APELLIS R&D DAY

APELLISR&D DAYJune 30, 2021

A N D T H E Y ’ R E O F F !

APELLISR&D DAY

A N D T H E Y ’ R E O F F ! Welcome!

Cedric Francois, M.D., Ph.D.

Chief Executive Officer

Apellis Pharmaceuticals

APELLIS PROPRIETARY INFORMATION / FOR APELLIS USE ONLY

3

Statements in this presentation about future expectations, plans

and prospects, as well as any other statements regarding matters

that are not historical facts, may constitute “forward-looking

statements” within the meaning of The Private Securities Litigation

Reform Act of 1995. These statements include, but are not limited

to, statements relating to the implications of preliminary clinical

data. The words “anticipate,” “believe,” “continue,” “could,”

“estimate,” “expect,” “intend,” “may,” “plan,” “potential,” “predict,”

“project,” “should,” “target,” “will,” “would” and similar expressions

are intended to identify forward-looking statements, although not all

forward-looking statements contain these identifying words. Actual

results may differ materially from those indicated by such forward-

looking statements as a result of various important factors,

including: whether the company’s clinical trials will be fully enrolled

and completed when anticipated; whether preliminary or interim

results from a clinical trial will be predictive of the final results of the

trial; whether results obtained in preclinical studies and clinical

trials will be indicative of results that will be generated in future

clinical trials; whether pegcetacoplan will successfully advance

through the clinical trial process on a timely basis, or at all; whether

the results of the company’s clinical trials will warrant regulatory

submissions and whether pegcetacoplan will receive approval from

the FDA or equivalent foreign regulatory agencies for GA, PNH,

CAD, C3G, IC-MPGN, ALS or any other indication when expected

or at all; whether, if Apellis’ products receive approval, they will be

successfully distributed and marketed; and other factors discussed

in the “Risk Factors” section of Apellis’ Annual Report on Form 10-

K filed with the Securities and Exchange Commission on April 28,

2021 and the risks described in other filings that Apellis may make

with the Securities and Exchange Commission. Any forward-

looking statements contained in this press release speak only as of

the date hereof, and Apellis specifically disclaims any obligation to

update any forward-looking statement, whether as a result of new

information, future events or otherwise.

Forward-Looking Statements


4

Disclosures

B r u n o F a t t i z z o , M . D . Consultancy honoraria: Alexion, Amgen, Apellis, Momenta, and Novartis

A n g e l a G e n g e , M . D . Executive director CRU Montreal Neurological Institute and ALS center of Excellence

On Advisory boards of following companies: Alexion, Apellis, AL-S Pharma, ArgenX, Biogen, Amylyx,

Calico, UCB, Roche, Sanofi, Regeneron, UCB, MTPA

On DSMB:AZT therapeutics, Clene

Consulting CMO: Quralis

Chair Scientific Advisory Committee of CATALIS

N a n c y M . H o l e k am p , M . D .

Consultant: Allergan, Acucela, Apellis, Bayer, Lineage Cell Therapeutics, Clearside Biosciences,

Gemini, Genentech, Gyroscope, Katalyst Surgical, Nacuity, Notal Vision, Novartis, Polyactiva, Regeneron

• Speakers Bureau: Allergan, Genentech, Novartis, Regeneron, Spark

• Contracted Research: Genentech, Gemini, Gyroscope, Notal Vision

• Intellectual Property/Patent: Katalyst Surgical

M a t t hew P i c k e r i ng , P h . D . ,

M . B . , B . S .

