a 
pr oce d ur e b y w hic h a d y na m o meter is a p plie d t o t he b o d y of a n i n di vi d ual bei n g teste d. 6 6 
A n o n- A C p o wer e d d y na m o meter ( ma n ufact ure d b y H o g ga n Healt h I n d ustries, I nc ) will be use d 
at all cli nical sites . T hese meas ure me nts will be perf or me d pre d ose o n D a ys 0, 6 0, a n d 1 2 0, a n d 
o n Da ys 3 0, 8 4, 1 4 4, a n d 1 8 0/ E T. Stre n gt h meas ure me nts will be e val u ate d b y i n di vi d ual 
m uscles. 6 7 

Heli x mit h C o., Lt d. 
C O N FI D E N TI A L   
Pr ot oc ol: V M A L S- 0 0 2- 2 
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 
Versi o n 3. 0 
6 1 
Fi nal : 2 0 Ja n uar y 2 0 2 1 
8. 3. 3.  
Acc ur at e Test of Li m b Is o metric Stre n gt h  
T he Acc urate T est of Li m b Is o metric Stre n gt h (A T LI S ) is desi g ne d t o e v al uate m uscle stre n gt h 
a n d meas ur e t he is o metri c stre n gt h of 1 2 m uscle gr o u ps i n t he ar ms a n d le gs a n d will be 
c o n d ucte d at cli nical sites t hat ha ve A T LI S a v aila ble  a n d staff trai ne d a n d a vaila ble t o a d mi nister 
t he stre n gt h e val uati o n. A T LI S will be meas ure d pre d ose o n D a ys 0, 6 0, a n d 1 2 0, a n d at Visits 
o n Da ys 3 0, 8 4, 1 4 4, a n d 1 8 0/ E T 
8. 3. 4.  
M uscle Bi o psies  
Heli x mit h i nte n ds t o use m uscle bi o ps y sa m ples of t he gastr oc n e mi us t o e val uate bi o mar kers i n 
or der t o gai n f urt her u n d ersta n di n g of E n ge nsis’ mec ha nis m of acti o n  a n d m uscle atr o p h y i n 
A L S. Testi n g res ults c o ul d pr o vi de i nf or mati o n f or f ut ure uses of E n g e nsis i n A L S. A bi o ps y of 
t he gastr oc ne mi us will be c ollecte d (a n d st ore d) at Da y 0 pre d ose, a n d o n Da y s 8 4 ( o pti o nal) a n d 
1 4 4. See t he M uscle Bi o ps y G ui deli nes f or detail e d i nf or mati o n o n t he tec h ni q ues a n d 
pr oce d ur es t o be use d. 
8. 3. 5.  
Q u alit y of Life Assess me nt , P atie nt Re p orte d O utc o mes, a n d Cli nic al Re p orte d 
O utc o m es  
8. 3. 5. 1.  
A m y otr o p hic L ater al Scler osis Assess me nt Q uesti o n n aire 
T he A m y otr o p hic Lateral Scler osis Assess me nt Q uesti o n naire ( A L S A Q - 4 0) is a disease-s p ecific, 
Partici pa nt  self-r e p ort healt h stat us, or electr o nic patie nt -re p ort e d o utc o me (eP R O). T here are 
4 0 q uesti o ns i n t he A L S A Q- 4 0 wit h 5 discret e scales: p h ysic al m o bilit y ( 1 0 q uesti o ns), acti vities 
of dail y li vi n g a n d i n de pe n de nce ( 1 0 q uesti o ns), eati n g a n d dri n ki n g ( 3 q uesti o ns), 
c o m m u nicati o n ( 7 q uesti o ns), a n d e m oti o nal reacti o ns ( 1 0 q uesti o ns). T he A L S A Q - 4 0 will be 
meas ure d pr e d ose o n D a y 0 a n d at Visits o n Da ys 8 4 a n d 1 8 0/ E T. See Secti o n 1 0. 7 , A p pe n di x 7, 
f or t he A L S A Q - 4 0 q u esti o n naire. 
Partici pa nts are as ke d t o t hi n k a b o ut t he diffic ulties t hat t he y ma y ha ve e x p erie nce d d uri n g t he 
last t w o wee ks ( e. g., “I h a ve f o u n d it diffic ult to fee d m yself ”). Partici pa nts are as k e d t o i n dicate 
t he fre q u e nc y of eac h e v e nt b y selecti n g o ne of 5 o pti o ns ( Li kert scale): n e ver, rarel y, 
s o meti mes, ofte n, al wa ys, or ca n n ot d o at all. 
8. 3. 5. 2.  
P atie nt Gl o b al I m pressi o n of C h a n ge 
T he Partici pa nt’s i m pressi o n of c ha n ge after treat me nt will be meas ure d wit h t he Patie nt Gl o bal 
I m pr essi o n of C ha n ge ( P GI C) q uesti o n naire t hr o u g h use of t he e P R O. T his q uesti o n naire 
meas ures t he Partici pa nt’s perce pti o n of h o w treat me nt has affecte d t heir le vel of acti vit y, 
s y m pt o ms, e m oti o ns, a n d o verall q ualit y of life. E ac h descri pt or is ra n ke d o n a n i nte nsit y scale 
of 1 = Ver y M uc h I m pr o ve d; 2 = M uc h I m pr o v e d; 3 = Mi ni mall y I m pr o ve d; 4 = N o C ha n ge; 
5 = Mi ni mall y W orse; 6 = M uc h W ors e; 7 = V er y M uc h W orse. T h e test will be self -
a d mi nistere d d uri n g t he Da ys 8 4 a n d 1 8 0/ E T Visits. T he P GI C q uesti o n naire is prese nt e d i n 
Secti o n 1 0. 8 , A p pe n di x 8. 

Heli x mit h C o., Lt d. 
C O N FI D E N TI A L   
Pr ot oc ol: V M A L S- 0 0 2- 2 
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 
Versi o n 3. 0 
6 2 
Fi nal : 2 0 Ja n uar y 2 0 2 1 
U p o n c o m pleti o n of t he q uesti o n naire, t he st u d y c o or di nat or will c hec k t h e q uesti o n naire f or 
c o m plete ness. A n y o missi o ns or a m bi g u o us a ns wers will be clarifie d b y t h e Partici pa nt pri or t o 
lea vi n g t he cli nic.  
8. 3. 5. 3.  
Cli nic al Gl o b al I m pressi o n of C h a n ge  
T he Cli nical Gl o bal I m pr essi o n of C ha n ge ( C GI C ) is a vali date d i nstr u me nt c o m plete d b y 
o bser vers as a n ass ess me nt of Q o L. T he C GI C is a 7- p oi nt scale wit h sc ores ra n ge fr o m 1 ( ver y 
m uc h i m pr o ve d) t hr o u g h 7 ( ver y m uc h w orse). T h e test will be self -a d mi nistere d d uri n g t he 
Da ys 8 4 a n d 1 8 0/ E T Visits. T he C GI C q u esti o n naire is prese nt e d i n Secti o n 1 0. 8 , A p pe n di x 8. 
8. 4.  
Bl o o d S a m ples St ore d f or F ut ure Ge neti c Testi n g  
Bl o o d sa m ples will be c ollecte d fr o m all Partici pa nts t o be st ore d f or f ut ure ge netic testi n g at 
Scree ni n g.  
8. 5.  
A d verse E ve nts a n d Seri o us A d verse E ve nts  
T he defi niti o ns of A Es , T E A Es, S A Es  a n d T E S A Es  ca n be f o u n d i n Secti o n  1 0. 2 , A p pe n di x 2. 
8. 5. 1.  
Ti m e Peri o d a n d Fre q ue nc y f or C ollecti n g A E, T E A E, S A E , T E S A E 
I nf or m ati o n 
All st u d y -relate d A Es a n d S A Es  will be c ollecte d starti n g after c o m pleti o n of t he i nf or me d 
c o nse nt pr ocess at Scree ni n g t o Da y 0/ra n d o mizati o n. T E A Es a n d T E S A Es  will be c ollecte d 
after first i njecti o ns o n  Da y 0 t hr o u g h Da y 1 8 0/ E T or t he last St u d y Visit u p u ntil t he ti me t hat 
t he Partici pa nt wit h dra ws c o nse nt.  (see defi niti o n of T E A E, Secti o n  1 0. 2 ). A n y S A E occ urri n g 
after c o nse nt a n d bef ore t he first i njecti o n o n Da y 0 s h o ul d be rec or de d a n d re p orte d o nl y if 
ass ociate d wit h a pr ot o c ol -s pecifie d pr o ce d ure. A n y A Es re p orte d d uri n g Scree ni n g after 
c o m pleti o n of i nf or me d c o nse nt will be c ollecte d a n d rec or d e d se paratel y fr o m T E A Es re p orte d 
o n Da y 0 a n d t hr o u g h t he e n d of t he st u d y. 
Me dical occ urre n ces t hat be gi n bef or e t he start of st u d y i nter ve nti o n a n d n ot relate d t o re q uire d 
st u d y pr oce d ur es, b ut aft er o btai ni n g i nf or me d c o nse nt will be rec or d e d o n t he Me dical 
Hist or y/ C urre nt Me dical C o n diti o ns secti o n of t he e C R F a n d n ot as A Es. 
All S A Es will be rec or de d a n d re p ort e d t o t he S p o ns or or desi g nee i m me di atel y a n d u n der n o 
circ u msta nce s h o ul d t his e xcee d 2 4 h o urs, as i n dicate d i n Secti o n 1 0. 2. 6 , A p pe n di x 2. T he 
I n v esti gat or will s u b mit a n y u p date d S A E data t o t he S p o ns or wit hi n 2 4 h o urs of its a vaila bilit y. 
I n v esti gat ors ar e n ot o bli gate d t o acti vel y see k A Es or S A Es after c o ncl usi o n of t he st u d y 
partici pati o n. H o we v er, if t he I n vesti gat or lear ns of a n y S A E, i ncl u di n g a d eat h, at a n y ti me after 
a Partici pa nt  has bee n disc har ge d fr o m t he st u d y, a n d he/s he c o nsi ders t he e ve nt t o be p ossi bl y, 
pr o ba bl y, or defi nitel y relate d t o t he st u d y i nter ve nti o n or st u d y partici pati o n, t he I n vesti ga t or 
m ust pr o m ptl y n otif y t he S p o ns or. 

Heli x mit h C o., Lt d. 
C O N FI D E N TI A L   
Pr ot oc ol: V M A L S- 0 0 2- 2 
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 
Versi o n 3. 0 
6 3 
Fi nal : 2 0 Ja n uar y 2 0 2 1 
8. 5. 2.  
Met h o d of Detecti n g A Es, T E A Es, S A Es a n d T E S A Es  
T he met h o d of rec or di n g, e val uati n g, a n d ass essi n g ca usalit y of A Es, T E A Es, S A Es a n d 
T E S A Es , a n d t he pr oce d ures f or c o m pleti n g a n d tra ns mitti n g S A E re p orts are pr o vi d e d i n 
Secti o n 1 0. 2 , A p pe n di x 2. 
Care will be ta ke n n ot t o i ntr o d uce bias w he n d etecti n g A Es a n d/ or S A Es. O pe n-e n d e d a n d 
n o n-lea di n g ver b al q uesti o ni n g of t he Partici pa nt  is t he preferre d m et h o d t o i n q uire a b o ut A E 
occ urr e nces.  
8. 5. 3.  
S A E Re p orti n g t o t he S p o ns or or Desi g nee  
All S A Es s h o ul d be re p orte d t o t he S p o ns or or desi g nee wit hi n 2 4 h o urs of k n o wle d ge of t he 
S A E occ urri n g. 
8. 5. 4.  
A d verse E ve nts of S peci al I nterest  
C ate g ories of A E SIs  
T here are t hr ee  mai n cate g ories of A E SIs  as prese nte d bel o w: 1) t h ose c o nsi dere d t o be relate d t o 
t he a n gi o ge nesis p ote ntial of E n ge nsis, 2) ot her m e dical pr o ble ms i n t his patie nt p o p ulati o n, a n d 
3) i njecti o n site reacti o ns. 
8. 5. 4. 1.  
A E SI C o nsi dere d Rel ate d t o A n gi o ge n esis 
At her oscler osis  
H y per plasia of t he vasa v as or u m i n t he earl y sta g es of at her oscl er osis is i n de pe n de nt of 
a n gi o ge nesis, b ut t he i nti mal ne o vasc ularizati o n t hat f oll o ws t he h y per plasia of t he vasa v as or u m 
is a n gi o ge nesis- de pe n d e nt.6 8 A n gi o ge nesis i ncreas es o x y ge n a n d n utrie nts t o t he arter y wall a n d 
s u p p orts i nitial pla q ue gr o wt h. O nce t he at her oscl er otic pla q ue d e vel o ps, i nti mal a n gi o ge nesis is 
t h o u g ht t o c o ntri b ute t o c haract eristics of a n u nsta ble pla q ue, pla q ue h e m orr ha ge, a n d pl a q ue 
r u pt ure. T heref ore, dia g n oses s u g gesti ve of rece nt c or o nar y arter y disease si nce Baseli ne will be 
e val uate d as A E SIs.  
Ca ncer  
A n gi o ge nesis pla ys a n i m p orta nt r ole i n t he pr oliferati o n a n d m etastatic s prea d of ca n cer as t hese 
pr ocesses are d e pe n de nt o n a n a de q u ate s u p pl y of o x y ge n a n d n utrie nts a n d re m o val of w aste 
pr o d ucts. 6 9 A ll t y pes of ca ncer r e p orte d after ra n d o mizati o n will be dee me d t o be A E SIs. 
8. 5. 4. 2.  
Ot her Me dic al Pr o ble ms  i n A L S P atie nts 
Se veral me dical pr o ble ms are fre q ue ntl y o bser ve d i n patie nts wit h A L S t hat s h o ul d be 
c o nsi dere d A E SIs. T h ese me dical pr o ble ms are liste d bel o w. 
•  P ul m o nar y Me dical Pr o ble ms: Beca use patie nts wit h A L S are at a n i ncreas e d ris k t o 
de vel o p p ul m o nar y me di al pr o ble ms s uc h as as pirati o n of f o o d or li q ui ds. p ne u m o nia, 

Heli x mit h C o., Lt d. 
C O N FI D E N TI A L   
Pr ot oc ol: V M A L S- 0 0 2- 2 
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 
Versi o n 3. 0 
6 4 
Fi nal : 2 0 Ja n uar y 2 0 2 1 
a n d res pirat or y arrest, all e ve nts of t his t y pe t hat occ ur after ra n d o mizatio n will be 
c o nsi dere d A E SIs. 
•  Pr o gressi ve M uscle Wea k ness:  Beca use s o me p atie nts wit h A L S ma y de vel o p ra pi dl y 
pr o gressi ve m uscle wea k ness t hat res ults i n l oss of a bilit y t o care f or self, d ec u bit us 
ulcers, or w ei g ht l oss d ue t o i m paire d de gl utiti o n, all e ve nts of t his t y pe t hat occ ur after 
ra n d o mizati o n will be c o nsi dere d A E SIs. 
•  B ul bar Disease:  Partici pa nts ma y de vel o p b ul bar disease or w orse ni n g o n b ul bar disease 
f oll o wi n g ra n d o mizati o n ma nifeste d as c h alle n ges wit h d ysart hria, facial wea k ness, 
i m paire d t o ng ue p ulsi o n or palate el e vati o n, a n d i m paire d masticati o n a n d s wall o wi n g; 
all of t hese t y pes of e ve nts t hat occ ur aft er ra n d o mizati o n will be c o nsi dere d A E SIs.   
8. 5. 4. 3.  
I njecti o n Site Re acti o ns 
T he m ost c o m m o n I S Rs i n t he pri or P hase 1/ 2 st u d y i n A L S Partici pa nts were  l ocal pai n a n d 
br uisi n g at t he site of i njecti o n . A f oll o w- u p n otificati o n  f or IS R s will occ ur wit hi n 2 t o 3 da ys 
after eac h St u d y I njecti o n Visit. T he l ocati o n a n d te m p oral relati o ns hi p t o t he m ost rece nt 
i njecti o ns will deter mi ne w het her t he e ve nt is a n I S R a n d s h o ul d be re p orte d as a T E A E. F or a n 
A E t o q ualif y as a n I S R, t he reacti o n m ust be l ocate d i n cl ose pr o xi mit y t o a n i njecti o n site a n d 
be first o bser v e d a n d gr a de d wit hi n 4 8 h o urs f oll o wi n g St u d y I njecti o ns. I S Rs t hat re mai n 
u nres ol ve d aft er 4 8 h o urs will c o nti n ue t o be assesse d at s u bse q ue nt Visits as o n g oi n g A Es u ntil 
res ol ve d. 
8. 5. 5.  
F oll o w- u p of A Es, T E A Es,  S A Es, a n d A E SIs  
After t he i nitial A E / T E A E/ S A E re p ort, t he I n vesti gat or is re q uire d t o pr o acti vel y f oll o w eac h 
Partici pa nt  at s u bse q ue nt Visits/c o ntacts. All S A Es  a n d A E SIs  (see Secti o n 8. 5. 4 ) will be 
f oll o we d u ntil res ol uti o n, sta bilizati o n, t he e ve nt is ot her wise e x plai n e d, or t he Partici pa nt  is l ost 
t o f oll o w- u p (as defi ne d i n Secti o n  1 0. 2. 4 , A p pe n di x 2 ). 
8. 5. 6.  
Re g ul at or y Re p orti n g Re q uire me nts f or S A Es  
Pr o m pt n otificati o n b y t he I n vesti gat or t o t he S p o ns or of a n S A E is esse nti al t o e ns ure t hat le g al 
o bli gati o ns a n d et hical res p o nsi bilities t o war ds t he safet y of Partici p a nt s a n d t he safet y of a st u d y 
dr u g u n der cli nical i n vesti gati o n are met. 
T he S p o ns or has a le g al r es p o nsi bilit y t o n otif y b ot h t he l ocal re g ulat or y a ut h orit y a n d ot her 
re g ulat or y a g e ncies a b o ut t he safet y of a st u d y dr u g u n der cli nical i n vesti gati o n. T he S p o ns or 
will c o m pl y wit h c o u ntr y -s pecific re g ulat or y re q uire me nts relati n g t o safet y re p orti n g t o t he 
re g ulat or y a ut h orit y, I nstit uti o nal Re vie w B oar ds (I R Bs), a n d I n vesti gat ors.  
F or all st u dies, I n vesti gat or Safet y Re p orts m ust be pre pare d f or s us pect e d u ne x pecte d s eri o us 
a d verse reacti o ns ( S U S A Rs) acc or di n g t o l ocal re g ulat or y re q uire m e nts a n d S p o ns or p olic y a n d 
f or war de d t o I n vesti gat ors as necess ar y. 

