Clinical trial NCT04684394
Conditions: Neovascular Age-related Macular Degeneration Retinal Disease Retinal Degeneration Macular Degeneration
Sponsor: Gemini Therapeutics, Inc.
Start date: 2020-12-29; Completion date: 2022-02-18
Enrollment: 50 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This study is designed to investigate the safety and tolerability of GEM103 IVT injection + standard of care vs. sham + standard of care.

Detailed description:
This is a Phase 2a, multi-center, multiple dose study in subjects with Neovascular Age-related Macular Degeneration (nAMD) to investigate the safety and tolerability of GEM103 IVT injection + standard of care vs. sham + standard of care.

Subjects will undergo clinical and ophthalmic assessments for determination of inclusion in the study and who meet all eligibility criteria will be enrolled.

Arms: arm 1: Participants were administered SoC therapy defined as aflibercept (2 milligram \[mg\]/50 microliter \[mcL\]) first, followed by GEM103 (500 microgram \[mcg\]/50mcL) 15 minutes later. Administration occurred every other month (EOM) for a total of 6 doses during the 12-month study period. arm 2: Participants were administered SoC therapy defined as aflibercept (2mg/50mcL) first, followed by the Sham injection 15 minutes later. Administration occurred EOM for a total of 6 doses during the 12-month study period.
Interventions: intervention 1: GEM103 intervention 2: Aflibercept intervention 3: Sham
Intervention descriptions: intervention 1: GEM103 500 mcg/50 mcL intravitreal injection intervention 2: Aflibercept 2 mg/50 mcL (SOC) intravitreal injection

Sham intravitreal injection intervention 3: Sham intravitreal injection

Protocol documents:
Prot_000.pdf: 
G E M- C L- 1 0 3 1 1 Pr ot oc ol, Versi o n 3. 0  
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G E MI NI T H E R A P E U TI C S I N C P R O P RI E T A R Y A N D C O N FI D E N TI A L:  
D O N O T C O P Y O R DI S T RI B U T E WI T H O U T P E R MI S SI O N F R O M G E MI NI T H E R A P E U TI C S I N C.  
 
A M ultice nter, M ulti ple- D os e St u d y i n Ne o v asc ul ar A ge-rel ate d M ac ul ar De ge ner ati o n 
( n A M D) t o E v al u ate t h e S afet y, T oler a bilit y, P h ar m a c o d y n a mics, I m m u n o ge nicit y, a n d 
Cli nic al Effect of Re pe at I ntr a vitre al (I V T) I njecti o ns of G E M 1 0 3 as a n A dj u nct t o 
St a n d ar d of C are Afli berce pt T her a p y 
 
Pr ot oc ol N u m ber: 
G E M- C L- 1 0 3 1 1 
D ate of Pr ot oc ol: 
5 Ma y 2 0 2 1 
Pr ot oc ol V ersi o n: 
Versi o n 3. 0  
( P)I N D N u m ber: 
1 4 1 0 3 6 
Pr o d uct: 
Rec o m bi na nt H u ma n C o m ple me nt Fact or H ( G E M 1 0 3) 
I n dic ati o n: 
Ne o vasc ular A ge-rel ate d Mac ular De ge n erati o n 
S p o ns or: 
Ge mi ni T hera p e utics, I nc. 
3 0 0 O ne Ke n d all S q uare, 3 r d Fl o or 
Ca m bri d ge, M A 0 2 1 3 9, U S A  
T he st u d y will be c o n d ucte d acc or di n g t o t he I nter n at i o n al C o u ncil f or H ar m o nis ati o n tri p artite g ui deli ne 
E 6( R 2): G o o d Cli nic al Pr actice   
 
 
 
T H E C O N C E P T S A N D I N F O R M A TI O N C O N T AI N E D  I N T HI S D O C U M E N T O R G E N E R A T E D 
D U RI N G T H E S T U D Y A R E C O N SI D E R E D P R O P RI E T A R Y A N D M A Y N O T B E DI S C L O S E D I N 
W H O L E O R I N P A R T WI T H O U T T H E E X P R E S S W RI T T E N C O N S E N T O F G E MI NI T H E R A P E U TI C S, 
I N C. 


G E M- C L- 1 0 3 1 1 Pr ot oc ol, Versi o n 3. 0  
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G E MI NI T H E R A P E U TI C S I N C P R O P RI E T A R Y A N D C O N FI D E N TI A L:  
D O N O T C O P Y O R DI S T RI B U T E WI T H O U T P E R M I S SI O N F R O M G E MI NI T H E R A P E U TI C S I N C. 
C O N T E N T S 
C O N T E N T S....................................................................................................................... ........... ii 
LI S T O F T A B L E S ................................................................................................................ ..... vii 
LI S T O F FI G U R E S ............................................................................................................... ... viii 
A P P R O V A L SI G N A T U R E P A G E ........................................................................................... i x  
I N V E S TI G A T O R S T A T E M E N T .............................................................................................. x 
LI S T O F A B B R E VI A TI O N S .................................................................................................... xi  
C LI NI C A L S T U D Y S Y N O P SI S ............................................................................................. xiii 
1  
I N T R O D U C TI O N.......................................................................................................... 2 0 
1. 1  
B ac k gr o u n d ........................................................................................................ 2 0  
1. 1. 1  
Disease .................................................................................................. 2 0  
1. 1. 2  
Me dical Rati o nale f or G E M 1 0 3 ........................................................... 2 1  
1. 2  
I n vesti g ati o n al Me dici n al Pr o d uct ( G E M 1 0 3) ................................................ 2 2 
1. 3  
N o ncli nic al S u m m ar y ........................................................................................ 2 2  
1. 4  
Cli nic al S u m m ar y .............................................................................................. 2 4  
1. 5  
D ose R ati o n ale a n d Ris k/ Be nefits ..................................................................... 2 4  
1. 5. 1  
St u d y D ose Rati o nale............................................................................ 2 4  
1. 5. 2  
Ris k/ Be nefit Assess me nt f or St u d y Dr u g a n d St u d y 
Pr oce d ures .............................................................................................  2 5  
2  
S T U D Y O B J E C TI V E S A N D E N D P OI N T S ................................................................  2 8  
3  
I N V E S TI G A TI O N A L P L A N ....................................................................................... 3 0 
3. 1  
O ver all Desi g n a n d Pl a n of t he St u d y .............................................................. 3 0  
3. 2  
St u d y Desi g n a n d Criteri a f or D osi n g .............................................................. 3 0  
3. 3  
R ati o n ale f or St u d y Desi g n ............................................................................... 3 1  
3. 4  
R ati o n ale f or D ose .............................................................................................. 3 2  
3. 5  
St u d y E n d p oi nts ................................................................................................. 3 2  
4  
S T U D Y P O P U L A TI O N ................................................................................................ 3 3  
4. 1  
T ar get P o p ul ati o n .............................................................................................. 3 3  
4. 2  
N u m ber of S u bjects ............................................................................................ 3 3 
4. 3  
Eli gi bilit y Criteri a .............................................................................................. 3 3  
4. 3. 1  
I ncl usi o n Criteria .................................................................................. 3 3 
4. 3. 2  
E xcl usi o n Criteria ................................................................................. 3 3  
4. 4  
Met h o d f or Assi g ni n g S u bjects t o Tre at me nt Gr o u ps.................................... 3 5  
4. 5  
S u bject Restricti o ns D u ri n g t he St u d y ............................................................. 3 5  


G E M- C L- 1 0 3 1 1 Pr ot oc ol, Versi o n 3. 0  
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G E MI NI T H E R A P E U TI C S I N C P R O P RI E T A R Y A N D C O N FI D E N TI A L:  
D O N O T C O P Y O R DI S T RI B U T E WI T H O U T P E R M I S SI O N F R O M G E MI NI T H E R A P E U TI C S I N C. 
4. 5. 1  
Ge neral a n d Dietar y .............................................................................. 3 5  
4. 5. 2  
C o ntrace pti o n a n d Pre g na nc y A v oi da nce P r oce d ures .......................... 3 5 
4. 6  
C o nc o mit a nt Me dic ati o ns a n d Tre at me nts ..................................................... 3 5  
4. 7  
Disc o nti n u ati o n of S u bjects ............................................................................... 3 6  
4. 7. 1  
Pre mat ure Wit h dra wal fr o m St u d y Partici pati o n.................................. 3 6  
4. 7. 2  
Pr oce d ures f or Disc o nti n uati o n ............................................................ 3 6  
4. 8  
S u bject Re pl ace me n t P olic y .............................................................................. 3 6 
4. 9  
S u bject Res cree ni n g ........................................................................................... 3 6 
5  
S T U D Y P R O C E D U R E S ............................................................................................... 3 7  
5. 1  
St u d y Assess me nts ............................................................................................. 3 7  
5. 1. 1  
I nf or me d C o nse nt ................................................................................. 3 7 
5. 1. 2  
Ge netic Sa m ple C ollecti o n ................................................................... 3 7  
5. 1. 3  
Me dical a n d Oc ular Hist or y .................................................................. 3 7  
5. 1. 4  
De m o gra p hic I nf or mati o n..................................................................... 3 7  
5. 1. 5  
P h ysical E xa mi nati o n ........................................................................... 3 7  
5. 1. 6  
O p ht hal mic  E xa mi nati o n ...................................................................... 3 8  
5. 1. 7  
Vital Si g n Meas ure me nts ...................................................................... 3 8  
5. 2  
Cli nic al L a b or at or y Assess me nts ..................................................................... 3 8  
5. 2. 1  
D N A Sa m p le ......................................................................................... 3 8 
5. 2. 2  
E x pl orat or y Bi o mar kers ........................................................................ 3 9  
5. 2. 3  
P K a n d I m m u n o ge nicit y Assess me nts .................................................. 3 9  
5. 3  
I m a gi n g Assess me nts ......................................................................................... 3 9 
5. 4  
Deter mi n ati o n of St u d y E ye .............................................................................. 4 0  
6  
S T U D Y T R E A T M E N T S ............................................................................................... 4 1  
6. 1  
Tre at me nts A d mi nistere d  ................................................................................. 4 1 
6. 1. 1  
D ose A dj ust me nts ................................................................................. 4 1  
6. 1. 2  
D ose Escalati o n..................................................................................... 4 1  
6. 2  
St o p pi n g R ules .................................................................................................... 4 1  
6. 2. 1  
St o p pi n g R ules i n I n di vi d ual S u bjects .................................................. 4 1  
6. 2. 2  
St o p pi n g R ules f or M ulti ple S u bjects ................................................... 4 1  
6. 3  
Descri pti o n of St u d y Dr u g................................................................................. 4 1  
6. 4  
St or a ge a n d Dis p ositi o n of St u d y Dr u g ............................................................ 4 1  
6. 4. 1  
Recei pt of Dr u g S u p plies ...................................................................... 4 1  


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G E MI NI T H E R A P E U TI C S I N C P R O P RI E T A R Y A N D C O N FI D E N TI A L:  
D O N O T C O P Y O R DI S T RI B U T E WI T H O U T P E R M I S SI O N F R O M G E MI NI T H E R A P E U TI C S I N C. 
6. 4. 2  
Ma na ge me nt of Cli nical S u p plies ......................................................... 4 2  
6. 4. 3  
St ora ge .................................................................................................. 4 2  
6. 4. 4  
Dis p ositi o n ............................................................................................ 4 2  
6. 5  
Pre p ar ati o n a n d A d mi nistr ati o n of St u d y Dr u g ............................................. 4 2  
6. 5. 1  
Pre parati o n of St u d y Dr u g .................................................................... 4 2  
6. 5. 2  
A d mi nistrati o n of St u d y Dr u g .............................................................. 4 3  
6. 6  
R a n d o miz ati o n of t he St u d y Dr u g .................................................................... 4 3  
6. 7  
Destr ucti o n of t he St u d y Dr u g .......................................................................... 4 4  
7  
A S S E S S M E N T O F S A F E T Y ........................................................................................ 4 5  
7. 1  
A Es a n d L a b or at or y A b n or m alities ................................................................. 4 5  
7. 1. 1  
Cli nical A Es .......................................................................................... 4 5  
7. 1. 2  
La b orat or y Test A b n or malit y ............................................................... 4 6  
7. 2  
Rec or di n g of A Es ............................................................................................... 4 7  
7. 3  
Re p orti n g a n d H a n dli n g of S afet y P ar a meters ............................................... 4 7  
7. 3. 1  
S A Es (I m me diatel y Re p orta ble t o t he S p o ns or) ................................... 4 7  
7. 3. 2  
A E Re p orti n g Peri o d ............................................................................. 4 7  
7. 3. 3  
I n vesti gat or Re p orti n g:  N otif yi n g t he S p o ns or .................................... 4 8 
7. 3. 4  
I n vesti gat or Re p orti n g:  N otif yi n g t he I R B/I E C................................... 4 8 
7. 3. 5  
S p o ns or Re p orti n g:  N otif yi n g Re g ulat or y A ut h orities ........................ 4 8  
7. 3. 6  
S p o ns or Re p orti n g:  N otif yi n g Partici pati n g I n vesti gat ors................... 4 8  
7. 3. 7  
Treat me nt a n d F oll o w- u p of A Es ......................................................... 4 8  
7. 3. 8  
F oll o w- u p of A b n or mal La b orat or y Test Val ues ................................. 4 9  
7. 3. 9  
Pre g na nc y.............................................................................................. 4 9  
7. 4  
Me dic al Re vie w C o m mittee ( M R C) ................................................................. 4 9  
8  
S T A TI S TI C A L P L A N ................................................................................................... 5 0  
8. 1  
Ge ner al C o nsi der ati o ns ..................................................................................... 5 0  
8. 2  
Deter mi n ati o n of S a m ple Size ........................................................................... 5 0  
8. 3  
A n al ysis Sets ....................................................................................................... 5 0  
8. 3. 1  
C o nse nte d S u bject Set .......................................................................... 5 0  
8. 3. 2  
Bi o mar ker Set ....................................................................................... 5 0  
8. 3. 3  
F ull A nal ysis Set ................................................................................... 5 0  
8. 4  
De m o gr a p hics a n d S afet y A n al ysis .................................................................. 5 0  
8. 5  
Bi o m ar ker, I m a gi n g, a n d Cli nic al E n d p oi nt A n al ysis ................................... 5 1  


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G E MI NI T H E R A P E U TI C S I N C P R O P RI E T A R Y A N D C O N FI D E N TI A L:  
D O N O T C O P Y O R DI S T RI B U T E WI T H O U T P E R M I S SI O N F R O M G E MI NI T H E R A P E U TI C S I N C. 
8. 6  
S u m m aries of D at a Pri or t o St u d y C o m pleti o n .............................................. 5 1  
8. 6. 1  
Ha n dli n g of Missi n g Data ..................................................................... 5 2  
9  
D A T A Q U A LI T Y A N D A S S U R A N C E, S U B J E C T D A T A H A N D LI N G, 
A N D R E C O R D K E E PI N G ........................................................................................... 5 3  
9. 1  
S o urce D oc u me nts .............................................................................................. 5 3  
9. 2  
C ase Re p ort F or ms ( C R Fs) ............................................................................... 5 3  
9. 3  
Rec or ds Rete nti o n .............................................................................................. 5 3  
1 0  
S T U D Y M O NI T O RI N G, A U DI TI N G, A N D I N S P E C TI N G .................................... 5 4  
1 0. 1  
St u d y M o nit ori n g Pl a n ...................................................................................... 5 4  
1 0. 2  
A u diti n g a n d I ns pecti n g .................................................................................... 5 4  
1 0. 3  
M a n a ge me nt of Pr ot oc ol A me n d me nts a n d De vi ati o ns ................................. 5 4  
1 0. 3. 1  
M o dificati o n of t he Pr ot oc ol ................................................................. 5 4  
1 0. 3. 2  
Pr ot oc ol De viati o ns............................................................................... 5 4  
1 0. 4  
St u d y Ter mi n ati o n ............................................................................................. 5 5  
1 1  
I N V E S TI G A T O R O B LI G A TI O N S ............................................................................. 5 6 
1 1. 1  
C o nfi de nti alit y .................................................................................................... 5 6  
1 1. 2  
I nstit uti o n al Re vie w ........................................................................................... 5 6 
1 1. 3  
S u bject C o nse nt .................................................................................................. 5 6  
1 1. 4  
Fi n a nci al Discl os ure a n d O bli g ati o ns............................................................... 5 6  
1 1. 5  
St u d y C o n d uct a n d A d here nce t o Pr ot oc ol ..................................................... 5 7  
1 1. 6  
D at a C ollecti o n ................................................................................................... 5 7  
1 1. 7  
Re p orti n g A d verse E ve nts ................................................................................. 5 7  
1 1. 8  
Rec or ds Rete nti o n .............................................................................................. 5 7  
1 1. 9  
P u blic ati o ns ........................................................................................................ 5 7  
1 2  
E T HI C A L C O N SI D E R A TI O N S .................................................................................. 5 8  
1 3  
C LI NI C A L S T U D Y R E P O R T A N D D A T A DI S C L O S U R E .................................... 5 9  
1 3. 1  
Fi n al Re p ort ........................................................................................................ 5 9  
1 4  
R E F E R E N C E S ............................................................................................................... 6 0  
1 5  
A P P E N DI C E S ................................................................................................................ 6 3  
A p pe n di x A:  Sc he d ule of Assess me nts ........................................................................ 6 4  
A p pe n di x B:  Bi ol o gic al S a m ple C ollecti o n a n d S hi p pi n g I nstr ucti o ns.................... 6 7  
A p pe n di x C:  C ol or F u n d u s P h ot o gr a p h y ( C F P) ....................................................... 6 8 
A p pe n di x D:  F u n d us A ut ofl u oresce nce ( F A F) ........................................................... 6 9  
A p pe n di x E:  Fl u orescei n A n gi o gr a p h y ( F A) .............................................................. 7 0  


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G E MI NI T H E R A P E U TI C S I N C P R O P RI E T A R Y A N D C O N FI D E N TI A L:  
D O N O T C O P Y O R DI S T RI B U T E WI T H O U T P E R M I S SI O N F R O M G E MI NI T H E R A P E U TI C S I N C. 
A p pe n di x F:  S pectr al D o m ai n O ptic al C o here nce T o m o gr a p h y ( S D-
O C T).................................................................................................................... 7 1  
A p pe n di x G:  O ptic al C o here nce T o m o gr a p h y – A n gi o gr a m ( O C T- A) .................. 7 2  
A p pe n di x H:  Ne ar I nfr are d Reflect a nce I m a gi n g ( NI R) .......................................... 7 3  
A p pe n di x I:  Mi n nes ot a L o w- visi o n Re a di n g Test ( M N Re a d) C h arts...................... 7 4  
A p pe n di x J:  N ati o n al E ye I nstit ute Vis u al F u ncti o ni n g Q uesti o n n aire 
2 5-ite m Versi o n ( N EI- V F Q- 2 5) wit h Ne ar a n d Dist a nce Acti vit y 
S u bsc ale Sc ores................................................................................................... 7 6  
A p pe n di x K:  Gr a di n g Sc ale f or U veitis ...................................................................... 8 8  
A p pe n di x L:  Me dic ati o ns K n o w n t o P ote nti all y E x acer b ate M ac ul ar 
E de m a or M ac ul ar De ge ner ati o n ..................................................................... 8 9  
 


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D O N O T C O P Y O R DI S T RI B U T E WI T H O U T P E R M I S SI O N F R O M G E MI NI T H E R A P E U TI C S I N C. 
LI S T O F T A B L E S 
T a ble 1.  
St u d y O bjecti v es a n d E n d p oi nts ..................................................................................... 2 8  
T a ble 2.  
Assess me nt of Ca usalit y ................................................................................................ 4 6  
 


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G E MI NI T H E R A P E U TI C S I N C P R O P RI E T A R Y A N D C O N FI D E N TI A L:  
D O N O T C O P Y O R DI S T RI B U T E WI T H O U T P E R M I S SI O N F R O M G E MI NI T H E R A P E U TI C S I N C. 
LI S T O F FI G U R E S 
Fi g ure 1  
St u d y Desi g n ..................................................................................................................  3 1 
 


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G E MI NI T H E R A P E U TI C S I N C P R O P RI E T A R Y A N D C O N FI D E N TI A L:  
D O N O T C O P Y O R DI S T RI B U T E WI T H O U T P E R MI S SI O N F R O M G E MI NI T H E R A P E U TI C S I N C.  
A P P R O V A L SI G N A T U R E P A G E 
Pr ot oc ol Title: 
A M ultice nter, M ulti ple- D ose St u d y i n Ne o v asc ul ar A ge- Relate d 
Mac ular De ge n erati o n ( n A M D) t o E val uate t h e Safet y, 
T olera bilit y, P har m ac o d y na mics, I m m u n o ge nicit y, a n d Cli nical 
Effect of Re peat I ntra vitreal (I V T) I njecti o ns of G E M 1 0 3 as a n 
A dj u nct t o Sta n dar d of Care Afli berce pt T hera p y  
Pr ot oc ol N u m ber: 
G E M- C L- 1 0 3 1 1 
Pr ot oc ol V ersi o n: 
Versi o n 3. 0 
D ate of Pr ot oc ol: 
5 Ma y 2 0 2 1 
 
R E VI E W E D/ A P P R O V E D B Y: 
 
 
 
S p o ns or a p pr o val  
 
Si g nat ure 
Date              
Title of s p o ns or a p pr o ver 
 
 
 
P P D
P P D
P P D


G E M- C L- 1 0 3 1 1 Pr ot oc ol, Versi o n 3. 0  
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G E MI NI T H E R A P E U TI C S I N C P R O P RI E T A R Y A N D C O N FI D E N TI A L:  
D O N O T C O P Y O R DI S T RI B U T E WI T H O U T P E R M I S SI O N F R O M G E MI NI T H E R A P E U TI C S I N C. 
I N V E S TI G A T O R S T A T E M E N T 
I a gree t o c o n d uct t his cli nical st u d y i n acc or da nce wit h t he desi g n a n d s pecific pr o visi o ns of t his 
pr ot oc ol. 
I u n dersta n d t hat I ma y ter mi nate or s us pe n d e nr oll me nt i n t he st u d y at a n y ti me if it bec o mes 
necessar y t o pr otect t he best i nte rests of t he st u d y s u bjects.  T his st u d y ma y be ter mi nate d at a n y 
ti me b y t he S p o ns or, wit h or wit h o ut ca use. 
I a gree t o pers o nall y c o n d uct a n d s u per vise t his i n vesti gati o n at m y i nstit uti o n a n d t o e ns ure t hat 
all ass ociates, c ollea g ues, a n d e m pl o yees assisti n g i n t he c o n d uct of t his st u d y are i nf or me d 
a b o ut t heir o bli gati o ns i n meeti n g t hese c o m mit me nts. 
I will c o n d uct t he st u d y i n acc or da nce wit h G o o d Cli nical Practice, t he Declarati o n of Helsi n ki, 
a n d t he m oral, et hical, a n d scie ntific pri nci ples t hat j ustif y me dical researc h.  T he st u d y will be 
c o n d ucte d i n acc or da nce wit h all rele va nt la ws a n d re g ulati o ns relati n g t o cli nical st u dies a n d t he 
pr otecti o n of s u bjects.   
I will e ns ure t hat t he re q uire me nts relati n g t o I nstit uti o nal Re vie w B oar d/I n de pe n de nt Et hics 
C o m mittee (I R B/I E C) re vie w a n d a p pr o val are met.  I will pr o vi de t he S p o ns or wit h a n y 
material t hat is pr o vi de d t o t he I R B/I E C f or et hical a p pr o val. 
I a gree t o mai ntai n a de q uate a n d acc urate rec or ds a n d t o ma ke t h ose rec or ds a vaila ble f or a u dit 
a n d i ns pecti o n i n acc or da nce wit h rele va nt re g ulat or y re q uire me nts. 
I a gree t o pr o m ptl y re p ort t o t he I R B/I E C a n y c ha n ges i n t he researc h acti vit y a n d all 
u na ntici pate d pr o ble ms i n v ol vi n g ris ks t o h u ma n s u bjects or ot hers.  A d diti o nall y, I will n ot 
ma ke a n y c ha n ges i n t he researc h wit h o ut I R B/I E C a n d S p o ns or a p pr o val, e xce pt w here 
necessar y t o e ns ure t he safet y of st u d y s u bjects. 
 
 
 
I n vesti gat or Na me  
  I n vesti gat or Si g nat ure  
  
Date 
 
 
I n vesti gati o nal site or na me of i nstit uti o n  
 
 


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G E MI NI T H E R A P E U TI C S I N C P R O P RI E T A R Y A N D C O N FI D E N TI A L:  
D O N O T C O P Y O R DI S T RI B U T E WI T H O U T P E R M I S SI O N F R O M G E MI NI T H E R A P E U TI C S I N C. 
LI S T O F A B B R E VI A TI O N S 
A b b re vi ati o n
 Defi niti o n
 
A D A
 a nti dr u g
 
a nti b o d y(ies)
 
A E(s)
 a d v erse
 
e v e nt(s)
 
A M D
 a g e-relat e d
 
mac ular
 
d e g e n erati o n
 
A P
 alter n ati v e
 
p at h wa y
 
A U C
 are a
 
u n d er
 
c ur v e
 
B C V A 
b est c orre cte d vis u al a c uit y 
B L A
 Bi ol o gics
 
Lice nse
 
A p plicati o n
 
C F H
 c o m ple me nt
 
fact or
 
H
 
C F R
 C o d e
 
of
 
F e d eral
 
R e g ulati o ns
 
CI
 c o nfi d e n ce
 
i nter v al
 
C ma x  ma xi m u m
 c o n ce ntrati o n
 
C N V
 c h or oi d al
 
n e o v asc ulari zati o n
 
C P T 
ce nter p oi nt t hic k ness 
C S R
 cli nic al
 
st u d y
 
re p ort
 
C S T 
ce ntral s u bfiel d t hic k ness 
E C G
 ele ctr o car di o gra m
 
e C R F  
ele ctr o nic case r e p ort f or m 
E O M
 e v er y
 
ot h er
 
m o nt h
 
E O S  
e n d of st u d y 
E T D R S  
E arl y Treat me nt Dia b eti c R eti n o p at h y St u d y 
E U
 E ur o pea n
 
U ni o n
 
F A
 fl u oresc ei n
 
a n gi o gra p h y
 
F A F
 f u n d us
 
a ut ofl u oresce n ce
 
F A S  
F ull A nal ysis Set 
F D A  
F o o d a n d Dr u g A d mi nistrati o n 
G A
 g e o gra p hic
 
atr o p h y
 
G C P
 G o o d
 
Cli nical
 
Practi ce
 
G L P  
G o o d L a b orat or y Practice 
I C F
 i nf or me d
 
c o nse nt
 
f or m
 
I C H  
I nter n ati o n al C o u n cil f or H ar m o nisati o n 
I E C
 I n de pe n de nt
 
Et hics
 
C o m mittee
 
I O P
 i ntra o c ular
 
press ure
 
I R B
 I nstit uti o n al
 
Re vie w
 
B o ar d
 
I V T
 i ntra vitr eal
 
L L V A  
l o w l u mi n a n ce vis u al ac uit y 
M A
 m ac ular
 
atr o p h y
 
Me d D R A  
Me dical Dicti o n ar y f or Re g ulat or y Acti vities 
M N Rea d  
Mi n n es ota L o w- visi o n Rea di n g Test 
M R C
 Me dical
 
Re vie w
 
C o m mittee
 
n A M D  
N e o v asc ular A g e- R elate d Mac ular D e g e n erati o n 
N EI- V F Q- 2 5  
Nati o n al E y e I nstit ute Vis u al F u n cti o ni n g Q uesti o n n aire- 2 5 


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G E MI NI T H E R A P E U TI C S I N C P R O P RI E T A R Y A N D C O N FI D E N TI A L:  
D O N O T C O P Y O R DI S T RI B U T E WI T H O U T P E R M I S SI O N F R O M G E MI NI T H E R A P E U TI C S I N C. 
A b b re vi ati o n
 Defi niti o n
 
NI R  
n ear i nfrare d reflecta n ce i m a gi n g 
O C T
 o ptical
 
c o h ere n ce
 
t o m o gra p h y
 
O C T- A 
o ptical c o h ere n ce t o m o gra p h y – a n gi o gra m/a n gi o gra p h y 
P D
 p h ar mac o d y n a mic(s)
 
P K
 p h ar mac o ki n etic(s)
 
P T
 preferre d
 
ter m
 
r h C F H 
rec o m bi n a nt h u ma n C F H 
R P E 
reti n al pi g me nt e pit h eli u m 
S A E(s)
 seri o us
 
a d v ers e
 
e v e nt(s)
 
S A P 
Statistic al A n al ysis Pla n 
S D- O C T 
s p ectr al d o mai n o ptical c o h ere n c e t o m o gra p h y 
S O A
 sc h e d ule
 
of
 
assess me nts
 
S o C
 sta n d ar d
 
of
 
care
 
S O C
 s yste m
 
or g a n
 
class
 
T E A E 
treat me nt-e m er g e nt a d v erse e v e nt 
U S 
U nite d States ( of A meric a) 
V A
 vis u al
 
ac uit y
 
V E G F 
v asc ular e n d ot h elial gr o wt h fact or 
 
 


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G E MI NI T H E R A P E U TI C S I N C P R O P RI E T A R Y A N D C O N FI D E N TI A L:  
D O N O T C O P Y O R DI S T RI B U T E WI T H O U T P E R M I S SI O N F R O M G E MI NI T H E R A P E U TI C S I N C. 
C LI NI C A L S T U D Y S Y N O P SI S 
P r ot o c ol Title 
A M ultice nter, M ulti ple- D ose St u d y i n N e o v asc ular A g e-r elate d Mac ular 
De ge nerati o n ( n A M D) t o E val uate t h e Safet y, T olera bilit y, P har mac o d y na mics, 
I m m u n o g e nicit y, a n d Cli nical Effect of Re p eat I ntra vitr eal (I V T) I njecti o ns of 
G E M 1 0 3 as a n A dj u n ct t o Sta n d ar d of C are Afli b er ce pt T h era p y 
P r ot o c ol N u m b er 
G E M- C L- 1 0 3 1 1 
Cli nic al P h ase 
P h ase 2 a 
( P)I N D N u m ber 
1 4 1 0 3 6 
I n dic ati o n 
N e o v asc ular A g e- R elate d Mac ular D e g e n erati o n 
O bjecti v es a n d 
E n d p oi nts 
T h e pri mar y e n d p oi nt will assess t h e s afet y a n d t olera bilit y of 
G E M 1 0 3 +sta n d ar d of care ( S o C) vs s h a m + S o C ( S o C is d efi n e d as afli b er ce pt 
e v er y ot h er m o nt h [ E O M]) t hr o u g h 1 2 m o nt hs.  S ec o n d ar y a n d e x pl orat or y 
e n d p oi nts will ass ess G E M 1 0 3 + S o C vs s h a m + S o C at m o nt h 1 2 a n d o v er ti m e. 
O bjecti v es
 E n d p oi nts
 
P ri m a r y 
 
 
Descri b e t h e saf et y a n d t olera bilit y 
of G E M 1 0 3 + S o C vs s h a m + S o C 
 
O c ular a n d n o n- o c ular 
treat me nt-e m er g e nt 
a d v erse e v e nts ( T E A Es) 
 
C h a n g es i n o p ht h al mic 
e x a ms 
 
R es ults of vis u al f u n cti o n 
ass ess m e nts 
 S ec o n d a r y
 
 
 
T o e v al u ate t otal c o m ple me nt 
fact or H ( C F H) i n a q u e o us h u m or 
after G E M 1 0 3 I V T i njecti o n, 
w h e n e v er p ossi ble 
 
A q u e o us h u m or c o n ce ntrati o ns of 
t otal C F H  
 
 
Descri b e t h e eff ect o n b est 
c orrecte d vis u al ac uit y ( B C V A) 
 
Mea n c h a n g e i n B C V A fr o m 
b aseli n e i n Earl y Treat m e nt 
Dia b etic R eti n o p at h y St u d y 
( E T D R S) letters 
 
 
Descri b e t h e eff ect o n mac ular 
atr o p h y ( M A) size i n s u bjects wit h 
M A prese nt at b aseli n e 
 
Mea n c h a n ge i n size of M A 
e v al u ate d b y f u n d us 
a ut ofl u oresce n c e ( F A F)  
 
E x pl o r at o r y 
 
 
T o e v al u ate t h e i m m u n o g e nicit y of 
G E M 1 0 3 i n ser u m after G E M 1 0 3 
I V T i njecti o n, w h e n e v er p ossi ble 
 
Ge n er ati o n of ser u m G E M 1 0 3 
a nti dr u g a nti b o dies 
 
 
D escri b e t h e eff ect of G E M 1 0 3 
I V T i njecti o n o n bi o mar k ers i n 
a q u e o us h u m or 
 
C h a n g e fr o m b aseli n e i n 
c o m ple me nt pr otei n, c o m ple m e nt 
s plit pr o d u cts, a n d relate d 
c yt o ki n es pr otei n v al u es i n 
a q u e o us h u m or 


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D O N O T C O P Y O R DI S T RI B U T E WI T H O U T P E R M I S SI O N F R O M G E MI NI T H E R A P E U TI C S I N C. 
 
 
D escri b e t h e eff ect o n i n ci d e n ce of 
ne w M A i n s u bjects wit h o ut M A 
at b aseli n e 
 
Ne w M A e v al uate d b y F A F  
 
 
D escri b e t h e eff ect o n c h or oi d al 
n e o v asc ulariz ati o n ( C N V) size 
 
Mea n re d u cti o n fr o m b aseli n e i n 
C N V size as e v al u at e d b y 
fl u oresc ei n a n gi o gra p h y ( F A) 
 
 
D escri b e t h e eff ect o n t hic k n ess of 
reti n al la y ers 
 
Mea n c h a n g e fr o m b aseli n e i n 
ce nter p oi nt t hic k n ess a n d ce ntral 
s u bfiel d t hic k n ess i n μ m as 
e v al u ate d b y s p ectral d o mai n 
o ptical c o h ere n ce t o m o gra p h y 
( S D- O C T) 
 
 
D escri b e t h e eff ect o n s u breti n al 
a n d i ntrareti n al fl ui d 
 
T h e pr o p orti o n of p atie nts wit h 
i ntrar eti n al or s u breti n al fl ui d as 
e v al u ate d b y S D- O C T 
 
 
Descri b e t h e eff ect o n l o w 
l u mi na nce vis u al ac uit y ( L L V A) 
 
Mea n c h a n g e i n L L V A fr o m 
b aseli n e i n E T D R S letters 
 
 
D escri b e t h e eff ect o n N ati o n al 
E y e I nstit ute Vis u al F u n cti o ni n g 
Q u esti o n n aire 2 5 ite m V ersi o n 
( N EI- V F Q- 2 5)  
 
D escri b e t h e eff ect o n Mi n n es ota 
L o w- visi o n Rea di n g Test 
( M N Rea d) 
 
Mea n c h a n g e i n sc ore fr o m 
b aseli n e o n N EI- V F Q- 2 5  
 
Mea n c h a n g e i n ma xi m u m rea di n g 
s p ee d fr o m b aseli n e o n M N Rea d 
Test 
Met h o d ol o g y 
Ge mi ni T h era p e utics, I n c. (t h e S p o ns or) is d e v el o pi n g G E M 1 0 3 (rec o m bi n a nt 
h u ma n c o m ple me nt fact or H [r h C F H]) as a n alter n ati v e pat h wa y ( A P) 
c o m ple m e nt m o d ulat or y t h era p y f or t h e treat m e nt of n e o v asc ular a g e-rel ate d 
mac ular de ge nerati o n ( n A M D).  G E M 1 0 3 is bei n g de vel o pe d t o rest ore 
a p pr o priate re g ulati o n of t h e c o m ple m e nt s yste m i n n A M D p atie nts. 
G E M 1 0 3 is i nte n de d t o be use d as a n A P c o m ple me nt m o d ulat or y t h era p y f or 
t h e treat me nt of n A M D b y pr o vi di n g s u pra p h ysi ol o gical r h C F H b y I V T 
i njecti o n. 
T his is a P h ase 2 a, si n gle- mas k e d, s h a m-c o ntr olle d, m ultice nter, m ulti ple- d ose 
st u d y i n s u bjects wit h n A M D t o e v al u ate t h e safet y, t oler a bilit y, 
i m m u n o ge nicit y, p h ar mac o ki netic/ p har mac o d y na mic, c o m ple me nt bi o mar k ers, 
a n d cli nical effe ct d uri n g 1 2 m o nt hs of G E M 1 0 3 I V T i njecti o ns E O M as a n 
a dj u n ct t o S o C afli b erce pt t h era p y. 
St u d y dr u g or s h a m, al o n g wit h S o C afli b erce pt, will be a d mi nistere d t o 1 e y e 
o nl y, w hic h will b e d esi g n ate d d uri n g t h e scre e ni n g pr o cess, b ase d o n 
eli gi bilit y, a n d pri or t o a n y baseli ne meas ure me nts.  If b ot h e y es meet all e y e-
s p ecific e ntr y criteria, t h e n t h e st u d y e y e will b e d eter mi n e d b y t h e I n v esti g at or 
a n d t h e s u bject t o g et h er.  All assess me nts will b e p erf or me d i n t h e st u d y e y e as 
well as t h e f ell o w e y e w h e n e v er feasi ble. 
Detail e d ass ess m e nts of i ntra o c ular press ure (I O P), vis u al ac uit y ( V A) a n d 
f u n cti o n, a n d reti n al p ara met ers s u c h as C N V a n d M A lesi o n size will b e 
p erf or me d f or eac h s u bject e nr olle d. 


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G E MI NI T H E R A P E U TI C S I N C P R O P RI E T A R Y A N D C O N FI D E N TI A L:  
D O N O T C O P Y O R DI S T RI B U T E WI T H O U T P E R M I S SI O N F R O M G E MI NI T H E R A P E U TI C S I N C. 
D ata will b e c olle ct e d o n d e m o gra p hics, m e dical a n d o c ular hist or y, fa mil y 
hist or y, a n d c o n c o mita nt m e dicati o ns.  A d diti o n all y, o p ht h al mic a n at o mic 
ass ess m e nts a n d m ulti m o d al i ma gi n g, e x pl orat or y g e n etic a n d bi o mar k er 
a n al yses, a n d a q u e o us h u m or sa m pli n g will b e d o n e f or eac h s u bject e nr olle d. 
T h e I n v esti g at or will m o nit or t h e safet y of st u d y pr o ce d ures acc or di n g t o l o cal 
i nstit uti o n al p olic y.  All A Es will b e rec or d e d i n t h e electr o nic cas e re p ort f or m.  
Acc u m ulati n g safet y data will be re vie we d o n a n o n g oi n g basis. 
St u d y D u r ati o n 
T h e mi ni m u m pla n n e d d urati o n of eac h s u bject’s p artici p ati o n is a p pr o xi matel y 
1 3 m o nt hs:  1 m o nt h f or scree ni n g a n d 1 2 m o nt hs f or d osi n g a n d f oll o w- u p. 
St u d y C e nters 
It is a nti ci p at e d t h at a p pr o xi matel y 4 0 st u d y ce nters will p arti ci p ate i n t his 
st u d y. 
N u m b er of S u bjects 
Pl a n n e d 
A p pr o xi matel y 4 5 s u bjects ( ~ 3 0 treate d wit h G E M 1 0 3 + S o C a n d ~ 1 5 treate d 
wit h s h a m + S o C) are pla n n e d f or i n cl usi o n i n t h e st u d y. 
I n cl usi o n a n d 
E x cl usi o n Criteri a 
I ncl usi o n Criteri a: 
S u bjects m ust meet all of t h e f oll o wi n g i n cl usi o n criteri a t o be c o nsi d ere d f or 
p artici p ati o n: 
1.  At least 5 0 y ears ol d at t h e ti me of si g n e d i nf or me d c o nse nt; s u bjects 
y o u n g er t h a n 5 0 m a y b e c o nsi d ere d f or p artici p ati o n after c o ns ultati o n 
wit h t h e Me dical M o nit or 
2.  C N V relate d t o n A M D wit h t h e f oll o wi n g feat ures, as d eter mi n e d b y t h e 
I ma g e R ea di n g C e nter 
a. Ma xi m u m C N V lesi o n size of 1 2 disc areas 
b.  
 
3.   M ust b e o n afli b erce pt tr eat me nt pri or t o Da y 1 ( wit h at least o n e 
afli b erce pt d ose re cei v e d wit hi n 2 m o nt hs pri or t o D a y 1) A N D b e a ble 
t o c o nti n u e afli b erce pt at a n e v er y- ot h er- m o nt h fre q u e n c y f or t h e 
d urati o n of t h e st u d y 
4.  B C V A i n t h e st u d y e y e of 2 4 t o 7 5 letters usi n g t h e E T D R S C h art V A 
S cale ( a p pr o xi m atel y e q ui v ale nt t o S n elle n V A of b et wee n 2 0/ 3 2 a n d 
2 0/ 3 2 0) 
5.  S ufficie ntl y cl ear o c ular m e di a, a d e q u ate p u pillar y dilati o n, fi x ati o n t o 
p er mit q u alit y f u n d us i ma gi n g, a n d a ble t o c o o p erate s uffi ci e ntl y f or 
a d e q u ate o p ht h al mic vis u al f u n cti o n testi n g a n d a n at o mic assess me nt i n 
t h e st u d y e y e 
6.  U n d ersta n ds t h e f ull n at ure a n d p ur p ose of t h e st u d y, i n cl u di n g p ossi ble 
ris ks of st u d y pr o ce d ures, a n d pr o vi d es i nf or me d c o nse nt pri or t o 
i nitiati o n of a n y st u d y pr o ce d ure 
7.  All s u bjects wit h re pr o d u cti v e p ote ntial m ust a gree t o use eff ecti v e 
c o ntrace pti v e m et h o ds t hr o u g h t h e e n d of st u d y ( E O S) visit. 
E x cl usi o n C riteri a: 
A s u bject w h o meets a n y of t h e f oll o wi n g e x cl usi o n criteria will b e i n eli gi ble t o 
p artici p ate: 
1.  Prese n ce of t h e f oll o wi n g o c ular c o n diti o ns i n t he st u d y e y e: 


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D O N O T C O P Y O R DI S T RI B U T E WI T H O U T P E R M I S SI O N F R O M G E MI NI T H E R A P E U TI C S I N C. 
a. A n y acti v e o c ular dise as e or c o n diti o n t h at c o ul d c o nf o u n d t h e 
ass ess m e nt of t h e mac ula or b e a c o ntrai n dicati o n t o I V T i njecti o n, 
e. g., reti nal pi g me nt e pit h eli u m tears or ri ps i n v ol vi n g t h e mac ula, 
mac ular h ole (a n y sta g e, i n cl u di n g la mellar h ole), e pireti n al 
me m bra n e, M A or mac ul o p at hies d u e t o a n y dise ase ot h er t h a n 
A M D, u nc o ntr olle d gla u c o ma (I O P of > 2 4 m m H g w he n o n 2 or 
m ore I O P-l o w eri n g me dicati o ns), se v ere gla u c o ma (c u p t o disc rati o 
0. 8), dia b etic reti n o p at h y gra d e d as m o d erate n o n pr oliferati v e 
dia b etic r eti n o p at h y or w orse ( wit h or wit h o ut dia b etic m ac ular 
e d e ma) 
b.  A n y i ntra o c ular s ur g er y, e. g., a n y gla u c o ma s ur g eries i n cl u di n g 
micr oi n v asi v e gla u c o m a s ur g er y a n d/ or a n y i ntra o c ular s ur g er y 
re q uiri n g vitrect o m y.  H o we v er, sta ble i ntra o c ular le ns re pl ace m e nt 
s ur g er y t h at was p erf or me d m ore t h a n 3 m o nt hs pri or t o c o nse nt will 
be all o we d. 
c. A p h a kia or c o m plete a bse n ce of t h e p osteri or ca ps ule 
d.  Pri or c or n eal tra ns pla nt 
e. 
 