Apellis Pharmaceuticals, Alexion Pharmaceuticals, Gemini Therapeutics, Gyroscope Therapeutics

I l e n e W e i t z , M . D . Honoraria, consultancy: Alexion, Apellis

Speakers bureau: Alexion


5

Disclosures

C h a r l e s W yk o f f , M . D . , P h . D . Consulting: Adverum, Aerie Pharmaceuticals, Allergan, Allgenesis, Apellis, Arctic Vision, Arrowhead

Pharmaceuticals, Bausch + Lomb, Bayer, Bionic Vision Technologies, Chengdu Kanghong

Biotechnologies (KHB), Clearside Biomedical, EyePoint Pharmaceuticals, Genentech, Gyroscope, IVERIC

Bio, Kato Pharmaceuticals, Kodiak Sciences, Long Bridge Medical, NGM Biopharmaceuticals, Novartis,

OccuRx, Ocular Therapeutix, ONL Therapeutics, Opthea Limited, Oxurion, Palatin, PolyPhotonix,

RecensMedical, Regeneron, RegenXBio, Roche, SAI MedPartners, Surrozen Takeda, Verana Health

Research: Adverum, Aerie Pharmaceuticals, Aldeyra, Alimera Sciences, Allergan, Amgen, Apellis, Asclepix,

Bayer, Boehringer Ingelheim, Chengdu Kanghong Biotechnology, Clearside Biomedical, Gemini,

Genentech, Graybug Vision, Gyroscope, IONIS Pharmaceutical, iRENIX, IVERIC bio, Kodiak Sciences,

LMRI, Neurotech Pharmaceuticals, NGM Biopharmaceuticals, Novartis, Oxurion, RecensMedical,

Regeneron, RegenXBio, Roche, SamChunDang Pharm, Taiwan Liposome Company, Xbrane BioPharma

Ownership/Stock: ONL Therapeutics, PolyPhotonix, RecensMedical, Visgenx

A p e l l i s / S o b i C o l l a b o ra t i on Sobi has global co-development and ex-U.S. commercialization rights for systemic pegcetacoplan


6

Growing Our Pipeline for Long-Term Leadership in Complement

Transforming Treatment

across Rare, Complement-

Driven Diseases Be #1 in the Retina

Building a Portfolio

of Brain-Active

Complement Therapies

APELLIS:

Global Leader

in Complement


7

• EMPAVELI™ (pegcetacoplan) launch off to strong start

• Platform potential for EMPAVELI with four new registrational programs

• New molecular entities in development to sustain long-term growth in existing and new indications

Global Leader in Complement, Today and Tomorrow

R A R E D I S E A S E

N E U R O L O G Y

O P H T H A L M O L O G Y

• Optimistic heading into DERBY and OAKS readout in September 2021

• Significant unmet need and blockbuster opportunity

• New molecular entities in development in GA, wet and intermediate AMD

• C3 plays a key role in a wide range of neurodegenerative conditions

• Apellis to pioneer targeted C3 therapies in neurodegeneration


APELLISR&D DAY


Transforming Treatment

across Rare, Complement-

Driven Diseases

Victoria Brown

Senior Vice President, Rare Disease Program Executive



9

Transforming Treatment Across Rare,

Complement-Driven Diseases


10

• Advance four additional

registrational programs

Expand Rare Disease

Portfolio

Transforming Treatment Across Rare, Complement-Driven

Diseases

• Ensure access for adults

with PNH

Establish EMPAVELI in PNH

• Launch Enable device

• Develop siRNA +

EMPAVELI

• Develop oral alternative

pathway inhibitor

Enhance Patient Experience

& New Indications


11



Expand Rare Disease

Portfolio


Diseases


with PNH



• Develop siRNA +

EMPAVELI


pathway inhibitor


& New Indications


IC-MPGN

/ C3GPNH ALS HSCT-TMACAD

Paroxysmal Nocturnal

Hemoglobinuria (PNH)

David Acheson

Senior Vice President, North America Commercial



13

U.S. Launch Priorities Driving Strategic Activities

Ensure EMPAVELI commercial supply

Establish Apellis & the PNH unmet need

Ensure patient access and reimbursement

Leverage the clinical data to differentiate the brand


14

Early Indicators Confirm Unmet Need for PNH Patients

McKinley ASH 2017 Abstract/p2/para2/L1-6; Dingli ASH 2020 Abstract/ p.1/ Methods/ ln.1-2; p.2/ Results/ln.7-9; ln.14-15