Heli x mit h C o., Lt d. 
C O N FI D E N TI A L   
Pr ot oc ol: V M A L S- 0 0 2- 2 
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 
Versi o n 3. 0 
6 5 
Fi nal : 2 0 Ja n uar y 2 0 2 1 
A n I n vesti gat or w h o r ecei ves a n I n vesti gat or Safet y Re p ort descri bi n g a n S A E or ot her s pecific 
safet y i nf or mati o n ( e. g., s u m mar y or listi n g of S A Es) fr o m t he S p o ns or will re vie w a n d t he n 
n otif y t he I R B if a p pr o priate acc or di n g t o l ocal re q uire me nts. 
8. 5. 7.  
S p o ns or’s  Res p o nsi bilit y  
All A Es a n d S A Es will be re p ort e d o n a n a n n u al b asis t o F D A i n acc or d a nce wit h t he I N D 
re g ulati o n ( 2 1 C F R 3 1 2). Per t he 2 0 1 0 F D A G ui d a nce D o c u me nt f or I n d ustr y a n d I n vesti gat ors 
“ Safet y Re p orti n g Re q uir e me nts f or I N Ds a n d B A/ B E St u dies,” e ve nts cate g orize d as “ p ossi bl y” 
or “ pr o ba bl y ” relat e d will be treate d as “s us pecte d a d verse reacti o ns.” E ve nts cate g orize d as 
“ defi nitel y” r elate d will be treate d as a n “a d verse reacti o n.”  
All seri o us a n d u ne x pecte d st u d y- dr u g- relate d or s us pecte d a d v erse reacti o ns will be re p orte d t o 
F D A a n d t o all partici pati n g I n vesti gat ors i n a n I N D Safet y Re p ort wit hi n 1 5 cale n dar da ys of 
t he e ve nt aft er t he S p o ns or deter mi nes t hat t he s us pecte d a d v erse reacti o n q ualifies f or re p orti n g 
( 2 1 C F R 3 1 2. 3 2). A n y u ne x pecte d fatal or life-t hreate ni n g st u d y- dr u g-relat e d a d vers e reacti o n  or 
s us pecte d a d v erse reacti o n will be re p orte d t o t he A ge nc y wit hi n 7 cal e n dar da ys after t he 
S p o ns or’s i nitial recei pt of t he i nf or mati o n. 
T he S p o ns or will n otif y all partici pati n g I n v esti gat ors of a n y ne w safet y i nf or mati o n t hat alters 
t he c urr e nt ris k- be nefit assess me nt of t he st u d y me dicati o n or t hat w o ul d b e s ufficie nt t o c o nsi der 
c ha n ges i n E n ge nsis a d mi nistrati o n or i n t he o verall c o n d uct of t he st u d y. 
8. 5. 8.  
Pre g n a nc y a n d C o ntr ace pti o n 
8. 5. 8. 1.  
Pre g n a nc y Test ( W o m e n of C hil d be ari n g P ote nti al O nl y) a n d C o ntr ace pti o n 
Fe male Partici pa nt s m ust be n o n pre g na nt, n o nlact ati n g, a n d eit her p ost me n o pa usal f or at least 
1 year, or s ur gicall y sterile f or at least 3 m o nt hs, or a gree t o use d o u ble- b arrier c o ntrace pti o n 
fr o m 1 4 da ys pri or t o r a n d o mizati o n a n d/ or t heir last c o nfir me d me nstr u al peri o d pri or t o st u d y 
ra n d o mizati o n ( w hic h e ver is l o n ger) u ntil 2 m o nt hs after t he last visit o n Da y 1 8 0. 
D o u ble- barrier c o ntrace pti o n ma y i ncl u de, b ut is n ot li mite d t o, i ntra uteri ne de vice wit h 
s per mici de, fe m ale c o n d o m wit h s per mici de, dia p hra g m wit h s per mici de, cer vical ca p wit h 
s per mici de; ha vi n g a mal e se x ual part ner w h o a grees t o use a mal e c o n d o m wit h s per mici de; or 
ha vi n g a sterile se x u al part ner.  
F or w o me n of c hil d beari n g p ote ntial, a uri ne beta h u ma n c h ori o nic g o na d otr o pi n ( β -H C G) test 
will be perf or me d d uri n g Scree ni n g a n d b ef ore ra n d o mizati o n ( Da y 0); res ults of t he test m ust be 
ne gati ve. T he  β - H C G test will als o be perf or me d at Da y 1 8 0/ E T t o e val u ate w het her t h e 
Partici pa nt  is pre g na nt. 
T he r h yt h m met h o d is n ot c o nsi dere d acce pta ble met h o d of c o ntrace pti o n. 
8. 5. 8. 2.  
Pre g n a nc y  
T he I n vesti gat or will c oll ect pre g n a nc y i nf or m ati o n o n a n y fe male Partici pa n t w h o bec o mes 
pre g na nt w hile partici pati n g i n t his st u d y. T he i nitial i nf or mati o n will be s u b mitte d t o t he 
S p o ns or wit hi n 2 4 h o urs of lear ni n g of a Partici pa nt ’s pre g na nc y. 

Heli x mit h C o., Lt d. 
C O N FI D E N TI A L   
Pr ot oc ol: V M A L S- 0 0 2- 2 
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 
Versi o n 3. 0 
6 6 
Fi nal : 2 0 Ja n uar y 2 0 2 1 
F urt her d osi n g will be disc o nti n ue d f or a n y fe mal e Partici pa nt  w h o bec o mes pre g na nt d uri n g t he 
st u d y. 
T he Partici pa nt  will be f oll o we d t o deter mi ne t he o utc o me of t he pre g na nc y. T he I n vesti gat or 
will c ollect f oll o w - u p i nf or mati o n o n t he Partici pa nt  a n d t he ne o nate, a n d t he i nf or mati o n will be 
f or war de d t o t he S p o ns or. Ge ner all y, f oll o w- u p will n ot be re q uire d f or l o n ger t ha n 6 t o 8 wee ks 
be y o n d t he esti mate d deli ver y date. 
W hile pre g na n c y itself is n ot c o nsi dere d t o be a n A E or S A E, a n y pre g na n c y c o m plicati o n or 
electi ve ter mi nati o n of a pre g na nc y f or me dical reas o ns will be re p orte d as a n A E or S A E. A 
s p o nta ne o us a b orti o n ( occ urri n g at < 2 2 wee ks g estati o nal a ge) or still birt h ( occ urri n g at 
> 2 2 wee ks g estati o nal a ge) is al wa ys c o nsi dere d t o be a n S A E a n d will be re p orte d as s uc h. 
Ot her a b n or m al pre g na n c y o utc o mes (e. g., fetal deat h, c o n g e nital a n o malies, ect o pic pre g n a nc y) 
are als o c o nsi dere d S A Es a n d will be re p ort e d. 
A n y p ost-st u d y pre g na nc y-relate d S A E c o nsi dere d p ossi bl y, pr o ba bl y, or defi nitel y relate d t o t he 
st u d y dr u g b y t he I n vesti gat or will be re p ort e d t o t he S p o ns or. W hile t he I n vesti gat or is n ot 
o bli gate d t o acti vel y see k t his i nf or mati o n i n f or mer st u d y Partici pa nt s, he or s he ma y lear n of a n 
S A E t hr o u g h v ol u ntar y r e p orti n g. 
T he I n vesti gat or will rec or d a narrati ve des cri pti o n of t he c o urs e of eac h pre g na nc y a n d its 
o utc o me. 
8. 5. 9.  
Di se ase-R el ate d E ve nts a n d/ or Dise ase - Rel ate d O utc o mes N ot Q u alif yi n g as A Es 
or S A Es  
E xce pt f or si g ns a n d s y m pt o ms of A L S  (i.e., n u m b ness, pai n, ti n gli n g or b ur ni n g se nsati o n, 
cra m ps, a n d i ncreas e d se nsiti vit y t o t o uc h), all disease -relate d e ve nts or dis ease-relate d o ut c o mes 
q ualif y as A Es or S A Es. 
8. 6.  
St u d y  C o m pleti o n  
8. 6. 1.  
E n d of St u d y Defi niti o n  
T he e n d of t he st u d y is d efi ne d as t he d ate o n w hi c h t he last Partici pa nt  i n t he st u d y c o m pletes 
t he Da y 1 8 0 Visit  or is disc o nti n ue d. 
8. 6. 2.  
C o m plete d P artici p a nt s 
A Partici pa nt  is c o nsi der e d t o ha ve c o m plet e d t he st u d y if t he Partici pa nt c o m pletes all p hases of 
t he st u d y i ncl u di n g t he last Visit  o n Da y 1 8 0 or t he last sc he d ule d pr o ce d ure s h o w n i n t he S o A.  

Heli x mit h C o., Lt d. 
C O N FI D E N TI A L   
Pr ot oc ol: V M A L S- 0 0 2- 2 
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 
Versi o n 3. 0 
6 7 
Fi nal : 2 0 Ja n uar y 2 0 2 1 
9.  
S T A TI S TI C A L C O N SI D E R A TI O N S  
Detaile d statistical met h o ds are des cri be d i n t he St atistical A nal ysis Pla n ( S A P). 
9. 1.  
S a m ple Size Deter mi n ati o n  
A sa m ple size of 1 8 Partici pa nts was c h os e n f or safet y assess me nts a n d preli mi nar y e val uati o n of 
e x pl orat or y e n d p oi nts.  
9. 2.  
P o p ul ati o n f or A n al ysis: S afet y P o p ul ati o n 
T he safet y a nal ysis p o p ulati o n will c o ntai n all P artici pa nts w h o are ra n d o mi ze d a n d recei ve at 
least o ne St u d y I nj ecti o n . Partici pa nt s will be gr o u pe d acc or di n g t o t heir act ual treat me nt 
recei v e d, n ot acc or di n g t o t heir ra n d o mizati o n assi g n me nt (as ra n d o mize d). Partici pa nts treate d 
wit h a n y E n ge nsis d ose will be gr o u pe d i n t he E n ge nsis gr o u p; P artici pa nt s treate d wit h o ut a n y 
E n ge nsis will be gr o u pe d i n t he Place b o  gr o u p. 
9. 3.  
St atistic a l A n al yses 
T he S A P will be fi nalize d pri or t o data base l o c k a n d will i ncl u de a m ore tec h nical a n d d etaile d 
descri pti o n of t he statistical a nal yses d escri b e d i n t his secti o n . T his secti o n is a s u m mar y of t he 
pla n ne d e n d p oi nts. 
9. 3. 1.  
Pri m ar y E n d p oi nt s 
Safet y a nal yses i n t his st u d y will e val uate t he safet y pr ofile of E n ge nsis as c o m pare d wit h 
Place b o.  T he pri mar y e n d p oi nts f or safet y are as f oll o ws: 
•  I n ci de nce of T E A Es a n d T E S A Es f or E n ge nsis c o m pare d t o Place b o  
•  I n ci de nce of i njecti o n site reacti o ns f or E n ge nsis c o m pare d t o Place b o 
•  I n ci de nce of cli nicall y si g nifica nt la b orat or y v al u es f or E n ge nsis c o m p are d t o Place b o 
N o f or mal statistical testi n g will be c o n d ucte d f or t he safet y a n al yses . All P artici pa nt s i n t he 
safet y s u bset will be i ncl u de d i n t hese a nal ys es. Partici pa nts will be gr o u pe d b y treat me nt 
recei v e d. All s u m maries will be deri ve d bas e d o n a vaila ble data . N o i m p utati o n will be 
perf or me d f or missi n g val ues. All safet y a nal ys es will be ma de o n t he Safet y P o p ulati o n. 
9. 3. 2.  
E x pl or at or y E n d p oi nts  
T he e x pl orat or y e n d p oi nts i ncl u de: 
•  C ha n ge fr o m Baseli ne ( Da y 0) i n t otal mea n A L S F R S-R sc ores at Da y 1 8 0 f or E n ge nsis 
c o m pare d t o Place b o  

Heli x mit h C o., Lt d. 
C O N FI D E N TI A L   
Pr ot oc ol: V M A L S- 0 0 2- 2 
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 
Versi o n 3. 0 
6 8 
Fi nal : 2 0 Ja n uar y 2 0 2 1 
•  C ha n ge fr o m Baseli ne ( Da y 0) i n A L S F R S- R s u bsc ores f or Fi ne a n d Gr oss M ot or 
F u ncti o ns (s u m of sc or es f or ite ms 4 t o 9) a n d f or B ul bar F u ncti o n (s u m of sc ores f or 
ite ms 1 t o 3) o n Da ys 3 0, 6 0, 8 4, 1 2 0, 1 4 4, a n d 1 8 0 f or E n ge nsis c o m pare d t o Place b o  
•  C ha n ges i n t he sl o pe of t he t otal A L S F R S -R sc ore o ver ti me f or E n ge nsis c o m pare d t o 
Place b o  
•  C ha n ge fr o m Baseli ne ( Da y 0) i n m uscle stre n gt h assesse d bilaterall y b y H H D i n m uscles 
i n t he u p per a n d l o wer e xtre mities o n Da ys 3 0, 6 0, 8 4, 1 2 0, 1 4 4, a n d 1 8 0 f or E n ge nsis 
c o m pare d t o Place b o  
•  C ha n ge f r o m Baseli ne ( Da y 0) i n t he A T LI S tests, w here a vaila ble , at Da ys 3 0, 6 0, 8 4, 
1 2 0, 1 4 4, a n d 1 8 0 f or E n ge nsis c o m pare d t o Place b o  
•  C ha n ge fr o m Baseli ne ( Da y 0) i n Q o L usi n g t he A L S A Q- 4 0 o n Da ys 8 4 a n d 1 8 0 f or 
E n ge nsis i njecti o ns c o m pare d t o Place b o  
•  P GI C  a nd C GI C at Da ys 8 4 a n d 1 8 0 f or E n g e nsis c o m pare d t o Place b o 
•  C ha n ge fr o m Baseli ne ( Da y 0) i n S V C o n Da ys 3 0, 6 0, 8 4, 1 2 0, 1 4 4, a n d 1 8 0 f or 
E n ge nsis c o m pare d t o Pl ace b o 
•  Ti me t o trac he ost o m y f or E n ge nsis c o m pare d t o Pl ace b o 
•  Ti me t o all -ca use m ortalit y b y Da y 1 8 0 f or E n g e nsis c o m pare d t o Place b o  
•  C ha n ge fr o m Baseli ne ( Da y 0) i n bi o mar kers f or m uscle atr o p h y i n bi o psies c ollecte d 
bef ore a n d aft er i njecti o ns f or E n ge nsis c o m pare d t o Place b o  
9. 4.  
D at a S afet y M o nit ori n g B o ar d 
A n i n de pe n de nt D ata Saf et y M o nit ori n g B oar d ( D S M B ) will peri o dicall y re vie w bli n de d 
(n o nc o m parati ve) data as a li mite d set of u n bli n de d ta bles a n d/ or listi n gs, i ncl u di n g all re p orte d 
A Es  a n d S A Es. T he o bjecti ves of t he D S M B meeti n gs are t o re vie w t he safet y o utc o mes of t he 
st u d y a n d pr o vi de g ui da n ce t o st u d y s p o ns or re g ar di n g t he safet y of E n g e nsis. T he data a n al yses 
f or t he D S M B meeti n gs will be directl y pr o vi de d t o t he D S M B me m bers, a n d n o data will be 
releas e d t o t he st u d y s p o ns or or bli n de d desi g nees. N o  a dj ust me nt will be ma de  f or m ulti ple 
testi n g d ue t o t he D S M B data re vie w. F urt her det ails of D S M B res p o nsi bilities are i ncl u de d i n 
t he D S M B C harter. 