2.  Prese n ce of a n y of t h e f oll o wi n g o c ular c o n diti o ns – i n eit h er e y e: 
a. Hist or y of h er p etic i nfecti o n, i di o p at hic p ol y p oi d al c h or oi d al 
v asc ul o p at h y ( P C V), p at h ol o gic m y o pia, ce ntral ser o us 
c h ori oreti n o p at h y ( C S C R), a d ult- o nset f o v eal p atter n d ystr o p h y 
b.  C o n c urre nt disease t h at c o ul d re q uire me dical or s ur gical 
i nter v e nti o n d uri n g t h e st u d y p eri o d 
c. Acti v e/s us p e cte d o c ular/ p eri o c ular i nfe cti o n or acti v e i ntr a o c ular 
i nfla m mati o n 
d.  Hist or y of i di o p at hic or a ut oi m m u n e-ass o ci ate d u v eitis 
3.  I n t h e o pi ni o n of t h e I n v esti g at or, t h e s u bject h as a n y pri or or o n g oi n g 
me dical c o n diti o n (e. g., oc ular ot her t h a n wet A M D, s yste mic, 
ps y c hiatric) or cli nic all y si g nific a nt scr ee ni n g la b orat or y v al u e t h at m a y 
prese nt a safet y ris k, i nterfere wit h st u d y c o m plia n ce, i nterf er e wit h 
c o nsiste nt st u d y f oll o w- u p, or c o nf o u n d d ata i nter pretati o n t hr o u g h o ut 
t h e l o n git u di n al f oll o w- u p p eri o d 
4.  S u bject h as e x p erie n ce d a car di o v as c ular or c ere br o v asc ular e v e nt wit hi n 
1 2 m o nt hs of i nf or me d c o nse nt 
5.  F e m ale s u bjects m ust n ot b e pre g n a nt or lactati n g, n or pla n t o b ec o m e 
pre g n a nt d uri n g t h e st u d y 


G E M- C L- 1 0 3 1 1 Pr ot oc ol, Versi o n 3. 0  
5 Ma y 2 0 2 1 
Pa ge 1 7 of 8 9 
G E MI NI T H E R A P E U TI C S I N C P R O P RI E T A R Y A N D C O N FI D E N TI A L:  
D O N O T C O P Y O R DI S T RI B U T E WI T H O U T P E R M I S SI O N F R O M G E MI NI T H E R A P E U TI C S I N C. 
6.  C urre nt use of m e dicati o ns k n o w n t o b e t o xic t o t h e le ns, reti n a, or o ptic 
n er v e ( d efer o x a mi n e, c hl or o q ui n e/ h y dr o x y c hl or o q ui n e [ Pla q u e nil ®], 
ta m o xife n, p h e n ot hiazi n es, et h a m b ut ol, di g o xi n, a n d a mi n o gl y c osi d es).  
( C urre nt use is d efi n e d as t h e a d mi nistrati o n of first d ose of G E M 1 0 3 
wit hi n 5 h alf-li v es of t h e pr o hi bite d me dicati o n).  P ast use of t h ese 
m e dicati o ns, wit h o ut hist or y of o c ular si d e eff ects, is n ot c o nsi d ere d 
e x cl usi o n ar y.  Use of me dicati o ns t h at ma y p ote ntiall y e x acer b ate 
m ac ular e d e ma or m ac ular d e g e n erati o n is p er mitte d if, i n t h e o pi ni o n of 
t h e I n v esti g at or, i n c o ns ultati o n wit h t h e Me dical M o nit or, s u c h use will 
n ot c o nf o u n d t h e i nter pretati o n of st u d y res ults 
7.  Use of a n y i n v esti g ati o n al n e w dr u g or ot h er e x p eri m e ntal tre at me nt i n 
t h e last 6 m o nt hs, a n d/ or recei pt at a n y ti m e of a n y pri or g e n e t h era p y 
(e. g., A d e n o-ass o ciat e d vir us), cell t h er a p y, or oc ular de vice 
i m pla ntati o n ( ot h er t h a n p osteri or c h a m b er i ntra o c ular l e ns place me nt 
after catar act s ur g er y) 
I n v esti g ati o n al 
P r o d u ct ( a n d 
Refer e n ce T her a p y), 
D ose, R o ute, 
Re gi me n 
G E M 1 0 3 (r h C F H) will b e s u p plie d i n si n gle- use vials wit h a 0. 2 5 m L fill 
v ol u m e at a c o n ce ntrati o n of 1 0 m g/ m L r h C F H. 
Afli b erc e pt a d mi nister e d I V T E O M is S o C t hera p y.  S u bjects assi g n e d t o t h e 
G E M 1 0 3 + S o C gr o u p w ill b e a d mi nistere d afli b erce pt ( 2 m g/ 5 0 μ L) first, 
f oll o we d b y G E M 1 0 3 ( 5 0 0 μ g/ 5 0 μ L) 1 5 mi n utes ( ± 5 mi n utes) lat er.  St u d y 
dr u g m ust n ot be mi xe d i n t h e sa me s yri n ge wit h ot her pr o d ucts. 
S u bjects will b e ra n d o mize d t o 1 of 2 treat me nt gr o u ps:  G E M 1 0 3 + S o C or 
s h a m + S o C.  S u bjects ra n d o mize d t o t h e G E M 1 0 3 + S o C treat me nt gr o u p will 
rec ei v e tr eat me nt E O M ( 6 d oses).  All s u bjects assi g n e d t o t h e G E M 1 0 3 + S o C 
treat me nt will b e tre at e d wit h 5 0 0 μ g G E M 1 0 3 p er e y e. 
S u bjects ra n d o mize d t o t h e s h a m + S o C treat me nt gr o u p will recei v e S o C wit h a 
s h a m I V T i njecti o n i nstea d of G E M 1 0 3, t o k ee p t h e s u bject mas k e d t o t h eir 
treat me nt assi g n me nt. 
St atistic al Met h o ds  
Ge ner al C o nsi der ati o ns 
D escri pti v e s u m m ar y statisti cs will b e pr o vi d e d f or d e m o gra p hics, dis p ositi o n, 
a n d d ose e x p os ure.  T h e n u m b er a n d p erce nta g e of s u bjects w h o disc o nti n u e d 
fr o m t h e st u d y, al o n g wit h reas o ns f or disc o nti n u ati o ns, will b e ta b ulate d a n d 
d escri b e d i n listi n gs.  All d escri pti v e s u m mari es will b e pr o vi d e d b y treat me nt 
gr o u p ( G E M 1 0 3 vs s h a m). 
C o nti n u o us d ata will b e s u m m arize d usi n g d escri pti v e statistics ( n u m b er of 
s u bjects, mea n, sta n dar d de viati o n, me dia n, mi ni m u m, a n d ma xi m u m) a n d, 
w h ere a p pr o priate, gra p hic re prese nt ati o n, a n d t w o-
i nter v als ( CI); c ate g oric al d ata will b e s u m marize d b y sa m ple size, pr o p orti o ns, 
a n d t w o-
 
A n y re p orte d p- val u es will be c o nsi d ere d part of t h e descri pti v e a n al yses (i. e., 
h y p ot h esis- g e n erati n g) a n d will n ot b e a dj uste d f or m ulti plicit y.  T h e p hrase 
“st atistic all y si g nifi ca nt” ma y b e use d i nterc h a n g ea bl y wit h “ n o mi n all y 
statisticall y si g nific a nt” t o i n dicate t h at a n o mi n al p-
 


G E M- C L- 1 0 3 1 1 Pr ot oc ol, Versi o n 3. 0  
5 Ma y 2 0 2 1 
Pa ge 1 8 of 8 9 
G E MI NI T H E R A P E U TI C S I N C P R O P RI E T A R Y A N D C O N FI D E N TI A L:  
D O N O T C O P Y O R DI S T RI B U T E WI T H O U T P E R M I S SI O N F R O M G E MI NI T H E R A P E U TI C S I N C. 
S a m ple Size 
T h e pla n n e d t otal sa m ple siz e of a p pr o xi matel y 4 5 s u bjects ( ~ 3 0 treat e d wit h 
G E M 1 0 3 + S o C, ~ 1 5 treate d wit h s h a m + S o C) is b ase d o n feasi bilit y 
c o nsi d erati o ns, rat h er t h a n a n y s p ecifi c st atisti cal t est. 
A n al ysis S ets 
T h e C o nse nte d S u bject S et will i n cl u d e s u bjects w h o si g n e d t h e i nf or me d 
c o nse nt f or m a n d will be use d t o create a dia gra m t o ill ustrate s u bject fl o w fr o m 
c o nse nt t hr o u g h dis p ositi o n (si milar t o a C o ns oli d ate d Sta n d ar ds of R e p orti n g 
Trials [ C O N S O R T] dia gra m f or a ra n d o mize d trial). 
T he Bi o mar ker Set will i n cl u de s u bjects wit h s ufficie nt data t o assess bi o m ar k er 
res ults. 
T h e F ull A n al ysis S et ( F A S) will i n cl u d e all s u bjects w h o recei v e at l east 1 
d ose of st u d y dr u g/refere n c e t h era p y ( G E M 1 0 3 or s h a m).  S afet y a n al yses will 
be perf or me d o n t h e F A S.  A nal yses o n t h e F A S are c o nsiste nt wit h t h e 
i nte nti o n-t o-treat pri n ci ple. 
S afet y A n al ysis 
D escri pti v e statistics will b e c o m p ute d f or safet y p ara m eters, as a p pr o priate.  
N u m b er a n d p erce nta g e of s u bjects w h o disc o nti n u e d fr o m t h e st u d y b eca use of 
A Es will b e ta b ulate d acr oss d ose c o h orts; se v erit y a n d fre q u e n c y of A Es a n d 
seri o us a d v ers e e v e nts ( S A Es) will als o b e ta b ulate d acr oss tre at me nt gr o u ps.  
All ot h er safet y d ata will b e pr o vi d e d i n listi n gs.  P h ysical e x a mi n ati o n 
fi n di n gs, cli nical la b orat or y v al u es, a n d vital si g ns will b e s u m m arize d b y d ose 
c o h ort. 
T h e pr o p orti o n of s u bjects wit h m eas ura bl e a nti b o dies t o G E M 1 0 3 will b e 
dis pla y e d. 
F urt h er statisti cal e v al u ati o ns will b e a p plie d f or select e n d p oi nts, if w arra nte d.  
All b aseli n e d at a a n d safet y d ata c oll ecte d d uri n g t h e st u d y will b e liste d f or 
eac h s u bject. 
All A Es will b e c o d e d usi n g a c o nsiste nt v ersi o n of t h e Me dical Dicti o n ar y f or 
Re g ulat or y Acti vities ( Me d D R A, versi o n 2 2. 0 or hi g h er) a n d will be classifie d 
b y Me d D R A s yste m or g a n class ( S O C) a n d preferre d ter m ( P T). 
A E a n al yses will i n cl u d e t h e f oll o wi n g ta b ular s u m maries: 
•
 S u m mar y
 
of
 
all
 A Es
 
•  
I n ci d e n ce of A Es b y S O C a n d P T 
•  
I n ci d e n ce of A Es b y se v erit y 
•  
I n ci d e n ce of S A Es 
•  
I n ci d e n ce of treat me nt-r elate d A Es 
Bi o m a r ker, I m a gi n g, a n d Cli nic al E n d p oi nt A n al ysis 
A q u e o us h u m or will b e c ollect e d pri or t o t h e first d ose, a n d j ust pri or t o eac h 
s u bse q u e nt I V T i njecti o n of G E M 1 0 3 t o e v al uate c o m ple m e nt pr otei ns a n d 
p ossi bl y i nfla m mat or y c yt o ki n e pr ofiles t o d eter mi n e t h eir p ote ntial as P D 
bi o mar k ers f or usef ul n ess i n a pi v otal st u d y.  T otal C F H c o nce ntrati o ns i n 
a q u e o us h u m or will b e e v al u ate d. 


G E M- C L- 1 0 3 1 1 Pr ot oc ol, Versi o n 3. 0  
5 Ma y 2 0 2 1 
Pa ge 1 9 of 8 9 
G E MI NI T H E R A P E U TI C S I N C P R O P RI E T A R Y A N D C O N FI D E N TI A L:  
D O N O T C O P Y O R DI S T RI B U T E WI T H O U T P E R M I S SI O N F R O M G E MI NI T H E R A P E U TI C S I N C. 
I ma gi n g e n d p oi nts s u c h as C N V lesi o n size, M A lesi o n size, reti n al la y er 
t hic k ness or prese n ce of fl ui d, a n d cli nical e n d p oi nts s u c h as B C V A, L L V A, 
a n d l o w l u mi n a n ce d eficit, will b e c ollecte d as d escri b e d i n t h e sc h e d ule of 
ass ess m e nts. 
A n al yses of bi o mar k ers, i ma gi n g assess m e nts, a n d cli nical e n d p oi nts will b e 
d escri pti v e, a n d will s u m mariz e act u al v al u es a n d c h a n g es fr o m b aseli n e o v er 
ti me.  Gra p hic al dis pla ys will als o b e create d. 
A n al ysis of bi o m ar k er, i ma gi n g, a n d cli nical e n d p oi nt c h a n g es fr o m b aseli n e 
will pri maril y e m pl o y t h e Wilc o x o n ra n k-s u m test. 
F ull a n al ysis d etails will b e pr o vi d e d i n t h e Statistic al A n al ysis Pla n. 
 


G E M- C L- 1 0 3 1 1 Pr ot oc ol, Versi o n 3. 0  
5 Ma y 2 0 2 1 
Pa ge 2 0 of 8 9 
G E MI NI T H E R A P E U TI C S, I N C.  P R O P RI E T A R Y A N D C O N FI D E N TI A L: 
D O N O T C O P Y O R DI S T RI B U T E WI T H O U T P E R M I S SI O N F R O M G E MI NI T H E R A P E U TI C S, I N C. 
1  I N T R O D U C TI O N 
T his st u d y will be c o n d ucte d acc or di n g t o G o o d Cli nical Practice ( G C P), as defi ne d b y t he 
I nter nati o nal C o u ncil f or Har m o nisati o n (I C H) a n d t he et hical pri nci ples u n derl yi n g E ur o pea n 
U ni o n ( E U) Directi ves 2 0 0 1/ 2 0/ E C  a n d E U Directi ves 2 0 0 5/ 2 8/ E C ; t he U nite d States ( U S) C o de 
of Fe deral Re g ulati o ns ( C F R), Title 2 1, Parts 5 0 a n d 3 1 2 ( 2 1 C F R 5 0, 2 1 C F R 3 1 2) ; a n d all 
a p plica ble g o ver n me nt re g ulati o ns a n d i nstit uti o nal researc h p olicies a n d pr oce d ures. 
1. 1  B ac k gr o u n d 
1. 1. 1  Dise ase 
A ge-relate d mac ular de ge nerati o n ( A M D) is a c o n diti o n affecti n g ol der pe o ple t hat i n v ol ves t he 
pr o gressi ve l oss of t he ce ntral fiel d of visi o n a n d it is t he lea di n g ca use of irre versi ble bli n d ness 
i n t he wester n w orl d (W orl d Healt h Or ga nizati o n [ W H O] 2 0 1 9 ).  T w o f or ms of a d va nce d A M D 
ca n be disti n g uis he d: ne o vasc ular ( wet) A M D ( n A M D) a n d dr y A M D.  Ne o vasc ular A M D is 
visi o n l oss i n t he wester n w orl d i n i n di vi d uals 5 5 years or ol der.  Alt h o u g h n A M D acc o u nts f or 
wit h t he disease ( K ha na ni 2 0 2 0, H ole ka m p 2 0 1 9 ).  T he c urre nt sta n dar d of care ( S o C) f or 
n A M D is t he i ntra vitreal deli ver y of f u ncti o nal a nta g o nists of vasc ular e n d ot helial gr o wt h fact or 
( V E G F), a pr otei n i n v ol ve d i n t he m olec ular orc hestrati o n of t he pat h ol o gic ne o vasc ular casca de 
(Sa h ni 2 0 2 0 , Jaffe 2 0 1 6).  H o we ver, t here are se veral practical li mitati o ns t o a nti- V E G F t hera p y, 
i ncl u di n g t he nee d f or fre q ue nt i ntra vitreal i njecti o ns, i nc o m plete res p o nse, a n d/ or fail ure t o 
mai ntai n res p o nse i n s o me patie nts ( Jaffe 2 0 1 6).  A d diti o nall y, t here is s o me c o ncer n t hat l o n g-
ter m use of a nti- V E G F a ge nts ma y ha ve a n u n desira ble effect o n t he mac ula, p ossi bl y relate d t o 
t he r ole t hat V E G F pla ys i n mai ntai ni n g t he i nte grit y of t he reti nal pi g me nt e pit heli u m 
(Gillies 2 0 2 0 ).  De vel o p me nt of mac ular atr o p h y ( M A) i n e yes wit h ne o vasc ular A M D treate d 
wit h a ge nts tar geti n g V E G F has als o bee n re p orte d i n se veral st u dies ( Sa d da 2 0 1 8 , Gillies 2 0 2 0 ). 
Ne o vasc ular A M D is c haracterize d b y t he u nc o ntr olle d pr oliferati o n of a b n or mal mac ular bl o o d 
vessels t hat ca n lea k fl ui d a n d bl o o d, res ulti n g i n da ma ge t o t he p h ot orece pt ors a n d t he  reti nal 
pi g me nt e pit heli u m ( R P E), a pr ocess k n o w n as c h or oi dal ne o vasc ularizati o n ( C N V) 
(H ole ka m p 2 0 1 9 ).  V E G F, t he pri nci pal dri ver of ne o vasc ularizati o n i n A M D, i n d uces 
a n gi o ge nesis a n d i ncreases vasc ular per mea bilit y a n d i nfla m mati o n.  O ver ti me, t his ca uses 
pr o gressi ve de ge nerati o n of p h ot orece pt ors a n d t he R P E, a n d reti nal fl ui d ca n acc u m ulate, 
lea di n g t o e de ma a n d f u ncti o nal deteri orati o n (H ole ka m p 2 0 1 9, K ha na ni 2 0 2 0 ).  D ysre g ulati o n 
of R P E- deri ve d V E G F is ass ociate d wit h ne o vasc ularizati o n i n n A M D.  Si nce ge netic varia nts i n  
c o m ple me nt fact or H ( C F H) are k n o w n ris k fact ors f or A M D; i n a meta nal ysis, C F H 
p ol y m or p his m rs 1 0 6 1 1 7 0 was a pre dict or of treat me nt res p o nse of ne o vasc ular A M D, es peciall y 
f or a nti- V E G F a ge nts ra ni biz u ma b a n d be vaciz u ma b (C he n 2 0 1 2 ).  I n di vi d uals h o m oz y g o us f or 
t he varia nt ris k C-allele c orres p o n de d t o a decrease d res p o nse t o treat me nt b y a p pr o xi matel y 
1. 6-f ol d w he n c o m pare d wit h patie nts carr yi n g h o m oz y g o us f or T-allele ( C he n 2 0 1 2 ).  Dr use n 
de p osits ass ociate d wit h ge netic varia nts of i nterest t o t he S p o ns or ha ve als o bee n s h o w n t o 
i ncrease t he ris k of pr o gressi o n fr o m earl y or i nter me diate A M D t o a d va nce d A M D ( ge o gra p hic 
atr o p h y [ G A] a n d n A M D) ( C ha vali 2 0 1 5 , Merle 2 0 2 0).  I n b ot h dr y a n d n A M D patie nts, oc ular 
c o m ple me nt acti vati o n has bee n re p orte d wit h c o m ple me nt de p osits detecte d i n dr use n, o n R P E 


G E M- C L- 1 0 3 1 1 Pr ot oc ol, Versi o n 3. 0  
5 Ma y 2 0 2 1 
Pa ge 2 1 of 8 9 
G E MI NI T H E R A P E U TI C S, I N C.  P R O P RI E T A R Y A N D C O N FI D E N TI A L: 
D O N O T C O P Y O R DI S T RI B U T E WI T H O U T P E R M I S SI O N F R O M G E MI NI T H E R A P E U TI C S, I N C. 
cells, Br uc h’s me m bra ne, c h ori oca pillaris, a n d c o m ple me nt acti vati o n pr o d ucts ha ve als o bee n 
s h o w n i n a q ue o us h u m or (Keir 2 0 1 7 , Sc hic k 2 0 1 7 , Alta y 2 0 1 9 ). 
E n d o ge n o us (i ntra oc ular) C F H is cr ucial i n re g ulati n g t he alter nati ve pat h wa y ( A P) of 
c o m ple me nt a m plificati o n l o o p.  I ntra oc ular h u ma n rec o m bi na nt C F H has als o bee n s h o w n t o 
re d uce C N V as efficie ntl y as c urre ntl y use d a nti- V E G F a nti b o d y i n a m o use m o del f or n A M D 
(B orras 2 0 2 0 ).  F u ncti o nal C F H als o has r oles i n A M D t hat are necessar y t o mai ntai n 
h o me ostasis i n t he s u breti nal s pace, i ncl u di n g assista nce i n R P E cleara nce of pr o d ucts of li pi d 
o xi dati o n a n d cell ular de bris t hat are necessar y t o mai ntai n h o me ostasis i n t he s u breti nal s pace, 
a n d w hic h are n o n-ca n o nical a n d se parate fr o m t he c o m ple me nt re g ulati o n pr o vi de d b y 
f u ncti o nal C F H (Cali p pe 2 0 1 7 , Matta pallil 2 0 1 7,  La n d o ws ki 2 0 1 9 , Y u 2 0 2 0 ).  T heref ore, 
pr o vi di n g s u pra p h ysi ol o gical r h C F H ( G E M 1 0 3) as a n A P c o m ple me nt m o d ulat or y t hera p y has 
p ote ntial t o be a n effecti ve treat me nt f or n A M D t o a de q uatel y a d dress h y peracti ve c o m ple me nt 
acti vati o n, R P E f u ncti o nal deficits, a n d res ulta nt reti nal atr o p h y ca use d b y C F H i ns ufficie nc y 
(Keir 2 0 1 7 , B orras 2 0 2 0 ).  Ta ke n t o get her, t hese res ults clearl y i de ntif y n o vel mec ha nis ms of 
C F H i n t he n A M D pr ocess a n d de m o nstrate t he p ote ntial of G E M 1 0 3 as a n o vel, t hera pe utic 
o pti o n f or patie nts wit h n A M D. 
1. 1. 2  Me dic al R ati o n ale f or G E M 1 0 3 
Ge mi ni T hera pe utics, I nc. (t he S p o ns or) is de vel o pi n g G E M 1 0 3 (rec o m bi na nt h u ma n 
c o m ple me nt fact or H [r h C F H]) as a n A P c o m ple me nt m o d ulat or y t hera p y f or t he treat me nt of 
n A M D.  G E M 1 0 3 is a gl yc o pr otei n of a p pr o xi matel y 1 5 5 kil o dalt o ns ( k Da) ma de u p of 2 0 of t he 
C F H c o ntr ol pr otei n m o d ules j oi ne d b y s h ort li n kers ( 3 t o 8 a mi n o aci ds i n le n gt h).  T he c urre nt 
S o C f or n A M D is t he i ntra vitreal deli ver y of f u ncti o nal a nta g o nists of V E G F, a pr otei n i n v ol ve d 
i n t he m olec ular orc hestrati o n of t he pat h ol o gic ne o vasc ular casca de (Sa h ni 2 0 2 0 , Jaffe 2 0 1 6).  
H o we ver, si g nifica nt u n met nee d e xists wit h a nti- V E G F m o n ot hera p y ( Jaffe 2 0 1 6).  T h us, n o vel, 
alter nati ve, a n d m ulti-tar get t hera pies t hat pr o vi de rest orati o n of reti nal healt h, i m pr o ve d efficac y 
a n d e xte n de d d ura bilit y o ver a nti- V E G F t hera p y are nee de d f or patie nts wit h n A M D 
(Sa h ni 2 0 2 0 , B orras 2 0 2 0 ). 
F u ncti o nal C F H is critical f or re g ulati n g t he A P a m plificati o n l o o p as well as C 3 c o n vertase 
acti vit y (Br o dsz ki 2 0 2 0 , Trie b wasser 2 0 1 5 , Geerli n gs 2 0 1 7 ).  Rest ori n g reti nal healt h b y 
pr o vi di n g f u ncti o nal C F H has a p ote ntial f or be nefit t o patie nts wit h n A M D.  C F H has a n a bilit y 
t o a d dress R P E f u ncti o nal deficits a n d res ulta nt reti nal atr o p h y ca use d b y C F H i ns ufficie nc y 
(Keir 2 0 1 7 , B orras 2 0 2 0 ).  A d diti o nall y, i n a m uri ne m o del of n A M D, i ntra oc ular h u ma n 
rec o m bi na nt C F H has bee n s h o w n t o re d uce C N V as efficie ntl y as c urre ntl y use d a nti- V E G F 
a nti b o d y ( B orras 2 0 2 0 ).  G E M 1 0 3 is i nte n de d t o b ot h rest ore a p pr o priate re g ulati o n of t he 
c o m ple me nt s yste m a n d t o hel p mai ntai n reti nal healt h.  I n vitr o a nal yses s u p p ort t he h y p ot hesis 
t hat G E M 1 0 3 rest ores a p pr o priate re g ulati o n b y bl oc ki n g t he detri me ntal effects (e. g., 
i na p pr o priate cell l ysis, i m m u ne res p o nse) w hile retai ni n g t he be neficial effects (e. g., cleara nce 
of e xtracell ular de bris, re pair of o xi dati ve da ma ge) of p h ysi ol o gic c o m ple me nt acti vit y.  
F u ncti o nal C F H als o has r oles i n t he oc ular c o m part me nt, i ncl u di n g assista nce i n R P E cleara nce 
of pr o d ucts of li pi d o xi dati o n a n d cell ular de bris t hat are necessa r y t o mai ntai n h o me ostasis i n 
t he s u breti nal s pace, a n d w hic h are n o n-ca n o nical a n d se parate fr o m t he c o m ple me nt re g ulati o n 
pr o vi de d b y f u ncti o nal C F H ( Cali p pe 2 0 1 7 , Matta pallil 2 0 1 7 , Y u 2 0 2 0 ).  G E M 1 0 3 is i nte n de d t o 


G E M- C L- 1 0 3 1 1 Pr ot oc ol, Versi o n 3. 0  
5 Ma y 2 0 2 1 
Pa ge 2 2 of 8 9 
G E MI NI T H E R A P E U TI C S, I N C.  P R O P RI E T A R Y A N D C O N FI D E N TI A L: 
D O N O T C O P Y O R DI S T RI B U T E WI T H O U T P E R M I S SI O N F R O M G E MI NI T H E R A P E U TI C S, I N C. 
be use d as a n A P c o m ple me nt m o d ulat or y t hera p y f or t he treat me nt of n A M D b y pr o vi di n g 
s u pra p h ysi ol o gical r h C F H b y i ntra vitreal (I V T) i njecti o n. 
G E M 1 0 3 has bee n teste d i n a variet y of bi oc he mical assa ys a n d n o ncli nical st u dies ( Secti o n 1. 3 ) 
a n d ha d a p pr o priate acti vit y, oc ular e x p os ure, a n d safet y pr ofile t o s u p p ort cli nical testi n g of 
G E M 1 0 3 i n n A M D patie nts.  I n a d diti o n, G E M 1 0 3 was e val uate d i n a n o n g oi n g P hase 1 si n gle 
asce n di n g d ose st u d y ( G E M- C L- 1 0 3 0 1) a n d is bei n g e val uate d i n a n o n g oi n g P hase 2a m ulti ple-
d ose st u d y ( G E M- C L- 1 0 3 0 2) i n patie nts wit h dr y A M D.  A vaila ble preli mi nar y cli nical data as 
of 3 0 Se pte m ber 2 0 2 0 fr o m t he o n g oi n g st u dies i n patie nts wit h dr y A M D, pri maril y after si n gle 
d oses of G E M 1 0 3, i n dicate t hat G E M 1 0 3 is well-t olerate d, ac hie ves s u pra p h ysi ol o gical le vels of 
G E M 1 0 3 i n a q ue o us h u m or, s h o ws a tre n d f or p ositi ve effects o n e x pl orat or y bi o mar kers of 
c o m ple me nt acti vati o n, a n d s h o ws a tre n d f or mai ntai ne d or i m pr o ve d vis ual ac uit y ( V A) 
(Secti o n 1. 4 ).  T hese data s u p p ort t he pla n ne d cli nical e val uati o n of G E M 1 0 3 i n n A M D patie nts 
i n t his P hase 2a cli nical st u d y. 
1. 2  I n vesti g ati o n al Me dici n al Pr o d uct ( G E M 1 0 3) 
G E M 1 0 3, r h C F H, is a gl yc o pr otei n of a p pr o xi matel y 1 5 5 kil o dalt o ns ma de u p of 2 0 of t he C F H 
c o ntr ol pr otei n m o d ules j oi ne d b y s h ort li n kers ( 3 t o 8 a mi n o aci ds i n le n gt h).  G E M 1 0 3 is 
f or m ulate d i n 0
v ol u me p ol ys or bate 2 0, p H 7. 0 f or a d mi nistrati o n via I V T i njecti o n, pr o vi di n g direct access i nt o 
t he tar get or ga n ( or) tiss ue.  T he G E M 1 0 3 dr u g pr o d uct will be ma n ufact ure d as a f or m ul ate d, 
b uffere d s ol uti o n at 1 0 m g/ m L r h C F H c o nce ntrate d li q ui d t hat, ca n be dil ute d (as nee de d) t o t he 
a p pr o priate c o nce ntrati o n pri or t o d osi n g at t he site. 
1. 3  N o ncli nic al S u m m ar y 
T he p har mac ol o g y, p har mac o ki netics ( P K), a n d t o xic ol o g y of G E M 1 0 3 were e val uate d i n a 
series of i n vitr o a n d i n vi v o n o ncli nical st u dies. 
T he bi ol o gical acti vit y of G E M 1 0 3 was f o u n d t o be c o m para ble t o e n d o ge n o us h u ma n 
plas ma- p urifie d C F H, a n d c o nsiste nt wit h literat ure-re p orte d val ues of C F H i n t he sa me i n vitr o 
m o dels.  T hese data de m o nstrate t hat G E M 1 0 3 e xerts t he desire d bi ol o gical effect, a n d t he 
p ote nc y of G E M 1 0 3 is c o m para ble a n d e q ui vale nt t o t hat of e n d o ge n o us h u ma n C F H.  I n 
a d diti o n, G E M 1 0 3 e x vi v o acti vit y e val uate d b y t he c o m ple me nt fact or I c ofact or assa y o n 
vitre o us sa m ples o btai ne d fr o m G E M 1 0 3-treate d c y n o m ol g us m o n ke ys s h o we d t hat acti vit y was 
mai ntai ne d fr o m 1 4 t o 2 7 da ys after a si n gle I V T a d mi nistrati o n of G E M 1 0 3 at d oses ra n gi n g 
fr o m 1 5 0 μ g/e ye t o 1 0 0 0 μ g/e ye.  Literat ure s u p p orts t he a bilit y of C F H t o a d dress t he R P E 
f u ncti o nal deficits a n d res ulta nt reti nal atr o p h y ca use d b y C F H i ns ufficie nc y (Keir 2 0 1 7 , 
B orras 2 0 2 0, Di n g 2 0 1 5 ).  A d diti o nall y, i n a m uri ne m o del of n A M D, i ntra oc ular h u ma n 
rec o m bi na nt C F H has bee n s h o w n t o re d uce C N V as efficie ntl y as c urre ntl y use d a nti- V E G F 
a nti b o d y ( B orras 2 0 2 0 ). 
se q ue nce h o m ol o g y bet wee n h u ma ns a n d c y n o m ol g us m o n ke ys c o m pare d wit h ot her s pecies’ 
pr otecte d c y n o m ol g us m o n ke y er yt hr oc ytes fr o m he m ol ysis i n C F H- de plete d h u ma n ser u m b ut 
di d n ot pr otect ra b bit er yt hr oc ytes i n t he sa me assa y.  T he res ults of t hese st u dies de m o nstrate d 
t hat n o n h u ma n pri mates are t he m ost rele va nt s pecies f or t he n o ncli nical safet y assess me nt of 
G E M 1 0 3. 


G E M- C L- 1 0 3 1 1 Pr ot oc ol, Versi o n 3. 0  
5 Ma y 2 0 2 1 
Pa ge 2 3 of 8 9 
G E MI NI T H E R A P E U TI C S, I N C.  P R O P RI E T A R Y A N D C O N FI D E N TI A L: 
D O N O T C O P Y O R DI S T RI B U T E WI T H O U T P E R M I S SI O N F R O M G E MI NI T H E R A P E U TI C S, I N C. 
Safet y p har mac ol o g y assess me nts of ce ntral ner v o us, res pirat or y, a n d car di o vasc ular s yste ms 
after si n gle a n d 3- m o nt h o nce m o nt hl y re peate d d oses of I V T a d mi nistrati o n i n c y n o m ol g us 
m o n ke ys s h o we d n o G E M 1 0 3-relate d effects o n t he f u ncti o n of t hese or ga n s yste ms at 5 0, 1 0 0, 
or 2 5 0 μ g/e ye. 
T he P K, t o xic o ki netic, a n d distri b uti o n pr o perties of G E M 1 0 3 were e val uate d base d o n t he 
ser u m, vitre o us h u m or, a q ue o us h u m or, reti na, R P E, a n d c h or oi d after si n gle or re peate d I V T 
a d mi nistrati o n t o c y n o m ol g us m o n ke ys.  After I V T i njecti o n, t he vitre o us h u m or, a q ue o us 
h u m or, reti na, R P E, a n d c h or oi d c o nce ntrati o n of G E M 1 0 3 were s ustai ne d i n c y n o m ol g us 
m o n ke ys, s u p p orti n g t he i nte n de d I V T r o ute of a d mi nistrati o n i n h u ma ns.  G E M 1 0 3 e x p os ure 
i ncrease d wit h i ncrease i n d ose i n a n a p pr o xi matel y pr o p orti o nal ma n ner after I V T i njecti o n.  
G E M 1 0 3 ra pi dl y distri b ute d t o a q ue o us h u m or, reti na, R P E, a n d c h or oi d wit h eli mi nati o n half-
life ra n gi n g fr o m 2. 9 8 t o 4. 4 3 da ys i n vitre o us h u m or, fr o m 2. 8 6 t o 4. 2 7 da ys i n a q ue o us h u m or, 
fr o m 2. 5 3 t o 6. 8 3 da ys i n reti na, fr o m 6. 2 7 t o 8. 2 7 da ys i n R P E, a n d fr o m 6. 1 2 t o 9. 5 0 da ys i n 
c h or oi d.  G E M 1 0 3 was f o u n d t o be relati vel y sta ble i n t he d ose site ( vitre o us h u m or) a n d at t he 
tar get tiss ue ( R P E).  G E M 1 0 3 efficie ntl y distri b ute d i nt o t he a q ue o us h u m or, reti na, R P E, a n d 
c h or oi d wit h ma xi m u m c o nce ntrati o n ( C ma x
t hat of vitre o us h u m or Cma x , res pecti vel y, a n d wit h area u n der c ur ve ( A U C) val ues of 
distri b uti o n at stea d y-state is a p pr o xi matel y 1-f ol d t o 5. 9-f ol d greater t ha n c y n o m ol g us m o n ke y 
vitre o us v ol u me, a n d is a p pr o xi matel y 0. 7-f ol d t o 3. 9-f ol d greater t ha n c y n o m ol g us m o n ke y 
w h ole e ye v ol u me t hat s u g gest t hat G E M 1 0 3 is mai nl y c o ntai ne d t o t he e ye.  T he t otal cleara nce 
of G E M 1 0 3 is a p pr o xi matel y t he rate of drai na ge of a q ue o us h u m or fr o m t he u ve o-scleral r o utes 
b y t he a nteri or c ha m ber or b y c o n ve nti o nal r o utes. 
T he s yste mic e x p os ure of G E M 1 0 3 after a si n gle i njecti o n was mi ni mal at a p pr o xi matel y 
After re peate d ( o nce m o nt hl y) d oses f or a t otal of 3 d oses at 5 0, 
1 0 0, or 2 5 0 μ g/e ye, s yste mic G E M 1 0 3 e x p os ure was mi ni mal a n d o bser ve d i n t he 1 0 0 a n d 
2 5 0 μ g/e ye d ose gr o u ps after t he first d ose b ut n ot after t he sec o n d or t hir d d ose.  T his ma y be a 
res ult of t he m o derate t o se vere i nfla m mati o n o bser ve d i n t he a ni mals after t he first d ose d ue t o 
ge nerati o n of G E M 1 0 3 a nti dr u g a nti b o dies ( A D A), as A D A detecti o n ge nerall y c orres p o n de d 
wit h t o xic o ki netic sa m ples t hat were bel o w t he li mit of q ua ntificati o n. 
T he t o xicit y pr ofile of G E M 1 0 3 has bee n well-c haracterize d i n si n gle- d ose ra n ge-fi n di n g st u dies, 
G o o d La b orat or y Practice ( G L P)-c o m plia nt, e x pa n de d, ac ute, si n gle- d ose, 3- m o nt h a n d 6- m o nt h 
re peate d- d ose ( o nce m o nt hl y) t o xic ol o g y st u dies, as well as si n gle- d ose a n d 3- m o nt h re peate d 
d ose ( o nce m o nt hl y) safet y p har mac ol o g y st u dies i n c y n o m ol g us m o n ke ys.  T here were n o 
G E M 1 0 3-relate d s yste mic t o xicities i n cli nical pat h ol o g y or s yste mic hist o pat h ol o g y effects 
o bser ve d.  G E M 1 0 3-attri b uta ble oc ular fi n di n gs i n t he t o xic ol o g y st u dies were c o nsiste nt acr oss 
st u dies a n d li mite d t o oc ular i nfla m mat or y reacti o ns t hat were li kel y i m m u ne-relate d res p o nses 
res ulti n g fr o m t he ge nerati o n of G E M 1 0 3 A D A after t he a d mi nistrati o n of a rec o m bi na nt h u ma n 
pr otei n t o c y n o m ol g us m o n ke ys ( S h ort 2 0 0 8 , Bi ol o gics Lice nse A p plicati o n [ B L A] 1 2 5 1 5 6 , 
B L A 1 2 5 3 8 7 ).  G E M 1 0 3 A D As were m ostl y o bser ve d starti n g o n Da y 1 5 i n all G E M 1 0 3-treate d 
a ni mals acr oss st u dies a n d teste d d oses.  T o xic ol o g y st u dies i n dicate d t hat fi n di n gs of 
i nfla m mati o n i n t he e ye c oi nci de d wit h t he ti me of A D A ge nerati o n i n m ost a ni mals. 
A n o- o bser va ble-a d verse-effect le vel c o ul d n ot be deter mi ne d f or eit her t he si n gle- d ose, 3- m o nt h 
or 6- m o nt h re peat- d ose ( o nce m o nt hl y) st u dies beca use of a nti b o d y pr o d ucti o n a gai nst a h u ma n 
pr otei n.  T hese G L P-c o m plia nt st u dies i n dicate d t hat G E M 1 0 3 was t olera ble u p t o t he hi g h d ose 