14

E A R LY P O S I T I V E I N D I C AT O R SPAT I E N T S E G M E N T S

Congratulations to Apellis, I’m

excited to start patients on therapy KOL at a major PNH

treatment center

I will be following up with my physician,

as I was not aware of EMPAVELI until

receiving the “Now Approved” emailPNH Patient

You guys (Apellis) are the poster child

of what good looks like in the pharma/biotech spaceLead, Pharmacy Trade Relations at a

major pharmacy benefits manager

Hemoglobin near or at

normal levels

Transfusions to

address falling

hemoglobin

Hemoglobin

below normal

and symptoms

like fatigue

Initial Area

of Focus

U.S. PNH patients

on C5 inhibitors

1,500Newly diagnosed eligible PNH

patients in the U.S. annually

150


15

Market Access Team Having Significant Early Impact

15

O U R M A R K E T A C C E S S P R I O R I T I E S

EMPAVELI demonstrated superior clinical

efficacy in improving hemoglobin levels

compared to Soliris® (eculizumab) in a

head-to-head trial

We expect costs will be reduced to the

healthcare system by switching patients to

EMPAVELI (e.g., avoidance of transfusions

& hospitalizations)1

Apellis is committed to ensuring that every

eligible patient who wants EMPAVELI will

have access regardless of ability to pay

E NS URI NG A CCE S S

C L I N I C A L E F F I C A C Y

R E M O V I N G C O S T S

of our “Top 20” payers

have received EMPAVELI

clinical presentations

of PNH patients

reside in 20 health

plans or PBMs

Major payers have

accelerated EMPAVELI

formulary reviews

4

85%100%

Payer has already

placed EMPAVELI

on formulary

1


16

Patient Journey & Early Lead Indicators

25%

50%

25%

EMPAVELI-Treated Patients

by Payer Segment

Early Launch Days from

Prescription to First Dose

Physician Enrollment in REMS

Since Launch

7-10 >50

MEDICAID MEDICARE

COMMERCIAL

Have had RXs from all three payer channels

submitted & approved


17

Great Start for EMPAVELI Launch

17

Product in channel within 5 days

90% of top payers have received clinical

presentations

Sales organization live meetings have

increased to 38% from 8% post-PDUFA

>50 physicians have enrolled in REMS

90% of payer formulary reviews to be

complete

Engage 100% of priority accounts via

Apellis sales organization

T O D A Y Q 4 2 0 2 1

Engage 85% of priority physicians via

Apellis sales organization

Maintain & enhance high patient

confidence score for self-infusion within

2 weeks on therapy

ApellisAssist early operational

effectiveness is rated high by patients

O R G A N I Z A T I O N F O C U S I S O N 2 K H C P S & 9 0 T A R G E T E D T R E A T M E N T C E N T E R S


Q&A with Dr. Ilene Weitz

Ilene Weitz, M.D.

Hematology Specialist, Professor of Clinical

Medicine

Keck School of Medicine at the University of

Southern California

Monica Fay

Senior Vice President, Medical Affairs



19



Expand Rare Disease

Portfolio


Diseases


with PNH



• Develop siRNA +

EMPAVELI


pathway inhibitor


& New Indications


IC-MPGN

/ C3GPNH HSCT-TMACAD

Immune Complex Membranoproliferative

Glomerulonephritis (IC-MPGN) /

C3 Glomerulopathy (C3G)

ALS

Matthew Pickering, Ph.D., M.B., B.S.

