Conditions: Amyotrophic Lateral Sclerosis Motor Neuron Disease
Keywords: Amyotrophic Lateral Sclerosis ALS Motor Neuron Disease APL-2 APL2 Pegcetacoplan
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 249
Healthy volunteers: no

Brief summary:
This is a 24-month, Phase 2, multicenter, randomized, double-blind, placebo-controlled study to evaluate the efficacy and safety of pegcetacoplan in subjects with amyotrophic lateral sclerosis (ALS)

Detailed description:

Arms:
arm 1: administered subcutaneously twice weekly arm 2: None

Interventions: intervention 1: Pegcetacoplan (APL-2) intervention 2: Placebo
Intervention descriptions: intervention 1: Complement (C3) Inhibitor intervention 2: Sterile solution of equal volume to active arm

Protocol document:
Prot_000.pdf: 
A pellis P har mace uticals, I nc  
Pa ge 1  
 
C o nfi de ntial  
 
 
A P L 2 -A L S - 2 0 6 
 
A P H A S E  2, R A N D O MI Z E D, D O U B L E -B LI N D, 
P L A C E B O- C O N T R O L L E D, M U L TI C E N T E R S T U D Y T O 
E V A L U A T E T H E E F FI C A C Y A N D S A F E T Y O F 
P E G C E T A C O P L A N  I N S U B J E C T S WI T H 
A M Y O T R O P HI C L A T E R A L S C L E R O SI S ( A L S)  
 
 
A M E N D M E N T 6  
 
1 3 J A N U A R Y  2 0 2 3 
 
E u dr a C T n u m ber: 2 0 1 9 - 0 0 3 7 9 7- 1 0 
 
I N D N u m ber: 
 
 
 
C CI




Pegcetacoplan
 
APL2
- ALS
- 206 Protocol Amendment 6
 
13 
January
 202
3 
Apelis Pharmaceuticals, Inc 
Page 
3 
 
Confidential
 
INVESTIGATOR’S AGREMENT
 
 
I have received and read the Investigator’s Brochure for pegcetacoplan. I have read the 
APL2
- ALS
-206 Protocol and agre to conduct the study as outlined. I agre to maintain the 
confidentiality of al information received or developed in conection with this protocol. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Printed Name of Investigator 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Signature of Investigator 
 
 
 
 
 
 
 
 
Date
 




Pegcetacoplan 
APL2-ALS-206 Protocol Amendment 6 
13 January 2023 
Apellis Pharmaceuticals, Inc 
Page 5 
 
Confidential 
Updated the blinding description 
The open-label treatment period and long-term 
extension is treatment periods are not blinded. 
Synopsis 
Changed language to 
reflect that the new 
long-term treatment 
period is also not 
blinded. 
Updated the statistical methodology for the 
secondary efficacy endpoints. 
Synopsis 
Updated to align with 
Section 12.3 
Added the newly approved medication, Relyvrio. 
Section 4.1  
Relyvrio was recently 
approved for the 
treatment of ALS. 
Updated the study summaries to reflect more 
recent report results. 
Section 4.4  
Updates were needed to 
some of the originally 
presented study 
summaries. 
Added the following paragraph which was from 
the French Addendum 5.1: 
Systemic hypersensitivity reactions (eg, facial 
swelling, rash, urticaria) have occurred in patients 
treated with pegcetacoplan. One patient (less than 
1% in clinical studies) experienced a serious allergic 
reaction which resolved after treatment with 
antihistamines. If a severe hypersensitivity reaction 
(including anaphylaxis) occurs, discontinue 
pegcetacoplan infusion immediately, institute 
appropriate treatment, per standard of care, and 
monitor until signs and symptoms are resolved. 
Section 4.5  
Added to the protocol for 
additional information to 
the study sites, it was 
previously included with 
the French Addendum 5.1, 
Amendment 1. 
Updated the language regarding vaccinations to 
provide further clarity. 
Table 2 (footnote b), 
Section 8.4  
Further clarity was 
needed regarding the 
vaccinations. 
Updated the language regarding anti–
pegcetacoplan peptide antibody and anti-PEG 
antibody collection. 
Table 2 (footnote k), 
Table 3 (footnote i), 
Section 11.1.9  
Updated this language to 
more accurately reflect 
the practice of assessing 
these antibodies. 
Added a new footnote (p) regarding returning 
unused investigational product: 
p 
Only subjects not enrolling in Part 4 will 
return unused investigational product 
Table 3 (footnote p) 
Added to provide further 
instructions to the study 
sites. 
Updated the language in footnote m to provide 
further clarity. 
Table 3 (footnote m) 
Further clarity was 
needed regarding IP 
dispensation. 
Updated the definition of the end of the trial from 
the open-label treatment period to the open-label, 
long-term extension period 
Section 6.5, Section 7.3  
Updated as there is now a 
longer opportunity for 
treatment. 
Updated Section 6.6.6 to be Early Termination 
Follow-Up Visit (previously was Section 6.6.5) 
Created a new Section 6.6.7, Unscheduled Visit(s) 
(previously was Section 6.6.6) 
Section 6.6.6, 
Section 6.6.7  
Sections needed to move 
down due to the addition 
of the new Section 6.6.5 
which describes the new 
open-label long-term 
extension period. 


Pe gcetac o pla n  
A P L 2 -A L S -2 0 6 Pr ot oc ol A me n d me nt 6  
1 3 Ja n uar y 2 0 2 3 
A pellis P har mace uticals, I nc  
Pa ge 6  
 
C o nfi de ntial  
Pre vi o us Secti o n 6. 6. 6, U nsc he d ule d Visit(s) has 
bee n m o ve d t o Secti o n 6. 6. 7  
Secti o n  6. 6. 7  
M o ve d t o i nc or p orate 
ne w secti o n.  
A d de d la n g ua ge  re gar di n g s ur vi val stat us f or 
s u bjects w h o wit h dra w fr o m t he st u d y: 
If a s u bject wit h dra ws fr o m t he st u d y, t he n t he 
s u bject a n d/ or t heir care gi vers will be c o ntacte d 
b y t he st u d y site t o pr o vi de p ost -disc o nti n uati o n 
s ur vi val stat us at 6-m o nt h i nter vals u ntil t he st u d y 
c o m pletes.  
Secti o n  7. 3   
A d de d la n g ua ge t o 
c ollect s ur vi val stat us of 
s u bjects w h o ha ve 
wit h dra w n  fr o m t he 
st u d y. 
U p date d t he f oll o wi n g: 
S u bjects are re q uire d t o disc o nti n ue t he 
i n vesti gati o nal pr o d uct a n d wit h dra w fr o m t he 
st u d y if t he y meet t he bel o w criteria: 
•  
A d mi nister a pr o hi bite d  
me dicati o n(s) c o m ple me nt i n hi bit or  
d uri n g t he peri o d o utli ne d i n 
Secti o n  8. 6. 1.  
•  
I nte nti o nall y u n bli n de d t he msel ves. 
Secti o n  7. 3. 1. 1   
U p dat e d  the la n g ua ge t o 
m ore acc uratel y reflect  
t he i nten ti o n of t his 
reas o n f or re q uiri n g a 
s u bject t o wit h dra w. 
A d de d la n g ua ge t o clarif y t hat b ot h ril uz ole a n d 
e dara v o ne ca n n ot be i nitiate d  d uri n g Part 2 of t he 
st u d y.   
Als o, t he f oll o wi n g ne w la n g ua ge was a d de d t o 
t his secti o n: 
•  
S u bjects s h o ul d n ot be gi n Rel y vri o  
( A M X 0 0 3 5) d uri n g Part 2 of t he st u d y 
a n d if a d mi nistere d d uri n g Part 3 or 4, 
t he dates of a d mi nistrati o n m ust be 
d oc u me nte d i n t he s u bject’s s o urce 
d oc u me nt a n d s u bject’s e C R F.  
Secti o n  8. 5   
Clarificati o n nee de d t hat 
ril uz ole a n d e dara v o ne 
are n ot all o we d t o be 
i nitiate d d uri n g Part 2 of 
t he st u d y. 
Rel y vri o  was ne wl y 
a p pr o ve d f or t he treat me nt 
of A L S a n d t his secti o n 
pr o vi des g ui da nce 
re gar di n g if a n d w he n it 
ca n be c o nc o mita ntl y 
a d mi nistere d d uri n g t his 
st u d y 
A d de d t he n u m ber of c ollecti o n ti me p oi nts f or 
t he ne w o pe n-la bel, l o n g-ter m e xte nsi o n peri o d. 
U p d ate d t he sa m ple v ol u me  a m o u nts o ver t he 
c o urse of t he st u d y t o reflect t he a d diti o nal 
c ollecti o n ti me p oi nts .  
Ta ble  5  
U p dates necessar y t o 
reflect t he ne wl y a d de d 
o pe n -la bel, l o n g-ter m 
e xte nsi o n peri o d. 
A d de d t he f oll o wi n g la n g ua ge: 
All deat h e ve nts s h o ul d be re p orte d as t he fatal 
o utc o me of a n S A E, wit h t he date a n d ca use of 
deat h i ncl u de d. T he me dical e ve nt lea di n g t o t he 
s u bject’s deat h (e g, res pirat or y fail ure, 
p ne u m o nia) s h o ul d be re p orte d as t he S A E ter m. 
If n o alter nati ve ca use of deat h is i de ntifie d, 
“ pr o gressi o n of A L S” ma y be re p orte d as t he 
e ve nt ter m if dee me d me dicall y a p pr o priate b y t he 
i n vesti gat or. 
Secti o n  1 1. 2. 1. 3   
T his c ha n ge clarifies t hat 
all deat h e ve nts m ust be 
rec or de d as t he o utc o me 
of a n S A E.  


Pegcetacoplan 
APL2-ALS-206 Protocol Amendment 6 
13 January 2023 
Apellis Pharmaceuticals, Inc 
Page 7 
 
Confidential 
Updated language as follows: 
Serious events (including events related to 
efficacy endpoints) that are considered 
ALS-related should be reported as “not related” 
SAEs. “ALS” or “disease progression” should not 
be reported as event terms if a more precise term 
for the , but instead the complication or actual 
cause of hospitalization/death (eg, respiratory 
failure) shouldcan be reported.  
“Disease progression” is considered a worsening 
of a subject’s ALS symptoms (weakness, 
spasticity, respiratory insufficiency, respiratory 
arrest, dysphasia). It may reflect an increase in the 
severity of the disease or an increase in symptoms. 
Any event experienced by a subject which is 
solely regarded as part of disease progression and, 
can be considered as a direct consequence of ALS, 
but does not result in death, should not be reported 
as an AE/SAE; examples include: respiratory 
insufficiency, dysphagia, respiratory failure, 
dysarthria, etc. However, if a subject should 
experience worsening of ALS-related disease 
symptoms that are not considered anticipated 
disease progression for that given subject, the 
investigator should report these findings as an AE. 
Examples of this might include: pneumonia, 
malnutrition, fall, or aspiration. If there is any 
uncertainty as to whether an event is due to 
anticipated disease progression, it should be 
reported as an AE. 
Section 11.2.1.3.1  
These changes reflect the 
update made in 
Section 11.2.1.3 and 
provide further 
clarification regarding 
adverse events associated 
with ALS disease 
progression. 
Updated language as follows: 
The intent-to-treat (ITT) set will include all 
randomized subjects who receive at least one dose 
of randomized treatment (pegcetacoplan or 
placebo). Subjects will be analyzed according to 
their assigned treatment, regardless of the 
treatment actually received. 
Section 12.2.3  
Updated to clarify the 
ITT population more 
accurately. 
Updated language as follows: 
The primary efficacy analysis for the primary 
endpoint (CAFS) will be conducted on the mITT 
set and will be repeated for the ITT and PP sets to 
evaluate the robustness of the results from the 
primary analysis 
Section 12.3.1  
Updated to align with the 
SAP. 


Pegcetacoplan 
APL2-ALS-206 Protocol Amendment 6 
13 January 2023 
Apellis Pharmaceuticals, Inc 
Page 8 
 
Confidential 
Updated Section 12.3.2 language as follows: 
(2nd, 3rd, and 4th paragraphs of Section 12.3.2) 
Absolute values and changes from baseline in 
secondary efficacy endpoints (ALSFRS-R, in-clinic 
percentage of predicted SVC, HHD, and 
ALSAQ-40) will be summarized, using descriptive 
statistics, by treatment and visit. Baseline will be 
taken as the measurement closest, but prior, 
to randomizationthe first dose of investigational 
product. 
Changes from baseline in secondary efficacy 
outcomes (ALSFRS-R, in-clinic percentage of 
predicted SVC, HHD, and ALSAQ-40) will be 
summarized by treatment group and analyzed using 
a mixed model for repeated measures repeated 
measurements analysis of covariance. The model 
will include fixed categorical effects for treatment, 
study visit, and the study visit-by-treatment 
interaction, as well as the continuous, fixed covariate 
of baseline and the visit-by-baseline interaction term, 
time from symptoms onset to the first dose of 
investigational product, and the randomization 
stratification factors. Initially an unstructured 
covariance matrix will be investigated. If this 
analysis fails to converge, other covariance 
structures will be used; details will be provided in the 
SAP. The Kenward-Roger approximation will be 
used to estimate denominator degrees of freedom. 
For the secondary endpoints of time to death and 
time to death, permanent tracheostomy, 
or permanent assisted ventilation, Kaplan-Meier 
analysis will be used to describe the survival data. 
The comparison of the survival time between 
treatment groups will be provided using a Cox 
proportional hazard model adjusting for the same 
covariates used in CAFS ANCOVA. For subjects 
who did not experience an event, the time to event 
will be censored at the last observation date for 
the Kaplan-Meier plot. Subjects who were 
randomized but did not receive any treatment will 
be censored at the randomization date. Subjects 
who are lost to follow-up or who discontinued the 
study will be censored at the date of 
discontinuation or lost to follow-up date. 
Section 12.3.2  
Updated to provide more 
clarity and to align with 
the SAP. 


Pegcetacoplan 
APL2-ALS-206 Protocol Amendment 6 
13 January 2023 
Apellis Pharmaceuticals, Inc 
Page 9 
 
Confidential 
Updated Section 12.3.3 language as follows: 
Absolute values and changes from baseline in 
exploratory endpoints (EQ 5D 5L, ZBI, at home 
%SVC, NfL, pNfH, and EIM) will be 
summarized, using descriptive statistics, by 
treatment and visit: 
• 
EQ-5D-5L, ZBI, NfL, pNfH, and 
EIM at weeks 52, 104, and 156).  
• 
At-home %SVC at weeks 52 and 
104 
• 
ALSFRS-R, % SVC in-clinic, HHD, 
and ALSAQ-40 at week 156 
Baseline will be taken as the measurement closest 
to but prior to randomization, with the exception 
of at home %SVC, for which baseline is the first 
assessment (which may be done after the first 
dose of study treatment). Time to percutaneous 
endoscopic gastrostomy tube placement up to 
weeks 52, 104, and 156 will be computed and 
summarized by treatment group., as will time to 
death, permanent tracheostomy, or permanent 
assisted ventilation up to week 156; and time to 
death up to week 156. Additional analyses might 
be performed for these endpoints and will be 
detailed in SAP. 
Section 12.3.3  
Updated due to the 
addition of the new 
exploratory endpoints. 
Updated the amendment history to include the 
summary of changes from Amendment 5. 
Appendix 1  
Change made for 
accuracy. 
 


Pe gcetac o pla n  
A P L 2 -A L S -2 0 6 Pr ot oc ol A me n d me nt 6  
1 3 Ja n uar y 2 0 2 3 
A pellis P har mace uticals, I nc  
Pa ge 1 0   
 
C o nfi de ntial  
1.  
S Y N O P SI S  
N a me of S p o ns or/ C o m p a n y:  
A pellis P h ar m ace utic als, I nc.  
N a me of Acti ve S u bst a nce:  
Pe gcetac o pla n (als o k n o w n as A P L - 2) 
Pr ot oc ol N u m ber:  
A P L 2 -A L S - 2 0 6 
P h ase:  
2  
 
Title of St u d y:  
A p hase  2, ra n d o mize d, d o u ble-bli n d, place b o -c o ntr olle d, m ultice nter st u d y t o e val uate t he efficac y 
a n d safet y of pe gcetac o pla n i n s u bjects wit h a m y otr o p hic lateral scler osis ( A L S)  
St u d y peri o d:  
Esti mate d 4 5 m o nt hs  
O bjecti ves  
Pri m ar y O bjecti ve: T o assess t he efficac y of t wice per wee k s u bc uta ne o us ( S C) d oses of 
pe gcetac o pla n 1 0 8 0 m g c o m pare d t o place b o i n s u bjects wit h s p ora dic A L S as meas ure d b y t he 
C o m bi ne d Assess me nt of F u ncti o n a n d S ur vi val ( C A F S) ra n k sc ore (j oi nt-ra n k sc ore) 
Sec o n d ar y O bjecti ves:   
•  
T o assess t he effect of pe gcetac o pla n  c o m pare d t o place b o as meas ure d b y t he Re vise d 
A L S F u ncti o nal Rati n g Scale ( A L S F R S -R) sc ore  
•  
T o assess t he effect of pe gcetac o pla n c o m pare d t o place b o o n disease pr o gressi o n as 
meas ure d b y res pirat or y f u ncti o n t hr o u g h perce nta ge of sl o w vital ca pacit y ( % S V C)  
•  
T o deter mi ne t he e ffect of pe gcetac o pla n c o m pare d t o place b o o n m uscle stre n gt h as 
meas ure d b y ha n d hel d d y na m o metr y ( H H D) 
•  
T o deter mi ne t he effect of pe gcetac o pla n c o m pare d t o place b o o n s ur vi val or s pecifie d 
state of disease pr o gressi o n 
•  
T o assess t he ef fect of pe gcetac o pla n c o m pare d t o place b o o n healt h- relate d q ualit y of life 
as meas ure d b y A L S Assess me nt Q uesti o n naire ( A L S A Q - 4 0) 
•  
T o assess t he safet y of pe gcetac o pla n d uri n g t he ra n d o mize d a n d o pe n -la bel treat me nt 
peri o ds t hr o u g h i nci de nce a n d se verit y o f treat me nt-e mer ge nt a d verse e ve nts ( T E A Es), 
cli nical la b orat or y tests ( he mat ol o g y, c he mistr y), vital si g ns, a n d p h ysical e xa mi nati o ns  
•  
T o assess t he l o n g -ter m efficac y of pe gcetac o pla n usi n g A L S F R S-R, % S V C, H H D, 
a n d A L S A Q - 4 0 d uri n g t he o pe n-la bel treat me nt peri o d 
 


Pegcetacoplan 
APL2-ALS-206 Protocol Amendment 6 
13 January 2023 
Apellis Pharmaceuticals, Inc 
Page 11 
 
Confidential 
Endpoints 
Primary Efficacy Endpoint: 
• 
CAFS rank score (joint-rank score) at week 52 
Secondary Efficacy Endpoints: 
• 
Change from baseline in ALSFRS-R at week 52 
• 
Change from baseline in %SVC (at clinic visits) at week 52  
• 
Change from baseline in HHD megascore at week 52 
• 
Time to death, permanent tracheostomy, or permanent assisted ventilation up to 
week 52 
• 
Time to death up to week 52 
• 
Change from baseline in ALSAQ-40 at week 52 
• 
Change from baseline of the randomized treatment period (visit 2) and of the 
open-label treatment period (visit 15) to week 104 for ALSFRS-R, %SVC, HHD, and 
ALSAQ-40 
• 
Time to death, permanent tracheostomy, or permanent assisted ventilation up to 
week 104 
• 
Time to death up to week 104 
Primary Safety Endpoints: 
• 
Incidence and severity of TEAEs 
• 
Change from baseline in vital signs and clinical laboratory tests 
• 
Positive responses (Yes) to the Columbia Suicide Severity Rating Scale 


Pegcetacoplan 
APL2-ALS-206 Protocol Amendment 6 
13 January 2023 
Apellis Pharmaceuticals, Inc 
Page 12 
 
Confidential 
Exploratory Endpoints: 
• Change from baseline in European Quality of Life–5 Dimensions–5 Level at 
week 52, week 104, and week 156 
• 
Change from baseline in Zarit Burden Interview score at week 52, week 104, 
and week 156 
• 
Change from baseline of %SVC (home spirometry) at week 52 and week 104 
• 
Time to percutaneous endoscopic gastrostomy tube placement up to week 52, 
week 104, and week 156 
• 
Change from baseline in serum neurofilament light chain at week 52, week 104, 
and week 156 
• 
Change from baseline in serum phosphorylated neurofilament heavy chain at week 52, 
week 104, and week 156 
• 
Change from baseline in electrical impedance myography at week 52, week 104, 
and week 156 (only at select investigational sites chosen to complete this) 
• 
Pegcetacoplan pharmacokinetic concentrations at week 52, week 104, and week 156 
• 
Changes from baseline at week 52, week 104, and week 156 in complement 
biomarkers: 
− 
Classical hemolytic complement pathway activity  
− 
Alternative hemolytic complement pathway activity  
− 
C3 levels 
• 
Immunogenicity: presence of antibodies to polyethylene glycol moiety and peptide 
moiety of pegcetacoplan during the randomized and open-label treatment periods 
• 
Change from baseline of the randomized treatment period (week 1) and of the 
open-label treatment period (week 52) to week 156 for ALSFRS-R, %SVC (in-clinic), 
HHD, and ALSAQ-40 
• 
Time to death, permanent tracheostomy, or permanent assisted ventilation up to 
week 156 
• 
Time to death up to week 156  


Pegcetacoplan 
APL2-ALS-206 Protocol Amendment 6 
13 January 2023 
Apellis Pharmaceuticals, Inc 
Page 13 
 
Confidential 
Study Design: 
This is a phase 2, randomized, double-blind, placebo-controlled, multicenter, efficacy and safety study 
of SC pegcetacoplan 1080 mg twice per week conducted in approximately 228 subjects with ALS. 
The planned length of participation in the study for each subject is a maximum of approximately 
168 weeks. This study will consist of 5 parts:  
• 
Part 1: Up to 6-week screening period 
• 
Part 2: 52-week randomized treatment period 
• 
Part 3: 52-week open-label (pegcetacoplan) treatment period 
• 
Part 4: 52-week open-label long-term extension treatment period 
• 
Part 5: 6-week off-treatment follow-up period 
Part 1 
Screening (Up to 6 Weeks) 
• 
Informed consent will be obtained at screening prior to any study-related procedures being 
conducted 
• 
Subjects (and/or caregiver) will be trained on the use of at-home assessments. 
Part 2 
Randomized Treatment Period (52 Weeks) 
• 
Approximately 228 subjects who meet all of the inclusion criteria and none of the 
exclusion criteria will be randomized 2:1 to either the pegcetacoplan treatment group or to 
the placebo treatment group. Safety and efficacy will be assessed and will include once per 
week at-home measurements, monthly calls, and clinic visits.  
• 
Pegcetacoplan treatment group  
− 
Subjects randomized to pegcetacoplan will receive SC pegcetacoplan 1080 mg twice 
per week for 52 weeks.  
• 
Placebo treatment group 
− 
Subjects randomized to placebo will receive SC placebo twice per week for 52 weeks.  
Subjects who discontinue treatment early and do not complete Part 2 will continue to Part 5. 
Part 3 
Open-Label (Pegcetacoplan) Treatment Period (52 weeks) 
At the end of Part 2, all subjects from both treatment groups will continue to Part 3. All subjects 
participating in Part 3 will be treated with pegcetacoplan 1080 mg twice per week up to week 104. 
Subjects who complete Part 3 will enter Part 4. Subjects who do not continue to Part 3, or who have 
started Part 3 but discontinue treatment early, will continue to Part 5. 
Part 4 
Open-Label (Pegcetacoplan) Long-Term Extension Treatment Period (52 weeks) 
At the end of Part 3, any subject who, in the opinion of the investigator, is experiencing clinical benefit 
from pegcetacoplan administration will be invited to continue to Part 4, the open-label long-term 
extension treatment period. All subjects participating in Part 4 will be treated with pegcetacoplan 
1080 mg twice per week up to week 156. Subjects who complete Part 4 will enter Part 5. Subjects who 
do not continue to Part 4, or who have started Part 4 but discontinue treatment early, will continue to 
Part 5. 


Pegcetacoplan 
APL2-ALS-206 Protocol Amendment 6 
13 January 2023 
Apellis Pharmaceuticals, Inc 
Page 14 
 
Confidential 
Part 5 
Off-Treatment Follow-up Period (6 weeks) 
During Part 5, all subjects who have discontinued the investigational product (blinded 
pegcetacoplan/placebo or open-label pegcetacoplan) will complete a follow-up visit 6 weeks later. 
Diagnosis: Subjects with a diagnosis of sporadic ALS 
Main Criteria for Inclusion: 
1. Sporadic ALS diagnosed as definite, probable, or laboratory-supported probable as defined 
by the revised El Escorial criteria (Brooks et al. 2000)  
2. At least 18 years of age 
3. Slow vital capacity ≥60% of the predicted value at screening 
4. Onset of ALS symptoms within 72 weeks prior to screening 
5. Total ALSFRS-R score of ≥30 at screening 
6. Women of childbearing potential defined as any woman who has experienced menarche 
and who is NOT permanently sterile or postmenopausal  
a. must have a negative pregnancy test at screening and  
b. must agree to use protocol defined methods of contraception for the duration of the 
study and 90 days after their last dose of investigational product. 
i. Postmenopausal is defined as 12 consecutive months with no menses 
without an alternative medical cause. 
7. Males must agree to 
a. use protocol defined methods of contraception and  
b. refrain from donating sperm for the duration of the study and 90 days after their 
last dose of investigational product. 
8. Have vaccination against Streptococus pneumoniae
, Neiseria meningitidis
 (types A, C, 
W, Y, and B), and Haemophilus influenzae
 (type B) either within 5 years prior to baseline 
visit 2b, or agree to receive vaccination at least 7 days prior to baseline visit 2b. 
Vaccination is mandatory, unless documented evidence exists that subjects are 
nonresponders to vaccination (as evidenced by titers or display titer levels within 
acceptable local limits). 
9. Willing and able to give informed consent and comply with study procedure and 
assessments (including at-home assessments) 


Pegcetacoplan 
APL2-ALS-206 Protocol Amendment 6 
13 January 2023 
Apellis Pharmaceuticals, Inc 
Page 15 
 
Confidential 
Main Criteria For Exclusion: 
1. Confirmed or suspected other causes of neuromuscular weakness 
2. Diagnosis of another neurodegenerative disease(s)  
3. Subject with significant cognitive impairment, clinical dementia, or psychiatric illness that 
in the opinion of the investigator may increase subject’s risk by participating in the study 
or confound the outcome of the study 
4. Subjects with a significant pulmonary disorder not attributed to ALS or who require 
treatments that might complicate the evaluation of the effect of ALS on respiratory 
function (eg, chronic obstructive pulmonary disease, pulmonary fibrosis, cystic fibrosis, 
pulmonary arterial hypertension) 
5. Current use or anticipated need, in the opinion of the investigator, of a diaphragm pacing 
system during the randomized treatment period 
6. Riluzole initiation or change in dose within 30 days prior to the start of the screening 
period or planned initiation during study participation. If using riluzole, the subject should 
remain on the drug throughout Part 2 of study participation, but the dosage may be altered 
or the drug discontinued at any time by the investigator for any safety concern. 
Riluzole-naïve subjects are allowed in the study. 
7. Edaravone initiation or change in dose within 60 days prior to the start of the screening 
period or planned initiation during study participation. If using edaravone, the subject 
should remain on the drug throughout Part 2 of study participation, but the dosage may be 
altered or the drug discontinued at any time by the investigator for any safety concern. 
Edaravone-naïve subjects are allowed in the study. 
8. Positive response to Item 4 or 5 of the Columbia Suicide Severity Rating Scale 
9. Subjects with detectable hepatitis C by polymerase chain reaction at screening 
10. Subjects with chronic inactive hepatitis B with viral loads >1000 IU/mL (>5000 
copies/mL) at screening. Eligible subjects who are chronic active carriers (≤1000 IU/mL) 
must receive prophylactic antiviral treatment according to local country guidelines 
(eg, entecavir, tenofovir, lamivudine) 
11. History of an aggressive lymphoma or presence of a lymphoma requiring therapy by itself 
12. Active or overt malignant disease other than basal cell carcinoma or cutaneous squamous 
cell carcinoma 
13. Received organ transplant 
14. Presence or suspicion of liver dysfunction as indicated by elevated alanine aminotransferase, 
aspartate aminotransferase, or bilirubin levels >2 × the upper limit of normal  
15. Presence or suspicion of severe recurrent or chronic infections that, in the opinion of the 
investigator, increase the subject’s risk by participating in the study 


Pegcetacoplan 
APL2-ALS-206 Protocol Amendment 6 
13 January 2023 
Apellis Pharmaceuticals, Inc 
Page 16 
 
Confidential 
16. Participation in any other investigational drug trial or exposure to other investigational 
agent, device, or procedure within 30 days or within 5-half lives of the treatment 
(whichever is longer) prior to the start of the screening period or during study participation 
17. Use of any other complement inhibitor within 30 days or within 5-half lives of the treatment 
(whichever is longer) prior to the start of the screening period or during study participation 
18. If breastfeeding, unwilling to discontinue for the duration of the study and for at least 
6 months after final dose of drug 
19. Inability to cooperate or any condition that, in the opinion of the investigator, could increase 
the subject’s risk by participating in the study or confound the outcome of the study 
20. Subjects with known allergy or hypersensitivity to pegcetacoplan or to any of the components 
21. Known or suspected hereditary fructose intolerance 
Investigational Product, Dosage, and Mode of Administration:  
• 
Pegcetacoplan, 1080 mg twice per week, SC 
• 
Placebo, twice per week, SC 
Duration of Treatment:  
168 weeks total (screening: up to 6 weeks; randomized treatment: 52 weeks; open-label 
[pegcetacoplan] treatment: 52 weeks; open-label [pegcetacoplan] long-term extension period: 
52 weeks; follow-up: 6 weeks) 
Blinding: 
This is a double-blind study during the randomized treatment period. The open-label and long-term 
extension treatment periods are not blinded.  


Pegcetacoplan 
APL2-ALS-206 Protocol Amendment 6 
13 January 2023 
Apellis Pharmaceuticals, Inc 
Page 17 
 
Confidential 
Statistical Methodology for Primary Efficacy Endpoint:  
The primary efficacy endpoint is the CAFS rank score (joint-rank score) at week 52.  
The CAFS ranks score will be summarized by treatment group using descriptive statistics. 
The CAFS ranks score will be analyzed using analysis of covariance (ANCOVA) model with 
treatment as a fixed effect, adjusted for baseline ALSFRS-R total score, duration from symptoms 
onset to the first dose of study treatment, and stratification factors. 
Statistical Methodology for Secondary Efficacy Endpoints:   
To preserve the Type 1 error, a fixed-sequence testing strategy will be used. The ordering of the 
secondary endpoints in this testing strategy will match the order in which they are presented in the 
secondary endpoint section.  
Changes from baseline in secondary efficacy outcomes will be summarized by treatment group and 
analyzed using a mixed model for repeated measures repeated measurements. The model will 
include fixed categorical effects for treatment, study visit, and the study visit-by-treatment 
interaction, as well as the continuous, fixed covariate of baseline and the visit-by-baseline 
interaction term, time from symptoms onset to the first dose of investigational product, and the 
randomization stratification factors. Initially, an unstructured covariance matrix will be 
investigated. If this analysis fails to converge, other covariance structures will be used; details will 
be provided in the statistical analysis plan. The Kenward-Roger approximation will be used to 
estimate denominator degrees of freedom. 
For the secondary endpoints of time to death and time to death, permanent tracheostomy, or permanent 
assisted ventilation, Kaplan-Meier will be used to describe the survival data. The comparison of the 
survival time between treatment groups will be provided using a Cox proportional hazard model 
adjusting for the same covariates used for the CAFS ANCOVA. For subjects who did not experience an 
event, the time to event will be censored at the last observation date for the Kaplan-Meier plot. Subjects 
who are lost to follow-up or discontinue study will be censored at the date of discontinuation or lost to 
follow-up. 


Pegcetacoplan 
APL2-ALS-206 Protocol Amendment 6 
13 January 2023 
Apellis Pharmaceuticals, Inc 
Page 18 
 
Confidential 
Planned Interim Analysis: 
No interim analysis is planned. 
Statistical Methodology for Safety Endpoints:   
All safety measures, including AEs and clinical laboratory results (hematology, chemistry if 
appropriate), will be descriptively summarized by treatment group at baseline and for each 
postbaseline visit. 
The number and percentage of subjects with TEAEs will be presented. Treatment-emergent 
adverse events are defined as adverse events (AEs) that start or deteriorate on or after the date of 
the first dose of investigational product until the study follow-up visit or the early termination 
follow-up visit.  
Pharmacokinetic concentration will be summarized by treatment group and visit using descriptive 
statistics. 
Sample Size Justification: 
A sample size of 180 randomized subjects (2:1 allocation ratio to pegcetacoplan:placebo) would 
provide approximately 86% power to detect a significant difference (33%) in the primary outcome 
(CAFS score) between the 2 treatment groups at a 2-sided alpha of 5% with 75% power to detect a 
35% improvement in the rate of decline in the ALSFRS-R score and 39% power to detect a 10% 
improvement in survival.  
The estimates were based on the following assumptions: 
• 
Mean monthly rate of decline in ALSFRS-R is 1 unit for the placebo treatment group 
and pooled standard deviation of 0.84 units/month 
• 
52-week mortality rate with placebo at 20% 
• 
Approximately 40-week subject enrollment period 
• 
52 weeks of follow-up for assessing survival outcomes after each subject enrolls 
• 
52 weeks of follow-up for assessing functional outcomes after each subject enrolls 
Subjects will be randomized and stratified by location of first muscle weakness (limb or bulbar) 
and riluzole and edaravone use. 
Approximately 228 subjects (152:76) will be randomized to account for an anticipated 20% of 
randomized subjects prematurely discontinuing the study without providing a postbaseline 
ALSFRS-R measurement. 
 


Pe gcetac o pla n  
A P L 2 -A L S -2 0 6 Pr ot oc ol A me n d me nt 6  
1 3 Ja n uar y 2 0 2 3 
A pellis P har mace uticals, I nc  
Pa ge 1 9   
 
C o nfi de ntial  
2.  
T A B L E O F C O N T E N T S  
TI T L E P A G E  ................................................................................................................................... 1 
SI G N A T U R E P A G E  ....................................................................................................................... 2 
I N V E S TI G A T O R’ S A G R E E M E N T ............................................................................................... 3 
A M E N D M E N T 6: S U M M A R Y O F C H A N G E S F R O M T H E P R E VI O U S V E R SI O N  ................ 4 
1.  
S Y N O P SI S  ................................................................................................................. 1 0 
2.  
T A B L E O F C O N T E N T S  ........................................................................................... 1 9 
LI S T O F T A B L E S  ......................................................................................................................... 2 5 
LI S T O F FI G U R E S  ....................................................................................................................... 2 5 
3.  
LI S T O F A B B R E VI A TI O N S A N D D E FI NI TI O N S O F T E R M S ............................. 2 6 
4.  
I N T R O D U C TI O N ...................................................................................................... 2 8 
4. 1.  
A m y otr o p hic Later al Scler osis a n d U n met Me dical Nee d  ......................................... 2 8 
4. 2.  
I nf or mati o n o n t he I n v esti gati o nal Pr o d uct ( Pe gcet ac o pla n) ..................................... 2 8 
4. 3.  
St u d y Rati o nale ........................................................................................................... 2 9  
4. 4.  
S u m mar y of Cli nical E x perie nce Wit h Pe gcet ac o pla n  ............................................... 3 0 
4. 4. 1.  D o se Rati o nale ...................................................................................................... 3 1 
4. 5.  
Cli nical Ris ks/ Be nefits of Pe gcetac o pla n  ................................................................... 3 1 
4. 5. 1.  Safet y Meas ur es Wit h E nr oll me nt  ........................................................................ 3 2 
4. 5. 2.  C O VI D - 1 9 Ris k Miti gati o n Meas ures .................................................................. 3 3 
5.  
T RI A L O BJ E C TI V E S A N D E N D P OI N T S  ............................................................... 3 4 
5. 1.  
O bjecti ves  ................................................................................................................... 3 4 
5. 1. 1.  Pri mar y O bjecti ve  ................................................................................................. 3 4 
5. 1. 2.  Sec o n dar y O bj ecti ves  ........................................................................................... 3 4 
5. 2.  
E n d p oi nts .................................................................................................................... 3 4  
5. 2. 1.  Pri mar y Efficac y E n d p oi nt ................................................................................... 3 4  
5. 2. 2.  Sec o n dar y Efficac y E n d p o i nts .............................................................................. 3 4 
5. 2. 3.  
Pri mar y Safet y E n d p oi nts  ....................................................................................... 3 5 
5. 2. 4.  
E x pl orat or y E n d p oi nts  ........................................................................................... 3 5 
6.  
I N V E S TI G A TI O N A L P L A N ..................................................................................... 3 7 
6. 1.  
O verall St u d y Desi g n .................................................................................................. 3 7  
6. 1. 1.  Part  1: Scree ni n g Peri o d ( U p t o 6 Wee ks) ............................................................ 3 7 
6. 1. 2.  Part  2: Ra n d o mize d Treat me nt Peri o d ( 5 2 Wee ks) .............................................. 3 7 


Pegcetacoplan 
APL2-ALS-206 Protocol Amendment 6 
13 January 2023 
Apellis Pharmaceuticals, Inc 
Page 20 
 
Confidential 
6.1.2.1. 
Pegcetacoplan Treatment Group ...............................................................37 
6.1.2.2. 
Placebo Treatment Group .........................................................................37 
6.1.3. 
Part 3: Open-Label (Pegcetacoplan) Treatment Period (52 Weeks) ....................38 
6.1.4. 
Part 4: Open-Label (Pegcetacoplan) Long-Term Extension Treatment 
Period (52 Weeks) ..........................................................................................38 
6.1.5. 
Part 5: Off-Treatment Follow-up Period (6 Weeks) .............................................38 
6.2. 
Number of Subjects ....................................................................................................38 
6.3. 
Treatment Assignment ................................................................................................38 
6.4. 
Criteria for Study Termination ...................................................................................38 
6.5. 
End of Trial Definition ...............................................................................................47 
6.6. 
Study Procedures ........................................................................................................47 
6.6.1. 
Screening Period: Visit 1 ......................................................................................47 
6.6.2. 
Baseline: Visit 2a and Visit 2b .............................................................................48 
6.6.2.1. 
Baseline: Visit 2a ......................................................................................48 
6.6.2.2. 
Baseline: Visit 2b ......................................................................................49 
6.6.3. 
Randomized Treatment Period (Core) Visits .......................................................50 
6.6.3.1. 
Randomized Treatment Period (Core)—Clinic Visits: Visits 3, 5, 
8, 11, 15 ....................................................................................................50 
6.6.3.2. 
Randomized Treatment Period (Core)—Home Assessments ...................51 
6.6.3.3. 
Randomized Treatment Period (Core)—Telephone Visits: 
Visits 4T, 6-7T, 9-10T, 12-14T ................................................................52 
6.6.3.4. 
Follow-Up (Core) Visit: Visit 15b ............................................................52 
6.6.4. 
Open-Label (Pegcetacoplan) Treatment Period Visits .........................................53 
6.6.4.1. 
Open-Label (Pegcetacoplan) Treatment Period—Clinic Visits: 
Visits 16, 21, 28 ........................................................................................53 
6.6.4.2. 
Open-Label (Pegcetacoplan) Treatment Period—Home 
Assessments ..............................................................................................55 
6.6.4.3. 
Open-Label (Pegcetacoplan) Treatment Period—Telephone 
Visits: Visits 17T-20T, 22T-27T ..............................................................55 
6.6.4.4. 
Open-Label (Pegcetacoplan) Treatment Period—Follow-up Visit: 
Visit 28b....................................................................................................55 
6.6.5. 
Open-Label (Pegcetacoplan) Long-Term Extension Treatment Period ...............56 
6.6.5.1. 
Open-Label (Pegcetacoplan) Long-Term Extension Treatment 
Period—Clinic Visits: Visits 31, 36, 41 ...................................................57 


Pegcetacoplan 
APL2-ALS-206 Protocol Amendment 6 
13 January 2023 
Apellis Pharmaceuticals, Inc 
Page 21 
 
Confidential 
6.6.5.2. 
Open-Label (Pegcetacoplan) Long-Term Extension Treatment 
Period—Home Assessments .....................................................................58 
6.6.5.3. 
Open-Label (Pegcetacoplan) Long-Term Extension Treatment 
Period—Telephone Visits: Visits 29T, 30T, 32T-35T, 37T-40T .............58 
6.6.5.4. 
Open-Label (Pegcetacoplan) Long-Term Extension Treatment 
Period—Follow-up Visit: Visit 41b ..........................................................58 
6.6.6. 
Early Termination Follow-Up Visit ......................................................................59 
6.6.7. 
Unscheduled Visit(s) ............................................................................................61 
7. 
SELECTION AND WITHDRAWAL OF SUBJECTS ..............................................62 
7.1. 
Subject Inclusion Criteria ...........................................................................................62 
7.2. 
Subject Exclusion Criteria ..........................................................................................62 
7.3. 
Subject Completion and Withdrawal Criteria.............................................................64 
7.3.1. 
Reasons for Discontinuation .................................................................................64 
7.3.1.1. 
Mandatory Study Discontinuation/Withdrawal Criteria ...........................65 
7.3.2. 
Subjects “Lost to Follow-up” Prior to Last Scheduled Visit ................................65 
8. 
TREATMENT OF SUBJECTS ..................................................................................66 
8.1. 
Identity of the Investigational Product .......................................................................66 
8.2. 
Treatment Assignment ................................................................................................66 
8.2.1. 
Blinding the Treatment Assignment .....................................................................66 
8.2.2. 
Randomization ......................................................................................................66 
8.2.3. 
Unblinding Prior to Study Completion .................................................................67 
8.3. 
Dosing of the Investigational Product ........................................................................67 
8.4. 
Vaccinations ...............................................................................................................67 
8.4.1. 
Prophylactic Antibiotics .......................................................................................68 
8.5. 
Concomitant Medications ...........................................................................................68 
8.6. 
Prohibited Medications or Procedures ........................................................................69 
8.6.1. 
Prohibited Medications .........................................................................................69 
8.6.2. 
Prohibited Procedures ...........................................................................................69 
8.7. 
Treatment Compliance ................................................................................................69 
9. 
INVESTIGATIONAL PRODUCT MATERIALS AND MANAGEMENT .............70 
9.1. 
Investigational Product ...............................................................................................70 
9.1.1. 
Pegcetacoplan .......................................................................................................70 
9.1.2. 
Placebo ..................................................................................................................70 


Pegcetacoplan 
APL2-ALS-206 Protocol Amendment 6 
13 January 2023 
Apellis Pharmaceuticals, Inc 
Page 22 
 