G E M- C L- 1 0 3 1 1 Pr ot oc ol, Versi o n 3. 0  
5 Ma y 2 0 2 1 
Pa ge 2 4 of 8 9 
G E MI NI T H E R A P E U TI C S, I N C.  P R O P RI E T A R Y A N D C O N FI D E N TI A L: 
D O N O T C O P Y O R DI S T RI B U T E WI T H O U T P E R M I S SI O N F R O M G E MI NI T H E R A P E U TI C S, I N C. 
of 2 5 0 μ g/e ye, wit h o nl y oc ular i nfla m mat or y fi n di n gs d ue t o a n i m m u n o ge nic res p o nse of 
G E M 1 0 3 A D A ge nerati o n as a ntici pate d f or a n I V T-a d mi nistere d h u ma n pr otei n ( S h ort 2 0 0 8 ). 
F urt her details o n t he n o ncli nical p har mac ol o g y, P K, a n d t o xic ol o g y of G E M 1 0 3 ma y be f o u n d 
i n t he I n vesti gat or’s Br oc h ure. 
1. 4  Cli nic al S u m m ar y 
As of 2 3 Se pte m ber 2 0 2 0, 1 2 dr y A M D s u bjects ( 3 per d ose) wit h bilateral G A ha d recei ve d a 
si n gle d ose of G E M 1 0 3 i n t he P hase 1 si n gle asce n di n g d ose cli nical st u d y ( G E M- C L- 1 0 3 0 1) at 
5 0, 1 0 0, 2 5 0 a n d 5 0 0 
-li miti n g t o xicities a n d n o relate d a d verse e ve nts ( A Es) 
were re p orte d.  Base d o n a vaila ble preli mi nar y data, t here were n o si g ns of i ntra oc ular 
i nfla m mati o n a n d n o cli nicall y rele va nt c ha n ges i n best c orrecte d vis ual ac uit y ( B C V A), 
i ntra oc ular press ure (I O P), e n d o ge n o us plas ma C F H le vels, or safet y la b orat or y res ults.  I n 
a d diti o n, t he preli mi nar y res ults e val uati n g t he ge nerati o n of a nti b o dies a gai nst G E M 1 0 3 i n 
ser u m of patie nts recei vi n g 5 0 μ g/e ye t o 5 0 0 μ g/e ye at all assesse d ti me p oi nts were ne gati ve. 
G E M 1 0 3 mea n c o nce ntrati o n i n a q ue o us h u m or was mai ntai ne d at or a b o ve 6 8. 3 n g/ m L ( mea n 
e n d o ge n o us le vel of C F H i n n or mal s u bjects) f or a d urati o n of at least 2 8 da ys after I V T 
i njecti o n at all d oses teste d, i n dicati n g ac hie ve me nt of s u pra p h ysi ol o gical le vels of G E M 1 0 3. 
A vaila ble preli mi nar y mea n p har mac o d y na mic ( P D) data s h o we d a tre n d f or p ositi ve effects o n 
e x pl orat or y mar kers of c o m ple me nt acti vati o n ( C 3a a n d Ba), at all d oses. 
As of 3 0 Se pte m ber 2 0 2 0, 1 0 dr y A M D s u bjects ha ve als o recei ve d a si n gle d ose of G E M 1 0 3 i n 
t he P hase 2a m ulti ple- d ose) cli nical st u d y ( G E M- C L- 1 0 3 0 2); t he first dr y A M D s u bject i n t his 
st u d y has recei ve d 2 d oses of G E M 1 0 3.  N o seri o us a d verse e ve nts ( S A Es) were re p orte d.  
Ser u m A D A f or t he 1 s u bject w h o recei ve d 2 d oses a n d w h o ha d p ost- d ose sa m pli n g after t heir 
first d ose as per pr ot oc ol was ne gati ve at Da y 3 0; t he ne xt sa m pli n g ti me p oi nt f or ser u m A D A 
per pr ot oc ol is after t he f o urt h d ose.  Base d o n a vaila ble preli mi nar y P K data fr o m t he first 
s u bject t hat recei ve d 2 d oses as of 3 0 Se pte m ber 2 0 2 0, s u pra p h ysi ol o gical le vels of C F H were 
mai ntai ne d.  N o P D data were a vaila ble fr o m t his st u d y as 3 0 Se pte m ber 2 0 2 0. 
Details o n t he cli nical pr ofile of G E M 1 0 3 are pr o vi de d i n t he I n vesti gat or’s Br oc h ure. 
1. 5  D ose R ati o n ale a n d Ris k/ Be nefits 
1. 5. 1  St u d y D ose R ati o n ale 
T his P hase 2a st u d y ( G E M- C L- 1 0 3 1 1) will e val uate t he safet y, t olera bilit y, i m m u n o ge nicit y, 
P K/ P D, c o m ple me nt bi o mar kers, a n d cli nical efficac y of re peat I V T i njecti o ns of 
G E M 1 0 3 +sta n dar d of care ( S o C) defi ne d as afli berce pt e ver y ot her m o nt h [ E O M]; c o m pare d 
wit h s ha m + S o C) i n s u bjects wit h n A M D. 
Data fr o m eac h d ose i n t he P hase 1 si n gle asce n di n g d ose st u d y ( G E M- C L- 1 0 3 0 1) i n dr y A M D 
patie nts has bee n e val uate d f or safet y, G E M 1 0 3 e x p os ure, a n d bi o mar ker res p o nse, a n d has bee n 
use d t o i nf or m t he selecti o n of t he 5 0 0 μ g/e ye d ose f or e val uati o n i n t his P hase 2a m ulti ple- d ose 
st u d y i n s u bjects wit h n A M D. 
Re peat d oses of G E M 1 0 3 will be a d mi nistere d b y I V T i njecti o n t o s u bjects wit h n A M D.  T he 
5 0 0 μ g/e ye was base d o n safet y data fr o m si n gle- a n d re peat- d ose ( u p t o 3 a n d u p t o 6 o nce 
m o nt hl y) I V T t o xic ol o g y st u dies i n c y n o m ol g us m o n ke ys, P K m o deli n g a n d si m ulati o n of t he 
pr ofiles of G E M 1 0 3 after a si n gle I V T i njecti o n i n c y n o m ol g us m o n ke ys, a n d t he e n d o ge n o us 
le vel of C F H i n h u ma n R P E (t he tar get oc ular tiss ue of G E M 1 0 3 re place me nt t hera p y i n dr y 


G E M- C L- 1 0 3 1 1 Pr ot oc ol, Versi o n 3. 0  
5 Ma y 2 0 2 1 
Pa ge 2 5 of 8 9 
G E MI NI T H E R A P E U TI C S, I N C.  P R O P RI E T A R Y A N D C O N FI D E N TI A L: 
D O N O T C O P Y O R DI S T RI B U T E WI T H O U T P E R M I S SI O N F R O M G E MI NI T H E R A P E U TI C S, I N C. 
A M D patie nts), as well as data fr o m t he P hase 1 si n gle asce n di n g d ose st u d y ( G E M- C L- 1 0 3 0 1) 
as descri be d i n Secti o n 1. 4 .  T he 5 0 0 μ g/e ye d ose le vel (i n G E M- C L- 1 0 3 0 2 pr ot oc ol versi o n 2. 0) 
was base d o n t he cli nical e x perie nce wit h 5 0, 1 0 0, 2 5 0, a n d 5 0 0 μ g i n t he P hase 1 si n gle 
asce n di n g d ose st u d y ( G E M- C L- 1 0 3 0 1). 
N o ncli nical G L P-c o m plia nt, si n gle- a n d re peat- d ose ( o nce m o nt hl y) I V T st u dies i n dicate d t hat 
G E M 1 0 3 was t olera ble u p t o t he hi g h d ose of 2 5 0 μ g/e ye, wit h o nl y oc ular i nfla m mat or y 
fi n di n gs d ue t o a n i m m u n o ge nic res p o nse of G E M 1 0 3- A D A ge nerati o n as a ntici pate d f or a n 
I V T-a d mi nistere d h u ma n pr otei n (S h ort 2 0 0 8 ).  T he h u ma n e q ui vale nt d ose f or t he hi g hest teste d 
t olera ble d ose ( 2 5 0 μ g/e ye) i n c y n o m ol g us m o n ke ys (f or t he e x pa n de d ac ute si n gle- d ose a n d 
3- m o nt h re peat- d ose [ o nce m o nt hl y f or a t otal of 3 d oses] a n d 6- m o nt h re peat d ose [ o nce 
m o nt hl y f or a t otal of 6 d oses] t o xicit y st u dies) is 5 0 0 μ g/e ye, calc ulate d base d o n a 2-f ol d lar ger 
h u ma n vitre o us v ol u me ( h u ma n vitre o us v ol u me is a p pr o xi matel y 4 m L, w hereas c y n o m ol g us 
m o n ke y vitre o us v ol u me is a p pr o xi matel y 2 m L).  A brief s u m mar y of a vaila ble cli nical safet y 
data is pr o vi de d i n Secti o n 1. 4 . 
D ose selecti o n was base d o n b ot h t he P K m o deli n g a n d si m ulati o n of t he pr ofiles of G E M 1 0 3 
after a si n gle I V T i njecti o n i n c y n o m ol g us m o n ke y, a n d t he e n d o ge n o us le vel of C F H i n h u ma n 
R P E, t he tar get oc ular tiss ue of G E M 1 0 3 re place me nt t hera p y i n A M D.  T he a vera ge 
e n d o ge n o us le vel of C F H i n R P E is olate d fr o m fr oze n ca da ver h u ma n e yes is 1 5 7 7 n g/ g (ra n ge 
fr o m 4 8 8. 0 6 t o 3 4 6 9. 7 n g/ g).  T his was ass u me d t o be t he n or mal e n d o ge n o us le vel f or t he 
p ur p ose of pr ojecti o n of effecti ve G E M 1 0 3 c o nce ntrati o ns a n d d urati o n of effect p ost I V T 
a d mi nistrati o n.  C F H ha pl oi ns ufficie nc y has bee n i de ntifie d as a ris k fact or f or dr y A M D, w hic h 
(Trie b wasser 2 0 1 5 , Geerli n gs 2 0 1 7 ).  T heref ore, f or C F H re place me nt t hera p y i n A M D patie nts, 
 n g/ g) of t he n or mal e n d o ge n o us c o nce ntrati o ns of 
C F H i n R P E is c o nsi dere d t o be s ufficie nt f or cli nical effect.  Base d o n t his ass u m pti o n, P K 
m o deli n g a n d si m ulati o n were c o n d ucte d usi n g c y n o m ol g us m o n ke y P K para meters t o pr oject 
 n g/ g after a si n gle I V T a d mi nistrati o n i n 
h u ma ns at d oses ra n gi n g fr o m 5 0 t o 7 5 0 μ g/e ye.  T he P K m o del ass u me d t hat t he half-life of 
G E M 1 0 3 i n h u ma n R P E is 2- t o 3-f ol d l o n ger t ha n i n c y n o m ol g us m o n ke y R P E, a n d t hat t he 
vitre o us v ol u me i n h u ma n is 2-f ol d greater t ha n i n c y n o m ol g us m o n ke y ( Ga u drea ult 2 0 0 5 , 
Kr o h ne 2 0 1 2 , X u 2 0 1 3 ).  G E M 1 0 3 R P E c o nce ntrati o ns are e x pecte d t o be > 8 0 0 n g/ g f or 8 7 t o 
1 3 2 da ys after a si n gle I V T d ose of 5 0 0 μ g/e ye i n h u ma ns.  O verall, t he data i n dicate t hat t he 
n o ncli nical oc ular P K, distri b uti o n, a n d s yste mic P K c haracteristics of G E M 1 0 3 s u p p ort t he 
i nte n de d cli nical r o ute of a d mi nistrati o n (I V T i njecti o n), d ose, a n d re gi me n ( o nce m o nt hl y, or 
less fre q ue ntl y) f or t he treat me nt of A M D. 
1. 5. 2  Ris k/ Be nefit Assess me nt f or St u d y Dr u g a n d St u d y Pr oce d ures 
P ote nti al Ris ks of G E M 1 0 3:  I m m u n o ge nicity a n d I nfl a m m ati o n 
T he pre d o mi na nt o p ht hal mic a n d hist o pat h ol o gic fi n di n gs i n c y n o m ol g us m o n ke ys were 
se q uelae ass ociate d wit h, a n d sec o n dar y t o, a n i m m u n o ge nic res p o nse, c o nsiste nt wit h a n 
e x pecte d i m m u n o ge nic res p o nse t o a h u ma n pr otei n.  N o de ge nerati ve or a p o pt otic disr u pti o ns 
were n ote d.  T hese i m m u n o ge nic res p o nses are less li kel y t o be ge nerate d i n t he cli nic si nce 
G E M 1 0 3 is a h u ma n rec o m bi na nt pr otei n. 
M ost I V T bi ol o gics pr o d uce oc ular i nfla m mati o n i n n o ncli nical test s pecies, a n d i nfla m mati o n 
was o bser ve d wit h G E M 1 0 3 i n c y n o m ol g us m o n ke ys.  I n ge neral, mil d, dr u g-i n d uce d 
i nfla m mati o n is c o nsi dere d t o be a n acce pta ble safet y ris k i n p osteri or se g me nt diseases, si nce it 


G E M- C L- 1 0 3 1 1 Pr ot oc ol, Versi o n 3. 0  
5 Ma y 2 0 2 1 
Pa ge 2 6 of 8 9 
G E MI NI T H E R A P E U TI C S, I N C.  P R O P RI E T A R Y A N D C O N FI D E N TI A L: 
D O N O T C O P Y O R DI S T RI B U T E WI T H O U T P E R M I S SI O N F R O M G E MI NI T H E R A P E U TI C S, I N C. 
is re versi ble, treata ble, a n d m o nit ora ble i n h u ma ns (S h ort 2 0 0 8 ).  De vel o p me nt of A D A will be 
m o nit ore d i n t he st u d y. 
T he P hase 1 si n gle asce n di n g d ose st u d y ( G E M- C L- 1 0 3 0 1) di d n ot ha ve a n y fi n di n gs of oc ular 
i nfla m mati o n f oll o wi n g d oses ra n gi n g fr o m 5 0 t o 5 0 0 m g a d mi nistere d i ntra vitreall y i n dr y 
A M D s u bjects.  F urt her m ore, t here were n o A D As detecte d i n t his st u d y, c o nsiste nt wit h t he 
e x pectati o n t hat a h u ma n pr otei n s h o ul d n ot elicit a n i m m u ne res p o nse i n h u ma n s u bjects. 
 
P ote nti al Ris ks of a nti- V E G F St a n d ar d of C are tre at me nt: 
O p ht hal m ol o gists are acc ust o me d t o pr o vi di n g fre q ue nt I V T i njecti o ns f or n A M D.  A re p ort b y 
t he A merica n Aca de m y of O p ht hal m ol o g y c o ncl u de d t hat i ntra vitreal a nti- V E G F 
p har mac ot hera p y is a safe a n d effecti ve treat me nt f or ne o vasc ular A M D o ver a 2- year peri o d 
(Ba kri 2 0 1 9 ).  A d verse oc ular e ve nts after I V T i njecti o n of a nti- V E G F a ge nts, i ncl u di n g 
e n d o p ht hal mitis, reti nal detac h me nt, a n d i ncrease d I O P are rare.  Arterial t hr o m b oe m b olic e ve nts 
i n ass ociati o n wit h use of a nti-
patie nts 
(Ba kri 2 0 1 9 ).  A rece nt p u blicati o n (Ba u mal, 2 0 2 0 ), reiterates t he i m p orta nce of effecti vel y 
ma na gi n g t he s pectr u m of i ntra oc ular i nfla m mati o n after treat me nt wit h a nti- V E G F a ge nts i n 
n A M D patie nts.  It is rec o m me n de d t hat as s o o n as a patie nt is dia g n ose d wit h i ntra oc ular 
i nfla m mati o n, reti nal vasc ulitis, a n d/ or a reti nal vasc ular occl usi ve e ve nt, a nti- V E G F treat me nt 
s h o ul d be s us pe n de d.  T he patie nt s h o ul d be m o nit ore d re g ularl y a n d f ut ure treat me nt o pti o ns f or 
n A M D ma y be deter mi ne d base d o n t he o utc o mes of t he a b o ve e ve nts a n d t he patie nt’s cli nical 
stat us.  T he cli nicia n ma y c o nsi der treat me nt m o dalities base d o n a n i n di vi d ualize d a p pr oac h a n d 
t he l ocall y a vaila ble S o C (Ba u mal, 2 0 2 0 ). 
 
P ote nti al Ris ks of G E M 1 0 3 t o get her wit h a nti- V E G F St a n d ar d of C are tre at me nt: 
C urre ntl y t here is n o n o ncli nical or cli nical i nf or mati o n o n effects of a d mi nisteri n g G E M 1 0 3 as 
a n a dj u nct t o a S o C afli berce pt t hera p y i ncl u di n g a n y p ote ntial si de effects.  H o we ver, I V T 
rec o m bi na nt h u ma n Fact or H has bee n use d i n a C N V m uri ne m o del i n c o m bi nati o n wit h a nti-
V E G F ( B orras 2 0 2 0 ). 
St u d y dr u g will n ot be i njecte d wit h ot her pr o d ucts i n t he sa me s yri n ge, as t he c o m pati bilit y of 
G E M 1 0 3 i n s ol uti o n wit h ot her pr o d ucts has n ot bee n e val uate d.  Afli berce pt is a d mi nistere d 
first, f oll o we d b y G E M 1 0 3 1 5 mi n utes ( ± 5 mi n utes) later (see Secti o n 6. 5. 2 ). 
 
Pr oce d ur al Ris ks:  I V T I njecti o n a n d A q ue o us H u m or S a m pli n g 
T he ris k of se vere c o m plicati o ns after I V T i njecti o n s uc h as u veitis, reti nal detac h me nt, 
A ver y 2 0 1 4 ).  
O p ht hal m ol o gists are acc ust o me d t o pr o vi di n g fre q ue nt ( m o nt hl y) I V T i njecti o ns f or n A M D, 
s o meti mes f or years.  A nteri or c ha m ber parace ntesis ( use d t o ac q uire a q ue o us h u m or sa m ples) 
has bee n wi del y use d a n d is c o nsi dere d safe, si m ple, a n d necessar y f or t he re d ucti o n of I O P i n a 
m ultit u de of e ye e mer ge ncies, i ncl u di n g ac ute a n gle cl os ure gla uc o ma, u veitis, h y p he ma, reti nal 
arter y occl usi o n, a n d e n d o p ht hal mitis i n or der t o pre ve nt f urt her irre versi ble visi o n l oss, 
es peciall y if use d i n c o nj u ncti o n wit h ot her me dical m o dalities. 
 


G E M- C L- 1 0 3 1 1 Pr ot oc ol, Versi o n 3. 0  
5 Ma y 2 0 2 1 
Pa ge 2 7 of 8 9 
G E MI NI T H E R A P E U TI C S, I N C.  P R O P RI E T A R Y A N D C O N FI D E N TI A L: 
D O N O T C O P Y O R DI S T RI B U T E WI T H O U T P E R M I S SI O N F R O M G E MI NI T H E R A P E U TI C S, I N C. 
P ote nti al Be nefit:  Rest or ati o n of C o m ple me nt Re g ul ati o n  
T he c urre nt S o C f or n A M D is I V T deli ver y of f u ncti o nal a nta g o nists of V E G F ( Sa h ni 2 0 2 0 , 
Jaffe 2 0 1 6).  H o we ver, t here are se veral practical li mitati o ns t o a nti- V E G F t hera p y, i ncl u di n g t he 
nee d f or fre q ue nt I V T i njecti o ns, i nc o m plete res p o nse, a n d/ or fail ure t o mai ntai n res p o nse i n 
s o me patie nts (Jaffe 2 0 1 6).  G E M 1 0 3 is i nte n de d t o b ot h rest ore a p pr o priate re g ulati o n of t he 
c o m ple me nt s yste m a n d t o hel p mai ntai n reti nal healt h.  I n vitr o a nal yses s u p p ort t he h y p ot hesis 
t hat G E M 1 0 3 rest ores a p pr o priate re g ulati o n b y bl oc ki n g A P h y peracti vit y a n d t he detri me ntal 
effects (e. g., i na p pr o priate cell l ysis, i m m u ne res p o nse) w hile retai ni n g t he be neficial effects 
(e. g., cleara nce of e xtracell ular de bris, re pair of o xi dati ve da ma ge) of p h ysi ol o gic c o m ple me nt 
acti vit y.  F u ncti o nal C F H als o has r oles i n t he oc ular c o m part me nt, i ncl u di n g assista nce i n R P E 
cleara nce of pr o d ucts of li pi d o xi dati o n a n d cell ular de bris t hat are necessar y t o mai ntai n 
h o me ostasis i n t he s u breti nal s pace, a n d w hic h are n o n-ca n o nical a n d se parate fr o m t he 
c o m ple me nt re g ulati o n pr o vi de d b y f u ncti o nal C F H ( Cali p pe 2 0 1 7 , Matta pallil 2 0 1 7 , Y u 2 0 2 0 ).  
T he be nefit of a t hera p y t hat ca n rest ore n or mal C F H a n d A P c o m ple me nt f u ncti o n, a n d w hic h 
has a n a bilit y t o a d dress R P E f u ncti o nal deficits i n n A M D patie nts is li kel y t o o ut wei g h t he 
a b o ve- me nti o ne d p ote ntial ris ks. 




G E M- C L- 1 0 3 1 1 Pr ot oc ol, Versi o n 3. 0  
5 Ma y 2 0 2 1 
Pa ge 2 9 of 8 9 
G E MI NI T H E R A P E U TI C S, I N C.  P R O P RI E T A R Y A N D C O N FI D E N TI A L: 
D O N O T C O P Y O R DI S T RI B U T E WI T H O U T P E R M I S SI O N F R O M G E MI NI T H E R A P E U TI C S, I N C. 
O bjecti ves
 E n d p oi nts
 
Descri be t he eff ect o n L L V A 
 Mea n c ha n ge i n L L V A fr o m baseli ne i n E T D R S 
letters 
 
Descri be t he eff ect o n N EI- V F Q- 2 5  
 
Descri be t he eff ect o n M N Rea d 
 Mea n c ha n ge i n sc or e fr o m baseli ne o n 
N EI- V F Q- 2 5  
 Mea n c ha n ge i n ma xi m u m rea di n g s pee d fr o m 
baseli ne o n M N Rea d T est 
A b br e viati o ns: A D A =a nti dr u g a nti b o dies; A E =a d verse  e ve nt; B C V A = best c orr ecte d vis ual ac uit y; 
C F H =c o m ple me nt fact or H; C N V =c h or oi dal ne o vasc ularizati o n;  C P T =ce nter p oi nt t hic k ness;  C S T =c e ntral s u bfiel d 
t hic k ness; E T D R S = E arl y Tr eat me nt Dia betic Reti n o pat h y St u d y; F A =fl u or escei n a n gi o gr a p h y; F A F =f u n d us 
a ut ofl u or esce nce; I V T =i ntr a vitr eal; L L V A =l o w l u mi na nce vis ual ac uit y; M A = mac ular atr o p h y; 
M N Rea d = Mi n nes ot a L o w- visi o n Rea di n g T est; N EI- V F Q- 2 5 = Nati o nal E ye I nstit ute Vis ual F u ncti o ni n g 
Q uesti o n nair e- 2 5; O C T = o ptical c o her e nce t o m o gr a p h y; S D- O C T = S pectr al D o mai n O ptical C o her e nce 
T o m o gr a p h y; S o C = Sta n dar d of Car e ( 2 m g afli ber ce pt e ver y ot her m o nt h) 


G E M- C L- 1 0 3 1 1 Pr ot oc ol, Versi o n 3. 0  
5 Ma y 2 0 2 1 
Pa ge 3 0 of 8 9 
G E MI NI T H E R A P E U TI C S, I N C.  P R O P RI E T A R Y A N D C O N FI D E N TI A L: 
D O N O T C O P Y O R DI S T RI B U T E WI T H O U T P E R M I S SI O N F R O M G E MI NI T H E R A P E U TI C S, I N C. 
3  I N V E S TI G A TI O N A L P L A N 
3. 1  O ver all Desi g n a n d Pl a n of t he St u d y 
T his is a P hase 2a, si n gle- mas ke d, s ha m-c o ntr olle d, m ultice nter, m ulti ple- d ose st u d y i n s u bjects 
wit h n A M D t o e val uate t he safet y, t olera bilit y, i m m u n o ge nicit y, P K/ P D, c o m ple me nt 
bi o mar kers, a n d cli nical efficac y d uri n g 1 2 m o nt hs of G E M 1 0 3 I V T i njecti o ns E O M as a n 
a dj u nct t o S o C afli berce pt t hera p y. 
St u d y dr u g or s ha m, al o n g wit h S o C afli berce pt, will be a d mi nistere d t o 1 e ye o nl y, w hic h will 
be desi g nate d d uri n g t he scree ni n g pr ocess, base d o n eli gi bilit y, a n d pri or t o a n y baseli ne 
meas ure me nts.  See Secti o n 5. 4 f or deter mi nati o n of st u d y e ye. 
Detaile d assess me nts of I O P, V A a n d f u ncti o n, a n d reti nal para meters s uc h as C N V a n d M A 
lesi o n size will be perf or me d as descri be d i n t he sc he d ule of assess me nts ( S O A) i n A p pe n di x A . 
Data will be c ollecte d o n de m o gra p hics, me dical a n d oc ular hist or y, fa mil y hist or y, a n d 
c o nc o mita nt me dicati o ns.  A d diti o nall y, o p ht hal mic a nat o mic assess me nts a n d m ulti m o dal 
i ma gi n g, e x pl orat or y ge netic a n d bi o mar ker a nal yses, a n d a q ue o us h u m or sa m pli n g will be d o ne 
f or eac h s u bject e nr olle d. 
T he I n vesti gat or will m o nit or t he safet y of st u d y pr oce d ures acc or di n g t o l ocal i nstit uti o nal 
p olic y.  All A Es will be rec or de d i n t he electr o nic case re p ort f or m (e C R F). 
T he mi ni m u m pla n ne d d urati o n of eac h s u bject’s partici pati o n is a p pr o xi matel y 1 3 m o nt hs:  
1 m o nt h f or scree ni n g a n d 1 2 m o nt hs f or d osi n g a n d f oll o w- u p. 
3. 2  St u d y Desi g n a n d Criteri a f or D osi n g 
S u bjects will be ra n d o mize d t o 1 of 2 treat me nt gr o u ps:  G E M 1 0 3 + S o C or s ha m + S o C ( S o C 
defi ne d as 2 m g afli berce pt E O M).  See Secti o n 6. 6 f or ra n d o mizati o n of t he st u d y dr u g). 
All s u bjects treate d wit h G E M 1 0 3 will recei ve 5 0 0 μ g G E M 1 0 3 I V T, w hic h was t he hi g hest 
d ose teste d i n t he P hase 1 si n gle asce n di n g d ose st u d y i n dr y A M D ( G E M- C L- 1 0 3 0 1) a n d is t h us 
deter mi ne d t o be t he hi g hest t olera ble d ose t hat ac hie ve d s u pra p h ysi ol o gical le vels of G E M 1 0 3 
i n a q ue o us h u m or a n d was ass ociate d wit h P D acti vit y.  O ne d osi n g re gi me n ( E O M) will be 
e val uate d i n eac h treat me nt gr o u p.  A st u d y sc he matic is prese nte d i n Fi g ure 1 . 
Acc u m ulati n g safet y data will be re vie we d o n a n o n g oi n g basis ( See Secti o n 7. 4 ). 




G E M- C L- 1 0 3 1 1 Pr ot oc ol, Versi o n 3. 0  
5 Ma y 2 0 2 1 
Pa ge 3 2 of 8 9 
G E MI NI T H E R A P E U TI C S, I N C.  P R O P RI E T A R Y A N D C O N FI D E N TI A L: 
D O N O T C O P Y O R DI S T RI B U T E WI T H O U T P E R M I S SI O N F R O M G E MI NI T H E R A P E U TI C S, I N C. 
t otal of 6 I V T i njecti o ns will be a d mi nistere d o ver t he 1 2- m o nt h st u d y peri o d.  T he E O M I V T 
i njecti o n re gi me n of afli berce pt is use d i n sta n dar d cli nical d osi n g i n s u bjects wit h n A M D a n d is 
als o si milar t o t he d osi n g fre q ue nc y bei n g e val uate d i n ot her M A st u dies c o n d ucte d wit h a nti-
c o m ple me nt a ge nts (Lia o 2 0 2 0, Jaffe 2 0 2 0 ).  P K m o deli n g a n d si m ulati o n as well as oc ular P K 
data fr o m t he o n g oi n g P hase 1 si n gle asce n di n g d osi n g st u d y ( G E M- C L- 1 0 3 0 1) s u p p orts b ot h 
t he pr o p ose d d ose a n d d osi n g re gi me n of G E M 1 0 3 i n t his st u d y. 
3. 4  R ati o n ale f or D ose 
St u d y d ose rati o nale is descri be d i n Secti o n 1. 5. 1 . 
3. 5  St u d y E n d p oi nts 
St u d y e n d p oi nts are descri be d i n Ta ble 1 . 


G E M- C L- 1 0 3 1 1 Pr ot oc ol, Versi o n 3. 0  
5 Ma y 2 0 2 1 
Pa ge 3 3 of 8 9 
G E MI NI T H E R A P E U TI C S, I N C.  P R O P RI E T A R Y A N D C O N FI D E N TI A L: 
D O N O T C O P Y O R DI S T RI B U T E WI T H O U T P E R M I S SI O N F R O M G E MI NI T H E R A P E U TI C S, I N C. 
4  S T U D Y P O P U L A TI O N 
4. 1  T ar get P o p ul ati o n 
T he tar get p o p ulati o n f or t his st u d y is s u bjects wit h n A M D  w h o are u n der g oi n g treat me nt (at 
least 1 pri or d ose) wit h afli berce pt t hera p y. 
4. 2  N u m ber of S u bjects 
A p pr o xi matel y 4 5 s u bjects ( ~ 3 0 treate d wit h G E M 1 0 3 + S o C a n d ~ 1 5 treate d wit h s ha m + S o C; 
S o C defi ne d as afli berce pt E O M) are pla n ne d f or i ncl usi o n i n t he st u d y. 
4. 3  Eli gi bilit y Criteri a 
4. 3. 1  I ncl usi o n Criteri a 
S u bjects m ust meet all of t he f oll o wi n g i ncl usi o n criteria t o be c o nsi dere d f or partici pati o n: 
1.  At least 5 0 years ol d at t he ti me of si g ne d i nf or me d c o nse nt; s u bjects y o u n ger t ha n 
5 0 ma y be c o nsi dere d f or partici pati o n after c o ns ultati o n wit h t he Me dical M o nit or 
2.  C N V relate d t o n A M D wit h t he f oll o wi n g feat ures, as deter mi ne d b y t he I ma ge Rea di n g 
Ce nter 
a. Ma xi m u m C N V lesi o n size of 1 2 disc areas 
b.  S
 
3.  M ust be o n afli berce pt treat me nt pri or t o Da y 1 ( wit h at least o ne afli berce pt d ose 
recei ve d wit hi n 2 m o nt hs pri or t o Da y 1) A N D be a ble t o c o nti n ue afli berce pt at a n 
e ver y- ot her- m o nt h fre q ue nc y f or t he d urati o n of t he st u d y 
4.  B C V A i n t he st u d y e ye of 2 4 t o 7 5 letters usi n g t he Earl y Treat me nt Dia betic 
Reti n o pat h y St u d y ( E T D R S) C hart V A Scale (a p pr o xi matel y e q ui vale nt t o S nelle n V A of 
bet wee n 2 0/ 3 2 a n d 2 0/ 3 2 0) 
5.  S ufficie ntl y clear oc ular me dia, a de q uate p u pillar y dilati o n, fi xati o n t o per mit q ualit y 
f u n d us i ma gi n g, a n d a ble t o c o o perate s ufficie ntl y f or a de q uate o p ht hal mic vis ual 
f u ncti o n testi n g a n d a nat o mic assess me nt i n t he st u d y e ye 
6.  U n dersta n ds t he f ull nat ure a n d p ur p ose of t he st u d y, i ncl u di n g p ossi ble ris ks of st u d y 
pr oce d ures, a n d pr o vi des i nf or me d c o nse nt pri or t o i nitiati o n of a n y st u d y pr oce d ure 
7.  All s u bjects wit h re pr o d ucti ve p ote ntial m u st a gree t o use effecti ve c o ntrace pti ve 
met h o ds liste d i n Secti o n 4. 5. 2  t hr o u g h t he e n d of st u d y ( E O S) visit. 
4. 3. 2  E xcl usi o n Criteri a 
A s u bject w h o meets a n y of t he f oll o wi n g e xcl usi o n criteria will be i neli gi ble t o partici pate: 
1.  Prese nce of t he f oll o wi n g oc ular c o n diti o ns i n t he st u d y e ye: 
a. A n y acti ve oc ular disease or c o n diti o n t hat c o ul d c o nf o u n d t he assess me nt of t he 
mac ula or be a c o ntrai n dicati o n t o I V T i njecti o n, e. g., R P E tears or ri ps i n v ol vi n g 
t he mac ula, mac ular h ole (a n y sta ge, i ncl u di n g la mellar h ole), e pireti nal 
me m bra ne, M A or mac ul o pat hies d ue t o a n y disease ot her t ha n A M D, 
u nc o ntr olle d gla uc o ma (I O P of > 2 4 m m H g w he n o n 2 or m ore I O P-l o weri n g 
me dicati o ns), se vere gla uc o ma (c u p-t o-


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G E MI NI T H E R A P E U TI C S, I N C.  P R O P RI E T A R Y A N D C O N FI D E N TI A L: 
D O N O T C O P Y O R DI S T RI B U T E WI T H O U T P E R M I S SI O N F R O M G E MI NI T H E R A P E U TI C S, I N C. 
gra de d as m o derate n o n pr oliferati ve dia betic reti n o pat h y or w orse ( wit h or 
wit h o ut dia betic mac ular e de ma) 
b.  A n y i ntra oc ular s ur ger y, e. g., a n y gla uc o ma s ur geries i ncl u di n g micr oi n vasi ve 
gla uc o ma s ur ger y a n d/ or a n y i ntra oc ular s ur ger y re q uiri n g vitrect o m y.  H o we ver, 
sta ble i ntra oc ular le ns re place me nt s ur ger y t hat was perf or me d m ore t ha n 
3 m o nt hs pri or t o c o nse nt will be all o we d. 
c. A p ha kia or c o m plete a bse nce of t he p osteri or ca ps ule 
d.  Pri or c or neal tra ns pla nt 
e. 
 
2.  Prese nce of a n y of t he f oll o wi n g oc ular c o n diti o ns i n eit her e ye: 
a. Hist or y of her petic i nfecti o n, i di o pat hic p ol y p oi dal c h or oi dal vasc ul o pat h y 
( P C V), pat h ol o gic m y o pia, ce ntral ser o us c h ori oreti n o pat h y ( C S C R), a d ult o nset 
f o veal patter n d ystr o p h y 
b.  C o nc urre nt disease t hat c o ul d re q uire me dical or s ur gical i nter ve nti o n d uri n g t he 
st u d y peri o d 
c. Acti ve/s us pecte d oc ular/ peri oc ular i nfecti o n or acti ve i ntra oc ular i nfla m mati o n 
d.  Hist or y of i di o pat hic or a ut oi m m u ne-ass ociate d u veitis ( gra di n g scale f or u veitis 
is a vaila ble i n A p pe n di x K ) 
3.  I n t he o pi ni o n of t he I n vesti gat or, t he s u bject has a n y pri or or o n g oi n g me dical c o n diti o n 
(e. g., oc ular ot her t ha n n A M D, s yste mic, ps yc hiatric) or cli nicall y si g nifica nt scree ni n g 
la b orat or y val ue t hat ma y prese nt a safet y ris k, i nterfere wit h st u d y c o m plia nce, i nterfere 
wit h c o nsiste nt st u d y f oll o w- u p, or c o nf o u n d data i nter pretati o n t hr o u g h o ut t he 
l o n git u di nal f oll o w- u p peri o d 
4.  S u bject has e x perie nce d a car di o vasc ular or cere br o vasc ular e ve nt wit hi n 1 2 m o nt hs of 
i nf or me d c o nse nt 
5.  Fe male s u bjects m ust n ot be pre g na nt or lactati n g, n or pla n t o bec o me pre g na nt d uri n g 
t he st u d y 
6.  C urre nt use of me dicati o ns k n o w n t o be t o xic t o t he le ns, reti na, or o ptic ner ve 
( defer o xa mi ne, c hl or o q ui ne/ h y dr o x yc hl or o q ui ne [ Pla q ue nil® ], ta m o xife n, p he n ot hiazi nes, 
et ha m b ut ol, di g o xi n, a n d a mi n o gl yc osi des).  ( C urre nt use is defi ne d as t he a d mi nistrati o n 
of first d ose of G E M 1 0 3 wit hi n 5 half-li ves of t he pr o hi bite d me dicati o n).  Past use of 
t hese me dicati o ns, wit h o ut hist or y of oc ular si de effects, is n ot c o nsi dere d e xcl usi o nar y.  
A p pe n di x L  pr o vi des a list of me dicati o ns t hat ma y p ote ntiall y e xacer bate mac ular e de ma 
or mac ular de ge nerati o n.  Use of t hese me dicati o ns is per mitte d if, i n t he o pi ni o n of t he 
I n vesti gat or, i n c o ns ultati o n wit h t he Me dical M o nit or, s uc h use will n ot c o nf o u n d t he 
i nter pretati o n of st u d y res ults. 
7.  Use of a n y i n vesti gati o nal ne w dr u g or ot her e x peri me ntal treat me nt i n t he last 6 m o nt hs 
pri or t o Da y 1, a n d/ or recei pt at a n y ti me of a n y pri or ge ne t hera p y (e g A de n o-ass ociate d 


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D O N O T C O P Y O R DI S T RI B U T E WI T H O U T P E R M I S SI O N F R O M G E MI NI T H E R A P E U TI C S, I N C. 
vir us), cell t hera p y, or oc ular de vice i m pla ntati o n ( ot her t ha n p osteri or c ha m ber 
i ntra oc ular le ns place me nt after cataract s ur ger y) 
4. 4  Met h o d f or Assi g ni n g S u bjects t o Tre at m e nt Gr o u ps 
S u bjects will be ra n d o ml y assi g ne d t o a treat me nt c o h ort i n a 2: 1 ra n d o mizati o n patter n wit h 
2 s u bjects assi g ne d t o treat me nt wit h G E M 1 0 3 + S o C ( S o C defi ne d as afli berce pt E O M) f or e ver y 
1 s u bject assi g ne d t o treat me nt wit h s ha m + S o C. 
4. 5  S u bject Restricti o ns D uri n g t he St u d y 
4. 5. 1  Ge ner al a n d Diet ar y 
N ot a p plica ble. 
4. 5. 2  C o ntr ace pti o n a n d Pre g n a nc y A v oi d a nce Pr oce d ures 
If of c hil d beari n g p ote ntial (all fe male s u bjects u nless a me n orr heic f or > 1 year or ha ve 
u n der g o ne s ur gical sterilizati o n), s u bjects are re q uire d t o practice at least 2 me dicall y a p pr o ve d 
a n d hi g hl y effecti ve met h o ds of c o ntrace pti o n ( defi ne d as t h ose w hic h res ult i n a l o w fail ure rate 
 
All fe male s u bjects of c hil d beari n g p ote ntial m ust ha ve a ne gati ve pre g na nc y test at scree ni n g 
a n d bef ore d osi n g wit h st u d y dr u g.  W o me n of c hil d beari n g p ote ntial m ust a gree t o a bstai n fr o m 
heter ose x ual se x ual i nterc o urse fr o m date of i nf or me d c o nse nt, a n d at a mi ni m u m t hr o u g h t he 
3 m o nt hs after t he last I V T i njecti o n, or a gree t o c o nsiste ntl y use at least 2 of a n y of t he 
f oll o wi n g met h o ds of c o ntrace pti o n fr o m date of i nf or me d c o nse nt a n d f or at least 3 m o nt hs after 
t he last I V T i njecti o n:  c o n d o ms ( male or fe male) 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, i ntra uteri ne de vice, h or m o nal c o ntrace pti o n (e. g., oral or patc h 
c o ntrace pti ves, N or pla nt ® , De p o- Pr o vera® ), or ot her F o o d a n d Dr u g A d mi nistrati o n 
( F D A)-a p pr o ve d c o ntrace pti ve met h o d desi g ne d t o pr otect a gai nst pre g na nc y.  Peri o dic 
a bsti ne nce (e. g., cale n dar, o v ulati o n, s y m pt ot her mal, p ost- o v ulati o n met h o ds) a n d wit h dra wal 
are n ot acce pta ble met h o ds of c o ntrace pti o n. 
Male s u bjects m ust a gree t o c o nsiste ntl y use a p pr o priate c o ntrace pti o n a n d t o refrai n fr o m s per m 
d o nati o n fr o m c o nse nt t hr o u g h 3 m o nt hs after t he fi nal d ose. 
S u bjects will be pr o vi de d wit h i nf or mati o n o n acce p ta ble met h o ds of c o ntrace pti o n as part of t he 
s u bject i nf or me d c o nse nt pr ocess a n d will be as ke d t o si g n a n i nf or me d c o nse nt f or m (I C F) 
stati n g t hat t he y u n dersta n d t he re q uire me nts f or acce pta ble meas ures of birt h c o ntr ol. 
4. 6  C o nc o mit a nt Me dic ati o ns a n d Tre at m e nts 
C o nc o mita nt me dicati o ns i ncl u de prescri pti o n a n d o ver-t he-c o u nter me dicati o ns, pr o p h ylactic 
a n d t hera pe utic vacci nes, her bal me dicati o ns, vita mi ns, a n d dietar y/ n utriti o nal s u p ple me nts, as 
well as a n y i n vesti gati o nal me dicati o ns t he s u bject ma y ha ve recei ve d.  See A p pe n di x L  f or a list 
of me dicati o ns t hat ma y p ote ntiall y e xacer bate mac ular e de ma or mac ular de ge nerati o n.  
C o nc o mita nt treat me nts i ncl u de dia g n ostic, palliati ve, or i nter ve nti o nal pr oce d ures (e. g., 
he mat o p oietic ste m cell tra ns pla nt, b o ne marr o w tra ns pla nt). 
At t he scree ni n g visit, i nf or mati o n o n all me dicati o ns a n d treat me nts recei ve d b y t he s u bject 
wit hi n t he prece di n g 4 wee ks will be rec or de d.  T hereafter, reas o na ble eff orts will be ma de t o 
ascertai n all c ha n ges i n c o nc o mita nt me dicati o ns a n d treat me nts fr o m scree ni n g u ntil t he s u bject 
c o m pletes t he E O S visit.  S u bjects w h o are o n a sta ble d osi n g re gi me n f or a n y of t he me dicati o ns 
liste d i n A p pe n di x L at t he ti me of scree ni n g, ma y be e nr olle d a n d re mai n o n t he d osi n g re gi me n 


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G E MI NI T H E R A P E U TI C S, I N C.  P R O P RI E T A R Y A N D C O N FI D E N TI A L: 
D O N O T C O P Y O R DI S T RI B U T E WI T H O U T P E R M I S SI O N F R O M G E MI NI T H E R A P E U TI C S, I N C. 
d uri n g t he st u d y if, i n t he o pi ni o n of t he I n vesti gat or, s uc h use will n ot c o nf o u n d t he 
i nter pretati o n of st u d y res ults.  If d uri n g t he c o urse of t he st u d y a s u bject de vel o ps a c o n diti o n 
t hat re q uires treat me nt wit h o ne of t he me dicati o ns liste d i n A p pe n di x L , t he s u bject s h o ul d be 
treate d as cli nicall y i n dicate d; h o we ver, t he Me dical M o nit or m ust be c o ns ulte d pri or t o 
c o nti n ui n g treat me nt i n t he st u d y.  I nf or mati o n o n all c o nc o mita nt me dicati o ns a n d treat me nts 
will be rec or de d i n t he e C R F a n d will i ncl u de t he na me of t he me dicati o n ( bra n d or ge neric) or 
t hera p y, reas o n f or use, start date, a n d st o p date. 
D uri n g t he c o urse of t he st u d y, if i n t he o pi ni o n of t he I n vesti gat or, t he pr ot oc ol re q uire d d osi n g 
of afli berce pt e ver y 6 0 da ys is i ns ufficie nt f or ma na gi n g t he s u bject’s cli nical c o n diti o n, 
a d diti o nal d oses of afli berce pt ma y be a d mi nistere d as nee de d.  T he Me dical M o nit or s h o ul d be 
n otifie d t hat a d diti o nal d osi n g has bee n a d mi nistere d ( per missi o n d oes n ot nee d t o be re q ueste d 
pri or t o treat me nt), a n d all d oses of afli berc e pt a d mi nistere d m ust be d oc u me nte d. 
4. 7  Disc o nti n u ati o n of S u bjects 
4. 7. 1  Pre m at ure Wit h dr a w al fr o m St u d y P artici p ati o n 
S u bjects ha ve t he ri g ht t o wit h dra w fr o m t he st u d y at a n y ti me f or a n y reas o n. 
T he I n vesti gat or ca n als o wit h dra w a s u bject u p o n t he re q uest of t he S p o ns or or if t he S p o ns or 
ter mi nates t he st u d y.  U p o n occ urre nce of a seri o us or i nt olera ble A E, t he I n vesti gat or will 
c o nfer wit h t he S p o ns or or desi g nee.  If a s u bject is disc o nti n ue d beca use of a n A E, t he e ve nt 
will be f oll o we d u ntil it is res ol ve d or u ntil sta ble, or t he S p o ns or a n d I n vesti gat or a gree t hat 
f urt her f oll o w- u p is n ot nee de d (Secti o n 7 ). 
4. 7. 2  Pr oce d ures f or Disc o nti n u ati o n 
If a s u bject disc o nti n ues at a n y ti me after bei n g treate d wit h G E M 1 0 3 or s ha m, all eff orts s h o ul d 
be ma de t o ha ve t he s u bject c o m plete t he f oll o w- u p visit pr oce d ures, i ncl u di n g E O S/ Earl y 
Wit h dra wal visit as per t he S O A ( A p pe n di x A ).  All s u bjects w h o wit h dra w will be as ke d a b o ut 
t he reas o n(s) f or t heir disc o nti n uati o n a n d a b o ut t he prese nce of a n y A Es.  T he date a n d t he 
reas o n f or disc o nti n uati o n will be rec or de d i n t he e C R F. 
W he n a s u bject fails t o ret ur n f or sc he d ule d assess me nts, t he f oll o wi n g eff orts s h o ul d be ma de t o 
c o ntact hi m/ her t o deter mi ne a reas o n f or t he fail ure t o ret ur n:  3 p h o ne atte m pts, i ncl u di n g t he 
date a n d ti me, will be d oc u me nte d i n t he s u bject’s c hart.  If t here is n o res p o nse t o t he tele p h o ne 
calls, a certifie d letter will be se nt.  After t hese eff orts ha ve bee n c o m plete d, a s u bject will be 
c o nsi dere d as l ost t o f oll o w- u p.  All atte m pts at c o ntact s h o ul d be d oc u me nte d i n t he s u bject’s 
me dical rec or d. 
4. 8  S u bject Re pl ace m e nt P olic y 
All s u bjects w h o recei ve at least 1 d ose of G E M 1 0 3 or refere nce t hera p y (s ha m) will be i ncl u de d 
i n s u m maries of safet y res ults.  I n t his se nse, treate d s u bjects are n ot “re place d.” 
If a s u bject disc o nti n ues fr o m t he st u d y bef ore c o m pleti n g 3 d oses, t he S p o ns or ma y c h o ose t o 
e nr oll a d diti o nal s u bjects . 
4. 9  S u bject Rescree ni n g 
D uri n g t he 3 5- da y scree ni n g peri o d, s u bjects will be all o we d t o retest a scree ni n g pr oce d ure(s) 
wit h a p pr o val fr o m t he S p o ns or a n d Me dical M o nit or.  Retests be y o n d t he 3 5- da y wi n d o w will 
re q uire t he s u bject t o be rec o nse nte d. 