Professor of Rheumatology and Wellcome Trust Senior Fellow in Clinical Science

Imperial College London via Imperial Consultants


21

IC-MPGN and C3G are Rare, Chronic, Complement-Mediated

Glomerular Diseases Resulting in Kidney Damage and Failure

• MPGN pattern of injury

• Complement alternative and

classical pathway implicated

• Immunoglobulin deposition

dominant or co-dominant

with C3

• Complement alternative pathway

implicated

• C3-dominant glomerular deposits

• Two subtypes

– DDD

– C3GN

• Similar clinical presentation, features, and disease course

• Heterogenous disease pathology (i.e., genetic or acquired)

M P G N C 3 G L O M E R U L O PAT H Y

C3 & immunoglobulin

depositionDominant C3 deposition

Overlap of MPGN and C3 Glomerulopathy

Dense

deposit

disease

FHR5

nephropathy

Adapted from: JASN January 2018, 29 (1) 9-1

C3GN


22

Key Clinical Signs and Symptoms

• Proteinuria and/or hematuria

• Low serum C3

• Decreased GFR

• High blood pressure

Key Pathological Findings

• Positive C3 staining

– C3G and IC-MPGN

• IC-MPGN also has Ig deposition

No Disease-Modifying Treatments

No Approved Treatments for IC-MPGN or C3G

Illustrative. Adapted from Kidney International (2014) 85, 450–456

C3

IgG


23

• ~18,000 patients in US and EU with primary C3G or

IC-MPGN

• ~50% of patients progress to ESRD in 5-10 years and

require chronic dialysis or transplant

• Kidney transplantation is not curative. Disease

recurrence has been reported in as many as 85%

transplanted patients

• Proteinuria is an important marker of renal

damage and the key clinical marker, along with GFR,

used by clinicians to measure progression of the

disease

IC-MPGN and C3G Represent Areas of High Unmet Need

Garam et al. Clin Kidney J. 2020

C3GN

DDD

IC-MPGN


24

IC-MPGN/C3G Interferes with Life Physically and Emotionally

“Physically, I gained weight in the beginning because of this

disease.”

“With C3G being such a rare disease, I am often faced with

new challenges that do not have solutions.”

“Mentally, the medication that I was taking made it hard

for me to focus.”


25

EMPAVELI Targets C3 for Comprehensive Control of

IC-MPGN and C3G

C3

Alternative

Pathway

Classical

Pathway

Lectin

Pathway

C3a Structural damage to kidney

MAC

C3b

C5a C5b

C5

STOP STOP

STOP STOP

E M PAV E L I

Inflammation

Inflammation

Co

ntro

ls a

ll do

wn

stre

am

effe

cts

Structural damage to kidney


26

Phase 2 DISCOVERY Design and Study Goals

C3G, C3 glomerulopathy; CKD-EPI, Chronic Kidney Disease Epidemiology Collaboration; eGFR, estimated glomerular filtration rate; Q2W, every 2 weeks; QD, once daily; TEAE,

treatment-emergent adverse event; uPCR, urine protein to creatinine ratio.

1. Levey et al. Ann Intern Med. 2009;150:604-612.

48 weeks

EMPAVELI 360 mg QD SCTransition to 1080 mg Q2W ≥week 24N=8 C3G patients

Primary

endpoint

readoutScreening

4 weeks 24 weeks

Long-term

extension

APL2-201; NCT03453619

Population: Biopsy-confirmed adult

or adolescent patients with C3G or

biopsy-confirmed adult patients with

IgAN, LN, or primary MN

Primary endpoint: Change from

baseline in proteinuria as quantified

by uPCR

Secondary endpoints include:

Change in estimated glomerular

filtration rate and serum complement

markers, including C3


27

EMPAVELI Demonstrated 73% Reduction in Mean Proteinuria

as Measured by 24h uPCR at Week 48 in DISCOVERY

Treatment with EMPAVELI resulted in proteinuria reduction at week 48

Figure error bars represent standard error. Five patients were included at each time point.