Heli x mit h C o., Lt d. 
C O N FI D E N TI A L   
Pr ot oc ol: V M A L S- 0 0 2- 2 
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 
Versi o n 3. 0 
6 9 
Fi nal : 2 0 Ja n uar y 2 0 2 1 
1 0.  
S U P P O R TI N G D O C U M E N T A TI O N A N D O P E R A TI O N A L 
C O N SI D E R A TI O N S  
1 0. 1.  
A p pe n di x 1 . Re g ul at or y, Et hic al , a n d St u d y O versi g ht C o nsider ati o ns  
1 0. 1. 1.  
Re g ul at or y a n d Et hic al C o nsi der ati o ns 
1 0. 1. 1. 1.  I nstit uti o n al Re vie w  B o ar d 
Pri or t o t he i nitiati o n of t he st u d y, t he pr ot oc ol, t he i nf or me d c o ns e nt f or m, a n d I n vesti gat or’s 
Br oc h ure will be s u b mitte d t o t he I R B f or a p pr o v al. B y si g ni n g t he “ State me nt of I n vesti gat or” 
f or m ( F or m F D A 1 5 7 2), t he I n v esti gat or is e ns uri n g t hat a n I R B c o m plia nt wit h t he re q uire me nts 
set f ort h i n 2 1 C F R 5 6 will be res p o nsi ble f or t he i nitial a n d c o nti n ui n g re vie w of t he pr o p os e d 
cli nical st u d y. A c o p y of t he I R B a p pr o val letter f or t he pr ot oc ol, t he i nf or me d c o nse nt, a n d t he 
pr ot oc ol si g nat ure pa g e m ust be s u b mitte d t o t he S p o ns or pri or t o releas e of i n vesti gati o nal 
s u p plies t o t he St u d y Site. T he a p pr o v al letter m ust refer t o t he s p ecific pr ot oc ol a n d t he 
i nf or me d c o nse nt f or m. T he St u d y Site m ust mai ntai n a n acc urate a n d c o m plete rec or d of all 
re p orts, d oc u me nts, a n d ot her s u b missi o ns ma de t o t he I R B c o n cer ni n g t his pr ot oc ol. A list of 
t he I R B me m bers, t heir titles or occ u pati o ns, a n d t heir i nstit uti o nal affiliati on, or a n I R B 
ass ura nce n u m ber m ust b e pr o vi de d t o t he S p o ns or pri or t o release of st u d y s u p plies. 
Healt h a ut h orit y re g ul ati o ns re q uire t hat all a d v ertise me nts f or Partici pa nt  recr uit me nt be 
a p pr o ve d b y a n I R B pri or t o i m ple me ntati o n. T he c o m plete te xt a n d f or mat m ust be s u b mitte d t o 
t he S p o ns or f or a p pr o v al pri or t o I R B s u b missi o n. 
T he I n vesti gat or is r es p o nsi ble f or n otif yi n g t he I R B of a n y S A Es as re q uire d b y t he I R B. A 
c o p y of t he n otificati o n m ust be f or war d e d t o t he S p o ns or or its desi g nee. 
Stat us re p o rts m ust be s u b mitte d t o t he I R B at least o nce a year ( or m ore fre q ue ntl y as re q uire d 
b y t he I R B), a n d t he I R B m ust be n otifie d of c o m pleti o n or ter mi nati o n of t he st u d y. 
1 0. 1. 1. 2.  I nf or m e d C o nse nt Pr ocess  
T he I n vesti gat or h as t he r es p o nsi bilit y t o i nf or m eac h Partici pa nt, pri or t o t he Scree ni n g 
e val uati o n, of t he p ur p os e of t his cli nical st u d y, i ncl u di n g p ossi ble ris ks a n d be nefits, a n d 
d oc u me nt t he i nf or me d c o nse nt pr ocess i n t he Partici pa nt’s c hart. A n i nf or me d c o nse nt f or m 
c o ntai ni n g t he re q uir e d ele me nts of i nf or me d c o ns e nt m ust be ge nerate d b y t he I n v esti gat or. 
After a p pr o val b y t he S p o ns or, t he i nf or me d c o ns e nt f or m (I C F) m ust be s u b mitte d t o a n d 
a p pr o ve d b y a n I R B. Pri or t o e ntr y i nt o t he st u d y or i nitiati o n of a n y st u d y- relate d pr o ce d ures, 
t he Partici pa nt m ust rea d, si g n, a n d date t he I C F. T he pers o n e x ec uti n g t he c o nse nt m ust als o 
si g n a n d date t he I R B-a p pr o ve d I C F. O ne ori gi nal I C F is t o be retai n e d b y t he St u d y Site, a n d a 
c o p y is t o be gi ve n t o t he Partici pa nt. T he i nf or me d c o nse nt pr ocess m ust be d oc u me nte d i n t he 
Partici pa nt’s s o urce/ me di cal rec or d.  
T he I C F m ust be writte n i n a la n g ua ge i n w hic h t h e Partici pa nt  is fl ue nt. If a f orei g n la n g u a ge 
tra nslati o n is re q uire d, a state me nt of certificati o n of t he tra nslati o n m ust be iss ue d. Re g ulati o ns 
re q uire t hat f orei g n la n g u a ge I C Fs b e s u b mitte d t o t he I R B f or a p pr o v al. T he I n vesti gat or m ust 

Heli x mit h C o., Lt d. 
C O N FI D E N TI A L   
Pr ot oc ol: V M A L S- 0 0 2- 2 
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 
Versi o n 3. 0 
7 0 
Fi nal : 2 0 Ja n uar y 2 0 2 1 
f or war d a c o p y of t he I C F, t he certifie d f orei g n la n g ua ge tra nslati o n, a n d a n I R B a p pr o v al letter 
t o t he S p o ns or. 
T he I n vesti gat or will e x plai n t he st u d y p ur p ose, pr oce d ures , a n d Partici pa nt ’s res p o nsi bilities t o 
t he Partici pa nt. T he Parti ci pa nt ’s willi n g ness a n d a bilit y t o meet t he f oll o w- u p re q uire m e nts will 
be deter mi ne d a n d writte n i nf or me d c o nse nt will be o btai ne d. T he Partici pa nt  will si g n a n d date 
t he I C F. T he I n vesti gat or or a q ualifie d d esi g nee will als o si g n a n d date t he I C F. T h e ori gi nal 
I C F will be retai n e d wit h t he Partici pa nt ’s rec or ds; a c o p y will be pr o vi de d t o t he Partici pa nt .  
If t he I C F is a me n de d d uri n g t he st u d y, t he I n v esti gat or or a q u alifie d desi g nee m u st f oll o w all 
a p plica ble r e g ulat or y r e q uire me nts pertai ni n g t o a p pr o val of t he a m e n de d I C F b y t he I R B. F or 
eac h n e w versi o n of t he I C F, t he I R B will be c o ns ulte d t o deter mi ne if Partici pa nt s w h o ha ve n ot 
c o m plete d t he st u d y m ust be re- c o nse nte d t o t he n e w I C F.  
1 0. 1. 1. 3.  O bli g ati o ns of t he S p o ns or a n d t he I n vesti g at or 
T he S p o ns or will select I n vesti gat ors o n t he basis of m ulti ple criteria t hat i ncl u de t heir e x p ertise 
i n t he area of A L S , t heir Site pers o n nel’s e x perie n ce i n c o n d ucti n g i n vesti g ati o nal cli nical 
st u dies, t heir pr os pects f or recr uiti n g Partici pa nt s t o t he st u d y, a n d t he pr ofi cie nc y wit h w hic h 
he/s he res p o n ds t o t he r e q uire me nts of t he S p o ns or. 
T he S p o ns or a n d I n vesti gat or m ust c o m pl y wit h all a p plica ble re g ulati o ns. I n a d diti o n, t he 
I n v esti gat or m ust f oll o w l ocal a n d i nstit uti o nal re q uire me nts pertai ni n g, b ut n ot li mite d, t o 
i n vesti gati o nal pr o d uct, cli nical researc h, i nf or m e d c o nse nt i ncl u di n g t he use a n d discl os ure of 
t he P artici pa nt s’ pr otecte d healt h i nf or mati o n ( P HI), a n d I R B re g ul ati o ns. T he S p o ns or will 
n otif y t he I n v esti gat or of pr ot oc ol a n d a me n d me nt a p pr o vals b y re g ulat or y a ut h orities w he n 
a p plica ble.  
T he I n vesti gat or a n d cli nical researc h c o or di nat or will be a vaila b le t o res p o n d t o reas o na ble 
re q uests a n d a u dit q ueries ma de b y t he a ut h orize d re g ulat or y a g e nc y re prese ntati ves. T he 
I n v esti gat or a n d cli nical researc h c o or di nat or will pr o vi de t he S p o ns or wit h a d va nce writte n 
n otificati o n if t he y pla n t o rel ocate t o a n ot h er i nstit uti o n. 
E xce pt w here t he I n v esti gat or’s si g nat ure is s pecificall y re q uire d, t he ter m “I n vesti gat or” as use d 
i n t his pr ot oc ol a n d pr ot oc ol-relat e d d oc u me nts is u n derst o o d t o refer t o t he Pri nci pal 
I n v esti gat or ( PI) or a p pr o priate St u d y Site pers o n nel w h o m t he PI d esi g nates t o perf or m a certai n 
d ut y. T his dele gati o n of a ut h orit y nee ds t o be d oc u me nte d a p pr o pri atel y a n d si g ne d b y t he PI. 
T he PI is ulti matel y res p o nsi ble f or t he c o n d uct of all as pects of t h e cli nical  st u d y. 
S u b-i n vesti gat ors or ot her a p pr o priat e St u d y Site pers o n nel (e. g., liste d o n t he F or m F D A 1 5 7 2) 
are eli gi ble t o si g n f or t h e PI o n la b orat or y re p orts a n d ma y be desi g nat e d t o verif y a n d 
electr o nicall y si g n e C R Fs.  

Heli x mit h C o., Lt d. 
C O N FI D E N TI A L   
Pr ot oc ol: V M A L S- 0 0 2- 2 
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 
Versi o n 3. 0 
7 1 
Fi nal : 2 0 Ja n uar y 2 0 2 1 
1 0. 1. 2.  
Fi n a nci al Discl os ure  
1 0. 1. 2. 1.  C o nflict of I nterest P oli c y  
T he i n de pe n de n ce of t he st u d y fr o m a n y act ual or percei v e d i nfl ue nce is critical. T heref ore, a n y 
act ual c o nflict of i nterest or fi na ncial i nterest of pers o ns w h o ha ve a r ole i n t he desi g n, c o n d uct, 
a nal ysis, p u blicati o n, or a n y as pect of t his st u d y s h o ul d be discl ose d. F urt h er m ore, p ers o ns w h o 
ha ve a p ercei ve d c o nflict of i nterest or fi na n cial i nterest will be re q uire d t o ha ve s uc h c o nflicts 
ma na ge d i n a w a y t hat is a p pr o priate t o t heir p artici pati o n i n t he desi g n a n d c o n d uct of t his 
st u d y. 
1 0. 1. 2. 2.  Fi n a nci al Discl os ure  
I n v esti gat ors a n d s u b-i n v esti gat ors will pr o vi de t he S p o ns or wit h s ufficie nt, acc urate fi n a ncial 
i nf or mati o n as re q u este d t o all o w t he S p o ns or t o s u b mit c o m plete a n d acc urate fi na n cial 
certificati o n or discl os ure state me nts t o t he a p pr o priate re g ul at or y a u t h orities. I n v esti gat ors are 
res p o nsi ble f or pr o vi di n g i nf or mati o n o n fi na ncial i nterests d uri n g t he c o urs e of t he st u d y a n d f or 
1 year after c o m pleti o n of t he st u d y. 
1 0. 1. 3.  
P artici p a nt Selecti o n a n d I nf or me d C o nse nt Pr ocess  
T he I n vesti gat or will scr ee n Partici pa nt s w h o meet t he eli gi bilit y criteria. T he I n vesti gat or will 
n ot e xercise s electi vit y, s o t hat bias is pre ve nte d. All Partici pa nt s m ust si g n a n I C F t hat has b ee n 
a p pr o ve d b ot h b y t he S p o ns or a n d b y t he re vie wi n g I E C/I R B. T he i nf or m e d c o nse nt s h o ul d be i n 
acc or d a nce wit h t he c urr e nt re visi o n of t he Declarati o n of Helsi n ki as well as c urre nt I C H a n d 
G o o d Cli nical Practice ( G C P) g ui deli nes.  
Pri or t o ra n d o mizati o n, Partici pa nt s will recei ve a c o m pre he nsi ve e x pla nati o n of t he pr o p ose d 
treat me nt i ncl u di n g t he n ature a n d ris ks of t he st u d y, alter nate t hera pies, a n y k n o w n A Es, t he 
i n vesti gati o nal stat us of t he pr o d uct, a n d t he ot h er ele me nts t hat are part of o btai ni n g pr o per 
i nf or me d c o nse nt. P ote ntial Partici pa nts will als o recei ve a detaile d e x pla nati o n of t he pr o p ose d 
use a n d discl os ure of t heir pr otecte d h ealt h i nf or m ati o n, i ncl u di n g s pecificall y a n y sa ve d bl o o d 
sa m ples. P ote ntial Partici pa nt s will be all o we d s ufficie nt ti me t o c o nsi der p artici pati o n i n t he 
st u d y after ha vi n g t he n at ure a n d ris ks of t h e st u d y e x plai ne d t o t he m. T he I C F m ust n ot i ncl u de 
a n y e xc ul pat or y st ate me nts. T he I C F a n d a n y se parate Healt h I ns ura n ce P orta bilit y a n d 
Acc o u nta bilit y Act ( HI P A A) a ut h orizati o n f or m, if a p plica ble, s h o ul d be re vie we d a n d a p pr o v e d 
b y t he S p o ns or pri or t o I R B/I E C s u b missi o n.  
T he S p o ns or will pr o vi de t o t he I n v esti gat or, i n writi n g, a n y ne w i nf or mati o n t hat si g nifica ntl y 
bears o n t he Partici pa nt s’ ris k i n recei vi n g t he st u d y dr u g. T his ne w i nf or mati o n will be 
c o m m u nicate d b y t he I n v esti gat or t o Partici pa nts i n acc or d a nce wit h I R B/I E C re q uire me nts. T he 
I C F will be u p date d, a n d Partici pa nt s will be re-c o nse nte d, if necessar y.  
Site staff ma y c o n d uct st a n dar d -of -care pr oce d ures a n d e m pl o y recr uit me nt eff orts pri or t o 
Partici pa nt  c o nse nt; h o w e ver, bef ore a n y pr ot oc ol-s pecifie d pr oce d ures are perf or me d t o 
deter mi ne pr ot oc ol eli gi bilit y, a n I C F m ust be si g n e d. Partici pa nts will be gi ve n a c o p y of all 
c o nse nt f or ms t hat t he y si g n. 