Confidential 
9.2. 
Investigational Product Packaging and Labeling .......................................................70 
9.2.1. 
Packaging ..............................................................................................................70 
9.2.2. 
Labeling ................................................................................................................70 
9.3. 
Investigational Product Storage and Handling ...........................................................70 
9.4. 
Administration ............................................................................................................71 
9.5. 
Infusion Supplies ........................................................................................................72 
9.6. 
Investigational Product Accountability ......................................................................72 
9.7. 
Investigational Product Disposal ................................................................................72 
10. 
EFFICACY AND EXPLORATORY ASSESSMENTS ............................................73 
10.1. 
Efficacy Assessments .................................................................................................73 
10.1.1. 
Primary Efficacy Assessment .........................................................................73 
10.1.1.1. 
CAFS Scale ...............................................................................................73 
10.1.2. 
Secondary Efficacy Assessments .....................................................................73 
10.1.2.1. 
Slow Vital Capacity—Clinic ....................................................................74 
10.1.2.2. 
ALSAQ-40 ................................................................................................74 
10.1.2.3. 
Handheld Dynamometry ...........................................................................74 
10.2. 
Exploratory Assessments ............................................................................................74 
10.2.1. 
EQ-5D-5L........................................................................................................75 
10.2.2. 
Zarit Burden Interview .....................................................................................75 
10.2.3. 
Slow Vital Capacity—Home ............................................................................76 
10.2.4. 
Neurofilaments ...............................................................................................76 
10.2.5. 
Electrical Impedance Myography ...................................................................76 
11. 
SAFETY ASSESSMENTS ........................................................................................77 
11.1. 
Safety Parameters .......................................................................................................77 
11.1.1. 
Demographic/Medical History .......................................................................77 
11.1.2. 
Vital Signs ......................................................................................................77 
11.1.3. 
Electrocardiogram ...........................................................................................77 
11.1.4. 
Weight and Height ..........................................................................................77 
11.1.5. 
Physical Examination .....................................................................................78 
11.1.6. 
Injection/Infusion Site/Pump Safety Assessment ...........................................78 
11.1.7. 
C-SSRS ...........................................................................................................78 
11.1.8. 
Laboratory Assessments .................................................................................78 
11.1.8.1. 
Pregnancy Screen ......................................................................................81 


Pegcetacoplan 
APL2-ALS-206 Protocol Amendment 6 
13 January 2023 
Apellis Pharmaceuticals, Inc 
Page 23 
 
Confidential 
11.1.9. 
Anti–Pegcetacoplan Peptide Antibody and Anti-PEG Antibody 
Assessments ....................................................................................................81 
11.1.10. 
Genetic Mutation(s) Results ...........................................................................81 
11.1.11. 
COVID-19 Assessment ..................................................................................82 
11.2. 
Adverse and Serious Adverse Events .........................................................................82 
11.2.1. 
Definitions ......................................................................................................82 
11.2.1.1. 
Adverse Events .........................................................................................82 
11.2.1.2. 
Unexpected Adverse Event .......................................................................82 
11.2.1.3. 
Serious Adverse Events ............................................................................82 
11.3. 
Relationship to Investigational Product ......................................................................83 
11.4. 
Severity of Events .......................................................................................................84 
11.5. 
Recording Adverse Events .........................................................................................84 
11.6. 
Reporting Adverse Events ..........................................................................................85 
11.7. 
Pregnancy ...................................................................................................................85 
11.7.1. 
Acceptable Methods of Contraception ...........................................................85 
11.8. 
Abuse, Misuse, Overdose, and Medication Error .......................................................86 
12. 
STATISTICS ..............................................................................................................87 
12.1. 
Determination of Sample Size ....................................................................................87 
12.2. 
Analysis Set ................................................................................................................87 
12.2.1. 
Screened Set ....................................................................................................87 
12.2.2. 
Safety Set ........................................................................................................87 
12.2.3. 
Intent-to-Treat Set ...........................................................................................87 
12.2.4. 
Modified Intent-to-Treat Set ...........................................................................88 
12.2.5. 
Per-Protocol Set ..............................................................................................88 
12.2.6. 
Pharmacokinetic Set .......................................................................................88 
12.2.7. 
Pharmacodynamic Set ....................................................................................88 
12.2.8. 
Data Review for Analysis Set .........................................................................88 
12.3. 
Efficacy Analysis ........................................................................................................88 
12.3.1. 
Analysis of Primary Efficacy Endpoint ..........................................................88 
12.3.2. 
Analysis of Secondary Efficacy Endpoints ....................................................89 
12.3.3. 
Analysis of Exploratory Efficacy Endpoints ..................................................90 
12.4. 
Safety Analysis ...........................................................................................................90 
12.5. 
Pharmacokinetic Analysis ..........................................................................................91 


Pegcetacoplan 
APL2-ALS-206 Protocol Amendment 6 
13 January 2023 
Apellis Pharmaceuticals, Inc 
Page 24 
 
Confidential 
12.6. 
Pharmacodynamic Analysis........................................................................................91 
12.7. 
Other Analyses ............................................................................................................91 
12.8. 
Interim Analysis ..........................................................................................................91 
12.9. 
Data Monitoring Committee .......................................................................................91 
13. 
DIRECT ACCESS TO SOURCE DATA/DOCUMENTS.........................................92 
13.1. 
Audits and Inspections ................................................................................................93 
13.2. 
Institutional Review Board/Independent Ethics Committee ......................................93 
14. 
QUALITY CONTROL AND QUALITY ASSURANCE .........................................94 
15. 
ETHICS ......................................................................................................................95 
15.1. 
Ethics Review .............................................................................................................95 
15.2. 
Ethical Conduct of the Study ......................................................................................95 
15.3. 
Written Informed Consent ..........................................................................................95 
16. 
DATA HANDLING AND RECORDKEEPING .......................................................97 
16.1. 
Inspection of Records .................................................................................................97 
16.2. 
Retention of Records ..................................................................................................97 
17. 
PUBLICATION POLICY ..........................................................................................98 
18. 
LIST OF REFERENCES ............................................................................................99 
19. 
APPENDICES ..........................................................................................................102 
Appendix 1. 
Amendment History ......................................................................................103 
Appendix 2. 
Long-term Extension Phase ..........................................................................111 
 


Pegcetacoplan 
APL2-ALS-206 Protocol Amendment 6 
13 January 2023 
Apellis Pharmaceuticals, Inc 
Page 25 
 
Confidential 
LIST OF TABLES 
Table 1: 
Abbreviations and Specialist Terms ...........................................................................26 
Table 2: 
Schedule of Assessments—Randomized Treatment Period (Core) ...........................40 
Table 3: 
Schedule of Assessments—Open-Label (Pegcetacoplan) Treatment Period .............44 
Table 4: 
Laboratory Assessments .............................................................................................79 
Table 5: 
Blood Volumes Collected ...........................................................................................80 
Table 6: 
Definitions of Adverse Event Relatedness .................................................................83 
Table 7: 
Severity of Events .......................................................................................................84 
Table 8: 
Schedule of Assessments—Open-Label (Pegcetacoplan) Long-Term 
Extension Treatment Period .....................................................................................112 
 
LIST OF FIGURES 
Figure 1: 
Study Design ...............................................................................................................39 
 


Pegcetacoplan 
APL2-ALS-206 Protocol Amendment 6 
13 January 2023 
Apellis Pharmaceuticals, Inc 
Page 26 
 
Confidential 
3. 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
The following abbreviations and specialist terms are used in this study protocol. 
Table 1: 
Abbreviations and Specialist Terms 
Abbreviation or Specialist 
Term 
Explanation 
%SVC 
percentage of slow vital capacity 
ADA 
anti-drug antibodies 
AE 
adverse event 
AH50 
50% alternative hemolytic complement pathway activity 
AIHA 
autoimmune hemolytic anemia 
ALS 
amyotrophic lateral sclerosis 
ALSAQ-40 
Amyotrophic Lateral Sclerosis Assessment Questionnaire, 
40-item 
ALSFRS-R 
Revised Amyotrophic Lateral Sclerosis Functional Rating Scale 
aPTT 
activated partial thromboplastin time 
CAD 
cold agglutinin disease 
CAFS 
Combined Assessment of Function and Survival 
CH50 
50% classical hemolytic complement pathway activity 
CNS 
central nervous system 
CRF 
case report form 
C-SSRS 
Columbia Suicide Severity Rating Scale 
DPS 
diaphragm pacing system 
DMC 
data monitoring committee 
ECG 
electrocardiogram 
eCRF 
electronic case report form 
EDC 
electronic data capture 
EIM 
electrical impedance myography 
EQ-5D-5L 
5-Level EuroQoL-5 Dimension 
ETFU 
early termination follow-up 
GA 
geographic atrophy 
GCP 
Good Clinical Practice 
HHD 
handheld dynamometry 
HRQoL 
health-related quality of life 


Pegcetacoplan 
APL2-ALS-206 Protocol Amendment 6 
13 January 2023 
Apellis Pharmaceuticals, Inc 
Page 27 
 
Confidential 
Table 1: 
Abbreviations and Specialist Terms 
Abbreviation or Specialist 
Term 
Explanation 
IB 
Investigator’s Brochure 
ICF 
informed consent form 
ICH 
International Council for Harmonisation 
IEC 
independent ethics committee 
IRB 
institutional review board 
ITT 
intent-to-treat 
LDH 
lactate dehydrogenase 
MedDRA 
Medical Dictionary for Regulatory Activities 
mITT 
modified intent-to-treat 
MN 
motor neuron 
NfL 
neurofilament light chain 
PCV13 
pneumococcal conjugate vaccine 13 
PD 
pharmacodynamic 
PEG 
polyethylene glycol  
PK 
pharmacokinetic(s) 
pNfH 
phosphorylated neurofilament heavy chain 
PP 
per-protocol 
PPSV23 
pneumococcal polysaccharide vaccine 23 
QTcF 
QT interval corrected using Fridericia’s method 
SAE 
serious adverse event 
sALS 
sporadic amyotrophic lateral sclerosis 
SAP 
statistical analysis plan 
SC 
subcutaneous 
SVC 
slow vital capacity 
TEAE 
treatment-emergent adverse event 
WOCBP 
women of childbearing potential 
ZBI 
Zarit Burden Interview 
 


Pegcetacoplan 
APL2-ALS-206 Protocol Amendment 6 
13 January 2023 
Apellis Pharmaceuticals, Inc 
Page 28 
 
Confidential 
4. 
INTRODUCTION 
This study is being conducted as part of a series of studies for the clinical development of 
pegcetacoplan (also known as APL-2). The study will be conducted in compliance with the 
protocol, Good Clinical Practice (GCP), and applicable regulatory requirements. The subject 
population will comprise of adult male and female subjects with sporadic amyotrophic lateral 
sclerosis (sALS). 
4.1. 
Amyotrophic Lateral Sclerosis and Unmet Medical Need 
Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder of unknown etiology 
for which there is no effective treatment. Progressive denervation of neuromuscular synapses in 
the peripheral nervous system and degeneration of upper and lower motor neurons in the central 
nervous system (CNS) result in muscle weakness, atrophy, paralysis, and ultimately death within 
2-3 years from the onset of symptoms. Initial presentation of ALS varies between affected 
individuals, and typically presents as spinal-onset disease (muscle weakness of the limbs), 
or bulbar-onset disease (difficulty with speech and swallowing). Sporadic ALS accounts for 90% 
of cases and has no clear etiology, while familial ALS accounts for 10% of cases and contains an 
underlying genetic component. However, while these 2 forms differ in causation, they appear 
pathologically and clinically indistinguishable. 
There is no known cure for ALS. There are 3 approved medications to treat ALS, riluzole, 
edaravone, and Relyvrio. Riluzole, approved in 1995 and available globally, is administered orally 
twice daily and delays time to tracheostomy or death in patients with ALS 
(Riluzole Package Insert 2016), prolonging survival by 2-3 months (Miller 2002). Edaravone, 
approved in the US in 2017, is administered in courses intravenously 
(Edaravone Package Insert 2017) and shows efficacy in only a small subset of patients with early 
ALS (Abe et al. 2017).  
Relyvrio (AMX0035), approved in the United States in 2022, is administered orally or via 
feeding tube twice daily and slows the loss of physical function in patients with ALS as 
measured by ALSFRS-R (Relyvrio Package Insert 2022).  
4.2. 
Information on the Investigational Product (Pegcetacoplan) 
Pegcetacoplan, the active ingredient in pegcetacoplan solution for subcutaneous infusion 
1080 mg/20 mL is a symmetrical molecule comprised of 2 pentadecapeptides covalently bound 
to the ends of a linear 40 kDa polyethylene glycol molecule. The peptide moieties bind to 
complement C3 and exert a broad inhibition of the complement cascade. The 40 kDa 
polyethylene glycol moiety imparts improved solubility and longer residence time in the body 
after administration of the drug product. 
Pegcetacoplan is provided as a solution in acetate buffer solution containing sorbitol for 
subcutaneous (SC) administration.  
Further details can be found in the current version of the pegcetacoplan Investigator’s Brochure (IB). 


Pegcetacoplan 
APL2-ALS-206 Protocol Amendment 6 
13 January 2023 
Apellis Pharmaceuticals, Inc 
Page 29 
 
Confidential 
4.3. 
Study Rationale 
There is considerable evidence for the key role of neuroinflammation in ALS characterized by 
microglia activation, reactive astroglia, macrophage and lymphocyte infiltration, and 
overproduction of inflammatory cytokines, which correlate with motor neuron (MN) 
degeneration and disease progression (Chen et al. 2014; Murdock et al. 2017; 
Brettschneider et al. 2012; Turner et al. 2004; Ehrhart et al. 2015). Microglia maintain 
homeostasis by direct contact with the synaptic terminals and can respond to microenvironment 
signals and damage by removing defunct axon terminals (Kettenmann et al. 2013). During ALS 
progression, microglia transition from a protective phenotype to a proinflammatory and 
neurotoxic phenotype due to a proinflammatory stimuli, which results in synapse loss and the 
release of inflammatory factors that trigger the neurotoxic activity of astrocytes in the CNS 
(Liao et al. 2012; Chiu et al. 2013; Liddelow et al. 2017). Infiltrated muscle macrophages at the 
neuromuscular junction (NMJ) also result in denervation by phagocytizing presynaptic terminals 
(Wang et al. 2017). These neurotoxic mechanisms and interplays lead to self-destruction of MNs 
and, subsequently, the brain lose its ability to initiate and control the movement of muscles, 
including respiratory muscles. Uncontrolled inflammation is believed to drive, or actively 
participate, to disease progression. Therefore, therapy aimed at modulating the inflammatory and 
immune environment to preserve the remaining MNs may be beneficial in patients with ALS.  
The complement system is a pivotal component of both innate and adaptive immunity, 
contributing to immune surveillance, inflammation, and homeostasis (Kolev et al. 2014). 
Its 3 activation pathways (alternative, lectin and classical) converge to C3 and lead to its 
cleavage into its effectors, C3a and C3b, which in turn will lead to the formation of C5 
convertase and to C5 cleavage into C5a and C5b, and formation of the membrane attack 
complex. Overactivation of complement is a hallmark of many neurodegenerative diseases. 
Its diverse functions include C3a/C5a-triggered recruitment and activation of immune cells in 
particular microglia, macrophages, and lymphocytes, activation of glial cells by C3a/C3a 
receptor, C3b-mediated opsonization of neurons and synapse loss, and neuronal cell lysis by the 
membrane attack complex (Carpanini et al. 2019).  
Investigations in ALS animal models and patients with ALS demonstrate that complement-driven 
immune response may contribute to MN degeneration and progression of the disease. In animal 
model of ALS, disease progression significantly correlates with an upregulation of all complement 
effectors in muscles, peripheral nervous system, and spinal cord tissues, and an increased number of 
activated microglia/macrophages in the CNS and at the NMJ (Lee et al. 2018; Wang et al. 2017; 
Chiu et al. 2009). Inhibition of the complement downstream of C3 has been identified as a potential 
therapeutic target to slow disease progression in ALS in animal models (Lee et al. 2017). In patients 
or donors with ALS, high levels of complement C3 and downstream active fragments are present in 
blood, cerebral serum fluid, and in CNS tissues, in particular deposited on microglia and damaged 
neurites of the spinal cord and brain (Kawamata et al. 1992; Goldknopf et al. 2006; Sta et al. 2011; 
Ganesalingam et al. 2011; El Idrissi et al. 2016). The deposition of complement effectors, including 
C3/C3b, at the NMJ occurs early in the progression of ALS and precedes both motor end-plate 
denervation and degeneration of MNs (El Idrissi et al. 2016).  


Pe gcetac o pla n  
A P L 2 -A L S -2 0 6 Pr ot oc ol A me n d me nt 6  
1 3 Ja n uar y 2 0 2 3 
A pellis P har mace uticals, I nc  
Pa ge 3 0   
 
C o nfi de ntial  
T he site of i nitiati o n of A L S is still u nclear. A m y otr o p hic lateral scl er osis was i nitiall y descri be d 
as a disease t h at ca us es t he pr o gressi ve l oss of M Ns i n t he C N S  f oll o we d b y a x o nal de ge n erati o n 
a n d m uscle atr o p h y. Gr o wi n g e vi de nce i n a ni mal m o dels a n d cli nical ne ur o p h ysi ol o g y s u p p ort a 
sec o n d h y p ot hesis i n w hic h M N pat h ol o g y ma y be gi n as a distal a x o n o pat h y a n d pr ocee d bac k t o 
t he C N S i n a “ d yi n g bac k” patter n (N ot o et al. 2 0 1 1 ; Fisc her et al. 2 0 0 4 ). Ot hers ha ve pr o p ose d 
a n i n de pe n de nt a n d ra n d o m de ge ner ati o n of u p per a n d l o wer M Ns ( Ra vits a n d La S pa da 2 0 0 9 ; 
va n de n B os et al. 2 0 1 9 ). W het her t he dis ease starts i n t he C N S or at t he N MJ, st o p pi n g t he 
i nfla m mati o n a n d i m m u ne res p o nse dri ve n b y c o m ple me nt s h o ul d de m o nstrate a p ositi ve effect 
o n disease pr o gr essi o n. Alt h o u g h pe gcetac o pla n d oes n ot cr oss t he bl o o d- brai n barri er, t here is 
gr o wi n g e vi de nce t hat t he bl o o d- brai n barrier is c o m pr o mise d i n patie nts wit h A L S 
(Gar b u z o va- Da vis a n d S a n ber g 2 0 1 4 ) a n d pe g cet ac o pla n ma y reac h t he brai n i n a d diti o n t o its 
p ote ntial be neficial i m pact o n i nfla m mati o n a n d p ha g oc yt osis at t he N MJ.  
St u dies of A L S pat h ol o g y ha ve i n v ol ve d all c o m ple me nt pat h wa ys a n d effect ors. Gi ve n t hat C 3 
is acti n g as a p oi nt of c o n ver ge nce of all acti vati o n pat h wa ys, e x erti n g direct effect or f u ncti o ns, 
a n d hel pi n g t o c o or di nate d o w nstrea m i m m u ne res p o nses, C 3 is a n attracti v e tar get t o treat A L S. 
Ta ke n t o get her, tar geti n g t he c o m ple me nt s yste m at t he le vel of C 3 usi n g pe gcetac o pla n ma y 
re vers e t he i m m u ne res p o nse, w hic h ma y st o p or sl o w d o w n A L S pr o gressi o n. 
4. 4.  
S u m m ar y of Cli nic al E x perie nce Wit h Pe gcet ac o pl a n  
Pe gcetac o pl a n is bei n g st u die d i n A L S a n d m ulti ple ot her c o m ple me nt- me diate d i n dicati o ns 
( par o x ys mal n oct ur n al he m o gl o bi n uria [ P N H], c ol d a g gl uti ni n disease [ C A D], 
c o m ple me nt - de pe n d e nt n e p hr o pat hies, a n d g e o gra p hic atr o p h y [ G A] sec o n dar y t o a ge-relat e d 
mac ular de g e nerati o n).  
T o date, pe gcetac o pl a n at d oses of ≥2 7 0 m g/ d a y a n d 1 0 8 0 m g t wice wee kl y ha ve bee n ge nerall y 
safe a n d well t olerate d w he n a d mi nistere d via S C i nf usi o n. N o e x pecte d s eri o us a d verse dr u g 
reacti o ns ha v e bee n i de ntifie d, a n d n o deat hs h a ve occ urre d t hat are c o nsi dere d rel ate d t o 
treat me nt wit h pe gcetac o pla n.  
St u d y A P L 2- 3 0 2, a ra n d o mize d, m ultice nter, o pe n- la bel, acti ve-c o m parat or, c o ntr olle d st u d y i n 
patie nts wit h P N H, de m o nstrate d t hat pe gcetac o pl a n 1 0 8 0 m g t wice wee kl y (a n d 1 0 8 0 m g e ver y 
t hir d da y d osi n g a dj ust me nt o pti o n) S C i nf usi o n pr o d uce d c o nsiste nt a n d m ea ni n gf ul effects o n 
rele va nt cli nical effi cac y meas ures wit h a fa v ora ble safet y pr ofile. Pe gcetac o pla n de m o nstrate d 
c o ntr ol of b ot h i ntra vasc ular a n d e xtr a vasc ul ar he m ol ysis b y i m pr o vi n g ke y he mat ol o gical 
ma nifestati o ns of P N H, r e d uci n g t he b ur de n of tra nsf usi o ns, a n d i m pr o vi n g patie nt-re p ort e d 
s y m pt o ms of fati g ue. Ta ke n t o get her, t hes e a nal yses pr o vi de str o n g e vi de n ce t hat treat me nt wit h 
pe gcetac o pla n pr o vi des a cli nicall y mea ni n gf ul a n d si g n ifica nt treat me nt be nefit i n t he treat me nt 
of P N H.  
St u d y 
 is a n on g oi n g  o pe n -la bel, pr os pecti ve, phase  2 st u d y ( Gertz  et al. 2 0 1 9 ) 
t hat i ncl u des s u bjects wit h war m a ut oi m m u ne he m ol ytic a ne mia ( w AI H A) a n d C A D t hat has 
c o m plete d t he i nitial Part A ( 3 3 6 da ys) a n d is c o nti n ui n g wit h Part B, t he l o n g -ter m e xte nsi o n p hase. 
Res ults fr o m Part A c o m prise d  2 4  s u bjects ( 1 2 dia g n ose d wit h w AI H A; 1 2 dia g n ose d wit h C A D) 
a n d i n dicate t hat pe gcetac o pla n is a ble t o ra pi dl y i ncrease he m o gl o bi n val ues wit hi n t he first wee ks 
of treat me nt a n d t his effect persiste d f or 4 8 wee ks. Res ults als o s h o we d i m pr o ve me nts i n he m ol ysis 
(s h o w n b y re d ucti o n of retic ul oc yte, lactate de h y dr o ge nase, a n d i n direct bilir u bi n). 
C CI


Pe gcetac o pla n  
A P L 2 -A L S -2 0 6 Pr ot oc ol A me n d me nt 6  
1 3 Ja n uar y 2 0 2 3 
A pellis P har mace uticals, I nc  
Pa ge 3 1   
 
C o nfi de ntial  
F urt her,  pe gcetac o pla n was ge nera ll y well t olerate d i n t his st u d y. S u bjects  i n t his st u d y are 
a d mi nistere d pe gcetac o pl a n s u bc uta ne o usl y at d os es of 2 7 0 m g/ da y or 3 6 0 m g/ da y.  
St u dies c o n d ucte d i n s u bjects wit h G A sec o n d ar y t o a ge-relate d mac ul ar de ge nerati o n  i ncl u de a 
p hase  2 st u d y (P O T- C P 1 2 1 6 1 4), a n d 2 phase 3 st u dies ( A P L 2 - 3 0 3 an d A P L 2- 3 0 4), as w ell as a 
l o n g-ter m e xte nsi o n st u d y 
. I n all of t hese st u dies t hat ha v e re p ort e d o utc o mes, 
u p t o 2 4 m o nt hs, pe gcetac o pla n a d mi nistere d i ntra vitreall y ( 1 5 m g) m o nt hl y or e ver y ot h er 
m o nt h was f o u n d t o be b ot h efficaci o us a n d ha d a t olera ble safet y pr ofile.   
Alt h o u g h t he a d mi nistrati o n r o ute of pe gcetac o pl a n i n patie nts wit h G A (i ntra vitre o us) is n ot t he 
o ne t hat will be use d t o tr eat patie nts wit h A L S (s u bc uta ne o us), t he m ec ha nis m b y w hic h 
c o m ple me nt C 3 a n d micr o glia c o o perat e t o eli mi nate t he tar g ete d cells (reti nal cells vers us m ot or 
ne ur o ns) is belie ve d t o b e si milar. 
Please ref er t o t he latest versi o n of t he pe g cetac o pla n I B f or m ore i nf or mati o n o n t he cli nical 
trials usi n g pe gcetac o pl a n.  
4. 4. 1.  
D ose R ati o n ale 
I n t his st u d y, pe gcetac o pl a n will be a d mi nistere d as a s u bc uta ne o us i nf usi o n at a d ose of 
1 0 8 0 m g t wice per w ee k. T he d ose selecti o n is base d o n pri or cli nical e x perie nce wit h 
pe gcetac o pla n. Re peate d S C d oses of 1 0 8 0 m g t wice per wee k h a ve b ee n a d mi nistere d t o healt h y 
s u bjects i n st u d y  
 f or 4 wee ks a n d a d ult s u bjects wit h P N H i n St u d y A P L 2- 3 0 2 f or at 
least 1 6 wee ks a n d were f o u n d t o be well t olerat e d i n b ot h st u dies. P har mac o d y na mic 
o bser vati o ns of s ustai ne d re d ucti o n of 5 0 % alter nati ve he m ol ytic c o m ple me nt pat h wa y acti vit y 
( A H 5 0) le v els a n d i ncr ease d C 3 le vels fr o m b ot h st u dies were c o nsiste nt wit h a c o ncl usi o n t hat 
pe gcetac o pla n i n hi bits alter nati ve c o m ple m e nt acti vit y. Statisticall y si g nifica nt i m pr o ve me nt i n 
efficac y bi o mar k er r es p o nse (e g, i ncr eas e i n he m o gl o bi n le vels) were o bs er ve d i n P N H s u bjects 
i n st u d y A P L 2-3 0 2 after treat me nt wit h pe gcetac o pla n. Pe gcetac o pla n is e x pecte d t o be 
p har mac ol o gicall y acti ve t o re g ulate ot her c o m ple me nt- dri ve n i m m u ne res p o nses i ncl u di n g 
t h ose t hat ma y c o ntri b ute t o M N de ge nerati o n a n d pr o gressi o n of t he diseas e i n s A L S patie nts. 
T he S C d oses of 1 0 8 0 m g t wice per w ee k of pe gcetac o pla n is dee me d t he a p pr o priate re gi me n 
f or t his cli nical trial t o treat a d ult male a n d fe mal e s u bjects wit h s A L S.  
Please ref er t o t he latest versi o n of t he pe g cetac o pla n I B f or t he o verall ris k/ be ne fit assess me nt 
a n d t he m ost acc urate a n d c urre nt i nf or mati o n re g ar di n g t he dr u g meta b olis m, p har mac o ki netics 
( P K), effi cac y, a n d saf et y of pe gcet ac o pla n. 
4. 5.  
Cli nic al Ris ks/ Be nefits of Pe gcet ac o pl a n  
Pe gcetac o pl a n has t he p ote ntial t o sl o w t he pr o gressi o n of A L S b y tar geti n g t he c o m ple me nt 
s yste m at t he le vel of C 3 a n d t h us pre ve nti n g t he d e ge nerati o n of m ot or ne ur o ns.  
T he safet y of s u bc uta ne o us pe gcetac o pla n a d mi nistrati o n has bee n st u die d i n m ulti ple p hase  2 a n d 3 
st u dies f or AI H A, C 3 gl o mer ul o ne p hr o pat hies, a n d P N H, wit h a n acce pta ble safet y pr ofile t o date. 
N o net heless, a n u m ber of safet y m o nit ori n g practices are bei n g e m pl o ye d b y t his pr ot oc ol t o e ns ure 
s u bject safet y, i ncl u di n g p h ysical e xa mi nati o n, vital si g ns m o nit ori n g, he mat ol o g y, ser u m c he mistr y, 
uri n al ysis, as well as pr o m pt re p orti n g of seri o us a d verse e ve nts ( S A Es).  
C CI
C CI


Pegcetacoplan 
APL2-ALS-206 Protocol Amendment 6 
13 January 2023 
Apellis Pharmaceuticals, Inc 
Page 32 
 
Confidential 
Injection/infusion site/pump safety will be assessed during clinical visits when dosing coincides 
with clinic visit, and any significant finding from the assessment will be reported as an AE 
(see Section 11.2).  
Systemic complement inhibition might predispose individuals to infections caused by encapsulated 
organisms, including Streptococcus pneumoniae, Neisseria meningitidis (serogroups A, C, W, Y, 
and B), and Haemophilus influenzae type B. Subjects will be required to have documented evidence 
of vaccination against these organisms or agree to receive the vaccines (see Section 8.4). 
Administration of prophylactic antibiotic therapy chronically may be conducted, at the discretion of 
the treating investigator, in accordance with local treatment guidelines.  
Body temperature and vital signs will be monitored at all clinic visits, as well as relevant blood 
parameters throughout the study, to assess for signs of infection. Subjects will be provided with 
emergency study cards that include a list of symptoms associated with infections. This study card 
also guides subjects with instructions to contact their study physician or seek emergency medical 
care in the event they experience any of the listed symptoms. In the event of a suspected 
infection, the investigator should provide guidance on appropriate action to be taken. 
Systemic hypersensitivity reactions (eg, facial swelling, rash, urticaria) have occurred in patients 
treated with pegcetacoplan. One patient (less than 1% in clinical studies) experienced a serious 
allergic reaction which resolved after treatment with antihistamines. If a severe hypersensitivity 
reaction (including anaphylaxis) occurs, discontinue pegcetacoplan infusion immediately, institute 
appropriate treatment, per standard of care, and monitor until signs and symptoms are resolved.  
The use of silica reagents in coagulation panels should be avoided. Apellis previously conducted 
an investigation into prolonged activated partial thromboplastin times (aPTTs) observed in 
subjects treated with pegcetacoplan. It was confirmed that false positive aPTT prolongation 
occurred when coagulation panels were performed using a Stago Analyzer and, specifically, 
silica reagents. It was determined that there was interference between the silica reagents and 
PEGylated pegcetacoplan, resulting in artificially prolonged aPTTs. 
Subjects should be instructed to take the investigational product (pegcetacoplan or placebo) 
as prescribed, and to contact the investigator immediately for guidance in the event of any 
missed doses. The sponsor’s medical monitor should be contacted before interrupting or 
discontinuing the investigational product. 
Apellis is not currently aware of any evidence associating pegcetacoplan use with specific risks or 
complications of COVID-19. Apellis recognizes the need to consider the public health risks of the 
COVID-19 pandemic within the context of conducting a clinical trial. Since these risks may change 
as the pandemic evolves, and may vary based on geographic location, Apellis will continue to 
evaluate the risk/benefit around study conduct on an ongoing and patient-by-patient basis. 
4.5.1. 
Safety Measures With Enrollment  
Because this is the first time pegcetacoplan is being studied in the ALS patient population, 
measurements are in place to closely monitor safety at the beginning of the study.  
Enrollment will be limited to a maximum of 20 subjects in the 4 weeks following first subject 
enrolled, and a maximum of 40 subjects during the first 8 weeks of the study. After the 8 weeks, 
enrollment will not be limited. 


Pegcetacoplan 
APL2-ALS-206 Protocol Amendment 6 
13 January 2023 
Apellis Pharmaceuticals, Inc 
Page 33 
 
Confidential 
The data monitoring committee (DMC) will meet after 20 subjects have completed visit 3 
(week 4), and at regular intervals throughout the study as outlined in the DMC charter 
(see Section 12.9 for additional information).  
4.5.2. 
COVID-19 Risk Mitigation Measures 
In the event that an investigative site is closed, or subject is unable/unwilling to travel due to 
COVID-19, and, if in the opinion of the investigator it is in the subject’s best interest to continue 
in the study, the following mitigation measures may be implemented for the study and utilized if 
deemed necessary and authorized by the sponsor, including but not limited to:  
• In locations where home nursing services may be utilized, a home nursing vendor 
may be set up to complete assessments at a subject’s home. 
• Minimum safety assessments to be drawn at a certified local laboratory will be identified.  
• The electronic data capture (EDC) system will capture any missed assessments 
related to COVID-19. 
• Any change in COVID-19 status (serology or antigen), if available, will be 
captured separately in the EDC system. 
• Where applicable, relevant study documentation will be updated and communicated 
to health authorities and/or institutional review board (IRBs)/independent ethics 
committee (IECs) as required. 


Pegcetacoplan 
APL2-ALS-206 Protocol Amendment 6 
13 January 2023 
Apellis Pharmaceuticals, Inc 
Page 34 
 
Confidential 
5. 
TRIAL OBJECTIVES AND ENDPOINTS 
5.1. 
Objectives 
5.1.1. 
Primary Objective 
The primary objective of this study is to assess the efficacy of twice per week SC doses of 
pegcetacoplan 1080 mg compared to placebo in subjects with sALS as measured by the 
Combined Assessment of Function and Survival (CAFS) rank score (joint-rank score). 
5.1.2. 
Secondary Objectives 
The following are the secondary objectives of this study: 
• To assess the effect of pegcetacoplan compared to placebo as measured by the 
Revised ALS Functional Rating scale (ALSFRS-R) score 
• To assess the effect of pegcetacoplan compared to placebo on disease progression as 
measured by respiratory function through percentage of slow vital capacity (%SVC) 
• To determine the effect of pegcetacoplan compared to placebo on muscle strength as 
measured by handheld dynamometry (HHD) 
• To determine the effect of pegcetacoplan compared to placebo on survival or 
specified state of disease progression 
• To assess the effect of pegcetacoplan compared to placebo on health-related quality 
of life (HRQoL) as measured by ALS Assessment Questionnaire (ALSAQ-40)  
• To assess the safety of pegcetacoplan during the randomized and open-label treatment 
periods through incidence and severity of TEAEs, clinical laboratory tests 
(hematology, chemistry), vital signs, and physical examinations 
• To assess the long-term efficacy of pegcetacoplan using ALSFRS-R, %SVC, HHD, 
and ALSAQ-40 during the open-label treatment period 
5.2. 
Endpoints 
5.2.1. 
Primary Efficacy Endpoint 
The primary efficacy endpoint is the difference in CAFS rank score (joint-rank score) at week 52. 
5.2.2. 
Secondary Efficacy Endpoints 
The secondary efficacy endpoints are as follows: 
• Change from baseline in ALSFRS-R at week 52 
• Change from baseline in %SVC (at clinic visits) at week 52 
• Change from baseline in HHD megascore at week 52 
• Time to death, permanent tracheostomy, or permanent assisted ventilation up to week 52 
• Time to death up to week 52 


Pegcetacoplan 
APL2-ALS-206 Protocol Amendment 6 
13 January 2023 
Apellis Pharmaceuticals, Inc 
Page 35 
 
Confidential 
• Change from baseline in ALSAQ-40 at week 52 
• Change from baseline of the randomized treatment period (visit 2) and of the open-label 
treatment period (visit 15) to week 104 for ALSFRS-R, %SVC, HHD, and ALSAQ-40 
• Time to death, permanent tracheostomy, or permanent assisted ventilation up to 
week 104 
• Time to death up to week 104 
5.2.3. 
Primary Safety Endpoints 
The primary safety endpoints are as follows: 
• Incidence and severity of TEAEs  
• Change from baseline in vital signs and clinical laboratory tests 
• Positive responses (Yes) to the Columbia Suicide Severity Rating Scale (C-SSRS) 
5.2.4. 
Exploratory Endpoints 
The exploratory endpoints are as follows: 
• Change from baseline in European Quality of Life–5 Dimensions–5 Level (EQ-5D-5L) 
at week 52, week 104, and week 156 
• Change from baseline in Zarit Burden Interview (ZBI) score at week 52, week 104, 
and week 156 
• Change from baseline of %SVC (home spirometry) at week 52 and week 104 
• Time to percutaneous endoscopic gastrostomy tube placement up to week 52, week 104, 
and week 156 
• Change from baseline in serum neurofilament light chain (NfL) at week 52, week 104, 
and week 156 
• Change from baseline in serum phosphorylated neurofilament heavy chain (pNfH) at 
week 52, week 104, and week 156 
• Change from baseline in electrical impedance myography (EIM) at week 52, week 104, 
and week 156 (only at select investigational sites chosen to complete this) 
• Pegcetacoplan PK concentrations at week 52, week 104, and week 156 
• Changes from baseline at week 52, week 104, and week 156 in complement biomarkers: 
− Classical hemolytic complement pathway activity (CH50) 
− AH50 
− C3 levels 
• Immunogenicity: presence of antibodies to PEG moiety and peptide moiety of 
pegcetacoplan during the randomized and open-label treatment periods 


Pegcetacoplan 
APL2-ALS-206 Protocol Amendment 6 
13 January 2023 
Apellis Pharmaceuticals, Inc 
Page 36 
 
Confidential 
• Change from baseline of the randomized treatment period (week 1) and of the open-label 
treatment period (week 52) to week 156 for ALSFRS-R, %SVC (in-clinic), HHD, 
and ALSAQ-40 
• Time to death, permanent tracheostomy, or permanent assisted ventilation up to 
week 156 
• Time to death up to week 156 
 


Pegcetacoplan 
APL2-ALS-206 Protocol Amendment 6 
13 January 2023 
Apellis Pharmaceuticals, Inc 
Page 37 
 
Confidential 
6. 
INVESTIGATIONAL PLAN 
See Figure 1 for the study design, Table 2 for the schedule of assessments for the randomized 
treatment period, and Table 3 for the schedule of assessments for the open-label (pegcetacoplan) 
treatment period; Table 8 for the schedule of assessments for the open-label (pegcetacoplan) 
long-term extension treatment period. 
6.1. 
Overall Study Design 
This is a phase 2, randomized, double-blind, placebo-controlled, multicenter, efficacy and safety 
study of SC pegcetacoplan 1080 mg twice per week conducted in approximately 228 subjects 
with ALS. The study has been designed to minimize the burden on subjects with use of at-home 
assessments and limited number of clinic visits. 
The planned length of participation in the study for each subject is a maximum of approximately 
168 weeks. This study will consist of 5 parts: 
• Part 1: Up to 6-week screening period 
• Part 2: 52-week randomized treatment period 
• Part 3: 52-week open-label (pegcetacoplan) treatment period 
• Part 4: 52-week open-label (pegcetacoplan) long-term extension treatment period 
• Part 5: 6-week off-treatment follow-up period 
Throughout this protocol, “investigational product” refers to the blinded treatment, whether that 
is pegcetacoplan or placebo.  
6.1.1. 
Part 1: Screening Period (Up to 6 Weeks) 
• Informed consent will be obtained at screening prior to any study-related procedures 
being conducted. 
• Subjects (and/or caregivers) will be trained on the use of at-home assessments. 
6.1.2. 
Part 2: Randomized Treatment Period (52 Weeks) 
Approximately 228 subjects who meet all of the inclusion criteria and none of the exclusion 
criteria will be randomized 2:1 to either the pegcetacoplan treatment group or the placebo group. 
Safety and efficacy will be assessed and will include once per week at-home measurements, 
monthly calls, and clinic visits. Subjects who discontinue treatment early and do not complete 
Part 2 will continue to Part 5. 
6.1.2.1. 
Pegcetacoplan Treatment Group 
• Subjects randomized to pegcetacoplan will receive SC pegcetacoplan 1080 mg twice 
per week for 52 weeks.  
6.1.2.2. 
Placebo Treatment Group 
• Subjects randomized to placebo will receive SC placebo twice per week for 52 weeks. 


Pegcetacoplan 
APL2-ALS-206 Protocol Amendment 6 
13 January 2023 
Apellis Pharmaceuticals, Inc 
Page 38 
 
Confidential 
6.1.3. 
Part 3: Open-Label (Pegcetacoplan) Treatment Period (52 Weeks) 
At the end of Part 2, all subjects from both treatment groups will continue to Part 3. All subjects 
participating in Part 3 will be treated with pegcetacoplan 1080 mg twice per week up to 
week 104. Subjects who complete Part 3, will enter Part 4. Subjects who do not continue to 
Part 3, or who have started Part 3 but discontinue treatment early, will continue to Part 5. 
6.1.4. 
Part 4: Open-Label (Pegcetacoplan) Long-Term Extension Treatment Period 
(52 Weeks) 
At the end of Part 3, any subject who, in the opinion of the investigator, is experiencing clinical 
benefit from pegcetacoplan administration will be invited to continue to Part 4, the open-label 
long-term extension treatment period. All subjects participating in Part 4 will be treated with 
pegcetacoplan 1080 mg twice per week up to week 156. Subjects who complete Part 4 will enter 
Part 5. Subjects who do not continue to Part 4, or who have started Part 4 but discontinue 
treatment early, will continue to Part 5. 
6.1.5. 
Part 5: Off-Treatment Follow-up Period (6 Weeks) 
During Part 5, all subjects who have discontinued the investigational product (blinded 
pegcetacoplan/placebo or open-label pegcetacoplan) will complete a follow-up visit 6 weeks later.  
6.2. 
Number of Subjects 
There will be approximately 228 subjects diagnosed with sALS enrolled in the study. 
6.3. 
Treatment Assignment 
All subjects who meet all the inclusion criteria and none of the exclusion criteria will be enrolled 
in the study, until such time that approximately 228 subjects have been enrolled in the study. 
At the first visit of Part 2, subjects will be randomized after confirmation of study eligibility in a 
ratio of 2:1 via a computer-generated randomization schedule to receive pegcetacoplan or 
placebo. The randomization will be performed centrally and stratified by location of first muscle 
weakness (limb or bulbar) and riluzole and edaravone use. The stratification by location of onset 
and riluzole use will ensure balance between treatment groups for the respective stratification 
factors. Fixed block randomization will be used to ensure that approximately equals number of 
subjects are assigned each treatment within strata.  
6.4. 
Criteria for Study Termination 
The sponsor reserves the right to suspend or discontinue this study for administrative and/or 
safety reasons, at any time. The investigator reserves the right to discontinue dosing subjects, 
at any time, for safety reasons. 
 


Pegcetacoplan 
APL2-ALS-206 Protocol Amendment 6 
13 January 2023 
Apellis Pharmaceuticals, Inc 
Page 39 
 
Confidential 
Figure 1: 
Study Design 
 
 
Abbreviations: ALSFRS-R = Revised Amyotrophic Lateral Sclerosis Functional Rating Scale; EQ-5D-5L = European Quality of Life–5 Dimensions–5 Level; 
W = week(s); ZBI = Zarit Burden Interview. 
Notes: The initial baseline (visit 2b) spirometry assessments will be conducted in the clinic; every subsequent spirometry assessment will be conducted at home. 
ALSFRS-R questionnaire will be administered via the phone, including at screening. 
 
 
 
 
 
 
  
 
 
 
 
  
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
  
 
 
 
 
 








Pegcetacoplan 
APL2-ALS-206 Protocol Amendment 6 
13 January 2023 
Apellis Pharmaceuticals, Inc 
Page 43 
 
Confidential 
g Zarit Burden Interview will be administered to the same caregiver throughout the subject’s study participation. If subject is not actively being assisted by a caregiver at baseline, 
ZBI will be administered to the subject’s anticipated caregiver. If subject does not have an anticipated caregiver/relative at baseline, ZBI administration will begin when/if the 
subject starts requiring a caregiver. Please see Section 10.2.2 for the definition of a caregiver. 
h At investigational sites selected to conduct EIM, EIM will occur before HHD. 
i Blood pregnancy assessment and urine pregnancy test will be completed for WOCBP at the scheduled time points indicated. 
j Blood samples will be taken after vital signs and 12-lead ECG have been completed. 
k Additional samples for anti–pegcetacoplan peptide antibody and anti-PEG antibody will be collected every 6 months from last dose until it can be determined that the subject’s 
antibody levels are at baseline or that further testing is not needed. 
l At baseline visit 2b, in addition to the at-clinic %SVC using the clinic spirometer, subjects will also complete %SVC using their at-home devices. Training for the at-home SVC 
assessments will occur at baseline visit 2b after completion of the assessments using the at-home devices. Research personnel will provide training to the subject (and/or 
caregiver) until the subject (and/or caregiver) is able to perform the assessments independently. Only subjects (and/or caregivers) trained to perform the at-home assessments 
will be allowed to continue in the study.  
m At-home %SVC will occur on a dosing day each week. 
n Subjects (or caregiver) will administer SC pegcetacoplan, after receiving appropriate training by a nurse or other research personnel. The research personnel providing training 
will be made available for a minimum of 6 days on treatment (2 doses) to ensure the subject (or caregiver) has been trained to conduct self-administration; the duration can be 
shortened if ability to self-administer happens sooner. During training, the subject (or caregiver) must demonstrate to the research personnel his/her ability to safely and 
effectively administer study drug using the infusion pump. Following self-administration training, subject (or caregiver) may self-administer the SC infusions without 
supervision on all dosing days.  
o Between clinic visits, subjects will be instructed to report any injection site reaction and/or any other AEs to the study coordinator.  
p Investigational product dispensation for home administration may occur at different times throughout the study.  
q Baseline is divided into visit 2a and visit 2b so questionnaires can be completed at the subject’s home prior to dosing.  
a.  
Visit 2a will be conducted at home via the telephone one day prior to visit 2b.  
b. 
Visit 2b will be conducted at clinic; please confirm completion of visit 2a assessments before starting visit 2b assessments. 
r Only subjects not enrolling in Part 3 will return unused investigational product. 
s Visit 15b is only applicable for subjects who do not enter Part 3. 
t Subjects who discontinue early should complete an early termination follow-up visit 6 weeks (±7 days) after treatment discontinuation. 
u At-home measurements will be performed once per week on a dosing day through the last clinic visit.  
 