CFB, change from baseline; uPCR, urine protein to creatinine ratio. A Normal ranges for each parameter: first morning uPCR, <0.200 mg/mg, serum albumin, 3.5 -5.50 g/dL; B Baseline was the most recent result before the first dose.C eGFR was calculated using the CKD-EPI creatinine equation

Parameter, mean (SE), [range]a

Baselineb

(N=5)

Week 48

(N=5)

24-hour uPCR, mg/mg 3.48 (0.82)

[1.74, 6.55]

0.93 (0.27)

[0.34, 1.69]

Percentage CFB in 24-hour

uPCR

NA -67.73 (10.50)

[-94.12, -37.31]

Serum albumin, g/dL 3.50 (0.30)

[2.40, 4.10]

4.08 (0.24)

[3.30, 4.60]

eGFRc, mL/min/1.73 m2 88.00 (22.61)

[29.00, 138.00]

86.60 (20.44)

[41.00, 142.00]

Decreased uPCR, increased serum albumin, and

stable renal function were observed at week 48

-100

-80

-60

-40

-20

0

0 48

Cha

nge

fro

m b

ase

line

in m

ea

n 2

4-h

ou

r u

PC

R, %

Week

Patient 1

Patient 2

Patient 3

Patient 4

Patient 9

Mean

APL2-201; NCT03453619


28

Phase 2 DISCOVERY Study: EMPAVELI Targets Underlying

Disease Process of C3G

Serum C3 levels increased after initiation of EMPAVELI

Graphed error bars represent standard error. Normal ranges are indicated by shading: serum C3, 90 -180 mg/dL

a Normal ranges for each of the biomarkers: serum C3, 0.94 -1.66 mg/mL; CH50, 176-382 U/mL; AH50, 77-159 U/mL. b Baseline was the most recent result before the

first dose.

Biomarker, mean (SD), [range]a Baselineb Week 48

Serum C3, mg/mL 61.60 (20.42)

[11.00, 116.00]

252.00 (52.82)

[82.00, 407.00]

Serum C4, mg/dL 19.20 (4.22)

[5.00, 31.00]

17.75 (2.17)

[14.00, 22.00]

CH50, U/mL 183.40 (53.17)

[23.00, 298.00]

214.00 (12.52)

[190.00, 248.00]

AH50, U/mL 62.00 (25.59)

[0.00, 113.00]

60.75 (22.40)

[0.00, 96.00]

Levels of key complement biomarkers increased from baseline to week 48

0

100

200

300

400

500

-4 0 4 8 12 16 20 24 28 32 36 40 44 48

Se

rum

C3

, m

g/d

L

Week

APL2-201; NCT03453619


29

EMPAVELI Safety Profile in C3G Cohort of DISCOVERY

There were no discontinuations due to treatment emergent adverse events

(TEAEs) and no serious or severe adverse events

The majority of TEAEs were considered unrelated to study drug

APL2-201; NCT03453619


30

Phase 2 Study in Post-Transplant Recurrence Is Ongoing

and Phase 3 Study Is Expected to Initiate in 2H21

I C - M P G N / C 3 G PAT I E N T J O U R N E Y

S E V E R EP O S T- T R AN S P L AN T

R E C U R R E N C E

Ph 3 study

population

Ph 2 and

Ph 3 study

population

E S R D & K I D N E Y

T R AN S P L AN T

P H A S E 3 I C - M P G N / C 3 G S T U D Y G O A L S :

Assess functional

outcomes

Evaluate impact on

key disease

parameters

Evaluate efficacy

through proteinuria

Evaluate safety and

tolerability

M I L D


31

Key Takeaways

IC-MPGN and C3G are rare, chronic, complement-mediated diseases resulting in

kidney damage and failure with no approved therapies

Excessive deposition of C3 breakdown products in the kidney is the primary driver of

kidney damage in patients with IC-MPGN and C3G

EMPAVELI achieved proof of concept in C3G by demonstrating a 73% reduction in

mean proteinuria at 48 weeks

Phase 2 study ongoing; Phase 3 expected to initiate in 2H21


IC-MPGN

/ C3GPNH ALS HSCT-TMACAD

Amyotrophic Lateral

Sclerosis (ALS)