Heli x mit h C o., Lt d. 
C O N FI D E N TI A L   
Pr ot oc ol: V M A L S- 0 0 2- 2 
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 
Versi o n 3. 0 
7 2 
Fi nal : 2 0 Ja n uar y 2 0 2 1 
B y si g ni n g t he I C F, t he P artici pa nt  a grees t o c o m plete all e val uati o ns re q uire d b y t he st u d y 
u nless t he Partici pa nt wit h dra ws v ol u ntaril y or is ter mi nate d fr o m t he st u d y f or a n y reas o n. 
1 0. 1. 4.  
D at a Pr ot ecti o n a n d C o nfi de nti alit y 
T he data r es ulti n g fr o m t his st u d y will be t he pr o prietar y i nf or m ati o n of t he S p o ns or a n d ma y be 
ma de p u blic after all data ha ve bee n  a nal y ze d a n d t he st u d y res ults are a v aila ble. At t he e n d of 
t he st u d y, a cli nical st u d y re p ort will be writte n b y t he S p o ns or. 
1 0. 1. 4. 1.  C o nfi de nti alit y  
Partici pa nt c o nfi de ntialit y a n d pri vac y are stri ctl y hel d i n tr ust b y t he I n v esti gat ors, t heir staff, 
a n d t he S p o ns or. T his c o nfi de ntialit y is e xte n de d t o c o ver testi n g of bi ol o gical sa m ples i n 
a d diti o n t o t he cli nical i nf or mati o n relati n g t o Partici pa nt s. T heref ore, t he st u d y pr ot oc ol, 
d oc u me ntati o n, data, a n d all ot her i nf or mati o n ge n erate d will be h el d i n strict c o nfi de nce. N o 
i nf or mati o n c o ncer ni n g t he st u d y or data will be release d t o a n y u n a ut h orize d t hir d part y wit h o ut 
pri or writte n a p pr o v al of t he S p o ns or. 
All resear c h acti vities will be c o n d ucte d i n as pri v ate a setti n g as p ossi ble.  
T he st u d y m o nit or, ot her a ut h orize d r e pres e ntati ves of t he S p o ns or, re prese ntati ves of t he I R B, 
re g ulat or y a g e ncies, or p har mace utical c o m pa ni es s u p pl yi n g st u d y pr o d uct ma y i ns pect all 
d oc u me nts a n d rec or ds r e q uire d t o be mai ntai ne d b y t he I n vesti gat or i ncl u di n g, b ut n ot li mite d 
t o, me dical rec or ds ( office, cli nic, or h os pital) a n d p har mac y rec or ds f or Partici pa nt s. T he 
Cli nical St u d y Site will per mit access t o s uc h rec or ds.  
T he Partici pa nt ’s c o nt act i nf or mati o n will be sec urel y st ore d at eac h Cli nical Site f or i nter nal use 
d uri n g t he st u d y. At t he e n d of t he st u d y, all rec or ds will c o nti n ue t o be ke pt i n a sec ure l o cati o n 
f or as l o n g a p eri o d as di ctate d b y t he re vie wi n g I R B/I E C, a p plica ble re g ul at or y a ge n cies, 
i nstit uti o nal p olicies, a n d/ or S p o ns or re q uire me nts. 
Partici pa nt resear c h d ata, w hic h is f or p ur p oses of statistical a nal ysis a n d scie ntific re p orti n g, 
will be tra ns mitte d t o a n d st ore d b y t he S p o ns or or t heir desi g nee. T his will n ot i ncl u de t he 
Partici pa nt ’s c o ntact or i de ntif yi n g i nf or mati o n. Rat her, i n di vi d ual Partici pa nt s a n d t heir res earc h 
data will be i de ntifie d b y a u ni q ue st u d y i de ntificati o n n u m ber. T he st u d y data e ntr y a n d st u d y 
ma na ge me nt s yste ms use d b y Cli nical Sites a n d b y researc h staff will be sec ure d a n d p ass w or d 
pr otecte d. At t he e n d of t he st u d y, all st u d y d ata bases will be de -i de ntifie d a n d arc hi v e d. 
1 0. 1. 4. 2.  D at a  Pr ot ecti o n  
I n acc or da n ce wit h G C P a n d wit h t he nati o nal dat a pr otecti o n la ws, all i nf or mati o n c o ncer ni n g 
t he Partici pa nts i n t he st u d y m ust be treate d as stri ctl y c o nfi de ntial b y all pers o ns i n v ol ve d i n t he 
st u d y. 
T he I n vesti gat or ac k n o wl e d ges t hat a n y a n d all i nf or mati o n ac q uire d fr o m t he S p o ns or or 
de vel o pe d or ac q uir e d i n c o n necti o n wit h t he st u d y is strictl y c o nfi de ntial. T he I n vesti gat or will 
n ot discl ose a n y c o nfi de ntial i nf or mati o n t o a n y t hir d part y n or use c o nfi de ntial i nf or mati o n f or 
a n y p ur p ose wit h o ut first o btai ni n g t he c o nse nt of t he S p o ns or i n writi n g. S uc h c o nse nt will be 

Heli x mit h C o., Lt d. 
C O N FI D E N TI A L   
Pr ot oc ol: V M A L S- 0 0 2- 2 
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 
Versi o n 3. 0 
7 3 
Fi nal : 2 0 Ja n uar y 2 0 2 1 
dee me d t o ha v e bee n gi v e n f or discl os ure t o a n y p ers o n f or w h o m t he I n vesti gat or is res p o nsi ble 
at his/ her ce nter, b ut o nl y s o far as re q uire d f or t he p ur p oses of t he st u d y, a n d, i n t h e case of 
discl os ures t o staff, o nl y if s uc h staff are b o u n d b y o bli gati o ns of c o nfi de ntialit y n o less strict 
t ha n t h ose set o ut herei n. 
P ote ntial Partici pa nt s m ust be i nf or me d t hat t heir pers o nal st u d y-relate d data will be use d b y t he 
S p o ns or i n acc or d a nc e wit h l ocal data pr otecti o n l a w. T he le v el of discl os ure m ust als o be 
e x plai ne d t o t he Partici pa nt  w h o will be re q uire d t o gi ve c o nse nt f or t heir d ata t o be use d as 
descri be d i n t he I C F. 
P ote ntial Partici pa nt s m ust be i nf or me d t hat t heir me dical rec or ds ma y be e xa mi ne d b y Cli nical 
Q ualit y Ass ura nce a u dit ors or ot her a ut h orize d pers o n nel a p p oi nte d b y t he S p o ns or, b y 
a p pr o priate I R B me m bers, a n d b y i ns pect ors fr o m re g ulat or y a ut h orities. 
1 0. 1. 5.  
C o m mittee Str uct ure  
1 0. 1. 5. 1.  D at a S afet y M o nit ori n g B o ar d 
A n i n de pe n de nt D S M B has bee n c h artere d f or t his st u d y t o re vie w all safet y data d uri n g t he 
st u d y a n d safe g u ar d t he i nterests of t he Partici pa nt s. T he o bjecti ves of t he D S M B meeti n gs are t o 
re vie w t he s afet y o utc o m es of t he st u d y a n d pr o vi de g ui da nce t o t he S p o ns or re gar di n g t he safet y 
of E n ge nsis. T he D S M B will meet peri o dicall y a n d re vie w a li mite d set of u n bli n de d or 
n o nc o m parati ve ta bl es a n d/ or listi n gs of all re p orte d A Es / T E A Es, A E SIs, a n d S A Es/ T E S A Es. If 
a safet y si g nal is i de ntifie d d uri n g t he n o nc o m parati ve a nal ysis, t his will be f oll o we d b y a 
c o m parati ve a nal ysis as pr o m pte d b y o bser vati o ns. T he data a n al yses f or t he D S M B meeti n gs 
will be directl y pr o vi de d t o t he D S M B me m bers; n o data will be release d t o t he S p o ns or or 
bli n de d desi g nees. N o a dj ust me nt will be ma de f or m ulti ple testi n g d ue t o t he D S M B data 
re vie w. 
T he D S M B will c o nsist of t w o p h ysicia ns wit h e x pertise i n cli nical st u dies a n d o ne statisticia n. 
Me m bers of t he D S M B will be i n de pe n de nt of st u d y c o n d uct a n d f ree of c o nflict of i nterest, or 
meas ures s h o ul d be i n pl ace t o mi ni mize percei ve d c o nflicts of i nterest. A n i n de pe n de nt 
bi ostatisticia n will be a vaila ble f or c o ns ultati o n.  
T he D S M B will o perate u n der t he r ules of t he c h arter, w hic h h a ve bee n re vie we d at 
or ga nizati o nal meeti n gs of t he D S M B. Eac h data ele me nt t hat t he D S M B re q uires t o assess t he 
safet y of E n g e nsis will be a gree d u p o n pri or t o st u d y start. R o uti ne D S M B meeti n gs will be 
re g ularl y sc h e d ule d per t he D S M B C hair t o re vie w safet y a n d p o ol e d all-ca use m ortalit y data, 
i ncl u di n g u n bli n de d Partici pa nt  narr ati ves . T he D S M B C hair ma y re q uest a d diti o nal u n bli n de d 
i nf or mati o n at a n y ti me t o f urt her u n dersta n d a s afet y tre n d. A d h oc D S M B meeti n gs ca n be 
c o n ve ne d at a n y ti me at t he discreti o n of t he D S M B C hair or t he S p o ns or. H o we ver, t he D S M B 
C hair ma y n ot s hare a n y u n bli n de d i nf or mati o n wit h t he S p o ns or u nless it is dee me d necessar y 
f or t he S p o ns or t o a d dr ess a p ote ntial safet y c o n cer n. T he D S M B will pr o vi de rec o m me n d ati o ns 
t o t he S p o ns or i n acc or da nce wit h the D S M B C harter.  

Heli x mit h C o., Lt d. 
C O N FI D E N TI A L   
Pr ot oc ol: V M A L S- 0 0 2- 2 
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 
Versi o n 3. 0 
7 4 
Fi nal : 2 0 Ja n uar y 2 0 2 1 
1 0. 1. 5. 2.  I nstit uti o n al Bi os afet y C o m mittee  
T he Sites at w hic h t his st u d y is bei n g c o n d ucte d will e ns ure t hat a n I nstit uti o nal Bi osafet y 
C o m mittee (I B C) is i n place. T h e I B C will e ns ure t hat t he Site c o nf or ms t o t he re q uire m e nts set 
f ort h i n t he Secti o n I V- B- 2 of t he Nati o nal I nstit ut es of Healt h ( NI H) G ui deli nes f or Researc h 
I n v ol vi n g Rec o m bi na nt or S y nt hetic N ucleic A ci d M olec ules ( A pril 2 0 1 9), pr o m ul gate d b y t he 
NI H Office of Sci e nce P olic y ( O S P).  
T he I n vesti gat or will be r es p o nsi ble f or petiti o ni n g t he I B C a n d o btai ni n g a p pr o val pri or t o 
e nr olli n g a n y Partici pa nt  i n t he st u d y. T he I n v esti gat or will als o be re q uire d t o o btai n a n d f oll o w 
all bi o hazar d s afet y g ui d eli nes pr o m ul gate d b y t h e I B C, a n d t o re p ort all fi n di n gs as re q uire d t o 
t he I B C a n d t he O S P.  
1 0. 1. 6.  
D at a Q u alit y Ass ur a nce 
1 0. 1. 6. 1.  Cli nic al M o nit ori n g  
T he S p o ns or or desi g nee will visit (i n pers o n or re m otel y, acc or di n g t o F D A G ui da nce o n 
C o n d uct of Cli nical Trials of Me dical Pr o d uct d uri n g C O VI D- 1 9 Pa n de mic, Marc h 2 0 2 0, 
u p date d 0 3 J u n 2 0 2 0) t he Cli nical Site f or m o nit ori n g. T he S p o ns or’s cli nical m o nit or s hall 
e ns ure t hat t he I n v esti gat or u n dersta n ds t he i n vesti gati o nal stat us of t he pr o d uct, all pr ot oc ol 
re q uire me nts, a n d his/ her re g ulat or y r es p o nsi bilities as a n I n v esti gat or. T he cli nical m o nit ors will 
v isit (i n pers o n or re m otel y) Cli nical Sites at a p pr o priate i nter vals t o e ns ure c o m plia nce wit h t he 
pr ot oc ol a n d t o verif y t he acc ur ac y, c o m plete ness, a n d c orrect ness of data re p orte d a n d 
acc o u nta bilit y of E n ge nsis s u p plies. 
T he cli nical m o nit or s hall be a v aila ble f or c o ns ult ati o n b y t he I n v esti gat or a n d ser ves as a liais o n 
bet wee n t he Cli nical Site a n d t he S p o ns or. T he cli nical m o nit or or ot her a ut h orize d 
re pres e ntati ves of t he S p o ns or ma y i ns pect all dat a, d oc u me nts, a n d rec or ds re q uire d t o be 
mai ntai ne d b y t he I n vesti gat or i ncl u di n g, b ut n ot li mite d t o, me dical rec or ds ( office, cli nic, or 
h os pital) a n d p har mac y r ec or ds f or Partici pa nt s. T he Cli nical Site will per mit access t o s uc h 
rec or ds. T h e I n vesti gat or will o btai n, as part of t he i nf or me d c o ns e nt pr ocess, HI P A A-c o m plia nt 
a ut h orizati o n fr o m Partici pa nt s t o use a n d discl ose t he re q uisite a n d rele va nt P HI a n d p er missi o n 
f or a ut h orize d re prese nt ati ves of t he S p o ns or, or re g ulat or y a ut h orities i ncl u di n g t he F D A, t o 
re vie w, i n c o nfi de nce, a n y rec or ds i de ntif yi n g Partici pa nt s i n t he cli nical st u d y. 
1 0. 1. 6. 2.  Access t o St u d y D oc u me nts a n d St u d y  M o nit ori n g  
T he S p o ns or has desi g nate d a C R O t o m o nit or t he pr o gress of t his st u d y. T he cli nical m o nit or, as 
a re pr ese ntati ve of t he S p o ns or, has t he o bli gati o n t o f oll o w t his st u d y cl osel y. 
T he S p o ns or or its desi g nee ma y meet wit h I n v esti gat ors pri or t o t he i nitiati o n of t he st u d y i n 
or der t o re vi e w t he a d e q u ac y of t he Partici pa nt  p o p ulati o n, facilities, a n d e q ui p me nt wit h res pect 
t o t he nee ds of t he st u d y, a n d t o fa miliarize t he I n vesti gat or wit h t he st u d y pr ot oc ol. 

Heli x mit h C o., Lt d. 
C O N FI D E N TI A L   
Pr ot oc ol: V M A L S- 0 0 2- 2 
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 
Versi o n 3. 0 
7 5 
Fi nal : 2 0 Ja n uar y 2 0 2 1 
T he S p o ns or or its desi g nee ma y meet wit h t he I n v esti gat or(s) at t he ti me t h at st u d y Partici pa nt s 
be gi n t o be e nr olle d t o e ns ure t hat Partici pa nt s are bei n g pr o perl y selecte d a n d t hat st u d y data are 
bei n g c orr ectl y rec o r de d. 
D uri n g t he st u d y, t he cli nical m o nit or will visit (i n pers o n or re m otel y) t he st u d y facilities 
re g ularl y a n d us e tele p h o ne a n d writte n c o m m u nicati o ns o n a n o n g oi n g basis t o mai ntai n c urre nt 
k n o wle d ge of t he st u d y. D uri n g peri o dic visits t o t he Cli nical Site (i n pers o n or re m otel y), t he 
m o nit or will re vie w t he s o urce d oc u m e nts use d f or data e ntr y i n t he E D C s yste m t o verif y t he 
acc ur ac y a n d c o m plete n ess of t he i nf or mati o n c o ntai ne d i n t h ose re p orts i n pre parati o n f or 
retrie val. S o urce d oc u me nts m ust c ontai n all data e ntere d i n t he E D C s yste m. All data ge nerate d 
d uri n g t his st u d y a n d t he s o urce d oc u m e nts fr o m w hic h t he y ori gi nate d are s u bject t o i ns pecti o n 
b y t he S p o ns or or its re pr ese ntati ves, a n d t he F D A a n d ot her re g ulat or y a g e ncies. 
U p o n c o m pleti o n o f t he st u d y, t he cli nical m o nit or will c o n d uct a fi nal visit (cl ose o ut) t o t he 
Site. T he o bjecti ves of t his visit are t o ascertai n t h at all re g ulat or y rec or ds are c o m plete, v erif y 
t hat st u d y dr u g a n d ot her s u p plies ha ve bee n acc o u nte d f or, a n d e ns ure t hat t he I n v esti gat or is 
a war e of his/ her r es p o nsi bilities p ost-st u d y. 
1 0. 1. 6. 3.  Q u alit y Ass ur a nce a n d Q u alit y C o ntr ol 
Eac h Cli nical Site will perf or m i nter nal q u alit y ma na ge me nt of st u d y c o n d u ct, data a n d 
bi ol o gical s peci me n c ollecti o n, d oc u me ntati o n, a n d c o m pleti o n. 
Q u alit y c o ntr ol ( Q C) pr o ce d ures will be c o n d ucte d wit hi n t he E D C. A n y missi n g data or data 
a n o malies will be c o m m u nicate d t o t he sites f or clarificati o n/res ol uti o n.  
F oll o wi n g writte n Sta n dar d O per ati n g Pr oce d ures ( S O Ps), t he m o nit ors will verif y t hat t he 
clinical st u d y is c o n d ucte d, data ar e ge nerate d, a n d bi ol o gical s peci me ns are c ollecte d, 
d oc u me nte d (r ec or d e d), a n d re p ort e d i n c o m plia n ce wit h t he pr ot oc ol, I C H G C P, a n d a p plica ble 
re g ulat or y r e q uire me nts ( e. g., G o o d La b orat or y Practices ( G L P)). 
T he Cli nical  Site will pr o vi de direct access t o all st u d y -relate d s o urce d ata d oc u me nts a n d 
re p orts f or t he p ur p ose of m o nit ori n g a n d a u diti n g b y t he S p o ns or, a n d i ns pecti o n b y l ocal a n d 
re g ulat or y a ut h orities. 
T he P har macist m ust e ns ure t hat E n ge nsis a n d Place b o are st ore d as s pecifi e d i n t he pr ot oc ol a n d 
P har mac y Ma n u al. T he P har macist m ust mai ntai n acc urate rec or ds of t he recei pt of all E n ge nsis 
a n d Place b o s u p plies a n d details of t he dis pe nsi n g a n d a d mi nistrati o n as s pecifie d i n t he 
P har mac y Ma n u al. T he  E n ge nsis a n d Place b o m ust be a d mi nistere d o nl y at t he i nstit uti o n 
s pecifie d o n t he F or m F D A 1 5 7 2 f or t he Site. 
T he st u d y will be c o n d ucte d i n acc or d a nce wit h t he pri nci ples of G C Ps: 2 1 C F R 5 0, 2 1 C F R 5 4, 
2 1 C F R 5 6, a n d 2 1 C F R 3 1 2, S u b part D; t he 2 0 1 6 I C H G ui d eli ne o n G o o d Cli nical Practice 
(I C H E 6( R 2)); a n d  HI P A A.  
T he I n vesti gat or at a Cli nical Site m ust si g n t he I n vesti gat or State me nt of  A gree me nt.  