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G E MI NI T H E R A P E U TI C S, I N C.  P R O P RI E T A R Y A N D C O N FI D E N TI A L: 
D O N O T C O P Y O R DI S T RI B U T E WI T H O U T P E R M I S SI O N F R O M G E MI NI T H E R A P E U TI C S, I N C. 
5  S T U D Y P R O C E D U R E S 
5. 1  St u d y Assess m e nts 
T he S O A is prese nte d i n A p pe n di x A.   T he S O A pr o vi des detaile d i nf or mati o n re gar di n g t he 
ti me p oi nts f or all of t hese assess me nts. 
5. 1. 1  I nf or me d C o nse nt 
T he I n vesti gat or is re q uire d t o o btai n i nf or me d c o nse nt acc or di n g t o t his pr ot oc ol a n d 
a p pr o priate l ocal re q uire me nts a n d re g ulati o ns pri or t o e nr olli n g a s u bject i n t his st u d y.  A c o p y 
of t he si g ne d a n d date d I C F will be gi ve n t o t he s u bject.  T he ori gi nal f or m s hall be mai ntai ne d 
i n t he s u bject’s me dical rec or ds at t he site.  If t he I C F is re vise d d uri n g t he c o urse of t he st u d y, 
sites will rec o nse nt all acti ve partici pati n g s u bjects. 
5. 1. 2  Ge netic S a m ple C ollecti o n 
All s u bjects will pr o vi de a w h ole bl o o d sa m ple f or e x pl orat or y ge netics pri or t o t heir first st u d y 
dr u g d ose.  Refer t o t he la b orat or y ma n ual f or f urt her details.  T he sa m ples will be se nt t o a 
c o ntract la b orat or y selecte d b y t he S p o ns or f or tar gete d se q ue nci n g usi n g t he S p o ns or’s ge netic 
testi n g assa y (Secti o n 5. 2. 1 ). 
5. 1. 3  Me dic al a n d Oc ul ar Hist or y 
A me dical hist or y f or t he past 6 m o nt hs, pl us a n y si g nifica nt, rele va nt me dical hist or y s uc h as 
pri or car di o vasc ular e ve nts, dia betes mellit us, or ca ncer will be o btai ne d f or eac h s u bject at 
scree ni n g.  C o n diti o ns o n g oi n g at baseli ne will be d oc u me nte d.  S ocial hist or y, t o i ncl u de 
s m o ki n g hist or y a n d use of m ulti vita mi n s u p ple me nts, will als o be o btai ne d. 
A n o p ht hal mic me dical hist or y will be o btai ne d t o i ncl u de a n y past or c urre nt oc ular c o n diti o ns, 
s ur geries, a n d s y m pt o ms, as well as c o n diti o ns f or w hic h t he s u bject is u n der g oi n g pre-e m pti ve 
o bser vati o n, e. g., gla uc o ma scree ni n g.  S pecificall y, a n y hist or y of A M D i ncl u di n g hist or y of 
I V T i njecti o ns will be ca pt ure d.  S u bjects will als o be re q ueste d t o pr o vi de a fa mil y o p ht hal mic 
hist or y if a vaila ble. 
Refer t o Secti o n 4. 6  f or details o n c ollecti o n of me dicati o n hist or y a n d c o nc o mita nt 
me dicati o ns/treat me nts. 
5. 1. 4  De m o gr a p hic I nf or m ati o n 
T he f oll o wi n g de m o gra p hic i nf or mati o n will be c ollecte d at scree ni n g acc or di n g t o l ocal 
re g ulati o ns:  date of birt h, ge n der, race, a n d et h nicit y. 
5. 1. 5  P h ysic al E x a mi n ati o n 
P h ysical e xa mi nati o ns will be perf or me d b y t he I n vesti gat or or q ualifie d desi g nee at t he 
ti me p oi nts s pecifie d i n t he S O A i n A p pe n di x A .  C o m plete p h ysical e xa mi nati o ns will i ncl u de 
a n assess me nt of t he s u bject’s ge neral a p peara nce; s ki n, H E E N T ( hea d, e yes, ears, n ose, t hr oat), 
heart, l u n gs, a b d o me n, e xtre mities/j oi nts, a n d ne ur ol o gical stat us.  A 1 2-lea d electr ocar di o gra m 
( E C G) will be ta ke n at scree ni n g, after l yi n g s u pi ne f or 5 mi n utes, as part of t he car diac 
e xa mi nati o n.  A b n or mal fi n di n gs will be rec or de d i n t he e C R F a n d referre d f or a p pr o priate 
i n vesti gati o n b y a pri mar y care p h ysicia n or ot her healt hcare pr o vi der at t he deter mi nati o n of t he 
I n vesti gat or. 


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5 Ma y 2 0 2 1 
Pa ge 3 8 of 8 9 
G E MI NI T H E R A P E U TI C S, I N C.  P R O P RI E T A R Y A N D C O N FI D E N TI A L: 
D O N O T C O P Y O R DI S T RI B U T E WI T H O U T P E R M I S SI O N F R O M G E MI NI T H E R A P E U TI C S, I N C. 
5. 1. 6  O p ht h al mic E x a mi n ati o n 
A c o m pre he nsi ve o p ht hal mic e xa mi nati o n of b ot h t he st u d y a n d fell o w e ye will be perf or me d b y 
t he I n vesti gat or or q ualifie d desi g nee at t he ti me p oi nts s pecifie d i n t he S O A i n A p pe n di x A.   
T hese e xa mi nati o ns will i ncl u de a n assess me nt of t he V A ( b ot h B C V A a n d L L V A) a n d vis ual 
f u ncti o n, a c o m plete o p ht hal mic bi o micr osc o p y e xa mi nati o n i ncl u di n g f u n d us e xa mi nati o n, I O P 
( pretreat me nt I O P is re q uire d O U, p ost treat me nt I O P is o nl y re q uire d i n t he S E), a n d oc ular 
i ma gi n g tests t o vis ualize t he a p peara nce a n d pat h ol o g y of t he reti na a n d ass ociate d oc ular 
tiss ues.  All fi n di n gs will be rec or de d i n t he e C R F.  F urt her details o n t hese e xa mi nati o ns are 
f o u n d i n res pecti ve st u d y ma n uals. 
O n d osi n g da ys, I O P assess me nts are o btai ne d pri or t o t he d ose O U, a n d 3 0 ± 1 5 mi n utes after t he 
d ose o nl y i n t he S E ( O U o pti o nal).  A n a d diti o nal assess me nt fr o m t he S E s h o ul d be ta ke n at 
6 0 ±
 m m H g at t he 3 0- mi n ute assess me nt.  If t he 
I O P c o nti n ues t o e xcee d 3 0 m m H g, t he n sta n dar d I O P-l o weri n g i nter ve nti o ns ( per i nstit uti o nal 
i nstit uti o nal g ui deli nes.  Re gar dless of w het her a p pla nati o n t o n o metr y or a T o n o- Pe n®  is use d t o 
meas ure I O P, t he sa me met h o d s h o ul d be use d f or t he s u bject f or t he e ntiret y of t heir 
partici pati o n i n t his st u d y. 
5. 1. 7  Vit al Si g n Me as ure me nts 
Vital si g n meas ure me nts will i ncl u de s yst olic a n d diast olic bl o o d press ures, heart rate, 
res pirat or y rate, a n d b o d y te m perat ure.  T he s u bject will be seate d f or at least 5 mi n utes bef ore 
all meas ure me nts are ta ke n.  Vital si g ns will be meas ure d at t he ti me p oi nts i n dicate d i n t he S O A 
i n A p pe n di x A . 
W he n pr oce d ures o verla p a n d are sc he d ule d t o occ ur at t he sa me ti me p oi nt, vital si g ns s h o ul d be 
assesse d pri or t o a n y bl o o d c ollecti o n. 
Ma na ge me nt of s u bject safet y re gar di n g vital si g ns, i ncl u di n g t he a p pr o priate ness of d osi n g if 
vital si g ns are o ut of ra n ge, is t he res p o nsi bilit y of t he I n vesti gat or.   
5. 2  Cli nic al L a b or at or y Assess m e nts 
A list of all cli nical la b orat or y tests t hat will be perf or me d, as well as t he ti me p oi nts f or sa m ple 
c ollecti o n, are s pecifie d i n t he S O A i n A p pe n di x A . 
Ce ntral la b orat or y refere nce ra n ges will be use d t hr o u g h o ut t he st u d y.  All re q uire d tests will be 
perf or me d b y a q ualifie d la b orat or y. 
Cli nical la b orat or y sa m ples will be st ore d b y t he S p o ns or or desi g nee i n a sec ure a n d c o ntr olle d 
e n vir o n me nt u ntil a nal ysis a n d will be destr o ye d b y t he S p o ns or or desi g nee after all o bli gati o ns 
ha ve bee n met, or s o o ner if re q uire d b y l ocal re g ulati o ns. 
Refer t o t he la b orat or y ma n ual f or f urt her details re gar di n g t he c ollecti o n, pr ocessi n g, a n d 
st ora ge of cli nical la b orat or y sa m ples. 
5. 2. 1  D N A S a m ple 
After c o nse nt is pr o vi de d a n d pri or t o d osi n g, a w h ole bl o o d sa m ple will be c ollecte d fr o m eac h 
s u bject f or D N A e xtracti o n (Secti o n 5. 1. 2 ). 
D N A se q ue nces, i ncl u di n g b ot h t he pr otei n c o di n g se q ue nces a n d t he n o nc o di n g se q ue nces 
i n v ol ve d i n tra nscri pti o nal a n d tra nslati o nal re g ulati o n, a n d ot her bi ol o gical f u ncti o ns, will be 


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D O N O T C O P Y O R DI S T RI B U T E WI T H O U T P E R M I S SI O N F R O M G E MI NI T H E R A P E U TI C S, I N C. 
a nal yze d b y t he S p o ns or f or ge netic m o dificati o ns t hat ma y c o ntri b ute t o a n d/ or m o dif y t he 
disease p he n ot y pe or rate of pr o gressi o n of n A M D.  S uc h D N A se q ue nces, w hic h ma y be 
i n vesti gate d i ncl u de, b ut are n ot li mite d t o t he f oll o wi n g:  ge n o me- wi de ass ociate d varia nts f or 
A M D ris k a n d/ or pr o gressi o n, a n d selecte d pr otei n c o di n g varia nts i n ge nes near s uc h 
ge n o me- wi de ass ociati o n si g nals. 
D N A sa m ples will be st ore d b y t he S p o ns or, or desi g nee, i n a sec ure a n d c o ntr olle d e n vir o n me nt 
u ntil a nal ysis, a n d will be destr o ye d b y t he S p o ns or after all o bli gati o ns ha ve bee n met, or s o o ner 
if re q uire d b y l ocal re g ulati o ns or if re q ueste d i n writi n g b y t he s u bject. 
Refer t o A p pe n di x B  a n d t he la b orat or y ma n ual f or f urt her details re gar di n g t he c ollecti o n, 
pr ocessi n g, a n d st ora ge of t hese sa m ples. 
5. 2. 2  E x pl or at or y Bi o m ar k ers 
Bl o o d sa m ples f or plas ma is olati o n will be o btai ne d at t he ti me p oi nts s pecifie d i n t he S O A f or 
e x pl orat or y a nal yses t o i de ntif y a n d e val uate disease-relate d bi o mar kers, w here l ocal re g ulati o ns 
a n d bl o o d v ol u me per mits (see A p pe n di x A ).  A s pecific sa m ple f or e x pl orat or y bi o mar ker 
a nal ysis is bei n g c ollecte d i n t his st u d y; h o we ver, re mai ni n g bl o o d sa m ples c ollecte d i n t his 
st u d y ma y als o be use d t o a nal yze a d diti o nal bi o mar kers of p ote ntial cli nical i nterest, if t here is 
s ufficie nt sa m ple a n d w here l ocal re g ulati o ns per mit. 
A q ue o us h u m or sa m ples will be o btai ne d at t he ti me p oi nts s pecifie d i n t he S O As f or e x pl orat or y 
a nal yses t o i de ntif y a n d e val uate disease-relate d bi o mar kers (see A p pe n di x A ).  A q ue o us h u m or 
sa m ples c ollecte d will be o btai ne d f or t he pri mar y p ur p ose of P D bi o mar ker a nal ysis. 
C ollecti o n of sa m ples f or e x pl orat or y bi o mar ker a nal ysis will be s u bject t o discreti o nar y 
a p pr o val fr o m eac h ce nter’s I nstit uti o nal Re vie w B oar d (I R B)/I n de pe n de nt Et hics C o m mittee 
(I E C) a n d t he s pecific writte n c o nse nt of t he s u bject.  T his secti o n of t he pr ot oc ol o nl y a p plies if 
a p pr o val f or c ollecti o n of t hese a d diti o nal sa m ples has bee n gra nte d b y t he I R B/I E C a n d c o nse nt 
is pr o vi de d b y t he s u bject. 
Sa m ples will be st ore d b y t he S p o ns or or desi g nee i n a sec ure a n d c o ntr olle d e n vir o n me nt u ntil 
a nal ysis.  T he y will be destr o ye d b y t he S p o ns or or desi g nee after all o bli gati o ns ha ve bee n met, 
or s o o ner if re q uire d b y l ocal re g ulati o ns. 
Refer t o t he la b orat or y ma n ual f or f urt her details re gar di n g t he c ollecti o n, pr ocessi n g, a n d 
st ora ge of t hese sa m ples. 
5. 2. 3  P K a n d I m m u n o ge nicit y Assess me nts 
A q ue o us h u m or sa m ples will be c ollecte d f or P K (assesse d as t otal C F H c o nce ntrati o n i n 
a q ue o us h u m or)/ P D.  Bl o o d sa m ples will be c ollecte d f or A D A e val uati o n at t he ti me p oi nts 
s pecifie d i n A p pe n di x A  a n d i n t he la b orat or y ma n ual. 
5. 3  I m a gi n g Assess m e nts 
C ol or f u n d us p h ot o gra p h y ( A p pe n di x C ), f u n d us a ut ofl u oresce nce ( F A F; A p pe n di x D ), 
fl u orescei n a n gi o gra p h y ( F A; A p pe n di x E ), s pectral d o mai n – o ptical c o here nce t o m o gra p h y 
( O C T; A p pe n di x F ), o ptical c o here nce t o m o gra p h y – a n gi o gra p h y ( O C T- A; A p pe n di x G ), a n d 
near i nfrare d reflecta nce i ma gi n g ( A p pe n di x H ) will be e val uate d at t he ti me- p oi nts s pecifie d i n 
A p pe n di x A . 
F ull i nstr ucti o ns o n i ma ge ac q uisiti o n a n d a nal ysis will be pr o vi de d i n t he i ma gi n g ma n ual(s). 


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D O N O T C O P Y O R DI S T RI B U T E WI T H O U T P E R M I S SI O N F R O M G E MI NI T H E R A P E U TI C S, I N C. 
5. 4  Deter mi n ati o n of St u d y E ye 
O nl y 1 e ye will be selecte d as t he st u d y e ye.  If b ot h e yes meet all e ye-s pecific e ntr y criteria, 
t he n t he st u d y e ye will be deter mi ne d b y t he I n vesti gat or a n d t he s u bject t o get her.  All 
assess me nts will be perf or me d i n t he st u d y e ye as well as t he fell o w e ye w he ne ver feasi ble. 
Si nce st u d y e ye selecti o n is base d o n b ot h V A a n d i ma gi n g assess me nts, t his deter mi nati o n will 
be ma de after res ults f or scree ni n g assess me nts are a vaila ble, b ut bef ore t he baseli ne visit a n d 
ra n d o mizati o n. 


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D O N O T C O P Y O R DI S T RI B U T E WI T H O U T P E R M I S SI O N F R O M G E MI NI T H E R A P E U TI C S, I N C. 
6  S T U D Y T R E A T M E N T S 
6. 1  Tre at m e nts A d mi nistere d 
6. 1. 1  D ose A dj ust me nts 
D ose a dj ust me nts are n ot pla n ne d f or i n di vi d ual s u bjects.  A dj ust me nts t o d ose le vel a n d/ or 
fre q ue nc y ma y be i m ple me nte d base d o n re vie w of e mer gi n g data. 
6. 1. 2  D ose Esc al ati o n 
D ose escalati o n is n ot pla n ne d f or i n di vi d ual s u bjects. 
6. 2  St o p pi n g R ules 
6. 2. 1  St o p pi n g R ules i n I n di vi d u al S u bjects 
If a s u bject e x perie nces a n S A E c o nsi dere d relate d t o G E M 1 0 3, t he s u bject’s d osi n g will be 
pa use d u ntil t he S A E has res ol ve d, or u ntil t he I n vesti gat or deci des, i n c o ns ultati o n wit h t he 
S p o ns or, t hat t he s u bject ma y c o nti n ue wit h st u d y dr u g. 
6. 2. 2  St o p pi n g R ules f or M ulti ple S u bjects 
u ne x pecte d seri o us a d verse reacti o n ( S U S A R), t he S p o ns or will c o n ve ne t he Me dical Re vie w 
C o m mittee ( M R C, see Secti o n 7. 4 ) t o deter mi ne w het her t o c o nti n ue t he st u d y i n a ma n ner s uc h 
t hat be nefits o ut wei g h ris ks, or t o cease f urt her e nr oll me nt.  T he S p o ns or will c o n d uct o n g oi n g 
re vie ws f or detecti o n of p ote ntial safet y si g nals.  At a n y ti me d uri n g t his st u d y, if a cli nicall y 
rele va nt si g nal is esta blis he d, t he S p o ns or ma y re q uest a pa use i n d osi n g t o re vie w re p orte d 
safet y e ve nts a n d all a vaila ble data.  If a pa use is i nstit ute d, d osi n g ma y res u me o nl y after re vie w 
of a vaila ble data b y t he M R C. 
6. 3  Descri pti o n of St u d y Dr u g 
T he refere nce d oc u me nt f or G E M 1 0 3 is t he I n vesti gat or’s Br oc h ure.  G E M 1 0 3 m ust be 
a d mi nistere d u n der cl ose s u per visi o n of t he I n vesti gat or, or desi g nee. 
T he st u d y dr u g will be pr o vi de d i n sterile, si n gle- use vials as a 1 0 m g/ m L c o nce ntrate d li q ui d.  
T he dr u g pr o d uct ma y be ase pticall y dil ute d t o t he a p pr o priate d ose c o nce ntrati o n acc or di n g t o 
t he pr oce d ures o utli ne d i n t he p har mac y ma n ual as necessar y. 
A d diti o nal details are pr o vi de d i n  Secti o n 1. 2 . 
6. 4  St or a ge a n d Dis p ositi o n of St u d y Dr u g 
6. 4. 1  Recei pt of Dr u g S u p plies 
U p o n recei pt of t he st u d y treat me nt s u p plies, a n  i n ve nt or y m ust be perf or me d, a n d a dr u g recei pt 
l o g fille d o ut a n d si g ne d b y t he pers o n acce pti n g t he s hi p me nt.  Recei pt of st u d y dr u g a n d u pl oa d 
of s hi p me nt te m perat ure m o nit or re p orts m ust als o occ ur i n t he a p pr o priate I R T s yste m i n or der 
t o ma ke t he st u d y dr u g a vaila ble f or dis pe nsati o n.  It is i m p orta nt t hat t he desi g nate d st u d y staff 
c o u nts a n d verifies t hat t he s hi p me nt c o ntai ns all t he ite ms n ote d i n t he s hi p me nt i n ve nt or y.  A n y 
da ma ge d or u n usa ble G E M 1 0 3 vials i n a gi ve n s hi p me nt will be d oc u me nte d i n t he st u d y files.  
If a n y part of a n i n vesti gati o nal me dici nal pr o d uct kit is da ma ge d, t he e ntire kit will be re place d.  
T he I n vesti gat or m ust n otif y t he S p o ns or of a n y da ma ge d or u n usa ble st u d y treat me nts t hat were 
s u p plie d t o t he I n vesti gat or’s site. 


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6. 4. 2  M a n a ge me nt of Cli nic al S u p plies 
T he S p o ns or will pr o vi de t he I n vesti gat or a n d st u d y site wit h a de q uate q ua ntities of G E M 1 0 3.  
G E M 1 0 3 will be la bele d “f or cli nical trial use” a n d ha ve all re q uire d la beli n g per re g ulati o ns.  
Eac h vial will be i n di vi d uall y la bele d f or f ut ure s u bject i de ntificati o n p ur p oses. 
G E M 1 0 3 will be s u p plie d i n si n gle- use vials wit h a 0. 2 5 m L fill v ol u me at a c o nce ntrati o n of 
1 0 m g/ m L C F H.  T he st u d y site p har mac y pers o n nel will pre pare a si n gle d ose f or eac h s u bject.  
A p har mac y ma n ual will be ma de a vaila ble a n d trai ni n g pr o vi de d t o e ns ure p har mac y staff ca n 
c o m pl y wit h all dr u g st ora ge, pre parati o n, a d mi nistrati o n, a n d dr u g acc o u nta bilit y pr oce d ures. 
6. 4. 3  St or a ge 
G E M 1 0 3 m ust be st ore d i n a sec ure area wit h li mite d access, pr otecte d fr o m m oist ure a n d li g ht, 
a n d be st ore d at 5° C ± 3° C ( 2- 8° C).  T he refri gerat or s h o ul d ha ve a n a ut o mate d te m perat ure 
rec or di n g a n d alert s yste m.  I n ad diti o n, dr u g acc o u nta bilit y st u d y pers o n nel are re q uire d t o kee p 
a te m perat ure l o g t o esta blis h a rec or d of c o m plia nce wit h t hese st ora ge c o n diti o ns.  O nl y dr u g 
acc o u nta bilit y pers o n nel s h o ul d ha ve access t o t he pr o d uct use d i n t his st u d y. 
6. 4. 4  Dis p ositi o n 
T he I n vesti gat or or desi g nee will be res p o nsi ble f or mai ntai ni n g acc urate rec or ds f or all s u p plies 
use d.  O pe ne d vials of G E M 1 0 3 c o ntai ni n g resi d ual v ol u me will u n der g o G E M 1 0 3 
acc o u nta bilit y/rec o nciliati o n.  F oll o wi n g G E M 1 0 3 acc o u nta bilit y, t he S p o ns or will pr o vi de 
a ut h orizati o n t o t he I n vesti gat or t o ret ur n or destr o y a n y re mai ni n g i n vesti gati o nal pr o d uct as 
descri be d i n Secti o n 6. 7 . 
U n der n o circ u msta nces will G E M 1 0 3 be use d ot her t ha n as directe d i n t he pr ot oc ol.  Refer t o 
t he p har mac y ma n ual f or a d diti o nal details. 
T he site is res p o nsi ble f or re p orti n g t o t he site m o nit or a n d t o t he a p pr o priate S p o ns or 
re prese ntati ve a n y vials of G E M 1 0 3 t hat were n ot te m perat ure-c o ntr olle d d uri n g s hi p me nt or 
d uri n g st ora ge.  S uc h vials will be retai ne d f or i ns pecti o n b y t he site m o nit or a n d ne xt ste ps will 
be disc usse d wit h t he S p o ns or’s S u p pl y Ma na ger.  Vials deter mi ne d t o be q uesti o na ble or 
u ns uita ble ma y be q uara nti ne d or dis p ose d of u p o n a p pr o val b y t he S p o ns or acc or di n g t o 
a p pr o ve d met h o ds. 
It is t he I n vesti gat or’s res p o nsi bilit y t o e ns ure t hat t hat t he p har mac y pers o n nel mai ntai n acc urate 
rec or ds of recei pt of all G E M 1 0 3 vials, i ncl u di n g dates of recei pt.  I n a d diti o n, acc urate rec or ds 
will be ke pt re gar di n g w he n a n d h o w m uc h G E M 1 0 3 is dis pe nse d a n d use d b y eac h s u bject i n 
t he st u d y (i ncl u di n g d oc u me ntati o n of eac h dil uti o nal rec or d use d t o pre pare t he dr u g f or 
i njecti o n).  Reas o ns f or de part ure fr o m t he e x pecte d dis pe nsi n g re gi me n m ust als o be rec or de d.  
T o satisf y re g ulat or y re q uire me nts re gar di n g dr u g acc o u nta bilit y, all G E M 1 0 3 vials will be 
rec o ncile d a n d retai ne d u ntil st u d y c o ncl usi o n.  At t hat ti me, G E M 1 0 3 vials will be destr o ye d or 
ret ur ne d t o t he S p o ns or acc or di n g t o a p plica ble re g ulati o ns. 
6. 5  Pre p ar ati o n a n d A d mi nistr ati o n of St u d y Dr u g 
6. 5. 1  Pre p ar ati o n of St u d y Dr u g 
D ose pre parati o n a n d a d mi nistrati o n s h o ul d be perf or me d usi n g sterile, n o n p yr o ge nic dis p osa ble 
materials i ncl u di n g, b ut n ot restricte d t o s yri n ges, nee dles, tra nsfer t u bi n g, a n d st o pc oc ks. 
T w o s yri n ges will be pre pare d: 1 f or afli berce pt a n d 1 f or G E M 1 0 3/s ha m.  I njecti o ns will be 
ma de wit h 2 se parate s yri n ges acc or di n g t o t he met h o ds i n t he st u d y ma n ual.  T he s yri n ge 


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D O N O T C O P Y O R DI S T RI B U T E WI T H O U T P E R M I S SI O N F R O M G E MI NI T H E R A P E U TI C S, I N C. 
c o ntai ni n g G E M 1 0 3 s h o ul d be pre pare d j ust pri or t o t he start of i njecti o n.  It is prefera ble t hat 
t he pre pare d s yri n ge is use d wit hi n 2 h o urs, alt h o u g h it ma y be st ore d at r o o m te m perat ure f or u p 
t o 4 h o urs.  Part of t he pre parati o n ma y i ncl u de dil uti o n. 
F or s u bjects assi g ne d t o t he s ha m + S o C treat me nt gr o u p, a s yri n ge s h o ul d be pre pare d t o ser ve as 
s ha m t o mi mic a real I V T i njecti o n.  F or t he i njecti o n, t he nee dle is re m o ve d a n d o nl y t he h u b of 
t he s yri n ge is hel d t o t he e ye. 
Pri or t o pre parati o n of t he i njecti o n, t he vials of st u d y dr u g s h o ul d be vis uall y i ns pecte d.  T he 
s ol uti o n s h o ul d n ot be use d if it c o ntai ns f orei g n partic ulate matter or is disc ol ore d.  T he c o nte nts 
s h o ul d N O T be war me d usi n g a micr o wa ve or ot her heat s o urce.  G E M 1 0 3 is a pr otei n t hat 
s h o ul d be n ot be s ha ke n a n d s h o ul d be ha n dle d a n d mi xe d ge ntl y t o pre ve nt f oa mi n g. 
Refer t o t he p har mac y ma n ual f or detaile d i nstr ucti o ns re gar di n g t he pre parati o n of t he i njecti o n. 
6. 5. 2  A d mi nistr ati o n of St u d y Dr u g 
All I V T i njecti o ns m ust be a d mi nistere d b y t he I n vesti gat or, or desi g nee ( S u bi n vesti gat or) usi n g 
ase ptic tec h ni q ue c o nsiste nt wit h acce pte d g ui deli nes (e. g., A A O G ui deli nes f or I ntra vitreal 
I njecti o ns 2 0 1 5, R o yal C olle ge of O p ht hal m ol o gists O p ht hal mic Ser vice G ui da nce f or 
I ntra vitreal i njecti o n t hera p y Ma y 2 0 1 8).  St u d y dr u g m ust n ot be i njecte d wit h ot her pr o d ucts i n 
t he sa me s yri n ge, as t he c o m pati bilit y of G E M 1 0 3 i n s ol uti o n wit h ot her pr o d ucts has n ot bee n 
e val uate d.  It is rec o m me n de d t hat all i njecti o ns of G E M 1 0 3 be a d mi nistere d usi n g a 3 0- ga u ge 
nee dle a n d a 1 m L s yri n ge. 
S ha m i njecti o ns will be perf or me d usi n g t he h u b of a 1 m L s yri n ge wit h t he nee dle re m o ve d, t o 
mi mic t he I V T a d mi nistrati o n of st u d y dr u g. 
At eac h d osi n g visit, 2 I V T i njecti o ns ( or s ha m ) will be a d mi nistere d; afli berce pt a n d G E M 1 0 3 
( or s ha m).  T he y will be a d mi nistere d se paratel y t o t he sa me e ye, wit h t he sec o n d i njecti o n 
a d mi nistere d at 9 0°, or 3 cl oc k h o urs dista nce, fr o m t he l ocati o n of t he first i njecti o n.  G E M 1 0 3 
a n d afli berce pt will u n der n o circ u msta nces be a d mi nistere d as 1 c o m bi ne d i njecti o n fr o m t he 
sa me s yri n ge.  T he i ntra vitreal i njecti o ns will be a d mi nistere d i n acc or da nce wit h S o C 
a n d a sterile li d s pec ul u m.  A d mi nister 
afli berce pt ( 2 m g/ 5 0 μ L) first, f oll o we d b y G E M 1 0 3 ( 5 0 0 μ g/ 5 0 μ L) 1 5 mi n utes ( ± 5 mi n utes) 
later.  Meas ure I O P after I V T i njecti o ns as descri be d i n t he S O A (A p pe n di x A ). 
Refer t o t he p har mac y ma n ual f or detaile d i nstr ucti o ns o n t he a d mi nistrati o n of G E M 1 0 3 a n d 
s ha m.  A d mi nister afli berce pt f oll o wi n g t he i nstr ucti o ns i n t he c urre nt, a p pr o ve d f ull prescri bi n g 
i nf or mati o n a n d a n y a vaila ble i nstit uti o nal g ui deli nes, if a p plica ble. 
6. 6  R a n d o miz ati o n of t he St u d y Dr u g 
All s u bjects i n b ot h treat me nt gr o u ps will recei ve E O M treat me nt. 
S u bjects will be ra n d o mize d t o 1 of 2 treat me nts:  G E M 1 0 3 + S o C or s ha m + S o C ( S o C defi ne d as 
afli berce pt E O M) f or a t otal of 6 d oses d uri n g t he 1 2- m o nt h st u d y peri o d. 
P ossi ble c ha n ges t o ra n d o mizati o n a n d s u bse q ue nt a nal ysis base d o n disc o nti n uati o n of 
assi g n me nt t o a st u d y ar m are descri be d i n Secti o n 8. 6 . 


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5 Ma y 2 0 2 1 
Pa ge 4 4 of 8 9 
G E MI NI T H E R A P E U TI C S, I N C.  P R O P RI E T A R Y A N D C O N FI D E N TI A L: 
D O N O T C O P Y O R DI S T RI B U T E WI T H O U T P E R M I S SI O N F R O M G E MI NI T H E R A P E U TI C S, I N C. 
6. 7  Destr ucti o n of t he St u d y Dr u g 
All st u d y dr u g vials are si n gle- use.  All vials wit h left o ver st u d y dr u g after a d mi nistrati o n will be 
destr o ye d at t he site after acc o u nta bilit y/rec o nciliati o n is c o m plete a n d i n acc or da nce wit h site 
sta n dar d o perati n g pr oc e d ures a n d p olicies g o ver ni n g dr u g destr ucti o n. 
If a n y u n use d st u d y dr u g material is re mai ni n g u p o n c o m pleti o n of t he st u d y, t he material will be 
ret ur ne d t o t he S p o ns or or desi g nee or destr o ye d o nl y after t he S p o ns or or desi g nee has 
perf or me d fi nal dr u g a cc o u nta bilit y/rec o nciliati o n a n d pr o vi de d writte n a ut h orizati o n f or t he 
ret ur n or destr ucti o n of t he st u d y dr u g.  Refer t o t he p har mac y ma n ual f or f urt her i nstr ucti o ns. 


G E M- C L- 1 0 3 1 1 Pr ot oc ol, Versi o n 3. 0  
5 Ma y 2 0 2 1 
Pa ge 4 5 of 8 9 
G E MI NI T H E R A P E U TI C S, I N C.  P R O P RI E T A R Y A N D C O N FI D E N TI A L: 
D O N O T C O P Y O R DI S T RI B U T E WI T H O U T P E R M I S SI O N F R O M G E MI NI T H E R A P E U TI C S, I N C. 
7  A S S E S S M E N T O F S A F E T Y 
T he met h o ds f or c ollecti n g safet y data are descri be d bel o w.  All pers o n nel i n v ol ve d wit h t he 
st u d y m ust e ns ure t he y are fa miliar wit h t he c o nte nt of t his secti o n. 
7. 1  A Es a n d L a b or at or y A b n or m alities 
7. 1. 1  Cli nic al A Es 
A n A E is a n y u nt o war d me dical occ urre nce i n a s u bject w hic h d oes n ot necessaril y ha ve a ca usal 
relati o ns hi p wit h t he st u d y dr u g.  A n A E ca n t heref ore be a n y u nfa v ora ble a n d u ni nte n de d si g n, 
s y m pt o m, or disease te m p orall y ass ociate d wit h t he use of t he st u d y dr u g, w het her or n ot 
c o nsi dere d relate d t o t he me dici nal pr o d uct.  Pre-e xisti n g c o n diti o ns t hat w orse n i n se verit y 
d uri n g t he c o urse of t he st u d y are t o be re p orte d as A Es.  Vital si g ns c o nsi dere d cli nicall y 
si g nifica nt b y t he I n vesti gat or s h o ul d be d oc u me nte d as A Es. 
All A Es (i ncl u di n g pr oce d ure-relate d A Es) occ urri n g d uri n g t he cli nical st u d y f oll o wi n g t he 
si g ni n g of c o nse nt will be re p orte d i n t he A E e C R F. 
T he I n vesti gat or will assess t he se verit y, ca usalit y (relati o ns hi p t o st u d y dr u g), a n d seri o us ness 
of eac h A E. 
Se verit y:  T he I n vesti gat or will assess t he se verit y of all A Es as mil d, m o derate, or se vere base d 
o n t he f oll o wi n g defi niti o ns de vel o pe d fr o m t he Cli nical Data I nterc ha n ge Sta n dar ds C o ns orti u m 
St u d y Data Ta b ulati o n M o del v 3. 1. 1 sta n dar d ter mi n ol o g y. 
 Mil d:   A t y pe of A E t hat is us uall y tra nsie nt a n d ma y re q uire o nl y mi ni mal treat me nt or 
t hera pe utic i nter ve nti o n.  T he e ve nt d oes n ot ge nerall y i nterfere wit h us ual acti vities of 
dail y li vi n g. 
 M o der ate:   A t y pe of A E t hat is us uall y alle viate d wit h a d diti o nal s pecific t hera pe utic 
i nter ve nti o n.  T he e ve nt i nterferes wit h us ual acti vities of dail y li vi n g, ca usi n g 
disc o mf ort, b ut p oses n o si g nifica nt or per ma ne nt ris k of har m t o t he researc h s u bject. 
 Se vere:   A t y pe of A E t hat i nterr u pts us ual acti vities of dail y li vi n g, or si g nifica ntl y 
affects cli nical stat us, or ma y re q uire i nte nsi ve t hera pe utic i nter ve nti o n. 
Ca usalit y:  A Es/ S A Es will be assesse d as n ot relate d, u nli kel y relate d, p ossi bl y relate d, pr o ba bl y 
relate d, or defi nitel y relate d t o st u d y dr u g.  Ta ble 2  pr o vi des ge neral g ui da nce o n t he assess me nt 
of ca usalit y.  F or data re p orti n g p ur p oses, A Es assesse d as n ot relate d or u nli kel y relate d will be 
classifie d as u nrelate d t o st u d y dr u g, a n d A Es assesse d as p ossi bl y relate d, pr o ba bl y relate d, or 
defi nitel y relate d will be classifie d as relate d t o st u d y dr u g.  Assess me nt of ca usalit y s h o ul d be 
base d o n t he I n vesti gat or’s me dical j u d g me nt a n d t he o bser ve d s y m pt o ms ass ociate d wit h t he 
e ve nt. 
E x pecte d ness: A Es/ S A Es will be c o nsi dere d u ne x pecte d if t he e ve nt is n ot liste d i n t he 
I n vesti gat or’s Br oc h ure or is n ot liste d at t he s pecificit y or se verit y t hat has bee n o bser ve d. 


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5 Ma y 2 0 2 1 
Pa ge 4 6 of 8 9 
G E MI NI T H E R A P E U TI C S, I N C.  P R O P RI E T A R Y A N D C O N FI D E N TI A L: 
D O N O T C O P Y O R DI S T RI B U T E WI T H O U T P E R M I S SI O N F R O M G E MI NI T H E R A P E U TI C S, I N C. 
T a ble 2.  Assess me nt of C a us alit y 
Rel ati o ns hi p t o St u d y Dr u g 
Crite ri a f o r J u d g me nt 
Defi nitel y Rel ate d 
R eas o n a ble te m p oral relati o ns hi p of t h e cli nic al e v e nt t o st u d y dr u g 
a d mi nistrati o n A N D ca n n ot b e reas o n a bl y e x plai n e d b y ot h er fact ors 
(s u c h as t h e s u bject’s cli nical state, c o n c o mita nt t h era p y, a n d/ or ot h er 
i nter v e nti o ns). 
Pr o b a bl y R elate d 
T h e te m p oral relati o ns hi p of t h e cli nical e v e nt t o st u d y dr u g 
a d mi nistrati o n m a k es ca usal r elati o ns hi p pr o ba ble b ut n ot p ossi ble 
A N D ot h er dr u gs, t h era p e utic i nter v e nti o ns, or u n d erl yi n g c o n diti o ns 
d o n ot pr o vi d e a s uffici e nt e x pla n ati o n f or t h e o bser v e d e v e nt. 
P ossi bl y R elate d 
T h e te m p oral relati o ns hi p of t h e cli nical e v e nt t o st u d y dr u g 
a d mi nistrati o n m a k es ca usal r elati o ns hi p p ossi ble b ut n ot u nli k el y 
A N D ot h er dr u gs, t h era p e utic i nter v e nti o ns, or u n d erl yi n g c o n diti o ns 
d o n ot pr o vi d e a s uffici e nt e x pla n ati o n f or t h e o bser v e d e v e nt. 
U nli k el y Relate d 
T h e te m p oral relati o ns hi p of t h e cli nical e v e nt t o st u d y dr u g 
a d mi nistrati o n m a k es ca usal r elati o ns hi p u nli kel y b ut n ot i m p ossi ble 
A N D ot h er dr u gs, t h era p e utic i nter v e nti o ns, or u n d erl yi n g c o n diti o ns 
pr o vi d e a pla usi ble e x pla n ati o n f or t h e o bser v e d e v e nt. 
N ot Relate d 
Data ar e a v ail a ble t o cle arl y i d e ntif y a n alter n ati v e ca us e f or t h e 
rea cti o n. 
Seri o us ness:  A Es will be classifie d as seri o us or n o nseri o us acc or di n g t o t he defi niti o ns 
pr o vi de d bel o w. 
A n S A E is a n y A E t hat is or lea ds t o a n y of t he f oll o wi n g: 
 Deat h 
 I m me diatel y life-t hreate ni n g.  A n A E is c o nsi dere d “life-t hreate ni n g” if, i n t he vie w of 
eit her t he I n vesti gat or or S p o ns or, its occ urre nce places t he s u bject at i m me diate ris k of 
deat h.  It d oes n ot i ncl u de a n A E t hat, ha d it occ urre d i n a m ore se vere f or m, mi g ht ha ve 
ca use d deat h. 
 Re q uires i n- patie nt h os pitalizati o n or pr ol o n gati o n of e xisti n g h os pitalizati o n 
 C o n ge nital a n o mal y/ birt h defect 
 Persiste nt or si g nifica nt disa bilit y or i nca pacit y 
 A n i m p orta nt me dical e ve nt t hat ma y n ot res ult i n deat h, be life-t hreate ni n g, or re q uire 
h os pitalizati o n ma y be c o nsi dere d a n S A E w he n, base d u p o n a p pr o priate me dical 
j u d g me nt, t he e ve nt ma y je o par dize t he s u bject a n d ma y re q uire me dical or s ur gical 
i nter ve nti o n t o pre ve nt o ne of t he o utc o mes liste d a b o ve 
7. 1. 2  L a b or at or y Test A b n or m alit y 
La b orat or y test res ults eit her will be rec or de d o n t he e C R F or a p pear o n t he la b orat or y re p orts 
s u b mitte d directl y fr o m t he ce ntral la b orat or y.  O ut- of-ra n ge la b orat or y test val ues s h o ul d n ot be 
re p orte d as A Es u nless t he y are c o nsi dere d cli nicall y si g nifica nt a b n or malities b y t he 
I n vesti gat or. 