Pegcetacoplan 
APL2-ALS-206 Protocol Amendment 6 
13 January 2023 
Apellis Pharmaceuticals, Inc 
Page 46 
 
Confidential 
e Zarit Burden Interview will be administered to the same caregiver throughout the subject’s study participation. If subject is not actively being assisted by a caregiver at baseline, 
ZBI will be administered to the subject’s anticipated caregiver. If subject does not have an anticipated caregiver/relative at baseline, ZBI administration will begin when/if the 
subject starts requiring a caregiver. Please see Section 10.2.2 for the definition of a caregiver. 
f At investigational sites selected to conduct EIM, EIM will occur before HHD. 
g Urine pregnancy test will be completed for WOCBP.  
h Blood samples will be taken after vital signs and 12-lead ECG have been completed.  
i Additional samples for anti–pegcetacoplan peptide antibody and anti-PEG antibody will be collected every 6 months from last dose until it can be determined that the subject’s 
antibody levels are at baseline or that further testing is not needed. 
j At-home %SVC will occur on a dosing day each week. 
k Subjects (or caregiver) will administer SC pegcetacoplan, after receiving appropriate training by a nurse or other research personnel.  
l Between clinic visits, subjects will be instructed to report any injection site reaction and/or any other AEs to the study coordinator. 
m Investigational product dispensation for home administration may occur at different times throughout the study. At weeks 64 and 88, which are between clinic visits, subjects or 
their caregiver(s) may be required to come into the clinic to pick-up additional IP and supplies. Depending on the length of time between the week 88 additional IP pick-up visit 
and the week 104 clinic visit, an unscheduled dispensation visit for pick-up of IP and/or supplies may be necessary. 
n Subjects who discontinue early should complete an early termination follow-up visit 6 weeks (± 7 days) after treatment discontinuation. 
o At-home measurements will be performed once per week, on the same day as when subject was receiving treatment, through the last clinic visit.  
p Only subjects not enrolling in Part 4 will return unused investigational product. 


Pegcetacoplan 
APL2-ALS-206 Protocol Amendment 6 
13 January 2023 
Apellis Pharmaceuticals, Inc 
Page 47 
 
Confidential 
6.5. 
End of Trial Definition 
A participant is considered to have completed the study if he/she has completed all parts of the 
study including the last scheduled procedure shown in Table 8, Schedule of Assessments–
Open-Label (Pegcetacoplan) Long-Term Extension Treatment Period. The end of the study is 
defined as the date of the last scheduled procedure shown in the schedule of assessments for the 
last participant in the trial globally. 
6.6. 
Study Procedures 
Please see the schedule of assessments (Table 2, Table 3, and Table 8) for a summary of the 
schedule of study participation and procedures. The schedule of visit dates for Part 2, 
randomized treatment period, and Part 3, open-label (pegcetacoplan) treatment period should be 
established, either prior to or at the time of screening, allowing subjects an opportunity to assess 
whether there are likely to be significant conflicts with other activities or planned absences. 
6.6.1. 
Screening Period: Visit 1 
The subject will be screened to confirm that the subject-selection criteria for the study has been met. 
Informed consent will be obtained at screening prior to any study-related procedures being 
conducted.  
During the screening period (from week -6 to baseline), pulmonary function tests (slow vital 
capacity [SVC]) and clinical laboratory tests (eg, hematology, coagulation, serum chemistry, 
urinalysis) may be repeated once with written approval from the sponsor (including the assigned 
medical monitor), with no requirement to designate the subject as a screen failure, unless the 
subject fails the second time. Subjects who do not meet screening SVC of ≥60% or clinical 
laboratory-related screening criteria may still qualify for study entry without having to complete 
the full rescreening process as long as the %SVC and all clinical laboratory-related values meet 
the criteria for study entry within the screening period.  
With the exception of %SVC and clinical laboratory-related entry criteria, subjects who have 
given informed consent and fail to meet at least 1 of the inclusion and/or exclusion criteria and 
have not been randomized or administered investigational product(s) will be designated as a 
screen failure. Any subject designated as a screen failure may only be rescreened once with 
written approval from the sponsor and will be required to recomplete the full screening process. 
Any %SVC or clinical laboratory test that is reconducted to confirm eligibility must be 
conducted within the screening period after written approval from the sponsor/medical monitor 
has been received, or the subject will be designated as a screen failure.  
At the screening visit, the following assessments will be performed: 
Note: 12-lead electrocardiogram (ECG) and vital sign measurements must be performed prior to 
blood sampling.  
• Informed consent 
• Demographics 
• Medical and treatment history 


Pegcetacoplan 
APL2-ALS-206 Protocol Amendment 6 
13 January 2023 
Apellis Pharmaceuticals, Inc 
Page 48 
 
Confidential 
• Inclusion and exclusion criteria, including 
− ALSFRS-R via the telephone at clinic 
− %SVC using clinic spirometer 
− C-SSRS 
• Concomitant medications  
• Vaccination history (see Section 8.4), administration of required vaccination(s) 
• Physical examination 
• Weight and height 
• Vital sign measurements (prior to blood sampling) 
• 12-lead ECG (prior to blood sampling) 
• Urinalysis 
• Blood (after vital sign measurements and 12-lead ECG) 
− Hematology 
− Chemistry 
− Pregnancy (β–human chorionic gonadotropin and follicle-stimulating hormone) 
for women of childbearing potential (WOCBP) 
− Hepatitis C virus, hepatitis B surface antigen 
• Assess subject’s (or caregiver’s) ability to perform SVC measurements using the at-home 
devices. Subjects will not take home any of these devices from the screening visit. 
Subjects missing documented evidence of any of the required vaccinations (within 5 years of 
baseline visit 2b) must receive the vaccinations at least 7 days prior to baseline visit 2b 
(see Section 8.4.1).  
6.6.2. 
Baseline: Visit 2a and Visit 2b 
6.6.2.1. 
Baseline: Visit 2a 
At the baseline visit 2a, the following assessments will be performed at home: 
• Questionnaires via the telephone: 
− ALSFRS-R 
− EQ-5D-5L  
− ZBI  


Pegcetacoplan 
APL2-ALS-206 Protocol Amendment 6 
13 January 2023 
Apellis Pharmaceuticals, Inc 
Page 49 
 
Confidential 
6.6.2.2. 
Baseline: Visit 2b 
At the baseline visit 2b, the following assessments will be performed at clinic: 
Note: 12-lead ECG and vital sign measurements must be performed prior to blood sampling, 
EIM must be performed prior to HHD (if applicable). All assessments must be performed prior 
to dosing (with the exception of injection site assessments, adverse reaction review, and postdose 
vital sign measurements)  
• Confirmation of inclusion and exclusion criteria  
• Confirm age at time of visit 2b 
• Concomitant medications  
• Vaccination history (see Section 8.4) 
• Physical Examination 
• Weight 
• Predose vital sign measurements (prior to blood sampling and dosing)  
• 12-lead ECG (prior to blood sampling and dosing) 
• Questionnaires: 
− ALSAQ-40 
− C-SSRS 
• %SVC using clinic spirometer  
• %SVC using at-home spirometer 
• Training on at-home assessments 
• EIM (only at select investigational sites) (prior to HHD) 
• HHD (after EIM, if applicable) 
• Urinalysis 
• Urine pregnancy test for WOCBP 
• Blood (after vital sign measurements and 12-lead ECG) 
− Hematology 
− Chemistry 
− Pharmacokinetics 
− Anti–pegcetacoplan peptide antibody and anti-PEG antibody assays 
− Complement profile (C3, CH50, and AH50) 
− NfL 
− pNfH 


Pegcetacoplan 
APL2-ALS-206 Protocol Amendment 6 
13 January 2023 
Apellis Pharmaceuticals, Inc 
Page 50 
 
Confidential 
• Investigational product administration: baseline dosing will be administered at the 
clinic by a nurse. 
− Injection site assessment 
− Adverse events review 
− Postdose vital sign measurements 
At the visit, subjects will receive the at-home devices. Trained research personnel will train the 
subject (and/or caregiver) to perform both the administration of pegcetacoplan and the at-home 
assessments independently. Only subjects/caregivers who have been trained to self-administer 
pegcetacoplan and the at-home assessments will be able to continue in the study. If subjects 
require caregiver assistance in administering pegcetacoplan and the at-home assessments, 
the caregiver must continue assisting in the administration of at-home assessments for the 
duration of study participation.  
(Note: throughout this protocol, the term “self-administration” refers to administration of the 
at-home assessments/investigational product by either a trained subject or trained caregiver). 
6.6.3. 
Randomized Treatment Period (Core) Visits 
Part 2 (randomized treatment period) of this study is composed of 4 different types of visits: 
• Clinic visits (Section 6.6.3.1)  
• Home visits (Section 6.6.3.2) 
• Telephone visits (Section 6.6.3.3) 
• Follow-up (core) visit (Section 6.6.3.4)  
6.6.3.1. 
Randomized Treatment Period (Core)—Clinic Visits: Visits 3, 5, 8, 11, 15 
In the randomized treatment period, prior to the clinic visits, the following should be assessed on 
a dosing day, at home, within visit window before the day of the clinic visit: 
• Questionnaires via the telephone: 
− ALSFRS-R 
− EQ-5D-5L  
− ZBI 
At the clinic visits, the following assessments will be performed: 
Note: 12-lead ECG and vital sign measurements must be performed prior to blood sampling, 
EIM must be performed prior to HHD (if applicable). If clinic visit coincides with a dosing day, 
all assessments must be performed prior to dosing (with the exception of injection site 
assessments and adverse reaction review).  
• Concomitant medications 
• Weight 
• Vital sign measurements (prior to blood sampling) 


Pegcetacoplan 
APL2-ALS-206 Protocol Amendment 6 
13 January 2023 
Apellis Pharmaceuticals, Inc 
Page 51 
 
Confidential 
• 12-lead ECG (prior to blood sampling) 
• Questionnaires: 
− ALSAQ-40 
− C-SSRS 
• %SVC using clinic spirometer 
• EIM (only at select investigational sites) (prior to HHD) 
• HHD (after EIM, if applicable) 
• Urinalysis 
• Urine pregnancy test for WOCBP 
• Blood sample (after vital sign measurements and 12-lead ECG) 
− Hematology 
− Chemistry 
− Pharmacokinetics 
− Anti–pegcetacoplan peptide antibody and anti-PEG antibody assays 
− Complement profile (C3, CH50, and AH50) 
− NfL 
− pNfH 
• Investigational product administration (if applicable) 
• Injection site assessment (if applicable) 
• AEs review 
• Return of unused investigational product (only at visit 15 for subjects not enrolling in 
Part 3) 
After visit 15, subjects will enroll in Part 3, the open-label (pegcetacoplan) treatment period. 
If the subject chooses not to participate in Part 3, they will complete the follow-up (core) visit 
(Study visit 15b), 6 weeks after visit 15.  
6.6.3.2. 
Randomized Treatment Period (Core)—Home Assessments  
During the randomized treatment period, on days when there are no clinic or telephone visits, 
the following assessments will be performed at the subject’s home beginning after baseline:  
• Twice per week: 
− Investigational product administration. Subjects and/or caregivers will be trained 
by research personnel before subject/caregiver can self-administer 
(see Section 9.4). Subjects should not deviate from their dosing schedule: Day 1 
and Day 4 of each treatment week (eg, Tuesday/Friday/Tuesday). 


Pegcetacoplan 
APL2-ALS-206 Protocol Amendment 6 
13 January 2023 
Apellis Pharmaceuticals, Inc 
Page 52 
 
Confidential 
• Once per week on a dosing day:  
− %SVC with handheld spirometry (self-administration) 
• Throughout the randomized treatment period: 
− Self-reported injection site assessment 
− AEs review  
6.6.3.3. 
Randomized Treatment Period (Core)—Telephone Visits: Visits 4T, 6-7T, 
9-10T, 12-14T 
At telephone visits in the randomized treatment period, the following assessments will be 
performed on a dosing day:  
• Questionnaires via the telephone: 
− ALSFRS-R  
− EQ-5D-5L  
− ZBI  
• Self-reported injection site assessment  
• AEs review 
• Urine pregnancy test for WOCBP (only at visit 13T) 
6.6.3.4. 
Follow-Up (Core) Visit: Visit 15b 
If the subject chooses not to participate in Part 3, they will complete the follow-up (core) visit, 
6 weeks after visit 15.  
Prior to the follow-up (core) visit, the following should be assessed, at home, within visit 
window before the day of the follow-up (core) visit: 
• Questionnaires: 
− ALSFRS-R 
− EQ-5D-5L  
− ZBI  
At the follow-up (core) visit, the following assessments will be performed: 
Note: 12-lead ECG and vital sign measurements must be performed prior to blood sampling, 
EIM must be performed prior to HHD (if applicable).  
• Concomitant medications 
• Physical examination 
• Weight  
• Vital sign measurements (prior to blood sampling) 


Pegcetacoplan 
APL2-ALS-206 Protocol Amendment 6 
13 January 2023 
Apellis Pharmaceuticals, Inc 
Page 53 
 
Confidential 
• 12-lead ECG (prior to blood sampling) 
• Questionnaires: 
− ALSAQ-40 
− C-SSRS 
• %SVC using clinic spirometer 
• EIM (only at select investigational sites) (prior to HHD) 
• HHD (after EIM, if applicable) 
• Urinalysis 
• Urine pregnancy test for WOCBP 
• Blood sample (after vital sign measurements and 12-lead ECG) 
− Hematology 
− Chemistry 
− Pharmacokinetics 
− Anti–pegcetacoplan peptide antibody and anti-PEG antibody assays 
− Complement profile (C3, CH50, and AH50) 
− NfL 
− pNfH 
• AEs review  
• Return of at-home devices 
6.6.4. 
Open-Label (Pegcetacoplan) Treatment Period Visits 
Part 3 (open-label [pegcetacoplan] treatment period) of this study is composed of 4 different 
types of visits: 
• Clinic visits (Section 6.6.4.1) 
• Home assessments (Section 6.6.4.2) 
• Telephone visits (Section 6.6.4.3) 
• Follow-up (open-label) visit (Section 6.6.4.4) 
6.6.4.1. 
Open-Label (Pegcetacoplan) Treatment Period—Clinic Visits: Visits 16, 21, 28 
In the open-label (pegcetacoplan) treatment period, prior to the clinic visits, the following should 
be assessed on a dosing day, at home, within visit window before the day of the clinic visit: 
• Questionnaires via the telephone: 
− ALSFRS-R  
− EQ-5D-5L  
− ZBI 


Pegcetacoplan 
APL2-ALS-206 Protocol Amendment 6 
13 January 2023 
Apellis Pharmaceuticals, Inc 
Page 54 
 
Confidential 
At the clinic visits, the following assessments will be performed:  
Note: 12-lead ECG and vital sign measurements must be performed prior to blood sampling, 
EIM must be performed prior to HHD (if applicable). If clinic visit coincides with a dosing day, 
all assessments must be performed prior to dosing (with the exception of injection site 
assessments and adverse reaction review).  
• Concomitant medications 
• Weight  
• Vital sign measurements (prior to blood sampling) 
• 12-lead ECG (prior to blood sampling) 
• Questionnaires: 
− ALSAQ-40 
− C-SSRS 
• %SVC using clinic spirometer 
• EIM (only at select investigational sites) (prior to HHD) 
• HHD (after EIM, if applicable) 
• Urinalysis 
• Urine pregnancy test for WOCBP 
• Blood sample (after vital sign measurements and 12-lead ECG) 
− Hematology 
− Chemistry 
− Pharmacokinetics 
− Anti–pegcetacoplan peptide antibody and anti-PEG antibody assays 
− Complement profile (C3, CH50, and AH50) 
− NfL 
− pNfH 
• Investigational product administration (if applicable) 
• Injection site assessment (if applicable) 
• AEs review 
• Return of unused investigational product (only at visit 28) 


Pegcetacoplan 
APL2-ALS-206 Protocol Amendment 6 
13 January 2023 
Apellis Pharmaceuticals, Inc 
Page 55 
 
Confidential 
6.6.4.2. 
Open-Label (Pegcetacoplan) Treatment Period—Home Assessments 
During the open-label (pegcetacoplan) treatment period, on days when there are no clinic or 
telephone visits, the following assessments will be performed at home:  
• Twice per week: 
− Pegcetacoplan administration. Subjects and/or caregivers will be trained by a 
nurse or other research personnel before subject can self-administer 
(see Section 9.4). Subjects should not deviate from their dosing schedule: day 1 and 
day 4 of each treatment week (eg, Tuesday/Friday/Tuesday). 
• Once per week on a dosing day:  
− %SVC with handheld spirometry (self-administration) 
• Throughout the open-label period: 
− Self-reported injection site assessment 
− AEs review 
6.6.4.3. 
Open-Label (Pegcetacoplan) Treatment Period—Telephone Visits: 
Visits 17T-20T, 22T-27T 
At telephone visits in the open-label (pegcetacoplan) treatment period, the following assessments 
will be performed on a dosing day: 
• Questionnaires via the telephone: 
− ALSFRS-R  
− EQ-5D-5L 
− ZBI  
• Self-reported injection site assessment 
• AEs review 
• Urine pregnancy test for WOCBP (only at visits 18T, 24T, and 26T) 
6.6.4.4. 
Open-Label (Pegcetacoplan) Treatment Period—Follow-up Visit: Visit 28b 
Prior to the follow-up (open-label) visit, the following should be assessed, at home, within visit 
window before the day of the follow-up (open-label) visit: 
• Questionnaires via the telephone: 
− ALSFRS-R  
− EQ-5D-5L  
− ZBI 


Pegcetacoplan 
APL2-ALS-206 Protocol Amendment 6 
13 January 2023 
Apellis Pharmaceuticals, Inc 
Page 56 
 
Confidential 
At the follow-up (open-label) visit, the following assessments will be performed: 
Note: 12-lead ECG and vital sign measurements must be performed prior to blood sampling, 
EIM must be performed prior to HHD (if applicable).  
• Concomitant medications 
• Physical examination 
• Weight  
• Vital sign measurements (prior to blood sampling) 
• 12-lead ECG (prior to blood sampling) 
• Questionnaires: 
− ALSAQ-40 
− C-SSRS 
• %SVC using clinic spirometer 
• EIM (only at select investigational sites) (prior to HHD) 
• HHD (after EIM, if applicable) 
• Urinalysis 
• Urine pregnancy test for WOCBP 
• Blood sample (after vital sign measurements and 12-lead ECG) 
− Hematology 
− Chemistry 
− Pharmacokinetics 
− Anti–pegcetacoplan peptide antibody and anti-PEG antibody assays 
− Complement profile (C3, CH50, and AH50) 
− NfL 
− pNfH 
• AEs review  
• Return of at-home devices 
6.6.5. 
Open-Label (Pegcetacoplan) Long-Term Extension Treatment Period 
Part 4 (open-label [pegcetacoplan] long-term extension period) of this study is composed of 
4 different types of visits: 
• Clinic visits (Section 6.6.5.1) 
• Home assessments (Section 6.6.5.2) 
• Telephone visits (Section 6.6.5.3) 
• Follow-up (open-label) visit (Section 6.6.5.4) 


Pegcetacoplan 
APL2-ALS-206 Protocol Amendment 6 
13 January 2023 
Apellis Pharmaceuticals, Inc 
Page 57 
 
Confidential 
6.6.5.1. 
Open-Label (Pegcetacoplan) Long-Term Extension Treatment Period—Clinic 
Visits: Visits 31, 36, 41 
In the open-label (pegcetacoplan) long-term extension treatment period, prior to the clinic visits, 
the following should be assessed on a dosing day, at home, within visit window before the day of 
the clinic visit: 
• Questionnaires via the telephone: 
− ALSFRS-R  
− EQ-5D-5L  
− ZBI 
At the clinic visits, the following assessments will be performed:  
Note: 12-lead ECG and vital sign measurements must be performed prior to blood sampling, 
EIM must be performed prior to HHD (if applicable). If clinic visit coincides with a dosing day, 
all assessments must be performed prior to dosing (with the exception of injection site 
assessments and adverse reaction review).  
• Concomitant medications 
• Weight  
• Vital sign measurements (prior to blood sampling) 
• 12-lead ECG (prior to blood sampling) 
• Questionnaires: 
− ALSAQ-40 
− C-SSRS 
• %SVC using clinic spirometer 
• EIM (only at select investigational sites) (prior to HHD) 
• HHD (after EIM, if applicable) 
• Urinalysis 
• Urine pregnancy test for WOCBP 
• Blood sample (after vital sign measurements and 12-lead ECG) 
− Hematology 
− Chemistry 
− Pharmacokinetics 
− Anti–pegcetacoplan peptide antibody and anti-PEG antibody assays 
− Complement profile (C3, CH50, and AH50) 
− NfL 
− pNfH 


Pegcetacoplan 
APL2-ALS-206 Protocol Amendment 6 
13 January 2023 
Apellis Pharmaceuticals, Inc 
Page 58 
 
Confidential 
• Investigational product administration (if applicable) 
• Injection site assessment (if applicable) 
• AEs review 
• Return of unused investigational product (only at visit 41) 
6.6.5.2. 
Open-Label (Pegcetacoplan) Long-Term Extension Treatment Period—Home 
Assessments 
During the open-label (pegcetacoplan) long-term extension treatment period, on days when there 
are no clinic or telephone visits, the following assessments will be performed at home:  
• Twice per week: 
− Pegcetacoplan administration. Subjects and/or caregivers will be trained by a 
nurse or other research personnel before subject can self-administer 
(see Section 9.4). Subjects should not deviate from their dosing schedule: day 1 
and day 4 of each treatment week (eg, Tuesday/Friday/Tuesday). 
• Throughout the open-label period: 
− Self-reported injection site assessment 
− AEs review 
6.6.5.3. 
Open-Label (Pegcetacoplan) Long-Term Extension Treatment Period—
Telephone Visits: Visits 29T, 30T, 32T-35T, 37T-40T 
At telephone visits in the open-label (pegcetacoplan) long-term extension treatment period, 
the following assessments will be performed on a dosing day: 
• Questionnaires via the telephone: 
− ALSFRS-R  
• Self-reported injection site assessment 
• AEs review 
• Urine pregnancy test for WOCBP (only at Visits 34T and 39T) 
6.6.5.4. 
Open-Label (Pegcetacoplan) Long-Term Extension Treatment Period—
Follow-up Visit: Visit 41b 
Prior to the follow-up (open-label, long-term extension) visit, the following should be assessed, 
at home, within visit window before the day of the follow-up (open-label) visit: 
• Questionnaires via the telephone: 
− ALSFRS-R  
− EQ-5D-5L  
− ZBI  


Pegcetacoplan 
APL2-ALS-206 Protocol Amendment 6 
13 January 2023 
Apellis Pharmaceuticals, Inc 
Page 59 
 
Confidential 
At the follow-up (open-label) visit, the following assessments will be performed: 
Note: 12-lead ECG and vital sign measurements must be performed prior to blood sampling, 
EIM must be performed prior to HHD (if applicable).  
• Concomitant medications 
• Physical examination 
• Weight  
• Vital sign measurements (prior to blood sampling) 
• 12-lead ECG (prior to blood sampling) 
• Questionnaires: 
− ALSAQ-40 
− C-SSRS 
• %SVC using clinic spirometer 
• EIM (only at select investigational sites) (prior to HHD) 
• HHD (after EIM, if applicable) 
• Urinalysis 
• Urine pregnancy test for WOCBP 
• Blood sample (after vital sign measurements and 12-lead ECG) 
− Hematology 
− Chemistry 
− Pharmacokinetics 
− Anti–pegcetacoplan peptide antibody and anti-PEG antibody assays 
− Complement profile (C3, CH50, and AH50) 
− NfL 
− pNfH 
• AEs review  
• Return of at-home devices 
6.6.6. 
Early Termination Follow-Up Visit 
Subjects who discontinue prior to the follow-up (core)/follow-up (open-label)/follow-up (open-label, 
long-term extension) visit will complete an early termination follow-up visit 6 weeks (±7 days) after 
their last dose of the investigational product.  
Prior to the early termination follow-up visit, the following will be assessed, at home, within visit 
window before the day of the early termination follow-up visit: 


Pegcetacoplan 
APL2-ALS-206 Protocol Amendment 6 
13 January 2023 
Apellis Pharmaceuticals, Inc 
Page 60 
 
Confidential 
• Questionnaires via the telephone: 
− ALSFRS-R 
− EQ-5D-5L 
− ZBI 
At the early termination follow-up visit, the following assessments will be performed: 
Note: 12-lead ECG and vital sign measurements must be performed prior to blood sampling, 
and EIM must be performed prior to HHD (if applicable).  
• Concomitant medications 
• Physical examination 
• Weight  
• Vital sign measurements (prior to blood sampling) 
• 12-lead ECG (prior to blood sampling) 
• Questionnaires: 
− ALSAQ-40 
− C-SSRS 
• %SVC using clinic spirometer 
• EIM (only at select investigational sites) (prior to HHD) 
• HHD (after EIM, if applicable) 
• Urinalysis 
• Urine pregnancy test for WOCBP 
• Blood sample (after vital sign measurements and 12-lead ECG) 
− Hematology 
− Chemistry 
− Pharmacokinetics 
− Anti–pegcetacoplan peptide antibody and anti-PEG antibody assays 
− Complement profile (C3, CH50, and AH50) 
− NfL 
− pNfH 
• AEs review 
• Return of at-home devices 


Pegcetacoplan 
APL2-ALS-206 Protocol Amendment 6 
13 January 2023 
Apellis Pharmaceuticals, Inc 
Page 61 
 
Confidential 
6.6.7. 
Unscheduled Visit(s) 
Subjects may be asked to return to the clinic for additional visits if considered necessary by the 
investigator. Unscheduled visits may include (but are not limited to) any of the procedures listed 
in the schedule of assessments (see Table 2, Table 3, and Table 8). 


Pegcetacoplan 
APL2-ALS-206 Protocol Amendment 6 
13 January 2023 
Apellis Pharmaceuticals, Inc 
Page 62 
 
Confidential 
7. 
SELECTION AND WITHDRAWAL OF SUBJECTS 
7.1. 
Subject Inclusion Criteria 
1. Sporadic ALS diagnosed as definite, probable, or laboratory-supported probable as 
defined by the revised El Escorial criteria (Brooks et al. 2000) 
2. At least 18 years of age 
3. SVC ≥60% of the predicted value based on age, sex, and height at screening 
4. Onset of ALS symptoms within 72 weeks prior to screening 
5. Total ALSFRS-R score of ≥30 at screening 
6. WOCBP, defined as any woman who has experienced menarche and who is NOT 
permanently sterile or postmenopausal  
a. must have a negative pregnancy test at screening and  
b. must agree to use protocol defined methods of contraception for the duration of the 
study and 90 days after their last dose of the investigational product 
− Postmenopausal is defined as 12 consecutive months with no menses without an 
alternative medical cause 
7. Males must agree to 
a. use protocol defined methods of contraception and  
b. refrain from donating sperm for the duration of the study and 90 days after their last 
dose of the investigational product 
8. Have vaccination against Streptococcus pneumoniae, N meningitidis (types A, C, W, Y, 
and B), and H influenzae (type B) either within 5 years prior to baseline visit 2b, or agree 
to receive vaccination at least 7 days prior to baseline visit 2b. Vaccination is mandatory, 
unless documented evidence exists that subjects are non-responders to vaccination 
(as evidenced by titers or display titer levels within acceptable local limits)   
9. Willing and able to give informed consent and comply with study procedure and 
assessments (including at-home assessments) 
7.2. 
Subject Exclusion Criteria 
1. Confirmed or suspected other causes of neuromuscular weakness 
2. Diagnosis of another neurodegenerative disease(s)  
3. Subject with significant cognitive impairment, clinical dementia, or psychiatric illness 
that in the opinion of the investigator may increase subject’s risk by participating in the 
study or confound the outcome of the study 
4. Subjects with a significant pulmonary disorder not attributed to ALS or who require 
treatments that might complicate the evaluation of the effect of ALS on respiratory 
function (eg, chronic obstructive pulmonary disease, pulmonary fibrosis, cystic fibrosis, 
pulmonary arterial hypertension) 


Pegcetacoplan 
APL2-ALS-206 Protocol Amendment 6 
13 January 2023 
Apellis Pharmaceuticals, Inc 
Page 63 
 
Confidential 
5. Current use or anticipated need, in the opinion of the investigator, of a diaphragm pacing 
system (DPS) during the randomized treatment period 
6. Riluzole initiation or change in dose within 30 days prior to the start of the screening 
period or planned initiation during study participation. If using riluzole, the subject 
should remain on the drug throughout Part 2 of study participation, but the dosage may be 
altered or the drug discontinued at any time by the investigator for any safety concern. 
Riluzole-naïve subjects are allowed in the study. 
7. Edaravone initiation or change in dose within 60 days prior to the start of the screening 
period or planned initiation during study participation. If using edaravone, the subject 
should remain on the drug throughout Part 2 of study participation, but the dosage may be 
altered or the drug discontinued at any time by the investigator for any safety concern. 
Edaravone-naïve subjects are allowed in the study. 
8. Positive response to Item 4 or 5 of the C-SSRS 
9. Subjects with detectable hepatitis C by polymerase chain reaction at screening 
10. Subjects with chronic inactive hepatitis B with viral loads >1000 IU/mL 
(>5000 copies/mL) at screening. Eligible subjects who are chronic active carriers 
(≤1000 IU/mL) must receive prophylactic antiviral treatment according to local country 
guidelines (eg, entecavir, tenofovir, lamivudine) 
11. History of an aggressive lymphoma or presence of a lymphoma requiring therapy by itself 
12. Active or overt malignant disease other than basal cell carcinoma or cutaneous squamous 
cell carcinoma 
13. Received organ transplant 
14. Presence or suspicion of liver dysfunction as indicated by elevated alanine aminotransferase, 
aspartate aminotransferase, or bilirubin levels >2 × the upper limit of normal  
15. Presence or suspicion of severe recurrent or chronic infections that, in the opinion of the 
investigator, increase the subject’s risk by participating in the study 
16. Participation in any other investigational drug trial or exposure to other investigational agent, 
device, or procedure within 30 days or within 5-half lives of the treatment (whichever is 
longer) prior to the start of the screening period or during study participation 
17. Use of any other complement inhibitor within 30 days or within 5-half lives of the treatment 
(whichever is longer) prior to the start of the screening period or during study participation 
18. If breastfeeding, unwilling to discontinue for the duration of the study and for at least 
6 months after final dose of investigational product 
19. Inability to cooperate or any condition that, in the opinion of the investigator, could increase 
the subject’s risk by participating in the study or confound the outcome of the study 
20. Subjects with known allergy or hypersensitivity to pegcetacoplan or to any of the 
components 
21. Known or suspected hereditary fructose intolerance 


Pegcetacoplan 
APL2-ALS-206 Protocol Amendment 6 
13 January 2023 
Apellis Pharmaceuticals, Inc 
Page 64 
 
Confidential 
7.3. 
Subject Completion and Withdrawal Criteria 
Subjects will be considered to have completed the study when they have: 
• Completed the open-label long-term extension period. 
Subjects will be considered to have withdrawn from the study when they have: 
• Completed any early termination activities. 
A subject may withdraw from the study at any time, for any reason, without prejudice to his/her 
future medical care by the physician or at the institution. The investigator or sponsor may 
withdraw the subject at any time (eg, in the interest of the subject’s safety). If a subject 
discontinues or is withdrawn from the investigational product for any reason, the study site must 
immediately notify the medical monitor. Once a subject is withdrawn from the study, the subject 
may not re-enter the study. 
Subjects who discontinue the investigational product prior to the follow-up (core)/follow-up 
(open-label)/follow-up (open-label, long-term extension) visits will undergo all remaining visits 
and procedures through the relevant follow-up visit, unless unwilling or unable, or consent has 
been withdrawn. Subjects who wish to fully withdraw from the study before completion will 
complete the early termination follow-up visit 6 weeks (±7 days) after their last dose of the 
investigational product (see Table 2, Table 3, and Table 8). 
If a subject withdraws from the study, then the subject and/or their caregivers will be contacted 
by the study site to provide post-discontinuation survival status at 6-month intervals until the 
study completes. 
7.3.1. 
Reasons for Discontinuation 
The reason for withdrawal must be determined by the investigator and recorded in the subject’s 
medical record and on the electronic case report form (eCRF). If a subject is withdrawn for more 
than 1 reason, each reason should be documented in the source document and the most clinically 
relevant reason should be entered on the eCRF. 
The following list includes the reasons for discontinuation from treatment and/or withdrawal 
from the study: 
• adverse events 
• death 
• lost to follow-up 
• withdrawal by subject 
• study terminated by sponsor 
• physician decision 
• pregnancy 


Pegcetacoplan 
APL2-ALS-206 Protocol Amendment 6 
13 January 2023 
Apellis Pharmaceuticals, Inc 
Page 65 
 
Confidential 
• major protocol violation deemed, after consultation with study medical monitor, 
to potentially impact the subject’s safety and study data interpretation 
• lack of efficacy, defined as inadequate response to study drug in the investigator’s 
opinion 
7.3.1.1. 
Mandatory Study Discontinuation/Withdrawal Criteria 
Subjects are required to discontinue the investigational product and withdraw from the study if 
they meet the below criteria: 
• Administer a complement inhibitor during the period outlined in Section 8.6.1  
• Intentionally unblinded themselves  
7.3.2. 
Subjects “Lost to Follow-up” Prior to Last Scheduled Visit 
A minimum of 3 documented attempts must be made to contact any subject lost to follow-up at 
any time point prior to the last scheduled contact. At least 1 of these documented attempts must 
include a written communication sent to the subject’s last known address via courier or mail 
(with an acknowledgement of receipt request) asking that he/she return to the site for final safety 
evaluations and to return any unused investigational product and study devices. 


Pegcetacoplan 
APL2-ALS-206 Protocol Amendment 6 
13 January 2023 
Apellis Pharmaceuticals, Inc 
Page 66 
 
Confidential 
8. 
TREATMENT OF SUBJECTS 
8.1. 
Identity of the Investigational Product 
Throughout this protocol, “investigational product” refers to the blinded treatment, whether that 
is pegcetacoplan or placebo. Additional information on pegcetacoplan and placebo is available in 
Section 9. 
8.2. 
Treatment Assignment 
8.2.1. 
Blinding the Treatment Assignment 
This is a randomized, double-blinded, placebo-controlled study. The intent of blinding is to limit 
the occurrence of conscious and unconscious bias in the conduct and interpretation of the clinical 
study. Bias could arise from the influence that the knowledge of a specific treatment assignment 
may have on the recruitment and allocation of subjects, their subsequent care, the assessment of 
endpoints, the handling of withdrawals, and so on. The essential aim of blinding, therefore, is to 
prevent identification of the treatments by the subject and the blinded assessors associated with 
the conduct of the study until all such opportunities for bias have passed. 
Designated blinded study staff (eg, research coordinators, nurses, technicians administering 
questionnaires, subjects, spirometry and dynamometer central reading centers, assigned 
evaluating physician(s), and the sponsor) will be blinded to treatment assignment. Only the drug 
supply distributor/logistics personnel who are not site personnel will be unblinded to study 
treatment. These individuals are not allowed to discuss treatment and/or subject outcome with 
blinded study staff, including the evaluating physician. The principal investigator must be 
blinded to subjects’ treatment assignment.  
8.2.2. 
Randomization 
To prevent bias in treatment assignment, randomization will occur through the interactive 
response technology system.  
The randomization will only be available to the drug supply distributor/logistics personnel. 
The randomization will not be made available to the sponsor, subjects, or clinic staff responsible 
for the monitoring and evaluation of safety assessments. 
All subjects who meet all the inclusion criteria and none of the exclusion criteria will be enrolled in 
the study, until such time that approximately 228 subjects have been enrolled in the study. At the first 
visit of the randomized treatment period, subjects will be randomized after confirmation of study 
eligibility in a ratio of 2:1 via a computer-generated randomization schedule to receive pegcetacoplan 
or placebo. The randomization will be performed centrally and stratified by location of first muscle 
weakness (limb or bulbar), riluzole, and edaravone use. The stratification by location of onset and 
riluzole and edaravone use will ensure balance between treatment groups for the respective 
stratification factors. Fixed block randomization will be used to ensure that approximately equal 
number of subjects are assigned each treatment within strata.  




Pegcetacoplan 
APL2-ALS-206 Protocol Amendment 6 
13 January 2023 
Apellis Pharmaceuticals, Inc 
Page 68 
 
Confidential 
vaccination (as evidenced by titers or display titer levels within acceptable local limits). 
The investigator will discuss with the sponsor regarding individual subject circumstances.  
If the subject requires vaccination against N meningitidis, both vaccinations (N meningitidis A, 
C, W, Y and N meningitidis B) should be administered at least 7 days prior to baseline visit 2b. 
If the subject requires vaccination against Streptococcus pneumoniae, PCV13 will be 
administered at least 7 days prior to baseline visit 2b, and PPSV23 will be administered after at 
least 8 weeks.  
Revaccination should be consistent with the recommendations of the Centers for Disease Control 
and Prevention (or local guidelines) as follows:  
• N meningitidis types A, C, W, Y: every 5 years 
• N meningitidis type B: 1 year after the primary series and repeated every 2-3 years  
• Streptococcus pneumoniae (PPSV23):  5 years after previous PPSV23 dose  
• Haemophilus influenzae type B (Hib vaccine): no revaccination needed 
It is recommended that subjects also be vaccinated annually against influenza (flu) during study 
participation in accordance with guidelines in the country of residence. 
8.4.1. 
Prophylactic Antibiotics 
Administration of prophylactic antibiotic therapy chronically may be conducted, at the discretion 
of the treating investigator, in accordance with local treatment guidelines. 
8.5. 
Concomitant Medications 
All medications administered and procedures performed within 12 weeks of screening will be 
collected as prior medications and procedures. Medications administered and procedures 
performed from the time of informed consent through the early termination follow-up/follow-up 
(core)/follow-up (open-label)/follow-up (long-term extension) visit will be documented.  
• Use of riluzole during the study is allowed as long as the subject remains on the drug 
throughout Part 2 of study participation, but the dosage may be altered or the drug 
discontinued by the investigator at any time for any safety concern. Riluzole initiation 
or change in dose within 30 days prior to the start of the screening period or during 
Part 2 of study participation is not allowed. Riluzole-naïve subjects are allowed in 
study. If riluzole is initiated or discontinued or if dose is changed during Parts 3 or 4 
of the study, the dates of administration must be documented in the subject’s source 
document and subject’s eCRF. 
• Use of edaravone during the study is allowed as long as the subject remains on the 
drug throughout Part 2 of study participation, but the dosage may be altered or the 
drug discontinued at any time by the investigator for any safety concern. Edaravone 
initiation or change in dose within 60 days prior to the start of the screening period or 
during Part 2 of study participation is not allowed. Edaravone-naïve subjects are 
allowed in study. If edaravone is initiated or discontinued or if dose is changed during 
Parts 3 or 4 of the study, the dates of administration must be documented in the 
subject’s source document and subject’s eCRF. 


Pegcetacoplan 
APL2-ALS-206 Protocol Amendment 6 
13 January 2023 
Apellis Pharmaceuticals, Inc 
Page 69 
 
Confidential 
• Subjects should not begin Relyvrio (AMX0035) during Part 2 of the study and if 
administered during Part 3 or 4, the dates of administration must be documented in 
the subject’s source document and subject’s eCRF. 
Concomitant treatment refers to all treatment taken between the dates of the first dose of 
investigational product and the end of the follow-up period, inclusive. Concomitant treatment 
information must be recorded on the appropriate eCRF page. Except for complement inhibitors 
(other than pegcetacoplan [eg, eculizumab or ravulizumab]), any concomitant medication 
deemed necessary for the subject’s standard of care during the study, or for the treatment of any 
AE (along with the allowed medications described below) may be given at the discretion of the 
investigator. It is the responsibility of the investigator to ensure that the details regarding all 
medications are recorded in full in the subject’s eCRF. 
8.6. 
Prohibited Medications or Procedures 
8.6.1. 
Prohibited Medications 
Subjects are prohibited from taking the below medications: 
• Any other complement inhibitor within 30 days or within 5-half lives of the treatment 
(whichever is longer) prior to the start of the screening period or during study 
participation 
8.6.2. 
Prohibited Procedures 
Subjects are prohibited from having a DPS implanted prior to or during Part 2. Subjects who 
have a DPS implanted during Part 2 will be required to withdraw from the study. If a subject has 
a DPS implanted during Part 3 or 4, the date of the implantation must be documented in the 
subject’s source document and subject’s eCRF. 
8.7. 
Treatment Compliance 
Investigational product accountability will be performed to ensure subjects are dosing according 
to assigned treatment group. Subjects should not skip or deviate from their dosing schedule: 
day 1 and day 4 of each treatment week (eg, Tuesday/Friday/Tuesday). Dosing will be recorded 
in the dosing diaries.  
Subjects must be instructed to bring their empty/unused investigational product packaging to 
every visit. The pharmacist/nominated person will record details on the drug accountability form. 
Refer to the Pharmacy Manual for further details. 


Pegcetacoplan 
APL2-ALS-206 Protocol Amendment 6 
13 January 2023 
Apellis Pharmaceuticals, Inc 
Page 70 
 
Confidential 
9. 
INVESTIGATIONAL PRODUCT MATERIALS AND 
MANAGEMENT 
9.1. 
Investigational Product 
9.1.1. 
Pegcetacoplan  
Pegcetacoplan (also known as APL-2) drug product (DP) solution for injection or infusion will be 
provided as a sterile solution of pegcetacoplan with a concentration of 54 mg/mL in 10 mM acetate 
buffer, pH 5.0, containing 4.1% sorbitol supplied in stoppered glass vials. Additional information is 
provided in the pegcetacoplan DP IB.  
9.1.2. 
Placebo 
Placebo will be provided as a sterile solution of 10 mM acetate buffer, pH 5.0, containing 4.1% 
sorbitol supplied in stoppered glass vials. 
9.2. 
Investigational Product Packaging and Labeling 
9.2.1. 
Packaging 
Investigational product is supplied in 20-cc glass vials. Please refer to the Pharmacy Manual for 
details. 
Changes to sponsor-supplied packaging prior to dosing may not occur without full agreement, 
in advance, by the sponsor. 
9.2.2. 
Labeling 
Labels containing study information and pack identification are applied to the investigational 
product container. 
All investigational product (pegcetacoplan DP or placebo) is labeled with a minimum of the 
following: protocol number, dosage form (including product name and quantity in pack), route of 
administration, directions for use, storage conditions, batch number and/or packaging reference, 
statements required per local regulations (eg, “For clinical trial use only”), and name and address 
of the sponsor. 
Space is allocated on the label so that the clinic representative can record a unique subject 
identifier and date dispensed. 
Additional labels may, on a case-by-case basis, be applied to the investigational product in order to 
satisfy national, local, or institutional requirements but must not do any of the following: contradict 
the clinical study label, obscure the clinical study label, identify the study subject by name. 
Additional labels may not be added without the sponsor’s prior full agreement. 
9.3. 
Investigational Product Storage and Handling 
The investigational product is to be stored refrigerated at 2 to 8°C.  