Angela Genge, M.D., FRCP(C)

Executive Director, Clinical Research Unit & Director of ALS Center of Excellence

Montreal Neurological Institute


33

2/3 initially present with muscle weakness of the limbs2

1/3 initially present with difficulty with speech and swallowing2

1 Brown RH and Al-Chalabi A. N Engl J Med 2017; 377:162-72. Arthur KC, et al. Nat Commun 2015 Aug 11;7:12408. Brown RH and Al-Chalabi A. N Engl J Med 2017;377:162-72

Significant Unmet Need for People Living with ALS

ALS is a fatal neurodegenerative disorder, characterized by

progressive loss of upper and lower motor neurons1

Currently, no treatment targets the neuroinflammation

caused by an overactive immune response

ALS affects 225,000 people globally. ~90% of cases are

sporadic and death typically occurs 3-5 years from

disease onset1,2


34

Extensive evidence suggests that complement activation plays a role in disease progression:

• Disease progression is correlated with elevated C3

• Complement C3 is elevated in the serum, brain, and spinal cord compared to nonaffected controls

• Individuals with ALS have high levels of activated C3 at the neuromuscular junction where neurons communicate directly to muscle cells

Kjældgaard AL, Pilely K, Olsen KS, et al. J Inflamm Res. 2021;14:1043-1053; Sta M, et al. Neurobiol Dis. 2011;42(3):211-220; Goldknopf IL, et al. Biochem Biophys Res Commun. 2006;342(4):1034-1039;

Ganesalingam J, et al. J Neurochem. 2011;117(3):528-537’ El Idrissi NB, et al. J Neuroinflamm. 2016;13(1):72.

Complement-Mediated Neuroinflammation Is a Key Driver of

Neurodegeneration

Brain

Spinal Cord

N E U R O M U S C U L A R S Y S T E M

Peripheral nerves

NMJ

Terminal

Schwann Cell

Muscle

C3


35El Idrissi N, et al. J Neuroinflammation. 2016;13(1):72

Complement C3 and its Breakdown Products Are Deposited at

the Neuromuscular Junctions of People with ALS

Control ALS

Motor Nerve Terminal Motor nerve terminal + C3/C3b

Terminal Schwann Cell

Terminal Schwann Cell + C3/C3b


36

EMPAVELI Targets C3 to Slow Disease Progression in ALS

C3

Alternative

Pathway

Classical

Pathway

Lectin

Pathway

C3a Neurodegeneration

MAC

C3b

C5a C5b

C5

STOP STOP

STOP STOP

Co

ntro

ls a

ll do

wn

stre

am

effe

cts

E M PAV E L I

Neuroinflammation


37

MERIDIAN: Phase 2 Study in ALS Expected to Complete

Enrollment by End of 2021

EMPAVELI1080mg SC twice weekly N=152

Primary

endpoint

readoutScreening

52 weeks

Open-label

extension

Placebo SC twice weekly

N=76

2:1

R

AN

DO

MIZ

AT

IO

N

52 weeks

EMPAVELI

APL2-ALS-206; NCT04579666

Population: Adult patients with

sporadic ALS

Primary endpoint: Combined

Assessment of Function and

Survival (CAFS) rank scores

Secondary endpoints include:

Measures of lung function, muscle

strength, and quality of life


38

Key Takeaways

Urgent and significant need for treatments for ALS, a fatal neurodegenerative disorder

Evidence suggests complement activation and elevated levels of C3 play a role in

disease progression

Controlling complement activation centrally at C3 with EMPAVELI may have the

potential to slow the progression of ALS

Phase 2 enrollment completion expected by the end of 2021


IC-MPGN


Cold Agglutinin Disease

(CAD)

Bruno Fattizzo, M.D.