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5 Ma y 2 0 2 1 
Pa ge 4 7 of 8 9 
G E MI NI T H E R A P E U TI C S, I N C.  P R O P RI E T A R Y A N D C O N FI D E N TI A L: 
D O N O T C O P Y O R DI S T RI B U T E WI T H O U T P E R M I S SI O N F R O M G E MI NI T H E R A P E U TI C S, I N C. 
7. 2  Rec or di n g of A Es 
At eac h c o ntact wit h t he s u bject, t he I n vesti gat or will elicit i nf or mati o n o n A Es.  A n y 
i nf or mati o n o n A Es s h o ul d be rec or de d i n t he s o urce d oc u me ntati o n a n d i n t he e C R F.  All 
clearl y relate d si g ns, s y m pt o ms, a n d a b n or mal dia g n ostic pr oce d ures res ults s h o ul d be rec or de d 
u n der 1 dia g n osis. 
A n y A Es re mai ni n g u nres ol ve d s h o ul d be rec or de d as “ o n g oi n g.”  O n g oi n g A Es/ S A Es s h o ul d 
c o nti n ue t o be f oll o we d u p f or t he peri o d s pecifie d i n Secti o n 7. 3. 2 .  H o we ver, f oll o w- u p 
i nf or mati o n o n S A Es m ust be re p orte d t o t he S p o ns or or desi g nee as descri be d i n Secti o n 7. 3. 1 .  
A n y S A E t hat occ urs after t he st u d y peri o d a n d is c o nsi dere d t o be relate d or p ossi bl y relate d t o 
t he st u d y treat me nt or st u d y partici pati o n s h o ul d be rec or de d a n d re p orte d i m me diatel y. 
All A Es will be rec or de d b y ti me a n d date.  T he ti me a n d date w he n t he A E starte d a n d st o p pe d, 
t he i nte nsit y, seri o us ness, acti o n ta ke n wit h re gar d t o G E M 1 0 3, ca usalit y assess me nt, a n d 
o utc o me of t he e ve nt will be rec or de d f or eac h A E. 
A Es will be re p orte d f or a mi ni m u m of 3 0 da ys after t he last a d mi nistrati o n of st u d y treat me nt. 
7. 3  Re p orti n g a n d H a n dli n g of S afet y P ar a m eters 
7. 3. 1  S A Es (I m me di atel y Re p ort a ble t o t he S p o ns or) 
All S A Es m ust be re p orte d t o t he S p o ns or or desi g nee i m me diatel y a n d n o later t ha n 2 4 h o urs 
after t he I n vesti gat or’s first k n o wle d ge of t he e ve nt (e x pe dite d re p orti n g).  T o re p ort s uc h e ve nts, 
a n S A E f or m m ust be c o m plete d b y t he I n vesti gat or.  T he I n vesti gat or will kee p a c o p y of t his 
S A E f or m o n file at t he st u d y site. 
T he I n vesti gat or will pr o vi de a n y a d diti o nal i nf or mati o n wit hi n 2 4 h o urs of bec o mi n g a ware of 
t his i nf or mati o n.  T his u p date s h o ul d i ncl u de a c o p y of t he c o m plete d S A E f or m, a n d a n y ot her 
i nf or mati o n t hat will assist wit h t he u n dersta n di n g of t he e ve nt.  Si g nifica nt ne w i nf or mati o n o n 
o n g oi n g S A Es m ust be re p orte d t o t he S p o ns or or desi g nee i m me diatel y a n d n o later t ha n 
2 4 h o urs after t he I n vesti gat or’s bec o mes a ware of t his i nf or mati o n. 
Re p orti n g Seri o us A d verse E ve nts 
 
T he f oll o wi n g c o ntact i nf or mati o n is t o be use d f or S A E re p orti n g:  
 
S y ne os Healt h P har mac o vi gila nce 
T o Re p ort a n S A E se n d t o: safet yre p orti n g @s y ne os healt h.c o m or Fa x t o: 8 7 7- 4 6 4- 7 7 8 7. 
 
T he defi niti o n a n d re p orti n g re q uire me nt are i n acc or da nce wit h I C H G ui deli ne f or Cli nical 
Safet y Data Ma na ge me nt, Defi niti o ns a n d Sta n dar ds f or E x pe dite d Re p orti n g ( T o pic E 2, 1 9 9 5). 
7. 3. 2  A E Re p orti n g Peri o d 
T he st u d y peri o d d uri n g w hic h A Es m ust be re p orte d is defi ne d as t he peri o d fr o m si g nat ure of 
t he i nf or me d c o nse nt t o t he E O S treat me nt f oll o w- u p.  F or t his st u d y, t he st u d y treat me nt f oll o w-
u p is defi ne d as a mi ni m u m of 3 0 da ys after t he last a d mi nistrati o n of st u d y treat me nt.  If t he 


G E M- C L- 1 0 3 1 1 Pr ot oc ol, Versi o n 3. 0  
5 Ma y 2 0 2 1 
Pa ge 4 8 of 8 9 
G E MI NI T H E R A P E U TI C S, I N C.  P R O P RI E T A R Y A N D C O N FI D E N TI A L: 
D O N O T C O P Y O R DI S T RI B U T E WI T H O U T P E R M I S SI O N F R O M G E MI NI T H E R A P E U TI C S, I N C. 
I n vesti gat or bec o mes a ware of a n S A E t hat is c o nsi dere d t o be relate d t o st u d y treat me nt at a n y 
ti me after t he st u d y, it m ust be re p orte d t o t he S p o ns or. 
7. 3. 3  I n vesti g at or Re p orti n g:  N otif yi n g t he S p o ns or 
S A Es m ust be re p orte d i n acc or da nce wit h t he pr ocess a n d ti meli nes descri be d i n Secti o n 7. 3. 1 . 
7. 3. 4  I n vesti g at or Re p orti n g:  N otif yi n g t he I R B/I E C 
U na ntici pate d pr o ble ms p osi n g ris ks t o s u bjects or ot hers as n ote d a b o ve will be re p orte d t o t he 
I R B/I E C acc or di n g t o l ocal re g ulati o ns.  C o pies of eac h re p ort a n d d oc u me ntati o n of I R B/I E C 
n otificati o n a n d recei pt will be ke pt i n t he I n vesti gat or’s st u d y file. 
7. 3. 5  S p o ns or Re p orti n g:  N otif yi n g Re g ul at o r y A ut h orities 
T he S p o ns or is re q uire d t o re p ort certai n st u d y e ve nts i n a n e x pe dite d ma n ner t o t he F D A.  T he 
f oll o wi n g descri bes t he safet y re p orti n g re q uire me nts b y ti meli ne f or re p orti n g a n d ass ociate d 
t y pe of e ve nt: 
 I m me diatel y a n d wit hi n 7 cale n dar da ys 
o  A n y s us pecte d a d verse reacti o n t hat is:  ass ociate d wit h t he use of t he st u d y dr u g, 
u ne x pecte d, a n d fatal or life-t hreate ni n g 
o  F oll o w- u p i nf or mati o n m ust be re p orte d i n t he f oll o wi n g 8 cale n dar da ys 
 I m me diatel y a n d wit hi n 1 5 cale n dar da ys  
o  A n y s us pecte d a d verse reacti o n t hat is:  ass ociate d wit h t he use of t he st u d y dr u g, 
u ne x pecte d, a n d seri o us, b ut n ot fatal or life-t hreate ni n g 
o  A n y fi n di n g fr o m tests i n la b orat or y a ni mals t hat s u g gest a si g nifica nt ris k f or 
h u ma n s u bjects i ncl u di n g re p orts of m uta ge nicit y, terat o ge nicit y, or 
carci n o ge nicit y 
o  A n y e ve nt i n c o n necti o n wit h t he c o n d uct of t he st u d y or t he de vel o p me nt of t he 
i n vesti gati o nal me dici nal pr o d uct t hat ma y affect t he safet y of t he st u d y s u bjects 
o  F oll o w- u p i nf or mati o n m ust be re p orte d wit hi n 1 5 cale n dar da ys 
F or t he p ur p oses of e x pe dite d re p orti n g, t he deter mi nati o n of ca usalit y will be t he res p o nsi bilit y 
of t he S p o ns or wit h c o nsi derati o n of t he I n vesti gat or's assess me nt of ca usalit y. 
T he S p o ns or will c o m pl y wit h all a d diti o nal l ocal safet y re p orti n g re q uire me nts, as a p plica ble. 
7. 3. 6  S p o ns or Re p orti n g:  N otif yi n g P artici p ati n g I n vesti g at ors 
It is t he res p o nsi bilit y of t he S p o ns or or desi g nee t o i m me diatel y n otif y all partici pati n g 
I n vesti gat ors of a n y A E ass ociate d wit h t he use of t he dr u g t hat is b ot h seri o us a n d u ne x pecte d, 
as well as a n y fi n di n g fr o m tests i n la b orat or y a ni mals t hat s u g gest a si g nifica nt ris k f or h u ma n 
s u bjects. 
7. 3. 7  Tre at me nt a n d F oll o w- u p of A Es 
D uri n g t he st u d y, all S A Es a n d oc ular A Es will be f oll o we d u p u ntil t he y ha ve ret ur ne d t o 
baseli ne stat us or sta bilize d or u ntil t he I n vesti gat or a n d S p o ns or a gree t hat f oll o w- u p is n o 
l o n ger necessar y.  If a clear e x pla nati o n is esta blis he d, it s h o ul d be d oc u me nte d. 


G E M- C L- 1 0 3 1 1 Pr ot oc ol, Versi o n 3. 0  
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G E MI NI T H E R A P E U TI C S, I N C.  P R O P RI E T A R Y A N D C O N FI D E N TI A L: 
D O N O T C O P Y O R DI S T RI B U T E WI T H O U T P E R M I S SI O N F R O M G E MI NI T H E R A P E U TI C S, I N C. 
Treat me nt of A Es is at t he discreti o n of t he I n vesti gat or a n d s h o ul d f oll o w t he sta n dar ds of 
me dical care at t he I n vesti gat or’s i nstit uti o n. 
7. 3. 8  F oll o w- u p of A b n or m al L a b or at or y Test V al ues 
I n t he e ve nt of u ne x plai ne d cli nicall y si g nifica nt a b n or mal la b orat or y val ues, t he tests s h o ul d be 
re peate d i m me diatel y a n d f oll o we d u p u ntil t he y ha ve ret ur ne d t o baseli ne val ues a n d/ or a n 
a de q uate e x pla nati o n of t he a b n or malit y is f o u n d.  If a clear e x pla nati o n is esta blis he d, it s h o ul d 
be rec or de d; t his f oll o w- u p ma y occ ur wit h t he s u bject’s pri mar y care p h ysicia n. 
7. 3. 9  Pre g n a nc y 
C o ntrace pti o n a n d pre g na nc y a v oi da nce pr oce d ures are descri be d i n Secti o n 4. 5. 2 . 
A fe male s u bject m ust be a d vise d t o i m me diatel y i nf or m t he I n vesti gat or if s he bec o mes 
pre g na nt d uri n g t he st u d y a n d m ust n ot recei ve f urt her G E M 1 0 3 i njecti o ns.  Pre g na ncies 
occ urri n g t hr o u g h t he E O S m ust be re p orte d t o t he I n vesti gat or.  T he I n vesti gat or m ust re p ort all 
pre g na ncies t o t he S p o ns or wit hi n 2 4 h o urs of n otificati o n.  T he I n vesti gat or s h o ul d c o u nsel t he 
s u bject disc ussi n g t he ris ks of c o nti n ui n g wit h t he pre g na nc y a n d t he p ossi ble effects o n t he 
fet us.  M o nit ori n g of t he s u bject s h o ul d c o nti n ue u ntil c o ncl usi o n of t he pre g na nc y. 
Pre g na nc y occ urri n g i n t he part ner of a s u bject partici pati n g i n t he st u d y (t hr o u g h t he E O S) m ust 
als o be re p orte d t o t he I n vesti gat or a n d t he S p o ns or.  T he part ner s h o ul d be c o u nsele d a n d 
f oll o we d as descri be d a b o ve (Secti o n 4. 5. 2 ). 
7. 4  Me dic al Re vie w C o m mittee ( M R C) 
A n M R C c o nsisti n g of S p o ns or me dical pers o n nel a n d i n de pe n de nt me dical e x pert(s) will meet 
a p pr o xi matel y q uarterl y t o re vie w safet y i nf or mati o n f or t he st u d y.  T he first meeti n g is pla n ne d 
t o occ ur after at least 3 s u bjects ha ve c o m plete d 3 d oses of G E M 1 0 3 + S o C.  T he M R C ma y als o 
be c o n ve ne d f or a n a d h oc meeti n g t o disc uss i nteri m safet y fi n di n gs at t he discreti o n of t he 
S p o ns or (e. g., if 2 or m ore s u bjects re p ort cli nicall y si milar st u d y dr u g-relate d S A Es). 


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G E MI NI T H E R A P E U TI C S, I N C.  P R O P RI E T A R Y A N D C O N FI D E N TI A L: 
D O N O T C O P Y O R DI S T RI B U T E WI T H O U T P E R M I S SI O N F R O M G E MI NI T H E R A P E U TI C S, I N C. 
8  S T A TI S TI C A L P L A N 
8. 1   Ge ner al C o nsi der ati o ns 
Descri pti ve s u m mar y statistics will be pr o vi de d f or de m o gra p hics, dis p ositi o n, a n d d ose 
e x p os ure.  T he n u m ber a n d perce nta ge of s u bjects w h o disc o nti n ue d fr o m t he st u d y, al o n g wit h 
reas o ns f or disc o nti n uati o ns, will be ta b ulate d a n d descri be d i n listi n gs.  All descri pti ve 
s u m maries will be pr o vi de d b y treat me nt gr o u p ( G E M 1 0 3 vs s ha m). 
C o nti n u o us data will be s u m marize d usi n g descri pti ve statistics ( n u m ber of s u bjects, mea n, 
sta n dar d de viati o n, me dia n, mi ni m u m, a n d ma xi m u m) a n d, w here a p pr o priate, gra p hic 
re prese ntati o n, a n d t w o-
s u m marize d b y sa m ple size, pr o p orti o ns, a n d t w o-
 
A n y re p orte d p- val ues will be c o nsi dere d part of t he descri pti ve a nal yses (i.e., h y p ot hesis-
ge nerati n g) a n d will n ot be a dj uste d f or m ulti plicit y.  T he p hrase “statisticall y si g nifica nt” ma y 
be use d i nterc ha n gea bl y wit h “ n o mi nall y statisticall y si g nifica nt” t o i n dicate t hat a n o mi nal 
p-
 
F ull a nal ysis details will be pr o vi de d i n a se parate Statistical A nal ysis Pla n ( S A P). 
8. 2  Deter mi n ati o n of S a m ple Size 
T he pla n ne d t otal sa m ple size of a p pr o xi matel y 4 5 s u bjects ( ~ 3 0 treate d wit h G E M 1 0 3 + S o C, 
~ 1 5 treate d wit h s ha m + S o C; S o C defi ne d as afli berce pt E O M) is base d o n feasi bilit y 
c o nsi derati o ns, rat her t ha n a n y s pe cific statistical test. 
8. 3  A n al ysis Sets 
8. 3. 1  C o nse nte d S u bject Set 
T he C o nse nte d S u bject Set will i ncl u de s u bjects w h o si g ne d t he I C F a n d will be use d t o create a 
dia gra m t o ill ustrate s u bject fl o w fr o m c o nse nt t hr o u g h dis p ositi o n (si milar t o a C o ns oli date d 
Sta n dar ds of Re p orti n g Trials [ C O N S O R T] dia gra m f or a ra n d o mize d trial). 
8. 3. 2  Bi o m ar ker Set 
T he Bi o mar ker Set will i ncl u de s u bjects wit h s ufficie nt data t o assess bi o mar ker res ults. 
8. 3. 3  F ull A n al ysis Set 
T he F ull A nal ysis Set ( F A S) will i ncl u de all s u bjects w h o recei ve at least 1 d ose of st u d y dr u g 
( G E M 1 0 3 or s ha m).  Safet y a nal yses will be perf or me d o n t he F A S.  A nal yses o n t he F A S are 
c o nsiste nt wit h t he i nte nti o n-t o-treat pri nci ple. 
8. 4  De m o gr a p hics a n d S afet y A n al ysis 
De m o gra p hic baseli ne c haracteristic data will be s u m marize d acc or di n g t o t he met h o ds 
descri be d i n Secti o n 8. 1 . 
Vari o us a nal yses t o descri be s u bject c haracteristics will be perf or me d s uc h as le n gt h of pri or 
afli berce pt treat me nt, t y pe of C N V lesi o ns, etc. 
Descri pti ve statistics will be c o m p ute d f or safet y para meters, as a p pr o priate.  N u m ber a n d 
perce nta ge of s u bjects w h o disc o nti n ue d fr o m t he st u d y beca use of A Es will be ta b ulate d acr oss 
d ose c o h orts; se verit y a n d fre q ue nc y of A Es a n d S A Es will als o be ta b ulate d acr oss treat me nt 


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D O N O T C O P Y O R DI S T RI B U T E WI T H O U T P E R M I S SI O N F R O M G E MI NI T H E R A P E U TI C S, I N C. 
gr o u ps.  All ot her safet y data will be pr o vi de d i n listi n gs.  P h ysical e xa mi nati o n fi n di n gs, cli nical 
la b orat or y val ues, a n d vital si g ns will be s u m marize d b y d ose c o h ort. 
T he pr o p orti o n of s u bjects wit h meas ura ble a nti b o dies t o G E M 1 0 3 will be dis pla ye d. 
F urt her statistical e val uati o ns will be a p plie d f or select e n d p oi nts, if warra nte d.  All baseli ne data 
a n d safet y data c ollecte d d uri n g t he st u d y will be liste d f or eac h s u bject. 
All A Es will be c o de d usi n g a c o nsiste nt versi o n of t he Me dical Dicti o nar y f or Re g ulat or y 
Acti vities ( Me d D R A, versi o n 2 2. 0 or hi g her) a n d will be classifie d b y Me d D R A s yste m or ga n 
class ( S O C) a n d preferre d ter m ( P T). 
A E a nal yses will i ncl u de t he f oll o wi n g ta b ular s u m maries: 
 S u m mar y of all A Es 
 I nci de nce of A Es b y S O C a n d P T 
 I nci de nce of A Es b y se verit y 
 I nci de nce of S A Es 
 I nci de nce of treat me nt-relate d A Es 
8. 5  Bi o m ar ker, I m a gi n g, a n d Cli nic al E n d p oi nt A n al ysis 
A q ue o us h u m or will be c ollecte d pri or t o t he first d ose, a n d j ust pri or t o eac h G E M 1 0 3/s ha m 
I V T i njecti o n t o e val uate c o m ple me nt pr otei ns a n d p ossi bl y i nfla m mat or y c yt o ki ne pr ofiles t o 
deter mi ne t heir p ote ntial as P D bi o mar kers f or usef ul ness i n a pi v otal st u d y.  T otal C F H 
c o nce ntrati o ns i n a q ue o us h u m or a n d plas ma will be e val uate d. 
I ma gi n g e n d p oi nts s uc h as C N V lesi o n size, M A lesi o n size, reti nal la yer t hic k ness or prese nce 
of fl ui d, a n d cli nical e n d p oi nts s uc h as B C V A, l o w l u mi na nce vis ual ac uit y ( L L V A), a n d l o w 
l u mi na nce deficit, will be a nal yze d acc or di n g t o t he met h o ds of Secti o n 8. 1 . 
A nal yses of bi o mar kers, i ma gi n g assess me nts, a n d cli nical e n d p oi nts will be descri pti ve, a n d 
will s u m marize act ual val ues a n d c ha n ges fr o m baseli ne o ver ti me.  Gra p hical dis pla ys will als o 
be create d. 
A nal ysis of bi o mar ker, i ma gi n g, a n d cli nical e n d p oi nt c ha n ges fr o m baseli ne will pri maril y 
e m pl o y t he Wilc o x o n ra n k-s u m test. 
F ull a nal ysis details will be pr o vi de d i n t he S A P. 
8. 6  S u m m aries of D at a Pri or t o St u d y C o m pleti o n 
I nteri m data ma y be s u m marize d f or prese ntati o n t o re g ulat or y a ut h orities or t o t he scie ntific 
c o m m u nit y t o facilitate disc ussi o ns a n d o btai n i n p ut o n late p hase st u d y desi g ns. 
As t he desi g n of t his st u d y is n ot base d o n a s pecific statistical test, n o a dj ust me nts will be ma de 
t o t he fi nal a nal yses f or t his t y pe of c ha n ge, b ut t he c ha n ge itself will be n ote d i n t he fi nal 
cli nical st u d y re p ort ( C S R), a n d se nsiti vit y a nal yses will be perf or me d t o assess p ote ntial i m pact 
of t he c ha n ge. 
F or s o me of t hese s u m maries, CIs ma y be c o m p ute d.  A d diti o nal details of t he pres pecifie d 
statistical a nal yses will be pr o vi de d i n t he S A P. 


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G E MI NI T H E R A P E U TI C S, I N C.  P R O P RI E T A R Y A N D C O N FI D E N TI A L: 
D O N O T C O P Y O R DI S T RI B U T E WI T H O U T P E R M I S SI O N F R O M G E MI NI T H E R A P E U TI C S, I N C. 
8. 6. 1  H a n dli n g of Missi n g D at a 
I n ge neral, missi n g res ults will n ot be i m p ute d.  A d diti o nal i nf or mati o n, i ncl u di n g i nf or mati o n 
a b o ut missi n g data relate d t o C O VI D- 1 9, ca n be f o u n d i n t he S A P. 


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G E MI NI T H E R A P E U TI C S, I N C.  P R O P RI E T A R Y A N D C O N FI D E N TI A L: 
D O N O T C O P Y O R DI S T RI B U T E WI T H O U T P E R M I S SI O N F R O M G E MI NI T H E R A P E U TI C S, I N C. 
9  D A T A Q U A LI T Y A N D A S S U R A N C E, S U B J E C T D A T A H A N D LI N G, 
A N D R E C O R D K E E PI N G 
All as pects of t he st u d y will be m o nit ore d f or c o m plia nce wit h a p plica ble g o ver n me nt 
re g ulati o ns wit h res pect t o c urre nt I C H har m o nise d tri partite g ui deli ne E 6( R 2):  G C P a n d c urre nt 
sta n dar d o perati n g pr oce d ures.  A n electr o nic data ca pt ure s yste m t hat is vali date d a n d c o m plia nt 
wit h U S Title 2 1 of t he C F R Part 1 1 will be use d. 
I nf or mati o n a b o ut st u d y s u bjects will be ke pt c o nfi de ntial a n d ma na ge d acc or di n g t o t he 
re q uire me nts of a p plica ble l ocal re g ulati o ns.  F urt her details are descri be d i n Secti o n 1 1. 1 . 
9. 1  S o urce D oc u m e nts 
S o urce data is all i nf or mati o n, ori gi nal rec or ds of cli nical fi n di n gs, o bser vati o ns, or ot her 
acti vities i n a cli nical st u d y necessar y f or t he rec o nstr ucti o n a n d e val uati o n of t he st u d y.  S o urce 
data are c o ntai ne d i n s o urce d oc u me nts.  E xa m ples of t hese ori gi nal d oc u me nts a n d data rec or ds 
i ncl u de:  h os pital rec or ds, cli nical a n d office c harts, la b orat or y n otes, me m ora n da, s u bjects’ 
diaries or e val uati o n c hec klists, p har mac y dis pe nsi n g rec or ds, rec or de d data 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 verificati o n as bei n g acc urate 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 me dia, X-ra ys, s u bject 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 dic o-tec h nical de part me nts. 
T he i ma ges pl us a u xiliar y i nf or mati o n will be st ore d l ocall y b ut als o tra ns mitte d t o t he S p o ns or 
i n Di gital I ma gi n g a n d C o m m u nicati o ns i n Me dici ne f or mat f or p ote ntial f urt her i nter nal 
a nal yses a n d f or ge nerati o n of ill ustrati ve i ma ges. 
9. 2  C ase Re p ort F or ms ( C R Fs) 
Re q uire d data f or t his st u d y will be ca pt ure d o n C R Fs via electr o nic data ca pt ure (e C R Fs) u nless 
ot her wise s pecifie d i n t his d oc u me nt.  E xce pt f or data p oi nts f or w hic h t he pr ot oc ol i n dicates t hat 
t he e C R F ma y ser ve as s o urce d oc u me ntati o n, data are t o be o btai ne d fr o m t he s u bject’s s o urce 
d oc u me nts a n d t he n e ntere d i nt o t he e C R F b y a ut h orize d pers o n nel.  Cli nical data t hat are n ot 
rec or de d o n t he e C R F will be ca pt ure d a n d tra nsferre d t o t he S p o ns or or its desi g nee. 
9. 3  Rec or ds Rete nti o n 
It is t he I n vesti gat or’s res p o nsi bilit y t o retai n st u d y esse ntial d oc u me nts f or at least 2 years after 
t he last a p pr o val of a mar keti n g a p plicati o n f or G E M 1 0 3 i n t heir c o u ntr y a n d u ntil t here are n o 
pe n di n g or c o nte m plate d mar keti n g a p plicati o ns i n t heir c o u ntr y or at least 2 years ha ve ela pse d 
si nce t he f or mal disc o nti n uati o n of cli nical de vel o p me nt of G E M 1 0 3.  T hese d oc u me nts s h o ul d 
be retai ne d f or a l o n ger peri o d if re q uire d b y t he l ocal le gislati o n re q uire me nts or a n a gree me nt 
wit h t he S p o ns or.  I n s uc h a n i nsta nce, it is t he res p o nsi bilit y of t he S p o ns or t o i nf or m t he 
I n vesti gat or/i nstit uti o n as t o w he n t hese d oc u me nts n o l o n ger nee d t o be retai ne d. 


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D O N O T C O P Y O R DI S T RI B U T E WI T H O U T P E R M I S SI O N F R O M G E MI NI T H E R A P E U TI C S, I N C. 
1 0  S T U D Y M O NI T O RI N G, A U DI TI N G, A N D I N S P E C TI N G 
1 0. 1  St u d y M o nit ori n g Pl a n 
T his st u d y will be m o nit ore d acc or di n g t o t he st u d y m o nit ori n g pla n.  T he I n vesti gat or will 
all ocate a de q uate ti me f or s uc h m o nit ori n g acti vities.  T he I n vesti gat or will als o e ns ure t hat t he 
m o nit or or ot her c o m plia nce or q ualit y ass ura nce re vie wer is gi ve n access t o all t he a b o ve n ote d 
st u d y-relate d d oc u me nts a n d st u d y-relate d facilities (e. g., dia g n ostic la b orat or y), a n d has 
a de q uate s pace t o c o n d uct t he m o nit ori n g visit. 
T he cli nical m o nit or, as a re prese ntati ve of t he S p o ns or, is o bli gate d t o f oll o w t he st u d y cl osel y.  
I n d oi n g s o, t he m o nit or will visit t he I n vesti gat or a n d st u d y facilit y at peri o dic i nter vals, i n 
a d diti o n t o mai ntai ni n g necessar y tele p h o ne a n d letter c o ntact.  T he m o nit or will mai ntai n 
c urre nt pers o nal k n o wle d ge of t he st u d y t hr o u g h o bser vati o n, re vie w of st u d y rec or ds a n d s o urce 
d oc u me ntati o n, a n d disc ussi o n of t he c o n d uct of t he st u d y wit h t he I n vesti gat or a n d staff. 
All as pects of t he st u d y will be caref ull y m o nit ore d b y t he S p o ns or or its desi g nee f or 
c o m plia nce wit h a p plica ble g o ver n me nt re g ulati o n wit h res pect t o c urre nt I C H E 6( R 2) 
g ui deli nes a n d sta n dar d o perati n g pr oce d ures. 
1 0. 2  A u diti n g a n d I ns pecti n g 
T he I n vesti gat or will per mit st u d y-relate d m o nit ori n g, a u dits, a n d i ns pecti o ns b y t he I R B/I E C, 
t he S p o ns or ( or t heir desi g nee), g o ver n me nt re g ulat or y b o dies, a n d q ualit y ass ura nce gr o u ps of 
all st u d y-relate d d oc u me nts (e. g., s o urce d oc u me nts, re g ulat or y d oc u me nts, data c ollecti o n 
i nstr u me nts, st u d y data).  I n t he e ve nt of a n a u dit, t he I n vesti gat or a grees t o all o w t he S p o ns or, 
t heir re prese ntati ves, t he F D A, t he De part me nt of Defe nse or fe deral re prese ntati ves, or ot her 
re g ulat or y a ge ncies access t o all st u d y rec or ds.  T he I n vesti gat or will e n s ure t he ca pa bilit y f or 
i ns pecti o ns of a p plica ble st u d y-relate d facilities (e. g., dia g n ostic la b orat or y). 
T he I n vesti gat or s h o ul d pr o m ptl y n otif y t he S p o ns or of a n y a u dits sc he d ule d b y a n y re g ulat or y 
a ut h orities a n d pr o m ptl y f or war d c o pies of a n y a u dit re p orts recei ve d t o t he S p o ns or. 
1 0. 3  M a n a ge m e nt of Pr ot oc ol A m e n d m e nts a n d De vi ati o ns 
1 0. 3. 1  M o dific ati o n of t he Pr ot oc ol 
A n y c ha n ges i n t his researc h acti vit y, e xce pt t h ose necessar y t o re m o ve a n a p pare nt, i m me diate 
hazar d t o t he s u bject, m ust be re vie we d a n d a p pr o ve d b y t he S p o ns or or desi g nee.  A me n d me nts 
t o t he pr ot oc ol m ust be s u b mitte d i n writi n g t o t he I n vesti gat or’s I R B f or a p pr o val bef ore 
s u bjects are e nr olle d i nt o a n a me n de d pr ot oc ol. 
1 0. 3. 2  Pr ot oc ol De vi ati o ns 
T he I n vesti gat or or desi g nee m ust d oc u me nt a n d e x plai n i n t he s u bject’s s o urce d oc u me ntati o n 
a n y de viati o n fr o m t he a p pr o ve d pr ot oc ol.  T he I n vesti gat or ma y i m ple me nt a de viati o n fr o m, or 
a c ha n ge t o, t he pr ot oc ol t o eli mi nate a n i m me diate hazar d t o st u d y s u bjects wit h o ut pri or I R B 
a p pr o val.  As s o o n as p ossi ble after s uc h a n occ urre nce, t he i m ple me nte d de viati o n or c ha n ge, 
t he reas o ns f or it, a n d a n y pr o p ose d pr ot oc ol a me n d me nts s h o ul d be s u b mitte d t o t he I R B f or 
re vie w a n d a p pr o val, t o t he S p o ns or f or a gree me nt, a n d t o t he re g ulat or y a ut h orities, if re q uire d. 
A st u d y de viati o n is a si g nifica nt or a n o nsi g nifica nt de viati o n fr o m t he pr ot oc ol or t o I C H G C P 
E 6 R 2 or a n o nc o m plia nce wit h a p plica ble re g ulat or y re q uire me nts.  N o nsi g nifica nt pr ot oc ol 
de viati o ns d o n ot i m pact t he e n d p oi nts or t he safet y or me ntal i nte grit y of a s u bject or t he 


G E M- C L- 1 0 3 1 1 Pr ot oc ol, Versi o n 3. 0  
5 Ma y 2 0 2 1 
Pa ge 5 5 of 8 9 
G E MI NI T H E R A P E U TI C S, I N C.  P R O P RI E T A R Y A N D C O N FI D E N TI A L: 
D O N O T C O P Y O R DI S T RI B U T E WI T H O U T P E R M I S SI O N F R O M G E MI NI T H E R A P E U TI C S, I N C. 
scie ntific val ue of t he st u d y.  A pr ot oc ol vi olati o n or si g nifica nt de viati o n occ urs w he n t he 
s u bject or I n vesti gat or di d n ot a d here t o t he pr ot oc ol, a n d t he de viati o n affects pri mar y efficac y 
a n d safet y assess me nts, t he safet y or me ntal i nte grit y of a s u bject, or t he scie ntific val ue of t he 
st u d y. 
All de viati o ns, si g nifica nt a n d n o nsi g nifica nt, will be re vie we d a n d d oc u me nte d b y t he cli nical 
tea m t hr o u g h o ut t he c o urse of t he st u d y.  T he I n vesti gat or will be n otifie d i n writi n g b y t he 
m o nit or of all de viati o ns.  T he I R B s h o ul d be n otifie d of all pr ot oc ol de viati o ns, if a p pr o priate, 
i n a ti mel y ma n ner.  T he cli nical tea m will f oll o w all de viati o ns u ntil res ol ve d. 
1 0. 4  St u d y Ter mi n ati o n 
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 at a n y ti me f or cli nical or a d mi nistrati ve 
reas o ns. 
T he E O S is defi ne d as t he date o n w hic h t he last s u bject c o m pletes t he last visit (i ncl u des t he 
E O S visit a n d a n y a d diti o nal l o n g-ter m f oll o w- u p).  A n y a d diti o nal l o n g-ter m f oll o w- u p t hat is 
re q uire d t o m o nit or t he res ol uti o n of a fi n di n g or A E ma y be re p orte d t hr o u g h a n a me n d me nt t o 
t he C S R. 


G E M- C L- 1 0 3 1 1 Pr ot oc ol, Versi o n 3. 0  
5 Ma y 2 0 2 1 
Pa ge 5 6 of 8 9 
G E MI NI T H E R A P E U TI C S, I N C.  P R O P RI E T A R Y A N D C O N FI D E N TI A L: 
D O N O T C O P Y O R DI S T RI B U T E WI T H O U T P E R M I S SI O N F R O M G E MI NI T H E R A P E U TI C S, I N C. 
1 1  I N V E S TI G A T O R O B LI G A TI O N S 
T he f oll o wi n g a d mi nistrati ve ite ms are mea nt t o g ui de t he I n vesti gat or i n t he c o n d uct of t he 
st u d y a n d ma y be s u bject t o c ha n ge base d o n i n d ustr y a n d g o ver n me nt sta n dar d o perati n g 
pr oce d ures, w or ki n g practice d oc u me nts, or g ui deli nes.  C ha n ges will be re p orte d t o t he I R B b ut 
will n ot res ult i n pr ot oc ol a me n d me nts. 
1 1. 1  C o nfi de nti alit y 
I nf or mati o n a b o ut st u d y s u bjects will be ke pt c o nfi de ntial a n d ma na ge d acc or di n g t o t he 
re q uire me nts of a p plica ble l ocal re g ulati o ns. 
All la b orat or y s peci me ns, e val uati o n f or ms, re p orts, a n d ot her rec or ds will be i de ntifie d i n a 
ma n ner desi g ne d t o mai ntai n s u bject c o nfi de ntialit y.  All rec or ds will be ke pt i n a sec ure st ora ge 
area wit h li mite d access.  Cli nical i nf or mati o n will n ot be release d wit h o ut t he writte n 
per missi o n of t he s u bject (t hr o u g h t he I C F), e xce pt as necessar y f or m o nit ori n g, a u diti n g, a n d 
a nal yses b y t he S p o ns or, its desi g nee, rele va nt re g ulat or y a ut h orit y, or t he I R B. 
T he I n vesti gat or a n d all e m pl o yees a n d c o w or kers i n v ol ve d wit h t his st u d y ma y n ot discl ose or 
use f or a n y p ur p ose ot her t ha n perf or ma nce of t he st u d y a n d f ut ure researc h, a n y data, rec or d, or 
ot her u n p u blis he d, c o nfi de ntial i nf or mati o n discl ose d t o t h ose i n di vi d uals f or t he p ur p ose of t he 
st u d y.  Pri or writte n a gree me nt fr o m t he S p o ns or or its desi g nee m ust be o btai ne d f or t he 
discl os ure of a n y sai d c o nfi de ntial i nf or mati o n t o ot her parties. 
1 1. 2  I nstit uti o n al Re vie w 
Fe deral re g ulati o ns a n d t he I C H E 6( R 2) g ui deli nes re q uire t hat a p pr o val be o btai ne d fr o m a n 
I R B bef ore partici pati o n of h u ma n s u bjects i n researc h st u dies.  Bef ore st u d y o nset, t he pr ot oc ol, 
I C F, a d vertise me nts t o be use d f or t he recr uit me nt of st u d y s u bjects, a n d a n y ot her writte n 
i nf or mati o n re gar di n g t his st u d y t o be pr o vi de d t o t he s u bject m ust be a p pr o ve d b y t he I R B.  
D oc u me ntati o n of all I R B a p pr o vals a n d of t he I R B c o m plia nce wit h t he I C H E 6( R 2) g ui deli nes 
will be mai ntai ne d b y t he site a n d will be a vaila ble f or re vie w b y t he S p o ns or or its desi g nee. 
1 1. 3  S u bject C o nse nt 
T he I n vesti gat or is re q uire d t o o btai n i nf or me d c o nse nt acc or di n g t o Secti o n 5. 1. 1  of t his 
pr ot oc ol a n d a p pr o priate l ocal re q uire me nts a n d re g ulati o ns pri or t o e nr olli n g a s u bject i n t his 
st u d y. 
1 1. 4  Fi n a nci al Discl os ure a n d O bli g ati o ns 
T he I n vesti gat or is re q uire d t o pr o vi de fi na ncial discl os ure i nf or mati o n t o all o w t he S p o ns or t o 
s u b mit t he c o m plete a n d acc urate certificati o n or discl os ure state me nts re q uire d u n der 
2 1 C F R 5 4.  I n a d diti o n, t he I n vesti gat or m ust pr o vi de t o t he S p o ns or a c o m mit me nt t o pr o m ptl y 
u p date t his i nf or mati o n if a n y rele va nt c ha n ges occ ur d uri n g t he c o urse of t he i n vesti gati o n a n d 
f or 1 year after t he c o m pleti o n of t he st u d y. 
Neit her t he S p o ns or, its dele gates, n or t he st u d y site is fi na nciall y res p o nsi ble f or f urt her testi n g 
or treat me nt of a n y me dical c o n diti o n t hat ma y be detecte d d uri n g t he scree ni n g pr ocess.  I n 
a d diti o n, i n t he a bse nce of s pecific arra n ge me nts, neit her t he S p o ns or, its ve n d ors, n or t he st u d y 
site is fi na nciall y res p o nsi ble f or f urt her treat me nt of t he disease u n der st u d y. 


G E M- C L- 1 0 3 1 1 Pr ot oc ol, Versi o n 3. 0  
5 Ma y 2 0 2 1 
Pa ge 5 7 of 8 9 
G E MI NI T H E R A P E U TI C S, I N C.  P R O P RI E T A R Y A N D C O N FI D E N TI A L: 
D O N O T C O P Y O R DI S T RI B U T E WI T H O U T P E R M I S SI O N F R O M G E MI NI T H E R A P E U TI C S, I N C. 
1 1. 5  St u d y C o n d uct a n d A d here nce t o Pr ot oc ol 
T he I n vesti gat or a grees t hat t he st u d y will be c o n d ucte d acc or di n g t o t he pri nci ples of 
I C H E 6( R 2).  T he I n vesti gat or will c o n d uct all as pects of t his st u d y i n acc or da nce wit h all 
nati o nal, state, a n d l ocal la ws or re g ulati o ns.  T he st u d y will be c o n d ucte d i n c o m plia nce wit h 
t he pr ot oc ol, c urre nt G C P g ui deli nes – a d o pti n g t he pri nci ples of t he Declarati o n of Helsi n ki – 
a n d all a p plica ble re g ulat or y re q uire me nts. 
1 1. 6  D at a C ollecti o n 
As part of t he res p o nsi bilities ass u me d b y partici pati n g i n t he st u d y, t he I n vesti gat or a grees t o 
mai ntai n a de q uate case hist ories f or s u bjects treate d as part of t he researc h u n der t his pr ot oc ol.  
T he I n vesti gat or a grees t o mai ntai n acc urate e C R Fs a n d s o urce d oc u me ntati o n as part of t he case 
hist ories.  T hese s o urce d oc u me nts ma y i ncl u de la b orat or y re p orts a n d si milar s o urces. 
Electr o nic C R Fs are accesse d t hr o u g h a n electr o nic data ca pt ure s yste m t hat is vali date d a n d 
c o m plia nt wit h 2 1 C F R 1 1. 
1 1. 7  Re p orti n g A d verse E ve nts 
B y partici pati n g i n t his st u d y, t he I n vesti gat or a grees t o s u b mit re p orts of S A Es acc or di n g t o t he 
ti meli ne a n d met h o ds o utli ne d i n t his pr ot oc ol (f or details refer t o Secti o n 7 ).  I n a d diti o n, t he 
I n vesti gat or a grees t o s u b mit a n n ual re p orts t o his I R B as a p pr o priate.  T he I n vesti gat or als o 
a grees t o pr o vi de t he S p o ns or wit h a n a de q uate re p ort, if a p plica ble, s h ortl y after c o m pleti o n of 
t he I n vesti gat or’s partici pati o n i n t he st u d y. 
1 1. 8  Rec or ds Rete nti o n 
Esse ntial d oc u me nts s h o ul d be retai ne d u ntil at least 2 years after t he last a p pr o val of a 
mar keti n g a p plicati o n i n a n I C H re gi o n a n d u ntil t here are n o pe n di n g or c o nte m plate d mar keti n g 
a p plicati o ns i n a n I C H re gi o n or at least 2 years ha ve ela pse d si nce t he f or mal disc o nti n uati o n of 
cli nical de vel o p me nt of t he st u d y dr u g.  T hese d oc u me nts s h o ul d be retai ne d f or a l o n ger peri o d, 
h o we ver, if re q uire d b y t he a p plica ble re g ulat or y re q uire me nts or b y a n a gree me nt wit h t he 
S p o ns or.  It is t he S p o ns or’s res p o nsi bilit y t o i nf or m t he I n vesti gat or/i nstit uti o n as t o w he n t hese 
d oc u me nts n o l o n ger nee d t o be retai ne d. 
1 1. 9  P u blic ati o ns 
After c o m pleti o n of t he st u d y, t he data ma y be c o nsi dere d f or re p orti n g at a scie ntific meeti n g or 
f or p u blicati o n i n a scie ntific j o ur nal.  I n t hese cases, t he S p o ns or will be res p o nsi ble f or t hese 
acti vities a n d will w or k wit h t he I n vesti gat ors t o deter mi ne h o w t he ma n uscri pt is writte n a n d 
e dite d, t he n u m ber a n d or der of a ut h ors, t he p u blicati o n t o w hic h it will be s u b mitte d, a n d ot her 
relate d iss ues.  T he S p o ns or has fi nal a p pr o val a ut h orit y o ver decisi o ns relate d t o data 
p u blicati o n. 
Data are t he pr o pert y of t he S p o ns or a n d ca n n ot be p u blis he d wit h o ut t heir pri or a ut h orizati o n. 