Heli x mit h C o., Lt d. 
C O N FI D E N TI A L   
Pr ot oc ol: V M A L S- 0 0 2- 2 
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 
Versi o n 3. 0 
7 6 
Fi nal : 2 0 Ja n uar y 2 0 2 1 
1 0. 1. 6. 4.  D at a Q u alit y Ass ur a nce  
T he S p o ns or’s e m pl o yees a n d/ or t heir c o ntracte d re pres e ntati ves use S O Ps desi g ne d t o e ns ure 
t hat researc h pr o ce d ur es a n d d oc u me ntati o n are c o nsiste ntl y c o n d ucte d/ pre pare d t o t he hi g h est 
q ualit y sta n dar ds. T hese S O Ps als o re q uire c o m plia nce wit h H ealt h A ut h orit y re g ulati o ns a n d 
G C P g ui da nce. 
A q ualit y ass ura nce a u dit ma y be c o n d uct e d b y t he S p o ns or or its desi g nee at a n y ti me d uri n g or 
after c o m pleti o n of a st u d y. T he I n vesti gat or will be gi ve n a de q u ate n otice if he/s he is selecte d 
f or a n a u dit. T he a u dit will i ncl u de, b ut is n ot li mite d t o, a re vie w of all I C Fs, s o urce d oc u m e nts, 
me dical re c or ds, a n d re g ulat or y d oc u me ntati o n; a n assess me nt of st u d y c o n d uct a n d pr ot oc ol 
c o m plia nce; a n d a re vie w of t he i n vesti gati o nal dr u g acc o u nt a bilit y. At t he c o ncl usi o n of a n 
a u dit, t he a u dit or will c o n d uct a brief m eeti n g wit h t he I n v esti gat or t o re vi e w t he n ote d 
o bser vati o ns. 
All Partici pa nt  data relati n g t o t he st u d y will be rec or de d o n el ectr o nic C R F u nless tra ns mitte d t o 
t he S p o ns or or desi g nee electr o nicall y (e. g., la b orat or y data). T h e I n v esti gat or is res p o nsi ble f or 
verif yi n g t hat data e ntries are acc ur ate , c orrect , a n d c o m plete b y p h ysicall y or electr o ni call y 
si g ni n g t he eC R F.  
T he I n vesti gat or m ust mai ntai n acc urate d o c u me ntati o n (s o urce dat a) t hat s u p p orts t he 
i nf or mati o n e ntere d i n t h e eC R F.  
T he I n vesti gat or m ust per mit st u d y-relate d m o nit ori n g, a u dits, I R B re vi e w, a n d re g ulat or y 
a ge nc y i ns pecti o ns a n d pr o vi de direct access t o s o urce dat a d oc u me nts. 
T he S p o ns or is res p o nsi ble f or t he dat a ma na ge m e nt of t his st u d y i ncl u di n g q ualit y c hec ki n g of 
t he data. 
T he S p o ns or ass u mes acc o u nta bilit y f or acti o ns d ele gate d t o ot her i n di vi d uals (e. g., C o ntract 
Researc h Or ga ni zati o ns).  
St u d y m o nit ors will perf or m o n g oi n g s o urce data verificati o n t o c o nfir m t hat data e ntere d i nt o 
t he e C R F b y a ut h orize d Site pers o n nel are acc urate, c o m plete, a n d v erifia ble fr o m s o urce 
d oc u me nts; t hat t he safet y a n d ri g hts of Partici pa nt s are bei n g pr otecte d; a n d t hat t he st u d y is 
bei n g c o n d ucte d i n acc or da nce wit h t he c urre ntl y a p pr o ve d pr ot o c ol a n d a n y ot her st u d y 
a gree m e nts, I C H G C P, a n d all a p plica ble re g ulat or y re q uire m e nts. 
1 0. 1. 6. 5.  D at a C o llecti o n a n d M a n a ge me nt Res p o nsi bilities  
Data c ollecti o n is t he res p o nsi bilit y of t he cli nical st u d y staff u n der t he s u p er visi o n of t he 
I n v esti gat or. D uri n g t he st u d y, t he I n v esti gat or will mai ntai n c o m plete a n d acc urate 
d oc u me ntati o n f or t he st u d y. T he I n vesti gat or s h o ul d e ns ure t hat t he Partici pa nt is pr o vi de d wit h 
i nstr ucti o ns a n d is trai ne d t o use t he eP R O  a n d t o c o m plete t he assess me nt t o ol pr o perl y bef ore 
data c ollecti o n be gi ns. 

Heli x mit h C o., Lt d. 
C O N FI D E N TI A L   
Pr ot oc ol: V M A L S- 0 0 2- 2 
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 
Versi o n 3. 0 
7 7 
Fi nal : 2 0 Ja n uar y 2 0 2 1 
All e C R F data will be e ntere d i nt o a vali date d d at a base c o m plia nt wit h 2 1 C F R Part 1 1. 
La b orat or y d ata will be eit her ma n uall y e ntere d or i m p orte d t o t he cli nical data base 
electr o nicall y. All data e ntr y, verificati o n, a n d v ali dati o n will be perf or me d i n acc or d a nce wit h 
t he c urr e nt S O Ps of t he S p o ns or or its desi g nee. T he data bas e will be a ut h orize d f or l o c k o nce n o 
data q ueries are o utsta n di n g, all st u d y data are c o nsi dere d clea n, a n d all defi ne d pr oce d ures are 
c o m plete d.  
T he Cli nical Site will be pr o vi de d wit h e C R Fs a n d  e P R O or electr o nic cli nical o utc o me 
assess me nts (e C O A) d e vices i n w hic h t o rec or d all t he pr ot oc ol-s pecifi e d d ata f or eac h 
Partici pa nt . E ntries ma de i n t he e C R F m ust be verifia ble a gai nst s o urce d oc u me nts, or i n certai n 
circ u msta nces as directe d b y t he S p o ns or, e ntries will ha ve bee n directl y e nt ere d i nt o t he e C R F; 
i n s uc h cases, t he e ntr y i n t he e C R F will be c o nsi dere d as t h e s o urce data. Data re p orte d i n t he 
e C R F t hat are d eri ve d fr o m s o urce d oc u me nts s h o ul d be c o nsiste nt wit h t he s o urce d oc u m e nts or 
t he discre pa n cies s h o ul d be e x plai ne d. T h e I n vesti gat or will be res p o nsi ble f or re vie wi n g all data 
a n d e C R F e ntries a n d will si g n a n d date t he desi g n ate d pa ges i n eac h Partici pa nt ’s e C R F, 
verif yi n g t hat t he i nf or m ati o n is tr ue a n d c orrect. Q ueries ge n erat e d b y Dat a Ma na ge m e nt will be 
se nt t o t he Cli nical Site f or res ol uti o n. T he I n vesti gat or is res p o nsi ble f or t h e re vie w a n d 
a p pr o val of all res p o nses t o e C R F q ueries. 
1 0. 1. 6. 6.  Pr ot oc ol D e vi ati o ns 
T he I n vesti gat or will n ot de viate fr o m t his pr ot oc ol f or a n y reas o n wit h o ut pri or writte n a p pr o v al 
b y t he M e dical M o nit or o n be half of t he S p o ns or e xce pt i n t he case of a m e dical e mer ge nc y 
w he n t he c h a n ge is necessar y t o eli mi nate a n a p p are nt a n d i m me diate hazar d t o t he Partici pa nt . 
Pr ot oc ol de viati o ns will be trac k e d t hr o u g h t he E D C. 
I n t he e ve nt of s u c h a n e mer ge nc y, t he I n vesti gat or will n otif y t he Me dical M o nit or i m me diatel y 
b y p h o ne, n otif y t he I R B, a n d c o nfir m wit h t he M e dical M o nit or i n writi n g wit hi n 5  w or ki n g 
da ys of t he c h a n ge bei n g i m ple me nte d. 
1 0. 1. 6. 7.  S o urce D oc u m e nts  
As defi ne d i n t he I C H G ui deli nes f or G o o d Cli nical Practice E 6( R 2), Secti o n 1. 5 2, s o urce 
d oc u me nts ma y i ncl u de: ori gi nal d oc u me nts, data, a n d rec or ds (e. g., h os pit al rec or ds, cli nical 
a n d office c harts, la b orat or y n otes, me m ora n da, P artici pa nt ’s diaries or e v al uati o n c hec klists, 
p har mac y dis pe nsi n g r ec or ds, rec or de d dat a fr o m a ut o mate d i nstr u me nts, c o pies or tra nscri pti o ns 
certifie d after v erificati o n as bei n g acc urat e a n d c o m plete, micr ofic hes, p h ot o gra p hic ne gati ves, 
micr ofil m or ma g netic m e dia, x ra ys, Partici pa nt  files, a n d rec or ds ke pt at t he p har mac y, at t he 
la b orat ories, a n d at me di c o-tec h nical de part me nts i n v ol ve d i n t he cli nical st u d y). 
S o urce d oc u me nts pr o vi d e e vi de nce f or t h e e xiste n ce of t he Partici pa nt  a n d s u bsta ntiate t he 
i nte grit y of t he data c ollecte d. S o urce d o c u me nts are file d at t he I n vesti gat or’s Site. 
T he I n vesti gat or ma y n ee d t o re q uest pre vi o us me dical rec or ds or tra nsfer rec or ds, de p e n di n g o n 
t he st u d y. C urre nt me dical rec or ds m ust als o be a vaila ble. 

Heli x mit h C o., Lt d. 
C O N FI D E N TI A L   
Pr ot oc ol: V M A L S- 0 0 2- 2 
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 
Versi o n 3. 0 
7 8 
Fi nal : 2 0 Ja n uar y 2 0 2 1 
1 0. 1. 7.  
D at a  M a n a ge m e nt  
All Partici pa nt  data will be e nter e d i nt o a pass w or d -pr otecte d v ali d ate d E D C s yste m b y 
a ut h orize d Site pers o n n el acc or di n g t o t he C R O’s S O Ps.  
Data discr e pa nci es i de ntifie d via pr o gr a m me d e dit c hec ks, ma n u al data re vi e w or disc o vere d 
d uri n g data m o nit ori n g will be a d dresse d a n d res ol ve d. A n a u dit trail i n t he E D C s yste m wil l list 
all c ha n ges ma d e t o t he d ata, wit h a date/ti me sta m p a n d user i nitials. U p o n data base l oc k, 
occ urri n g after d ata are d eclar e d clea n a n d e C R Fs ha ve bee n a p pr o v e d b y t he I n vesti gat or, t he 
C R O will pr o vi de S A S datasets t o t he S p o ns or a n d desi g nate d Sta tisticia n f or data a nal ysis via 
sec ure d ata tra nsfer s p ecifie d i n t he St u d y Data M a na ge me nt Pla n.  
1 0. 1. 8.  
Rec or d kee pi n g a n d  Ret e nti o n  
Data ge n erate d f or t he st u d y s h o ul d be st ore d i n a li mite d- access file area a n d be accessi ble o nl y 
t o re prese nt ati ves of t he Cli nical Site, t he S p o ns or a n d its re pres e ntati ves, a n d F D A/rele va nt 
healt h a ut h orities/re g ulat or y a ge nci es. All re p orts a n d c o m m u nicati o ns relati n g t o Partici pa nt s 
will i de ntif y Partici pa nt s o nl y b y Partici pa nt  i de ntificati o n n u m ber. C o m plete Partici pa nt  
i de ntificati o n will be ke pt b y t he I n v esti gat or. T his i nf or mati o n will be treate d wit h strict 
a d here n ce t o pr ofessi o nal sta n dar ds of c o nfi de ntialit y. 
T he I n vesti gat or m ust i n reas o na bl e ti me, u p o n re q uest fr o m a n y pr o p erl y a ut h orize d officer or 
e m pl o yee of F D A/r ele va nt healt h a ut h orit y/re g ulat or y a ge nc y, p er mit s uc h officer or e m pl o yee 
t o ha ve access t o re q u est e d rec or ds a n d re p orts, a n d c o p y a n d verif y a n y rec or ds or re p orts ma d e 
b y t he I n vesti gat or. U p o n n otificati o n of a visit b y t he F D A/rele va nt healt h a ut h orit y/re g ulat or y 
a ge nc y, t he I n vesti gat or will c o ntact t he S p o ns or i m me diatel y. T he I n vesti gat or will als o gra nt 
t he S p o ns or’s re pr ese ntati ves t he sa me pri vile ges offere d t o F D A/rele v a nt healt h a ut h orit y or 
re g ulat or y a g e nts/ officers/e m pl o yees. 
T he I n ve sti gat or m ust pr o vi de t he S p o ns or or its desi g nee wit h t he f oll o wi n g d oc u me nts pri or t o 
st u d y i nitiati o n a n d retai n a c o p y i n t he st u d y file: 
•  A c o m plete d a n d si g ne d F or m F D A 1 5 7 2. If, d uri n g t he st u d y, a n y c ha n ges occ ur t hat are 
n ot reflect e d o n t he c urre nt 1 5 7 2, a ne w 1 5 7 2 m ust be c o m plete d a n d ret ur n e d t o t he 
S p o ns or or its desi g nee f or s u b missi o n t o t he F D A  
•  C urre nt si g ne d c urric ula vitae ( wit hi n 2 years pri or t o st u d y i nitiati o n) a n d c urre nt 
me dical lice nses f or t he I n vesti gat or a n d all c o -I n vesti gat ors liste d o n t he 1 5 7 2 
•  A c o p y of t he ori gi nal a p pr o val b y t he I R B f or c o n d ucti n g t he st u d y. Re ne wals, wit h 
c o nti n ua nce of t h e st u d y, m ust be s u b mitte d at yearl y i nter vals or as re q uire d b y I R B 
p olic y. 
•  A c o p y of t he I R B- a p pr o ve d I C F  
•  T he I R B me m ber list a n d/ or D H H S Ge neral Ass ura nce N u m b er (if t he I R B has  a n 
Ass ura nce n u m ber) 

Heli x mit h C o., Lt d. 
C O N FI D E N TI A L   
Pr ot oc ol: V M A L S- 0 0 2- 2 
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 
Versi o n 3. 0 
7 9 
Fi nal : 2 0 Ja n uar y 2 0 2 1 
•  A c o p y of t he ori gi nal a p pr o val b y t he I B C f or c o n d ucti n g t he st u d y, if a p plica ble. 
Re ne wals, wit h c o nti n ua nce of t he st u d y, m ust be s u b mitte d at yearl y i nter vals or as 
re q uire d b y IB C  p olic y. 
•  Si g ne d Fi na ncial Discl os ure F or ms f or all pers o n n el liste d o n t he 1 5 7 2 wit h a state me nt 
of n o n- v oti n g b y st u d y staff 
•  T he si g nat ure pa g e of t his pr ot oc ol si g ne d a n d dat e d b y t he I n v esti g at or 
•  T he si g nat ure pa g e of t he I B si g ne d a n d date d b y t he I nvesti gat or 
•  I n a d diti o n t o t he d oc u me nts liste d a b o ve, t he Cli nical Site will als o retai n t he f oll o wi n g 
ite ms: 
o  Certificati o ns a n d la b or at or y refere n ce ra n ges f or all l ocal la b orat ories us e d f or 
t his st u d y 
o  A c o p y of del e gati o n of a ut h orit y l o g 
o  C o pies of t he i nitiati o n visit re p ort, t he pr ot oc ol, I B, scree ni n g/e nr ol me nt l o gs, 
s u bject I D list ( n ot pr o vi de d t o s p o ns or/ C R O), i n vesti gati o nal pr o d uct 
acc o u nta bilit y rec or ds 
o  All ori gi nal I C Fs wit h re q uire d  si g nat ures 
o  All I R B c orres p o n de n ce (e. g., i nf or me d c o nse nt [i ncl u di n g a n y a p pr o ve d 
re visi o ns], pr ot oc ol, A E, a d vertise me nts, ne wslett ers)  
o  All I B C  c orres p o n d e nce 
o  A c o p y of t he St u d y M o nit ori n g L o g  
o  Cli nical a n d n o ncli nical s u p pl y s hi p me nt f or ms 
o  C o pies of all perti ne nt c orres p o n de n ce pertai ni n g t o t he st u d y (e xce pt b u d g et 
iss ues) bet wee n t h e S p o ns or, C R O, a n d t he Site  
o  C o pies of all S A E re p orts s u b mitte d t o t he S p o ns or 
o  C o pies of all I n v esti gat or Safet y Re p orts s u b mitte d t o t he Site b y  t he S p o ns or 
o  C o pies of a p pr o ve d p ac k a ge la belli n g, if a p plica bl e 
1 0. 1. 9.  
St u d y a n d Site St art a n d Cl os ure  
T he st u d y ma y be s us pe n de d te m p oraril y or ter mi nate d pre mat urel y if t here is s ufficie nt 
reas o na bl e ca us e. Writte n n otificati o n d oc u me nti n g t he reas o n f or st u d y s us pe nsi o n or 
ter mi nati o n will be pr o vi de d b y t he S p o ns or t o I n vesti gat ors a n d re g ul at or y a ut h orities. If t he 
st u d y is pre mat urel y ter mi nate d or s us pe n de d, t h e I n vesti gat or will pr o m ptl y i nf or m Partici pa nt s 
a n d t he I R B a n d will pr o vi de t he reas o ns f or t he t er mi nati o n or s us pe nsi o n. Partici pa nts will be 
c o ntacte d, as a p plica ble, a n d be i nf or me d of c ha n ges t o St u d y Visit sc he d ules. 
T he S p o ns or reser ves t he ri g ht t o disc o nti n ue t he st u d y f or a n y safet y, et hical, or a d mi nistrati ve 
reas o n at a n y ti me. 