Pegcetacoplan 
APL2-ALS-206 Protocol Amendment 6 
13 January 2023 
Apellis Pharmaceuticals, Inc 
Page 71 
 
Confidential 
If the investigational product is stored at investigator site (or documented storage location 
outside of subjects’ home), temperature monitoring is required to ensure that the investigational 
product is maintained within the established temperature range (2 to 8°C).  
The site pharmacist is responsible for the following: 
• ensuring that the investigational product is stored in a secure, limited-access location 
at the site 
• ensuring that the temperature is monitored throughout the duration of the study when 
the investigational product is at site and/or shipped to subject  
• ensuring that investigational product and supply records are maintained 
• dispensing the vials of investigational product to the subject and/or caregiver 
• entering the unique subject identifier on the investigational product bottle/carton 
labels as they are distributed 
The investigator or trained research personnel is responsible for ensuring subjects and/or 
caregivers are trained on how to appropriately store the investigational product. 
If the subject receives the investigational product from the site, it should be transported in a 
sponsor-approved bag or box, containing previously temperature-conditioned cold plates to 
ensure that the storage temperature (2 to 8°C) is maintained. Temperature monitoring will not be 
required at the subject’s residence. 
With sponsor prior approval, investigational product and/or ancillary supplies may be shipped from 
the study site to a subject’s designated location. Such shipments will be implemented only at sites 
where this activity is approved by the IRB/IEC and health authority (if required). Subject consent 
will be required prior to any subject information being provided to a courier. The responsibility to 
return empty vials and any unused investigational product shall remain unchanged. 
9.4. 
Administration 
The investigational product will be administered as a 20-mL SC infusion.  
The preferred site of infusion will be the abdomen. If administration into the abdomen is not feasible, 
alternative appropriate sites are acceptable (see Pump Instructions for Use for more details).  
Nurses or other research personnel will train and supervise the self-administration of SC 
infusions. The nurses/research personnel will be made available for a minimum of 6 days on 
treatment (2 doses) to ensure the subject or caregiver has been trained to conduct administration; 
the duration could be shortened if ability to self-administer happens sooner. During training, 
the subject (or caregiver) must demonstrate to the research personnel his/her ability to safely and 
effectively administer study drug using the infusion pump. Following self-administration 
training, subjects (or caregiver) may self-administer the SC infusions without supervision. 
If subject (or caregiver) is unable to self-administer study drug, a nurse may be made available 
for longer periods of time for study drug administration following consultation with the sponsor. 


Pegcetacoplan 
APL2-ALS-206 Protocol Amendment 6 
13 January 2023 
Apellis Pharmaceuticals, Inc 
Page 72 
 
Confidential 
9.5. 
Infusion Supplies  
The sponsor will supply syringes, vial adapters, infusion sets, and ambulatory syringe infusion 
pumps, as required. Refer to the Pharmacy Manual for further details. 
9.6. 
Investigational Product Accountability 
Accountability for the investigational product at the study center is the responsibility of the 
investigator. The investigator will ensure that the investigational product is used only in accordance 
with this protocol. Where allowed, the investigator may choose to delegate investigational product 
accountability responsibilities to a pharmacist or other appropriate individual. 
Investigators will be provided with sufficient amounts of the investigational product to carry out 
this protocol for the agreed number of subjects. The investigator/designee will acknowledge 
receipt of the investigational product, and documenting shipment content and condition. 
Accurate records of all investigational product dispensed, used, returned, and/or destroyed must 
be maintained. Accountability records will include dates, quantities, batch/serial numbers, 
expiration dates (if applicable), and participant numbers. The sponsor/designee will review 
investigational product accountability at the study center on an ongoing basis during monitoring 
visits. Investigational product must not be used for any purpose other than the present study. 
Investigational product that has been dispensed to a participant and returned unused must not be 
re-dispensed to a different participant. The investigator is responsible for ensuring the retrieval of 
all returnable study supplies from subjects. 
9.7. 
Investigational Product Disposal 
All unused and used study drug vials should be retained at the center until they are inventoried 
by the study monitor. At the conclusion of the study, any unused investigational product will 
either be destroyed or be returned to the sponsor or designee for destruction, and destruction will 
be documented appropriately. If no supplies remain, this fact will be documented appropriately. 


Pegcetacoplan 
APL2-ALS-206 Protocol Amendment 6 
13 January 2023 
Apellis Pharmaceuticals, Inc 
Page 73 
 
Confidential 
10. 
EFFICACY AND EXPLORATORY ASSESSMENTS 
10.1. 
Efficacy Assessments 
10.1.1. 
Primary Efficacy Assessment 
The primary efficacy assessment is the difference in the CAFS score at week 52. 
10.1.1.1. CAFS Scale 
The CAFS scale is a combined endpoint ranking subjects’ clinical outcomes based on ALSFRS-R 
and survival time. The worst outcome is assigned to the subject who dies first in the study and the 
best is assigned to the subject who survives with the least functional decline. Each subject’s outcome 
is compared to every other subject outcome in the trial in a series of pairwise comparisons, and the 
summed scores are ranked. A higher mean CAFS score indicates a better group outcome. 
Analysis will be completed by the sponsor. 
10.1.1.1.1. ALSFRS-R Scale 
The ALSFRS-R is a validated rating scale used to assess physical function in subjects with ALS. 
There are 12-items across 4 domains encompassing bulbar function, respiratory function, fine 
motor function, and gross motor function. Each question is scored from 0 (worst function) 
to 4 (best function), for a total maximum score of 48. The ALSFRS-R has been correlated to 
disease progression and survival and is validated for administration over the telephone to the 
subject. If the subject is unable to complete the ALSFRS-R assessment, the ALSFRS-R may be 
administered over the telephone to the caregiver (and must continue to be administered to the 
same caregiver for the rest of the subject’s participation in the study). In this study, ALSFRS-R 
will be assessed by qualified research personnel via the telephone during monthly telephone 
visits and on a dosing day within the visit window prior to clinic visits (except for screening). 
10.1.2. 
Secondary Efficacy Assessments 
The following are the secondary efficacy assessments for this study: 
• Change from baseline in ALSFRS-R at week 52  
• Change from baseline in %SVC (at clinic visits) at week 52  
• Change from baseline in HHD megascore at week 52 
• Change from baseline in ALSAQ-40 at week 52 
• Time to death, permanent tracheostomy, or permanent assisted ventilation up to week 52  
• Time to death up to week 52 
• Change from baseline of the randomized treatment period (visit 2) and of the open-label 
treatment period (visit 15) to week 104 for ALSFRS-R, %SVC, and HHD  
• Time to death, permanent tracheostomy, or permanent assisted ventilation up to 
week 104 
•  Time to death up to week 104 


Pegcetacoplan 
APL2-ALS-206 Protocol Amendment 6 
13 January 2023 
Apellis Pharmaceuticals, Inc 
Page 74 
 
Confidential 
10.1.2.1. Slow Vital Capacity—Clinic 
Slow vital capacity is a pulmonary function test measured during spirometry which reflects the 
maximum amount of air that can be exhaled slowly. The %SVC is the percentage of the 
predicted SVC value based on age, sex, and height. Slow vital capacity has been shown to 
closely correlate with forced vital capacity and is a predictor of functional loss in ALS.  
Slow vital capacity will be conducted at clinic visits with the clinic spirometer. 
10.1.2.2. ALSAQ-40 
The ALSAQ-40 is a 40-item validated questionnaire designed to assess HRQoL over the previous 
2 weeks in subjects with ALS or other MN diseases. The instrument measures 5 dimensions of health 
status: physical mobility, activities of daily living and independence, eating and drinking, 
communication, and emotional functioning. Dimension scores are converted to a scale of 0 
(perfect health as assessed by the measure) to 100 (worse health as assessed by the measure). 
The ALSAQ-40 will be administered at clinic visits. 
10.1.2.3. Handheld Dynamometry  
Handheld Dynamometry (HHD) is a quantitative method to measure muscle strength used in 
subjects with ALS. Assessments will be evaluated by combined muscle groups called 
megascores, which average scaled individual strength measures to produce an overall measure. 
Strength expressed as megascores have been shown to decline with ALS disease progression.  
The muscle groups that will be assessed are: first dorsal interosseous, wrist extension, elbow 
extension, elbow flexion, shoulder flexion, knee extension, knee flexion, and ankle dorsiflexion, 
on both sides of the body. HHD will be administered at clinic visits by qualified research personnel.  
10.2. 
Exploratory Assessments 
The following are the exploratory assessments for this study: 
• Change from baseline in EQ-5D-5L at week 52, week 104, and week 156 
• Change from baseline in ZBI score at week 52, week 104, and week 156 
• Change from baseline of %SVC (home spirometry) at week 52 and week 104 
• Time to percutaneous endoscopic gastrostomy tube placement up to week 52, 
week 104, and week 156 
• Change from baseline in serum NfL at week 52, week 104, and week 156 
• Change from baseline in serum pNfH at week 52, week 104, and week 156 
• Change from baseline in EIM at week 52, week 104, and week 156 (only at select 
investigational sites chosen to complete this) 
• Pegcetacoplan PK concentrations at week 52, week 104, and week 156 


Pegcetacoplan 
APL2-ALS-206 Protocol Amendment 6 
13 January 2023 
Apellis Pharmaceuticals, Inc 
Page 75 
 
Confidential 
• Changes from baseline at week 52, week 104, and week 156 in complement biomarkers: 
− 
CH50 
− 
AH50 
− 
C3 levels 
• Immunogenicity: presence of antibodies to PEG moiety and peptide moiety of 
pegcetacoplan during the randomized and open-label treatment periods 
• Change from baseline of the randomized treatment period (week 1) and of the 
open-label treatment period (week 52) to week 156 for ALSFRS-R, %SVC 
(in-clinic), HHD, and ALSAQ-40 
• Time to death, permanent tracheostomy, or permanent assisted ventilation up to 
week 156 
• Time to death up to week 156 
10.2.1. 
EQ-5D-5L 
The EQ-5D-5L is a standardized measure of health status developed to assess HRQoL by the 
EuroQoL Group. The questionnaire consists of a descriptive system and a visual analogue scale. 
The descriptive system contains 5 dimensions (mobility, self-care, usual activities, pain/discomfort, 
and anxiety/depression) with 5 levels in each dimension.  
EQ-5D-5L will be administered by qualified research personnel via the telephone during monthly 
telephone visits and within the visit window prior to clinic visits (but not in clinic).  
10.2.2. 
Zarit Burden Interview  
The ZBI is a 22-item self-reported measurement of caregiver burden. The caregiver responds to each 
item regarding the impact of the subject’s disability on their life using a 5-point scale from 0 (Never) 
to 4 (Nearly Always). The total minimal score is 0 and the maximum score is 88, with higher scores 
signifying increased burden. The ZBI has been used in several studies to assess burden in caregivers 
of subjects with ALS. 
The ZBI must be administered to the same caregiver throughout the subject’s study participation. 
“Caregiver” is defined as the family member who lives with the subject, or individual who spends 
the most time providing physical and/or emotional care to the subject. The ZBI should not be 
administered by third party home care support staff. If the subject is not actively being assisted by a 
caregiver at baseline, ZBI will be administered to the subject’s anticipated caregiver. If the subject 
does not have an anticipated caregiver/relative at baseline, ZBI administration will begin when/if the 
subject starts requiring a caregiver.  
The ZBI will be administered by qualified research personnel via the telephone during monthly 
telephone visits and within the visit window of clinic visits (but not in clinic).  


Pegcetacoplan 
APL2-ALS-206 Protocol Amendment 6 
13 January 2023 
Apellis Pharmaceuticals, Inc 
Page 76 
 
Confidential 
10.2.3. 
Slow Vital Capacity—Home 
As outlined in Section 10.1.2.1, slow vital capacity is a pulmonary function test measured during 
spirometry that reflects the maximum amount of air that can be exhaled slowly. The %SVC is the 
percentage of the predicted SVC value based on age, sex, and height. Slow vital capacity has been 
shown to closely correlate with forced vital capacity and is a predictor of functional loss in ALS.  
Slow vital capacity will be conducted once per week at home on a dosing day (with the exception of 
visit 2b) with a handheld spirometer. Slow vital capacity measured at subject’s home will be 
collected via the GoSpiro device and transmitted to a provisioned device via Bluetooth radio. 
The data stored on the device is then sent to the CarePortal (data platform) via Wi-Fi or cellular 
transmission. The subject and/or caregiver will receive training from a research nurse or other 
research personnel on the use of the spirometer for home use.  
10.2.4. 
Neurofilaments 
Neurofilaments are intermediate filaments and structural proteins of neurons. The most 
commonly- assessed neurofilament subunits in clinical trials are NfL and pNfH. Neurofilament 
levels in serum and cerebral spinal fluid are reflective of neuronal injury and both NfL and pNfH 
have been shown to correlate with extent of clinical upper and lower MN involvement in 
subjects with ALS. 
In this study, neurofilaments will be assessed with a blood sample.  
10.2.5. 
Electrical Impedance Myography  
Electrical impedance myography is a noninvasive, electrophysiological technique that has been 
shown to correlate with ALS disease progression. In this assessment, a high frequency, low-intensity 
electrical current is applied to a limb with the device and the resulting voltages are measured in the 
muscle. Changes in muscle structure such as atrophy, are detected as a change in impedance.  
Electrical impedance myography measurements will be performed bilaterally on the following 
muscles: quadriceps, tibialis anterior, gastrocnemius, wrist extensor compartment, biceps, 
and deltoids.  
Only select investigational sites will be chosen to perform this assessment on their subjects. 
Electrical impedance myography will be completed prior to HHD. 


Pegcetacoplan 
APL2-ALS-206 Protocol Amendment 6 
13 January 2023 
Apellis Pharmaceuticals, Inc 
Page 77 
 
Confidential 
11. 
SAFETY ASSESSMENTS 
11.1. 
Safety Parameters 
11.1.1. 
Demographic/Medical History 
Medical history will be recorded at screening. Investigators should document the occurrence, signs, 
and symptoms of the subject’s pre-existing conditions, including all prior significant illnesses, up to 
and including 1 year before screening. Additional preexisting conditions, present at the time when 
informed consent is given, up to the time of first dosing, are to be regarded as concomitant. 
Medical history will include alcohol consumption and smoking history, if applicable. 
Information regarding genetic markers, identified to be linked to ALS, will also be collected, 
if available (Section 11.1.10). 
Illnesses first occurring or detected during the study and/or worsening of a concomitant illness 
during the study are to be documented as AEs on the eCRF in accordance with Section 11.5.  
Additionally, demographic data will be collected for all subjects, as allowed per applicable 
regulations. 
11.1.2. 
Vital Signs 
Vital signs (body temperature, respiration rate, heart rate, and systolic and diastolic blood 
pressure measurements) will be evaluated at the visits indicated in the schedule of assessments 
tables (Table 2, Table 3, and Table 8). All vital signs will be measured after the subject has been 
resting in a sitting position for at least 5 minutes, except when they are supine or semireclined 
because of study procedures and/or AEs, or if deemed necessary by the investigator. Blood 
pressure measurements are to be taken in the same arm for the duration of the study.  
Vital sign measurements will be repeated, if clinically significant or if machine/equipment errors 
occur. Out-of-range blood pressure, respiratory rate, or heart rate measurements will be repeated, 
at the investigator’s discretion. Any confirmed, clinically significant vital signs measurements 
must be recorded as AEs. 
When investigational product is administered at the clinic, vital signs will be measured within 
2 hours preinfusion and at 30 minutes (±5 minutes) postdose.  
11.1.3. 
Electrocardiogram  
All 12-lead electrocardiograms (ECGs) will be measured once, prior to dosing (if applicable), 
at the time points outlined in the schedule of assessments (Table 2, Table 3, and Table 8). 
The ECG will be taken following resting in the supine position for at least10 minutes in a quiet 
environment and prior to any blood sampling procedures. The ECGs will be classified as normal, 
having a not clinically significant abnormality, or having a clinically significant abnormality. 
In addition, ECG parameters of ventricular rate, PR interval, QRS duration, and QT internal 
(uncorrected and corrected using Fridericia’s method) will be reviewed for ongoing safety. 
11.1.4. 
Weight and Height 
Body weight and height (both assessed without shoes on) will be recorded as outlined in the 
schedule of assessments (see Table 2, Table 3, and Table 8). 


Pegcetacoplan 
APL2-ALS-206 Protocol Amendment 6 
13 January 2023 
Apellis Pharmaceuticals, Inc 
Page 78 
 
Confidential 
11.1.5. 
Physical Examination 
All full physical examinations, performed by the investigator or designee, will include, at a 
minimum, assessment of the following: general, head, ears, eyes, nose, throat, dentition, thyroid 
(endocrine), heart, chest, lungs, abdomen, skin, extremities, back/neck, musculoskeletal, 
and lymph nodes.  
Brief physical examinations will include general appearance, heart, lungs, abdomen, extremities, 
and weight and are to be performed at all visits where a full physical examination does not occur.  
Additional symptom-driven physical examinations may be performed at any time, as deemed 
necessary by the investigator.  
See the schedule of assessments (Table 2, Table 3, and Table 8) for the details regarding which 
type of physical examination should be given at each visit. 
11.1.6. 
Injection/Infusion Site/Pump Safety Assessment 
Subjects (and/or caregivers) will be trained to administer the investigational product in the study.  
Subjects will be instructed to notify the investigator or other study personnel if an 
injection/infusion site reaction occurs after self-administration of pegcetacoplan. All clinically 
significant findings related to injection/infusion procedures will be recorded as AEs. 
11.1.7. 
C-SSRS 
The C-SSRS is a measure used to identify and assess individuals at risk for suicide. 
The questionnaire will assess suicidal thoughts and actions over the subject’s lifetime, prior 
6 months from screening and baseline, and changes from clinic visits. Questions are phrased for 
use in an interview format but can be completed as a self-report measure if necessary. 
The C-SSRS measures 4 constructs: the severity of ideation, the intensity of ideation, behavior, 
and lethality and is made up of 10 categories. The outcome of the C-SSRS is a numerical score 
obtained from the aforementioned categories. 
11.1.8. 
Laboratory Assessments 
Laboratory assessment samples (Table 4) are to be obtained at designated visits as detailed in the 
schedule of assessments tables (Table 2, Table 3, and Table 8). 
Labs will include, but will not be limited to, the following: 
 


Pegcetacoplan 
APL2-ALS-206 Protocol Amendment 6 
13 January 2023 
Apellis Pharmaceuticals, Inc 
Page 79 
 
Confidential 
Table 4: 
Laboratory Assessments 
Hematology 
Serum Chemistry 
Urine Studies 
Hb 
Hematocrit 
Platelet count 
RBC count 
WBC count with differential 
 
Albumin 
ALT 
ALP 
AST 
Bicarbonate 
Bilirubin (total, direct, and 
indirect) 
BUN 
Calcium 
Chloride 
Creatinine 
Creatine kinase  
Estimated glomerular filtration 
rate (using CKD-EPI 
formula) 
GGT 
Glucose 
HDL 
LDL 
Phosphorus 
Potassium 
Sodium 
Triglycerides 
Total cholesterol 
Total protein 
Uric acid 
Urinalysis 
• 
Blood 
• 
Bilirubin  
• 
Glucose 
• 
Ketones 
• 
Leukocyte esterase 
• 
Microscopic examination of 
urine sediment, including 
for presence of RBCs, 
WBCs, and casts, will be 
performed on all urinalyses 
• 
Nitrite 
• 
pH 
• 
Pregnancy, when applicable 
• 
Protein 
• 
Specific gravity 
• 
Urobilinogen 
Neurofilaments  
Additional 
NfL 
pNfH 
FSH (postmenopausal women) 
HBsAg 
HCV 
Serum pregnancy test 
Complement activation tests: 
(C3, AH50, and CH50) 
Anti–pegcetacoplan peptide antibody and anti-PEG antibody  
Abbreviations: AH50 = 50% alternative hemolytic complement pathway activity; ALP = alkaline phosphatase; ALT = alanine 
aminotransferase; AST = aspartate aminotransferase; BUN = blood urea nitrogen; CH50 = 50% classical hemolytic complement 
pathway activity; CKD-EPI = Chronic Kidney Disease–Epidemiology Collaboration; FSH = follicle-stimulating hormone; 
GGT = gamma-glutamyltransferase; Hb = hemoglobin; HBsAg = hepatitis B surface antigen; HCV = hepatitis C virus; 
HDL = high-density lipoproteins; LDL = low-density lipoproteins; NfL = neurofilament light chain; pNfH = phosphorylated 
neurofilament heavy chain; RBC = red blood cells; WBC = white blood cells. 
Note: The use of silica reagents in coagulation panels should be avoided in subjects treated with pegcetacoplan due to possible 
interference resulting in artificially prolonged aPTTs. Please refer to the IB for more details. 


Pegcetacoplan 
APL2-ALS-206 Protocol Amendment 6 
13 January 2023 
Apellis Pharmaceuticals, Inc 
Page 80 
 
Confidential 
Blood and urine samples will be analyzed at a central laboratory facility, as defined in the Laboratory 
Manual. Urine samples will be analyzed by dipstick and a microscopic analysis. All laboratory 
reports must be reviewed, signed, and dated by the investigator. A legible copy of all reports must be 
filed with both the subject’s eCRF and medical record (source document) for that visit.  
Clinically significant abnormal values occurring during the study will be followed up until repeat 
test results return to normal, stabilize, or are no longer clinically significant. 
Table 5 shows the blood volumes collected for the study. 
Table 5: 
Blood Volumes Collected 
Assay 
Number of collection  
time points 
Approximate volume 
per time point* (mL) 
Approximate sample 
volume over course 
of study (mL) 
Chemistry  
Screening: 1 
Randomized treatment 
visits: 6 
Open-label visits: 4 
Open-label Long-Term 
Extension:  4 
3.5 or 5.0 mL 
52.5 – 75.0 
HBsAg, HCV 
Screening: 1 
8.5 
8.5 
CH50 
Randomized treatment 
visits: 6 
Open-label visits 4 
Open-label Long-Term 
Extension:  4 
4.0 
56.0 
AH50 
Randomized treatment 
visits: 6 
Open-label visits: 4 
Open-label Long-Term 
Extension:  4 
4.0 
56.0 
NfL and pNfH 
Randomized treatment 
visits: 6 
Open-label visits: 4 
Open-label Long-Term 
Extension:  4 
5.0 
70.0 
Pharmacokinetics 
Randomized treatment 
visits: 6 
Open-label visits: 4 
Open-label Long-Term 
Extension:  4 
4.0 
56.0 
Anti–pegcetacoplan 
peptide and anti-PEG 
Ab 
Randomized treatment 
visits: 6 
Open-label visits: 4 
Open-label Long-Term 
Extension:  4 
4.0 
56.0 


Pegcetacoplan 
APL2-ALS-206 Protocol Amendment 6 
13 January 2023 
Apellis Pharmaceuticals, Inc 
Page 81 
 
Confidential 
Table 5: 
Blood Volumes Collected 
Assay 
Number of collection  
time points 
Approximate volume 
per time point* (mL) 
Approximate sample 
volume over course 
of study (mL) 
Hematology 
Screening: 1 
Randomized treatment 
visits: 6 
Open-label visits: 4 
Open-label Long-Term 
Extension:  4 
2.0 
30.0 
Total 
385 – 407.5 
Abbreviations: Ab = antibody; AH50 = 50% alternative hemolytic complement pathway activity; CH50 = 50% classical 
hemolytic complement pathway activity; HBsAg = surface antigen of the hepatitis B virus; HCV = hepatitis C virus; 
NfL = neurofilament light chain; PEG = polyethylene glycol; pNfH = phosphorylated neurofilament heavy chain.  
11.1.8.1. Pregnancy Screen 
For WOCBP, a serum pregnancy test will be performed at screening. Subjects with a positive 
result will be excluded or discontinued from the study. A urine pregnancy test will also be 
performed starting at baseline and at all indicated visits in the schedule of assessments (Table 2, 
Table 3, and Table 8). Male subjects will be counseled to avoid donating semen during the time 
between the first screening and the final follow-up (core)/follow-up (open-label)/open-label, 
long-term extension), and early termination follow-up visit and for 90 days after their last dose of 
investigational product. 
11.1.9. 
Anti–Pegcetacoplan Peptide Antibody and Anti-PEG Antibody Assessments 
The proposed anti-drug antibodies (ADA) sampling schedule was established to capture the 
ADA signal at baseline, along with any potential early onset and the dynamic profile (transient or 
persistent) of antibody formation.  
Samples that test positive will be characterized by an assay that will determine antibody titer and 
measure neutralizing capacity. Discontinued subjects will have ADA follow-up every 6 months 
from last dose until it can be determined that the subject’s antibody levels are at baseline or that 
further testing is not needed.  
Subjects will need to have ADA samples collected as outlined in the schedule of assessments 
(Table 2, Table 3, and Table 8). 
11.1.10. 
Genetic Mutation(s) Results 
Testing for genetic mutations is not performed as part of the study. However, subjects who have 
confirmed genetic mutations linked with ALS (eg, C9orf72, TARDBP, FUS, etc.) will be asked to 
provide this information, which will be documented as part of their medical history. Providing 
genetic mutations testing results is optional and a subject’s decision to not provide this information 
does not preclude them from participating in the study, if eligible. Genetic mutation data will be used 
in analysis for correlation with outcomes. 


Pegcetacoplan 
APL2-ALS-206 Protocol Amendment 6 
13 January 2023 
Apellis Pharmaceuticals, Inc 
Page 82 
 
Confidential 
11.1.11. 
COVID-19 Assessment 
If a subject has been tested for COVID-19, the results, if available, will be documented via eCRF. 
11.2. 
Adverse and Serious Adverse Events 
11.2.1. 
Definitions 
11.2.1.1. Adverse Events 
An AE is any untoward medical occurrence associated with the use of a drug in humans, whether 
or not it is considered drug related. An AE can, therefore, be any unfavorable and unintended 
sign, including a clinically significant abnormal laboratory finding, symptom, or disease 
temporally associated with the use of an investigational product, whether or not considered 
related to the investigational product. 
Adverse events can be spontaneously reported by the subject and/or in response to an open 
question from the study personnel or revealed by observation and will be recorded during the 
study at the investigational site. All identified AEs must be recorded and described on the 
appropriate AE or SAE page of the eCRF.  
Fluctuating or nonsignificant changes in laboratory values do not necessarily qualify for AE 
reporting. If changes in laboratory values are assessed as clinically significant and/or lead to 
discontinuation of administration of investigational product, they should be reported as an AE. 
If these laboratory values are linked to a diagnosis, only the diagnosis should be reported as an AE. 
11.2.1.2. Unexpected Adverse Event 
An AE or suspected adverse reaction is considered “unexpected” if it is not listed in the 
Reference Safety Information section of the investigator brochure (IB) that is in effect at the time 
of event onset. 
11.2.1.3. Serious Adverse Events 
An SAE is any AE or suspected adverse reaction that, in the view of the investigator, results in 
death, is life threatening, requires inpatient hospitalization or prolongation of existing 
hospitalization, results in a persistent or significant incapacity or substantial disruption of the 
ability to conduct normal life functions, or is a congenital anomaly or birth defect.  
Important medical events that may not result in death, be life threatening*, or require 
hospitalization may be considered serious when, according to appropriate medical judgment, 
they may jeopardize the subject or may require medical or surgical intervention to prevent one of 
the outcomes listed in the above definition.  
Examples of important medical events include allergic bronchospasm requiring intensive 
treatment in an emergency room or at home; blood dyscrasias or convulsions that do not result in 
inpatient hospitalization; or the development of drug dependency or drug abuse. 
*Life threatening is defined as an AE or suspected adverse reaction that, in the view of either the 
investigator or sponsor, placed the subject at immediate risk of death as it occurred. It does not 
include an AE or suspected adverse reaction that, had it occurred in a more severe form, might 
have caused death. 


Pegcetacoplan 
APL2-ALS-206 Protocol Amendment 6 
13 January 2023 
Apellis Pharmaceuticals, Inc 
Page 83 
 
Confidential 
All death events should be reported as the fatal outcome of an SAE, with the date and cause of 
death included. The medical event leading to the subject’s death (eg, respiratory failure, 
pneumonia) should be reported as the SAE term. If no alternative cause of death is identified, 
“progression of ALS” may be reported as the event term if deemed medically appropriate by the 
investigator.  
11.2.1.3.1. SAE Due to ALS 
Serious events (including events related to efficacy endpoints) that are considered ALS-related 
should be reported as “not related” SAEs. “ALS” or “disease progression” should not be reported 
as event terms if a more precise term for the complication or actual cause of hospitalization/death 
(eg, respiratory failure) can be reported.  
“Disease progression” is considered a worsening of a subject’s ALS symptoms (weakness, 
spasticity, respiratory insufficiency, respiratory arrest, dysphasia). It may reflect an increase in 
the severity of the disease or an increase in symptoms. 
Any event experienced by a subject which is solely regarded as part of disease progression and 
can be considered as a direct consequence of ALS, but does not result in death, should not be 
reported as an AE/SAE; examples include: respiratory insufficiency, dysphagia, respiratory 
failure, dysarthria, etc. However, if a subject should experience worsening of ALS-related 
disease symptoms that are not considered anticipated disease progression for that given subject, 
the investigator should report these findings as an AE. Examples of this might include: 
pneumonia, malnutrition, fall, or aspiration. If there is any uncertainty as to whether an event is 
due to anticipated disease progression, it should be reported as an AE. 
11.3. 
Relationship to Investigational Product 
The investigator will review each event and assess its relationship to investigational product 
treatment (not related, unlikely related, possibly related, or definitely related). The date and time 
of onset, time relationship to investigational product dosing, duration, and outcome 
(recovered/resolved, recovered/resolved with sequelae, recovering/resolving, not recovered/not 
resolved, fatal, or unknown) of each event will be noted. 
Table 6 should be considered when evaluating the relationship of AEs/SAEs to study treatment. 
Table 6: 
Definitions of Adverse Event Relatedness 
Classification 
Definition 
DEFINITELY 
RELATED 
Strong evidence of a causal relationship; the influence of other factors is unlikely 
POSSIBLY 
RELATED 
Some evidence of a causal relationship, but other factors may have caused or contributed 
to the event (eg, another illness or concomitant treatment) 
UNLIKELY 
RELATED 
A causal relationship is not a reasonable possibility, but it cannot be completely ruled out 
with the available evidence. 
NOT 
RELATED 
No evidence of a causal relationship 


Pegcetacoplan 
APL2-ALS-206 Protocol Amendment 6 
13 January 2023 
Apellis Pharmaceuticals, Inc 
Page 84 
 
Confidential 
11.4. 
Severity of Events 
The investigator will review each event and assess its severity. Note that severity is a measure of 
intensity, whereas seriousness is defined by the criteria in Section 11.2.1.2. An AE can be of 
severe intensity but not be considered serious. 
Table 7 presents the severity definitions that should be considered when evaluating the severity 
of AEs and SAEs.  
Table 7: 
Severity of Events 
Severity  
Definition/Description 
Mild 
Event results in mild or transient discomfort, not requiring intervention or treatment; 
does not limit or interfere with daily activities (eg, insomnia, mild headache). 
Moderate 
Event is sufficiently discomforting so as to limit or interfere with daily activities; may 
require interventional treatment (eg, febrile illness requiring oral medication). 
Severe 
Event results in significant symptoms that prevents normal daily activities; may require 
hospitalization or invasive intervention (eg, anemia resulting in blood transfusion). 
11.5. 
Recording Adverse Events 
Adverse events and SAEs will be collected from the signing of the informed consent form (ICF) 
until one of the following occurs: 
• follow-up (core) 
• follow-up (open-label) 
• follow-up (open-label, long-term extension) 
• early termination follow-up (ETFU) visit, 6 weeks after the last dose of 
pegcetacoplan.  
All SAEs will be followed until a final outcome of recovered, recovered with sequelae, or fatal, 
unless the subject withdraws consent or the investigator confirms that no additional information 
is available. 
All SAEs that are suspected of being related to study treatment must be reported immediately to 
the sponsor if the investigator becomes aware of them, regardless of the time since the 
completion of the clinical trial. 
Any events that occur prior to the start of dosing will be categorized as pretreatment events; 
events occurring after the start of dosing will be recorded as TEAEs (the start date of dosing and, 
therefore, categorization of the event will be dependent on randomization assignment). 
For each AE, the investigator will evaluate and report the onset date (and time if applicable), 
resolution date (and time, if applicable), intensity, causality, action taken, seriousness criteria 
met (if applicable), and whether or not the subject discontinued the study as a result of the event.  
If possible, the outcome of any AE resulting in permanent discontinuation or that was present at 
the end of the study should be reported, particularly if the AE was considered by the investigator 
to be related to the investigational product. Subjects experiencing AEs that cause interruption or 


Pe gcetac o pla n  
A P L 2 -A L S -2 0 6 Pr ot oc ol A me n d me nt 6  
1 3 Ja n uar y 2 0 2 3 
A pellis P har mace uticals, I nc  
Pa ge 8 5   
 
C o nfi de ntial  
disc o nti n uati o n of i n vesti gati o nal pr o d uct, or t h ose e x perie n ci n g A Es t hat are prese nt at t he 
f oll o w- u p (c or e)/f oll o w- u p ( o pe n-la b el)/f oll o w- u p ( o pe n-la b el, l o n g-ter m e xte nsi o n)/ E T F U visit 
s h o ul d recei ve f oll o w- u p as a p pr o priat e.  
All S A Es m ust be re p orte d t o t he s p o ns or/ A pellis Safet y via e C R F i m me di atel y, wit h o ut u n d ue 
dela y, u n der n o circ u mst a nces later t ha n 2 4 h o urs of bec o mi n g a w are of t he e ve nt, w het her or 
n ot t he e ve nt is dee me d treat me nt -r elate d. If t he el ectr o nic dat a ca pt ure ( E D C) s yste m is n ot 
o perati o nal ( or f or pa p er- base d st u dies), t he site m ust c o m plete t he pa per S A E f or m a n d e mail t o 
als o i m me diatel y, wit h o ut u n d ue dela y, u n der n o circ u msta nces later t ha n 
2 4 h o urs of bec o mi n g a w are of t h e e ve nt. T h e re p orte d i nf or mati o n s u b mitte d as a pa p er S A E 
m ust be e ntere d i nt o t he E D C s yste m o nce it bec o mes o perati o nal.  
A d verse e ve nts will be c o de d i n acc or da nce wit h t he Me dical Dicti o nar y f or Re g ulat or y 
Acti vities ( Me d D R A). If k n o w n, t he dia g n osis of t he u n derl yi n g ill ness or dis or der s h o ul d be 
rec or d e d, rat h er t ha n its i n di vi d ual s y m pt o ms. 
1 1. 6.  
Re p orti n g A d verse E ve nts  
T he s p o ns or has t he res p o nsi bilit y t o i nf or m c o ncer ne d healt h a ut h orities, et hic c o m mittees, 
a n d i n vesti gat ors a b o ut S U S A Rs i n li ne wit h G C P g ui da nce a n d a p plica ble re g ulat or y re q uire me nts.  
If re q uir e d, s pecific S A Es s h o ul d be re p orte d t o t h e c o ncer ne d et hic c o m mittees i n c o m plia nce 
wit h l ocal re q uire m e nts.  
1 1. 7.  
Pre g n a nc y  
Alt h o u g h pre g na nc y is n ot a n A E, all pre g n a ncies a n d s us pecte d pre g na n cies (i ncl u di n g a 
p ositi ve pre g na nc y test r e gar dless of a ge or diseas e state) occ urri n g wit h a fe male s u bject or t he 
fe male part ner of a male s u bject, m ust be f oll o we d t o c o ncl usi o n t o deter mi ne t heir o utc o me a n d 
are c o nsi d ere d i m me diat el y re p orta bl e e ve nts.  
A n y pre g na n c y, s us pect e d pre g na nc y, or p ositi ve pre g na nc y t est m ust be re p orte d t o 
A pellis  Safet y wit hi n 2 4 h o urs of t he I n vesti gat or bec o mi n g a ware of t h e e ve nt. Pre g na ncies 
s hall be re p orte d o n a Pre g na nc y Re p ort F or m, w hic h m ust be si g ne d a n d d ate d b y t he pri mar y 
i n vesti gat or a n d s u b mitte d via e mail t o 
 
T he i n vesti gat or m ust f oll o w t he s u bject u ntil c o m pleti o n of t he pre g na n c y a n d m ust re p ort t he 
o utc o me of t he pr e g na nc y (e g, deli ver y, t er mi nati o n, etc.) a n d n e o natal stat us u p t o 1 2 m o nt hs 
p ost deli ver y. A n a b n or m al o utc o me is defi ne d as t he birt h of a c hil d wit h p ersiste nt or si g nifica nt 
i nca pacit y or s u bsta ntial disr u pti o n of t he a bilit y t o c o n d uct n or mal life f u n cti o ns (f or merl y 
referre d t o as disa bilities), c o n ge nital a n o malies, or birt h defects. I n t he e v e nt of a n a b n or mal 
o utc o me, a n S A E m ust be re p ort e d usi n g t he S A E Re p ort F or m, as d escri b e d i n Secti o n  1 1. 4 . 
1 1. 7. 1.  
Acce pt a ble Met h o ds of C o ntr ace pti o n  
A p pr o ve d met h o ds of c o ntrace pti o n i ncl u de: 
•  C o m bi ne d (estr o ge n a n d pr o gest o ge n c o ntai ni n g) h or m o nal c o ntrace pti o n ass ociate d 
wit h i n hi biti o n of o v ulati o n: 
− oral, i ntra va gi nal, or tra ns der mal 
P P D
P P D


Pegcetacoplan 
APL2-ALS-206 Protocol Amendment 6 
13 January 2023 
Apellis Pharmaceuticals, Inc 
Page 86 
 
Confidential 
• Progestogen-only hormonal contraception associated with inhibition of ovulation: 
− oral, injectable, or implantable 
• Intrauterine device  
• Intrauterine hormone-releasing system  
• Bilateral tubal occlusion 
• Vasectomized partner (provided that partner is the sole sexual partner of the WOCBP 
trial participant and that the vasectomized partner has received medical assessment of 
the surgical success) 
• Sexual abstinence (defined as refraining from heterosexual intercourse during the 
entire period of risk associated with study treatments) 
• Male condom with or without spermicide (for male study subjects with female 
partners of childbearing potential only) 
Not all methods of contraception may be available in all of the countries in which the study is 
being conducted. 
Note: Sexual abstinence is only accepted when it is the preferred and usual lifestyle of the subject. 
Subjects must agree to use an approved method of contraception during the study and for 90 days 
after their last dose of investigational product.  
11.8. 
Abuse, Misuse, Overdose, and Medication Error 
Occurrences of events of drug abuse, drug misuse, drug overdose, and medication error must be 
reported to the sponsor. 
Abuse of a medicinal product: Persistent or sporadic, intentional, excessive use of medicinal 
products, which is accompanied by harmful physical or psychological effects. 
Misuse: Intentional and inappropriate use of a medicinal product not in accordance with the 
prescribed or authorized dose, route of administration, and/or intended indication(s), or not 
within the legal status of its supply. 
Overdose: Administration of a quantity of study drug per administration or per day, which is 
above the assigned dose. 
Medication Error: An error made in prescribing, dispensing, administration, and/or use of the 
study drug. Medication errors are reportable to the sponsor as defined below: 
• The dispensing, administration, and/or use of unassigned study drug. 
• The administration and/or use of an expired study drug. 
All AEs or SAEs associated with drug abuse, drug misuse, drug overdose, or medication error 
must be reported as appropriate. 


Pegcetacoplan 
APL2-ALS-206 Protocol Amendment 6 
13 January 2023 
Apellis Pharmaceuticals, Inc 
Page 87 
 
Confidential 
12. 
STATISTICS 
A formal statistical analysis plan (SAP) will be developed and finalized prior to locking the 
database. The full details of data presentations and analyses will be provided in the SAP. 
Additional statistical analyses other than those described in this section may be performed if 
deemed appropriate and included in the SAP. Any deviations from the final SAP or from what is 
outlined in the protocol will be discussed in the final study report.  
12.1. 
Determination of Sample Size 
A sample size of 180 randomized subjects (2:1 allocation ratio to pegcetacoplan:placebo) would 
provide approximately 86% power to detect a significant difference (33%) in the primary 
outcome (CAFS score) between the 2 treatment groups at a 2-sided alpha of 5% with 75% power 
to detect a 35% improvement in the rate of decline in the ALSFRS-R score and 39% power to 
detect a 10% improvement in survival. 
The estimates were based on the following assumptions: 
• Mean monthly rate of decline in ALSFRS-R is 1 unit for the placebo treatment group 
and pooled standard deviation of 0.84 units/month 
• 52-week mortality rate with placebo at 20% 
• Approximately 40-week subject enrollment period 
• 52 weeks of follow-up for assessing survival outcomes after each subject enrolls  
• 52 weeks of follow-up for assessing functional outcomes after each subject enrolls 
Subjects will be randomized and stratified by location of first muscle weakness (limb or bulbar), 
riluzole and edaravone use. 
Approximately 228 subjects (152:76) will be randomized to account for an anticipated 20% of 
randomized subjects prematurely discontinuing the study without providing a postbaseline 
ALSFRS-R measurement. 
12.2. 
Analysis Set 
12.2.1. 
Screened Set 
The screened set will include all subjects who provide written informed consent. This set will be 
used only for the purpose of describing subject disposition. 
12.2.2. 
Safety Set 
The safety set will include all subjects who receive at least 1 dose of any double-blind 
investigational product. Subjects will be analyzed according to the treatment they received. 
12.2.3. 
Intent-to-Treat Set 
The intent-to-treat (ITT) set will include all randomized subjects who receive at least one dose of 
randomized treatment (pegcetacoplan or placebo). Subjects will be analyzed according to their 
assigned treatment, regardless of the treatment actually received.  


Pegcetacoplan 
APL2-ALS-206 Protocol Amendment 6 
13 January 2023 
Apellis Pharmaceuticals, Inc 
Page 88 
 
Confidential 
12.2.4. 
Modified Intent-to-Treat Set 
The modified intent-to-treat (mITT) set will include all subjects in the ITT set who have at least 
1 postbaseline efficacy assessment. 
12.2.5. 
Per-Protocol Set 
The per-protocol (PP) set will include all subjects in the mITT set who have not violated any 
inclusion or exclusion criteria and/or deviated from the protocol in a way that could influence 
their efficacy assessment. Decisions concerning the exclusion of subjects from the PP analysis 
set will be made and documented prior to database lock. 
12.2.6. 
Pharmacokinetic Set 
The PK set will include all subjects in the safety set for whom the PK data are considered 
sufficient and interpretable.  
12.2.7. 
Pharmacodynamic Set 
The pharmacodynamic (PD) set will include all subjects in the safety set for whom the PD data 
are considered sufficient and interpretable.  
12.2.8. 
Data Review for Analysis Set 
After all the data have been verified/coded/entered into the database, a review will be performed. 
The purpose of this review will be to define the analysis populations. The review will also check 
the quality of the data, identifying outliers, and make decisions on how to deal with any data 
issues (eg, missing values, withdrawals, protocol deviations). After the preanalysis review, 
resolution of all issues and documentation of all decisions, the database will be locked. 
12.3. 
Efficacy Analysis 
12.3.1. 
Analysis of Primary Efficacy Endpoint 
The primary efficacy endpoint is the CAFS score at week 52.  
The CAFS score will be developed as follows: 
• The functional and survival outcomes are determined for every subject in the 
pegcetacoplan and placebo treatment groups. 
• All pairwise comparisons are performed and the scores of +1, 0, or –1 are assigned to 
a subject based on each pairwise comparison. The scores are assigned as follows: 
− If both subjects are deceased at the last point of contact, the subject with a longer 
survival receives a score of +1 and the other subject receives a score of –1. 
− If 1 subject is deceased and the other subject is alive at the last point of contact, 
the surviving subject receives a score of +1 and the deceased subject receives a 
score of –1. 