Professor, Consultant Hematologist and Clinical Researcher

Fondazione IRCCS Ca' Granda Policlinico Hospital, Milan, Italy


40

D I S E A S E B A C K G R O U N D :

• Chronic and severe red blood disorder

• Exacerbation of the condition in a cold environment

• Primarily affects older adults (age 50+)

• Symptoms include

– Hemolytic anemia and fatigue

– Transfusion requirements

– Cold-induced circulatory symptoms

– Increased risk of thrombotic events like stroke or heart attack

Cold Agglutinin Disease (CAD) Is a Chronic and Severe

Blood Disorder with No Approved Therapies


41

Phase 2 PLAUDIT Study Design

48 weeks

Randomized 1:1

EMPAVELI Daily 360mg QD SC

N=6

EMPAVELI Daily 270mg QD SCN=7

Primary

endpoint

readoutScreening

All

subjects

RA

ND

OM

IZ

AT

IO

N

APL2-CP-AIHA-208; NCT03226678

Population: CAD patients with

hemoglobin (Hb) levels <11 g/dL,

signs of hemolysis, and positive

direct antiglobulin test (DAT) for IgG

and/or complement C3

Primary endpoints:

• Safety

• Change in hematologic and blood

chemistry parameters and FACIT

PLAUDIT study also includes a parallel cohort of patients with warm antibody autoimmune hemolytic anemia (wAIHA)


42

PLAUDIT: Efficacy and Safety Results Support Further

Clinical Development of EMPAVELI in CAD

EMPAVELI Increased Hemoglobin within the First Weeks of

Treatment with Sustained Benefit with Longer Exposure

168 days of treatment

Hemoglobin (g/dL)

Additional Efficacy Outcomes

• 77% (n=10) patients were transfusion free at month 12

• FACIT score increased by 7.7 points from baseline to

week 24

Safety Profile Was Generally Consistent with Other

Studies

• All 13 CAD subjects experienced ≥1 treatment-emergent

adverse event (TEAE), mainly mild to moderate in severity

• Five subjects reported 13 serious adverse events (SAEs)

unrelated to EMPAVELI

• EMPAVELI was generally well tolerated

*FACIT- Clinically significant increase is 3 or more points

APL2-CP-AIHA-208; NCT03226678

CSR 11.4.1.1.2 PRBC Transfusions; CSR Table 21: Summary of FACIT-Fatigue Total Score by Visit—ITT Set; Fattizzo B, et al. European Hematology Association. June 13-16, 2019.


43

Key Takeaways

CAD is a chronic and severe blood disorder with no approved therapies

EMPAVELI may be able to control hemolysis in CAD by controlling complement

EMPAVELI demonstrated meaningful efficacy results across multiple hematologic

parameters and was well tolerated in PLAUDIT study

Sobi expects to initiate a Phase 3 study in H2 2021


IC-MPGN


Hematopoietic Stem Cell Transplant

Thrombotic Microangiopathy (HSCT-TMA)

Bruno Fattizzo, M.D.

Professor, Consultant Hematologist and Clinical Researcher

Fondazione IRCCS Ca' Granda Policlinico Hospital, Milan, Italy


45

• Multi-system disease characterized by microangiopathic

hemolytic anemia, consumptive thrombocytopenia and

microvascular thrombosis

• Patients who develop organ damage as a result of

HSCT-TMA are associated with high mortality rates

• C3 is believed to play a critical role in TMA based on

proinflammatory and procoagulant properties of C3a and

C3b

• sC5b9 is a high-risk feature of HSCT-TMA

C3 Plays a Critical Role in HSCT-TMA, a Multi-System

Disease

Khosla , Hematopoietic stem cell transplant-associated thrombotic microangiopathy: current paradigm and novel therapies, Bone Marrow Transplantation 2018; The EBMT handbook