G E M- C L- 1 0 3 1 1 Pr ot oc ol, Versi o n 3. 0  
5 Ma y 2 0 2 1 
Pa ge 5 8 of 8 9 
G E MI NI T H E R A P E U TI C S, I N C.  P R O P RI E T A R Y A N D C O N FI D E N TI A L: 
D O N O T C O P Y O R DI S T RI B U T E WI T H O U T P E R M I S SI O N F R O M G E MI NI T H E R A P E U TI C S, I N C. 
1 2  E T HI C A L C O N SI D E R A TI O N S 
T his st u d y is t o be c o n d ucte d i n acc or da nce wit h i nter nati o nal sta n dar ds of G C P (I C H, E U 
Directi ves 2 0 0 1/ 2 0/ E C a n d 2 0 0 5/ 2 8/ E C, a n d U S 2 1 C F R 5 0 a n d 2 1 C F R 3 1 2), as well as all ot her 
a p plica ble g o ver n me nt re g ulati o ns a n d i nstit uti o nal researc h p olicies a n d pr oce d ures. 
T his pr ot oc ol a n d a n y a me n d me nts will be s u b mitte d t o a pr o perl y c o nstit ute d I R B/I E C, i n 
a gree me nt wit h l ocal le gal re q uire me nts, f or f or mal a p pr o val of t he st u d y c o n d uct.  T he decisi o n 
of t he I R B/I E C c o ncer ni n g t he c o n d uct of t he st u d y will be ma de i n writi n g t o t he a p plica nt a n d 
a c o p y of t his decisi o n will be pr o vi de d t o t he S p o ns or bef ore c o m me nce me nt of t his st u d y.  T he 
I R B/I E C will be re q ueste d t o pr o vi de a list of I R B/I E C me m bers.  A me m ber w h o is affiliate d 
wit h t he S p o ns or s h o ul d n ot partici pate i n v oti n g o n t he I R B/I E C o pi ni o n. 
Eac h s u bject will be gi ve n a n I C F descri bi n g t his st u d y a n d pr o vi di n g s ufficie nt i nf or mati o n t o 
all o w t he s u bject t o ma ke a n i nf or me d decisi o n a b o ut t he s u bject’s partici pati o n i n t his st u d y.  
T his I C F will be s u b mitte d wit h t he pr ot oc ol f or re vie w a n d a p pr o val b y t he I R B/I E C f or t he 
st u d y.  T he f or mal c o nse nt of a s u bject, usi n g t he I R B/I E C-a p pr o ve d I C F, m ust be o btai ne d 
bef ore t hat s u bject u n der g oes a n y st u d y pr oce d ure.  T he I C F m ust be si g ne d b y t he s u bject, a n d 
t he I n vesti gat or- desi g nate d researc h pr ofessi o nal o btai ni n g t he c o nse nt. 
A n y c ha n ges i n t he st u d y pr ot oc ol, s uc h as c ha n ges i n t he st u d y desi g n, o bjecti ves or e n d p oi nts, 
i ncl usi o n a n d e xcl usi o n criteria, a n d/ or pr oce d ures (e xce pt t o eli mi nate a n i m me diate hazar d) 
will be i m ple me nte d o nl y after t he m ut ual a gree me nt of t he I n vesti gat or a n d t he S p o ns or or 
desi g nee.  All pr ot oc ol c ha n ges m ust be d oc u me nte d i n pr ot oc ol a me n d me nt(s).  Pr ot oc ol 
a me n d me nt(s) m ust be si g ne d b y t he I n vesti gat or a n d a p pr o ve d (if a p plica ble) b y t he I R B/I E C 
pri or t o i m ple me ntati o n.  A n y c ha n ges i n st u d y c o n d uct t hat res ult fr o m a pe n di n g a me n d me nt 
will be c o nsi dere d pr ot oc ol de viati o ns u ntil I R B/I E C a p pr o val is gra nte d.  D oc u me ntati o n of 
I R B/I E C a p pr o val m ust be ret ur ne d t o t he S p o ns or or desi g nee.  U p o n c o m pleti o n of t he st u d y, 
t he I n vesti gat or, w here a p plica ble, s h o ul d i nf or m t he i nstit uti o n; t he I n vesti gat or/i nstit uti o n 
s h o ul d pr o vi de t he I R B wit h a s u m mar y of t he st u d y’s o utc o me, a n d t he S p o ns or a n d re g ulat or y 
a ut h orit y(ies) wit h a n y re p orts re q uire d. 


G E M- C L- 1 0 3 1 1 Pr ot oc ol, Versi o n 3. 0  
5 Ma y 2 0 2 1 
Pa ge 5 9 of 8 9 
G E MI NI T H E R A P E U TI C S, I N C.  P R O P RI E T A R Y A N D C O N FI D E N TI A L: 
D O N O T C O P Y O R DI S T RI B U T E WI T H O U T P E R M I S SI O N F R O M G E MI NI T H E R A P E U TI C S, I N C. 
1 3  C LI NI C A L S T U D Y R E P O R T A N D D A T A DI S C L O S U R E 
A C S R will be pr o d uce d u p o n c o m pleti o n of t he st u d y.  A c o or di nati n g I n vesti gat or will be 
desi g nate d t o re vie w a n d si g n t he c o m plete d C S R. 
I nf or mati o n a b o ut t his st u d y will be p oste d o n t he htt p://cli nicaltrials. g o v a n d 
htt ps:// w w w.cli nicaltrialsre gister.e u we bsites (if a p plica ble) a n d, w here a p plica ble, o n ot her 
we bsites re q uire d b y t he l ocal re g ulat or y a ut h orities of partici pati n g c o u ntries. 
It is i nte n de d t hat t he res ults fr o m t his researc h will be s u b mitte d t o a peer-re vie we d me dical 
p u blicati o n, o nce t he st u d y is c o m plete d. 
1 3. 1  Fi n al Re p ort 
W het her t he st u d y is c o m plete d or pre mat urel y ter mi nate d, t he S p o ns or will e ns ure t hat a C S R is 
pre pare d a n d pr o vi de d t o t he re g ulat or y a ge nc y(ies) as re q uire d b y t he a p plica ble re g ulat or y 
re q uire me nt(s).  T he S p o ns or will als o e ns ure t hat C S Rs i n mar keti n g a p plicati o ns meet t he 
sta n dar ds of t he I C H har m o nise d tri partite g ui deli ne E 3:  Str uct ure a n d c o nte nt of C S Rs. 
W here re q uire d b y a p plica ble re g ulat or y re q uire me nts, a n I n vesti gat or si g nat or y will be 
i de ntifie d f or t he a p pr o val of t he C S R.  T he I n vesti gat or will be pr o vi de d reas o na ble access t o 
statistical ta bles, fi g ures, a n d rele va nt re p orts, a n d ha ve t he o p p ort u nit y t o re vie w c o m plete st u d y 
res ults. 
A C S R will c o ntai n all data c ollecte d t hr o u g h t o t he E O S. 
U p o n c o m pleti o n of t he C S R(s), t he S p o ns or will pr o vi de t he I n vesti gat or(s) wit h t he fi nal 
a p pr o ve d C S R(s). 


G E M- C L- 1 0 3 1 1 Pr ot oc ol, Versi o n 3. 0  
5 Ma y 2 0 2 1 
Pa ge 6 0 of 8 9 
G E MI NI T H E R A P E U TI C S, I N C.  P R O P RI E T A R Y A N D C O N FI D E N TI A L: 
D O N O T C O P Y O R DI S T RI B U T E WI T H O U T P E R M I S SI O N F R O M G E MI NI T H E R A P E U TI C S, I N C. 
1 4  R E F E R E N C E S 
Alta y L, Sit nils ka 1 V, Sc hic k T, et al.  Earl y l ocal acti vati o n of c o m ple me nt i n a q ue o us h u m o ur 
of patie nts wit h a ge-relate d mac ular de ge nerati o n.  E ye ( L o n d).  2 0 1 9; 3 3( 1 2): 1 8 5 9- 1 8 6 4. 
A ver y R L, Ba kri SJ, Bl u me n kra nz M S, et al. I ntra vitreal i njecti o n tec h ni q ue a n d m o nit ori n g: 
u p date d g ui deli nes of a n e x pert pa nel.  Reti na.  2 0 1 4; 3 4 S u p ple me nt 1 2: S 1- S 1 8. 
Ba kri SJ, T h or ne J E, H o A C, et al.  Safet y a n d Efficac y of A nti- Vasc ular E n d ot helial Gr o wt h 
Fact or T hera pies f or Ne o vasc ular A ge- Relate d Mac ular De ge nerati o n: A Re p ort b y t he 
A merica n Aca de m y of O p ht hal m ol o g y.  O p ht hal m ol o g y.  2 0 1 9; 1 2 6( 1): 5 5- 6 3. 
Ba u mal C R, S pai de R F, Vajz o vic L, et al.  Reti nal Vasc ulitis a n d I ntra oc ular I nfla m mati o n after 
I ntra vitreal I njecti o n of Br ol uciz u ma b.  2 0 2 0; 1 2 7( 1 0): 1 3 4 5- 1 3 5 9. 
B L A 1 2 5 1 5 6 A vaila ble fr o m: 
htt ps:// w w w.access data.f da. g o v/ dr u gsatf da _ d ocs/ n da/ 2 0 0 6/ 1 2 5 1 5 6s 0 0 0 0 _ L uce ntis _ P har m R. p df.  
Accesse d Oct o ber 2 0 1 9. 
B L A 1 2 5 3 8 7 A vaila ble fr o m: 
htt ps:// w w w.access data.f da. g o v/ dr u gsatf da _ d ocs/ n da/ 2 0 1 1/ 1 2 5 3 8 7 Ori g 1s 0 0 0 P har m R. p df.  
Accesse d Oct o ber 2 0 1 9. 
B orras C, Dela u na y K, Sla o ui Y, et al.  Mec ha nis ms of F H Pr otecti o n A gai nst Ne o vasc ular 
A M D.  Fr o ntiers i n I m m u n ol o g y.  2 0 2 0; 1 1: 4 4 3 
Br o dsz ki N, Frazer- A bel A, Gr u mac h A S, et al .  E ur o pea n S ociet y f or I m m u n o deficie ncies 
( E SI D) a n d E ur o pea n Refere nce Net w or k o n Rare Pri mar y I m m u n o deficie nc y, 
A ut oi nfla m mat or y a n d A ut oi m m u ne Diseases ( E R N RI T A) c o m ple me nt g ui deli ne: deficie ncies, 
dia g n osis, a n d ma na ge me nt.  J Cli n I m m u n ol.  2 0 2 0; 4 0( 4): 5 7 6- 5 9 1. 
Cali p pe B, A u g usti n S, Be g uier F, et al.  C o m ple me nt Fact or H I n hi bits C D 4 7- Me diate d 
Res ol uti o n of I nfla m mati o n.  I m m u nit y.  2 0 1 7; 4 6( 2): 2 6 1- 2 7 2. 
C ha vali V R, Di niz B, H ua n g J, Yi n g G S, Sa d da S R, Sta m b olia n D.  Ass ociati o n of O C T deri ve d 
dr use n meas ure me nts wit h A M D ass ociate d- ge n ot y pic S N Ps i n A mis h p o p ulati o n.  J Cli n Me d.  
 
C he n H, Y u K D, X u G Z.  Ass ociati o n bet wee n Varia nt Y 4 0 2 H i n A ge- Relate d Mac ular 
De ge nerati o n ( A M D) S usce pti bilit y Ge ne C F H a n d Treat me nt Res p o nse of A M D: A Meta-
A nal ysis.  Pl o S O N E 2 0 1 2; 7( 8): e 4 2 4 6 4.  d oi: 1 0. 1 3 7 1/j o ur nal. p o ne. 0 0 4 2 4 6 4 
Di n g J D, Kell y U, La n d o ws ki M, et al.  E x pressi o n of h u ma n c o m ple me nt fact or H pre ve nts a ge-
relate d mac ular de ge nerati o n-li ke reti na da ma ge a n d ki d ne y a b n or malities i n a ge d Cf h k n oc k o ut 
mice.  A m J Pat h ol.  2 0 1 5; 1 8 5( 1): 2 9- 4 2. 
E ur o pea n U ni o n ( E U) Directi ves 2 0 0 1/ 2 0/ E C. 
E ur o pea n U ni o n ( E U) Directi ves 2 0 0 5/ 2 8/ E C. 
Ga u drea ult J, Fei D, R usit J, S u b oc P, S hi u V. Precli nical p har mac o ki netics of Ra ni biz u ma b 
(r h u Fa b V 2) after a si n gle i ntra vitreal a d mi nistrati o n.  I n vest O p ht hal m ol Vis Sci.  
2 0 0 5 ; 4 6( 2) : 7 2 6 3 3. 
Geerli n gs MJ, de J o n g E K, de n H olla n der AI.  T he c o m ple me nt s yste m i n a ge-relate d mac ular 
de ge nerati o n : A re vie w of rare ge netic varia nts a n d i m plicati o ns f or pers o nalize d treat me nt.  
M olec I m m u n ol.  2 0 1 7 ; 8 4 : 6 5- 7 6. 


G E M- C L- 1 0 3 1 1 Pr ot oc ol, Versi o n 3. 0  
5 Ma y 2 0 2 1 
Pa ge 6 1 of 8 9 
G E MI NI T H E R A P E U TI C S, I N C.  P R O P RI E T A R Y A N D C O N FI D E N TI A L: 
D O N O T C O P Y O R DI S T RI B U T E WI T H O U T P E R M I S SI O N F R O M G E MI NI T H E R A P E U TI C S, I N C. 
Gillies M, H u n y or A, Ar n ol d J, et al.  Mac ular Atr o p h y i n Ne o vasc ular A ge- Relate d Mac ular 
De ge nerati o n : A Ra n d o mize d Cli nical Trial C o m pari n g Ra ni biz u ma b a n d Afli berce pt ( RI V A L 
St u d y).  O p ht hal m ol o g y 2 0 2 0; 1 2 7( 2): 1 9 8- 2 1 0. 
H ole ka m p N. Re vie w of Ne o vasc ular A ge- Relate d Mac ular De ge nerati o n Treat me nt O pti o ns.  
A m J Ma na g Care.  2 0 1 9 ; 2 5( 1 0 S u p pl) : S 1 7 2- S 1 8 1. 
I V E RI C bi o’s Zi m ura ®, a N o vel C o m ple me nt C 5 I n hi bit or, Met its Pri mar y E n d p oi nt a n d 
Reac he d Statistical Si g nifica nce i n a P hase 2 b Ra n d o mize d, C o ntr olle d Cli nical Trial i n 
Ge o gra p hic Atr o p h y Sec o n dar y t o Dr y A ge- Relate d Mac ular De ge nerati o n [ Press release].  Ne w 
Y or k, N Y: I V E RI C bi o; Oct o ber 2 8, 2 0 1 9.  htt ps://i n vest ors.i veric bi o.c o m/ ne ws-releases/ ne ws-
release- details/i veric- bi os-zi m urar- n o vel-c o m ple me nt-c 5-i n hi bit or- met-its.  Accesse d Ma y 1 3, 
2 0 2 0. 
Jaffe GJ, Eli ott D, Wells J A, Pre n ner J L, Pa p p A, Patel S.  A P hase 1 St u d y of I ntra vitre o us 
E 1 0 0 3 0 i n C o m bi nati o n wit h Ra ni biz u ma b i n Ne o vasc ular A ge- Relate d Mac ular De ge nerati o n. 
O p ht hal m ol o g y.  2 0 1 6; 1 2 3( 1): 7 8- 8 5. 
Jaffe GJ, West b y K, Csa k y K G, et al.  C 5 I n hi bit or a vaci nca pta d pe g ol f or ge o gra p hic atr o p h y 
d ue t o a ge-relate d mac ular de ge nerati o n: A ra n d o mize d pi v otal P hase 2/ 3 Trial.  O p ht hal m ol o g y.  
Pre pri nt 2 0 2 0.  d oi: htt ps:// d oi. or g/ 1 0. 1 0 1 6/j. o p ht ha. 2 0 2 0. 0 8. 0 2 7 
Keir L S, Firt h R, A p o ni k L, et al.  V E G F re g ulates l ocal i n hi bit or y c o m ple me nt pr otei ns i n t he 
e ye a n d ki d ne y.  J Cli n I n vest.  2 0 1 7; 1 2 7( 1): 1 9 9- 2 1 4. 
K ha na ni A M, S kell y A, Bezl ya k V, Gri ner R, T orres L R, Sa g kri otis A.  SI E R R A- A M D: A 
Retr os pecti ve, Real- W orl d E vi de nce St u d y of Patie nts wit h Ne o vasc ular A ge- Relate d Mac ular 
De ge nerati o n i n t he U nite d States.  O p ht hal m ol Reti na.  2 0 2 0; 4( 2): 1 2 2- 1 3 3. 
Kr o h ne T U, Li u Z, H olz F G, Me yer C H.  I ntra oc ular p har mac o ki netics of ra ni biz u ma b f oll o wi n g 
a si n gle i ntra vitreal i njecti o n i n h u ma ns.  A m J O p ht hal m ol.  2 0 1 2; 1 5 4: 6 8 2- 6 8 6. 
La n d o ws ki M, Kell y U, Ki n ge b or n M, et al.  H u ma n c o m ple me nt fact or H 4 0 2 H p ol y m or p his m 
ca uses a n a ge-relate d mac ular de ge nerati o n p he n ot y pe a n d li p o pr otei n d ysre g ulati o n i n mice. 
P N A S.  2 0 1 9; 1 1 6( 9): 3 7 0 3- 3 7 1 1. 
Lia o D S, Gr ossi F V, El Me h di D, et al.  C o m ple me nt C 3 I n hi bit or Pe gcetac o pla n f or Ge o gra p hic 
Atr o p h y Sec o n dar y t o A ge- Relate d Mac ular De ge nerati o n: A Ra n d o mize d P hase 2 Trial.  
O p ht hal m ol.  2 0 2 0; 1 2 7( 2): 1 8 6- 1 9 5. 
Matta pallil MJ a n d Cas pi R R.  C o m pli me nts of Fact or H: W hat’s i n it f or A M D? I m m u nit y. 
2 0 1 7: 4 6( 2): 1 6 7- 1 6 9. 
Merle M B, R os ner B, Se d d o n J M.  Ge netic s usce pti bilit y, diet q ualit y, a n d t w o-ste p pr o gressi o n 
i n dr use n size.  I n vesti gati ve O p ht hal m ol o g y & Vis ual Scie nce.  2 0 2 0; 6 1( 5), Article 1 7: 1- 1 2. 
Sa d da S R, T u o mi L L, Di n g B, F u n g A E, H o p ki ns JJ.  Mac ular Atr o p h y i n t he H A R B O R St u d y 
f or Ne o vasc ular A ge- Relate d Mac ular De ge nerati o n.  O p ht hal m ol o g y.  2 0 1 8; 1 2 5( 6): 8 7 8- 8 8 6. 
Sa h ni J, D u gel P U, Patel S S, et al.  Safet y a n d Efficac y of Differe nt D oses a n d Re gi me ns of 
Farici ma b vs Ra ni biz u ma b i n Ne o vasc ular A ge- Relate d Mac ular De ge nerati o n: T he A V E N U E 
P hase 2 Ra n d o mize d Cli nical Trial.  J A M A O p ht hal m ol.  2 0 2 0; 1 3 8( 9): 1- 1 0. 
Sc hic k T, Stei n ha uer M, Asla ni dis A et al.  L ocal c o m ple me nt acti vati o n i n a q ue o us h u m or i n 
patie nts wit h a ge-relate d mac ular de ge nerati o n.  E ye ( L o n d).  2 0 1 7; 3 1( 5): 8 1 0- 8 1 3. 


G E M- C L- 1 0 3 1 1 Pr ot oc ol, Versi o n 3. 0  
5 Ma y 2 0 2 1 
Pa ge 6 2 of 8 9 
G E MI NI T H E R A P E U TI C S, I N C.  P R O P RI E T A R Y A N D C O N FI D E N TI A L: 
D O N O T C O P Y O R DI S T RI B U T E WI T H O U T P E R M I S SI O N F R O M G E MI NI T H E R A P E U TI C S, I N C. 
S h ort B G.  Safet y E val uati o n of Oc ular Dr u g Deli ver y F or m ulati o ns: Tec h ni q ues a n d Practical 
C o nsi derati o ns.  T o xic ol Pat h ol.  2 0 0 8; 3 6: 4 9- 6 2. 
Ste ve ns S, Gil bert C, Ast b ur y N.  H o w t o meas ure i ntra oc ular press ure: a p pla nati o n t o n o metr y.  
C o m m u nit y E ye Healt h.  2 0 0 8; 2 0( 6 4): 7 4 – 7 5.  C orrecti o n i n: C o m m u nit y E ye Healt h.  2 1( 6 6): 3 4. 
T he U nite d States ( U S) C o de of Fe deral Re g ulati o ns ( C F R), Title 2 1, Parts 5 0 a n d 3 1 2 ( 2 1 C F R 
5 0, 2 1 C F R 3 1 2). 
Trie b wasser M P, R o bers o n E D, Y u Y, et al.  Rare Varia nts i n t he F u ncti o nal D o mai ns of 
C o m ple me nt Fact or H Are Ass ociate d wit h A ge- Relate d Mac ular De ge nerati o n.  I n vest 
O p ht hal m ol Vis Sci.  2 0 1 5; 5 6( 1 1): 6 8 7 3- 7 8. 
W orl d Healt h Or ga nizati o n.  Pri orit y e ye diseases.  Accesse d 0 3 Oct o ber 2 0 1 9.  
htt ps:// w w w. w h o.i nt/ bli n d ness/ca uses/ pri orit y/e n/i n de x 7. ht ml 
X u W W, H ua n g Y F, Wa n g L Q, Z ha n g M N.  C ycl o pe x y vers us vitrect o m y c o m bi ne d wit h 
i ntra oc ular ta m p o na de f or treat me nt of c ycl o dial ysis. I nt J O p ht hal m ol.  2 0 1 3; 6( 2): 1 8 7- 9 2. 
Y u C, R o u bei x C, Se n nla u b F, Sa ba n D R. Micr o glia vers us M o n oc ytes: Disti nct R oles i n 
De ge nerati ve Diseases of t he Reti na.  Tre n ds i n Ne ur oscie nces.  2 0 2 0; 4 3( 6): 4 3 3- 4 4 9. 
 


G E M- C L- 1 0 3 1 1 Pr ot oc ol, Versi o n 3. 0  
5 Ma y 2 0 2 1 
Pa ge 6 3 of 8 9 
G E MI NI T H E R A P E U TI C S, I N C.  P R O P RI E T A R Y A N D C O N FI D E N TI A L: 
D O N O T C O P Y O R DI S T RI B U T E WI T H O U T P E R M I S SI O N F R O M G E MI NI T H E R A P E U TI C S, I N C. 
1 5  A P P E N DI C E S 
 




G E M- C L- 1 0 3 1 1 Pr ot oc ol, Versi o n 3. 0  
5 Ma y 2 0 2 1 
Pa ge 6 5 of 8 9 
G E MI NI T H E R A P E U TI C S, I N C.  P R O P RI E T A R Y A N D C O N FI D E N TI A L: 
D O N O T C O P Y O R DI S T RI B U T E WI T H O U T P E R M I S SI O N F R O M G E MI NI T H E R A P E U TI C S, I N C. 
A b br e viati o ns:  A D A =a nti dr u g a nti b o dies; A E =a d verse e ve nt; B C V A = best c orr ecte d vis ual ac u it y; C F H =c o m ple me nt f act or H; E C =e xcl usi o n criteria; 
E C G =electr ocar di o gr a m; E O S = E n d of St u d y; E T D R S = E arl y Tr eat me nt Dia betic Reti n o pat h y St u d y; hr = h o ur; I C =i ncl usi o n criteria; I O P = i ntr a oc ular pr ess ure; 
L L V A =l o w l u mi na nce vis ual ac uit y; M N Re a d = Mi n nes ota L o w- visi o n Rea di n g T est; N EI V F Q- 2 5 = Nati o nal E ye I nstit ute Vis ual F u ncti o ni n g Q uesti o n nair e- 2 5; 
O C T = o ptical c o her e nce t o m o gr a p h y; O C T- A = O C T a n gi o gr a p h y; O U = oc ul us uter q ue ( b ot h e yes; e y es will be teste d se par atel y); S A E =ser i o us a d verse e ve nt; 
S D- O C T =s pe ctr al d o mai n O C T; S E =st u d y e ye; S o C =sta n dar d of car e ( 2 m g afli ber ce pt e ver y ot her m o nt h); V A = vis ual ac uit y  
* Assess me nt o btai ne d pri or t o d osi n g, as a p plica ble.  
* * I ma gi n g ( c ol or f u n d us p h ot o gr a p h y, f u n d us a ut ofl u or esce nce, fl u or escei n a n gi o gr a p h y, near i nfr are d r eflecta nce i ma gi n g, S D- O C T) s h o ul d be r e peate d at 
baseli ne if > 2 8 da ys after scr ee ni n g asse ss me nt, or desir e d b y t he I n vesti gat or. 
† Ra n d o mizati o n ma y occ ur u p t o 2 da ys pri or t o t he baseli ne visit. 
a  
Bl o o d sa m pli n g f or e x pl or at or y ge netics will occ ur pri or t o first d osi n g. 
b  
I nf or me d c o nse nt m ust be o btai ne d bef or e a n y st u d y assess me nt is perf or me d. 
c  
Me dical a n d oc ular hist or y als o i ncl u des s ocial hist or y a n d f a mil y o p ht hal mic hist or y ( Secti o n 5. 1. 3 ). 
d  
S o me e ntr y criteria a p pl y o nl y t o t he S E.  T her ef ore, t he S E m ust be i de ntifie d d uri n g t he scree ni n g pr ocess i n or der t o assess e ntr y criteria (Secti o n 5. 4 ). 
e  
Vital si g n meas ur e me nts i ncl u de s yst olic a n d diast olic bl o o d press ur es, heart r ate, r es pir at or y r ate, a n d b o d y te m per at ur e.  T he s u bject will be seate d f or at 
least 5 mi n utes bef or e all meas ur e me nts ar e ta ke n.  W he n pr oce d ur es o verla p a n d ar e sc he d ule d t o occ ur at t he sa me ti me p oi nt, vital si g n meas ure me nts 
s h o ul d pr ece de a n y bl o o d c ollecti o n (Secti o n 5. 1. 7 ). 
f  
N o I P/ S ha m tr eat me nt will be gi ve n at t he 4 8- wee k E O S visit; h o we ver, afli ber ce pt S o C s h o ul d be a d mi nister e d as cli nicall y i n d icate d.  It is acce pta ble f or a 
diff er e nt a nti- V E G F t her a p y t o be a d mi nister e d at t h is visit per t he i n vesti gator’s cli nical j u d ge me nt.    
g  
A Es will be r e p orte d f or a mi ni m u m of 3 0 da ys after t he last a dmi nistr ati o n of st u d y tr eat me nt.  If a s u bject e x perie nces a n S A E t hat is c o nsi der e d t o be 
r elate d t o st u d y tr eat me nt at a n y ti me after t he stu d y, it m ust be r e p orte d t o t he S p o ns or.  See Secti o n 7. 3  f or f ull A E re p orti n g pr oce d ur es. 
h  
C o m plete o p ht hal mic e xa mi nati o ns of b ot h t he st u d y a n d f ell o w e ye will i ncl u de  a n assess me nt of t he V A a n d vis ual f u ncti o n usin g vali date d assess me nt 
t o ols, a c o m plete o p ht hal mic bi o micr osc o p y e xa mi nati o n i ncl u di n g f u n d us e xa mi nati o n, I OP, a n d oc ular i ma gi n g tests t o vis ualize  t he a p pear a nce a n d 
pat h ol o g y of t he r eti na a n d ass ociate d oc ular tiss ues ( Secti o n 5. 1. 6 ). 
i 
O n d osi n g da ys, I O P assess me nts ar e o btai ne d pri or t o t he d ose O U, a n d 3 0 ± 1 5 mi n utes after t he d ose o nl y i n t he S E ( O U o pti o nal ).  A n a d diti o nal 
assess me nt fr o m t he S E s h o ul d be ta ke n at 6 0 ±
 m m H g at t he 3 0- mi n ute assess me nt.  If t he I O P c o nti n ues t o 
e xcee d 3 0 m m H g, t he n sta n dar d I O P-
 
tr eate d per i nstit uti o nal g ui deli nes.  Re gar dless of w het her a p pla nati o n t o n o metr y or a T o n o- Pe n®  is use d t o meas ur e I O P, t he sa me met h o d s h o ul d be use d 
f or t he s u bject f or t he e ntiret y of t heir partici pati o n i n t his st u d y. 
j  
E T D R S B C V A a n d B C V A L L V A will be perf or me d b y mas ke d assess ors.  
k  
T hese baseli ne i ma gi n g assess me nts ar e o nl y r e q uir e d if t he scr ee nin g i ma ges wer e o btai ne d > 2 8 da ys pri or t o baseli ne.  T he y m a y be r e d o ne at baseli ne if 
t he I n vesti gat or dee ms it cli nicall y rele va nt, or if t her e were q ualit y iss ues wit h t he scree ni n g i ma ges. 
l  
Baseli ne assess me nt of fl u or escei n a n gi o gr a p h y is n ot r e q uir e d, b ut ma y be assesse d if t he I n vesti gat or dee ms it cli nicall y r ele va nt, or if t her e were q ualit y 
iss ues wit h t he scree ni n g i ma ges. 
m 
Assess me nt is o pti o nal a n d w ill o nl y be c o n d ucte d if t he site has a p pr o val fr o m t he S p o ns or. 
n 
Assess me nt will be perf or me d as descri be d i n A p pe n di x I . 
o  
Assess me nt will be perf or me d as descri be d i n A p pe n di x J . 
p 
Hi g hl y se nsiti ve (ser u m or uri ne) h u ma n c h ori o nic g o na d otr o pi n pr e g na nc y test as nee de d f or w o me n of c hil d beari n g p ote ntial. 


G E M- C L- 1 0 3 1 1 Pr ot oc ol, Versi o n 3. 0  
5 Ma y 2 0 2 1 
Pa ge 6 6 of 8 9 
G E MI NI T H E R A P E U TI C S, I N C.  P R O P RI E T A R Y A N D C O N FI D E N TI A L: 
D O N O T C O P Y O R DI S T RI B U T E WI T H O U T P E R M I S SI O N F R O M G E MI NI T H E R A P E U TI C S, I N C. 
q  
Cli nical saf et y la b or at or y assess me nts i ncl u de t he f oll o wi n g: he mat ol o g y ( platelet c o u nt, r e d bl o o d cell c o u nt, he m o gl o bi n c o u nt, he mat ocrit, mea n 
c or p usc ular v ol u me, mea n c or p usc ular he m o gl o bi n, per ce nt r etic ul oc ytes, a n d w hite bl o o d cell c o u nt  wit h diff er e ntial) a n d cli nical c he mistr y ( bl o o d urea 
nitr o ge n, cr eati ni ne, gl uc ose, p otassi u m, s o di u m, t otal calci u m, as partate a mi n otr a nsf er ase, ala ni ne a mi n otr a nsf er ase, al kali ne p h os p hatase, t otal a n d dir ect 
bilir u bi n, t otal pr otei n, sta n dar d electr o l ytes – ma g nesi u m, p h os p hate, a n d c hl ori de). 
r  
R o uti ne uri nal ysis i ncl u des macr osc o pic a n d micr osc o pic e xa mi nati o n. 


G E M- C L- 1 0 3 1 1 Pr ot oc ol, Versi o n 3. 0  
5 Ma y 2 0 2 1 
Pa ge 6 7 of 8 9 
G E MI NI T H E R A P E U TI C S, I N C.  P R O P RI E T A R Y A N D C O N FI D E N TI A L: 
D O N O T C O P Y O R DI S T RI B U T E WI T H O U T P E R M I S SI O N F R O M G E MI NI T H E R A P E U TI C S, I N C. 
A p pe n di x B:  Bi ol o gic al S a m ple C ollecti o n a n d S hi p pi n g I nstr ucti o ns 
Bi ol o gic al S a m ples 
W h ole bl o o d a n d a q ue o us h u m or sa m ples f or t he assess me nt of c o m ple me nt pr otei n 
c o nce ntrati o ns (s uc h as, b ut n ot li mite d t o, c o m ple me nt fact or H, c o m ple me nt fact or I, 
c o m ple me nt fact or B, c o m ple me nt c o m p o ne nt 3); D N A a n d cells; a n d sa m ples f or ser u m 
c he mistr y will be c ollecte d at t he ti me p oi nts s pecifie d i n t he S O A i n A p pe n di x A . 
Refer t o t he la b orat or y ma n ual f or detaile d sa m ple c ollecti o n, st ora ge, a n d s hi p pi n g i nstr ucti o ns.  
All necessar y tra nsfer t u bes, Vac utai ner ® t u bes, la bels, s hi p pi n g b o xes, a n d f or ms, will be 
pr o vi de d b y t he ce ntral la b orat or y. 
A nteri or C h a m ber ( A q ue o us H u m or) S a m ple C ollecti o n 
T he f oll o wi n g pr oce d ures will be f oll o we d: 
 T he a q ue o us h u m or parace ntesis sa m ples will be c ollecte d usi n g ase ptic tec h ni q ue b y a 
q ualifie d p h ysicia n f oll o wi n g t he i nstr ucti o ns o utli ne d i n t he p har mac y ma n ual. 
 T he a q ue o us h u m or sa m ple c ollecti o n c o nsists of a n a nteri or c ha m ber parace ntesis ( A C P) 
(re m o vi n g a p pr o xi matel y 0. 1 m L of a q ue o us fl ui d fr o m t he a nteri or c ha m ber of t he e ye).  
T he pr oce d ure will be perf or me d b y passi n g a nee dle t hr o u g h t he li m b us usi n g t he 
p h ysicia n’s a nest hesia of c h oice f oll o wi n g a p plicati o n of t o pical a nti- bacterial s ol uti o n 
i nstr ucti o ns).   
Please refer t o la b orat or y ma n ual f or a d diti o nal details o n ha n dli n g of c ollecte d sa m ples. 
Sa m ples will be c ollecte d wit h t he kit pr o vi de d b y t he ce ntral la b orat or y a n d s hi p pe d o n dr y ice 
t o t he ce ntral la b orat or y as s o o n as p ossi ble after t he dra w. 
T he sa m ples will be a p pr o xi matel y 1 0 0 μ L, w hic h is e x pecte d t o be well-t olerate d wit h o ut pai n 
or ot her si de effects. 
 
 


G E M- C L- 1 0 3 1 1 Pr ot oc ol, Versi o n 3. 0  
5 Ma y 2 0 2 1 
Pa ge 6 8 of 8 9 
G E MI NI T H E R A P E U TI C S, I N C.  P R O P RI E T A R Y A N D C O N FI D E N TI A L: 
D O N O T C O P Y O R DI S T RI B U T E WI T H O U T P E R M I S SI O N F R O M G E MI NI T H E R A P E U TI C S, I N C. 
A p pe n di x C:  C ol or F u n d us P h ot o gr a p h y ( C F P) 
Sc o pe: 
C ol or f u n d us p h ot o gra p hs will be ta ke n b y trai ne d pers o n nel at t he st u d y sites.  F u n d us 
p h ot o gra p h y will be perf or me d at t he i nter vals s pecifie d i n t he S O A i n A p pe n di x A .  A nal ysis of 
f u n d us p h ot o gra p hs will be perf or me d b y t he I ma ge Rea di n g Ce nter. 
E q ui p me nt: 
See t he I ma ge Rea di n g Ce nter ma n ual. 
Pr oce d ure: 
T he I ma ge Rea di n g Ce nter will pr o vi de a ma n ual a n d trai ni n g materials.  T he f u n d us 
p h ot o gra p her a n d p h ot o gra p h y e q ui p me nt will be certifie d b y t he rea di n g ce nter bef ore a n y st u d y 
i ma ges are ta ke n.  See t he I ma ge Rea di n g Ce nter ma n ual f or f urt her details. 
St u d y site m ust ma ke best eff ort t o use t he sa me assess or t hr o u g h o ut t he st u d y f or eac h s u bject.  
If a differe nt assess or is use d f or t he sa me s u bject, t he rati o nale m ust be clearl y mar ke d i n t he 
s u bject’s st u d y bi n der a n d ma de a vaila ble if re q ueste d. 
 
 


G E M- C L- 1 0 3 1 1 Pr ot oc ol, Versi o n 3. 0  
5 Ma y 2 0 2 1 
Pa ge 6 9 of 8 9 
G E MI NI T H E R A P E U TI C S, I N C.  P R O P RI E T A R Y A N D C O N FI D E N TI A L: 
D O N O T C O P Y O R DI S T RI B U T E WI T H O U T P E R M I S SI O N F R O M G E MI NI T H E R A P E U TI C S, I N C. 
A p pe n di x D:  F u n d us A ut ofl u oresce nce ( F A F) 
Sc o pe: 
F A F will be perf or me d b y trai ne d pers o n nel at t he st u d y site w h o are certifie d b y t he 
I ma ge Rea di n g Ce nter.  F A F i ma gi n g will be o btai ne d at t he i nter vals s pecifie d i n t he S O A 
(A p pe n di x A ).  A nal ysis of F A F i ma ges will be perf or me d b y t he I ma ge Rea di n g Ce nter. 
E q ui p me nt: 
Di gital i ma gi n g s yste ms are re q uire d as descri be d i n t he I ma ge Rea di n g Ce nter ma n ual.  T he 
s yste m a n d s oft ware at t he site will be certifie d b y t he I ma ge Rea di n g Ce nter pri or t o o btai ni n g 
a n y st u d y i ma ges.  T his certificati o n a n d vali dati o n pr ocess will e ns ure t hat t he I ma ge Rea di n g 
Ce nter will be a ble t o c orrectl y calc ulate t he re q uire d meas ure me nts. 
N o pri nte d F A F i ma ges will be se nt t o t he I ma ge Rea di n g Ce nter. 
Pr oce d ures a n d Certificati o n: 
T he I ma ge Rea di n g Ce nter will pr o vi de a ma n ual.  T he F A F p h ot o gra p her a n d e q ui p me nt, 
s yste ms, a n d s oft ware will be certifie d b y t he rea di n g ce nter bef ore a n y st u d y i ma ges are ta ke n.  
See t he I ma ge Rea di n g Ce nter ma n ual f or f urt her details. 
St u d y site m ust ma ke best eff ort t o use t he sa me assess or t hr o u g h o ut t he st u d y f or eac h s u bject.  
If a differe nt assess or is use d f or t he sa me s u bject, t he rati o nale m ust be clearl y mar ke d i n t he 
s u bject’s st u d y bi n der a n d ma de a vaila ble if re q ueste d. 
 
 


G E M- C L- 1 0 3 1 1 Pr ot oc ol, Versi o n 3. 0  
5 Ma y 2 0 2 1 
Pa ge 7 0 of 8 9 
G E MI NI T H E R A P E U TI C S, I N C.  P R O P RI E T A R Y A N D C O N FI D E N TI A L: 
D O N O T C O P Y O R DI S T RI B U T E WI T H O U T P E R M I S SI O N F R O M G E MI NI T H E R A P E U TI C S, I N C. 
A p pe n di x E:  Fl u orescei n A n gi o gr a p h y ( F A) 
Sc o pe: 
F A will be perf or me d b y trai ne d pers o n nel at t he st u d y site w h o are certifie d b y t he I ma ge 
Rea di n g Ce nter.  T he fl u orescei n a n gi o gra ms will be o btai ne d at t he i nter vals s pecifie d i n t he 
S O A ( A p pe n di x A ).  A nal ysis of F As will be perf or me d b y t he I ma ge Rea di n g Ce nter. 
E q ui p me nt: 
Di gital a n gi o gra ms m ust be use d w hile c o n d ucti n g a n a n gi o gra p hic e val uati o n f or t he st u d y.  
Fil m- base d a n gi o gra p h y is n ot acce pta ble. 
Di gital i ma gi n g s yste ms are re q uire d.  T he s yste m a n d s oft ware at t he site will be certifie d b y t he 
I ma ge Rea di n g Ce nter pri or t o o btai ni n g a n y st u d y a n gi o gra ms.  T his certificati o n a n d vali dati o n 
pr ocess will e ns ure t hat t he I ma ge Rea di n g Ce nter will be a ble t o c orrectl y calc ulate t he re q uire d 
meas ure me nts. 
Pr oce d ures: 
T he I ma ge Rea di n g Ce nter will pr o vi de a ma n ual a n d trai ni n g materials.  T he p h ot o gra p her a n d 
p h ot o gra p h y e q ui p me nt, s yste ms a n d s oft ware will be certifie d b y t he I ma ge Rea di n g Ce nter 
bef ore a n y st u d y i ma ges are ta ke n.  See t he I ma ge Rea di n g Ce nter ma n ual f or f urt her details. 
St u d y site m ust ma ke best eff ort t o use t he sa me assess or t hr o u g h o ut t he st u d y f or eac h s u bject.  
If a differe nt assess or is use d f or t he sa me s u bject, t he rati o nale m ust be clearl y mar ke d i n t he 
s u bject’s st u d y bi n der a n d ma de a vaila ble if re q ueste d. 
 