Pegcetacoplan 
APL2-ALS-206 Protocol Amendment 6 
13 January 2023 
Apellis Pharmaceuticals, Inc 
Page 89 
 
Confidential 
− If both subjects are living at the last point of contact, the subject with a smaller 
change from baseline in the functional endpoint at the last point of contact 
receives a score of +1 and the other subject receives a score of –1.  
The scores from each pairwise comparison are added up for each subject. 
The CAFS ranks score will be summarized by treatment group using descriptive statistics. 
The CAFS ranks score will be analyzed using analysis of covariance (ANCOVA) model with 
treatment as a fixed effect, adjusted for baseline ALSFRS-R total score, duration from symptoms 
onset to the first dose of study treatment, and stratification factors. 
The primary efficacy analysis for the primary endpoint (CAFS) will be conducted on the mITT set 
and will be repeated for the PP set to evaluate the robustness of the results from the primary analysis. 
Other sensitivity analyses will be explored, and details will be provided in the SAP. 
12.3.2. 
Analysis of Secondary Efficacy Endpoints 
To preserve the Type 1 error, a fixed-sequence testing strategy will be used. The ordering of the 
secondary endpoints in this testing strategy will match the order in which they are presented in 
the secondary endpoint section.  
Absolute values and changes from baseline in secondary efficacy endpoints (ALSFRS-R, in-clinic 
percentage of predicted SVC, HHD, and ALSAQ-40) will be summarized, using descriptive 
statistics, by treatment and visit. Baseline will be taken as the measurement closest, but prior, to the 
first dose of investigational product. 
Changes from baseline in secondary efficacy outcomes (ALSFRS-R, in-clinic percentage of 
predicted SVC, HHD, and ALSAQ-40) will be summarized by treatment group and analyzed 
using a mixed model for repeated measures. The model will include fixed categorical effects for 
treatment, study visit, and the study visit-by-treatment interaction, as well as the continuous, 
fixed covariate of baseline and the visit-by-baseline interaction term, time from symptoms onset 
to the first dose of investigational product, and the randomization stratification factors. Initially 
an unstructured covariance matrix will be investigated. If this analysis fails to converge, other 
covariance structures will be used; details will be provided in the SAP. The Kenward-Roger 
approximation will be used to estimate denominator degrees of freedom. 
For the secondary endpoints of time to death and time to death, permanent tracheostomy, 
or permanent assisted ventilation, Kaplan-Meier analysis will be used to describe the survival 
data. The comparison of the survival time between treatment groups will be provided using a 
Cox proportional hazard model adjusting for the same covariates used in CAFS ANCOVA. 
For subjects who did not experience an event, the time to event will be censored at the last 
observation date for the Kaplan-Meier plot. Subjects who are lost to follow-up or who 
discontinued the study will be censored at the date of discontinuation or lost to follow-up date.  


Pegcetacoplan 
APL2-ALS-206 Protocol Amendment 6 
13 January 2023 
Apellis Pharmaceuticals, Inc 
Page 90 
 
Confidential 
12.3.3. 
Analysis of Exploratory Efficacy Endpoints 
Absolute values and changes from baseline in exploratory endpoints will be summarized, using 
descriptive statistics, by treatment and visit: 
• EQ-5D-5L, ZBI, NfL, pNfH, and EIM at weeks 52, 104, and 156  
• At-home %SVC at week 52 and week 104 
• ALSFRS-R, %SVC (in-clinic), HHD, and ALSAQ-40 at week 156 
Baseline will be taken as the measurement closest to but prior to randomization. Time to 
percutaneous endoscopic gastrostomy tube placement up to weeks 52, 104, and 156 will be 
computed and summarized by treatment group, as will time to death, permanent tracheostomy, 
or permanent assisted ventilation up to week 156; and time to death up to week 156. Additional 
analyses might be performed for these endpoints and will be detailed in SAP. 
12.4. 
Safety Analysis 
All safety analyses will be summarized for the safety set. 
Adverse events will be coded using MedDRA. All AEs, including TEAEs, will be summarized 
by System Organ Class, Preferred Term, treatment group for number of subjects, and proportion 
reporting the event. A similar summary will be produced for SAEs, AEs leading to termination, 
severe AEs, and AEs related to the investigational product. The intensity of AEs and the 
relationship to investigational product will be summarized for each System Organ Class and 
Preferred Term by treatment group.  
Withdrawals due to AEs will be summarized for each body system and Preferred Term by 
treatment group. 
Treatment-emergent adverse events are defined as those AEs that develop or worsen after the 
first dose of study medication until the study follow-up visit or the ETFU visit.  
The AE summaries will be presented across all subjects. All AEs will be listed by subject, along 
with information regarding onset, duration, relationship, and severity to investigational product, 
action taken with investigational product, treatment of event, and outcome. In addition, 
the number and incidence of rejection episodes and graft loss will be tabulated. 
Laboratory assessment and anti–pegcetacoplan peptide antibody/anti-PEG antibody test results 
will be summarized by treatment group using appropriate descriptive statistics. 
Changes from baseline in clinical laboratory tests will be summarized, using descriptive 
statistics, by visit and nominal time postdose. Baseline will be taken as the measurement closest, 
but prior, to randomization. Out-of-range values will be flagged in data listings.  
Changes from baseline in vital signs will be summarized, using descriptive statistics, 
by treatment, visit, and nominal time postdose. Baseline will be taken as the measurement 
closest, but prior, to randomization. 
Values of potential clinical significance will be flagged in listings and summarized by treatment. 
Changes in physical examinations will be described in a data listing. 
Positive responses (Yes) to the C-SSRS will be summarized by treatment. 


Pegcetacoplan 
APL2-ALS-206 Protocol Amendment 6 
13 January 2023 
Apellis Pharmaceuticals, Inc 
Page 91 
 
Confidential 
12.5. 
Pharmacokinetic Analysis 
The PK concentrations will be evaluated using the PK set. 
Concentrations will be summarized, using descriptive statistics, over time, in the randomized 
treatment group (pegcetacoplan group). 
Individual subject concentration-time data will be plotted against actual sampling time. 
Median profiles of the concentration-time data, using nominal sampling times, will also be 
presented. Both linear-linear and linear-log plots will be presented.  
12.6. 
Pharmacodynamic Analysis 
The PD endpoints will be evaluated using the PD set. 
Absolute values, changes from baseline, and percent changes from baseline will be summarized 
using descriptive statistics, over time by treatment group. 
Individual subject time profiles will be plotted against actual sampling time. Median profiles, 
over time, using nominal sampling time, will also be presented. 
The PD endpoints will be compared between treatment groups using mixed effect repeated 
measures analyses. 
12.7. 
Other Analyses 
Demographics, baseline characteristics, concomitant medication, medical history, and study 
medication exposure will be summarized by treatment group. 
World Health Organization and MedDRA coding dictionaries will be used for the concomitant 
medications and medical histories, respectively.  
12.8. 
Interim Analysis  
No interim analysis is planned. 
12.9. 
Data Monitoring Committee 
A DMC will review cumulative safety/tolerability data (eg, physical examinations, vital signs, 
clinical laboratory tests, and AEs). The DMC will also review data related to efficacy for the 
week 52 analysis and final analysis. The DMC will have the responsibility to conduct a thorough 
safety assessment at regular predefined intervals during the treatment period of the study. 
DMC meetings will be held according to the schedule in the DMC charter. An ad hoc DMC data 
review may be recommended by the DMC or requested by the sponsor at any time during the 
study. The first DMC meeting will be held after 20 subjects have completed visit 3 (week 4). 
The remit, roles, and responsibilities of the DMC will be specified in a separate DMC charter. 


Pegcetacoplan 
APL2-ALS-206 Protocol Amendment 6 
13 January 2023 
Apellis Pharmaceuticals, Inc 
Page 92 
 
Confidential 
13. 
DIRECT ACCESS TO SOURCE DATA/DOCUMENTS 
Before an investigational site can enter a subject into the study, a representative of the sponsor 
will contact the investigational study site to: 
• Determine the adequacy of the facilities 
• Discuss with the investigator(s) and other personnel their responsibilities with regard 
to protocol adherence, and the responsibilities of Apellis or its representatives. 
This will be documented in a Clinical Study Agreement between Apellis and the 
investigator. 
Subject information will be captured and managed by study sites on eCRFs by a web-based EDC 
tool developed and supported by the contract research organization (CRO) assisting with the conduct 
of the study and configured by the sponsor. It is recommended that data be entered into the EDC 
system within 5 business days, including batched records and records with source documents. 
Data management will be performed by the CRO according to their standard operating 
procedures. The data management plan will be approved by the sponsor. 
During the study, a monitor from Apellis or representative will have regular contacts with the 
investigational site, for, but not limited to, the following: 
• Provide information and support to the investigator(s) 
• Confirm that facilities remain acceptable 
• Confirm all participant data relating to the study will be recorded on printed or 
electronic case report form (CRF) unless transmitted to the sponsor or designee 
electronically (eg, laboratory data). The investigator is responsible for verifying that 
data entries are accurate and correct by physically or electronically signing the CRF. 
Any subject records or data sets that are transferred to the sponsor will contain the 
identifier only; subject names or any information which would make the subject 
identifiable will not be transferred.  
• Ensure that the investigator must maintain accurate documentation (source data) that 
supports the information entered in the CRF 
• Confirm that the investigational team is adhering to the protocol, that data are being 
accurately recorded in the case report forms, and that investigational product 
accountability checks are being performed 
• The sponsor/designee is responsible for the data management of this study, including 
quality checking of the data 
• Perform source data verification. This includes a comparison of the data in the case 
report forms with the subject’s medical records at the hospital or practice, and other 
records relevant to the study. This will require direct access to all original records for 
each subject (eg, clinic charts). Data reported on the CRF or entered in the eCRF that 
are transcribed from source documents must be consistent with the source documents 
or the discrepancies must be explained.  
• Record and report any protocol deviations not previously sent to Apellis. 


Pegcetacoplan 
APL2-ALS-206 Protocol Amendment 6 
13 January 2023 
Apellis Pharmaceuticals, Inc 
Page 93 
 
Confidential 
• Confirm that AEs and SAEs have been properly documented on eCRFs and confirm 
any SAEs have been forwarded to Apellis and those SAEs that met criteria for 
reporting have been forwarded to the IRB/IEC. 
The monitor will be available between visits if the investigator(s) or other staff need(s) 
information or advice. 
13.1. 
Audits and Inspections 
Authorized representatives of Apellis, a regulatory authority, an IEC or IRB may visit the site to 
perform audits or inspections, including source data verification. The purpose of an Apellis audit or 
inspection is to systematically and independently examine all study-related activities and documents 
to determine whether these activities were conducted, and data were recorded, analyzed, 
and accurately reported according to the protocol, local laws, GCP guidelines of the International 
Council for Harmonisation, and any applicable regulatory requirements. The investigator should 
contact Apellis immediately if contacted by a regulatory agency about an inspection. 
13.2. 
Institutional Review Board/Independent Ethics Committee 
The principal investigator must obtain IRB/IEC approval for the investigational protocol. 
Initial IRB approval, and all materials approved by the IRB for this study including the subject 
consent form and recruitment materials must be maintained by the investigator and made 
available for inspection. 


Pegcetacoplan 
APL2-ALS-206 Protocol Amendment 6 
13 January 2023 
Apellis Pharmaceuticals, Inc 
Page 94 
 
Confidential 
14. 
QUALITY CONTROL AND QUALITY ASSURANCE 
To ensure compliance with GCP and all applicable regulatory requirements, Apellis, and/or 
authorized representatives of Apellis, may conduct a quality assurance audit(s) or pre–agency 
inspection visit(s). Please see Section 13.1 for more details regarding the audit process. 


Pegcetacoplan 
APL2-ALS-206 Protocol Amendment 6 
13 January 2023 
Apellis Pharmaceuticals, Inc 
Page 95 
 
Confidential 
15. 
ETHICS 
15.1. 
Ethics Review 
The final study protocol, including the final version of the ICF, must be approved or given a 
favorable opinion in writing by an IRB or IEC as appropriate. The investigator must submit 
written approval to Apellis before he/she can enroll any subject into the study. 
The principal investigator is responsible for informing the IRB or IEC of any amendment to the 
protocol in accordance with local requirements. In addition, the IRB or IEC must approve all 
advertising used to recruit subjects for the study. The protocol must be re-approved by the IRB 
or IEC upon receipt of amendments and annually, as local regulations require. 
The principal investigator is also responsible for providing the IRB with reports of any reportable 
serious adverse investigational product reactions from any other study conducted with the 
investigational product. Apellis will provide this information to the principal investigator. 
Progress reports and notifications of serious adverse investigational product reactions will be 
provided to the IRB or IEC according to local regulations and guidelines. 
15.2. 
Ethical Conduct of the Study 
The study will be conducted in accordance with the protocol and with the following: 
• Consensus ethical principles derived from international guidelines including the 
Declaration of Helsinki and the Council for International Organizations of Medical 
Sciences International Ethical Guidelines 
• Applicable International Council for Harmonisation of Technical Requirements for 
Pharmaceuticals for Human Use (ICH) Good Clinical Practice (GCP) Guidelines 
• Applicable national laws and regulations 
15.3. 
Written Informed Consent 
The principal investigator(s) at each center will ensure that the subject is given full and adequate 
oral and written information about the nature, purpose, and possible risks and benefits of the 
study. Subjects must also be notified that they are free to discontinue from the study at any time. 
The subject is to be given the opportunity to ask questions and allowed time to consider the 
information provided. 
The subjects must be informed that their personal study-related data will be used by the sponsor 
in accordance with local data protection laws. The level of disclosure must also be explained to 
the subject, who will be required to give consent for their data to be used as described in the 
informed consent. 
The subjects must be informed that their medical records may be examined by clinical quality 
assurance auditors or other authorized personnel appointed by the sponsor, by appropriate 
IRB/IEC members, and by inspectors from regulatory authorities. 


Pegcetacoplan 
APL2-ALS-206 Protocol Amendment 6 
13 January 2023 
Apellis Pharmaceuticals, Inc 
Page 96 
 
Confidential 
The subject’s signed and dated informed consent must be obtained before conducting any study 
procedures. The caregiver’s signed and dated informed consent must be obtained before 
conducting any caregiver-related study procedures. 
The principal investigator(s) must maintain the original, signed ICF. A copy of the signed ICF 
must be given to the subject and caregiver, respectively. 


Pegcetacoplan 
APL2-ALS-206 Protocol Amendment 6 
13 January 2023 
Apellis Pharmaceuticals, Inc 
Page 97 
 
Confidential 
16. 
DATA HANDLING AND RECORDKEEPING 
16.1. 
Inspection of Records 
Apellis will be allowed to conduct site visits to the investigation facilities for the purpose of 
monitoring any aspect of the study. The investigator agrees to allow the monitor to inspect the 
investigational product storage area, investigational product stocks, investigational product 
accountability records, subject charts and study source documents, and other records relative to 
study conduct. 
16.2. 
Retention of Records 
The principal investigator must maintain all documentation relating to the study for a period of 
25 years end of the clinical trial. Medical files of subjects shall be archived in accordance with 
national law. If it becomes necessary for Apellis or the regulatory authority to review any 
documentation relating to the study, the investigator must permit access to such records. 


Pegcetacoplan 
APL2-ALS-206 Protocol Amendment 6 
13 January 2023 
Apellis Pharmaceuticals, Inc 
Page 98 
 
Confidential 
17. 
PUBLICATION POLICY 
Both the use of data and the publication policy are detailed within the clinical study agreement. 
Intellectual property rights (and related matters), generated by the investigator and others 
performing the clinical study, will be subject to the terms of a clinical study agreement that will 
be agreed between the institution and the sponsor or its designee. With respect to such rights, 
the sponsor or its designee will solely own all rights and interests in any materials, data, and 
intellectual property rights developed by investigators and others performing the clinical study 
described in this protocol, subject to the terms of any such agreement. In order to facilitate such 
ownership, investigators will be required to assign all such inventions, either to their institution 
or directly to the sponsor or its designee, as will be set forth in the clinical study agreement. 


Pegcetacoplan 
APL2-ALS-206 Protocol Amendment 6 
13 January 2023 
Apellis Pharmaceuticals, Inc 
Page 99 
 
Confidential 
18. 
LIST OF REFERENCES 
Abe K, Aoki M, Tsuji S, et al. Safety and efficacy of edaravone in well-defined patients 
with amyotrophic lateral sclerosis: a randomised, double-blind, placebo-controlled trial. 
Lancet Neurol. 2017;16(7):505-512. 
Brettschneider J, Libon DJ, Toledo JB, et al. Migroglial activation and TDP-43 pathology 
correlate with executive dysfunction in amyotrophic lateral sclerosis. Acta Neuropathol. 
2012;123(3):395-407. 
Brooks B, Miller R, Swash M, Munsat T, World Federation of Neurology Research Group 
on Motor Neuron Diseases. El Escorial revisited: revised criteria for the diagnosis of 
amyotrophic lateral sclerosis. Amyotroph Lateral Scler Other Motor Neuron Disord. 
2000;1(5):293-299. 
Carpanini SM, Torvell M, Morgan BP. Therapeutic inhibition of the complement system in 
diseases of the central nervous system. Front Immunol. 2019;10:362. 
Chen X, Feng W, Huang R, et al. Evidence for peripheral immune activation in amyotrophic 
lateral sclerosis. J Neurol Sci. 2014;347(1-2):90-95. 
Chiu IM, Morimoto ET, Goodarzi H, et al. A neurodegeneration-specific gene-expression 
signature of acutely isolated microglia from an amyotrophic lateral sclerosis mouse model. 
Cell Rep. 2013;4(2):385-401.  
Chiu IM, Phatnani H, Kuligowski M, et al. Activation of innate and humoral immunity in 
the peripheral nervous system of ALS transgenic mice. Proc Nat Acad Sci. 
2009;106(49):20960-20965. 
de Castro C, Weitz I, Deschatelets P, et al. Treatment with APL-2 in patients who remain 
anemic despite treatment with Soliris® leads to increases in hemoglobin, transfusion 
avoidance and broad control of hemolysis [abstract]. In: Brazilian Congress of Hematology, 
Hemotherapy and Cell Therapy - HEMO 2018 meeting program; 31 Oct-03 Nov 2018; 
São Paulo, Brazil; 2018:Abstract 161.  
Edaravone [package insert]. Jersey City, NJ: MT Pharma America, Inc.; 2017. 
Ehrhart J, Smith AJ, Kuzmin-Nichols N, et al. Humoral factors in ALS patients during 
disease progression. J Neuroinflammation. 2015;12:127. 
El Idrissi NB, Bosch S, Ramaglia V, Aronica E, Baas F, Troost D. Complement activation at 
the motor end-plates in amyotrophic lateral sclerosis. J Neuroinflammation. 2016;13:72. 
Fischer LR, Culver DG, Tennant P, et al. Amyotrophic lateral sclerosis is a distal 
axonopathy: evidence in mice and man. Exp Neurol. 2004;185(2):232-240. 
Ganesalingam J, An J, Shaw CE, Shaw G, Lacomis D, Bowser R. Combination of 
neurofilament heavy chain and complement C3 as CSF biomarkers for ALS. J Neurochem. 
2011;117(3):528-537. 
Garbuzova-Davis S, Sanberg PR. Blood-CNS barrier impairment in ALS patients versus an 
animal model. Front Cell Neurosci. 2014;8(21):1-9. 


Pegcetacoplan 
APL2-ALS-206 Protocol Amendment 6 
13 January 2023 
Apellis Pharmaceuticals, Inc 
Page 100 
 
Confidential 
Gertz M, Roman E, Fattizzo B, et al. Inhibition of C3 with APL-2 controls haemolysis and 
increases haemoglobin levels in subjects with autoimmune haemolytic anemia (AIHA). 
Paper presented at: 24th Congress of the European Haematology Association. 13-16 June 2019; 
Amsterdam, Netherlands. 
Goldknopf IL, Sheta EA, Bryson J, et al. Complement C3c and related protein biomarkers in 
amyotrophic lateral sclerosis and Parkinson’s disease. Biochem Biophys Res Commun. 
2006;342(4):1034-1039. 
Kawamata T, Akiyama H, Yamada T, McGeer PL. Immunologic reactions in amyotrophic 
lateral sclerosis brain and spinal cord tissue. Am J Path. 1992;140(3):691. 
Kettenmann H, Kirchhoff F, Verkhratsky A. Microglia: new roles for the synaptic stripper. 
Neuron. 2013;77(1):10-18. 
Kolev M, Le Friec G, Kemper C. Complement—tapping into new sites and effector systems. 
Nat Rev Immunol. 2014;14(12):811-820. 
Lee JD, Kumar V, Fung JN, Ruitenberg MJ, Noakes PG, Woodruff TM. Pharmacological 
inhibition of complement C5a-C5a1 receptor signaling ameliorates disease pathology in the 
hSOD1G93A mouse model of amyotrophic lateral sclerosis. Br J Pharmacol. 
2017;174(8):689-699. 
Lee JD, Levin SC, Willis EF, Li R, Woodruff TM, Noakes PG. Complement components 
are upregulated and correlate with disease progression in the TDP-43Q331K mouse model of 
amyotrophic lateral sclerosis. J Neuroinflammation. 2018;15:171. 
Liao B, Zhao W, Beers DR, Henkel JS, Appel SH. Transformation from a neuroprotective to 
a neurotoxic microglial phenotype in a mouse model of ALS. Exp Neurol. 
2012;237(1):147-152. 
Liao DS, Grossi FV, El Mehdi D, et al. Complement C3 inhibitor pegcetacoplan for 
geographic atrophy secondary to age-related macular degeneration. Ophthalmology. 
2020;127(2):186-195. 
Liddelow SA, Guttenplan KA, Clarke LE, et al. Neurotoxic reactive astrocytes are induced 
by activated microglia. Nature. 2017;541(7638):481-487. 
Miller RG, Mitchell JD, Lyon M, Moore DH. Riluzole for amyotrophic lateral sclerosis 
(ALS)/motor neuron disease (MND). Cochrane Database Syst Rev. 2002;CD001447.  
Murdock BJ, Zhou T, Kashlan SR, Little RJ, Goutman SA, Feldman EL. Correlation of 
peripheral immunity with rapid amyotrophic lateral sclerosis progression. JAMA Neurol. 
2017;74(12):1446-1454. 
Noto Y, Kanai K, Misawa S, et al. Distal motor axonal dysfunction in amyotrophic lateral 
sclerosis. J Neurol Sci. 2011;302(1-2):58-62. 
Ravits JM, La Spada AR. ALS motor phenotype heterogeneity, focality, and spread: 
deconstructing motor neuron degeneration. Neurology. 2009;73(10):805-811. 
Relyvrio [package insert]. Cambridge, MA: Amylyx Pharmaceuticals, Inc.;2022 
Riluzole [package insert]. Cary, NC: Covis Pharmaceuticals Inc.;2016. 


Pegcetacoplan 
APL2-ALS-206 Protocol Amendment 6 
13 January 2023 
Apellis Pharmaceuticals, Inc 
Page 101 
 
Confidential 
Sta M, Sylva-Steenland R, Casula M, et al. Innate and adaptive immunity in amyotrophic 
lateral sclerosis: evidence of complement activation. Neurobiol Dis. 2011;42(3):211-220. 
Turner MR, Cagnin A, Turkheimer FE, Miller CC, Shaw CE, Brooks DJ, et al. Evidence of 
widespread cerebral microglial activation in amyotrophic lateral sclerosis: an [11C] 
(R)-PK11195 positron emission tomography study. Neurobiol Dis. 2004;15(3):601-609. 
van den Bos MA, Geevasinga N, Higashihara M, Menon P, Vucic S. Pathophysiology and 
diagnosis of ALS: insights from advances in neurophysiological techniques. Int J Mol Sci. 
2019;20(11):2818. 
Wang H, Ricklin D, Lambris JD. Complement-activation fragment C4a mediates effector 
functions by binding as untethered agonist to protease-activated receptors 1 and 4. 
Proc Natl Acad Sci USA. 2017;114(41):10948-10953. 
Wong RS, Pullon HW, Deschatelets P, et al. Inhibition of C3 with APL-2 results in 
normalisation of markers of intravascular and extravascular hemolysis in patients with 
paroxysmal nocturnal hemoglobinuria (PNH). Blood. 2018;132:2314. 

SAP_001.pdf: 
Apellis Pharmaceuticals, Inc
Page 1 
 
Confidential 
STATISTICAL ANALYSIS PLAN
PEGCETACOPLAN
PHASE 2
A PHASE 2, RANDOMIZED, DOUBLE-BLIND, PLACEBO-CONTROLLED, 
MULTICENTER STUDY TO EVALUATE THE EFFICACY AND SAFETY OF 
PEGCETACOPLAN IN SUBJECTS WITH AMYOTROPHIC LATERAL SCLEROSIS 
(ALS)
PROTOCOL IDENTIFIER: APL2-ALS-206 
Study Sponsor(s):
Apellis Pharmaceuticals, Inc
100 5th Avenue 
Waltham, MA 02451
Author:
Protocol:
13 January 2023, Amendment 6
SAP Version #:
2.0
SAP Date:
12 April 2023
Status:
Final
PPD


Pegcetacoplan (APL-2) 
APL2-ALS-206 Statistical Analysis Plan 
12 April 2023 
Apellis Pharmaceuticals, Inc 
Page 2 
 
Confidential 
REVISION HISTORY 
Version  
Issue Date 
Summary of Changes 
Rationale 
1.0 
06 September 2022 Not applicable 
 
2.0 
31 March 2023 
Added MI-based CAFS in Section 
6.4.2.1 
Response to FDA question 
 
 
Added CAFS analysis for SVC 
(Section 6.5.2.2.1) and HHD 
(Section 6.5.3.2.1) 
Response to FDA question 
 
 
Added analysis plan for OLP in 
Section 6.7 
To prespecify analysis for 
OLP 
 
 
Changed stratification variable in 
the model and added baseline Log 
NfL in model as a covariate 
To fit model better and 
adjust for prognostic 
factor  
 
 
Updated subgroup model; Added 2 
subgroups; Added one AE summary 
by ADA response 
Statistical consideration 
 
 
Adding change of NfL at week 52 
to the list of secondary endpoints 
and positioned it at the last of the 
testing hierarchy 
Update per understanding 
of increasing importance 
of NfL 
 
 
Changed pNfH model to ANCOVA  Longitudinal data not 
available 
 
 
Added clarification languages 
 


P e gcetac o pla n  ( A P L-2)  
Statistical A nal ysis Pla n: A P L 2 -A L S -2 0 6  
1 2 A pril  2 0 2 3  
A pellis P har mace uticals, I nc  
P a ge 3  
 
C o nfi de ntial  
A P P R O V A L SI G N A T U R E S  
Se ni or Direct or, Bi ostatistics  
A pellis P har mace uticals, I n c.  
 
 
 
A pellis P har mace uticals, I n c  
 
P P D
P P D
C CI


Pegcetacoplan (APL-2) 
APL2-ALS-206 Statistical Analysis Plan 
12 April 2023 
Apellis Pharmaceuticals, Inc 
Page 4 
 
Confidential 
TABLE OF CONTENTS 
TITLE PAGE .............................................................................................................................. 1 
REVISION HISTORY ................................................................................................................ 2 
APPROVAL SIGNATURES ...................................................................................................... 3 
TABLE OF CONTENTS ............................................................................................................ 4 
LIST OF TABLES ...................................................................................................................... 9 
LIST OF FIGURES .................................................................................................................... 9 
ABBREVIATIONS .................................................................................................................. 10 
1. 
INTRODUCTION .................................................................................................. 12 
1.1. 
Background ............................................................................................................ 12 
1.2. 
Exceptional Circumstances ..................................................................................... 12 
2. 
OBJECTIVES AND ENDPOINTS ......................................................................... 13 
2.1. 
Objectives............................................................................................................... 13 
2.1.1. 
Primary Objective ............................................................................................. 13 
2.1.2. 
Secondary Objectives ........................................................................................ 13 
2.2. 
Endpoints ............................................................................................................... 13 
2.2.1. 
Primary Endpoint .............................................................................................. 13 
2.2.2. 
Secondary Endpoints ........................................................................................ 14 
2.2.3. 
Safety Endpoints ............................................................................................... 14 
2.2.4. 
Exploratory Endpoints ...................................................................................... 14 
3. 
STUDY DESIGN ................................................................................................... 16 
3.1. 
General Description ................................................................................................ 16 
3.2. 
Randomization........................................................................................................ 17 
3.3. 
Blinding.................................................................................................................. 17 
3.4. 
Sample Size and Power Considerations................................................................... 18 
3.5. 
Analysis Timing and Unblinding ............................................................................ 18 
4. 
STATISTICAL ANALYSIS SETS ......................................................................... 20 
4.1. 
Screened Set ........................................................................................................... 20 
4.2. 
Safety Set ............................................................................................................... 20 
4.3. 
Intent-to-Treat Set .................................................................................................. 20 
4.4. 
Modified Intent-to-Treat Set ................................................................................... 20 
4.5. 
Per-Protocol Analysis Set ....................................................................................... 20 


Pegcetacoplan (APL-2) 
APL2-ALS-206 Statistical Analysis Plan 
12 April 2023 
Apellis Pharmaceuticals, Inc 
Page 5 
 
Confidential 
4.6. 
Pharmacokinetic Set ............................................................................................... 20 
4.7. 
Pharmacodynamic Set............................................................................................. 21 
5. 
STUDY SUBJECTS ............................................................................................... 22 
5.1. 
Disposition of Subjects ........................................................................................... 22 
5.2. 
Demographic and Baseline Characteristics.............................................................. 23 
5.3. 
Medical History ...................................................................................................... 24 
5.4. 
Prior and Concomitant Medications ........................................................................ 24 
5.5. 
Prior and Concomitant Procedures .......................................................................... 24 
5.6. 
Exposure to Investigational Product ........................................................................ 25 
5.7. 
Measurements of Treatment Compliance ................................................................ 25 
5.8. 
Protocol Deviations ................................................................................................ 25 
6. 
EFFICACY ANALYSES ....................................................................................... 27 
6.1. 
Analysis Models ..................................................................................................... 27 
6.2. 
Multiplicity Adjustment .......................................................................................... 28 
6.3. 
Estimands ............................................................................................................... 29 
6.4. 
Analyses of Primary Efficacy Endpoint .................................................................. 33 
6.4.1. 
Main Analysis of Primary Efficacy Endpoint .................................................... 33 
6.4.2. 
Sensitivity Analyses of Primary Efficacy Endpoint ........................................... 33 
6.4.2.1. 
Multiple Imputation for Missing ALSFRS-R for CAFS Under 
MAR ..................................................................................................... 34 
6.4.2.2. 
Control-Based Multiple Imputation for CAFS ....................................... 34 
6.4.2.3. 
Tipping Point Analysis for CAFS .......................................................... 34 
6.4.3. 
Supplemental Analyses of Primary Efficacy Endpoint ...................................... 35 
6.4.3.1. 
Excluding Data After Changes in Concomitant ALS Treatment 
and Supportive Care .............................................................................. 35 
6.4.3.2. 
Interruptions due to COVID-19 and Ukraine Conflict ............................ 35 
6.4.3.3. 
PP Set.................................................................................................... 35 
6.4.4. 
Subgroup Analyses of Primary Efficacy Endpoint ............................................. 36 
6.4.5. 
Analysis of Covariates ...................................................................................... 36 
6.5. 
Analyses of Secondary Efficacy Endpoints ............................................................. 37 
6.5.1. 
Change From Baseline in ALSFRS-R at Week 52 (Total Score) ....................... 37 
6.5.1.1. 
Supportive Analyses of ALSFRS-R ....................................................... 37 
6.5.1.2. 
Sensitivity Analyses of ALSFRS-R ....................................................... 37 


Pegcetacoplan (APL-2) 
APL2-ALS-206 Statistical Analysis Plan 
12 April 2023 
Apellis Pharmaceuticals, Inc 
Page 6 
 
Confidential 
6.5.1.3. 
Supplemental Analyses of ALSFRS-R .................................................. 39 
6.5.1.4. 
Interruptions due to COVID-19 and Ukraine Conflict ............................ 39 
6.5.1.5. 
Subgroup Analyses of ALSFRS-R ......................................................... 39 
6.5.2. 
Change from Baseline in % Predicted SVC (at Clinic Visits) at Week 52 .......... 40 
6.5.2.1. 
Sensitivity Analyses of % Predicted SVC (at Clinic Visits) ................... 40 
6.5.2.2. 
Supplemental Analyses of % Predicted SVC ......................................... 40 
6.5.2.3. 
Subgroup Analyses of % Predicted SVC (at Clinic) ............................... 41 
6.5.3. 
Change from Baseline in HHD Megascore at Week 52 ..................................... 41 
6.5.3.1. 
Sensitivity Analyses of HHD ................................................................. 41 
6.5.3.2. 
Supplemental Analyses of HHD ............................................................ 41 
6.5.3.3. 
Subgroup Analyses of HHD Megascores ............................................... 42 
6.5.4. 
Time to Death, Permanent Tracheostomy, or Permanent Assisted 
Ventilation up to Week 52 ........................................................................... 42 
6.5.5. 
Time to Death up to Week 52............................................................................ 42 
6.5.6. 
Change from Baseline in ALSAQ-40 at Week 52 (Total Score) ........................ 44 
6.5.7. 
Change from Baseline in Serum NfL at week 52 ............................................... 44 
6.6. 
Analyses of Exploratory Endpoints ......................................................................... 44 
6.6.1. 
Change from Baseline in % Predicted SVC (Home Spirometry) at 
Week 52 ...................................................................................................... 47 
6.6.2. 
Change from Baseline in EQ-5D-5L at Week 52 ............................................... 47 
6.6.3. 
Change from Baseline in ZBI Scores at Week 52 .............................................. 47 
6.6.4. 
Time to Percutaneous Endoscopic Gastrostomy Tube Placement up to 
Week 52 ...................................................................................................... 48 
6.6.5. 
Change from Baseline in Serum pNfH at Week 52 ............................................ 48 
6.7. 
Analyses of Open-Label Periods (OLP) .................................................................. 49 
7. 
SAFETY ANALYSIS ............................................................................................ 50 
7.1. 
Adverse Events ....................................................................................................... 50 
7.2. 
Injection/Infusion Site Assessment ......................................................................... 51 
7.3. 
Clinical Laboratory Data......................................................................................... 51 
7.4. 
Vital Signs .............................................................................................................. 52 
7.5. 
Electrocardiogram .................................................................................................. 53 
7.6. 
Other Safety Data ................................................................................................... 53 
7.6.1. 
Columbia-Suicide Severity Rating Scale (C-SSRS) ........................................... 53 


Pegcetacoplan (APL-2) 
APL2-ALS-206 Statistical Analysis Plan 
12 April 2023 
Apellis Pharmaceuticals, Inc 
Page 7 
 
Confidential 
7.6.2. 
Immunogenicity ................................................................................................ 55 
7.6.2.1. 
Sample-Level ADA Assay Data ............................................................ 55 
7.6.2.2. 
ADA Response ...................................................................................... 55 
7.6.3. 
Physical Exam .................................................................................................. 57 
8. 
PHARMACOKINETIC ANALYSIS ...................................................................... 58 
8.1. 
Drug Concentration ................................................................................................ 58 
8.2. 
Handling BLQ Values ............................................................................................ 58 
8.2.1. 
Handling of BLQ Concentrations in Summary Tables ....................................... 58 
8.2.2. 
Handling of BLQ Concentrations in Figures ..................................................... 58 
8.3. 
Statistical Analysis ................................................................................................. 59 
9. 
PHARMACODYNAMIC ANALYSIS ................................................................... 60 
9.1. 
Pharmacodynamic Data .......................................................................................... 60 
9.1.1. 
Pharmacodynamic Endpoints and Analysis ....................................................... 60 
10. 
OTHER ANALYSES ............................................................................................. 61 
11. 
INTERIM ANALYSIS ........................................................................................... 62 
12. 
DATA MONITORING COMMITTEE/REVIEW COMMITTEE ........................... 63 
13. 
DATA HANDLING CONVENTIONS ................................................................... 64 
13.1. 
General Data Reporting Conventions ...................................................................... 64 
13.2. 
Definition of Relative Study Days .......................................................................... 64 
13.3. 
Mapping of Visits for Clinic SVC ........................................................................... 64 
13.4. 
Definition of Visit Windows ................................................................................... 64 
13.4.1. 
All Assessments Except At-Home SVC ...................................................... 64 
13.4.2. 
At-Home SVC ............................................................................................ 66 
13.5. 
Derived Efficacy Endpoints .................................................................................... 66 
13.5.1. 
ALSFRS-R.................................................................................................. 66 
13.5.2. 
SVC Measures ............................................................................................ 67 
13.5.3. 
HHD Megascore ......................................................................................... 67 
13.5.4. 
ALSAQ-40.................................................................................................. 68 
13.5.5. 
EQ-5D-5L ................................................................................................... 69 
13.5.6. 
ZBI ............................................................................................................. 69 
13.6. 
Repeated or Unscheduled Assessments of Safety Parameters .................................. 69 
13.7. 
Handling of Missing, Unused, and Spurious Data ................................................... 69 
13.7.1. 
Missing Date of Investigational Product ...................................................... 69 


Pegcetacoplan (APL-2) 
APL2-ALS-206 Statistical Analysis Plan 
12 April 2023 
Apellis Pharmaceuticals, Inc 
Page 8 
 
Confidential 
13.7.2. 
Missing Date Information for Prior or Concomitant Medications 
(Therapies/Procedures) ................................................................................ 70 
13.7.2.1. 
Incomplete Start Date ............................................................................ 70 
13.7.2.2. 
Incomplete Stop Date ............................................................................ 71 
13.7.3. 
Missing Date Information for Adverse Events ............................................. 71 
13.7.3.1. 
Incomplete Start Date ............................................................................ 72 
13.7.3.2. 
Incomplete Stop Date ............................................................................ 72 
13.7.4. 
Missing Date Information for Dates of ALS Symptom Onset or 
Disease Diagnosis ....................................................................................... 72 
13.7.5. 
Missing Severity Assessment for Adverse Events........................................ 72 
13.7.6. 
Missing Relationship to Investigational Product for Adverse Events ........... 72 
13.7.7. 
Character Values of Clinical Laboratory Variables ...................................... 72 
14. 
ANALYSIS SOFTWARE ...................................................................................... 73 
15. 
CHANGES TO ANALYSIS SPECIFIED IN PROTOCOL .................................... 74 
16. 
REFERENCES ....................................................................................................... 75 
17. 
APPENDICES ........................................................................................................ 76 
17.1. 
Schedule of Assessments ........................................................................................ 76 
17.2. 
MI Procedures ........................................................................................................ 84 
17.2.1. 
Control-based MI ........................................................................................ 84 
17.2.2. 
Imputation Based on the Delta-Adjusted Stress Testing Method .................. 85 
17.3. 
Select Sample SAS® Code ...................................................................................... 85 
17.3.1. 
ANCOVA Model ........................................................................................ 85 
17.3.1.1. 
ANCOVA Model with Subgroups ......................................................... 86 
17.3.2. 
MMRM ....................................................................................................... 86 
17.3.2.1. 
MMRM with Subgroups ........................................................................ 87 
17.3.3. 
Time-to-Event Analyses .............................................................................. 88 
17.3.3.1. 
Kaplan-Meier Estimates ........................................................................ 88 
17.3.3.2. 
Cox Proportional Hazards Models ......................................................... 88 
17.3.4. 
Mixed Effects Model for Slope Analysis of Continuous Outcomes.............. 88 
17.3.5. 
MI for ALSFRS, HHD and SVC ................................................................. 90 
17.3.5.1. 
Control-based Imputation  for ALSFRS ................................................. 90 
17.3.5.2. 
Tipping Point Analysis for ALSFRS ..................................................... 95 
17.3.6. 
MI for CAFS ............................................................................................... 98 


Pegcetacoplan (APL-2) 
APL2-ALS-206 Statistical Analysis Plan 
12 April 2023 
Apellis Pharmaceuticals, Inc 
Page 9 
 
Confidential 
17.3.6.1. 
Control-based Imputation and Tipping Point Analysis for CAFS ........... 98 
17.3.6.2. 
MI Based CAFS .................................................................................. 104 
 
LIST OF TABLES 
Table 1: 
Estimands and Attributes for Primary and Secondary Endpoints ........................ 31 
Table 2: 
Seed for Multiple Imputation ............................................................................. 34 
Table 3: 
Estimands and Attributes for Comparative Exploratory Endpoints ..................... 45 
Table 4: 
Criteria for Potentially Clinically Significant Vital Signs ................................... 52 
Table 5: 
Criteria for Potentially Clinically Significant ECG Values ................................. 53 
Table 6: 
Postbaseline Analysis Visit Windows for Unscheduled and Early Termination 
Visits for Assessments Done Every 4 Weeks...................................................... 65 
Table 7: 
Postbaseline Analysis Visit Windows for Unscheduled and Early Termination 
Visits for Assessments Done at Baseline and Weeks 4, 12, 24, 36, and 52 .......... 66 
Table 8: 
Mean Strength and Standard Deviation for Healthy Subjects .............................. 68 
Table 9: 
Schedule of Assessments—Randomized Treatment Period (Core) ......................... 77 
Table 10: 
Schedule of Assessments—Open-Label (Pegcetacoplan) Treatment Period ............ 81 
 
LIST OF FIGURES 
Figure 1: 
Study Design ..................................................................................................... 16 
 


Pegcetacoplan (APL-2) 
APL2-ALS-206 Statistical Analysis Plan 
12 April 2023 
Apellis Pharmaceuticals, Inc 
Page 10 
 
Confidential 
ABBREVIATIONS 
ADA 
antidrug antibodies 
ADAY 
analysis study day 
AE 
adverse event 
ALP 
alkaline phosphatase  
ALS 
amyotrophic lateral sclerosis 
ALSAQ-40 
ALS Assessment Questionnaire 
ALSFRS 
ALS Functional Rating Scale 
ALSFRS-R 
Revised ALS Functional Rating Scale 
ALT 
alanine aminotransferase  
ANCOVA 
analysis of covariance 
AR 
autoregressive 
AST 
aspartate aminotransferase  
BLQ 
below the limit of quantification 
BUN 
blood urea nitrogen  
CAFS 
Combined Assessment of Function and Survival 
CI 
confidence interval 
CKD-EPI 
Chronic Kidney Disease–Epidemiology Collaboration 
C-SSRS 
Columbia-Suicide Severity Rating Scale 
DMC 
data monitoring committee 
DPS 
diaphragm pacing system 
ECG 
electrocardiogram 
EIM 
electrical impedance myography 
GCP 
Good Clinical Practice 
GGT 
gamma-glutamyltransferase  
HDL 
high-density lipoproteins  
HHD 
handheld dynamometry 
ICE 
intercurrent event 
ITT 
intent-to-treat 
LDL 
low-density lipoproteins  
LLN 
lower limit of normal 
LS 
least squares 
MAR 
missing at random 
MedDRA 
medical dictionary for regulatory activities 
MI 
multiple imputation 
mITT 
modified intent-to-treat 
MMRM 
mixed model for repeated measures 
MNAR 
missing not at random 
NfL 
neurofilament light chain 
PCS 
potentially clinically significant  


Pegcetacoplan (APL-2) 
APL2-ALS-206 Statistical Analysis Plan 
12 April 2023 
Apellis Pharmaceuticals, Inc 
Page 11 
 
Confidential 
PD 
pharmacodynamic 
PEG 
polyethylene glycol 
PK 
pharmacokinetic 
pNfH 
phosphorylated neurofilament heavy chain 
PP 
per protocol 
PT 
Preferred Term 
QTcF 
QT interval corrected for heart rate using Fridericia’s formula 
RBC 
red blood cell  
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SC 
subcutaneous 
SE 
standard error 
SI 
système international 
SOC 
System Organ Class 
SVC 
slow vital capacity 
TEAE   
treatment-emergent adverse event 
ULN 
upper limit of normal 
VAS 
visual analogue scale 
WBC 
white blood cell  
WHO 
World Health Organization 
ZBI 
Zarit Burden Interview 
 


Pegcetacoplan (APL-2) 
APL2-ALS-206 Statistical Analysis Plan 
12 April 2023 
Apellis Pharmaceuticals, Inc 
Page 12 
 
Confidential 
1. 
INTRODUCTION 
1.1. 
Background 
This study is being conducted as part of a series of studies for the clinical development of 
pegcetacoplan (also known as APL-2). It is conducted in compliance with the protocol, GCP, 
and applicable regulatory requirements. The study population comprises adult male and female 
subjects with sporadic amyotrophic lateral sclerosis (ALS). 
This statistical analysis plan (SAP) provides a technical and detailed elaboration of the statistical 
analyses of efficacy, safety, and pharmacokinetic (PK) data as described in the final study 
protocol dated 13 January 2023 incorporating the most recent Amendment 6. Specifications for 
tables, figures, and listings are contained in a separate document. 
The current SAP describes analysis of randomized controlled period (ie, up to week 52). An 
outline for efficacy analyses for the open-label periods is provided in Section 6.7. The details for 
analysis of the open-label periods will be provided in a separate SAP. 
1.2. 
Exceptional Circumstances 
Two exceptional circumstances, which require special consideration, occurred during the 
conduct of this trial: 
• COVID-19 pandemic 
• war in Ukraine. 
The war in Ukraine had a number of impacts on study conduct, including discontinuation of 
subjects from treatment and study follow-up, transfer of affected subjects to sites outside 
Ukraine, and data not entered in the database.  
The handling of these circumstances with respect to the study’s estimands is described in 
Section 6.3 and Table 1 for the primary and secondary endpoints, and in Section 6.6 and Table 3 
for the exploratory endpoints, and a supplemental analysis of the primary endpoint accounting 
for treatment interruptions due to COVID-19 is described in Section 6.4.3.2. 