Heli x mit h C o., Lt d. 
C O N FI D E N TI A L   
Pr ot oc ol: V M A L S- 0 0 2- 2 
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 
Versi o n 3. 0 
8 0 
Fi nal : 2 0 Ja n uar y 2 0 2 1 
T he S p o ns or or desi g nee reser v es t he ri g ht t o cl ose a Cli nical Site or ter mi nate t he st u d y at a n y 
ti me f or a n y reas o n at t he s ole discreti o n of t he S p o ns or. St u d y sites will be cl ose d u p o n st u d y 
c o m pleti o n. 
T he I n vesti gat or ma y i nitiate Cli nical Site cl os ure at a n y ti me, pr o vi de d reas o na ble ca us e a n d 
s ufficie nt n otice is gi ve n i n a d va nce of t he i nte n de d ter mi nati o n. 
Reas o ns f or t he earl y cl os ure of a Cli nical Site b y t he S p o ns or or I n vesti gat or ma y i ncl u de b ut 
are n ot li mite d t o:  
•  Fail ure of t he I n vesti gat or t o c o m pl y wit h t he pr ot oc ol, t he re q uire me nts of t he 
I R B/I E C or l ocal h ealt h a ut h orities, t he S p o ns or’s pr oce d ures, or G C P g ui deli nes 
•  I n a de q uat e recr uit me nt of Partici pa nts b y t he I n vesti gat or 
•  Disc o nti n uati o n of f urt her st u d y dr u g de vel o p me nt 
If t he st u d y is pre mat ur el y ter mi nate d or s us pe n d e d, t he S p o ns or will pr o m ptl y i nf or m t he 
I n v esti gat ors, I R Bs, t he r e g ulat or y a ut h orities, a n d a n y C R Os use d i n t he st u d y of t he reas o n f or 
ter mi nati o n or s us pe nsi o n, as s pecifie d b y t he a p plica ble re g ulat or y re q uire me nts. T he 
I n v esti gat or will pr o m ptl y i nf or m t he Partici pa nt s a n d s h o ul d e ns ure a p pr o priate Partici pa nt  
t hera p y a n d/ or f oll o w- u p. 
1 0. 1. 1 0.  
P u blic ati o n P olic y  
T he st u d y will be c o n d ucte d i n acc or d a nce wit h t he p u blicati o n a n d data s h ari n g p olicies a n d 
re g ulati o ns as defi n e d i n t he a gree me nt bet wee n t he S p o ns or a n d t he i nstit uti o n. I n a d diti o n, t his 
st u d y will be re gistere d at w w w. Cli nical Trials. g o v a n d i n a n y ot her pr ot o c ol re gistries re q uire d 
b y t he re gi o ns i n w hic h t he st u d y is c o n d ucte d, a n d t he res ults fr o m t his st u d y will bec o me 
p u blicl y a vaila ble. 
N o ne of t he d ata res ulti n g fr o m t his st u d y will be all o we d t o be pres e nte d or p u blis he d i n a n y 
f or m b y t he I n vesti gat or or a n y ot her p ers o n wit h o ut t he pri or writte n a p pr o val of t he S p o ns or. 
1 0. 1. 1 1.  
I ns ur a nce 
Matters relati n g t o i ns ura nce f or t his st u d y are t o be defi ne d i n t he a gree me nt bet wee n t he 
S p o ns or a n d t he i nstit uti o n. 
 
 

Heli x mit h C o., Lt d. 
C O N FI D E N TI A L   
Pr ot oc ol: V M A L S- 0 0 2- 2 
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 
Versi o n 3. 0 
8 6 
Fi nal : 2 0 Ja n uar y 2 0 2 1 
1 0. 3.  
A p pe n di x 3.   
Gr a di n g of I njecti o n Site Re acti o ns 
T he f oll o wi n g gra di n g g ui deli nes were c o m pile d fr o m s o urces fr o m t he F D A7 0 a n d t he Nati o nal 
Ca ncer I nstit ute7 1 f or I njecti o n Site Reacti o ns (Ta ble 6 ). I njecti o n sites s h o ul d be assesse d i n 
eac h u p p er a n d eac h l o w er li m b. A gl o bal assess me nt of all i njecti o n sites o n eac h ar m a n d o n 
eac h le g is t o be p erf or me d f oll o wi n g eac h treat m e nt. T he i njecti o n site reacti o n wit h t he m ost 
se vere p ai n/te n der n ess, er yt he ma/itc hi n g/ urticaria, a n d br uisi n g/s welli n g/ blee di n g o n eac h ar m 
a n d o n eac h le g is t o be use d as t he refere nce p oi nt f or t he i njecti o n site reacti o n gra di n g 
f oll o wi n g eac h tr eat me nt. N ote t hat t he m ost se vere pai n/te n der n ess i njecti o n site ma y n ot be t he 
sa me i njecti o n site reacti o n wit h t he m ost se vere br uisi n g/s welli n g/ blee di n g. 
T a ble 6: 
I njecti o n Site Re acti o n Gr a di n g 
Re acti o n at 
I njecti o n Sitea 
Mil d  
( Gr a de 1) 
M o der ate  
( Gr a de 2) 
Se v ere  
( Gr a de 3) 
P ote nti all y Life -
T hre ate ni n g  
( Gr a de 4) 
Pai n, 
te n der ness 
Mil d disc o mf ort 
t o t o u c h, wit h or 
wit h o ut war mt h, 
er yt h e ma, itc hi n g 
S y m pt o ms wit h or 
wit h o ut s welli n g 
a n d/ or p hle bitis 
S y m pt o ms wit h or 
wit h o ut s welli n g 
or p hle bitis or 
mil d i nfecti o n  
S y m pt o ms wit h 
se v ere i nfecti o n or 
tiss u e i nj ur y or 
ulcerati o n  
D o es n ot 
i nterfere wit h 
d ail y acti vit y  
I nterferes wit h d ail y 
acti vit y 
Precl u d es 
d ail y acti vit y  
Re q uires a d v a n ce d 
me dical a n d/ or 
s ur gical care, 
i n cl u di n g i ntra v e n o us 
(I V) me dicati o ns  
N o or l o cal 
treat me nt 
Use of 
n o n -n arc otic p ai n 
relie v er 
Use of n arc otic 
p ai n relie v er 
a n d/ or oral 
a nti bi otics 
Er yt he ma, 
itc hi n g, 
urticaria  
Mil d, l o calize d 
itc hi n g, er yt h e ma 
or urticaria  
S y m pt o ms wit h s ki n 
c h a n g es b e y o n d l o cal 
i njecti o n site(s) 
S y m pt o ms 
wit h 
wi d es prea d 
s ki n c h a n g es 
Br o n c h os p as m, 
a n a p h ylact oi d, or 
a n a p h ylactic 
reacti o n 
D o es n ot 
i nterfere wit h 
acti vit y 
I nterferes wit h 
m o v e me nt a n d d ail y 
acti vit y 
I nterferes wit h 
d ail y acti vit y  
Re q uires a d v a n ce d 
me dical care, 
i n cl u di n g I V 
me dicati o n  
Use of t o pical 
treat me nt 
Use of N S AI Ds a n d/ or 
a nti hista mi n es 
Use of oral 
ster oi ds or 
i m m u no- 
s u p pressi v es 
Br uisi n g, 
s welli n g, 
blee di n g  
Mil d, l o calize d 
s welli n g, 
ecc h y m osis or 
h e mat o ma  
M o d erate ecc h y m osis 
or h e mat o ma  
E xte nsi v e 
ecc h y m oses, 
lar g e h e mat o ma 
H y p ote nsi o n, 
life- t hreate ni n g 
c o nse q u e n ces 
D o es n ot 
i nterfere wit h 
acti vit y 
I nterferes wit h d ail y 
acti vit y 
Precl u d es  acti vit y 
Re q uires tra nsf usi o n, 
ur g e nt i nter v e nti o n  
N o treat me nt  
Re q uires le g ele v ati o n, 
c o nser v ati v e treat me nt 
Re q uires 
mi ni mall y 
i n v asi v e drai n a g e  
A b bre viati o ns: N S AI D = n o n -ster oi d al a nti-i nfla m mat or y dr u gs 
a  I njecti o n site reacti o ns are a cate g or y of A ESI s a n d s h o ul d b e rec or d e d as A Es usi n g t h ese gra di n g g ui d eli n es.  
 
 

Heli x mit h C o., Lt d. 
C O N FI D E N TI A L   
Pr ot oc ol: V M A L S- 0 0 2- 2 
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 
Versi o n 3. 0 
8 7 
Fi nal : 2 0 Ja n uar y 2 0 2 1 
1 0. 4.  
A p pe n di x  4. List of A b bre vi ati o ns a n d Defi niti o ns  
1 0. 4. 1.  
A b bre vi ati o ns 
A b bre vi ati o n  
Defi niti o n  
A E  
a d verse e ve nt 
A E SI  
A d verse e ve nt of s pecial i nterest  
A L S  
a m y otr o p hic lateral scler osis  
A L T  
ala ni ne tra nsa mi nase ( S G P T)  
A L S A Q -4 0  
A m y otr o p hic Lateral Scler osis Assess me nt Q uesti o n naire  
A L S F R S - R 
Re vise d A m y otr o p hic Lateral Scler osis F u ncti o nal Rati n g Scale  
A nti -H C V  
he patitis C a nti b o dies  
A P B  
A b d uct or p ollicis bre vis  
A S T  
as partate tra nsa mi nase ( S G O T) 
A T LI S  
Acc urate Test of Li m b Is o metric Stre n gt h  
β -H C G  
beta h u ma n c h ori o nic g o na d otr o pi n  
B U N  
bl o o d urea nitr o ge n  
c D N A  
C o m pli me ntar y de o x yri b ose n ucleic aci d  
C D R C  
Cli nical Data Re vie w C o m mittee  
C F R  
C o de of Fe deral Re g ulati o n  
C GI C  
Cli nical Gl o bal I m pressi o n of C ha n ge  
C LI  
critical li m b isc he mia  
C O N S O R T  
C o ns oli date d Sta n dar ds of Re p orti n g Trials  
C R A  
Cli nical Researc h Ass ociate  
C R O  
cli nical researc h or ga nizati o n  
C S  
cli nicall y si g nifica nt  
C T C A E  
Nati o nal Ca ncer I nstit ute: C o m m o n Ter mi n ol o g y Criteria f or A d verse E ve nts  
D M C  
Data M o nit ori n g C o m mittee  
D N A  
de o x yri b o n ucleic aci d  
D P N  
dia betic peri p heral ne ur o pat h y  
D S M B  
Data Safet y M o nit ori n g B oar d  
E A A T 2  
excitat or y a mi n o aci d tra ns p orter 2  
E C G  
electr ocar di o gra m 
e C O A  
electr o nic cli nical o utc o me assess me nt  
e C R F  
electr o nic case re p ort f or m  
E D C  
electr o nic data ca pt ure s yste m  
e P R O  
electr o nic patie nt re p orte d o utc o me  
E T  
earl y ter mi nati o n fr o m t he st u d y  
F D A  
F o o d a n d Dr u g A d mi nistrati o n  
F DI  
first d orsal i nter osse us 
F V C  
f orce d vital ca pacit y 

Heli x mit h C o., Lt d. 
C O N FI D E N TI A L   
Pr ot oc ol: V M A L S- 0 0 2- 2 
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 
Versi o n 3. 0 
8 8 
Fi nal : 2 0 Ja n uar y 2 0 2 1 
A b bre vi ati o n  
Defi niti o n  
G C P  
g o o d cli nical p ractices 
G G T  
ga m ma -gl uta m yl tra ns pe pti dase  
G L P  
g o o d la b orat or y practices  
H B V  
he patitis B vir us  
H Bc A b  
he patitis B c ore a nti b o d y (I g G a n d I g M)  
H Bs A b  
a nti b o d y t o He patitis B s urface a nti ge n  
H Bs A g  
he patitis B s urface a nti ge n  
H C G  
h u ma n c h ori o nic g o na d otr o pi n  
H C V  
he patitis C vir us  
H C M V  
h u ma n c yt o me gal o vir us  
H D L C - C 
Hi g h -de nsit y li p o pr otei n c h olester ol  
H E E N T  
hea d, e yes, ears, n ose, a n d t hr oat  
H G F  
he pat o c yte gr o wt h fact or 
H G F -X 7  
h y bri d he patic gr o wt h fact or c o di n g se q ue nce e x pressi n g t w o is of or ms of 
H G F, H G F 7 2 8 a n d H G F 7 2 3 
H H D  
Ha n d hel d D y na m o meter  
HI P A A  
Healt h I ns ura nce P orta bilit y a n d Acc o u nta bilit y Act  
HI V  
h u ma n i m m u n o deficie nc y vir us  
H T L V  
h u m a n T cell l y m p h otr o pic vir us  
I B 
I n vesti gat or’s Br oc h ure 
I B C 
I nstit uti o nal Bi osafet y C o m mittee 
I C F 
I nf or me d C o nse nt F or m 
I D 
i de ntifier 
I L- 6 
i nterle u ki n 6 
I M 
i ntra m usc ular 
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 R B 
I nstit uti o nal Re vie w B oar d 
I S R 
I njecti o n site reacti o n 
I V 
i ntra ve n o us 
L L O Q  
l o wer li mit of q ua ntitati o n 
L M N  
l o wer m ot or ne ur o ns 
M C P - 1 
m o n oc yte c he m oattracta nt pr otei n 1  
M R C  
Me dical Researc h C o u ncil  
N C S  
n ot cli nicall y si g nifica nt  
N D A  
Ne w Dr u g A p plicati o n  
N H U  
n o n heali n g f o ot ulcers  
NI H  
Nati o nal I nstit utes of Healt h  
N M D A  
N- met h yl - D-as partate 

Heli x mit h C o., Lt d. 
C O N FI D E N TI A L   
Pr ot oc ol: V M A L S- 0 0 2- 2 
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 
Versi o n 3. 0 
8 9 
Fi nal : 2 0 Ja n uar y 2 0 2 1 
A b bre vi ati o n  
Defi niti o n  
N O  
nitr o us o xi de  
N O A E L  
N o o bser ve d a d verse e ve nt le vel  
N S AI D  
n o n -ster oi dal a nti-i nfla m mat or y dr u g 
O S P  
Office of Scie nce P olic y , Nati o nal I nstit utes of Healt h 
P A D  
peri p heral arterial disease  
P E  
p h ysical e xa mi nati o n  
P G E 2  
pr osta gla n di n E 2  
P GI C  
Patie nt Gl o bal I m pressi o n of C ha n ge  
P HI  
pr otecte d healt h i nf or mati o n  
P R O  
patie nt re p orte d o utc o me  
P T  
pr ot hr o m bi n ti me  
P T T  
partial pr ot hr o m bi n ti me  
Q C  
q ualit y c o ntr ol  
Q o L  
Q ualit y of Life  
R N A  
ri b o n ucleic aci d 
S A E  
seri o us a d verse e ve nt 
S A P  
Statistical A nal ysis Pla n  
S o A  
Sc he d ule of A cti vities 
S O D 1  
s u per o xi de dis m utase 1 
S O P  
sta n dar d o perati n g pr oce d ure 
S U S A R  
s us pecte d u ne x pecte d seri o us a d verse reacti o n  
S V C  
Sl o w Vital Ca pacit y  
T E A E  
treat me nt-e mer ge nt a d verse e ve nt 
T E S A E  
treat me nt-e mer ge nt seri o us a d verse e ve nt  
T N F  
t u m or necr osis fact or 
U M N  
u p per m ot or ne ur o n  
V E G F  
vasc ular e n d ot helial gr o wt h fact or  
W FI  
water f or i njecti o n 
 