 


G E M- C L- 1 0 3 1 1 Pr ot oc ol, Versi o n 3. 0  
5 Ma y 2 0 2 1 
Pa ge 7 1 of 8 9 
G E MI NI T H E R A P E U TI C S, I N C.  P R O P RI E T A R Y A N D C O N FI D E N TI A L: 
D O N O T C O P Y O R DI S T RI B U T E WI T H O U T P E R M I S SI O N F R O M G E MI NI T H E R A P E U TI C S, I N C. 
A p pe n di x F:  S pectr al D o m ai n O ptic al C o here nce T o m o gr a p h y ( S D- O C T) 
Sc o pe: 
S D- O C T will be perf or me d b y trai ne d pers o n nel at t he st u d y site w h o are certifie d b y t he I ma ge 
Rea di n g Ce nter.  S D- O C T i ma gi n g will be o btai ne d at t he i nter vals s pecifie d i n t he S O A 
(A p pe n di x A ) a n d f or war de d t o t he I ma ge Rea di n g Ce nter. 
E q ui p me nt: 
Di gital i ma gi n g s yste ms are re q uire d as descri be d i n t he I ma ge Rea di n g Ce nter ma n ual.  T he 
s yste m a n d s oft ware at t he site will be certifie d b y t he I ma ge Rea di n g Ce nter pri or t o o btai ni n g 
a n y st u d y i ma ges.  T his certificati o n a n d vali dati o n pr ocess will e ns ure t hat t he I ma ge Rea di n g 
Ce nter will be a ble t o c orrectl y calc ulate t he re q uire d meas ure me nts.   
N o pri nte d S D- O C T i ma ges will be se nt t o t he I ma ge Rea di n g Ce nter. 
Pr oce d ures a n d Certificati o n: 
T he I ma ge Rea di n g Ce nter will pr o vi de a ma n ual a n d trai ni n g materials.  T he S D- O C T 
tec h nicia n a n d e q ui p me nt, s yste ms, a n d s oft ware will be certifie d b y t he I ma ge Rea di n g Ce nter 
bef ore a n y st u d y i ma ges are ta ke n.  See t he I ma ge Rea di n g Ce nter ma n ual f or f urt her details. 
 
 


G E M- C L- 1 0 3 1 1 Pr ot oc ol, Versi o n 3. 0  
5 Ma y 2 0 2 1 
Pa ge 7 2 of 8 9 
G E MI NI T H E R A P E U TI C S, I N C.  P R O P RI E T A R Y A N D C O N FI D E N TI A L: 
D O N O T C O P Y O R DI S T RI B U T E WI T H O U T P E R M I S SI O N F R O M G E MI NI T H E R A P E U TI C S, I N C. 
A p pe n di x G:  O ptic al C o here nce T o m o gr a p h y – A n gi o gr a m ( O C T- A) 
Sc o pe: 
O C T- A will be perf or me d b y trai ne d pers o n nel at t he st u d y site w h o are certifie d b y t he I ma ge 
Rea di n g Ce nter.  O C T- A i ma gi n g will be o btai ne d at t he i nter vals s pecifie d i n t he S O A 
(A p pe n di x A ) a n d f or war de d t o t he I ma ge Rea di n g Ce nter. 
E q ui p me nt: 
Di gital i ma gi n g s yste ms are re q uire d as descri be d i n t he I ma ge Rea di n g Ce nter ma n ual.  T he 
s yste m a n d s oft ware at t he site will be certifie d b y t he I ma ge Rea di n g Ce nter pri or t o o btai ni n g 
a n y st u d y i ma ges.  T his certificati o n a n d vali dati o n pr ocess will e ns ure t hat t he I ma ge Rea di n g 
Ce nter will be a ble t o c orrectl y calc ulate t he re q uire d meas ure me nts. 
N o pri nte d O C T- A i ma ges will be se nt t o t he I ma ge Rea di n g Ce nter. 
Pr oce d ures a n d Certificati o n: 
T he I ma ge Rea di n g Ce nter will pr o vi de a ma n ual a n d trai ni n g materials.  T he O C T- A tec h nicia n 
a n d e q ui p me nt, s yste ms, a n d s oft ware will be certifie d b y t he I ma ge Rea di n g Ce nter bef ore a n y 
st u d y i ma ges are ta ke n.  See t he I ma ge Rea di n g Ce nter ma n ual f or f urt her details. 
St u d y site m ust ma ke best eff ort t o use t he sa me assess or t hr o u g h o ut t he st u d y f or eac h s u bject.  
If a differe nt assess or is use d f or t he sa me s u bject, t he rati o nale m ust be clearl y mar ke d i n t he 
s u bject’s st u d y bi n der a n d ma de a vaila ble if re q ueste d. 
 
 


G E M- C L- 1 0 3 1 1 Pr ot oc ol, Versi o n 3. 0  
5 Ma y 2 0 2 1 
Pa ge 7 3 of 8 9 
G E MI NI T H E R A P E U TI C S, I N C.  P R O P RI E T A R Y A N D C O N FI D E N TI A L: 
D O N O T C O P Y O R DI S T RI B U T E WI T H O U T P E R M I S SI O N F R O M G E MI NI T H E R A P E U TI C S, I N C. 
A p pe n di x H:  Ne ar I nfr are d Reflect a nce I m a gi n g ( NI R) 
Sc o pe: 
NI R i ma ges are ta ke n t o c o m ple me nt t he I ma ge Rea di n g Ce nter rea di n g ce nter e val uati o n of 
f u n d us a ut ofl u oresce nce i ma ges. 
NI R will be perf or me d b y trai ne d pers o n nel at t he st u d y site w h o are certifie d b y t he I ma ge 
Rea di n g Ce nter.  NI R will be o btai ne d at t he i nter vals s pecifie d i n t he S O A ( A p pe n di x A ) a n d 
f or war de d t o t he I ma ge Rea di n g Ce nter. 
E q ui p me nt: 
Di gital i ma gi n g s yste ms are re q uire d as descri be d i n t he I ma ge Rea di n g Ce nter ma n ual.  T he 
s yste m a n d s oft ware at t he site will be certifie d b y t he I ma ge Rea di n g Ce nter pri or t o o btai ni n g 
a n y st u d y i ma ges.  T his certificati o n a n d vali dati o n pr ocess will e ns ure t hat t he I ma ge Rea di n g 
Ce nter will be a ble t o c orrectl y calc ulate t he re q uire d meas ure me nts. 
N o pri nte d NI R i ma ges will be se nt t o t he I ma ge Rea di n g Ce nter. 
Pr oce d ures a n d Certificati o n: 
T he I ma ge Rea di n g Ce nter will pr o vi de a ma n ual a n d trai ni n g materials.  T he NI R tec h nicia n 
a n d e q ui p me nt, s yste ms, a n d s oft ware will be certifie d b y t he I ma ge Rea di n g Ce nter bef ore a n y 
st u d y i ma ges are ta ke n.  See t he I ma ge Rea di n g Ce nter ma n ual f or f urt her details. 
St u d y site m ust ma ke best eff ort t o use t he sa me assess or t hr o u g h o ut t he st u d y f or eac h s u bject.  
If a differe nt assess or is use d f or t he sa me s u bject, t he rati o nale m ust be clearl y mar ke d i n t he 
s u bjects’ st u d y bi n der a n d ma de a vaila ble if re q ueste d. 
 
 


G E M- C L- 1 0 3 1 1 Pr ot oc ol, Versi o n 3. 0  
5 Ma y 2 0 2 1 
Pa ge 7 4 of 8 9 
G E MI NI T H E R A P E U TI C S, I N C.  P R O P RI E T A R Y A N D C O N FI D E N TI A L: 
D O N O T C O P Y O R DI S T RI B U T E WI T H O U T P E R M I S SI O N F R O M G E MI NI T H E R A P E U TI C S, I N C. 
A p pe n di x I:  Mi n nes ot a L o w- visi o n Re a di n g Test ( M N Re a d) C h arts 
M N Re a d Re a di n g S pee d Assess me nt 
T he M N Rea d ac uit y car ds are c o nti n u o us-te xt rea di n g ac uit y car ds s uita ble f or meas uri n g t he 
rea di n g ac uit y a n d rea di n g s pee d of n or mal a n d l o w- visi o n s u bjects.  T hese car ds were 
de vel o pe d at t he Mi n nes ota La b orat or y f or L o w- Visi o n Researc h, U ni versit y of Mi n nes ota, 
Mi n nea p olis, Mi n nes ota, i n researc h f u n de d b y t he Nati o nal I nstit utes of Healt h. 
Meas uri n g Rea di n g S pee d: 
T he M N Rea d ac uit y car ds c o nsist of si n gle, si m ple se nte nces wit h e q ual n u m bers of c haracters.  
T he pri nt is a pr o p orti o nall y s pace d f o nt, si milar t o t hat f o u n d i n ma n y ne ws pa pers a n d b o o ks.  
T he car ds c o ntai n se nte nces wit h 1 9 differe nt pri nt sizes.  T he te xt is pri nte d wit h hi g h c o ntrast 
 c haracters (i ncl u di n g s pace bet wee n eac h w or d 
a n d t he e n d of eac h li ne) pri nte d as 3 li nes wit h e ve n left a n d ri g ht mar gi ns.  T he v oca b ul ar y 
use d i n t he se nte nces are selecte d fr o m w or ds a p peari n g wit h hi g h fre q ue nc y i n sec o n d- t o 
t hir d- gra de rea di n g materials. 
E q ui p me nt: 
M N Rea d ac uit y car ds are use d t o meas ure rea di n g s pee d at differe nt pri nt sizes t o deter mi ne t he 
pri nt t hat s u p p orts t he s u bject’s ma xi m u m rea di n g s pee d.  A st o p watc h is re q uire d t o rec or d ti me 
t o a te nt h of a sec o n d.  A n easel or a dj usta ble sta n d ma y be nee de d f or s o me s u bjects.   
Testi n g: 
Car d Ill u mi nati o n: 
T he car ds s h o ul d be e ve nl y lit s o t hat n o s ha d o ws or glare will i nterfere wit h rea di n g.  T he 
l u mi na nce of t he w hite bac k gr o u n d o n t he car ds s h o ul d be bet wee n 8 0- 1 2 0 c d/ m2. 
Vie wi n g Dista nce: 
T he pri nt sizes a n d mar ki n gs o n t he car ds are desi g ne d f or a testi n g dista nce of 4 0 c m, b ut ma y 
be teste d at a dista nce of 3 2 c m.  We rec o m me n d usi n g a hea drest set t o t he a p pr o priate vie wi n g 
dista nce i n fr o nt of t he car ds, t o pre ve nt t he s u bject fr o m cree pi n g f or war d t hr o u g h o ut t he test.  
F or s u bjects wit h ce ntral fiel d l oss, we fi n d it easier t o all o w t he s u bject t o p ositi o n t he M N Rea d 
car d s o t hat t he se nte nce t o be rea d will fall i nt o t heir preferre d l ocati o n f or rea di n g. 
Testi n g Pr oce d ure: 
T he M N Rea d assess me nt will be c o n d ucte d first i n eac h e ye se paratel y a n d t he n wit h b ot h e yes 
o pe n.  A differe nt car d m ust be use d f or eac h test t o pre ve nt me m orizati o n of t he pri nte d 
material.  R otate car ds fr o m o ne e xa mi nati o n t o a n ot her t o var y t he te xt f or eac h e ye.  C o n d uct 
t he rea di n g tests i n t he f oll o wi n g or der.  Start b y testi n g t he ri g ht e ye wit h t he left e ye occl u de d.  
Ne xt, c o n d uct t he s pee d-rea di n g test i n t he left e ye wit h t he ri g ht e ye occl u de d, a n d lastl y wit h 
b ot h e yes o pe n. 
T he car d s h o ul d be rea d fr o m a dista nce of e xactl y 3 2 c m.  T o kee p t he testi n g dista nce c o nsta nt, 
use a piece of tra ns pare nt fis hi n g li ne, pre- meas ure d at 3 2 c m fr o m t he car d.  Meas ure t he 3 2 c m 
t o t he s u bject’s e ye b y h ol di n g t he fis hi n g li ne parallel t o t he fl o or.  A r uler or 3 2 c m meas uri n g 
de vice ma y als o be use d t o set a n d m o nit or t he dista nce.  I nstr uct t he s u bject t hat t he car d ma y be 
m o ve d u p a n d d o w n or si de t o si de, b ut n ot cl oser or fart her fr o m t he e yes.  T he car d m ust 
re mai n u pri g ht a n d m ust n ot tilt a wa y fr o m or t o war d t he s u bjects.  Eit her t he s u bject or t he 


G E M- C L- 1 0 3 1 1 Pr ot oc ol, Versi o n 3. 0  
5 Ma y 2 0 2 1 
Pa ge 7 5 of 8 9 
G E MI NI T H E R A P E U TI C S, I N C.  P R O P RI E T A R Y A N D C O N FI D E N TI A L: 
D O N O T C O P Y O R DI S T RI B U T E WI T H O U T P E R M I S SI O N F R O M G E MI NI T H E R A P E U TI C S, I N C. 
e xa mi ner ma y h ol d t he car d, de pe n di n g o n t he p h ysical a bilit y of t he s u bject.  Alter nati vel y, t he 
car d ma y be place d o n a n easel or a dj usta ble sta n d. 
C hec k t o e ns ure t hat t he rea di n g car d n u m ber o n t he sc ori n g s heet c orres p o n ds t o t he rea di n g 
car d n u m ber t hat y o u are usi n g.  T he M N Rea d sc ori n g s heet c o ntai ns t he test se nte nces 
c orres p o n di n g t o t he car d be gi n ni n g o n t he left- ha n d c ol u m n i n desce n di n g or der of ac uit y.  
I n dicate w hic h e ye is bei n g teste d.  Start wit h t he lar gest se nte nce a n d m o ve o nt o t he s u bse q ue nt 
se nte nces.  Kee p g oi n g u ntil t he s u bject ca n n ot rea d a n y w or ds i n a se nte nce.  Use a bla n k car d 
t o c o ver eac h se nte nce as y o u w or k y o ur wa y d o w n t he car d:  u nc o ver t he se nte nce t o be rea d 
w he n y o u sa y “start.”  Prese nt t he test se nte nce; si m ulta ne o usl y, tell t he s u bject t o start rea di n g 
a n d acti vate t he st o p watc h t o start t he ti mer.  As t he s u bject rea ds t he te xt, stri ke o ut w or ds n ot 
rea d, n ot atte m pte d, or rea d i nc orrectl y.  Use a st o p watc h t o rec or d t he ti me ta ke n t o rea d eac h 
se nte nce (t o t he nearest 0. 1 sec o n d). 
I nstr ucti o ns t o t he S u bject: 
“ W he n I sa y ‘start,’ rea d t he se nte nce al o u d as q uic kl y as y o u ca n wit h o ut ma ki n g err ors.  B ut if 
y o u d o ma ke a n err or, or realize t hat y o u ha ve misse d a w or d, rea d t o t he e n d of t he se nte nce a n d 
t he n g o bac k a n d c orrect y o urself.” 
Sc ori n g: 
T w o pieces of i nf or mati o n are re q uire d t o be rec or de d o n t he sc ore s heet f or eac h test se nte nce:  
t he ti me a n d t he n u m ber of err ors.  Use a st o p watc h t o rec or d t he ti me ta ke n t o rea d eac h 
se nte nce (t o t he nearest 0. 1 sec o n d).  F or eac h se nte nce o n t he sc ore s heet, mar k t he t otal n u m ber 
of w or ds misse d, rea d i nc orrectl y or n ot a ble t o be rea d, a n d t he ti me ta ke n t o rea d t he se nte nce 
(i.e., t he ti me bet wee n w he n y o u sa y ‘start’ a n d w he n t he s u bject fi nis hes utteri n g t he last w or d 
i n t he se nte nce).  Se nte nces t hat c o ul d n ot be rea d or were n ot atte m pte d d ue t o visi o n s h o ul d be 
rec or de d as 0 f or ti me a n d 1 0 f or err ors. 
Meas uri n g Rea di n g F u ncti o n: 
S u bjects’ a vera ge rea di n g s pee d, critical pri nt size, a n d rea di n g ac uit y will be calc ulate d usi n g 
t he data tra nscri be d fr o m t he sc ori n g s heet t o t he electr o nic Case Re p ort F or m a n d will n ot be 
calc ulate d b y t he i nter vie wers. 
Det aile d T a ble f or A d mi nistr ati o n of M N Re a d 
Select e d C o u nt ries 
P ri m ar y L a n g u a ge 
M N Re a d 
U nite d States 
E n glis h, S pa nis h 
X 
U nite d Ki n g d o m 
E n glis h 
X 
Net herla n ds
 D utc h
 
X
St u d y site m ust ma ke best eff ort t o use t he sa me assess or t hr o u g h o ut t he st u d y f or eac h s u bject.  
If a differe nt assess or is use d f or t he sa me s u bject t he rati o nale m ust be clearl y mar ke d i n t he 
s u bject’s st u d y bi n der a n d ma de a vaila ble if re q ueste d. 
 
 


G E M- C L- 1 0 3 1 1 Pr ot oc ol, Versi o n 3. 0  
5 Ma y 2 0 2 1 
Pa ge 7 6 of 8 9 
G E MI NI T H E R A P E U TI C S, I N C.  P R O P RI E T A R Y A N D C O N FI D E N TI A L: 
D O N O T C O P Y O R DI S T RI B U T E WI T H O U T P E R M I S SI O N F R O M G E MI NI T H E R A P E U TI C S, I N C. 
A p pe n di x J:  N ati o n al E ye I nstit ute Vis u al F u ncti o ni n g Q uesti o n n ai re 2 5-ite m 
Versi o n ( N EI- V F Q- 2 5) wit h Ne ar a n d Dist a nce Acti vit y S u bsc ale Sc ores 
T he st u d y ce nter a n d I n vesti gat or will i ncl u de t he f oll o wi n g cre dit or attri b uti o n state me nt f or t he 
Nati o nal E ye I nstit ute Vis ual F u ncti o ni n g Q uesti o n naire- 2 5 ( N EI- V F Q- 2 5) q uesti o n naire i n a n y 
p u blic prese ntati o n, p u blicati o n, or ot her disse mi nati o n or refere nce t o t he N EI- V F Q- 2 5 as use d 
i n t his st u d y. 
T he f oll o wi n g f or m, base d u p o n N EI- V F Q- 2 5, was de vel o pe d at R A N D ( htt ps:// w w w.ra n d. or g) 
u n der t he s p o ns ors hi p of t he N EI a n d was a da pte d b y t he S p o ns or f or use i n t his st u d y. 
Si x q uesti o ns fr o m t he a p pe n di x of o pti o nal a d diti o nal q uesti o ns f or t he N EI- V F Q- 2 5, pertai ni n g 
t o t he near a n d dista nce acti vities, were a d de d t o t he f or m.  Mi n or c ha n ges ( n ot affecti n g t he 
ite ms of t he q uesti o n naire) were ma de t o t he f or m, a n d a hea der was a d de d wit h t he st u d y 
n u m ber, S p o ns or’s na me, visit, a n d s u bject i de ntifiers.   
I nstr ucti o ns t o S u bjects: 
“I a m g oi n g t o rea d y o u s o me state me nts a b o ut pr o ble ms, w hic h i n v ol ve y o ur visi o n or feeli n gs 
t hat y o u ha ve a b o ut t he c o n diti o n of y o ur visi o n.  After eac h q uesti o n, I will rea d y o u a list of 
p ossi ble a ns wers.  Please c h o ose t he res p o nse t hat best descri bes y o ur sit uati o n. 
Please a ns wer all t he q uesti o ns as if y o u were weari n g y o ur glasses or c o ntact le nses (if a n y). 
Please ta ke as m uc h ti me as y o u nee d t o a ns wer eac h q uesti o n.  All y o ur a ns wers are 
c o nfi de ntial.  I n or der f or t his st u d y s ur ve y t o i m pr o ve o ur k n o wle d ge a b o ut visi o n pr o ble ms a n d 
h o w t he y affect y o ur q ualit y of life, y o ur a ns wers m ust  be as acc urate as p ossi ble.  Re me m ber, if 
y o u wear glasses or c o ntact le nses f or a partic ular acti vit y, please a ns wer all of t he f oll o wi n g 
q uesti o ns as t h o u g h y o u were weari n g t he m.” 


G E M- C L- 1 0 3 1 1 Pr ot oc ol, Versi o n 3. 0  
5 Ma y 2 0 2 1 
Pa ge 7 7 of 8 9 
G E MI NI T H E R A P E U TI C S, I N C.  P R O P RI E T A R Y A N D C O N FI D E N TI A L:
D O N O T C O P Y O R DI S T RI B U T E WI T H O U T P E R M I S SI O N F R O M G E MI NI T H E R A P E U TI C S, I N C. 


G E M- C L- 1 0 3 1 1 Pr ot oc ol, Versi o n 3. 0  
5 Ma y 2 0 2 1 
Pa ge 7 8 of 8 9 
G E MI NI T H E R A P E U TI C S, I N C.  P R O P RI E T A R Y A N D C O N FI D E N TI A L:
D O N O T C O P Y O R DI S T RI B U T E WI T H O U T P E R M I S SI O N F R O M G E MI NI T H E R A P E U TI C S, I N C. 
 


G E M- C L- 1 0 3 1 1 Pr ot oc ol, Versi o n 3. 0  
5 Ma y 2 0 2 1 
Pa ge 7 9 of 8 9 
G E MI NI T H E R A P E U TI C S, I N C.  P R O P RI E T A R Y A N D C O N FI D E N TI A L:
D O N O T C O P Y O R DI S T RI B U T E WI T H O U T P E R M I S SI O N F R O M G E MI NI T H E R A P E U TI C S, I N C. 


G E M- C L- 1 0 3 1 1 Pr ot oc ol, Versi o n 3. 0  
5 Ma y 2 0 2 1 
Pa ge 8 0 of 8 9 
G E MI NI T H E R A P E U TI C S, I N C.  P R O P RI E T A R Y A N D C O N FI D E N TI A L:
D O N O T C O P Y O R DI S T RI B U T E WI T H O U T P E R M I S SI O N F R O M G E MI NI T H E R A P E U TI C S, I N C. 


G E M- C L- 1 0 3 1 1 Pr ot oc ol, Versi o n 3. 0  
5 Ma y 2 0 2 1 
Pa ge 8 1 of 8 9 
G E MI NI T H E R A P E U TI C S, I N C.  P R O P RI E T A R Y A N D C O N FI D E N TI A L:
D O N O T C O P Y O R DI S T RI B U T E WI T H O U T P E R M I S SI O N F R O M G E MI NI T H E R A P E U TI C S, I N C. 
 
 


G E M- C L- 1 0 3 1 1 Pr ot oc ol, Versi o n 3. 0  
5 Ma y 2 0 2 1 
Pa ge 8 2 of 8 9 
G E MI NI T H E R A P E U TI C S, I N C.  P R O P RI E T A R Y A N D C O N FI D E N TI A L:
D O N O T C O P Y O R DI S T RI B U T E WI T H O U T P E R M I S SI O N F R O M G E MI NI T H E R A P E U TI C S, I N C. 
 


G E M- C L- 1 0 3 1 1 Pr ot oc ol, Versi o n 3. 0  
5 Ma y 2 0 2 1 
Pa ge 8 3 of 8 9 
G E MI NI T H E R A P E U TI C S, I N C.  P R O P RI E T A R Y A N D C O N FI D E N TI A L:
D O N O T C O P Y O R DI S T RI B U T E WI T H O U T P E R M I S SI O N F R O M G E MI NI T H E R A P E U TI C S, I N C. 
 


G E M- C L- 1 0 3 1 1 Pr ot oc ol, Versi o n 3. 0  
5 Ma y 2 0 2 1 
Pa ge 8 4 of 8 9 
G E MI NI T H E R A P E U TI C S, I N C.  P R O P RI E T A R Y A N D C O N FI D E N TI A L:
D O N O T C O P Y O R DI S T RI B U T E WI T H O U T P E R M I S SI O N F R O M G E MI NI T H E R A P E U TI C S, I N C. 
 


G E M- C L- 1 0 3 1 1 Pr ot oc ol, Versi o n 3. 0  
5 Ma y 2 0 2 1 
Pa ge 8 5 of 8 9 
G E MI NI T H E R A P E U TI C S, I N C.  P R O P RI E T A R Y A N D C O N FI D E N TI A L:
D O N O T C O P Y O R DI S T RI B U T E WI T H O U T P E R M I S SI O N F R O M G E MI NI T H E R A P E U TI C S, I N C. 
 


G E M- C L- 1 0 3 1 1 Pr ot oc ol, Versi o n 3. 0  
5 Ma y 2 0 2 1 
Pa ge 8 6 of 8 9 
G E MI NI T H E R A P E U TI C S, I N C.  P R O P RI E T A R Y A N D C O N FI D E N TI A L:
D O N O T C O P Y O R DI S T RI B U T E WI T H O U T P E R M I S SI O N F R O M G E MI NI T H E R A P E U TI C S, I N C. 
 


G E M- C L- 1 0 3 1 1 Pr ot oc ol, Versi o n 3. 0  
5 Ma y 2 0 2 1 
Pa ge 8 7 of 8 9 
G E MI NI T H E R A P E U TI C S, I N C.  P R O P RI E T A R Y A N D C O N FI D E N TI A L:
D O N O T C O P Y O R DI S T RI B U T E WI T H O U T P E R M I S SI O N F R O M G E MI NI T H E R A P E U TI C S, I N C. 
 
 


G E M- C L- 1 0 3 1 1 Pr ot oc ol, Versi o n 3. 0  
5 Ma y 2 0 2 1 
Pa ge 8 8 of 8 9 
G E MI NI T H E R A P E U TI C S, I N C.  P R O P RI E T A R Y A N D C O N FI D E N TI A L: 
D O N O T C O P Y O R DI S T RI B U T E WI T H O U T P E R M I S SI O N F R O M G E MI NI T H E R A P E U TI C S, I N C. 
A p pe n di x K:  Gr a di n g Sc ale f or U veitis 
 
E n d p oi nt
 Gr a de
 
Descri pti o n
 
A nteri or Cells 
0 
< 1 cell i n t he fiel d 
0. 5 + 
1 t o 5 cells i n t he fiel d 
1 + 
6 t o 1 5 cells i n t he fiel d 
2 + 
1 6 t o 2 5 cells i n t he fiel d 
3 + 
2 6 t o 5 0 cells i n t he fiel d 
4 + 
> 5 0 cells i n t he fiel d 
A nteri or Flar e 
0
 N o
 
flar e
 
1 +
 Fai nt
 
2 + 
M o derate, iris a n d le ns details clear 
3 + 
Mar ke d, iris a n d le ns details haz y 
4 + 
I nte nse, fi bri n or plastic a q ue o us 
Vitr e o us Haze 
0 
N o ne, n o cli nical fi n di n gs 
1 
Mi ni mal, p osteri or p ole clearl y visi ble 
2 
Mil d, p osteri or p ole details sli g htl y haz y 
3 
M o der ate, p osteri or p ole details ver y haz y 
4 
Mar ke d, p osteri or p ole details bar el y visi ble 
5 
Se ver e, f u n d us details n ot visi ble 
N ote:  N u m ber of cells see n i n 1 m m x 1 m m hi g h- p o wer e d fiel d. 
 
 


G E M- C L- 1 0 3 1 1 Pr ot oc ol, Versi o n 3. 0  
5 Ma y 2 0 2 1 
Pa ge 8 9 of 8 9 
G E MI NI T H E R A P E U TI C S, I N C.  P R O P RI E T A R Y A N D C O N FI D E N TI A L: 
D O N O T C O P Y O R DI S T RI B U T E WI T H O U T P E R M I S SI O N F R O M G E MI NI T H E R A P E U TI C S, I N C. 
A p pe n di x L:  Me dic ati o ns K n o w n t o P ote nti all y E x acer b ate M ac ul a r E de m a 
or M ac ul ar De ge ner ati o n 
 
M ac ul ar E de m a  
M ac ul ar De ge ner ati o n  
Acetaz ola mi de 
All o p uri n ol 
Al u mi n u m Nic oti nate 
Beta x ol ol 
Br o x y q ui n oli ne 
C h y m otr y psi n 
Dicl or p he na mi de 
Di pi vefri n 
Di pi val yl e pi ne p hri ne ( D P E) 
E pi ne p hri ne 
Et h o xz ola mi de 
Grise of ul vi n 
He xa met h o ni u m 
I n d o met haci n (I n d o metaci n) 
I o di de a n d I o di ne S ol uti o ns a n d C o m p o u n ds 
I o d oc hl or h y dr o x y q ui n 
I o d o q ui n ol ( Dii o d o h y dr o x y q ui n oli ne) 
I ot hala mate Me gl u mi ne a n d/ or S o di u m 
I ot hala mic Aci d 
Le v o b u n ol ol 
Met haz ola mi de 
Na pr o xe n 
Niaci n ( Nic o ntic Aci d) 
Niaci na mi de 
Nic oti n yl Alc o h ol 
P he n yle p hri ne 
Q ui ni ne 
Ra di oacti ve i o di des 
Ta m o xife n (e xcl usi o nar y) 
Ti m ol ol 
All o p uri n ol 
A m o dia q ui n ne 
Br o x y q ui n oli ne 
C hl or o q ui ne 
Cl o ni di ne 
Grise of ul vi n 
H y dr o x yc hl or o q ui ne 
I b u pr ofe n 
I n d o met haci n (I n d o metaci n) 
I o d oc hl or h y dr o x y q ui n 
I o d o q ui n ol 
Q ui ni ne  
S o ur ce:  “ Me dicati o n Ca uti o ns i n  Mac ular De ge ner ati o n. ”  w w w  mac ular. or g/ me dicati o ns- use-ca uti o n.  
Accesse d 0 2 Oct o ber 2 0 1 9.  

SAP_001.pdf: 
 
 
 
 
 
This document is confidential. 
SAP Version 2.0 
Controlled Document ID: 3903A.02, Effective Date 31-Aug-2020 
Filing requirements: TMF 
Page 1 of 42 
Statistical Analysis Plan  
 
Sponsor Name: Gemini Therapeutics, Inc.  
 
Protocol Number: GEM-CL-10311 
Protocol Title: A Multicenter, Multiple-Dose Study in Neovascular Age-related Macular Degeneration 
(nAMD) to Evaluate the Safety, Tolerability, Pharmacodynamics, Immunogenicity, and Clinical Effect of 
Repeat Intravitreal (IVT) Injections of GEM103 as an Adjunct to Standard of Care Aflibercept Therapy  
 
Protocol Version and Date: (DD-Mmm-YYYY): 3.0, 05-May-2021 
Syneos Health Project Code: 7021030 
 
Authors: 
 
 
 
 
 
 
 
 
Notice of Confidential and Proprietary Information: 
The information contained in this document is confidential belonging to Gemini Therapeutics, Inc. 
Acceptance of this document constitutes agreement by the recipient that no information contained herein 
will be published or disclosed without prior written authorization from an official of Gemini Therapeutics, 
Inc.. However, this document may be disclosed to appropriate Institutional Review Board and Ethics 
Committees or duly authorized representatives of a national regulatory authority under the condition that 
they are requested to keep it confidential. In the event of an actual or suspected breach of this obligation, 
Syneos Health should be notified promptly. 
 
 
 
 
 
 
 
PPD




Statistical Analysis Plan 
Sponsor: Gemini Therapeutics, Inc; Protocol No.: GEM-CL-10311 
 
 
This document is confidential. 
SAP Version 2.0 
Controlled Document ID: 3903A.02, Effective Date 31-Aug-2020 
Filing requirements: TMF 
Page 3 of 42 
I confirm that I have reviewed this document and agree with the content. 
 
Approvals 
Syneos Health Approval 
 
 
Name, Title 
Lead Biostatistician  
 
Signature 
 
Date (DD-Mmm-
YYYY) 
 
 
Name, Title 
Senior Reviewing Biostatistician 
 
 
Signature 
 
Date (DD-Mmm-
YYYY) 
Gemini Therapeutics, Inc. Approval 
 
 
  
 
17-Feb-2022 
Name, Title 
Sponsor Contact 
 
Signature 
 
Date (DD-Mmm-
YYYY) 
 
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD


Statistical Analysis Plan
Sponsor: Gemini Therapeutics, Inc; Protocol No.: GEM-CL-10311
This document is confidential.
SAP Version 2.0
Controlled Document ID: 3903A.02, Effective Date 31-Aug-2020
Filing requirements: TMF
Page 4 of 42
Table of Contents
Revision History..........................................................................................................................2
Approvals ..................................................................................................................................3
Glossary of Abbreviations...................................................................................................7
Purpose............................................................................................................................10
Study Objectives ..............................................................................................................11
Study Details/Design........................................................................................................12
Endpoints .........................................................................................................................14
Analysis Sets....................................................................................................................15
General Aspects for Statistical Analysis ...........................................................................16


Statistical Analysis Plan
Sponsor: Gemini Therapeutics, Inc; Protocol No.: GEM-CL-10311
This document is confidential.
SAP Version 2.0
Controlled Document ID: 3903A.02, Effective Date 31-Aug-2020
Filing requirements: TMF
Page 5 of 42
Demographic, Other Baseline Characteristics and Medication .........................................19
Efficacy ............................................................................................................................22
Safety...............................................................................................................................26


Statistical Analysis Plan
Sponsor: Gemini Therapeutics, Inc; Protocol No.: GEM-CL-10311
This document is confidential.
SAP Version 2.0
Controlled Document ID: 3903A.02, Effective Date 31-Aug-2020
Filing requirements: TMF
Page 6 of 42
Other Variables ................................................................................................................30
Interim Analyses...............................................................................................................31
Changes from Analysis Planned in Protocol.....................................................................32
Reference List..................................................................................................................33
Programming Considerations ...........................................................................................34
Quality Control .................................................................................................................39
Appendices ......................................................................................................................40








Statistical Analysis Plan
Sponsor: Gemini Therapeutics, Inc; Protocol No.: GEM-CL-10311
This document is confidential.
SAP Version 2.0
Controlled Document ID: 3903A.02, Effective Date 31-Aug-2020
Filing requirements: TMF
Page 10 of 42
Purpose
The purpose of this statistical analysis plan (SAP) is to ensure that the data listings, summary tables and 
figures which will be produced, and the statistical methodologies which will be used, are complete and 
appropriate to allow valid conclusions regarding the study objectives.
This SAP is created based on Protocol Number GEM-CL-10311 version 3.0 dated 05 May 2021. The 
purpose of this SAP is to outline the planned analyses by Syneos Health (SYNH) to support the completion 
of the Clinical Study Report (CSR). This SAP describes in detail the statistical methodology and the 
statistical analyses to be conducted for the above mentioned protocol. The planned analyses identified in 
this SAP is following the Statistical Principles for Clinical Trials such as International Council for 
Harmonisation (ICH) guidelines, E4, and E9.
Responsibilities
Syneos Health will perform all statistical analyses, except pharmacokinetics (PK), and is responsible for 
the production and quality control of all tables, figures and listings.
Timings of Analyses
The primary analysis of safety and efficacy is planned after all subjects complete the final study visit or 
terminate early from the main phase of the study. Unless otherwise specified, the analysis includes all 
data collected in the database through the time of the database lock.
An independent Medical Review Committee (MRC) consisting of Sponsor medical personnel and 
independent medical expert(s) will meet approximately quarterly to review safety information for the study.
No descriptive summaries of safety findings are planned. 
Interim data may be summarized for presentation to regulatory authorities or to the scientific community to 
facilitate discussions and obtain input on late phase study designs.


Statistical Analysis Plan
Sponsor: Gemini Therapeutics, Inc; Protocol No.: GEM-CL-10311
This document is confidential.
SAP Version 2.0
Controlled Document ID: 3903A.02, Effective Date 31-Aug-2020
Filing requirements: TMF
Page 11 of 42
Study Objectives
Primary Objective
x
Describe the safety and tolerability of GEM103+ standard of care (SoC) vs sham+SoC.
Secondary Objective(s)
x
To evaluate total complement factor H (CFH) in aqueous humor after GEM103 intravitreal (IVT)
injection, whenever possible
x
Describe the effect on best corrected visual acuity (BCVA)
x
Describe the effect on macular atrophy (MA) size in subjects with MA present at baseline
Exploratory Objectives
x
To evaluate the immunogenicity of GEM103 in serum after GEM103 IVT injection, whenever 
possible
x
Describe the effect of GEM103 IVT injection on biomarkers in aqueous humor
x
Describe the effect on new MA in subjects without MA at baseline
x
Describe the effect on choroidal neovascularization (CNV) size
x
Describe the effect on thickness of retinal layers
x
Describe the effect on subretinal and intraretinal fluid
x
Describe the effect on low luminance visual acuity (LLVA)
x
Describe the effect on National Eye Institute Visual Functioning Questionnaire 25 item Version 
(NEI-VFQ-25) 
x
Describe the effect on Minnesota Low-vision Reading Test (MNRead)


Statistical Analysis Plan
Sponsor: Gemini Therapeutics, Inc; Protocol No.: GEM-CL-10311
This document is confidential.
SAP Version 2.0
Controlled Document ID: 3903A.02, Effective Date 31-Aug-2020
Filing requirements: TMF
Page 12 of 42
Study Details/Design
Brief Description
This is a Phase 2a, single-masked, sham-controlled, multicenter, multiple-dose study in subjects with 
neovascular age-related macular degeneration (nAMD) to evaluate the safety, tolerability, 
immunogenicity, pharmacokinetic/pharmacodynamic, complement biomarkers, and clinical efficacy during 
12 months of GEM103 IVT injections every other month (EOM) as an adjunct to standard of care (SoC)
aflibercept therapy. 
Study drug or sham, along with (SoC) aflibercept, will be administered to 1 eye only, which will be 
designated during the screening process, based on eligibility, and prior to any baseline measurements. If 
both eyes meet all eye-specific entry criteria, then the study eye will be determined by the Investigator 
and the subject together. All assessments will be performed in the study eye as well as the fellow eye 
whenever feasible.
Detailed assessments of intraocular pressure (IOP), visual acuity (VA) and function, and retinal 
parameters such as CNV and MA lesion size will be performed for each subject enrolled.
Data will be collected on demographics, medical and ocular history, family history, and concomitant 
medications. Additionally, ophthalmic anatomic assessments and multimodal imaging, exploratory genetic 
and biomarker analyses, and aqueous humor sampling will be done for each subject enrolled.
The Investigator will monitor the safety of study procedures according to local institutional policy. All 
Adverse Events (AEs) will be recorded in the electronic case report form. Accumulating safety data will be 
reviewed on an ongoing basis. The minimum planned duration of each subject’s participation is 
approximately 13 months: 1 month for screening and 12 months for dosing and follow-up.
Subject Selection
The target population for this study is subjects with nAMD who are undergoing treatment (at least 1 prior 
dose) with aflibercept therapy. Approximately 45 subjects (~30 treated with GEM103+SoC and ~15 
treated with sham+SoC; SoC defined as aflibercept EOM) are planned for inclusion in the study.
The full list of inclusion and exclusion criteria is provided in section 4.3.1 and 4.3.2 of the protocol.
Determination of Sample Size
The planned total sample size of approximately 45 subjects (~30 treated with GEM103+SoC, ~15 treated 
with sham+SoC; SoC defined as aflibercept EOM) is based on feasibility considerations, rather than any 
specific statistical test. 
Treatment Assignment and Masking
Subjects will be randomly assigned to a treatment cohort in a 2:1 randomization pattern with 2 subjects 
assigned to treatment with GEM103+SoC (SoC defined as aflibercept EOM) for every 1 subject assigned 
to treatment with sham+SoC.
Subjects randomized to the sham+SoC treatment group will receive SoC with a sham IVT injection 
instead of GEM103, to keep the subject masked to their treatment assignment.


Statistical Analysis Plan
Sponsor: Gemini Therapeutics, Inc; Protocol No.: GEM-CL-10311
This document is confidential.
SAP Version 2.0
Controlled Document ID: 3903A.02, Effective Date 31-Aug-2020
Filing requirements: TMF
Page 13 of 42
Administration of Study Medication
At each dosing visit, 2 IVT injections (or sham) will be administered; aflibercept and GEM103 (or sham). 
They will be administered separately to the same eye, with the second injection administered at 90°, or 3 
clock hours distance, from the location of the first injection. GEM103 and aflibercept will under no 
circumstances be administered as 1 combined injection from the same syringe. The intravitreal injections 
will be administered in accordance with SoC techniques including the use of 5% povidone iodine and a 
sterile lid speculum. Administer aflibercept (2 mg/50 μL) first, followed by GEM103 (500 μg/50 μL) 15 
minutes (±5 minutes) later. 
Study Procedures and Flowchart
The study procedures to be performed as summarized in the Schedule of Assessments table, is provided 
in the protocol Appendix A, Schedule of Assessments.


Statistical Analysis Plan
Sponsor: Gemini Therapeutics, Inc; Protocol No.: GEM-CL-10311
This document is confidential.
SAP Version 2.0
Controlled Document ID: 3903A.02, Effective Date 31-Aug-2020
Filing requirements: TMF
Page 14 of 42
Endpoints  
Primary Endpoint
x
Ocular and non-ocular treatment-emergent adverse events (TEAEs)
x
Changes in ophthalmic exams
x
Results of visual function assessments
Secondary Endpoints
x
Aqueous humor concentrations of total CFH
x
Mean change in BCVA from baseline in Early Treatment Diabetic Retinopathy Study (ETDRS) 
letters
x
Mean change in size of MA evaluated by fundus autofluorescence (FAF) 
Exploratory Endpoints
x
Generation of serum GEM103 antidrug antibodies
x
Change from baseline in complement protein, complement split products, and related cytokines 
protein values in aqueous humor
x
New MA evaluated by FAF 
x
Mean reduction from baseline in CNV size as evaluated by fluorescein angiography (FA) 
x
Mean change from baseline in center point thickness and central subfield thickness in μm as 
evaluated by spectral domain optical coherence tomography (SD-OCT)
x
The proportion of patients with intraretinal or subretinal fluid as evaluated by SD-OCT
x
Mean change in low luminance visual acuity (LLVA) from baseline in ETDRS letters
x
Mean change in score from baseline on National Eye Institute Visual Functioning Questionnaire-
25 (NEI-VFQ-25)
x
Mean change in maximum reading speed from baseline on Minnesota Low-vision Reading Test 
(MNRead)


Statistical Analysis Plan
Sponsor: Gemini Therapeutics, Inc; Protocol No.: GEM-CL-10311
This document is confidential.
SAP Version 2.0
Controlled Document ID: 3903A.02, Effective Date 31-Aug-2020
Filing requirements: TMF
Page 15 of 42
Analysis Sets
Consented Subject Set
The Consented Subject Set (CSS) will include subjects who signed the ICF and will be used to create a 
diagram to illustrate subject flow from consent through disposition (similar to a Consolidated Standards of 
Reporting Trials [CONSORT] diagram for a randomized trial). 
Biomarker Set
The Biomarker Set (BS) will include subjects with sufficient data to assess biomarker results. 
Full Analysis Set 
The Full Analysis Set (FAS) will include all randomized subjects who receive at least 1 dose of study drug 
(GEM103 or sham). Safety analyses will be performed on the FAS. Analyses on the FAS are consistent 
with the intention-to-treat principle. Subjects will be analyzed according to actual treatment  received. The 
FAS will be used for all analyses of primary, secondary and exploratory endpoints.
Protocol Deviations
All protocol deviations related to study inclusion or exclusion criteria, conduct of the trial, patient 
management, dosing, and sampling procedures or patient assessment will be listed. The list of protocol 
deviations will be reviewed by the Sponsor and the principal investigator and finalized before database 
lock. The final decision with respect to significant protocol violations will be made before database lock. A 
formal (blind) data review meeting is not necessary.
Protocol deviations will be summarized by the number and percent of subjects with any protocol 
deviations and with any significant protocol deviations. 