Pegcetacoplan (APL-2) 
APL2-ALS-206 Statistical Analysis Plan 
12 April 2023 
Apellis Pharmaceuticals, Inc 
Page 13 
 
Confidential 
2. 
OBJECTIVES AND ENDPOINTS 
2.1. 
Objectives 
2.1.1. 
Primary Objective 
The primary objective of the study is to assess the efficacy of twice per week subcutaneous (SC) 
doses of pegcetacoplan 1080 mg compared to placebo in subjects with sporadic ALS as measured by 
the Combined Assessment of Function and Survival (CAFS) rank score (joint-rank score) 
2.1.2. 
Secondary Objectives 
The following are the secondary objectives of this study: 
• To assess the effect of pegcetacoplan compared to placebo as measured by the 
Revised ALS Functional Rating Scale (ALSFRS-R) score 
• To assess the effect of pegcetacoplan compared to placebo on disease progression as 
measured by respiratory function through percentage of slow vital capacity (%SVC) 
• To determine the effect of pegcetacoplan compared to placebo on muscle strength as 
measured by handheld dynamometry (HHD) 
• To determine the effect of pegcetacoplan compared to placebo on survival or 
specified state of disease progression 
• To assess the effect of pegcetacoplan compared to placebo on health-related quality 
of life as measured by ALS Assessment Questionnaire (ALSAQ-40) 
• To assess the safety of pegcetacoplan during the randomized and open-label treatment 
periods through incidence and severity of treatment-emergent adverse events (TEAEs), 
clinical laboratory tests (hematology, chemistry), vital signs, and physical examinations  
• To assess the long-term efficacy of pegcetacoplan using ALSFRS-R, %SVC, HHD, 
and ALSAQ-40 during the open-label treatment period 
2.2. 
Endpoints 
2.2.1. 
Primary Endpoint 
The primary efficacy endpoint is the difference in CAFS rank score (joint-rank score) at 
week 52. 


Pegcetacoplan (APL-2) 
APL2-ALS-206 Statistical Analysis Plan 
12 April 2023 
Apellis Pharmaceuticals, Inc 
Page 14 
 
Confidential 
2.2.2. 
Secondary Endpoints 
The secondary efficacy endpoints are as follows: 
• Change from baseline in ALSFRS-R at Week 52 
• Change from baseline in %SVC (at clinic visits) at Week 52 
• Change from baseline in HHD megascore at Week 52 
• Time to death, permanent tracheostomy, or permanent assisted ventilation up to 
Week 52 
• Time to death up to Week 52 
• Change from baseline in ALSAQ-40 at Week 52 
• Change from baseline in serum neurofilament light chain (NfL) at Week 52 
• Change from baseline of the randomized treatment period (Visit 2) and of the open-
label treatment period (Visit 15) to Week 104 for ALSFRS-R, %SVC, HHD, and 
ALSAQ-40 
• Time to death, permanent tracheostomy, or permanent assisted ventilation up to 
Week 104 
• Time to death up to Week 104 
2.2.3. 
Safety Endpoints 
The primary safety endpoints are as follows: 
• Incidence and severity of TEAEs  
• Change from baseline in vital signs and clinical laboratory tests 
• Positive responses (Yes) to the Columbia-Suicide Severity Rating Scale (C-SSRS) 
2.2.4. 
Exploratory Endpoints 
The exploratory endpoints are as follows: 
• CAFS rank score (joint-rank score) at Week 104 and Week 156 
• Change from baseline in European Quality of Life–5 Dimensions–5 Level (EQ5D5L) 
at Week 52, Week 104, and Week 156 
• Change from baseline in Zarit Burden Interview (ZBI) score at Week 52 Week 104, 
and Week 156 
• Change from baseline in %SVC (home spirometry) at Week 52 and Week 104 
• Time to percutaneous endoscopic gastrostomy tube placement up to Week 52, Week 
104, and Week 156 
• Change from baseline in serum neurofilament light chain (NfL) at Week 104, and 
Week 156 
• Change from baseline in serum phosphorylated neurofilament heavy chain (pNfH) at 
Week 52, Week 104, and Week 156 
• Pegcetacoplan PK concentrations at Week 52, Week 104, and Week 156  


Pegcetacoplan (APL-2) 
APL2-ALS-206 Statistical Analysis Plan 
12 April 2023 
Apellis Pharmaceuticals, Inc 
Page 15 
 
Confidential 
• Changes from baseline at Week 52, Week 104, and Week 156 in complement 
biomarkers: 
− Classical hemolytic complement pathway activity (CH50) 
− AH50 
− C3 levels 
• Immunogenicity: presence of antibodies to polyethylene glycol (PEG) moiety and/or 
peptide moiety of pegcetacoplan during the randomized and open-label treatment 
periods 
• Change from baseline of the randomized treatment period (Week 1) and of the open-
label treatment period (Week 52) to week 156 for ALSFRS-R, %SVC (in clinic), 
HHD, and ALSAQ-40  
• Time to death, permanent tracheostomy, or permanent assisted ventilation up to Week 
156 
• Time to death up to Week 156 
 


Pegcetacoplan (APL-2) 
APL2-ALS-206 Statistical Analysis Plan 
12 April 2023 
Apellis Pharmaceuticals, Inc 
Page 16 
 
Confidential 
3. 
STUDY DESIGN 
3.1. 
General Description 
This is a phase 2, randomized, double-blind, placebo-controlled, multicenter, efficacy and safety 
study of SC pegcetacoplan 1080  mg twice per week conducted in approximately 228 subjects 
with diagnosis of sporadic ALS. 
The planned length of participation in the study for each subject is a maximum of approximately 
116 weeks. This study will consist of 5 parts (as shown in Figure 1): 
• Part 1: Up to 6-week screening period 
• Part 2: 52-week randomized treatment period 
• Part 3: 52-week open-label (pegcetacoplan) treatment period 
• Part 4: 52-week open-label long-term extension treatment period 
• Part 5: 6-week off-treatment follow-up period 
Part 1 - screening (up to 6 Weeks) 
Informed consent will be obtained at screening prior to any study-related procedures being 
conducted. Subjects (and/or caregiver) will be trained on the use of at-home assessments. 
Figure 1: 
Study Design 
 
Part 2 - Randomized Treatment Period (52 Weeks) 
Approximately 228 subjects who meet all of the inclusion criteria and none of the exclusion 
criteria will be randomized 2:1 to either the pegcetacoplan treatment group or the placebo group. 
Safety and efficacy will be assessed and will include once per week at-home measurements, 
monthly calls, and clinic visits. Subjects who discontinue treatment early and do not complete 
part 2 will continue to part 5. Subjects randomized to pegcetacoplan will receive SC pegcetacoplan 
1080  mg twice per week for 52 weeks. Subjects randomized to placebo will receive SC placebo 
twice per week for 52 weeks. Subjects who discontinue treatment early and do not complete part 2 
will continue to part 5. 
Part 3 - Open-Label (Pegcetacoplan) Treatment Period (52 weeks) 
At the end of part 2, all subjects from both treatment groups will continue to part 3. All subjects 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
  
 
 
 
 


Pegcetacoplan (APL-2) 
APL2-ALS-206 Statistical Analysis Plan 
12 April 2023 
Apellis Pharmaceuticals, Inc 
Page 17 
 
Confidential 
participating in part 3 will be treated with pegcetacoplan 1080 mg twice per week up to week 
104. Subjects who complete part 3, will enter part 4. Subjects who do not continue to part 3, or 
who have started part 3 but discontinue treatment early, will continue to part 5.  
Part 4: Open-Label (Pegcetacoplan) Long-Term Extension Treatment Period (52 Weeks)  
At the end of part 3, any subject who, in the opinion of the investigator, is experiencing clinical 
benefit from pegcetacoplan administration will be invited to continue to part 4, the open-label 
long-term extension treatment period. All subjects participating in part 4 will be treated with 
pegcetacoplan 1080 mg twice per week up to week 156. Subjects who complete part 4 will enter 
part 5. Subjects who do not continue to part 4, or who have started part 4 but discontinue 
treatment early, will continue to part 5. 
Part 5 - Off-Treatment Follow-up Period (6 weeks) 
During part 4, all subjects will discontinue the investigational product (blinded 
pegcetacoplan/placebo or open-label pegcetacoplan) and complete a follow-up visit 6 weeks 
later, unless they enter the sponsor-planned long-term extension protocol. 
3.2. 
Randomization 
To prevent bias in treatment assignment, randomization will occur through the interactive 
response technology system.  
Access to randomization codes will be strictly controlled as mandated in the study’s Blinding 
Management Plan. The randomization codes will not be made available to the sponsor, subjects, 
or clinic staff responsible for the monitoring and evaluation of efficacy or safety assessments. 
All subjects who meet all the inclusion criteria and none of the exclusion criteria will be enrolled in 
the study, until such time that approximately 228 subjects have been enrolled in the study. At the first 
visit of the randomized treatment period, subjects will be randomized after confirmation of study 
eligibility in a ratio of 2:1 via a computer-generated randomization schedule to receive pegcetacoplan 
or placebo. The randomization will be performed centrally and stratified by location of first muscle 
weakness (limb or bulbar), riluzole, and edaravone use. The stratification by (1) location of onset and 
(2) riluzole and edaravone use will ensure balance between treatment groups by the respective 
stratification factors. Fixed block randomization will be used to ensure that approximately equal 
number of subjects are assigned to each treatment within strata. 
3.3. 
Blinding 
This is a randomized, double-blinded, placebo-controlled study. The intent of blinding is to limit 
the occurrence of conscious and unconscious bias in the conduct and interpretation of the clinical 
study. Bias could arise from the influence that the knowledge of a specific treatment assignment 
may have on the recruitment and allocation of subjects, their subsequent care, the assessment of 
endpoints, the handling of withdrawals, and so on. The essential aim of blinding, therefore, is to 
prevent identification of the treatments by the subject and the blinded assessors associated with 
the conduct of the study until all such opportunities for bias have passed.  
Designated blinded study staff (eg, research coordinators, nurses, technicians administering 
questionnaires, subjects, spirometry and dynamometer central reading centers, assigned 


Pegcetacoplan (APL-2) 
APL2-ALS-206 Statistical Analysis Plan 
12 April 2023 
Apellis Pharmaceuticals, Inc 
Page 18 
 
Confidential 
evaluating physician(s), and the sponsor) will be blinded to treatment assignment. Access to 
unblinded study treatment information will be strictly limited as mandated in the study’s 
Blinding Management Plan; any individuals who are unblinded are not allowed to discuss 
treatment and/or subject outcome with blinded study staff, including the evaluating physician. 
The principal investigator must be blinded to subjects’ treatment assignment. 
Both pegcetacoplan and placebo are supplied in sterile solutions of 10 mM acetate buffer, 
pH 5.0, containing 4.1% sorbitol in stoppered 20-cc glass vials.  
In the OLP all participants will receive pegcetacoplan. However, to limit bias in data analyses for 
registrational purpose, a blinded analysis team will be established to conduct the analyses of 
OLP.  
3.4. 
Sample Size and Power Considerations 
A sample size of 180 randomized subjects (2:1 allocation ratio to pegcetacoplan:placebo) would 
provide approximately 86% power to detect a significant difference (33%) in the primary 
outcome (CAFS score) between the 2 treatment groups at a 2-sided alpha of 5% with 75% power 
to detect a 35% improvement in the rate of decline in the ALSFRS-R score and 39% power to 
detect a 10% improvement in survival. 
The estimates were based on the following assumptions: 
• Mean monthly rate of decline in ALSFRS-R is 1 unit for the placebo treatment group 
and pooled standard deviation of 0.84 units/month 
• 52-week mortality rate with placebo at 20% 
• Approximately 40-week subject enrollment period 
• 52 weeks of follow-up for assessing survival outcomes after each subject enrolls  
• 52 weeks of follow-up for assessing functional outcomes after each subject enrolls 
Subjects will be randomized and stratified by location of first muscle weakness (limb or bulbar), 
and use of riluzole and edaravone (neither, riluzole, edaravone, or both riluzole and edaravone). 
Approximately 228 subjects (152:76) will be randomized to account for an anticipated 20% of 
randomized subjects prematurely discontinuing the study without providing a postbaseline 
ALSFRS-R measurement. 
3.5. 
Analysis Timing and Unblinding 
The analysis of data from the randomized treatment period of the study will be performed when all 
subjects have completed the randomized treatment period or discontinued early and all 
corresponding data have been entered into the database, reviewed, cleaned, and finalized, and the 
Week 52 analysis database locked. At that time, the sponsor analysis team will be unblinded to the 
treatment codes, and the primary analysis will be performed; this will include all efficacy and safety 
analyses for the randomized treatment period (ie, week 52 endpoints). 
The analysis of the data from the open-label treatment period and open-label long-term extension 
period will be performed once all subjects have completed the open-label treatment period or 
open-label long-term extension period or discontinued early and all corresponding data have 


Pegcetacoplan (APL-2) 
APL2-ALS-206 Statistical Analysis Plan 
12 April 2023 
Apellis Pharmaceuticals, Inc 
Page 19 
 
Confidential 
been entered into the database, reviewed, cleaned, and finalized, and the analysis database 
locked.  


Pegcetacoplan (APL-2) 
APL2-ALS-206 Statistical Analysis Plan 
12 April 2023 
Apellis Pharmaceuticals, Inc 
Page 20 
 
Confidential 
4. 
STATISTICAL ANALYSIS SETS 
4.1. 
Screened Set 
The screened set will include all subjects who provide written informed consent. This set will be 
used only for the purpose of describing subject disposition. 
4.2. 
Safety Set 
The safety set will include all subjects who receive at least one dose of randomized treatment 
(pegcetacoplan or placebo). Subjects will be analyzed according to the treatment they actually 
received. Subjects will be presented under the pegcetacoplan group if they received at least one 
injection of pegcetacoplan during the study, but will be presented under the placebo group only if 
they did not receive any dose of pegcetacoplan. This population will be used for all safety analyses. 
4.3. 
Intent-to-Treat Set  
The intent-to-treat (ITT) set will include all randomized subjects who receive at least one dose of 
randomized treatment (pegcetacoplan or placebo). Subjects will be analyzed according to their 
assigned treatment, regardless of the treatment actually received. The ITT set will be used for all 
efficacy analyses except the primary endpoint, for which the mITT set will be used. 
4.4. 
Modified Intent-to-Treat Set  
The modified intent-to-treat (mITT) set will include all randomized subjects who receive at least 
one dose of randomized treatment (pegcetacoplan or placebo), and who die or have a 
postbaseline assessment of the endpoint that are used in CAFS. For example, in CAFS analysis 
of ALSFRS-R, it will be all randomized subjects who receive at least one dose of randomized 
treatment (pegcetacoplan or placebo), and who die or have a postbaseline assessment of 
ALSFRS-R. Subjects will be analyzed according to their assigned treatment, regardless of the 
treatment actually received.  
4.5. 
Per-Protocol Analysis Set  
The per-protocol (PP) set will include all subjects in the ITT set who have not violated any 
inclusion or exclusion criteria and/or deviated from the protocol in a way that could influence 
their efficacy assessment. Decisions concerning the exclusion of subjects from the PP analysis 
set will be made and documented prior to database Week 52 analysis database lock.  
The review and classification of protocol deviations is described in Section 5.8 and the study’s 
Protocol Deviation Handling Plan, where the criteria for major and minor deviations are also 
defined. Deviations that effect exclusion from the PP analysis set are a subset of protocol 
deviations; major protocol deviations do not necessarily result in exclusion of the subject from 
the PP analysis set. 
4.6. 
Pharmacokinetic Set  
The PK set will include all subjects in the safety set who have at least one quantifiable postdose 
concentration of pegcetacoplan (even with values below the limit of quantification [BLQ]) 
during the randomized treatment period. 


Pegcetacoplan (APL-2) 
APL2-ALS-206 Statistical Analysis Plan 
12 April 2023 
Apellis Pharmaceuticals, Inc 
Page 21 
 
Confidential 
4.7. 
Pharmacodynamic Set 
The pharmacodynamic (PD) set will include all subjects in the safety set who have at least one 
quantifiable postdose PD endpoint (NfL, pNfH, C3, CH50, or AH50) evaluated. 


Pegcetacoplan (APL-2) 
APL2-ALS-206 Statistical Analysis Plan 
12 April 2023 
Apellis Pharmaceuticals, Inc 
Page 22 
 
Confidential 
5. 
STUDY SUBJECTS 
In general, descriptive statistics (n, mean, standard deviation, minimum, median, and maximum) 
will be presented for continuous endpoints and number and percentage will be presented for 
categorical endpoints. 
5.1. 
Disposition of Subjects 
A listing of all Screen Failures (ie, subjects who were screened but not randomized) will be 
presented. The number of subjects screened, passed screening, screened failed and randomized 
will be presented overall based on screened set.  
The number of subjects who were included in each defined analysis set (ie, ITT, mITT, safety, 
and PP, PK, and PD) will be summarized by treatment group and overall, except for the screened 
set, which will be summarized only overall.  
The overall summary of subject disposition will be based on ITT set and provided by treatment 
group and by phase (randomized control period or open-label period) and overall, including the 
following: 
• Number of subjects completed treatment [through Week 52, as appropriate] 
• Number of subjects discontinued from treatment and reason for discontinuation (prior 
to Week 52 ) 
• Number of subjects completed study (through Week 52, as appropriate) 
• Number of subjects discontinued from study and reason for discontinuation (prior to 
Week 52) 
In addition, to assess the impact of the COVID-19 pandemic and the Ukraine conflict on 
disposition of subjects, the number of subjects discontinued from treatment due to each reason 
will be summarized. 
The number of subjects screened, randomized and completed will be tabulated by site and country.  


Pegcetacoplan (APL-2) 
APL2-ALS-206 Statistical Analysis Plan 
12 April 2023 
Apellis Pharmaceuticals, Inc 
Page 23 
 
Confidential 
5.2. 
Demographic and Baseline Characteristics 
Descriptive summaries of demographic and baseline characteristics will be presented by 
treatment group and overall for ITT set and safety set if the 2 sets are different. The following 
demographic characteristics will be summarized in the following order in the tables: 
• Age at baseline (<45, ≥45 – <65, ≥65 – <75, ≥75 years) 
• Sex 
• Childbearing Potential 
• Ethnicity 
• Race  
• Race defined by (American Thoracic Society/European Respiratory Society) 
ATS/ERS standards 
• Weight (kg) 
• Height (cm) 
• BMI (kg/m2) 
• Having reported ALS related genetic mutations 
• Stratification factors (at randomization):  
o location of first muscle weakness (limb or bulbar),  
o riluzole and edaravone use 
• Actual Stratification factors:  
o location of first muscle weakness (limb or bulbar),  
o riluzole and edaravone use 
• ALSFRS-R at baseline 
• ALSAQ-40 at baseline 
• HHD at baseline 
• % Predicted SVC at baseline 
• Neurofilament light chain (NfL) at baseline 
• Location of onset, including limb location and bulbar ALS functions affected 
• Time (months) from ALS symptom onset calculated as (date of first dose of study 
treatment – ALS symptom start date)/30.4375, or (date of randomization – ALS 
symptom start date)/30.4375 for untreated subjects 
• Time (months) from ALS diagnosis calculated as (date of first dose of study 
treatment  – ALS diagnosis date)/30.4375, or (date of randomization – ALS diagnosis 
date)/30.4375 for untreated subjects; (continuous; <= 6 months, >6 and ≤12 months; 
>12 months) 
• El Escorial Criteria assessment for ALS 
o Presence of signs of lower motor neuron (LMN) degeneration by clinical, 
electrophysiological or neuropathologic examination 


Pegcetacoplan (APL-2) 
APL2-ALS-206 Statistical Analysis Plan 
12 April 2023 
Apellis Pharmaceuticals, Inc 
Page 24 
 
Confidential 
o Presence of signs of upper motor neuron (UMN) degeneration by clinical 
examination 
o Presence of progressive spread of signs within a region or to other regions, as 
determined by history or examination 
o Absence of electrophysiological evidence of other disease processes that might 
explain the signs of LMN and/or UMN degenerations 
o Absence of neuroimaging evidence of other disease processes that might explain 
the observed clinical and electrophysiological signs 
5.3. 
Medical History 
Medical history will be collected at the screening visit (visit 1) and will be coded using the 
Medical Dictionary for Regulatory Activities (MedDRA) version 23.0. Summaries will be 
presented for the safety set and will be done by System Organ Class (SOC) and Preferred Term 
(PT) with counts and percentages by treatment group and overall. Each subject will be counted 
only once in each SOC or SOC/PT summary. 
5.4. 
Prior and Concomitant Medications  
Prior and concomitant medications will be coded using World Health Organization (WHO) Drug 
Dictionary version WHO Drug Global B3-format March 2020. Prior and concomitant 
medications will be summarized by Anatomical Therapeutic Class (ATC) level 2 and PT with 
the number and percentage of subjects for the safety set. Prior medications are defined as 
medications that started prior to the first dose of study drug. Concomitant medications are 
defined as medications that are taken on or after first dose of study drug. Medications that started 
before the first dose of study drug and continued on or after first dose of study drug will be 
considered as both prior and concomitant medications. Multiple medication usage by a subject in 
the same category will be counted only once. 
Use of riluzole only, edaravone only, or both riluzole and edaravone will be tabulated for prior 
use and concomitant use. Discrepancies between the values used for randomization stratification 
by riluzole and edaravone and actual usage of the 2 medications will be listed. 
All prior and concomitant medications will be listed for the ITT set. 
5.5. 
Prior and Concomitant Procedures 
Prior and concomitant procedures will be coded using MedDRA version 23.0 and will be presented 
for the safety set by SOC and PT with counts and percentages by treatment group and overall. 
A subject who had more than one procedure will be counted only once in the summary per SOC 
and PT. Prior procedures are defined as those that were started prior to the first dose of study drug. 
Concomitant procedures are defined as those that were started on or after first dose of study drug or 
ended on or after the first dose of study drug. Procedures that started before the first dose of study 
drug and continued on or after first dose of study drug will be considered as both prior and 
concomitant procedures. A data listing of all procedures will be provided for the ITT set. 


Pegcetacoplan (APL-2) 
APL2-ALS-206 Statistical Analysis Plan 
12 April 2023 
Apellis Pharmaceuticals, Inc 
Page 25 
 
Confidential 
5.6. 
Exposure to Investigational Product 
Exposure to investigational product will be summarized for the safety set by treatment group and 
overall using the parameters below. Exposure will be summarized for the randomized and open-
label treatment periods separately, and for the 2 periods combined. 
• Total dose administered (mg) 
• Duration of treatment (days), which is calculated as the number of days from the date 
of first dose of investigational product taken to the date of the last dose of 
investigational product taken (ie, treatment duration = date of last study drug infusion 
in the randomized treatment period – date of first study drug infusion + 4 [to account 
for twice weekly dosing]), inclusively 
• Number and percentage of subjects who received infusions in the following categories: 
o Number and percentage of subjects with all infusions completed 
o Number and percentage of subjects who received numbers of infusions 
(completed or not) in the following categories: 1 - 21 (1% - 20%), 22 - 42 
(21% - 40%), 43 - 62 (41% - 60%), 63 - 83 (61% - 80%), 84 - 104 (81% - 100%) 
• Total number of infusions 
o Number and percentage of infusions completed 
o Number and percentage of infusions interrupted 
A listing will be presented by subject number and week giving the date and time of dose 
administration. 
5.7. 
Measurements of Treatment Compliance  
Percent compliance will be calculated for the randomized and open-label treatment periods 
separately using the safety set. The percent compliance for twice weekly dosing is defined as: 
𝑃𝑃𝑃𝑃𝑃𝑃𝑃𝑃𝑃𝑃𝑃𝑃𝑃𝑃 𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝐶=
𝑇𝑇𝑇𝑇𝑇𝑇𝑇𝑇𝑇𝑇 𝑁𝑁𝑁𝑁𝑁𝑁𝑁𝑁𝑁𝑁𝑁𝑁 𝑜𝑜𝑜𝑜 𝐼𝐼𝐼𝐼𝐼𝐼𝐼𝐼𝐼𝐼𝐼𝐼𝐼𝐼𝐼𝐼𝐼𝐼 𝑅𝑅𝑅𝑅𝑅𝑅𝑅𝑅𝑅𝑅𝑅𝑅𝑅𝑅𝑅𝑅
[(𝐿𝐿𝐿𝐿𝐿𝐿𝐿𝐿 𝐷𝐷𝐷𝐷𝐷𝐷𝐷𝐷 𝐷𝐷𝐷𝐷𝐷𝐷𝐷𝐷−𝐹𝐹𝐹𝐹𝐹𝐹𝐹𝐹𝐹𝐹 𝐷𝐷𝐷𝐷𝐷𝐷𝐷𝐷 𝐷𝐷𝐷𝐷𝐷𝐷𝐷𝐷+ 3.5) 7
⁄ ] × 2 × 100 
The number and percentage of subjects will be presented by percentage of drug compliance in 
10 percentage point increments (ie, ≥ 80% − <90%, ≥ 90 − ≤100%, >100% − <110%, with 
additional ranges added as needed) by treatment and overall.  
A subject listing will be produced for treatment compliance and exposure. Calculated compliance 
data for each subject will be listed.  
5.8. 
Protocol Deviations 
Protocol deviations will be recorded outside the clinical database. The study team will classify 
major and minor protocol deviations per the agreed Protocol Deviation Handling Plan. 
The Apellis study team will review the protocol deviations and their classification throughout the 
study and before the Week 52 analysis database lock and treatment unblinding. 
Decisions of the review will include: 


Pegcetacoplan (APL-2) 
APL2-ALS-206 Statistical Analysis Plan 
12 April 2023 
Apellis Pharmaceuticals, Inc 
Page 26 
 
Confidential 
• Categorization of protocol deviations 
• Classification of major and minor protocol deviations 
A protocol deviation is classified as major if it has the potential to significantly impact the 
completeness, accuracy, and/or reliability of the study’s efficacy or safety data. As defined in 
Section 4.5, subjects with protocol deviations that could influence their efficacy assessment 
result in exclusion from the PP set; these deviations are a subset of protocol deviations; major 
protocol deviations do not necessarily result in exclusion of the subject from the PP analysis set. 
All protocol deviations occurring during the randomized treatment period will be identified, 
categorized, and classified prior to the Week 52 analysis database lock for the analysis of the 
randomized treatment period, and those occurring during the open-label treatment period will be 
identified, categorized, and classified prior to the week 104 analysis database lock for the 
open-label treatment period. Confirmed major and minor protocol deviations will be documented 
in the protocol deviation tracker for the study and finalized prior to database lock or treatment 
unblinding. Major/minor protocol deviations will be summarized by category and site for each 
treatment group and overall, for the safety set. Major/minor protocol deviations will be listed for 
the ITT set. 


Pegcetacoplan (APL-2) 
APL2-ALS-206 Statistical Analysis Plan 
12 April 2023 
Apellis Pharmaceuticals, Inc 
Page 27 
 
Confidential 
6. 
EFFICACY ANALYSES 
The primary efficacy analysis (ie, CAFS at week 52) will be done on the mITT set while all 
other efficacy analyses will be based on the ITT set; in both cases, subjects will be analyzed 
according to the treatment assigned at randomization. Baseline for all efficacy analyses is 
defined as the last observed value for the efficacy assessment prior to taking the first dose of 
investigational product (based on dates or date/times), or prior to the randomization date for 
subject who are not treated. 
All statistical tests will be performed at 2-sided 5% level of significance and all confidence 
intervals will be two-sided 95% confidence intervals.  
Unless otherwise noted, analysis of efficacy endpoints in the overall population will be adjusted 
for the following randomization stratification factors:  
• Location of first muscle weakness (limb or bulbar) 
• Use of riluzole and edaravone (4 values: neither, riluzole only, edaravone only, 
or both riluzole and edaravone) 
Because very few subjects used edaravone only, use of riluzole and edaravone was recategorized 
into 3 levels and will be included as a covariate in analyses (ie, neither, only one, or both). If 
subjects are found to have had the incorrect stratum assigned at randomization, they will be 
analyzed according to the randomization stratum. 
For baseline variables that are adjusted in models, missing values will be imputed as mean or 
mode of that variable at baseline. Due to skewness in distribution, natural log transformed 
baseline NfL value will be used as a covariate for adjustment in the analysis models. 
6.1. 
Analysis Models 
In general, data will be analyzed with the approaches described below. 
Analysis of covariance (ANCOVA)  
Analysis of covariance (ANCOVA) will be used to analyze the ranks of the CAFS score with 
treatment as a fixed effect, adjusted for baseline ALSFRS-R total score, time from symptom 
onset (defined in Section 5.3), baseline Log NfL, and the randomization stratification factors 
(location of first muscle weakness and use of riluzole and edaravone). Least squares (LS) means 
will be presented for each treatment group, along with the between-treatment difference and 95% 
confidence interval (CI). In addition, the relative benefit of pegcetacoplan to placebo will be 
presented (difference in LS mean CAFS score between the pegcetacoplan group and the placebo 
group, divided by the LS mean CAFS score in the placebo group). 
Mixed-effect model for repeated measures (MMRM) for continuous outcomes 
Longitudinal assessments for changes from baseline in continuous outcomes (with the exception 
of home % predicted SVC, which is measured weekly and which will use the Mixed Effects 
model for slope analysis of continuous outcomes below) will be analyzed using a MMRM. The 
model will include fixed categorical effects for treatment, visit, and the visit-by-treatment 
interaction, as well as the continuous, fixed covariate of the baseline value of the endpoint, and 
the visit-by-baseline interaction, time from symptoms onset to the first dose of investigational 
product, baseline Log NfL and the randomization stratification factors (location of first muscle 


Pegcetacoplan (APL-2) 
APL2-ALS-206 Statistical Analysis Plan 
12 April 2023 
Apellis Pharmaceuticals, Inc 
Page 28 
 
Confidential 
weakness and use of riluzole and edaravone). LS means with standard errors (SEs) and 95% CIs 
of the change from baseline will be presented by treatment group and visit; between-treatment 
differences and 95% CIs and p-values will be presented by visit. LS means (±SE) will be plotted 
over time-by-treatment group. 
The sandwich estimator (Diggle et al. 1994) will be used to estimate the SEs of the fixed effects 
parameters. Initially an unstructured covariance matrix [c=91, number of covariance parameters 
for endpoints assessed monthly] will be used. If the model fails to converge, the following 
covariance structures will be fit in this order with more and more constrained structures until 
convergence is met: (i) heterogenous first-order autoregressive AR(1) [c=14], (ii) Toeplitz 
[c=13], (iii) AR(1) + random effects for intercept and linear slope [c=5], (iv) AR(1) + random 
intercept [c=3], and (v) compound symmetry [c=2]. 
Mixed effects model for slope analysis of continuous outcomes 
For slope analysis of continuous outcomes, a mixed effects model using the baseline and all 
postbaseline assessments will be used and will include a random intercept and random slope over 
time, along with linear fixed effect for time, the time-by-treatment interaction, as well as the 
continuous, fixed covariate of the baseline value of the endpoint, time from symptoms onset to 
the first dose of investigational product, baseline Log NfL, and the randomization stratification 
factors (location of first muscle weakness and use of riluzole and edaravone). An unstructured 
covariance structure will be used for estimating correlation between random intercept and 
random slope. The estimated slope over a 4-week period (with 95% CI) will be presented by 
treatment group, along with the estimate, 95% CI, and P value for the between-treatment 
difference in slopes.  
Nonlinearity in the association between the outcome and time will be examined adding fixed 
effects for time^2 and the interaction term between treatment and time^2, and the random 
quadratic effect across time If there are no convergence issues, the models with and without 
these 3 additional terms will be compared based on the Akike Information Criteria (AIC); 
inference for the slope analysis will be based on better model based on AIC. If there are 
convergence issues, the quadratic random effect will be dropped, and the models with and 
without the 2 quadratic fixed effect terms will be then compared based on AIC. If model with 
quadratic effect is used as the final model, then the LSmean estimate and 95% CI by treatment 
group, along with difference in LS means between treatment group and P value will be presented 
every 4 weeks. 
Cox proportional hazards model 
For time-to-event endpoints, comparisons between treatment groups will be done using Cox 
proportional hazard models (Cox 1972) stratified by the randomization stratification factors 
(location of first muscle weakness and use of riluzole and edaravone) and adjusted for baseline 
ALSFRS-R, score and time from symptoms onset to the first dose of investigational product and 
baseline Log NfL. The number of events in each treatment group, the hazard ratio, 95% CI, and 
P value will be presented for the treatment over placebo. 
6.2. 
Multiplicity Adjustment 
The primary endpoint of the study will be tested at the 2-sided 0.05 level, and if the null hypothesis 
for the primary endpoint is rejected, the secondary endpoints will be tested. The secondary endpoints 


Pegcetacoplan (APL-2) 
APL2-ALS-206 Statistical Analysis Plan 
12 April 2023 
Apellis Pharmaceuticals, Inc 
Page 29 
 
Confidential 
will be tested sequentially in order in which they are presented in the secondary endpoint section 
above (Section 2.2.2); the testing will stop once a null hypothesis is not rejected. This fixed-sequence 
testing procedure will ensure that trial-wise error rate is controlled to be 0.05. Below is the ordering 
of the primary and secondary efficacy endpoints to be tested: 
• difference in CAFS rank score (joint-rank score) at Week 52. 
• change from baseline in ALSFRS-R at Week 52 (total score) 
• change from baseline in % predicted SVC (at clinic visits) at Week 52 
• change from baseline in HHD megascore at Week 52 
• time to death, permanent tracheostomy, or permanent assisted ventilation up to 
Week 52 
• time to death up to Week 52 
• change from baseline in ALSAQ-40 at Week 52 (total score) 
• change from baseline in serum NfL at week 52 
6.3. 
Estimands 
The primary objective of this study is to assess the efficacy of twice per week SC doses of 
pegcetacoplan 1080 mg compared to placebo in subjects with sporadic ALS as measured by the 
CAFS rank score (joint-rank score). 
The estimands and their attributes for the primary and all comparative secondary endpoints are 
shown in Table 1 below. This includes strategies for addressing the following intercurrent events 
(ICEs):  
• Dth = Death   
• RxDxIndep = Discontinuations from study treatment that are considered definitely 
unrelated to efficacy or safety; these included the Ukraine conflict and COVID-19 
(illness or site effect., eg, site closure).  
• RxDxRel = Discontinuations from study treatment that are potentially related to 
efficacy or safety; these include adverse events and lack of efficacy. Any other 
treatment discontinuation reason not included in RxDxIndep prior to database lock 
will be included here. 
• RxIntExc = Treatment interruptions longer than 2 weeks that are due to exceptional 
circumstances (ie., COVID-19 or the Ukraine conflict). 
• ALS-CM-Inc = increases (starting or dose increases) in concomitant use of ALS 
medications (riluzole or edaravone). 
• ALS-CM-Dec = decreases (stopping or dose decreases) in concomitant use of ALS 
medications (riluzole or edaravone). 
• CompInhib = use of any other complement inhibitor (Note: usage is prohibited within 
30 days or within 5-half lives of the medication [whichever is longer] prior to the start 
of the screening period or during study participation) 


Pegcetacoplan (APL-2) 
APL2-ALS-206 Statistical Analysis Plan 
12 April 2023 
Apellis Pharmaceuticals, Inc 
Page 30 
 
Confidential 
• DPS = diaphragm pacing system (DPS) implanted during randomized treatment 
period. (Note: implantation of a DPS is prohibited prior to and during the randomized 
treatment period, and subjects who have a DPS implanted during this period are 
required to withdraw from the study.) 


Pegcetacoplan (APL-2) 
APL2-ALS-206 Statistical Analysis Plan 
12 April 2023 
Apellis Pharmaceuticals, Inc 
Page 31
 
Confidential 
Table 1: 
Estimands and Attributes for Primary and Secondary Endpoints 
For all estimands: 
A. Population: subjects with sporadic ALS diagnosed as definite, probable, or laboratory-supported probable as defined by the revised El Escorial 
criteria and further defined in the protocol’s inclusion and exclusion criteria 
B. Treatment regimens of interest: 
• 
twice per week SC doses of pegcetacoplan 1080 mg plus concomitant use of riluzole or edaravone (or neither or both) for 52 weeks of 
treatment 
• 
twice per week SC doses of placebo plus concomitant use of riluzole or edaravone (or neither or both) for 52 weeks of treatment 
C: Variable (or endpoint) 
D: Strategies for addressing ICEs (event†: strategy‡) 
E: Population-level summary 
Primary Estimand 
CAFS rank score (joint-rank score) 
Dth: composite strategy 
RxDxIndep: hypothetical strategy 
RxDxRel, RxIntExc, ALS-CM-Inc/Dec, CompInhib, DPS: 
treatment policy strategy 
Difference in mean CAFS score between the 
pegcetacoplan group and the placebo group. 
Secondary Estimands (for comparative endpoints) 
Change from baseline in ALSFRS-R 
at week 52 
Dth: hypothetical strategy 
RxDxIndep: hypothetical strategy 
RxDxRel, RxIntExc, ALS-CM-Inc/Dec, CompInhib, DPS: 
treatment policy strategy 
Difference in mean change from baseline in 
ALSFRS-R at week 52 between the 
pegcetacoplan and placebo arms 
Change from baseline in % predicted 
SVC (at clinical visits) at week 52 
Dth: hypothetical strategy 
RxDxIndep: hypothetical strategy 
RxDxRel, RxIntExc, ALS-CM-Inc/Dec, CompInhib, DPS: 
treatment policy strategy 
Difference in mean change from baseline in 
%SVC (at clinic visits) at week 52 between the 
pegcetacoplan and placebo arms 
Change from baseline in HHD 
megascore at week 52 
Dth: hypothetical strategy 
RxDxIndep: hypothetical strategy 
RxDxRel, RxIntExc, ALS-CM-Inc/Dec, CompInhib, DPS: 
treatment policy strategy 
Difference in mean change from baseline in HHD 
megascore at week 52 between the pegcetacoplan 
and placebo arms 
Time to death, permanent 
tracheostomy or permanent assisted 
ventilation up to week 52 
Dth: not applicable 
RxDxIndep: hypothetical strategy 
RxDxRel, RxIntExc, ALS-CM-Inc/Dec, CompInhib, DPS: 
treatment policy strategy 
Hazard ratio (pegcetacoplan vs placebo arms) for 
time to death, permanent tracheostomy or 
permanent assisted ventilation  


Pegcetacoplan (APL-2) 
APL2-ALS-206 Statistical Analysis Plan 
12 April 2023 
Apellis Pharmaceuticals, Inc 
Page 32 
 
Confidential 
Table 1: 
Estimands and Attributes for Primary and Secondary Endpoints 
Time to death up to week 52 
Dth: not applicable 
RxDxIndep: hypothetical strategy 
RxDxRel, RxIntExc, ALS-CM-Inc/Dec, CompInhib, DPS: 
treatment policy strategy 
Hazard ratio (pegcetacoplan vs placebo arms) for 
time to death  
Change from baseline in ALSAQ-40 
at week 52 
Dth: hypothetical strategy 
RxDxIndep: hypothetical strategy 
RxDxRel, RxIntExc, ALS-CM-Inc/Dec, CompInhib, DPS: 
treatment policy strategy 
Difference in mean change from baseline in 
ALSAQ-40 at week 52 between the 
pegcetacoplan and placebo arms 
†ICE definitions: 
• 
Dth = Death   
• 
RxDxIndep = Discontinuations from study treatment that are considered definitely unrelated to efficacy or safety; these included the Ukraine 
conflict and COVID-19 (illness or site effect., eg, site closure). Other reasons may be added prior to database lock(other than due to death or 
COVID-19) 
• 
RxDxRel = Discontinuations from study treatment due to COVID-19 impact (illness or site effect) that are potentially related to efficacy or safety; 
these include adverse events and lack of efficacy. Any other treatment discontinuation reason not included in RxDxIndep prior to database lock will 
be included here. 
• 
RxIntExc = Treatment interruptions longer than 2 weeks that are due to exceptional circumstances (ie., COVID-19 or the Ukraine conflict). 
• 
ALS-CM-Inc = Increases (starting or dose increases) in concomitant use of ALS medications (riluzole or edaravone) 
• 
ALS-CM-Dec = Decreases (stopping or dose decreases) in concomitant use of ALS medications (riluzole or edaravone) 
• 
CompInhib = use of any other complement inhibitor 
• 
DPS = diaphragm pacing system 
‡Strategies: 
• 
Composite strategy: the occurrence of the ICE is considered part of the endpoint 
• 
Hypothetical strategy: values are considered as if the ICE had not occurred; in all cases above, this strategy is addressed by excluding the data after 
the ICE 
• 
Treatment policy strategy: the ICE is ignored; values after the ICE are used as if the ICE had not occurred. 