1 0. 4. 2.  
Defi niti o ns  
Acti ve I nfecti o n  
C hr o nic i nfecti o n or se vere acti ve i nfecti o n t hat ma y c o m pr o mise t he 
Partici pa nt ’s well bei n g or partici pati o n i n t he st u d y, i n t he I n vesti gat or’s 
j u d g me nt 
Da y 1 4, etc.  
Da y 1 4  (f or e xa m ple) refers s pecificall y t o t he act ual da y of t he Visit  
desi g nate d as t he Da y 1 4 Visit, a n d n ot t o t he 1 4 t h da y of t he st u d y f or a 
Partici pa nt . 
E n d of St u d y  
C o m pleti o n of t he last Visit  or pr oce d ure s h o w n i n t he Sc he d ule of Acti vities 
f or t he last Partici pa nt  re mai ni n g i n t he st u d y 

Heli x mit h C o., Lt d. 
C O N FI D E N TI A L   
Pr ot oc ol: V M A L S- 0 0 2- 2 
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 
Versi o n 3. 0 
9 0 
Fi nal : 2 0 Ja n uar y 2 0 2 1 
Hi g hl y Effecti ve C o ntrace pti o n 
Met h o d  
See C o ntrace pti ve G ui da nce  
I njecti o n Site Reacti o n 
A n A E l ocate d i n cl ose pr o xi mit y t o t he i njecti o n sites o n t he tar get m uscles 
a n d  first o bser ve d wit hi n 4 8 hr f oll o wi n g  St u d y I njecti o ns 
I n vesti gat or 
T he PI or a p pr o priate st u d y site pers o n nel w h o m t he PI desi g nates t o perf or m a 
certai n d ut y 
Place b o  
Place b o c o m prises 4 5 m g s o di u m c hl ori de a n d 5 5 m g s ucr ose i n 5 m L water 
f or i njecti o n. E n ge nsis vials c o ntai n t he sa me e xci pie nts.  
Safet y A nal ysis P o p ulati o n  
All Partici pa nt s w h o recei ve at least o ne St u d y I njecti o n  
S p o ns or  
Heli x mit h C o., Lt d. a n d its re prese ntati ves c o ntracte d t o pr o vi de ser vices f or 
st u d y c o n d uct 
St u d y Dr u g  
E n ge nsis or Place b o  
St u d y I njecti o n  
I njecti o n of E n ge nsis or Place b o  
Partici pa nt  
A n y o ne w h o is c o nse nte d f or Scree ni n g  
Treat me nt Ar m  
T he gr o u p of Partici pa nt s assi g ne d t o recei ve St u d y Dr u g or t he gr o u p 
assi g ne d t o recei ve Place b o d uri n g t he first 6 m o nt hs of treat me nt  
Treat me nt C ycle  
T w o  sets of St u d y I njecti o ns 1 4 da ys a part c o m prisi n g a si n gle d ose 
V M 2 0 2  
T he acti ve p har mace utical i n gre die nt of E n ge nsis: a n o vel ge n o mic 
c o m ple me ntar y de o x yri b o n ucleic aci d (c D N A) h y bri d h u ma n he pat oc yte 
gr o wt h fact or ( H G F) c o di n g se q ue nce ( H G F -X 7) e x pressi n g t w o is of or ms of 
H G F, H G F 7 2 8 a n d H G F 7 2 3 
 
 
 

Heli x mit h C o., Lt d. 
C O N FI D E N TI A L   
Pr ot oc ol: V M A L S- 0 0 2- 2 
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 
Versi o n 3. 0 
9 1 
Fi nal : 2 0 Ja n uar y 2 0 2 1 

Heli x mit h C o., Lt d. 
C O N FI D E N TI A L   
Pr ot oc ol: V M A L S- 0 0 2- 2 
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 
Versi o n 3. 0 
9 2 
Fi nal : 2 0 Ja n uar y 2 0 2 1 

Heli x mit h C o., Lt d. 
C O N FI D E N TI A L   
Pr ot oc ol: V M A L S- 0 0 2- 2 
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 
Versi o n 3. 0 
9 3 
Fi nal : 2 0 Ja n uar y 2 0 2 1 
1 0. 6.  
A p pe n di x 6. Re vise d A m y otr o p hic L ater al S cler osis F u ncti o n al R ati n g S c ale  
 
 
 

Heli x mit h C o., Lt d. 
C O N FI D E N TI A L   
Pr ot oc ol: V M A L S- 0 0 2- 2 
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 
Versi o n 3. 0 
9 4 
Fi nal : 2 0 Ja n uar y 2 0 2 1 
1 0. 7.  
A p pe n di x 7 . A m y otr o p hic L ater al Scler osis Assess me nt Q uesti o n n aire 
T he f oll o wi n g is a n e xa m ple of t he A L S A Q- 4 0 
Ple ase c o m plete t his q uesti o n n aire as s o o n as p ossi ble . If y o u ha v e a n y diffic ulties filli n g i n 
t he q uesti o n naire b y y o urself, please g et s o me o ne else t o hel p y o u wit h it. H o we ver, it is y o ur 
res p o nses t hat we ar e i ntereste d i n. 
T he q uesti o n naire c o nsists of a n u m ber of st ate me nts a b o ut diffic ulties t hat y o u ma y ha ve 
e x perie n ce d d uri n g t he l ast 2 wee ks. T here are n o ri g ht or wr o n g a ns w ers: y o ur fir st res p o nse is 
li kel y t o be t he m ost acc urate f or y o u. Please tic k t he b o x w hic h best descri bes y o ur o w n 
e x perie n ce or feeli n gs.  
Please tr y t o a ns wer e ver y q uesti o n e ve n t h o u g h s o me ma y see m rat her si milar t o ot hers or ma y 
n ot see m rele v a nt t o y o u. 
All t he  i nf or mati o n y o u gi ve will be treate d i n t he strictest c o nfi de nce. 
T he f oll o wi n g state me nts all refer t o diffic ulties t hat y o u  
ma y ha ve ha d d uri n g t he l ast 2 wee ks . 
Please i n dicate, b y tic ki n g t he a p pr o priat e b o x, h o w ofte n 
t he f oll o wi n g state me nts ha ve bee n tr ue f or y o u. 
 
 

Heli x mit h C o., Lt d. 
C O N FI D E N TI A L  
Pr ot oc ol: V M A L S- 0 0 2- 2 
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 
Versi o n 3. 0 
1 0 0 
Fi nal : 2 0 Ja n uar y 2 0 2 1 
 
Cli nic al I m pressi o n of C h a n ge Sc ale  
1. C GI C - Gl o b al Im pr o ve m e nt: Rate t otal i m pr o ve me nt w het her or n ot, i n y o ur j u d ge me nt, it is d ue e ntirel y t o dr u g treat me nt. 
C o m pare d t o his / her c o n diti o n at a d missi o n t o t he pr oject, h o w m uc h has h e/s he c ha n g e d?  
0 = N ot assesse d    
 
4 = N o c ha n ge  
1 = Ver y m uc h i m pr o ve d    
5 = Mi ni mall y w orse  
2 = M uc h i m pr o ve d   
 
6 = M uc h w orse  
3 = Mi ni mall y i m pr o ve d    
7 = Ver y m uc h w orse  
2. Effic ac y i n de x: Rate t his ite m o n t he basis of dr u g effect o nl y . 
Select t he ter ms w hic h b est descri be t he d e grees of t hera p e utic effect a n d si de effects a n d rec or d t he n u m ber i n t he b o x w here t he 
t w o ite ms i ntersect. 
E X A M P L E: T hera p e utic effect is rate d as ‘ M o derate’ a n d si de effects are j u d ge d ‘ D o n ot si g nifica ntl y i nterfere wit h patie nt’s 
f u ncti o ni n g’. 
T her a pe utic effect  
Si de effects  
 
 
N o ne  
D oes n ot si g nific a ntly 
i nterfere wit h p atie nt’s 
f u ncti o ni n g 
Si g nific a ntly 
i nterferes wit h 
p atie nt’s f u ncti o ni n g  
O ut wei g hs t her a pe utic 
effect 
M ar k e d  
Vast i m pr o ve me nt. C o m plete or nearl y  c o m plete 
re missi o n of all s y m pt o ms 
0 1  
0 2  
0 3  
0 4  
M o der ate  
Deci de d I m pr o ve me nt. Partial re missi o n of  
s y m pt o ms 
0 5  
0 6  
0 7  
0 8  
Mi ni m al  
Sli g ht i m pr o ve me nt w hic h d oes n’t alter stat us  
 of care of patie nt  
0 9  
1 0  
1 1  
1 2  
U nc h a n ge d or w orse  
1 3  
1 4  
1 5  
1 6  
N ot assesse d = 0 0  
 

Heli x mit h C o., Lt d. 
C O N FI D E N TI A L  
Pr ot oc ol: V M A L S- 0 0 2- 2 
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 
Versi o n 3. 0 
1 0 1 
Fi nal : 2 0 Ja n uar y 2 0 2 1 

Heli x mit h C o., Lt d. 
C O N FI D E N TI A L  
Pr ot oc ol: V M A L S- 0 0 2- 2 
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 
Versi o n 3. 0 
1 0 2 
Fi nal : 2 0 Ja n uar y 2 0 2 1 
1 1.  
R E F E R E N C E S  
 
1 S ufit R L, Ajr o u d -Driss S, Case y P, Kessler  J A. O pe n la bel st u d y t o assess t he safet y of V M 2 0 2 i n s u bjects wit h 
a m y otr o p hic lateral scler osis. A my otr o p h L ater al Scler Fr o nt ote m p or al De ge ner . 2 0 1 7; 1 8( 3-4): 2 6 9 -2 7 8. 
d oi: 1 0. 1 0 8 0/ 2 1 6 7 8 4 2 1. 2 0 1 6. 1 2 5 9 3 3 4  
2 Nels o n L M. E pi de mi ol o g y of A L S. Cli nic al Ne ur oscie nce . 1 9 9 5; 3: 3 2 7 -3 1.  
3 Har di ma n O, va n de n Ber g L H, Kier na n M C. Cli nical dia g n osis a n d ma na ge me nt of a m y otr o p hic lateral scler osis. 
N at ure revie ws Ne ur ol o gy . 2 0 1 1; 7: 6 3 9 -4 9.  
4 R ose n D R, Si d di q ue T, Patters o n D, et al. M utati o ns i n C u/ Z n s u per o xi de dis m utase ge ne are ass ociate d wit h 
fa milial a m y otr o p hic lateral scler osis. N at ure . 1 9 9 3;  3 6 2: 5 9 -6 2.  
5 L o gr osci n o G, Tra y n or BJ, Har di ma n O, et al. I nci de nce of a m y otr o p hic lateral scler osis i n E ur o pe. J o ur n al of 
N e ur ol o gy, N e ur os ur gery, a n d P syc hi atry. 2 0 1 0;  8 1: 3 8 5 -9 0.  
6 Cr o ni n S, Har di ma n O, Tra y n or BJ. Et h nic variati o n i n t he i nci de nce of A L S: a s yste mat ic re vie w. Ne ur ol o gy . 
2 0 0 7; 6 8: 1 0 0 2 -7.  
7 Fact or -Lit va k P, Al -C hala bi A, Asc heri o A, et al. C urre nt pat h wa ys f or e pi de mi ol o gical researc h i n a m y otr o p hic 
lateral scler osis. A my otr o p hic L ater al S cler osis & F r o nt ote m p or al D e ge ner ati o n . 2 0 1 3; 1 4 S u p pl 1: 3 3 -4 3.  
8 Zal di var T, G utierrez J, Lara G, et al. Re d uce d fre q ue nc y of A L S i n a n et h nicall y mi xe d p o p ulati o n: a p o p ulati o n -
base d m ortalit y st u d y. Ne ur ol o gy . 2 0 0 9; 7 2: 1 6 4 0 -5.  
9 He nr y K A, Fa glia n o J, J or da n H M, et al. Ge o gra p hic v ariati o n of am y otr o p hic lateral scler osis inci de nce i n Ne w 
Jerse y, 2 0 0 9-2 0 1 1. A m J E pi de mi ol . 2 0 1 5; 1 8 2: 5 1 2 -9.  
1 0 Wa n g H, O' Reill y EJ, Weiss k o pf M G, et al. S m o ki n g a n d ris k of a m y otr o p hic lateral scler osis: a p o ole d a nal ysis 
of 5 pr os pecti ve c o h orts. Arc hives of Ne ur ol o gy . 2 0 1 1; 6 8: 2 0 7 1 3.  
1 1 de J o n g S W, H uis ma n M H, S ute dja N A, et al. S m o ki n g, alc o h ol c o ns u m pti o n, a n d t he ris k of a m y otr o p hic lateral 
scler osis: a p o p ulati o n-base d st u d y. A meric a n J o ur n al of E pi de mi ol o gy . 2 0 1 2; 1 7 6: 2 3 3 -9.  
1 2 Bra dle y W G, Mas h D C. Be y o n d G ua m: t he c ya n o bacteria/ B M A A h y p ot hesis of t he ca use of A L S a n d ot her 
ne ur o de ge nerati ve diseases. A my otr o p hic L ater al S cler osis: O ffici al Pu blic ati o n of t he W orl d Fe der ati o n of 
Ne ur ol o gy Rese arc h Gr o u p o n M ot or Ne ur o n Dise ases . 2 0 0 9; 1 0 S u p pl 2: 7 -2 0.  
1 3 Caller T A, D o oli n J W, Ha ne y J F, et  al. A cl uster of a m y otr o p hic lateral scler osis i n Ne w Ha m ps hire: a p ossi ble 
r ole f or t o xic c ya n o bacteria bl o o ms. A my otr o p hic L ater al Scler osis: Offici al P u blic ati o n of t he W orl d Fe der ati o n of 
Ne ur ol o gy Rese arc h Gr o u p o n M ot or Ne ur o n Dise ases . 2 0 0 9; 1 0 S u p p l 2: 1 0 1-8.  
1 4 Caller T A, Fiel d N C, C hi p ma n J W, et al. S patial cl usteri n g of a m y otr o p hic lateral scler osis a n d t he p ote ntial r ole 
of B M A A. A my otr o p hic L ater al Scler osis: Offici al P u blic ati o n of t he W orl d Fe der ati o n of Ne ur ol o gy Rese arc h 
Gr o u p o n M ot or Ne ur o n  Dise ases . 2 0 1 2; 1 3: 2 5 -3 2.  
1 5 Ki hira T, Y os hi da S, K o n d o T, et al. A n i ncrease i n A L S i nci de nce o n t he Kii Pe ni ns ula, 1 9 6 0 -2 0 0 9: a p ossi ble 
li n k t o c ha n ge i n dri n ki n g water s o urce. A my otr o p hic L ater al Scler osis: Offici al P u blic ati o n of t he W orl d 
Fe der ati o n of Ne ur ol o gy Rese arc h Gr o u p o n M ot or Ne ur o n Dise ases . 2 0 1 2;  1 3: 3 4 7 -5 0.  
1 6 Jar o ne n M, Ve h vilai ne n P, Mal m T, et al. Pr otei n dis ulfi de is o merase i n A L S m o use glia li n ks pr otei n misf ol di n g 
wit h N A D P H o xi dase -catal yze d s u per o xi de pr o d ucti o n. H u m M ol Ge net. 2 0 1 3;  2 2: 6 4 6 -5 5 . 
1 7 C ozz oli n o M, Ferri A, Valle C, Carri M T. Mit oc h o n dria a n d A L S: I m plicati o ns fr o m n o vel ge nes a n d pat h wa ys. 
M ol Cell Ne ur osci. 2 0 1 2 3; 5 5: 4 4 -4 9 . 
1 8 Bar ber S C, S ha w PJ. O xi dati ve stress i n A L S: ke y r ole i n m ot or ne ur o n i nj ur y a n d t hera pe utic tar get. Free 
R a dic al Bi ol o gy & Me dici ne . 2 0 1 0; 4 8: 6 2 9 -4 1.  
1 9 Pa pa di mitri o u D, Le Verc he V, Jac q uier A, et al. I nfla m mati o n i n A L S a n d S M A: s orti n g o ut t he g o o d fr o m t he 
e vil. Ne ur o bi ol o gy of Dise ase . 2 0 1 0; 3 7: 4 9 3 -5 0 2.  
2 0 Mc C o m be P A, He n ders o n R D. T he R ole of i m m u ne a n d i nfla m mat or y mec ha nis ms i n A L S. C urre nt M olec ul ar 
Me dici ne . 2 0 1 1; 1 1: 2 4 6 -5 4.  
2 1 Wallis N, Za ga mi CJ, Beart P M, O' S hea R D. C o m bi ne d e xcit ot o xic -o xi dati ve st ress a n d t he c o nce pt of n o n-cell 
a ut o n o m o us pat h ol o g y of A L S: i nsi g hts i nt o m ot o ne ur o n a x o n o pat h y a n d astr o gli osis. Ne ur oc he mistry 
I nter n ati o n al. 2 0 1 2; 6 1: 5 2 3 -3 0.  
2 2 B oillee S, Va n de Vel de C, Cl e vela n d D W. A L S: a disease of m ot or ne ur o ns a n d t heir n o n ne ur o nal nei g h b ors. 
Ne ur o n . 2 0 0 6; 5 2: 3 9 -5 9  
2 3 Ferrai u ol o L, Kir b y J, Griers o n AJ, et al. M olec ular pat h wa ys of m ot or ne ur o n i nj ur y i n a m y otr o p hic lateral 
scler osis. N at ure Revie ws Ne ur ol o gy . 2 0 1 1; 7: 6 1 6 -3 0.  
 