Statistical Analysis Plan
Sponsor: Gemini Therapeutics, Inc; Protocol No.: GEM-CL-10311
This document is confidential.
SAP Version 2.0
Controlled Document ID: 3903A.02, Effective Date 31-Aug-2020
Filing requirements: TMF
Page 16 of 42
General Aspects for Statistical Analysis
General Methods
All analyses and summaries will be produced using Statistical Analysis System (SAS®) version 9.4 or 
higher. All SAS programs used to generate analytical results will be developed and validated according to 
SYNH programming standards and SAS validation procedures. Summaries will be presented by 
treatment group (GEM103+SoC vs Sham+SoC) unless otherwise specified.
Continuous data will be summarized using descriptive statistics (number of subjects (n), arithmetic mean
(Mean), standard deviation (SD), median, minimum, and maximum) and, where appropriate, graphic 
representation, and two-sided 95% confidence intervals (CI). The minimum and maximum will be 
displayed to the precision with which the data were collected. The mean and median will be displayed to 
one additional decimal place and the SD will be displayed to two additional decimal places.
Categorical data will be summarized by sample size, proportions, and, where appropriate, two-sided 95% 
CIs. The total number of subjects with a non-missing value for the given variable will be used as the 
denominator for percent calculations, unless stated otherwise. All percentages will be presented with one 
decimal, unless otherwise specified. Percentages equal to 100 will be presented as 100, and percentages 
will not be presented for zero frequencies.
All relevant subject data will be included in listings. All subjects entered into the database will be included 
in subject data listings. All pre- and post-dose assessments including repeat and unscheduled 
assessments will be included in the data listings.
Any reported p-values will be considered part of the descriptive analyses (i.e., hypothesis-generating) and 
will not be adjusted for multiplicity. The phrase “statistically significant” may be used interchangeably with 
“nominally statistically significant” to indicate that a nominal p-value was <0.05.
Key Definitions
Baseline
Unless otherwise specified, baseline is defined as the last non-missing observation prior to the first dose of 
study drug administration. 
Study Day
The day of first dose of study drug administration is defined as study Day 1. Subsequent days are numbered 
consecutively (Day 2, Day 3, etc.). Prior to the day of first dose of study drug administration, study days are 
numbered sequentially with negative values (i.e., Day -1, Day -2, etc.). There is no Day 0.
Missing Data
In general, missing data will not be imputed. All analyses will be based on observed cases. Sections 7.3.1
and 7.3.2 note the situations where missing data will be imputed.
Handling of Missing Dates/Months/Years for Prior/Concomitant Therapies
If the medication cannot be classified into concomitant medications or prior medications due to 
incomplete date, the rules below will be applied for the classification.


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For start date,
x
If the year and month are observed but the day is missing, the first day of the month will be used
unless month and year are the same as month and year of first dose date then impute using the 
day of first dose date  
x
If the year is observed but the month and day are missing, the first day of the year, 01 Jan, will be 
used unless year is the same as first dose date then the first dose date will be used
x
If the start date is completely missing, the medication will be considered concomitant unless the 
stop date is before study drug administration
x
If the start and stop dates are both completely missing, a therapy will be considered concomitant.
For end date,
x
If the year and month are observed but the day is missing, the last day of the month will be used
unless month and year are the same as month and year of last dose date, then impute the last 
dose date  
x
If the year is observed but the month and day are missing, the last day of the year, 31 Dec, will be 
used unless year is the same as last dose date then the last dose date will be used
x
If the end date is completely missing, if medication is still ongoing, then missing end date is not 
supposed to be imputed. If the medication is not ongoing and the start date is prior to first dose 
date, the end date will be imputed using 1st dose date. 
x
If both start and end dates are completely missing, medication will be considered concomitant.
The original partial or missing date will be shown in listings for all prior and concomitant medications.
Adverse Events Dates
For AEs with incomplete dates, the following rules will be used to impute start and/or stop dates for the sole 
purpose of determining if an AE is treatment-emergent. Imputed dates will not appear in the data listings.
For partial start dates:
x
If the month and year of AE onset are provided but day is missing
o
If the month and year match the month and the year of the date of first dosing 
administration, then the date of first dosing administration will be used and the AE will be 
considered treatment-emergent. 
o
Otherwise, the first of the month will be used. 
x
If the year of AE onset is provided, but the month and day are missing
o
If the year matches the year of the first dosing administration, then the date of first dosing 
administration will be used. 
o
Otherwise, the first day of the month and the first month of the year will be used.
o
If the stop date is not missing and the imputed onset date is after the stop date, then the 
stop date will be used.
o
If the onset date is completely missing and the stop date is on or after the date of first dose, 
the event will be considered a TEAE.
o
If both onset date and stop date are missing, the event will be considered a TEAE. Partial 
stop dates will not be imputed.


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o
If the stop date is complete and the imputed start date is after the actual stop date, then 
the start date will be imputed as the stop date.
Visit Windows
For all analyses, data will be summarized according to the scheduled visit and time points as outlined in 
the protocol and by the visit denoted on the electronic case report form (eCRF). There will be no derivation 
for visit windows in terms of summary assessments. Nominal visits will be used for by-visit tables.
Data collected at unscheduled visits that occurred outside the time windows specified in the protocol will 
be included in the data listings but will not be included in the analyses unless otherwise stated.
For data with repeated observations at a given visit, for example, laboratory assessments, the earliest of 
the available non-missing values at a visit should be used in summary tables. Other observations will be 
considered as unscheduled visits.
Pooling of Centers
Data from all sites will be summarized together for analyses.
Subgroups
No subgroup analyses are planned for the study.


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Demographic, Other Baseline Characteristics and Medication
Subject Disposition and Withdrawals
A summary table will be produced for all subjects detailing the number of subjects screened, screen failed 
and randomized, the number and percentages of all subjects in each analysis populations (Consented 
Subject Set, Biomarker Set, Full Analysis Set), subjects who completed the study, and subjects who 
prematurely discontinued the study. In addition, reasons leading to discontinuation from study will be 
summarized for all subjects for each treatment group. A listing of subject disposition will also be provided
for all subjects.
Subjects in each analysis population, and those excluded from each analysis population (CSS, BS, FAS) 
and reasons for exclusion will be listed. 
Screen failures are defined as all subjects who sign the informed consent but are not enrolled into the 
study. 
Demographic and Baseline Characteristics
Descriptive summaries of demographic and baseline characteristics will be tabulated by treatment group 
for the Full Analysis Set.
The following characteristics will be summarized: 
x
Study eye
x
Age at screening (years)
x
Gender 
x
Childbearing potential for females
x
Race
x
Ethnicity
x
Genetic Profile
x
Length of Prior Anti-VEGF Treatment (years)
x
Previous anti-VEGF treatment 
Genetic profile is based on a blood sample for exploratory genetics and will first be classified by Rare 
(presence of rare genetic variant) or Complotype Variant. The categories will be Rare, Complotype, 
402HH, 402HY, and 402YY. First, the number and percent of subjects with rare genetic variants will be 
summarized; appearing in the summary table as “Rare”. Second, the number and percent of subjects with 
Complotype variant (but not Rare) will be summarized. Finally, for subjects that are neither Rare nor 
Complotype, categories of 402HH, 402HY, and 402YY will be summarized. 
Genetic profile for Sub-Type HTRA/ARMS2 Variant will also be summarized.
The following baseline characteristics are observed at screening and/or baseline and will be summarized 
for the Full Analysis Set. In case of multiple measurements, the last available value before first application 
of the study drug will be used for summary tables.
x
NEI-VFQ-25 composite score
x
MNRead score (study eye)
x
MNRead score (fellow eye)
x
MNRead score (OU)


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x
MA size (mm2) (study eye)
x
MA size (mm2) (fellow eye)
x
Center Point Thickness (CPT) (study eye)
x
Center Point Thickness (CPT) (fellow eye)
x
Center Subfield Thickness (CST) (study eye)
x
Center Subfield Thickness (CST) (fellow eye)
x
BCVA measured by ETDRS letter score (study eye)
x
BCVA measured by ETDRS letter score (fellow eye)
x
LLVA measured by ETDRS letter score (study eye)
x
LLVA measured by ETDRS letter score (fellow eye)
x
Total CNV Area (study eye)
x
Total CNV Area (fellow eye)
x
Total Lesion Area Within ETDRS Grid (study eye)
x
Total Lesion Area Within ETDRS Grid (fellow eye)
Descriptive statistics will be provided for each continuous variable; whereas, frequencies and 
percentages will be provided for categorical variables. Calculation for length of prior anti-VEGF treatment 
is described below: 

Length of Prior Anti-VEGF Treatment (years) = (End date of prior anti-VEGF treatment - Start 
date of prior anti-VEGF treatment +1)/365.25
Medical History
Ocular and Non-Ocular Medical History will be summarized for the Full Analysis Set using Medical 
Dictionary for Regulatory Activities (MedDRA) system organ class (SOC) and preferred term (PT). The 
reported medical history terms will be coded using MedDRA Version 23.0 or higher. A subject 
experiencing a medical history within more than one SOC and PT will be counted only once within that 
SOC and PT, respectively. Medical History will be sorted by the highest occurrence in the GEM103+SoC
treatment group in decreasing order.
Medical history findings will also be listed by subject for the Full Analysis Set.
Medication and Procedures
All prior and concomitant medications and procedures will be classified using the Anatomical Therapeutic 
Chemical (ATC) classification codes and preferred drug names from the World Health Organization Drug 
Dictionary (WHO-DD), September 2020 or later.
Summaries of prior and concomitant medications and procedures will be presented for the Full Analysis 
Set separately in tabular form using the forth-level ATC term as an upper classification level and the 
preferred drug name as a lower classification level. All medications and procedures will be summarized 
and sorted by descending frequency of ATC level 4 and preferred drug name within a given ATC level 4 
term. If the medication or procedure does not have an ATC level 4 term, the ATC level 3 term is used. If 
the ATC level 3 term is also unavailable, the ATC level 2 term is used. The summary will consist of the 
frequency and percent of subjects who used the medication or procedure at least once. Medications and 
procedures will be listed separately.


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Prior and concomitant anti-VEGF therapy will be summarized by study eye and fellow eye similiary in 
addition to overall prior and concomitant medications and procedures.  
Prior Medication/Procedure
Any medication or procedure that started prior and did not continue on or after the first dose of study 
treatment will be classified as prior.
Concomitant Medication/Procedure
Any medication or procedure taken during the study period, including those which started before the first 
dose study treatment, but were reported ongoing at the first administration, will be classified as 
concomitant.


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Efficacy
All efficacy parameters will be summarized and presented in tables based on the Full Analysis Set (FAS).
Subjects will be analyzed as members of the treatment group to which they were randomized to. All CRF 
data will be listed, where applicable.
Observed values and changes from baseline for each secondary and exploratory endpoint in Section 5
will be summarized with descriptive statistics at each scheduled time point for the study eye. Subjects will 
be presented by treatment group. Study eye will be identified during the screening process. If both eyes 
meet all eye-specific entry criteria, then the study eye will be determined by the Investigator and the 
subject together.
For continuous data, a two-sided paired t-test will be used to test if the mean change from baseline at a 
scheduled timepoint is significantly different from zero at a 5% significance level. The 95% confidence 
interval (CI) for the mean change from baseline, the standard error of the mean, and the t-test p value will 
be presented. In addition, a two-sample t-test will be used to test if the mean change from baseline is 
significantly different from zero at a 5% significance level between GEM+SoC and Sham+SoC for best-
corrected visual acuity (BCVA), low luminance visual acuity (LLVA), and Macular Atrophy (MA) size. 
A figure will be provided for BCVA Score, LLVA Score, and MA size displaying the mean change from 
baseline and standard error for each treatment group by study eye and fellow eye plotted over time. 
Best Corrected Visual Acuity (BCVA) 
Best-corrected visual acuity (BCVA) assessment is done prior to dosing, as applicable. The mean 
change from baseline in BCVA score will be summarized, along with observed values, at each scheduled 
timepoint using the Early Treatment Diabetic Retinopathy Study (ETDRS) method for each treatment 
group, as specified in Section 7.1 for continuous data. Baseline will be taken as the last available non-
missing assessment prior to first study drug administration. 
The proportion of subjects with an increase from baseline of 15, 10, and 5 letters or more in BCVA using 
the ETDRS method will be summarized using descriptive statistics. Subjects will be considered to be 
fulfilling this criterion if they show a change from baseline value in BCVA of greater than or equal to 15, 
10, or 5 letters, respectively. The number and proportion of subjects will be calculated for each time point. 
The denominator of the proportion will be the number of subjects who have a non-missing value for BCVA 
assessment at the specified visit.
Low Luminance Visual Acuity (LLVA)
Low luminance visual acuity (LLVA) assessment is done prior to dosing, as applicable.  The mean 
change from baseline in LLVA score will be summarized, along with observed values, at each scheduled 
timepoint using the Early Treatment Diabetic Retinopathy Study (ETDRS) method for each treatment 
group, as specified in Section 7.1 for continuous data. Baseline will be taken as the last available non-
missing assessment prior to first study drug administration.
The analysis of the proportion of subject with an increase from baseline of 15, 10, and 5 letters or more in 
BCVA specified in Section 9.1 will be conducted for LLVA. 


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Macular Atrophy (MA) Size
Mean change from baseline in size of Macular Atrophy as evaluated by fundus autofluorescence (FAF)
will be summarized as a continuous variable for each treatment group for the study eye and fellow eye. 
Results for macular atrophy area size will be obtained from the data vendor Eyekor by FAF/NIR Grading 
Form question “Area and proximity of Hypo FAF” as specified in the Imaging & Grading Charter Revision 
1.0, 20-Jan-2021. Area size results will be used to calculate mean change from baseline; the range is 
from 0-42.00 and the units are mm2. Results of 0 mm2 will be included in the calculation of change from
baseline. Results of “Cannot Grade”, “Not Applicable”, or missing will not be used. 
If area size is missing but result for question “Macular atrophy presence at center point” is “Absent”, area 
size result of 0 mm2 will be imputed for that timepoint.
New Macular Atrophy (MA)
Incidence of new Macular Atrophy as evaluated by Fundus Autofluorescence (FAF) will be summarized 
using descriptive statistics for each treatment group for the study eye and fellow eye. 
Two summaries will be performed:
Presence of Macular Atrophy by Visit
Categorical analyses of presence of MA status derived from FAF will be based on the categorical variable 
“Macular atrophy presence Presence of hypo FAF and associated hypertransmission on OCT” included 
in the Imaging & Grading Charter. Incidence will be summarized by visit including baseline. Categories 
will be summarized by “Present” and “Not Present”. If results are either “Absent” or “Questionable” then 
MA is not present. If the results are “Definite” then MA is present. Results of “Cannot Grade”, “Not 
Applicable”, or missing will not be used for analysis.
Presence of New Macular Atrophy Since Last Visit
Categorical analyses of presence of new MA status derived from FAF will be based on the categorical 
variable “*Presence of new macular atrophy New area(s) of hypo FAF since last visit” included in the
Imaging & Grading Charter. Incidence will be summarized by visit. Categories will be summarized by 
“Present”. Category of “Not Present” will not be summarized.  If results are either “Absent” or 
“Questionable” then MA is not present. If the results are “Definite” then MA is present. Results of “Cannot 
Grade”, “Not Applicable”, or missing will not be used for analysis. The denominator will be the number of 
subjects who have “Absent” or “Questionable” for Presence of Macular Atrophy at Baseline.
Choroidal Neovascularization (CNV)
Mean reduction from baseline in choroidal neovascularization (CNV) size as evaluated by fluorescein 
angiography (FA) will be summarized using descriptive statistics for each treatment group for the study 
eye and fellow eye. 
Two analyses of CNV size derived from FA will be performed based on results obtained from the Image & 
Grading Charter under FA Grading Form question ”Total CNV area” and “Total lesion area within ETDRS 
grid”. Area size results will be used to calculate mean change from baseline; the range is from 0-42.00
and the units are mm2. Results of 0 mm2 will be included in the calculation of change from baseline. 
Results of “Cannot Grade”, “Not Applicable”, or missing will not be used for analysis.


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Retinal Layer Thickness 
Mean change from baseline in Center Point Thickness (CPT) and Central Subfield Thickness (CST) in 
millimeters (mm) as evaluated by Spectral Domain Optical Coherence Tomography (SD-OCT) will be 
summarized as a continuous variable for each treatment group for the study eye and fellow eye. 
Results for retinal layer thickness will be obtained from Image & Grading Charter SD-OCT Grading Form
field “Retinal thickness grid”, where variable CENTTHC captures Center Point Thickness and variable 
THSECC captures Center Subfield Thickness. The range for retinal thickness is from 0-2mm. Results of 0 
mm will be included in the calculation of change from baseline. Results of “Cannot Grade”, “Not 
Applicable”, or missing will not be used. 
Subretinal and Intraretinal Fluid
Proportion of patients with intraretinal and subretinal fluid, IRF and SRF respectively, as evaluated by SD-
OCT, will be summarized using descriptive statistics for each treatment group for the study eye and fellow
eye.
Three separate analyses of incidence of existing fluid will be performed based on the Image & Grading 
Charter SD-OCT Grading Form fields “IRF” and “SRF”. They include: Intraretinal Fluid (IRF) presence, 
Subretinal Fluid (SRF) presence, and combined IRF and SRF presence.
IRF
Results of “Definite, outside center subfield only”, “Definite, only non-cystoid, center subfield involved”, 
and “Definite, cystoid, center subfield involved” will correspond to present existing fluid, and will be 
summarized separately by the number and percent of subjects reporting each category. Results of 
“Absent” or “Questionable” will correspond to no present existing fluid. Results of “Cannot Grade”, “Not 
Applicable”, or missing will not be used for analysis.
SRF
Results of “Definite, outside center subfield only”, and “Definite, center subfield involved”, will correspond 
to present existing fluid, and will be summarized separately by the number and percent of subjects 
reporting each category. Results of “Absent” or “Questionable” will correspond to no present existing fluid. 
Results of “Cannot Grade”, “Not Applicable”, or missing will not be used for analysis.
IRF or SRF Combined
Results of IRF or SRF will be combined using same derivation of existing fluid specified in section 9.7.1 
and 9.7.2. Only “Present” and “Not Present” will be summarized.
National Eye Institute Visual Functioning Questionnaire 25-item Version (NEI-VFQ-25) 
Mean change from baseline in NEI-VFQ-25 will be summarized using descriptive statistics for each 
treatment group. 
The NEI-VFQ-25 composite score and sub-scale scores will be evaluated at each visit (baseline, month 6 
– day 181, and month 12 /EOS). The calculation for NEI-VFQ-25 sub-scale scores and composite score 
will be performed according to the “NEI VFQ-25 Scoring Algorithm – August 2000”. The most important 
instructions are displayed in appendix 16.1.
The scores and their changes from baseline to all post-baseline visits in the NEI VFQ-25 composite score 


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will be summarized descriptively, including p-value and 95% confidence intervals for the changes.
Minnesota Low-vision Reading Test (MNRead) 
The MNRead acuity cards are continuous-text reading acuity cards suitable for measuring the reading 
acuity and reading speed of normal and low-vision subjects. Mean change from baseline in MNRead
maximum reading speed will be summarized using descriptive statistics for each treatment group for the 
study eye, fellow eye, and both eyes (OU). Maximum reading speed is obtained from CRF MNRead 
Reading Assessment Chart 1, 2, and 3.
Formula for reading speed (words per minute) for each sentence is as follows: reading speed = 60 x (10 -
errors) / (time in seconds)


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Safety
The population used for safety analyses will be the Full Analysis Set (FAS). Safety will be assessed 
based on adverse event (AE), clinical laboratory data (hematology and clinical chemistry), physical 
examinations, vital signs, best-corrected visual acuity (BCVA), biomicroscopy, intraocular pressure (IOP), 
and ophthalmoscopy. Unless otherwise specified, table summaries will be presented by treatment group 
(GEM103+SoC and sham+SoC).
All safety information will be provided in subject listings.
Extent of Exposure
Study drug exposure will be summarized using the treatment duration (days) and number of doses for the 
Full Analysis Set for GEM103 or Sham and for Aflibercept administration. Treatment duration is the 
number of days between first and last study drug injection, defined as last injection date – first injection
date + 1. Continuous variables will be summarized with descriptive statistics of mean, SD, median, 
minimum, and maximum. 
Adverse Events
All adverse events will be classified by System Organ Class (SOC) and Preferred Term (PT) using 
MedDRA version 23.0.
A treatment-emergent AE (TEAE) is defined as any event not present before exposure to study treatment 
or any event already present that worsens in either intensity or frequency after exposure to study 
treatment.
A treatment-related intraocular adverse event (AE) is defined as any adverse event that is study 
medication-related and an ocular event, either right eye (OD) or left eye (OS).
An overall summary of TEAEs will be tabulated across all treatment groups, including the number and 
percent of subjects reporting the following categories:
x
TEAEs
x
Serious TEAEs
x
Study Drug-related Only TEAEs (not Study Procedure-related)
x
Study Drug-related Only Serious TEAEs (not Study Procedure-related)
x
Study Procedure-related TEAEs (not Study Drug-related)
x
Study Procedure-related Serious TEAEs (not Study Drug-related)
x
Study Drug- and Study Procedure-related TEAEs
x
Study Drug- and Study Procedure-related Serious TEAEs
x
TEAEs with a Severity of Severe
x
TEAEs leading to Permanent Discontinuation of study medication
Each category will be further summarized by Non-Ocular and Ocular relation. For the TEAEs that are 
categorized as Ocular-realted, a sub-category will include summarization by Study Eye and Fellow Eye.
A summary table of TEAEs (number and percentage of subjects who experienced an AE) grouped by 
primary SOC and PT will be presented across all treatment groups for the following categories of events:

All TEAEs


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
All Serious TEAEs

All Study Drug-related TEAEs 

All Study Drug-related Serious TEAEs 

All Study Procedure-related TEAEs 

All Study Procedure-related Serious TEAEs 

All Study Drug and Study Procedure-related TEAEs 

All Study Drug and Study Procedure-related Serious TEAEs 

All TEAEs by maximum severity

All TEAEs leading to study drug discontinuation

All TEAEs by Outcome
All summary tables will include separate summarization by Ocular and Non-Ocular-related TEAEs. For 
the TEAEs that are categorized as Ocular-realted, they will also be summarized by Study Eye and Fellow 
Eye.
AEs are assessed with respect to relationship status by the investigator, as not related, unlikely related, 
possibly related, probably related, and definitely related. An AE would be categorized in statistical 
presentations as “treatment-related” if it is assessed by the investigator as possibly related, probably 
related, or definitely related.  
A subject with more than one occurrence of the same AE in a particular SOC and PT will be counted only 
once in the total of subjects experiencing AEs in that particular SOC and PT, respectively. If a subject 
experiences the same AE at more than one severity, or with more than one relationship category, the 
most severe rating or the stronger causal relationship will be reported.
Any missing severity or relationship of an AE should be replaced by the worst case as follows:

If severity is missing, then the AE will be included in the “Severe” category

If relationship is missing, then the AE will be included as “treatment-related”
The tables will be sorted by descending frequency of SOC and then, within a SOC, by descending 
frequency of PT based on the subject count for the GEM103+SoC column.
All AEs will be listed by subject and chronologically by date and time of AE onset. This listing will include 
all data collected in the eCRF and the coded variables. Additional listings of SAEs, study-drug related 
TEAEs, AEs leading to discontinuation of study treatment, and deaths will be provided.
Laboratory Evaluations
Clinical laboratory tests will be performed at prespecified time points per the Schedule of Assessments in 
Appendix A of Protocol. 
A central study laboratory will be used for all protocol-specified clinical laboratory parameters.
Laboratory results will be displayed using standard units for all summaries and listings. Laboratory results 
collected in conventional units will be converted to International System of Units (SI) for all summaries 
and listings.
Shift tables using categories of low, normal, and high, comparing laboratory test results from Baseline to 
each visit will be presented with percentages based on subjects with a non-missing value at Baseline and 
post-baseline visit.  


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All laboratory values (including values, reference ranges, and possible flags (low, high)) will be presented 
in the subject data listings.
Clinical safety laboratory assessments include the following: hematology (platelet count, red blood cell 
count, hemoglobin count, hematocrit, mean corpuscular volume, mean corpuscular hemoglobin, percent 
reticulocytes, and white blood cell count with differential) and clinical chemistry (blood urea nitrogen, 
creatinine, glucose, potassium, sodium, total calcium, aspartate aminotransferase, alanine 
aminotransferase, alkaline phosphatase, total and direct bilirubin, total protein, standard electrolytes –
magnesium, phosphate, and chloride).
Vital Signs 
Vital sign measurements will consist of systolic and diastolic blood pressures (mmHg), heart rate (beats 
per minute), respiratory rate (breaths per minute), and body temperature (°C). Descriptive summaries 
(number of subjects, mean, standard deviation, median, minimum, and maximum) of actual values and 
changes from baseline will be presented for each visit and time point for each treatment group. Vital signs
will be performed at prespecified time points per the Schedule of Assessments in Appendix A of the
Protocol. 
Vital signs data will be listed chronologically by subject and visit for each vital sign parameter. 
ECG
A 12-lead electrocardiogram (ECG) will be taken at screening, after lying supine for 5 minutes, as part of 
the cardiac examination. The results will be recorded as normal, abnormal not clinically significant, and 
abnormal clinically significant on the eCRF. 
Physical Examination
A complete physical examination will include examination of the following parameters and body systems: 
general appearance, skin, HEENT (head, eyes, ears, nose, throat), heart, lungs, abdomen, 
extremities/joints, and neurological status. Abnormal findings will be recorded in the eCRF and referred for 
appropriate investigation by a primary care physician or other healthcare provider at the determination of 
the Investigator. A physical examination summary of abnormal clinically significant findings by assessment 
visit and body system will be provided.
A by-subject listing will be provided, including body system and result by treatment group.
Slit Lamp Examination 
Ocular Biomicroscopic Examination will be performed with findings reported for Lids/Lashes, Conjunctiva, 
Cornea, Anterior Chamber, and Iris/Pupil. In addition, Ophthalmoscopy Examation will be performed with 
findings reported for Vitreous, Optic Nerve, Macula, and Retina Periphery. The findings will be listed by 
subject.
Lens Status and Opacification will be summarized by the number and proportion of subjects with each 
status and opacification (Phakic, Pseudophakic, Aphakic). Nuclear Cataract, Cortical Cataract, and 
Posterior Subcapsular Cataract categories will be further summarized by severity grade. The findings will 
be listed by subject.


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The following Biomicroscopic (BMC) and Ophthalmoscopy (OPH) structures will be summarized by the 
number and proportion of subjects with each finding:
x
BMC – Lids/Lashes
x
BMC – Conjuctiva
x
BMC – Iris/Pupil
x
OPH – Optic Nerve
x
OPH – Retina Periphery
x
OPH – Macula
The following Biomicroscopic (BMC) and Ophthalmoscopy (OPH) structures will be summarized by the 
number and proportion of subjects with each finding and severity grade:
x
BMC – Anterior Chamber
x
BMC – Cornea
x
OPH – Vitreous
Intraocular Pressure (IOP)
The number and proportion of subjects with an increase in intraocular pressure (IOP) of 10 mm Hg or 
more from each pre-dose assessment will be calculated for each time point for the study eye. 
IOP will also be summarized by study visit and change from each pre-dose assessment using descriptive 
statistics for continious variables.
The findings will be listed by subject.
Best-corrected Visual Acuity (BCVA)
The proportion of subjects with a loss from baseline of 15, 10, and 5 letters or more in BCVA using the 
ETDRS method will be summarized using descriptive statistics. Subjects will be considered to be fulfilling 
this criterion if they show a change from baseline value in BCVA of less than or equal to 15, 10, or 5 
letters, respectively. The number and proportion of subjects will be calculated for each time point. The 
denominator of the proportion will be the number of subjects who have a non-missing value for BCVA 
assessment at the specified visit.
Low Luminance Visual Acuity (LLVA)
The proportion of subjects with a loss from baseline of 15, 10, and 5 letters or more in LLVA using the 
ETDRS method will be summarized using descriptive statistics. Subjects will be considered to be fulfilling 
this criterion if they show a change from baseline value in BCVA of less than or equal to 15, 10, or 5 
letters, respectively. The number and proportion of subjects will be calculated for each time point. The 
denominator of the proportion will be the number of subjects who have a non-missing value for LLVA 
assessment at the specified visit.


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Other Variables
The population used for analyses of variables specified in section 11 will be the Biomarker Set (BS).
Unless otherwise specified, table summaries will be presented by treatment group (GEM103+SoC and 
sham+SoC).
Plasma and Aqueous Humor Concentrations of Total Complement Factor H (CFH)
Observed continuous total complement factor H (CFH) concentration level in aqueous humor (ng/mL) and 
plasma data will be summarized by type of biological matrix by treatment group using descriptive statistics. 
Changes from baseline will also be presented for all continuous parameters by treatment group over time. 
A two-sided paired t-test and 95% confidence interval (CI) will be summarized for the mean change from 
baseline as specified in Section 9.
All total CFH values will be presented in the subject data listings.
A figure will be provided for CFH displaying the mean change from baseline and standard error for each 
treatment group plotted over time.
Generation of Serum GEM103 Antidrug Antibodies (ADA)
Shift tables using categories of negative, positive, and total, comparing ADA test results from Baseline to 
each visit will be presented with percentages based on subjects with a non-missing value at Baseline and 
post-baseline visit.  
All ADA values will be presented in the subject data listings.
Biomarkers in Aqueous Humor
Observed continuous biomarker level data will be summarized type of biological matrix by treatment group 
using descriptive statistics. Changes from baseline will also be presented for all continuous parameters by 
treatment group over time. A two-sided paired t-test and 95% confidence interval (CI) will be summarized 
for the mean change from baseline as specified in Section 9.
All biomarker values will be presented in the subject data listings.
A figure will be provided for Biomarkers displaying the mean change from baseline and standard error for 
each treatment group plotted over time.


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Interim Analyses
An interim analysis will be conducted on a subset of endpoints. Given the study is single-masked, where 
the subject is masked to their treatment assignment, there will not be unmasking activites by Syneos 
Health. A complete list of TFLs are to be determined.


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Changes from Analysis Planned in Protocol
Not Applicable. 


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Reference List
Protocol: A Multicenter, Multiple-Dose Study in Neovascular Age-Related Macular Degeneration (nAMD) 
to Evaluate the Safety, Tolerability, Pharmacodynamics, Immunogenicity, and Clinical Effect of Repeat 
Intravitreal (IVT) Injections of GEM103 as an Adjunct to Standard of Care Aflibercept Therapy.
Mangione, CM. NEI VFQ-25 Scoring Algorithm – August 2000, Version 2000, The National Eye Institute 
25-Item, Visual Function Questionnaire (VFQ-25)


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Programming Considerations
All TFLs), and statistical analyses will be generated using SAS for Windows, Release 9.4 (SAS Institute 
Inc., Cary, NC, USA). Computer-generated TFL output will adhere to the following specifications.  
General Considerations
x
One SAS program can create several outputs
x
Each output will be stored in a separate file
x
Output files will be delivered in Word format or portable document format pdf
x
Numbering of tables, listings and figures (TLFs) will follow International Conference on 
Harmonisation (ICH) E3 guidance
Table, Figure, and Listing Format
General
x
All TFLs will be produced in landscape format on A4/American letter size, unless otherwise 
specified.
x
All TFLs will be produced using the Courier New font, size 8 which is the smallest acceptable point 
size for the Regulatory Authorities.
x
The data displays for all TFLs will have a minimum blank 1-inch margin on all 4 sides.
x
Headers and footers for figures will be in Courier New font, size 8 which is the smallest acceptable 
point size for the Regulatory Authorities.
x
Legends will be used for all figures with more than 1 variable, group, or item displayed.
x
TFLs will be in black and white (no color), unless otherwise specified
x
Specialized text styles, such as bolding, italics, borders, shading, and superscripted and 
subscripted text, will not be used in the TFLs, unless otherwise specified. On some occasions, 
superscripts 1, 2, or 3 may be used.
x
Only standard keyboard characters will be used in the TFLs. Special characters, such as 
non-printable control characters, printer-specific, or font-specific characters, will not be used. 
Hexadecimal-derived characters will be used, where possible, if they are appropriate to help 
display math symbols (eg, μ). Certain subscripts and superscripts (e.g., cm2, Cmax) will be 
employed on a case-by-case basis.
x
Mixed case will be used for all titles, footnotes, column headers, and programmer-supplied formats, 
as appropriate.
Headers
x
All output should have the following header at the top left of each page:
Gemini Therapeutics, Inc.


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Protocol No: GEM-CL-10311
x
All output will have Page X of Y at the top or bottom right corner of each page. TFLs are internally 
paginated in relation to the total length (ie, the page number will appear sequentially as page n of 
N, where N is the total number of pages in the table)
x
The date the output was generated will appear along with the program name as a footer on each 
page
Display Titles
x
Each TFL are identified by the designation and a numeral. (ie, Table 14.1.1). ICH E3 numbering is 
strongly recommended, but sponsor preferences are obtained before final determination A decimal 
system (x.y and x.y.z) are used to identify TFLs with related contents. The title is centered. The 
analysis set are identified on the line immediately following the title. The title and table designation 
are single spaced. A solid line spanning the margins will separate the display titles from the body.
Table x.y.z
First Line of Title
Second Line of Title if Needed
(Full Analysis Set)
Column Headers
x
Column headings are displayed immediately below the solid line described above in initial upper-
case characters.
x
In the case of efficacy tables, the variable (or characteristic) column will be on the far left followed 
by the treatment group columns and total column (if applicable). 
x
For numeric variables, include “unit” in column or row heading when appropriate.
x
Analysis set sizes will be presented for each treatment group in the column heading as (N=xx) (or 
in the row headings, if applicable). This is distinct from the ‘n’ used for the descriptive statistics 
representing the number of subjects in the analysis set
x
The order of treatments in the tables and listings will be Active comparators first in the case of 
active comparator trials, followed by a total column (if applicable)
Body of the Data Display
15.2.5.1.
General Conventions
Data in columns of a table or listing are formatted as follows:
x
Alphanumeric values will be left-justified;
x
Whole numbers (eg, counts) will be right-justified; and
x
Numbers containing fractional portions will be decimal aligned.


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15.2.5.2. 
Table Conventions 
x Units will be included where available 
x For categorical parameters, all categories will be presented in the table, even if n = 0 for all 
treatment groups in a given category. For example, the frequency distribution for symptom severity 
would appear as: 
Severity Rating 
N 
severe 
0 
moderate 
8 
mild 
3 
 
Where percentages are presented in these tables, zero percentages will not be presented and so counts 
of 0 will be presented as 0 and not as 0 (0%). 
x If the categories are not ordered (e.g., Medical History, Reasons for Discontinuation from the 
Study, etc.), then only those categories for which there is at least 1 subject represented in 1 or 
more groups are included. 
x An Unknown or Missing category will be added to each parameter for which information is not 
available for 1 or more subjects 
x Unless otherwise specified, the estimated mean and median for a set of values will be printed out 
to 1 more significant digit than the original values, and standard deviations will be printed out to 
2 more significant digits than the original values. The minimum and maximum will report the same 
significant digits as the original values. For example, systolic blood pressure will be presented as 
follows: 
N 
 XX 
Mean 
XXX.X 
Std Dev 
   X.XX 
Median 
XXX.X 
Minimum 
XXX 
Maximum 
XXX 
x Percentage values are printed to one decimal place, in parentheses with no spaces, one space 
after the count (eg, 7 (12.8%), 13 (5.4%)). Pre-determine how to display values that round down to 
0.0.  A common convention is to display as '< 0.1', or as appropriate with additional decimal places. 
Unless otherwise noted, for all percentages, the number of subjects in the analysis set for the 
treatment group who have an observation will be the denominator. Percentages after zero counts 
should not be displayed and percentages equating to 100% are presented as 100%, without 
decimal places.  
x Tabular display of data for medical history, prior/concomitant medications, and all tabular displays 
of adverse event data will be presented by the body system, treatment class, or SOC with the 
highest occurrence in the active treatment group in decreasing order, assuming all terms are 
coded. Within the body system, drug class and SOC, medical history (by PT), drugs (by ATC1 
code), and AEs (by PT) will be displayed in decreasing order. If incidence for more than 1 term is 


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identical, they will then be sorted alphabetically. Missing descriptive statistics or p-values which 
cannot be estimated will be reported as ‘-’.
x
The percentage of subjects will normally be calculated as a proportion of the number of subjects 
assessed in the relevant treatment group (or overall) for the analysis set presented. However, 
careful consideration is required in many instances due to the complicated nature of selecting the 
denominator, usually the appropriate number of subjects exposed. Details will be described in 
footnotes or programming notes, as necessary.
x
For categorical summaries (number and percentage of subjects) where a subject can be included 
in more than one category, a footnote or programming note will be added describing whether the 
subject is included in the summary statistics for all relevant categories or just 1 category as well as
the selection criteria
x
Where a category with a subheading (such as SOC) has to be split over more than 1 page, output 
the subheading followed by ‘(cont)’ at the top of each subsequent page. The overall summary 
statistics for the subheading should only be output on the first relevant page
15.2.5.3.
Listing Conventions
x
Listings will be sorted for presentation in order of treatment groups as above, subject number, 
visit/collection day, and visit/collection time.
x
Missing data will be represented on subject listings as either a hyphen (‘-’) with a corresponding 
footnote (‘- = unknown or not evaluated’), or as ‘N/A’, with the footnote ‘N/A = not applicable’, 
whichever is appropriate.
x
Dates will be printed in SAS DATE9.format (‘DD_MMM_YYYY’: 01JUL2000). Missing portions of 
dates will be represented on subject listings as dashes (--JUL2000). Dates that are missing 
because they are not applicable for the subject will be output as ‘N/A’, unless otherwise specified.
x
All observed time values will be presented using a 24-hour clock HH:MM or HH:MM:SS format 
(e.g., 11:26:45, or 11:26). Time will only be reported if it was measured as part of the study.
x
Units will be included where available.
15.2.5.4.
Figure Conventions
x
Unless otherwise specified, for all figures, study visits will be displayed on the X-axis and endpoint 
(eg, treatment mean change from Baseline) values will be displayed on the Y-axis.
Footnotes
x
A solid line spanning the margins will separate the body of the data display from the footnotes. 
x
All footnotes will be left justified with single-line spacing immediately below the solid line 
underneath the data display.
x
Footnotes will always begin with ‘Note:’ if an informational footnote, or 1, 2, 3, etc. if a reference 
footnote. Each new footnote will start on a new line, where possible.
x
Subject specific footnotes are avoided, where possible.


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x Footnotes will be used sparingly and add value to the TFL. If more than six lines of footnotes are 
planned, then a cover page is strongly recommended to be used to display footnotes, and only 
those essential to comprehension of the data will be repeated on each page. 
x The last line of the footnote section will be a standard source line that indicates the name of the 
program used to produce the data display, the date the program was run, and the listing source (ie, 
‘Program : myprogram.sas  Listing source: 16.x.y.z’) 
x Sources and/or cross-references in footnotes will use the keyword prefix (in singular form) for each 
reference and will be separated by a comma when multiple cross-references are displayed. 
Example 
Listing source: Listing 16.2.4.1.1, Listing 16.2.4.1.2, Listing 16.2.4.2.1 


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Quality Control
SAS programs are developed to produce output such as analysis data sets, summary tables, data 
listings, figures or statistical analyses. An overview of the development of programs is detailed in Syneos 
Health Developing Statistical Programs SOP (3907) .
Syneos Health Developing Statistical Programs SOP (3907), Conducting the Transfer of Biostatistical 
Deliverables SOP (3908) and the SAS Programming and Validation Plan describes the quality control 
procedures that are performed for all SAS programs and output. Quality control is defined here as the 
operational techniques and activities undertaken to verify that the SAS programs produce the output by 
checking for their logic, efficiency and commenting and by review of the produced output.


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Appendices
Calculation of the NEI VFQ-25 scores
The calculation for NEI VFQ-25 sub-scale scores and composite score will be performed according to the 
“NEI VFQ-25 Scoring Algorithm – August 2000“. The most important instructions are displayed below:
The NEI VFQ-25 consists of a base set of 25 vision-targeted questions representing 11 vision-related 
constructs, plus an additional single-item general health rating question.
The NEI VFQ-25 generates the following vision-targeted subscales (number of questions):
x
global vision rating (1),
x
difficulty with near vision activities (3),
x
difficulty with distance vision activities (3),
x
limitations in social functioning due to vision (2),
x
role limitations due to vision (2),
x
dependency on others due to vision (3),
x
mental health symptoms due to vision (4),
x
driving difficulties (3),
x
limitations with peripheral (1),
x
color vision (1), and
x
ocular pain (2).
Additionally, the VFQ-25 contains the single general health rating question which has been shown to be a 
robust predictor of future health and mortality in population-based studies.
Scoring VFQ-25 is a two-step process:
1.
First, original numeric values from the survey are re-coded following the scoring rules outlined in 
Table 16.1. All items are scored so that a high score represents better functioning. Each item is 
then converted to a 0 to 100 scale so that the lowest and highest possible scores are set at 0 and 
100 points, respectively. In this format scores represent the achieved percentage of the total 
possible score, e.g. a score of 50 represents 50% of the highest possible score.
2.
In step 2, items within each sub-scale are averaged together to create the 12 sub-scale scores. 
Table 5 indicates which items contribute to each specific sub-scale. Items that are left blank 
(missing data) are not taken into account when calculating the scale scores. Sub-scales with at 
least one item answered can be used to generate a sub-scale score. Hence, scores represent the 
average for all items in the subscale that the respondent answered.