Pegcetacoplan (APL-2) 
APL2-ALS-206 Statistical Analysis Plan 
12 April 2023 
Apellis Pharmaceuticals, Inc 
Page 33 
 
Confidential 
6.4. 
Analyses of Primary Efficacy Endpoint 
The primary efficacy endpoint is the CAFS rank score (joint-rank score) at week 52. The null 
(H1,0) and alternative (H1,1) hypotheses for the primary efficacy analysis are: 
H1,0: 
There is no difference in CAFS rank scores between the pegcetacoplan and 
placebo treatment groups 
H1,1: 
There is a difference in CAFS rank scores between the pegcetacoplan and placebo 
treatment groups. 
The CAFS score will be developed as follows (and as proposed by Berry et al. 2013): 
• The functional (ALSFRS-R) and survival outcomes are determined for every subject in 
the pegcetacoplan and placebo treatment groups. 
• All pairwise comparisons are performed and the scores of +1, 0, or –1 are assigned to a 
subject based on each pairwise comparison. The scores are assigned as follows: 
− If both subjects are deceased at the last point of contact, the subject with a longer 
survival receives a score of +1 and the other subject receives a score of –1. If the 
2 subjects died on the same day, both receive a score of 0 
− Otherwise, if one subject is deceased and the other subject is alive at the last point 
of contact and this last point of contact is on or after the day of death, the 
surviving subject receives a score of +1 and the deceased subject receives a score 
of –1 
− Otherwise, the subject with a smaller decrease from baseline in ALSFRS-R at the 
last mutual time point receives a score of +1 and the other subject receives a score 
of –1 
− If the 2 subjects have the same decline from baseline in ALSFRS-R, or if they 
cannot be compared (eg, due to a lack of a mutual time point), both receive a 
score of 0. 
The scores from all pairwise comparisons are added up for each subject are used as the CAFS 
score, which will then be ranked and used in the analyses described in Analysis of Covariance in 
Section 6.1. 
6.4.1. 
Main Analysis of Primary Efficacy Endpoint 
ANCOVA will be used to analyze the CAFS ranks score with treatment as a fixed effect, 
adjusted for baseline ALSFRS-R total score, time from symptoms onset to the first dose of 
investigational product, baseline Log NfL, and the randomization stratification factors (location 
of first muscle weakness and use of riluzole and edaravone). Further details on the presentation 
of the results are described in the Analysis of Covariance section in Section 6.1 above. 
6.4.2. 
Sensitivity Analyses of Primary Efficacy Endpoint 
The following sensitivity analyses will be done to examine the robustness of the main analyses 
of CAFS endpoint under the main estimand. These analyses impute missing ALSFRS-R values 
under the assumptions of both missing at random (MAR) and missing not at random (MNAR).  


Pegcetacoplan (APL-2) 
APL2-ALS-206 Statistical Analysis Plan 
12 April 2023 
Apellis Pharmaceuticals, Inc 
Page 34 
 
Confidential 
6.4.2.1. 
Multiple Imputation for Missing ALSFRS-R for CAFS Under MAR 
Sensitivity analysis with multiple imputation for missing ALSFRS-R scores will be performed 
based on MAR assumption. For subjects who died by week 52, ALSFRS-R score will only be 
imputed before the death date. The imputation method will be implemented in SAS using the 3 
standard steps to generate inference from imputed data: imputation step, analysis step, and 
pooling step.  
• Missing ALSFRS-R are filled 100 times to generate 100 complete data sets and thus 
CAFS are derived for 100 times. 
• The 100 data sets are analyzed using the CAFS method as described in Section 6.1. 
• The results from 100 data sets are combined for inference. 
The method for the imputation step is described below. 
• The imputation model separate for each treatment group includes the following 
covariates: stratification variables, baseline Log NfL, duration from symptoms onset to 
the first dose of investigational product, ALSFRS-R values at baseline and all previous 
visits. 
• The Markov chain Monte Carlo (MCMC) method in PROC MI will be invoked with 
multiple chains (CHAIN=MULTIPLE), 200 burn-in iterations (NBITER=200) and a 
noninformative prior (PRIOR=JEFFREYS) to produce complete data set. The seed to be 
used is in Table 2. 
Combination of the results across the imputed data sets is described in Section 17.2.1. 
Table 2: 
Seed for Multiple Imputation 
Endpoints 
Seed 
ALSFRS-R 
975321 
SVC 
123456 
HHD 
230323 
6.4.2.2. 
Control-Based Multiple Imputation for CAFS 
Sensitivity analysis with control-based multiple imputation  for ALSFRS-R will be performed to 
consider the MNAR mechanism for monotone missing data in ALSFRS-R according to the 
reasons as describe in Section 6.5.1.2.1.  
Using the resulting complete data sets, the CAFS scores will be recalculated (as described above 
in Section 6.4). The analysis model and presentation of the multiply imputed data sets will be 
done as for the main analysis of CAFS using the ANCOVA model described in Section 6.1 
above, but with the results across the imputed data sets combined as in Section 17.2.1. 
6.4.2.3. 
Tipping Point Analysis for CAFS 
Multiple imputation based on the delta-adjusted stress testing (tipping point) analysis will be 
used to impute ALSFRS-R as described in Sections 6.5.1.2.2 and 17.2.2. The tipping point 
imputation approach will be based on the delta-adjusted stress testing method, also known as the 


Pegcetacoplan (APL-2) 
APL2-ALS-206 Statistical Analysis Plan 
12 April 2023 
Apellis Pharmaceuticals, Inc 
Page 35 
 
Confidential 
tipping point analysis (O’Kelly and Ratitch, 2014, Chapter 7). This method assumes that subjects 
who discontinue from the pegcetacoplan group experience worsening of ALSFRS-R defined by 
an adjustment (from -0.2 to -1 grid by -0.2) at all visits that are missing.  
Using the resulting complete data sets, the CAFS scores will be recalculated (as described above 
in Section 6.4). The analysis model and presentation of the imputed data sets will be done as for 
the main analysis of CAFS using the ANCOVA model described in Section 6.1 above, but with 
the results across the imputed data sets combined as in Section 17.2.2. 
6.4.3. 
Supplemental Analyses of Primary Efficacy Endpoint 
6.4.3.1. 
Excluding Data After Changes in Concomitant ALS Treatment and Supportive 
Care 
For this estimand, the treatment regimens of interest are: 
• twice per week SC doses of pegcetacoplan 1080 mg for 52 weeks of treatment 
• twice per week SC doses of placebo for 52 weeks of treatment 
with no changes in background ALS therapy (riluzole or edaravone). 
For the ALS-CM-Inc, ALS-CM-Dec, CompInhib, and DPS ICEs defined above (increases 
and decreases in the concomitant use of ALS treatments, use of other complement inhibitors, 
and DPS implantation respectively), the hypothetical strategy will be used: all ALSFRS-R 
and survival data after these ICEs will be excluded when deriving the CAFS score. Strategies for 
handling other ICEs will be the same as in the primary analysis. 
CAFS scores and then ranks will be re-derived based on steps laid out in Section 6.4, 
and ANCOVA will be used to analyze the new scores. 
6.4.3.2. 
Interruptions due to COVID-19 and Ukraine Conflict 
For this estimand, the treatment regimens of interest are: 
• twice per week SC doses of pegcetacoplan 1080 mg for 52 weeks of treatment 
• twice per week SC doses of placebo for 52 weeks of treatment 
with no interruptions longer than 2 weeks due to COVID-19 or the Ukraine conflict. 
For the RxIntExc (treatment interruptions longer than 2 weeks that are due to exceptional 
circumstances, ie, COVID-19 or the Ukraine conflict) the hypothetical strategy will be used: 
all ALSFRS-R and survival data after these ICEs will be excluded when deriving the CAFS 
score. Strategies for handling other ICEs will be the same as in the primary analysis. 
CAFS scores and then ranks will be re-derived based on steps laid out in Section 6.4, 
and ANCOVA will be used to analyze the new scores. 
6.4.3.3. 
PP Set 
The primary analysis described in Section 6.4.1 will be repeated using the PP set, as defined in 
Section 4.5. 


Pegcetacoplan (APL-2) 
APL2-ALS-206 Statistical Analysis Plan 
12 April 2023 
Apellis Pharmaceuticals, Inc 
Page 36 
 
Confidential 
6.4.4. 
Subgroup Analyses of Primary Efficacy Endpoint 
Subgroup analyses will be performed to evaluate the consistency of the primary analysis results 
across subgroups defined by demographic and baseline characteristics. Analyses will be performed 
for the primary efficacy endpoint for each of the subgroups below (as appropriate per actual 
subgroup sample size, levels with small sample size [<10%] may be pooled to allow for an analysis 
to be conducted).  The CAFS scores from the overall analysis will be used. The primary analysis as 
described in Section 6.4.1 will be repeated for each subgroup.  
• Age at ALS symptom onset: <45, ≥45 – <65, ≥65, where age at symptom start is 
calculated as age at baseline - round((informed consent date – date of symptom 
onset)/365.25,0.1) 
• Sex: male, female 
• Race, defined by ATS/ERS standards: Caucasian, non-Caucasian 
• Geographic region: Europe (Belgium, Czech Republic, France, Germany, Ireland, 
Italy, Netherlands, Poland, Spain, Ukraine, United Kingdom), Japan, South America 
(Argentina, Brazil), and Other (Australia, USA) 
• Location of onset: limb, bulbar; the reported (actual) location will be used, not 
necessarily the value of the stratification factor  
• Time (months) from ALS symptom onset (based on tertiles, rounded to the nearest 
month) 
• Time (months) from ALS diagnosis to first dose (based on tertiles, rounded to the 
nearest month) 
• Time (months) from ALS diagnosis to first dose (6 months, >6-12 months, and >12 
months) 
• Categorized baseline ALSFRS-R scores (based on tertiles, with cutoffs rounded to the 
nearest whole number) 
• El Escorial Criteria assessment 
• Baseline NfL (<=Median, > median) 
6.4.5. 
Analysis of Covariates 
ALS is a highly heterogeneous disease with various risk factors for disease progression. 
Although randomization is employed to achieve the potential of balancing risk factors between 
treatment groups, chance imbalance may occur. The baseline risk factors identified below will be 
evaluated for imbalance and additional supportive analyses of the primary and secondary 
endpoints will be performed adjusting for additional risk factors with major imbalance.  
• Age at symptom onset  
• Limb vs bulbar onset  
• Body mass index  
• Time from symptom onset to diagnosis  
• Baseline ALSFRS score  


Pegcetacoplan (APL-2) 
APL2-ALS-206 Statistical Analysis Plan 
12 April 2023 
Apellis Pharmaceuticals, Inc 
Page 37 
 
Confidential 
• Baseline %SVC  
• Neurofilament light chain.  
In addition, risk predicted based on baseline characteristics using advanced analytic methods 
such as AI may be explored for adjusted analysis.  
6.5. 
Analyses of Secondary Efficacy Endpoints 
The following subsections describe the analyses of the secondary efficacy endpoints of the study. 
All analyses of secondary endpoints will be done on the ITT set. 
6.5.1. 
Change From Baseline in ALSFRS-R at Week 52 (Total Score) 
The secondary efficacy endpoint of change from baseline in ALSFRS-R at week 52 (total score) 
will be examined with the following null (H2.1,0) and alternative (H2.1,1) hypotheses: 
H2.1,0: There is no difference in change from baseline in ALSFRS-R at Week 52 
(total score) between the pegcetacoplan and placebo treatment groups 
H2.1,1: There is a difference in change from baseline in ALSFRS-R at Week 52 
(total score) between the pegcetacoplan and placebo treatment groups. 
Derivations and data handling conventions for the ALSFRS-R endpoint are described in 
Section 13.5.1. Absolute values and changes from baseline in ALSFRS-R total scores as well as 
domain subscores [bulbar function, fine motor, gross motor, and respiratory] will be presented by 
treatment group and visit (up to week 52) using descriptive statistics.  
Changes from baseline in ALSFRS-R total scores up to week 52 will be analyzed using the 
MMRM described in Mixed-effect model for repeated measures (MMRM) for continuous 
outcomes in Section 6.1 above, with results presented as described there. 
6.5.1.1. 
Supportive Analyses of ALSFRS-R 
The following supplemental analyses will be done to further examine the change from baseline 
in ALSFRS-R scores. 
6.5.1.1.1. Slope Analysis 
The mean slope (rate of change) in observed ALSFRS-R scores will be compared between 
treatment groups using the mixed effects model for slope analysis of continuous outcomes 
described above in Mixed effects model for slope analysis of continuous outcomes in Section 6.1. 
Subjects with no postbaseline ALSFRS-R assessment will not be included. 
6.5.1.2. 
Sensitivity Analyses of ALSFRS-R 
The following sensitivity analyses will be done to further examine the robustness of the results 
for the analysis of change from baseline in ALSFRS-R scores. 
6.5.1.2.1. Control-Based Multiple Imputation 
Control-based multiple imputation approach will be used as a sensitivity analysis to consider the 
MNAR mechanism for monotone missing data. Changes from baseline in ALSFRS-R will be 


Pegcetacoplan (APL-2) 
APL2-ALS-206 Statistical Analysis Plan 
12 April 2023 
Apellis Pharmaceuticals, Inc 
Page 38 
 
Confidential 
analyzed based on the data observed while the subject remains on study treatment as well as the 
data imputed using multiple imputation (MI) methodology for the time points with missing 
values. The following strategy will be used: 
• In the placebo group, all missing values will be imputed based on the MAR 
assumption using the placebo group 
• In the pegcetacoplan group: 
− Nonmonotone missing values (ie, not due to dropout) will be imputed based on 
the MAR assumption using the pegcetacoplan group. 
− Monotone missing values (ie, postdropout) will be imputed as follows: 
 
If the reason for treatment or study discontinuation is not potentially 
related to safety or efficacy, ie, 'SITE TERMINATED BY SPONSOR', the 
values will be imputed based on the MAR assumption using the 
pegcetacoplan group. ‘SITE TERMINATED BY SPONSOR’ is the coded 
reason for discontinuation due to Ukraine conflicts or COVID-19 external 
factors. 
 
If the reason for treatment or study discontinuation is potentially related to 
safety or efficacy, the values will be imputed based on the placebo 
imputation model above. These reasons include all reasons except 'SITE 
TERMINATED BY SPONSOR'. 
This approach does not assume a sustained benefit of pegcetacoplan after discontinuation but 
rather assumes a postdiscontinuation effect like that of placebo. 
Details of the control-based MI procedure are given in Section 17.2.1. The analysis model and 
presentation of the multiply imputed data sets will be done as for the main analysis of the 
ALSFRS-R using the MMRM described in Mixed-effect model for repeated measures (MMRM) 
for continuous outcomes in Section 6.1 above, but with the results across the imputed data sets 
combined as in Section 17.2.1. 
6.5.1.2.2. Tipping Point Analysis 
MI based on the delta-adjusted stress testing (tipping point) analysis will be performed for 
ALSFRS-R and will be analyzed using the MMRM model used in the main analysis of this 
endpoint. 
The tipping point imputation approach will be based on the delta-adjusted stress testing method, 
also known as the tipping point analysis (O’Kelly and Ratitch, 2014). This method assumes that 
subjects who discontinue from the pegcetacoplan group experience worsening of ALSFRS-R 
defined by a prespecified adjustment (from -0.2 to -1 grid by -0.2) at each following visit. Then 
each imputed data set will be analyzed using MMRM and the results across the imputed data sets 
will be combined as in Section 17.2.1. 
Details of the delta-adjusted stress testing method procedure are given in Section 17.2.2. The analysis 
model and presentation of the multiply imputed data sets will be done as for the main analysis of the 
ALSFRS-R using the MMRM described in Mixed-effect model for repeated measures (MMRM) for 
continuous outcomes in Section 6.1 above. 


Pegcetacoplan (APL-2) 
APL2-ALS-206 Statistical Analysis Plan 
12 April 2023 
Apellis Pharmaceuticals, Inc 
Page 39 
 
Confidential 
6.5.1.3. 
Supplemental Analyses of ALSFRS-R 
The following supplemental analyses will be done to examine other estimands for the change 
from baseline in ALSFRS-R scores. 
6.5.1.3.1. Excluding Data After Changes in Concomitant ALS Therapy 
For this estimand, the treatment regimens of interest are: 
• twice per week SC doses of pegcetacoplan 1080 mg for 52 weeks of treatment 
• twice per week SC doses of placebo for 52 weeks of treatment 
with no changes in background ALS therapy (riluzole or edaravone), usage of complement 
inhibitors, or DPS. 
For the ALS-CM-Inc, ALS-CM-Dec, and CompInhib ICEs defined above (increases and 
decreases in the concomitant use of ALS treatments, and use of other complement inhibitors, 
respectively), the hypothetical strategy will be used: all ALSFRS-R after the ICE will be 
excluded from the analysis. The strategies for handling other ICEs listed in Section 6.2 are the 
same as the primary analysis. MMRM will be used assuming there is no change of background 
ALS therapy and ALSFRS-R score will follow the same trend as before the ICE occurs. 
6.5.1.4. 
Interruptions due to COVID-19 and Ukraine Conflict 
For this estimand, the treatment regimens of interest are: 
• twice per week SC doses of pegcetacoplan 1080 mg for 52 weeks of treatment 
• twice per week SC doses of placebo for 52 weeks of treatment 
with no interruptions longer than 2 weeks due to COVID-19 or the Ukraine conflict. 
For the RxIntExc (treatment interruptions longer than 2 weeks that are due to exceptional 
circumstances, ie, COVID-19 or the Ukraine conflict) the hypothetical strategy will be used: 
all ALSFRS-R and survival data after these ICEs will be excluded when deriving the CAFS 
score. Strategies for handling other ICEs will be the same as in the primary analysis. MMRM 
will be used assuming there is no change of background ALS therapy and ALSFRS-R score will 
follow the same trend as before the ICE occurs. 
6.5.1.4.1. PP Set 
The analysis described in Section 6.5.1 will be repeated using the PP set, which is defined in 
Section 4.5. 
6.5.1.5. 
Subgroup Analyses of ALSFRS-R 
Subgroup analyses will be performed for ALSFRS-R to evaluate the consistency of the results of 
the analyses across the subgroups specified in Section 6.4.4 above. Levels with low sample size 
may be pooled to allow for an analysis to be conducted. 
The MMRM used for the main analysis of ALSFRS-R will be repeated for each subgroup level 
respectively.  


Pegcetacoplan (APL-2) 
APL2-ALS-206 Statistical Analysis Plan 
12 April 2023 
Apellis Pharmaceuticals, Inc 
Page 40 
 
Confidential 
6.5.2. 
Change from Baseline in % Predicted SVC (at Clinic Visits) at Week 52 
The secondary efficacy endpoint of change from baseline in % predicted SVC (at clinic visits) at 
week 52 will be examined with the following null (H2.2,0) and alternative (H2.2,1) hypotheses: 
H2.2,0: There is no difference in change from baseline in % predicted SVC (at clinic 
visits) at Week 52 between the pegcetacoplan and placebo treatment groups 
H2.2,1: There is a difference in change from baseline in % predicted SVC (at clinic visits) 
at Week 52 between the pegcetacoplan and placebo treatment groups. 
Derivations and data handling conventions for the % predicted SVC endpoint are described in 
Section 13.5.2. Absolute values and changes from baseline in % predicted SVC will be presented 
by treatment group and visit (up to week 52) using descriptive statistics. Means (±SE) will also 
be plotted over time. 
Changes from baseline in % predicted SVC up to week 52 will be analyzed using the MMRM 
described in Section 6.1, with results presented as described there. 
6.5.2.1. 
Sensitivity Analyses of % Predicted SVC (at Clinic Visits)  
The following sensitivity analyses will be done to further examine the robustness of the results 
for the analysis of change from baseline in % predicted SVC (at clinic) scores. 
6.5.2.1.1. Control-Based MI 
Control-based MI approach will be used as a sensitivity analysis to consider the MNAR mechanism 
for monotone missing data. Changes from baseline in % predicted SVC will be analyzed based on 
the data observed while the subject remains on study treatment as well as the data imputed using MI 
methodology for the time points with missing values.  
Details of the control-based MI procedure are given in Section 6.5.1.2.1 and Section 17.2.1. The 
analysis model and presentation of the multiply imputed data sets will be done as for the main 
analysis of the % predicted SVC using the MMRM described in Mixed-effect model for repeated 
measures (MMRM) for continuous outcomes in Section 6.1, but with the results across the imputed 
data sets combined as in Section 17.2.1. 
6.5.2.2. 
Supplemental Analyses of % Predicted SVC 
6.5.2.2.1. CAFS Analysis for %Predicted SVC (at Clinic Visits) 
CAFS score and rank score will be derived combining %predicted SVC and death similarly as in 
Section 6.4 and analyzed by the ANCOVA model adjusting for baseline %predicted SVC, time 
from symptom onset (defined in Section 5.3), the randomization stratification factors (details in 
Section 6.1 and baseline Log NfL. The analysis will be done based on mITT set.  
6.5.2.2.2. PP Set 
The analysis described in Section 6.5.2 will be repeated using the PP set, which is defined in 
Section 4.5. 


Pegcetacoplan (APL-2) 
APL2-ALS-206 Statistical Analysis Plan 
12 April 2023 
Apellis Pharmaceuticals, Inc 
Page 41 
 
Confidential 
6.5.2.3. 
Subgroup Analyses of % Predicted SVC (at Clinic) 
Subgroup analyses will be performed for % predicted SVC to evaluate the consistency of the 
results of the analyses across the subgroups specified in Section 6.4.4. Levels with low sample 
size may be pooled to allow for an analysis to be conducted). 
The MMRM used for the main analysis of % predicted SVC will be applied for each subgroup 
level respectively. 
6.5.3. 
Change from Baseline in HHD Megascore at Week 52 
The secondary efficacy endpoint of change from baseline in HHD megascore at week 52 will be 
examined with the following null (H2.3,0) and alternative (H2.3,1) hypotheses: 
H2.3,0: There is no difference in change from baseline in HHD megascore at Week 52 
between the pegcetacoplan and placebo treatment groups 
H2.3,1: There is a difference in change from baseline in HHD megascore at Week 52 
between the pegcetacoplan and placebo treatment groups. 
Derivations and data handling conventions for the HHD megascore endpoint are described in 
Section 13.5.3. Absolute values and changes from baseline in HHD megascore will be presented 
by treatment group and visit (up to week 52) using descriptive statistics. Means (±SE) will also 
be plotted over time. 
Changes from baseline in HHD megascore up to week 52 will be analyzed using the MMRM 
described in Section 6.1, with results presented as described there. 
6.5.3.1. 
Sensitivity Analyses of HHD 
The following sensitivity analyses will be done to further examine the robustness of the results 
for the analysis of change from baseline in HHD megascores. 
6.5.3.1.1. Control-Based MI 
Control-based MI approach will be used as a sensitivity analysis to consider the MNAR 
mechanism for monotone missing data. Changes from baseline in HHD megascores will be 
analyzed based on the data observed while the subject remains on study treatment as well as the 
data imputed using MI methodology for the time points with missing values.  
Details of the control-based MI procedure are given in Section 6.5.1.2.1 and Section 17.2.1. The 
analysis model and presentation of the multiply imputed data sets will be done as for the main 
analysis of the HHD megascores using the MMRM described in Mixed-effect model for repeated 
measures (MMRM) for continuous outcomes in Section 6.1, but with the results across the imputed 
data sets combined as in Section 17.2.1. 
6.5.3.2. 
Supplemental Analyses of HHD 
6.5.3.2.1. CAFS Analysis for HHD  
CAFS score and rank score will be derived combining HHD and death similarly as in Section 6.4 
and analyzed by the ANCOVA model adjusting for baseline HHD, time from symptom onset 


Pegcetacoplan (APL-2) 
APL2-ALS-206 Statistical Analysis Plan 
12 April 2023 
Apellis Pharmaceuticals, Inc 
Page 42 
 
Confidential 
(defined in Section 5.3), baseline Log NfL, and the randomization stratification factors (details in 
Section 6.1. The analysis will be based on mITT set.  
6.5.3.2.2. PP Set 
The analysis described in Section 6.5.3 will be repeated using the PP set, which is defined in 
Section 4.5. 
6.5.3.3. 
Subgroup Analyses of HHD Megascores 
Subgroup analyses will be performed for HHD megascores to evaluate the consistency of the 
results of the analyses across the subgroups specified in Section 6.4.4. Levels with low sample 
size may be pooled to allow for an analysis to be conducted). 
The MMRM used for the main analysis of HHD megascores will be applied to each level of 
subgroups respectively. 
6.5.4. 
Time to Death, Permanent Tracheostomy, or Permanent Assisted Ventilation up 
to Week 52 
The secondary efficacy endpoint of time to death, permanent tracheostomy, or permanent 
assisted ventilation up to week 52 will be examined with the following null (H2.6,0) and 
alternative (H2.6,1) hypotheses: 
H2.6,0: There is no difference in time to death, permanent tracheostomy, or permanent 
assisted ventilation between the pegcetacoplan and placebo treatment groups 
H2.6,1: There is a difference in time to death, permanent tracheostomy, or permanent 
assisted ventilation between the pegcetacoplan and placebo treatment groups. 
For this endpoint, the first instance of any of the 3 events at or prior to week 52 will be considered an 
event. Subjects with an event after an ICE that is handled by a hypothetical strategy will be 
considered censored on the day of the ICE. Subjects with none of the events by the minimum of the 
week 52 visit date or date of first dose + 364 if week 52 is missing will be considered censored at the 
minimum of the last date of contact or their treatment discontinuation date for subjects whose ICE 
dictates hypothetical strategy, or their week 52 visit or first dose date+364 if week 52 is missing. 
Subjects who were randomized but did not receive any treatment will be censored at the 
randomization date. Time-to-event (or censor) will be calculated as date of event (or censor date) − 
date of randomization + 1. 
Time to death, permanent tracheostomy, or permanent assisted ventilation will be summarized 
with the Kaplan-Meier method (Kaplan and Meier 1958), using plots and presentation of median 
(and 95% CIs) for time-to-event. Analysis will be done by a Cox proportional hazards model as 
described in Section 6.1. 
6.5.5. 
Time to Death up to Week 52 
The secondary efficacy endpoint of time to death up to week 52 will be examined with the 
following null (H2.5,0) and alternative (H2.5,1) hypotheses: 
H2.5,0: There is no difference in time to death up to Week 52 between the pegcetacoplan 
and placebo treatment groups 


Pegcetacoplan (APL-2) 
APL2-ALS-206 Statistical Analysis Plan 
12 April 2023 
Apellis Pharmaceuticals, Inc 
Page 43 
 
Confidential 
H2.5,1: There is a difference in time to death up to Week 52 between the pegcetacoplan 
and placebo treatment groups. 
Deaths that occurred at or prior to week 52 will be included in the time to death analysis. 
Subjects who are alive at their week 52 visit date or date of first dose + 364 days if week 52 visit 
is missing will be censored. Subjects who had the ICE of discontinued treatment unrelated to 
efficacy or safety will also be censored at treatment discontinuation. Time to death is calculated 
as date of death – randomization date +1. Time to censoring for subjects who are alive is 
calculated as min (last contact date, week 52 visit date or first dose date+ 364 days if missing, 
treatment discontinuation date for ICE subjects) – randomization data +1. Time to death will be 
summarized with the Kaplan-Meier method, using plots and presentation of median (and 95% 
CIs) for time-to-event. Analysis will be done by a Cox proportional hazards model as described 
in Section 6.1. 


Pegcetacoplan (APL-2) 
APL2-ALS-206 Statistical Analysis Plan 
12 April 2023 
Apellis Pharmaceuticals, Inc 
Page 44 
 
Confidential 
6.5.6. 
Change from Baseline in ALSAQ-40 at Week 52 (Total Score) 
The secondary efficacy endpoint of change from baseline in ALSAQ-40 at week 52 (total score) 
will be examined with the following null (H2.4,0) and alternative (H2.4,1) hypotheses: 
H2.4,0: There is no difference in change from baseline in ALSAQ-40 at Week 52 
(total score) between the pegcetacoplan and placebo treatment groups 
H2.4,1: There is a difference in change from baseline in ALSAQ-40 at Week 52 
(total score) between the pegcetacoplan and placebo treatment groups. 
Derivations and data handling conventions for the ALSAQ-40 endpoint are described in 
Section 13.5.4; all presentation and analysis of ALSAQ-40 will use the scaled scores. Absolute 
values and changes from baseline in ALSAQ-40 score will be presented by treatment group and 
visit (up to week 52) using descriptive statistics. Means (±SE) will also be plotted over time. 
Changes from baseline in ALSAQ-40 score up to week 52 will be analyzed using the MMRM 
described in Section 6.1, with results presented as described there. 
6.5.7. 
Change from Baseline in Serum NfL at week 52 
The efficacy endpoint of change from baseline in serum NfL at week 52 will be examined with 
the following null (H3.5,0) and alternative (H3.5,1) hypotheses: 
H3.5,0: There is no difference in change from baseline in serum NfL at week 52 between 
the pegcetacoplan and placebo treatment groups 
H3.5,1: There is a difference in change from baseline in serum NfL at week 52 between the 
pegcetacoplan and placebo treatment groups. 
NfL values are expected to be highly skewed, so before analysis and presentation, values will be 
natural log transformed. The handling of values below a limit of detection (LOD) is described in 
Section 13.7.7. Geometric means will be presented for descriptive statistics. Geometric means and 
geometric mean ratios relative to baseline will be presented by treatment group and visit 
(up to week 52) using descriptive statistics. Geometric means (with 95% CIs) will also be plotted 
over time. 
Log-transformed NfL up to week 52 compared to baseline will be analyzed using the MMRM 
described in Section 6.1, with results presented as described there, with the exception that 
differences in LS means will reflect geometric mean ratios. 
6.6. 
Analyses of Exploratory Endpoints  
All analyses of exploratory endpoints will be done on the ITT set. Estimands and their attributes 
for comparative exploratory endpoints are stated in Table 3. 


Pegcetacoplan (APL-2) 
APL2-ALS-206 Statistical Analysis Plan 
12 April 2023 
Apellis Pharmaceuticals, Inc 
Page 45 
 
Confidential 
Table 3: 
Estimands and Attributes for Comparative Exploratory Endpoints 
For all estimands: 
A. Population: subjects with sporadic ALS diagnosed as definite, probable, or laboratory-supported probable as defined by the revised El Escorial 
criteria and further defined in the protocol’s inclusion and exclusion criteria 
B. Treatment regimens of interest: 
a. 
twice per week SC doses of pegcetacoplan 1080 mg plus concomitant use of riluzole or edaravone (or neither or both) for 52 weeks of 
treatment 
b. twice per week SC doses of placebo plus concomitant use of riluzole or edaravone (or neither or both) for 52 weeks of treatment 
C: Variable (or endpoint) 
D: Strategies for addressing ICEs (event†: strategy‡) 
E: Population-level summary 
Primary Estimand 
Change from baseline in % predicted 
SVC (home spirometry) at week 52 
Dth: hypothetical strategy 
RxDxIndep: hypothetical strategy 
RxDxRel, RxIntExc, ALS-CM-Inc/Dec, CompInhib, DPS: 
treatment policy strategy 
Difference in mean change from baseline in % 
predicted SVC (at-home visits) at week 52 
between the pegcetacoplan and placebo arms 
Change from baseline in EQ-5D-5L 
at week 52 
Dth: hypothetical strategy 
RxDxIndep: hypothetical strategy 
RxDxRel, RxIntExc, ALS-CM-Inc/Dec, CompInhib, DPS: 
treatment policy strategy 
Difference in mean change from baseline in 
EQ-5D-5L at week 52 between the pegcetacoplan 
and placebo arms 
Change from baseline in ZBI score at 
week 52 
Dth: hypothetical strategy 
RxDxIndep: hypothetical strategy 
RxDxRel, RxIntExc, ALS-CM-Inc/Dec, CompInhib, DPS: 
treatment policy strategy 
Difference in mean change from baseline in ZBI) 
score at week 52 between the pegcetacoplan and 
placebo arms 
Time to percutaneous endoscopic 
gastrostomy tube placement up to 
week 52 
Dth: not applicable 
RxDxIndep: hypothetical strategy 
RxDxRel, RxIntExc, ALS-CM-Inc/Dec, CompInhib, DPS: 
treatment policy strategy 
Hazard ratio (pegcetacoplan vs placebo arms) for 
time to percutaneous endoscopic gastrostomy 
tube placement 
Change from baseline in serum NfL 
at week 52 
Dth: hypothetical strategy 
RxDxIndep: hypothetical strategy 
RxDxRel, RxIntExc, ALS-CM-Inc/Dec, CompInhib, DPS: 
treatment policy strategy 
Difference in mean change from baseline in 
serum NfL at week 52 between the pegcetacoplan 
and placebo arms 
Change from baseline in serum 
pNfH at week 52 
Dth: not applicable 
RxDxIndep: hypothetical strategy 
RxDxRel, RxIntExc, ALS-CM-Inc/Dec, CompInhib, DPS: 
treatment policy strategy 
Difference in mean change from baseline in 
serum pNfH at week 52 between the 
pegcetacoplan and placebo arms 


Pegcetacoplan (APL-2) 
APL2-ALS-206 Statistical Analysis Plan 
12 April 2023 
Apellis Pharmaceuticals, Inc 
Page 46 
 
Confidential 
Table 3: 
Estimands and Attributes for Comparative Exploratory Endpoints 
Change from baseline in EIM at 
week 52 (only at select 
investigational sites chosen to 
complete this) 
Dth: hypothetical strategy 
RxDxIndep: hypothetical strategy 
RxDxRel, RxIntExc, ALS-CM-Inc/Dec, CompInhib, DPS: 
treatment policy strategy 
Difference in mean change from baseline in EIM 
at week 52 between the pegcetacoplan and 
placebo arms 
†ICE definitions: 
• 
Dth = Death   
• 
RxDxIndep = Discontinuations from study treatment that are considered definitely unrelated to efficacy or safety; these included the Ukraine 
conflict and COVID-19 (illness or site effect., eg, site closure). Other reasons may be added prior to database lock(other than due to death or 
COVID-19) 
• 
RxDxRel = Discontinuations from study treatment due to reasons that are potentially related to efficacy or safety; these include adverse events and 
lack of efficacy. Any other treatment discontinuation reason not included in RxDxIndep prior to database lock will be included here. 
• 
RxIntExc = Treatment interruptions longer than 2 weeks that are due to exceptional circumstances (ie., COVID-19 or the Ukraine conflict). 
• 
ALS-CM-Inc = Increases (starting or dose increases) in concomitant use of ALS medications (riluzole or edaravone) 
• 
ALS-CM-Dec = Decreases (stopping or dose decreases) in concomitant use of ALS medications (riluzole or edaravone) 
• 
CompInhib = use of any other complement inhibitor 
• 
DPS = diaphragm pacing system 
‡Strategies: 
• 
Composite strategy: the occurrence of the ICE is considered part of the endpoint 
• 
Hypothetical strategy: values are considered as if the ICE had not occurred; in all cases above, this strategy is addressed by the MMRM model 
assuming the effect at Week 52 excluding the data after the ICE 
• 
Treatment policy strategy: the ICE is ignored; values after the ICE are used as if the ICE had not occurred. 


Pegcetacoplan (APL-2) 
APL2-ALS-206 Statistical Analysis Plan 
12 April 2023 
Apellis Pharmaceuticals, Inc 
Page 47 
 
Confidential 
6.6.1. 
Change from Baseline in % Predicted SVC (Home Spirometry) at Week 52 
The exploratory efficacy endpoint of change from baseline in % predicted SVC (home spirometry) 
at week 52 will be examined with the following null (H3.1,0) and alternative (H3.1,1) hypotheses: 
H3.1,0: There is no difference in change from baseline in % predicted SVC (home 
spirometry) at Week 52 between the pegcetacoplan and placebo treatment groups 
H3.1,1: There is a difference in change from baseline in % predicted SVC (home 
spirometry) at Week 52 between the pegcetacoplan and placebo treatment groups. 
Derivations and data handling conventions for the at-home % predicted SVC endpoint are 
described in Section 13.5.2. Absolute values and changes from baseline in at-home % predicted 
SVC will be presented by treatment group and week (up to week 52) using descriptive statistics. 
Means (±SE) will also be plotted over time. 
Observed values for % predicted SVC up to week 52 will be analyzed using the Mixed effects 
model for slope analysis of continuous outcomes described in Section 6.1, with results presented 
as described there. 
6.6.2. 
Change from Baseline in EQ-5D-5L at Week 52 
Two endpoints will be presented for the EQ-5D-5L: 
• visual analog scale (VAS) 
• descriptive summary. 
The exploratory efficacy endpoint of change from baseline in EQ-5D-5L at week 52 will be 
examined with the following null (H3.2,0) and alternative (H3.2,1) hypotheses for the VAS component: 
H3.2,0: There is no difference in change from baseline in EQ-5D-5L VAS at Week 52 
between the pegcetacoplan and placebo treatment groups 
H3.2,1: There is a difference in change from baseline in EQ-5D-5L VAS at Week 52 
between the pegcetacoplan and placebo treatment groups. 
Derivations and data handling conventions for the EQ-5D-5L endpoint are described in 
Section 13.5.5. Absolute values and changes from baseline in the VAS will be presented by 
treatment group and visit (up to week 52) using descriptive statistics. Means (±SE) will also be 
plotted over time. 
Changes from baseline in the VAS up to week 52 will be analyzed using the MMRM described 
in Section 6.1, with results presented as described there. 
For the descriptive summary, the number and percentage of subjects will be presented by 
category (no problems, slight problems, moderate problems, severe problems, extreme 
problems/unable to do) at baseline, week 24 and week 52.  A shift table from baseline to last 
observed value (LOV) will also be presented. 
6.6.3. 
Change from Baseline in ZBI Scores at Week 52 
The exploratory efficacy endpoint of change from baseline in ZBI scores at week 52 will be 
examined with the following null (H3.3,0) and alternative (H3.3,1) hypotheses: 


Pegcetacoplan (APL-2) 
APL2-ALS-206 Statistical Analysis Plan 
12 April 2023 
Apellis Pharmaceuticals, Inc 
Page 48 
 
Confidential 
H3.3,0: There is no difference in change from baseline in ZBI scores at Week 52 between 
the pegcetacoplan and placebo treatment groups 
H3.3,1: There is a difference in change from baseline in ZBI scores at Week 52 between 
the pegcetacoplan and placebo treatment groups. 
Derivations and data handling conventions for the ZBI endpoint are described in Section 13.5.6. 
Absolute values and changes from baseline will be presented by treatment group and visit (up to 
week 52) using descriptive statistics. Means (±SE) will also be plotted over time. 
Changes from baseline up to week 52 will be analyzed using the MMRM described in 
Section 6.1, with results presented as described there. 
6.6.4. 
Time to Percutaneous Endoscopic Gastrostomy Tube Placement up to Week 52 
The exploratory efficacy endpoint of time to percutaneous endoscopic gastrostomy tube placement 
up to week 52 will be examined with the following null (H3.4,0) and alternative (H3.4,1) hypotheses: 
H3.4,0: There is no difference in time to percutaneous endoscopic gastrostomy tube 
placement between the pegcetacoplan and placebo treatment groups 
H3.4,1: There is a difference in time to percutaneous endoscopic gastrostomy tube 
placement between the pegcetacoplan and placebo treatment groups. 
Subjects who did not have the procedure at or prior to week 52 in study will be censored at the 
minimum of the last date of contact or their treatment discontinuation date for subjects whose ICE 
dictates hypothetical strategy, or their week 52 visit or first dose date+364 if week 52 is missing.. 
Subjects who were randomized but did not receive any treatment will be censored at the 
randomization date. Time to percutaneous endoscopic gastrostomy tube placement (or censor) will 
be calculated as date of death (or censor date) – date of randomization + 1. 
Time to percutaneous endoscopic gastrostomy tube placement will be summarized with the 
Kaplan-Meier method, using plots and presentation of median (and 95% CIs) for time-to-event. 
Analysis will be done by a Cox proportional model as described in Section 6.1. 
6.6.5. 
Change from Baseline in Serum pNfH at Week 52 
The exploratory efficacy endpoint of change from baseline in serum pNfH at week 52 will be 
examined with the following null (H3.6,0) and alternative (H3.6,1) hypotheses: 
H3.6,0: There is no difference in change from baseline in serum pNfH at Week 52 between 
the pegcetacoplan and placebo treatment groups 
H3.6,1: There is a difference in change from baseline in serum pNfH at Week 52 between 
the pegcetacoplan and placebo treatment groups. 
Values of pNfH are expected to be highly skewed, so before analysis and presentation, they will 
be natural log transformed. The handling of values below a LOD is described in Section 13.7.7. 
Geometric means will be presented for descriptive statistics. Geometric means and geometric 
mean ratios relative to baseline will be presented by treatment group and visit (up to week 52) 
using descriptive statistics.  
Due to operational reasons, samples are only analyzed for NfH at week 52 visit or the last visit if 
the patient early withdrew. Thus, log-transformed NfH at week 52 compared to baseline will be 


Pegcetacoplan (APL-2) 
APL2-ALS-206 Statistical Analysis Plan 
12 April 2023 
Apellis Pharmaceuticals, Inc 
Page 49 
 
Confidential 
analyzed using the ANCOVA described in Section 6.1, with results presented as described there, 
with the exception that differences in LS means will reflect geometric mean ratios. LS means of 
geometric means (with 95% CIs) at week 52 will also be plotted. 
6.7. 
Analyses of Open-Label Periods (OLP) 
Data collected from OLP, ie, part 3 and part 4, will be analyzed with data from RCP to provide 
long-term efficacy and safety assessment. Baseline will be the same as defined for Week 52 
analysis, and day 1 is the day of first dose in RCP. Patients will be analyzed according to the 
treatment assigned at randomization. CAFS analysis will be performed based on mITT set while 
other efficacy endpoints will be analyzed based on ITT set. The analyses compare early-start 
with delated-start of pegcetacoplan and provide further support for treatment effect to be 
observed in the randomized treatment period. For efficacy endpoints in OLP specified in Section 
2.2, absolute value and change from baseline will be summarized by visits by the randomized 
treatment groups. The same strategies to hand ICEs and models will be used as specified for 
week 52 analyses. Statistical tests will be conducted in the order specified below. For other 
long-term endpoints that are not included in multiplicity control below, models used for week 
52 analyses may still be used for analysis but only nominal p-values will be reported with 
estimates and 95% CI.  
Multiplicity control 
To control the overall type I error in OLP analyses, the endpoints will be tested in the following 
order: 
1.
Change from baseline in ALSFRS-R at week 104
2. Change from baseline in %SVC at week 104
3. Change from baseline in HHD at week 104
4. CAFS rank score at week 104
5. Time to death up to week 104
6. Time to death, permanent tracheostomy, or permanent assisted ventilation up to week 104
Analysis methods as described for the randomized treatment period will be used. Additional 
analysis using external control may be explored to evaluate the long-term effect of 
pegcetacoplan. Further details will be provided in a separate SAP.  