Heli x mit h C o., Lt d. 
C O N FI D E N TI A L  
Pr ot oc ol: V M A L S- 0 0 2- 2 
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 
Versi o n 3. 0 
1 0 3 
Fi nal : 2 0 Ja n uar y 2 0 2 1 
 
2 4 Frie dla n der R M. A p o pt osis a n d cas pases i n ne ur o de ge nerati ve diseases. T he Ne w E n gl a n d J o ur n al of Me dici ne . 
2 0 0 3; 3 4 8: 1 3 6 5 -7 5.  
2 5 Ferrai u ol o L, Kir b y J, Griers o n AJ, et al. M olec ular pat h wa ys of m ot or ne ur o n i nj ur y i n a m y otr o p hic lateral 
scler osis. N at ure Revie ws Ne ur ol o gy . 2 0 1 1; 7: 6 1 6 -3 0.  
2 6 Frie dla n der R M, Br o w n R H, Ga gliar di ni V, et al. I n hi biti o n of I C E sl o ws A L S i n mice. N at ure . 1 9 9 7; 3 8 8: 3 1.  
2 7 Li M, O na V O, G ue ga n C, et a l. F u ncti o nal r ole of cas pase-1 a n d cas pase -3 i n a n A L S tra ns ge nic m o use m o del. 
Scie nce . 2 0 0 0;  2 8 8: 3 3 5 -9.  
2 8 Pasi nelli P, H o use weart M K, Br o w n R H, Jr., Cle vela n d D W. Cas pase -1 a n d -3 are se q ue ntiall y acti vate d i n m ot or 
ne ur o n deat h i n C u, Z n s u per o xi de dis m u tase-me diate d fa milial a m y otr o p hic lateral scler osis. Pr ocee di n gs of t he 
N ati o n al Ac a de my of Scie nces of t he U nite d St ates of A meric a . 2 0 0 0; 9 7: 1 3 9 0 1 -6.  
2 9 Y ua n J, Ya n k ner B A. A p o pt osis i n t he ner v o us s yste m. N at ure . 2 0 0 0; 4 0 7: 8 0 2 -9.  
3 0 Marti n LJ. Ne ur o nal dea t h i n a m y otr o p hic lateral scler osis is a p o pt osis: p ossi ble c o ntri b uti o n of a pr o gra m me d 
cell deat h mec ha nis m. J o ur n al of Ne ur o p at h ol o gy a n d Ex peri me nt al Ne ur ol o gy . 1 9 9 9; 5 8: 4 5 9 -7 1.  
3 1 Miller R G, Mitc hell J D, M o ore D H. Ril uz ole f or a m y otr o p hic lateral scler os is ( A L S)/ m ot or ne ur o n disease 
( M N D). C oc hr a ne D at a b ase of Syste m atic Revie ws . 2 0 1 2; 3: C D 0 0 1 4 4 7.  
3 2 Fe derici T, B o ulis N M. Ge ne -base d treat me nt of m ot or ne ur o n diseases. M uscle Nerve . 2 0 0 6; 3 3: 3 0 2 -2 3.  
3 3 Sa da n O, S he mes h N, C o he n Y, Mela me d E, Offe n D. A d ult ne ur otr o p hic fact or -secreti n g ste m cells: a p ote ntial 
n o vel t hera p y f or ne ur o de ge nerati ve diseases. Isr Me d Ass oc J . 2 0 0 9; 1 1: 2 0 1 -4.  
3 4 Berr y J D, C u d k o wicz M E, Wi n de ba n k AJ, et al. N ur O w n, p hase 2, ra n d o mize d, cli nical trial i n patie nts wit h 
A L S: Safet y, cli nical, a n d bi o mar ker res ults. Ne ur ol o g y 2 0 1 9; 9 3:e 2 2 9 4 -e 3 0 5. 
3 5 Geij o -Barrie nt os E, Past ore -Ol me d o C, De Mi n g o P, et al. I ntra m usc ular injecti o n of b o ne m arr o w ste m cells i n 
am y otr o p hic lateral scler osis p atie nts: a ra n d o mize d cli nical trial. Fr o nt Ne ur osci. 2 0 2 0; 1 4: 1 -1 4 . 
3 6 Petr o u P, G ot helf Y, Ar g o v Z, et al. Safet y a n d cli nical effects of m ese nc h y mal ste m cells secreti n g n e ur otr o p hic 
fact or tra ns pla ntati o n i n p atie nts w it h am y otr o p hic lateral scler osis: res ults of p hase 1/ 2 a n d 2a cli nical trials. J A M A. 
Ne ur ol . 2 0 1 6; 7 3: 3 3 7 -4 4.  
3 7 B uss oli n o F, Di Re nz o M F, Zic he M, et al. He pat oc yte gr o wt h fact or is a p ote nt a n gi o ge nic fact or w hic h 
sti m ulates e n d ot helial cell m otilit y a n d gr o wt h. J Cell Bi ol. 1 9 9 2; 1 1 9: 6 2 9 -4 1.  
3 8 Mats u m ot o K, Na ka m ura T. E mer gi n g  m ulti p ote nt as pects of he pat oc yte gr o wt h fact or. J Bi oc he m . 
1 9 9 6; 1 1 9: 5 9 1 -6 0 0.  
3 9 Ja yasa n kar V, W o o YJ, Pir olli TJ, et al. I n d ucti o n of a n gi o ge nesis a n d i n hi biti o n of a p o pt osis b y he pat oc yte 
gr o wt h fact or effecti vel y treats p ostisc he mic heart fail ure. J C ard S ur g . 2 0 0 5; 2 0: 9 3 -1 0 1.  
4 0 Na ka ga mi H, Ka ne da Y, O gi hara T, M oris hita R. He pat oc yte gr o wt h fact or as p ote ntial car di o vasc ular t hera p y. 
Ex pert Rev C ar di ov asc T her . 2 0 0 5; 3: 5 1 3 -9.  
4 1 Gille J, K hali k M, K o ni g V, Ka uf ma n n R. He pat oc yte gr o wt h fact or/scatter fact or ( H G F/ S F) i n d uces vasc ular 
per mea bilit y fact or ( V P F/ V E G F) e x pressi o n b y c ult ure d kerati n oc ytes. J I nvest Der m at ol. 1 9 9 8; 1 1 1: 1 1 6 0 -5.  
4 2 M oris hita R, A o ki M, Y o Y, O gi hara T. He pat oc yte gr o wt h fact or as car di o vasc ular h or m o ne: r ole of H G F i n t he 
pat h o ge nesis  of car di o vasc ular disease . E n d ocr J. 2 0 0 2; 4 9: 2 7 3 -8 4 . 
4 3 Ja yasa n kar V, W o o YJ, Bis h L T, et al. Ge ne tra nsfer of he pat oc yte gr o wt h fact or atte n uates p osti nfarcti o n heart 
fail ure. Circ ul ati o n. 2 0 0 3; 1 0 8 S u p pl 1:II 2 3 0 -6.  
4 4 Has hi m ot o N, Ya ma na ka H, F u k u o ka T, et al. E x pressi o n of H G F a n d c Met i n t he peri p heral ner v o us s yste m of 
a d ult rats f oll o wi n g sciatic ner ve i nj ur y. Ne ur ore p ort . 2 0 0 1; 1 2: 1 4 0 3 -7.  
4 5 Giac o bi ni P, Messi na A, Wra y S, et al. He pat oc yte gr o wt h fact or acts as a m o t o ge n a n d g ui da nce si g nal f or 
g o na d otr o pi n h or m o ne -releasi n g h or m o ne-1 ne ur o nal mi grati o n. J Ne ur osci. 2 0 0 7; 2 7: 4 3 1 -4 5.  
4 6 Kat o N, Ne m ot o K, Na ka nis hi K, et al. N o n viral ge ne tra nsfer of h u ma n he pat oc yte gr o wt h fact or i m pr o ves 
stre pt oz ot oci n-i n d uce d dia betic ne ur o pat h y i n rats. Di a betes . 2 0 0 5; 5 4: 8 4 6 -5 4.  
4 7 K oi ke H, M oris hita R, I g uc hi S, et al. E n ha nce d a n gi o ge nesis a n d i m pr o ve me nt of ne ur o pat h y b y c otra nsfecti o n 
of h u ma n he pat oc yte gr o wt h fact or a n d pr ostac ycli n s y nt hase ge ne. F A S E B J . 2 0 0 3; 1 7: 7 7 9 -8 1.  
4 8 Ts uc hi hara T, O gata S, Ne m ot o K, et al. N o n viral Retr o gra de Ge ne Tra nsfer of H u ma n He pat oc yte Gr o wt h Fact or 
I m pr o ves Ne ur o pat hic Pai n-relate d P he n o me na i n Rats. M ol T her. 2 0 0 9; 1 7: 4 2 -5 0 . 
4 9 T o n ges L, Oste n d orf T, La m balle F, et al. He pat oc yte gr o wt h fact or pr otects reti nal ga n gli o n cells b y i ncreasi n g 
ne ur o nal s ur vi val a n d a x o nal re ge nerati o n i n vitr o a n d i n vi v o. J o ur n al of Ne ur o c he mistry . 2 0 1 1; 1 1 7: 8 9 2 -9 0 3.  
5 0 Kita m ura K, I wa na mi A, Na ka m ura M, et al. He pat oc yte gr o wt h fact or pr o m otes e n d o ge n o us re pair a n d 
f u ncti o nal rec o ver y after s pi nal c or d i nj ur y. J Ne ur osci Res. 2 0 0 7; 8 5: 2 3 3 2 -4 2.  
 

Heli x mit h C o., Lt d. 
C O N FI D E N TI A L  
Pr ot oc ol: V M A L S- 0 0 2- 2 
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 
Versi o n 3. 0 
1 0 4 
Fi nal : 2 0 Ja n uar y 2 0 2 1 
 
5 1 Ka d o ya ma K, F u na k os hi H, O h ya W, Na ka m ura T. He pat oc yte gr o wt h fact or ( H G F) atte n uates gli osis a n d 
m ot o ne ur o nal de ge nerati o n i n t he brai nste m m ot or n uclei of a tra ns ge nic m o use m o del of A L S. Ne ur oscie nce 
Rese arc h . 2 0 0 7; 5 9: 4 4 6 -5 6.  
5 2 T y n dall SJ, Wali k o nis R S. Si g nali n g b y he pat oc yte gr o wt h fact or i n ne ur o ns is i n d uce d b y p har mac ol o gical 
sti m ulati o n of s y na ptic acti vit y. Sy n a pse . 2 0 0 7; 6 1: 1 9 9 -2 0 4.  
5 3 S ha n g J, De g uc hi K, O hta Y, et al. Str o n g ne ur o ge nesis, a n gi o ge nesis, s y na pt o ge nesis, a n d a ntifi br osis of 
he pat oc yte gr o wt h fact or i n rats brai n after tra nsie nt mi d dle cere bral arter y occl usi o n. J o ur n al of Ne ur oscie nce 
Rese arc h.  2 0 1 1; 8 9: 8 6 -9 5.  
5 4 A kita H, Ta ka gi N, Is hi hara N, et al. He pat oc yte gr o wt h fact or i m pr o ves s y na ptic l ocalizati o n of t he N M D A 
rece pt or a n d i ntracell ular si g nali n g after e xcit ot o xic i nj ur y i n c ult ure d hi p p oca m pal ne ur o ns. Ex peri me nt al 
Ne ur ol o gy . 2 0 0 8; 2 1 0: 8 3 -9 4.  
5 5 Is hi hara N, Ta ka gi N, Nii m ura M, et al. I n hi biti o n of a p o pt osis-i n d uci n g fact or tra nsl ocati o n is i n v ol ve d i n 
pr otecti ve effects of he pat oc yte gr o wt h fact or a gai nst e xcit ot o xic cell deat h i n c ult ure d hi p p oca m pal ne ur o ns. 
J o ur n al of Ne ur oc he mistry . 2 0 0 5; 9 5: 1 2 7 7 -8 6.  
5 6 Is hi ga ki A, A o ki M, Na gai M, et al. I ntrat hecal deli ver y of he pat oc yte gr o wt h fact or fr o m a m y otr o p hic lateral 
scler osis o nset s u p presses dise ase pr o gressi o n i n rat a m y otr o p hic lateral scler osis m o del. J o ur n al of Ne ur o p at h ol o gy 
a n d Ex peri me nt al  Ne ur ol o gy . 2 0 0 7; 6 6: 1 0 3 7 -4 4.  
5 7 Li M, O na V O, G ue ga n C, et al. F u ncti o nal r ole of cas pase -1 a n d cas pase -3 i n a n A L S tra ns ge nic m o use m o del. 
Scie nce . 2 0 0 0; 2 8 8: 3 3 5 -9.  
5 8 Pasi nelli P, H o use weart M K, Br o w n R H, Jr., Cle vela n d D W. Cas pase -1 a n d -3 are se q ue ntiall y acti vate d i n m ot or 
ne ur o n deat h i n C u, Z n s u per o xi de dis m utase -me diate d fa milial a m y otr o p hic lateral scler osis. Pr ocee di n gs of t he 
N ati o n al  Ac a de my of Scie nces of t he U nite d St ates of A meric a . 2 0 0 0; 9 7: 1 3 9 0 1 -6.  
5 9 Ka d o ya ma K, F u na k os hi H, O h ya W, Na ka m ura T. He pat oc yte gr o wt h fact or ( H G F) atte n uates gli osis a n d 
m ot o ne ur o nal de ge nerati o n i n t he brai nste m m ot or n uclei of a tra ns ge nic m o use m o del of A L S. Ne ur osci Res . 
2 0 0 7; 5 9: 4 4 6 -5 6.  
6 0 Ka wai da K, Mats u m ot o K, S hi maz u H, Na ka m ura T. He pat oc yte gr o wt h fact or pre ve nts ac ute re nal fail ure a n d 
accelerates re nal re ge nerati o n i n mice. Pr ocee di n gs of t he N ati o n al Ac a de my of Scie nces of t he U nite d St ates of 
A meric a . 1 9 9 4; 9 1: 4 3 5 7 -6 1.  
6 1 Li u M L, Mar s W M, Zar ne gar R, Mic hal o p o ul os G K. U pta ke a n d distri b uti o n of he pat oc yte gr o wt h fact or i n 
n or mal a n d re ge nerati n g a d ult rat li ver. A m J P at h ol . 1 9 9 4; 1 4 4: 1 2 9 -4 0.  
6 2 S ufit R L, Ajr o u d -Driss S, Case y P, Kessler J A. O pe n la bel st u d y t o assess t he safet y of V M 2 0 2 i n Partici pa nt s 
wit h a m y otr o p hic lateral scler osis. A my otr o p h L ater al Scler Fr o nt ote m p or al De ge ner . 2 0 1 7; 1 8( 3-4): 2 6 9 -2 7 8.  
6 3 Bri n k ma n n J R, A n dres P, Me n d oza M, Sa nja k M. G ui deli nes f or t he use a n d perf or ma nce of q ua ntitati ve o utc o me 
meas ures i n A L S cli nical trials. J o ur n al of t he N e ur ol o gic al Scie nces. 1 9 9 7; 1 4 7: 9 7 -1 1 1.  
6 4 Miller R G, Jac ks o n C E, Kasars kis EJ, et al. Practice para meter u p date: t he care of t he patie nt wit h a m y otr o p hic 
lateral scler osis: m ulti disci pli n ar y care, s y m pt o m ma na ge me nt, a n d c o g niti ve/ be ha vi oral i m pair me nt (a n e vi de nce-
base d re vie w). Ne ur ol o gy . 2 0 0 9; 7 3: 1 2 2 7-1 2 3 3. ( Reaffir me d b y t he A merica n Ass ociati o n of Ne ur o m usc ular a n d 
Electr o dia g n ostic Me dici ne , Ja n uar y 1 1, 2 0 2 0) 
6 5 L u d ol p h A, Dr or y V, Har di ma n O, et al. A re visi o n of t he El Esc ori al criteria - 2 0 1 5. A my otr o p h L ater al Scler 
Fr o nt ote m p or al De ge ner . 2 0 1 5; 1 6: 2 9 1-2.  
6 6 Bri n k ma n n J R, A n dres P, Me n d oza M, Sa nja k M. G ui deli nes f or t he use a n d perf or ma nce of q ua ntitati ve o utc o me 
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7 0 F D A G ui da nce: T o xicit y Gra di n g Scale f or Healt h y A d ult a n d A d olesce nt V ol u nteers E nr olle d i n Pre ve nti ve 
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7 1 Nati o nal Ca ncer I nstit ute: C o m m o n Ter mi n ol o g y Criteria f or A d verse E ve nts ( C T C A E) v 5. 0, N o v. 2 7, 2 0 1 7.