Pegcetacoplan (APL-2) 
APL2-ALS-206 Statistical Analysis Plan 
12 April 2023 
Apellis Pharmaceuticals, Inc 
Page 50 
 
Confidential 
7. 
SAFETY ANALYSIS  
The safety analysis will be performed using the safety set. Safety variables include AEs, clinical 
laboratory variables, vital signs, and ECG variables. For each safety variable, the last value 
collected before the first dose of investigational product will be used as baseline for all analyses 
of that safety variable. 
All safety analyses will be conducted according to the treatment the subject actually received. 
7.1. 
Adverse Events  
Adverse events will be coded using version 23.0 of MedDRA. 
An AE will be considered treatment emergent (ie, a TEAE) if it has a start date on or after the 
first dose of randomized treatment or if it has a start date before the date of the first dose of 
double-blind investigational product, but increases in severity on or after the date of the first dose 
of double-blind investigational product. AEs that occur more than 56 days after the date of the 
last dose of investigational product will not be considered treatment emergent. (Eight weeks 
[56 days] is approximately 5 times the half-life of pegcetacoplan, which is about 10 days.)  
All summaries of adverse events will be restricted to TEAEs. Therefore, TEAEs are referred to 
as AEs, and treatment emergent serious AEs are referred to as serious adverse events (SAEs) in 
this document. 
An overall summary of the number of subjects with AEs will be presented, including the number 
and percentage of subjects with  
• any AE 
• AEs related to investigational product (evaluated by the investigator as definitely or 
possibly related) 
• AEs related to infusion procedure (evaluated by the investigator as definitely or possibly 
related) 
• injection/infusion site reactions 
• SAEs  
• SAEs related to investigational product (evaluated by the investigator as definitely or 
possibly related) 
• any AE by maximum severity 
• SAEs by maximum severity 
• severe AEs 
• AEs leading to interruption of study treatment 
• AEs leading to discontinuation of study treatment 
• AEs leading to study discontinuation 
• AEs leading to death 
• AEs in the following categories (with specific terms declared prior to unblinding): 
− hypersensitivity  
− sepsis  


Pegcetacoplan (APL-2) 
APL2-ALS-206 Statistical Analysis Plan 
12 April 2023 
Apellis Pharmaceuticals, Inc 
Page 51 
 
Confidential 
−
infections
The overall summary will also include the total number of events reported for all categories above. 
The number and percentage of subjects reporting AEs in each treatment group and overall will 
be tabulated alphabetically by SOC and PT for all of the itemized categories above. If more than 
one AE occurs with the same PT for the same subject, then the subject will be counted only once 
for that PT using the most severe and most related occurrence for the summarization by severity 
and by relationship to investigational product. The number of events will also be presented. 
These presentations will be sorted alphabetically by SOC then sorted within SOC using PT in the 
following hierarchy: (i) decreasing incidence in the pegcetacoplan group, (ii) decreasing 
incidence in the placebo group, and (iii) alphabetically. 
AEs will also be presented without classification by SOC sorted by PT in the following hierarchy 
(i) decreasing incidence in the pegcetacoplan group, (ii) decreasing incidence in the placebo 
group, and (iii) alphabetically.
AEs will be summarized by SOC and PT by ANTI-PEG response status (see Section 7.6.2.2). 
All AEs (treatment emergent or not) will be listed by subject, along with information regarding 
onset, duration, relationship to study treatment and infusion procedure, treatment emergent flag, 
severity, action taken with investigational product, seriousness, and outcome. 
7.2. 
Injection/Infusion Site Assessment 
Injection sites are to be assessed after each injection regardless of where the injection is done 
(home or clinic) and if there is a reaction, the attributes of the reaction are to be collected: 
redness, induration, swelling, bruising, rash, and other; and if the reaction is clinically 
significant, it is to be reported on the AE form. The incidence of injection site reactions, each 
attribute, and clinically significant injection site reactions will be summarized by treatment 
group. Injection site reactions reported as AEs will be presented in the appropriate AE sections. 
7.3. 
Clinical Laboratory Data 
Laboratory assays were to be done by a central laboratory. If laboratory parameters were assayed 
at a local laboratory, they will be normalized relative to central laboratory’s upper and lower 
limits of normal. 
Descriptive statistics for clinical laboratory values in SI units and changes from baseline at each 
assessment time point as well as shift tables (normal, abnormal low, and abnormal high) from 
baseline to each visit for quantitative variables will be presented by treatment group and overall 
for the following clinical laboratory variables:  
Hematology 
hemoglobin, hematocrit, platelet count, red blood cell (RBC) count, white blood cell 
(WBC) count with differential, and absolute neutrophil and lymphocyte counts 
Biochemistry albumin, alanine aminotransferase (ALT), alkaline phosphatase (ALP), aspartate 
aminotransferase (AST), bicarbonate, bilirubin (total, direct, and indirect), blood 
urea nitrogen (BUN), calcium, chloride, creatinine, creatine kinase, estimated 
glomerular filtration rate (using Chronic Kidney Disease–Epidemiology 


Pegcetacoplan (APL-2) 
APL2-ALS-206 Statistical Analysis Plan 
12 April 2023 
Apellis Pharmaceuticals, Inc 
Page 52 
 
Confidential 
Collaboration [CKD-EPI] formula), gamma-glutamyltransferase (GGT), glucose, 
high-density lipoproteins (HDL), low-density lipoproteins (LDL), phosphorus, 
potassium, sodium, triglycerides, total cholesterol, total protein, and uric acid 
Urinalysis 
blood, bilirubin, glucose, ketones, leukocyte esterase, microscopic examination 
of urine sediment (including for presence of RBCs, WBCs, and casts), nitrite, 
pH, pregnancy (when applicable), protein, specific gravity, and urobilinogen. 
For hematology and biochemistry tests, the number and percentage of subjects with abnormal 
clinical laboratory test values (<lower limit of normal [LLN] or >upper limit of normal [ULN]) 
will be tabulated by treatment group and overall. For urinalysis tests, the number and percentage 
of subjects with positive results (>0, ‘positive’, or ‘+’ or greater depending on the test) will be 
tabulated by treatment group and overall. The denominator is the total number of subjects with at 
least 1 postbaseline laboratory value for the parameter. All laboratory data will be listed for the 
safety set, and out-of-range values (ie, below LLN or above the ULN will be flagged. A listing of 
all abnormal laboratory values will also be presented. 
7.4. 
Vital Signs 
Descriptive statistics for vital signs (ie, systolic and diastolic blood pressure, heart rate, respiratory 
rate, temperature, and body weight) and their changes from baseline at each post-baseline visit and 
the LOV will be presented by treatment group and overall. 
Vital sign values will be considered potentially clinically significant (PCS) if they meet the 
criteria listed in Table 4. The number and percentage of subjects with PCS post-baseline values 
will be tabulated by treatment group and overall. The percentages will be calculated relative to 
the number of subjects with baseline and at least 1 post-baseline assessment. The numerator is 
the total number of subjects with at least 1 PCS post-baseline vital sign value. A supportive 
listing of subjects with post-baseline PCS values will be provided including the subject number, 
site, baseline, and post-baseline PCS values.  
Table 4: 
Criteria for Potentially Clinically Significant Vital Signs 
Vital Sign 
Criteria 
Heart Rate 
>100 bpm 
<40 bpm 
Systolic blood pressure 
>130 mm Hg 
>160 mm Hg 
>180 mm Hg 
>20 mm Hg increase from baseline 
<90 mm Hg  
>20 mm Hg decrease from baseline 
Diastolic blood pressure 
>90 mm Hg 
>15 mm Hg increase from baseline 
<40 mm Hg 
>15 mm Hg decrease from baseline 


Pegcetacoplan (APL-2) 
APL2-ALS-206 Statistical Analysis Plan 
12 April 2023 
Apellis Pharmaceuticals, Inc 
Page 53 
 
Confidential 
Table 4: 
Criteria for Potentially Clinically Significant Vital Signs 
Vital Sign 
Criteria 
Temperature 
>38℃ 
All vital signs data will be listed for the safety set. 
7.5. 
Electrocardiogram  
Descriptive statistics for ECG variables (ventricular rate, PR interval, QRS duration, QT interval, 
and QTcF interval) and their changes from baseline at each assessment time point will be 
presented by treatment group. ECG interpretation will be summarized by visit, and a shift table 
from baseline to each visit for qualitative ECG results will be presented.  
ECG values will be considered PCS if they meet or exceed the upper limit values listed in Table 5. 
The number and percentage of subjects with post-baseline PCS values will be tabulated by treatment 
group. The percentages will be calculated relative to the number of subjects with baseline and at least 
1 post-baseline assessment. The numerator is the total number of subjects with at least 1 PCS 
post-baseline ECG value. A listing of all subjects with post-baseline PCS value will be provided 
including the subject number, site, baseline, and post-baseline PCS values. 
Table 5: 
Criteria for Potentially Clinically Significant ECG Values 
ECG Parameter 
Abnormal  
Ventricular Rate 
<40 bpm 
>100 bpm 
PR interval 
>200 msec 
QRS interval 
>120 msec 
QTcF 
>450 msec 
>480 msec 
>500 msec 
QTcF increase from baseline 
>30 msec 
>60 msec 
7.6. 
Other Safety Data 
7.6.1. 
Columbia-Suicide Severity Rating Scale (C-SSRS) 
The C-SSRS asks about suicidal ideation and behavior; at both screening and baseline, the questions 
refer to both lifetime and the past 6 months, while at postbaseline visits, the questions refer to the 
time since the previous visit. 
The C-SSRS will be categorized as follows with binary response (yes/no):  
• Suicidal ideation questions 
− Category 1 – Wish to be Dead 
 


Pegcetacoplan (APL-2) 
APL2-ALS-206 Statistical Analysis Plan 
12 April 2023 
Apellis Pharmaceuticals, Inc 
Page 54 
 
Confidential 
− Category 2 – Nonspecific Active Suicidal Thoughts 
− Category 3 – Active Suicidal Ideation with Any Methods (Not Plan) without 
Intent to Act 
− Category 4 – Active Suicidal Ideation with Some Intent to Act, without Specific 
Plan 
− Category 5 – Active Suicidal Ideation with Specific Plan and Intent 
• Suicidal behavior questions 
− Category 6 – Preparatory Acts or Behavior 
− Category 7 – Aborted Attempt 
− Category 8 – Interrupted Attempt 
− Category 9 – Actual Attempt (nonfatal) 
− Category 10 – Completed Suicide 
The number and percentage of subjects for following endpoints will be summarized by visit: 
• Suicidal ideation: A “yes” answer to any one of the 5 suicidal ideation questions  
• Suicidal behavior: A “yes” answer to any one of the 5 suicidal behavior questions  
• Suicidal ideation or behavior: A “yes” answer to any one of the 10 suicidal ideation 
and behavior questions 
For screening and baseline, both the lifetime and past 6-month intervals will be presented. 
A shift table from baseline (lifetime and past 6 months) to postbaseline (by visit and worst-case 
postbaseline) will be presented. 
All C-SSRS data will be presented in a listing. 


Pegcetacoplan (APL-2) 
APL2-ALS-206 Statistical Analysis Plan 
12 April 2023 
Apellis Pharmaceuticals, Inc 
Page 55 
 
Confidential 
7.6.2. 
Immunogenicity 
7.6.2.1. 
Sample-Level ADA Assay Data 
Number and percentage of samples will be presented for the following. Samples will be 
classified as follows: 
• Evaluable Sample – when a sample could be tested for ADA status and has a result. 
• ADA-Positive Sample – when the sample is positive in the confirmatory assay 
• ADA-Negative Sample – when the sample is negative in the screening assay or the 
confirmatory assay, and drug is at a level that does not interfere with the ADA method 
• ADA-Inconclusive Sample – when the sample is negative in the screening assay or 
the confirmatory assay, and drug is at a level that interferes with the ADA method, 
then the sample is considered inconclusive 
• Unevaluable Sample – when a sample could not be tested for ADA status due to 
inadequate sample volume, mishandling, or errors in sample collection, processing, 
storage, etc. 
• NAb Positive– when the sample is positive in the antipeptide neutralizing antibody 
assay. 
• NAb Negative - when the sample is negative in the antipeptide neutralizing antibody 
assay. 
• NAb Inconclusive- when the sample is negative in the antipeptide neutralizing 
antibody assay, and drug is at a level that interferes with the method, then the sample 
is considered inconclusive 
The titer range will also be presented for each ADA positive sample (predose, and post--dose) by 
treatment and overall. 
7.6.2.2. 
ADA Response 
Subject-level responses for anti–pegcetacoplan peptide antibodies and anti-PEG antibodies will 
be presented as a number and percentage by treatment and total. 
The number of subjects with evaluable baseline samples will be presented, and the number 
(and percentage) of those subjects who have a positive baseline sample will be presented as 
subjects with pre-existing ADA.  
Subject-level response will be summarized in the following categories:  
• Evaluable Subject – A subject with at least one sample taken with a reportable result after 
first dosing during the treatment or follow-up period. The number (percentage) of evaluable 
subjects will be presented for the following categories 
o ADA-Positive Subjects/ADA Incidence – An evaluable subject with at least one 
predose sample and one treatment-emergent or treatment-boosted ADA-positive 


Pegcetacoplan (APL-2) 
APL2-ALS-206 Statistical Analysis Plan 
12 April 2023 
Apellis Pharmaceuticals, Inc 
Page 56 
 
Confidential 
sample at any time after dosing. All ADA positive subjects are equal to the ADA 
incidence 
 Treatment-Emergent ADA response: An evaluable patient with a baseline 
ADA-negative sample and an ADA positive sample after treatment. ADA 
developed de novo. 
 Treatment Boosted ADA response: An evaluable patient with a baseline 
ADA positive sample and a postdose ADA positive sample that was ≥ 4x the 
baseline titer (eg, baseline titer of 10 vs Postdose titer of 40) 
 For treatment-emergent or treatment boosted ADA response, the following 
subcategories will be presented: 
• Transient ADA Response 
o Treatment-emergent positive subjects were classified as 
having a transient response if they had only a single ADA 
positive sample (that was not the last assessment), or more 
than 1 ADA positive sample within < 112 days (16 weeks) 
and not thereafter. 
o Treatment Boosted ADA positive subjects were classified as 
having a transient response if they had only a single ADA 
boosted sample (that was not the last assessment), or more 
than 1 positive boosted sample within < 112 days (16 weeks) 
and not thereafter. 
• Persistent ADA Response 
o Treatment-emergent positive subjects were classified as 
having a persistent response if they had more than 1 positive 
ADA sample ≥ 112 days (16 weeks) apart, or a positive ADA 
sample at the last time point with no further results available. 
o Treatment Boosted ADA positive subjects were classified as 
having a persistent response if they had more than 1 positive 
boosted sample ≥ 112 days (16 weeks) apart, or a positive 
boosted sample at the last time point with no further results 
available. 
• Unclassified ADA Response 
o Any ADA positive subject that cannot be defined as having 
a transient or persistent ADA response. 
o ADA-Negative Subject – An evaluable subject without a treatment-emergent or 
treatment-boosted ADA-positive sample during the treatment or follow-up period. 
o ADA-Inconclusive Subject – An evaluable subject who cannot be classified as 
either ADA-positive or ADA-negative (eg, assay drug tolerance issues, postdose 


Pegcetacoplan (APL-2) 
APL2-ALS-206 Statistical Analysis Plan 
12 April 2023 
Apellis Pharmaceuticals, Inc 
Page 57 
 
Confidential 
positive without a baseline sample, positive baseline and positive postdose sample 
without a titer value, etc.)  
For subjects with pre- or postdose sample results, subject response level will also be summarized 
in categories:  
• Neutralizing ADA - Any subject with a NAb positive sample. From the total subject 
population including both the evaluable and unevaluable subjects 
• ADA Prevalence – The proportion of all ADA positive subjects, including those with 
pre-existing antibodies, computed as a percentage of the total number of subjects, 
including both the evaluable and unevaluable subjects. 
7.6.3. 
Physical Exam 
Changes in physical examinations will be described in a listing. 


Pegcetacoplan (APL-2) 
APL2-ALS-206 Statistical Analysis Plan 
12 April 2023 
Apellis Pharmaceuticals, Inc 
Page 58 
 
Confidential 
8. 
PHARMACOKINETIC ANALYSIS 
All summaries and analyses of the pharmacokinetic data will be based on the Pharmacokinetic 
set defined in Section 4.6. 
8.1. 
Drug Concentration 
Individual pegcetacoplan concentrations, actual sampling times and deviations from nominal 
sampling times will be presented in a data listing for all subjects included in 
the PK population. Placebo samples will also be included in the data listing if they were analyzed 
but will not be summarized.  
PK concentrations from unscheduled visits will be listed separately. In addition, subjects undergoing 
early termination, and subjects starting/stopping treatment at various time points will be listed 
separately. 
Pegcetacoplan concentrations will be summarized by treatment group at each scheduled time 
point using descriptive statistics (including mean, SD, coefficient of variation (CV), Median, 
Min, Max, Geometric Mean/%CV). The number of subjects with a BLQ concentration at each 
scheduled time point will also be tabulated. The handling of BLQ concentrations in the summary 
tables is described in Section 8.2.1. Missing values will be omitted from the calculation of 
descriptive statistics.  
Linear and semilogarithmic individual concentration-time profiles will be generated using actual 
sampling times. Linear and semilogarithmic mean (± SD) and median concentration plots will be 
generated using nominal sampling times. The number of subjects contributing to each mean or 
median value at a visit will be presented above the x-axis. 
8.2. 
Handling BLQ Values 
8.2.1. 
Handling of BLQ Concentrations in Summary Tables 
BLQ concentrations prior to first dosing (day 1): Pretreatment pegcetacoplan concentrations 
reported as BLQ will be taken as zero for the computation of descriptive statistics, except 
geometric mean. Geometric mean cannot be calculated and will be reported as “N/A” or “-”. 
 BLQ concentrations occurring at any time after first dosing: Pegcetacoplan concentrations 
reported as BLQ will be taken as half the lower limit of quantification (LLOQ/2). 
8.2.2. 
Handling of BLQ Concentrations in Figures 
BLQ concentrations prior to first dosing (day 1): Pretreatment pegcetacoplan concentrations 
reported as BLQ will be taken as zero for linear plots, and equal to half the lower limit of 
quantification (LLOQ/2) for semilogarithmic plots. 
BLQ concentrations occurring at any time after first dosing: Pegcetacoplan concentrations 
reported as BLQ will be taken as half the lower limit of quantification (LLOQ/2) for both linear 
and semilogarithmic plots. 


Pegcetacoplan (APL-2) 
APL2-ALS-206 Statistical Analysis Plan 
12 April 2023 
Apellis Pharmaceuticals, Inc 
Page 59 
 
Confidential 
8.3. 
Statistical Analysis 
Population pharmacokinetic and exposure-response modelling of the safety and efficacy data 
will be described in an APL-2 Population Pharmacokinetic/Pharmacodynamic Analysis Plan. 
The methods will be based on the FDA Guidance for both Exposure-Response and Population 
Pharmacokinetics (FDA Guidance for Industry Population Pharmacokinetics, FDA Guidance for 
Exposure-Response Relationships). Results of PK and exposure-response modelling may be 
presented in a report separate from the clinical study report. 


Pegcetacoplan (APL-2) 
APL2-ALS-206 Statistical Analysis Plan 
12 April 2023 
Apellis Pharmaceuticals, Inc 
Page 60 
 
Confidential 
9. 
PHARMACODYNAMIC ANALYSIS 
9.1. 
Pharmacodynamic Data 
9.1.1. 
Pharmacodynamic Endpoints and Analysis 
All summaries and analyses of the pharmacodynamic (PD) data will be based on the 
pharmacodynamic set.  
Observed values, changes from baseline and percentage changes from baseline will be summarized 
by treatment group at each visit using descriptive statistics for the following parameters:  
• Change from baseline to week 52 and week 104 of CH50 levels 
• Change from baseline to week 52 and week 104 of AH50 levels 
• Change from baseline to week 52 and week 104 of C3 levels 
Median profile plots will also be presented graphically by treatment group for the observed values 
and percentage changes from baseline. The nominal sampling time will be used on the x-axis. 
Changes from baseline and percentage changes from baseline will be included in listings. 


Pegcetacoplan (APL-2) 
APL2-ALS-206 Statistical Analysis Plan 
12 April 2023 
Apellis Pharmaceuticals, Inc 
Page 61 
 
Confidential 
10. 
OTHER ANALYSES 
No other analyses are planned for this study.


Pegcetacoplan (APL-2) 
APL2-ALS-206 Statistical Analysis Plan 
12 April 2023 
Apellis Pharmaceuticals, Inc 
Page 62 
 
Confidential 
11. 
INTERIM ANALYSIS  
No formal interim analysis was planned or performed. 


Pegcetacoplan (APL-2) 
APL2-ALS-206 Statistical Analysis Plan 
12 April 2023 
Apellis Pharmaceuticals, Inc 
Page 63 
 
Confidential 
12. 
DATA MONITORING COMMITTEE/REVIEW COMMITTEE  
A DMC will review cumulative safety/tolerability and efficacy data. The DMC’s responsibilities 
include conducting a thorough safety assessment at regular predefined intervals during the 
treatment period of the study, and recommendations for plans for study conduct, which may 
include continuation, modification, or termination based on the overall assessment of potential 
risks and benefits to the subjects. 
DMC meetings will be held according to the schedule in the DMC charter. An ad hoc DMC data 
review may be recommended by the DMC or requested by the sponsor at any time during the 
study. The first DMC meeting was held after 20 subjects had completed visit 3 (study week 4). 
The remit, roles, and responsibilities of the DMC will be specified in a separate DMC charter. 


Pegcetacoplan (APL-2) 
APL2-ALS-206 Statistical Analysis Plan 
12 April 2023 
Apellis Pharmaceuticals, Inc 
Page 64 
 
Confidential 
13. 
DATA HANDLING CONVENTIONS  
13.1. 
General Data Reporting Conventions  
Continuous variables will be summarized using the following descriptive statistics:  n, mean, median, 
standard deviation, 25th and 75th percentiles, minimum, and maximum; in addition, for variables that 
are log-transformed, geometric means and 95% CIs will be presented. The SE should be added to all 
tables containing between group statistical comparisons except where variables have been 
log-transformed, in which case, geometric means and 95% CIs will be presented.  
Categorical and count variables will be summarized by the number of subjects (n) and the 
percent of subjects in each category.  
Unless otherwise specified, the estimated mean and median for a set of values should be printed 
out to 1 more decimal place than the original values, and standard deviations should be printed 
out to 2 more decimal places than the original values. The minimum and maximum should report 
the same number of decimal places as the original values. Percentages will be displayed with 
1 decimal place; except percentages will not be presented when the count is zero and 100% will 
be presented as an integer. P-values should be presented to 4 decimal places. 
13.2. 
Definition of Relative Study Days  
Unless otherwise noted, the relative study day, or analysis study day (ADAY), of an evaluation is 
defined as the number of days relative to the first dose date of study drug, which is designated as 
day 1, and the preceding day is day -1, the day before that is day -2, etc. 
If the evaluation date is on or after first dose date then the relative study day is calculated as: 
ADAY = Evaluation date − first dose date of study drug + 1.  
If the evaluation date is before the first dose date then the relative study day is calculated as  
ADAY = Evaluation date − first dose date of study drug  
Relative study day takes on negative values if the evaluation date occurs prior to the first dose date 
and takes positive values if the evaluation date occurs on or after the first dose date of study drug. 
For subjects who were randomized but not treated, the date of randomization will replace the 
first dose date of study drug in the above calculations. 
13.3. 
Mapping of Visits for Clinic SVC 
For the clinic-based SVC assessments, which are obtained via vendor data transfer outside the 
electronic data capture clinical database system, assessments will be mapped to visit numbers 
based on exact matches of SVC assessment dates to visit dates in the clinical database. 
13.4. 
Definition of Visit Windows  
13.4.1. 
All Assessments Except At-Home SVC 
All assessments occurring on or before the first date of dosing (ADAY ≤ 1) will be assigned to 
the baseline analysis visit window.  


Pegcetacoplan (APL-2) 
APL2-ALS-206 Statistical Analysis Plan 
12 April 2023 
Apellis Pharmaceuticals, Inc 
Page 65 
 
Confidential 
Unless otherwise specified, the actual scheduled nominal postbaseline visit will be used for all 
summaries across time. Postbaseline unscheduled visits and early termination visits will be 
mapped to a scheduled visit and will be used in the analysis only if the nominal scheduled visit 
result is missing. Table 6 presents the analysis visit window mapping for unscheduled and early 
term visits for assessments done every 4 weeks (ALSFRS-R, EQ-5D-5L, and ZBI), and Table 7 
presents these for assessments done at baseline and weeks 4, 12, 24, 36, and 52 (HHD, in-clinic 
SVC, ALSAQ-40, labs, and pharmacodynamics). In the case that multiple unscheduled or early 
termination visits are in the same analysis window, the one closest to the target date will be used. 
In the event that the windowed visit is mapped to an illogical sequence of visits when 
considering nearby scheduled visits (ie, windowed visit is higher than the subsequent visit or 
lower than the preceding visit), the windowed visit will be set to the logical scheduled visit. 
Table 6: 
Postbaseline Analysis Visit Windows for Unscheduled and Early 
Termination Visits for Assessments Done Every 4 Weeks 
Analysis visit 
Target study day Analysis window (days) 
Week 4 
29 
2 to 43 
Week 8 
57 
44 to 71 
Week 12 
85 
72 to 99 
Week 16 
113 
100 to 127 
Week 20 
141 
128 to 155 
Week 24 
169 
156 to 183 
Week 28 
197 
184 to 211 
Week 32 
225 
212 to 239 
Week 36 
253 
240 to 267 
Week 40 
281 
268 to 295 
Week 44 
309 
296 to 323 
Week 48 
337 
324 to 351 
Week 52 
365 
• 352 to 379 for subjects who do not enter OLP 
• 352 to OLP RxStart for subjects who do enter OLP 
Week 56 
393 
OLP RxStart to 407 
Week 60 
421 
408 to 435 
Week 64 
449 
436 to 463 
Week 68 
477 
464 to 491 
Week 72 
505 
492 to 519 
Week 76 
533 
520 to 547 
Week 80 
561 
548 to 575 
Week 84 
589 
576 to 603 


Pegcetacoplan (APL-2) 
APL2-ALS-206 Statistical Analysis Plan 
12 April 2023 
Apellis Pharmaceuticals, Inc 
Page 66 
 
Confidential 
Table 6: 
Postbaseline Analysis Visit Windows for Unscheduled and Early 
Termination Visits for Assessments Done Every 4 Weeks 
Analysis visit 
Target study day Analysis window (days) 
Week 88 
617 
604 to 631 
Week 92 
645 
632 to 659 
Week 96 
673 
660 to 687 
Week 100 
701 
688 to 715 
Week 104 
729 
716 to 729 
Note: OLP RxStart: date of first dose of open-label treatment. 
 
 
Table 7: 
Postbaseline Analysis Visit Windows for Unscheduled and Early 
Termination Visits for Assessments Done at Baseline and Weeks 4, 12, 
24, 36, and 52 
Analysis visit 
Target study day Analysis window (days) 
Week 4 
29 
2 to 57 
Week 12 
85 
58 to 127 
Week 24 
169 
128 to 211 
Week 36 
253 
212 to 309 
Week 52 
365 
• 352 to 379 for subjects who do not enter OLP 
• 352 to OLP RxStart for subjects who do enter OLP 
Note: OLP RxStart: date of first dose of open-label treatment. 
13.4.2. 
At-Home SVC 
The first at-home SVC assessment will be used as the baseline. All other assessments will be 
assigned a week value based on ADAY, which is defined relative to the study start date and is 
defined in Section 13.2. 
All summaries over time of at-home SVC will be done by week assigned by the following 
formula: 𝑊𝑊𝑊𝑊𝑊𝑊𝑊𝑊= ⌈𝐴𝐴𝐴𝐴𝐴𝐴𝐴𝐴/7⌉, for ADAY greater than the first at-home SVC assessment date, 
and where ⌈𝑥𝑥⌉ indicates the ceiling function. 
13.5. 
Derived Efficacy Endpoints  
13.5.1. 
ALSFRS-R 
The ALSFRS-R includes 12 items, with each item scored on a five-point scale from 0 to 4. 
Individual item scores will be summed to produce a total score between 0 (worst) and 48 (best). 
Assessments without all 12 items completed will be excluded from analysis only at that 
particular time point. 


Pegcetacoplan (APL-2) 
APL2-ALS-206 Statistical Analysis Plan 
12 April 2023 
Apellis Pharmaceuticals, Inc 
Page 67 
 
Confidential 
Domain-specific scores (each with 3 items and a score of 0 to 12) will also be defined as follows: 
• Bulbar function: speech, salivation, and swallowing 
• Fine Motor: handwriting, cutting food and handling utensils, and dressing and hygiene 
• Gross Motor: turning in bed and adjusting bed clothes, walking, and climbing stairs 
• Respiratory: dyspnea, orthopnea, and respiratory insufficiency 
13.5.2. 
SVC Measures 
For SVC measurements, all measurements taken on the same day will be considered from the 
same assessment, and the maximum value (based on percent predicted SVC) will be used within 
a day. This will be done separately for in-clinic and at-home assessments. 
13.5.3. 
HHD Megascore 
Double trials of HHD will be performed for each subject at each visit. In the event that the 2 
trials differ by 15% or more, and the evaluator believes that one of the trials was inaccurate for 
any reason, a third test is to be performed. All 3 values shall be recorded. The assessment used 
for analysis for each muscle group is determined as follows: 
• If there is 1 measure (m1) taken, use m1 
• If there are 2 measures (m1 and m2) taken, use max(m1, m2) 
• If there are 3 measures (m1, m2, and m3) taken: 
− If all 3 are within 15% of each other (ie, max(m1, m2, m3) / min(m1, m2, m3) ≤1.15) 
then use max(m1, m2,  m3) 
− If all 3 measures are not within 15% of each other (including cases where one or 
more measurements are zero) then 
 If there is a unique set of the closest 2 then use max(of closest 2 of m1, m2, 
and m3) 
 If there is not a unique set of the closest 2 then use max(m1, m2, m3) 
For each subject, the megascore will be determined as following: 
1. For each muscle, using the measure selected above, calculate each muscle’s z-score as 
(muscle strength – mean of muscle strength of healthy subjects) divided by standard 
deviation of muscle strength of healthy subjects (see Table 8). Subjects who are “unable 
to test” for a given muscle (not simply ‘not done’) will have that muscle scored as a 0 
(zero). 
2. Next calculate megascore as average of overall z-scores over all muscles 
In order to calculate the megascore, at least 6 of the 16 muscle groups need to be present (ie, no more 
than 10 of 16 can be missing). 


Pegcetacoplan (APL-2) 
APL2-ALS-206 Statistical Analysis Plan 
12 April 2023 
Apellis Pharmaceuticals, Inc 
Page 68 
 
Confidential 
Table 8: 
Mean Strength and Standard Deviation for Healthy Subjects 
Muscle group 
Mean (lb) 
Standard deviation (lb) 
Left shoulder flexion 
29.71 
9.27 
Right shoulder flexion 
30.89 
9.05 
Left elbow flexion 
34.79 
11.51 
Right elbow flexion 
34.99 
11.77 
Left elbow extension 
28.23 
8.74 
Right elbow extension 
28.20 
8.33 
Left wrist extension 
25.02 
8.72 
Right wrist extension 
26.49 
8.75 
Left knee extension 
35.28 
13.30 
Left knee flexion 
36.71 
13.14 
Right knee flexion 
36.97 
12.58 
Right knee extension 
35.80 
14.16 
Left ankle dorsiflexion 
38.03 
15.24 
Right ankle dorsiflexion 
38.46 
15.49 
Left first dorsal interosseous 
11.18 
3.83 
Right first dorsal interosseous 
11.79 
4.34 
The results are based on 228 healthy reported in Shefner et al. 2016. 
If kg are used, the following conversion factor will be used: 1 lb = 0.453592 kg 
13.5.4. 
ALSAQ-40 
The ALSAQ-40 contains 40 questions with each scored from 0 (never, or best) to 4 (always, 
or worst), so the total possible score ranges from 0 to 160. The 40 questions represent 5 dimensions 
of health status: 
• Physical Mobility (10 items: 1-10; possible score of 0-40) addresses problems of 
mobility such as difficulties of walking, standing up, going up and down stairs and 
falling. 
• Activities of Daily Living/Independence (10 items: 11-20; possible score of 0-40) 
addresses a variety of limitations in ADL such as difficulties in washing oneself, 
dressing oneself, doing tasks around the house, as well as difficulty writing and 
getting dressed. 
• Eating and Drinking (3 items: 21-23; possible score of 0-12): addresses problems 
eating solid foods, swallowing and drinking liquids. 
• Communication (7 items: 24-30; possible score: 0-28) addresses a variety of 
problems communicating with others such as difficulties with speech such as talking 
slowly, stuttering whilst speaking and feeling self-conscious about speech. 


Pegcetacoplan (APL-2) 
APL2-ALS-206 Statistical Analysis Plan 
12 April 2023 
Apellis Pharmaceuticals, Inc 
Page 69 
 
Confidential 
• Emotional Functioning (10 items: 31-40; possible score: 0-40) addresses various 
emotional problems such as feeling lonely, bored, depressed, as feeling of 
embarrassment in social situations and feeling worried about the disease will progress 
in the future. 
The total score and the score of each dimension will be scaled to have a range from 0 (the best 
health status) to 100 (the worst health status) and will be calculated as: 
𝑆𝑆𝑆𝑆𝑆𝑆𝑆𝑆𝑆𝑆𝑆𝑆 𝑆𝑆𝑆𝑆𝑆𝑆𝑆𝑆𝑆𝑆 = 
𝑠𝑠𝑠𝑠𝑠𝑠 𝑜𝑜𝑓𝑓 𝑟𝑟𝑟𝑟𝑟𝑟 𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠 𝑖𝑖𝑖𝑖 𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑 [or total]
𝑚𝑚𝑚𝑚𝑚𝑚 𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝 𝑠𝑠𝑠𝑠𝑠𝑠 𝑜𝑜𝑜𝑜 𝑟𝑟𝑟𝑟𝑟𝑟 𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠 𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑 [or total] × 100 
13.5.5. 
EQ-5D-5L 
The EQ5D5L contains 2 components: the VAS, which is scored between 0 and 100, and the 5 
questions, each with 5 levels. 
The VAS will be summarized and analyzed as a simple numeric score. 
13.5.6. 
ZBI 
The ZBI is a 22-item self-reported measurement of caregiver burden. The caregiver responds to each 
item regarding the impact of the subject’s disability on their life using a 5-point scale from 0 (Never) 
to 4 (Nearly Always). The total minimal score is 0 and the maximum score is 88, with higher scores 
signifying increased burden.  
13.6. 
Repeated or Unscheduled Assessments of Safety Parameters  
If a subject has repeated assessments before the start of investigational product, then the results 
from the final assessment made prior to the start of investigational product will be used as 
baseline. If end of study assessments are repeated or unscheduled, the last postbaseline 
assessment will be used as the end of study assessment for generating descriptive statistics. 
However, all postbaseline assessments will be used for PCS value determination and all 
assessments will be presented in the data listings. 
13.7. 
Handling of Missing, Unused, and Spurious Data  
Missing data is addressed in the relevant sections elsewhere. Spurious data will be discussed with 
data management and others as appropriate to address with queries to sites or vendors. In general, 
all data will be used as reported (and after query resolutions); any decisions to remove data would be 
made and documented prior to unblinding. 
13.7.1. 
Missing Date of Investigational Product 
When the date of the last dose of investigational product is missing for a subject in the safety set, 
all efforts should be made to obtain the date from the investigator. If it is still missing after all 
efforts, then the last visit date when investigational product was returned will be used in the 
calculation of treatment duration. 


Pegcetacoplan (APL-2) 
APL2-ALS-206 Statistical Analysis Plan 
12 April 2023 
Apellis Pharmaceuticals, Inc 
Page 70 
 
Confidential 
13.7.2. 
Missing Date Information for Prior or Concomitant Medications 
(Therapies/Procedures) 
For prior or concomitant medications (and/or therapies/procedures), including rescue medications, 
incomplete (ie, partially missing) start date and/or stop date will be imputed. When the start date and 
the stop date are both incomplete for a subject, the start date first will be imputed first. 
13.7.2.1. Incomplete Start Date  
The following rules will be applied to impute the missing numerical fields. If the stop date is 
complete and the imputed start date is after the stop date, then the start date will be imputed 
using the stop date. 
13.7.2.1.1. Missing Day, Month, and Year 
In this case, no start date will be imputed. However, the medication will be assumed to be a prior 
medication. If the stop date is missing or if the stop date is on or after the date of the first dose of 
investigational product, the medication will also be considered a concomitant medication. 
13.7.2.1.2. Missing Day and Month 
• If the year of the incomplete start date is the same as the year of the date of the first 
dose of investigational product, then the day and month of the date of the first dose of 
investigational product will be assigned to the missing fields 
• If the year of the incomplete start date is before the year of the date of the first dose of 
investigational product, then December 31 will be assigned to the missing fields 
• If the year of the incomplete start date is after the year of the date of the first dose of 
investigational product, then 01 January will be assigned to the missing fields. 
13.7.2.1.3. Missing Month Only 
• The day will be treated as missing and both month and day will be replaced according 
to the above procedure. 
13.7.2.1.4. Missing Day Only 
• If the month and year of the incomplete start date are the same as the month and year 
of the date of the first dose of investigational product, then the day of the date of the 
first dose of investigational product will be assigned to the missing day 
• If either the year is before the year of the date of the first dose of investigational 
product or if both years are the same but the month is before the month of the date of 
the first dose of investigational product, then the last day of the month will be 
assigned to the missing day 
• If either the year is after the year of the date of the first dose of investigational 
product or if both years are the same but the month is after the month of the date of 
the first dose of investigational product, then the first day of the month will be 
assigned to the missing day. 


Pegcetacoplan (APL-2) 
APL2-ALS-206 Statistical Analysis Plan 
12 April 2023 
Apellis Pharmaceuticals, Inc 
Page 71 
 
Confidential 
13.7.2.2. Incomplete Stop Date  
The following rules will be applied to impute the missing numerical fields. If the date of the last 
dose of investigational product is missing, then replace it with the last visit date. If the imputed 
stop date is before the start date (imputed or nonimputed start date), then the imputed stop date 
will be equal to the start date. 
13.7.2.2.1. Missing Day and Month 
• If the year of the incomplete stop date is the same as the year as of the date of the last 
dose of investigational product, then the day and month of the date of the last dose of 
investigational product will be assigned to the missing fields 
• If the year of the incomplete stop date is before the year of the date of the last dose of 
investigational product, then 31 December will be assigned to the missing fields 
• If the year of the incomplete stop date is after the year of the date of the last dose of 
investigational product, then 01 January will be assigned to the missing fields. 
13.7.2.2.2. Missing Month Only 
• The day will be treated as missing and both month and day will be replaced according 
to the above procedure. 
13.7.2.2.3. Missing Day Only 
• If the month and year of the incomplete stop date are the same as the month and year 
of the date of the last dose of investigational product, then the day of the date of the 
last dose of investigational product will be assigned to the missing day 
• If either the year is before the year of the date of the last dose of investigational 
product or if both years are the same but the month is before the month of the date of 
the last dose of investigational product, then the last day of the month will be 
assigned to the missing day 
• If either the year is after the year of the last dose of investigational product or if both 
years are the same but the month is after the month of the date of the last dose of 
investigational product, then the first day of the month will be assigned to the 
missing day. 
13.7.3. 
Missing Date Information for Adverse Events  
For AEs with partial start dates, nonmissing date parts will be used to determine if the AE is 
treatment-emergent or not. If a determination cannot be made using the nonmissing date parts as 
to when the AE occurred relative to study drug administration, eg, AE start year and month are 
the same as the year and month of the first dose of investigational product, then the AE will be 
classified as treatment-emergent. 
To facilitate categorization of AEs as treatment emergent, imputation of dates can be used. 
For AEs, the default is to only impute incomplete (ie, partially missing) start dates. Incomplete 
stop dates may also be imputed when calculation of the duration of an AE is required per the 
protocol. If imputation of an incomplete stop date is required, and both the start date and the stop 
date are incomplete for a subject, impute the start date first. 


Pegcetacoplan (APL-2) 
APL2-ALS-206 Statistical Analysis Plan 
12 April 2023 
Apellis Pharmaceuticals, Inc 
Page 72 
 
Confidential 
13.7.3.1. Incomplete Start Date  
Follow the same rules as in Section 13.7.2.1, except in the case where the start date is completely 
missing (ie, missing day, month, and year): 
• If the stop date is missing or is on or after the date of the first dose of investigational 
product, the start date will be set to the date of the first dose of investigational product. 
• If the stop date is before the date of the first dose of investigational product, the start 
date will be set to stop date. 
13.7.3.2. Incomplete Stop Date  
Follow the same rules as in Section 13.7.2.2. 
13.7.4. 
Missing Date Information for Dates of ALS Symptom Onset or Disease 
Diagnosis 
Missing dates for ALS symptom onset and disease diagnosis will be imputed as follows: 
• Missing day and month: ‘02-July’ will be imputed for day-month 
• Missing day: ‘15’ will be imputed for day. 
If these imputations result in a symptom onset date after the diagnosis date, the symptom onset 
date will be set equal to the diagnosis date. 
13.7.5. 
Missing Severity Assessment for Adverse Events  
If severity is missing for an AE starting prior to the date of the first dose of investigational 
product, then a severity of “Mild” will be assigned. If the severity is missing for an AE starting 
on or after the date of the first dose of investigational product, then a severity of “Severe” will be 
assigned. The imputed values for severity assessment will be used for incidence summaries, 
while the actual values will be used in data listings. 
13.7.6. 
Missing Relationship to Investigational Product for Adverse Events  
If the relationship to investigational product is missing for an AE starting on or after the date of 
the first dose of investigational product, a causality of “Related” will be assigned. The imputed 
values for relationship to double-blind investigational product will be used for incidence 
summaries, while both the actual and the imputed values will be presented in data listings. 
13.7.7. 
Character Values of Clinical Laboratory Variables 
For numeric laboratory values below an LOD (eg, reported as “<LOD”), a value of 𝐿𝐿𝐿𝐿𝐿𝐿/√2 will 
be used for descriptive statistics, shift tables and PCS values. For values above a limit of 
quantification, LOQ (eg, reported as “>LOQ”), a value of 𝐿𝐿𝐿𝐿𝐿𝐿+ 0.0000000001 will be used 
for descriptive statistics, shift tables and PCS values. However, the actual values as reported in 
the database will be presented in data listings. 


Pegcetacoplan (APL-2) 
APL2-ALS-206 Statistical Analysis Plan 
12 April 2023 
Apellis Pharmaceuticals, Inc 
Page 73 
 
Confidential 
14. 
ANALYSIS SOFTWARE  
Statistical analyses will be performed using version 9.4 (or newer) of SAS on a suitably 
qualified environment. 


Pegcetacoplan (APL-2) 
APL2-ALS-206 Statistical Analysis Plan 
12 April 2023 
Apellis Pharmaceuticals, Inc 
Page 74 
 
Confidential 
15. 
CHANGES TO ANALYSIS SPECIFIED IN PROTOCOL 
The following changes were made to the analyses specified in the protocol. 
• The protocol stated that baseline for % predicted SVC from home spirometry was the 
first assessment which could be done after the first dose of study treatment. However, 
baseline for home SVC is required to be prior to first dose of study treatment. 
• For the time to death, permanent tracheostomy, or permanent assisted ventilation 
endpoint, the protocol stated: “Subjects who were randomized but who not receive 
any treatment will be censored at the randomization date.” However, given theses 
analyses will be based on the ITT population, which includes all randomized subjects, 
any postbaseline observations will be used in the analysis. 
• The MMRM models for continuous outcomes did not include the visit-by-baseline 
interaction term; this has been added; otherwise, if this term were not included, the 
effect of baseline on the outcome is assumed to be the same at all visits. 


Pegcetacoplan (APL-2) 
APL2-ALS-206 Statistical Analysis Plan 
12 April 2023 
Apellis Pharmaceuticals, Inc 
Page 75 
 
Confidential 
16. 
REFERENCES 
Berry JD, Miller R, Moore DH, Cudkowicz ME, Van Den Berg LH, Kerr DA, et al. The Combined 
Assessment of Function and Survival (CAFS): A new endpoint for ALS clinical trials. 
Amyotroph Lateral Scler Front Degener. 2013;14(3):162-168. doi: 10.3109/21678421.2012.762930 
Cox DR. Regression models and life-tables. J R Stat Soc Series B Stat Methodol. 1972; 34(2):187-
220. doi: 10.1111/j.2517-6161.1972.tb00899.x 
Diggle PJ, Liang K-Y, Zeger SL. Analysis of longitudinal data. 1994. Oxford: Clarendon Press. 
Kaplan EL and Meier P. Nonparametric estimation from incomplete observations. J Amer Stat 
Assoc. 1958;53(282):457-81. doi: 10.1080/01621459.10501452 
O’Kelly M and Ratitch B. Clinical trials with missing data: a guide for practitioners. 2014. Wiley. 
Chapter 7.  
Rubin DB. Multiple imputation for nonresponse in surveys. 1987. New York: Wiley. 
Shefner JM, Liu D, Leitner M, Schoenfeld D, Johns D, et al. Quantitative strength testing in ALS 
clinical trials. Neurol. 2016; 87(6): 617–624. doi: 10.1212/WNL.0000000000002941