2019; Moiseev, Clinical and morphological practices in the diagnosis of transplant associated microangiopathy: a study on behalf of Transpla nt Complications Working Party of the EBMT,

Bone Marrow Transplantation 2018


46

• ~9,000 and ~18,000 allogeneic transplants

conducted in U.S. and EU+ annually.1,2

• TMA incidence can be up to ~40% of allogenic

transplants3

• ~50% of HSCT-TMA cases can be severe3

• ~90% or more of severe HSCT-TMA is fatal3

1. Current Uses and Outcomes of Hematopoietic Cell Transplantation (HCT): CIBMTR Summary Slide; 2. Passweg et al, BMT. 2019, 38: 1575–1585; 3. Jodele et al, Blood. 2014,

124(4): 645–653

HSCT-TMA Is Associated with Very Poor Outcomes

He

ma

tolo

gy

HSCT without TMA

HSCT-TMA

HSCT without TMA:

Median survival 79.7 months

HSCT with TMA (HSCT-TMA):

Median survival 5.8 months

Kraft S, et al. Bone Marrow Transplant. 2019, 54, 540–548

1.0

0.8

0.6

0.4

0.2

0

Ove

rall

su

rviv

al

0 12 24 36 48 60 72 84 96 108

Follow-up (months)

P=9.82E-16


47

Endothelial Damage

Amplification Loop

Loss of Control & Detrimental Effects

Extremely High Levels of Complement Activation Post-Transplant

Leads to Severe Complement Dysregulation in HSCT-TMA

C3

Alternative

Pathway

Classical

Pathway

Lectin

Pathway

C3a

MAC

C3b

C5a C5b

C5

Blood Clots/Organ DamageInflammation



48

EMPAVELI Targets C3 to Control Complement Activation in

HSCT-TMA

C3

Alternative

Pathway

Classical

Pathway

Lectin

Pathway

C3a

MAC

C3b

C5a C5b

C5

STOP STOP

STOP STOP

Co

ntro

ls a

ll do

wn

stre

am

effe

cts

E M PAV E L I




49

Key Takeaways

HSCT-TMA is a multi-system disease associated with high mortality rates

EMPAVELI has the potential to control the extremely high levels of complement

activation associated with HSCT-TMA

Sobi expects to initiate a potentially registrational Phase 2 study in H2 2021


50

EMPAVELI: Comprehensive Control of Complement with

Broad Platform Potential

IC -MPGN

/ C3G

ALS CAD HSCT-TMA

First patient dosed

in Phase 3 study in

2H21 (Apellis)

Complete

enrollment by end

of 2021 (Apellis)Initiate Phase 3 trial

in 2H21 (Sobi)

Initiate potentially

registrational Phase

2 study in 2H21

(Sobi)

Protect organ

function and prevent

mortality

Increase survival

and slow the

progression of

symptoms

Best-in-class therapy

for late-stage and

transplant patients

Improve hemoglobin

levels and reduce

transfusion

dependency

PNH

~1,500*

The new

standard

of care

~5,000** ~5,000** ~4,000****~19,000***

*Based on complement-treated patient population

**Based on severe patient population

***Based on sporadic only, patients seeking treatment, and non-monotherapy patients

****Based on high-risk patients for developing TMA

Sobi has global co-development and ex-U.S. commercialization rights for systemic

pegcetacoplan

PNH: Hill A, et al. Blood. 2006; 108(11):985. CAD: Catenion using physician and literature consensus. TMA:

Current Uses and Outcomes of Hematopoietic Cell Transplantation (HCT): CIBMTR Summary Slides.Passweg

et al, BMT. 2019, 38: 1575–1585 . Jodele et al, Blood. 2014, 124(4): 645–653. C3G: ClearView Analysis using

physician and literature consensus. ALS: ClearView Analysis based on physician interviews

EMPAVELI

Ambition

U.S. launch is

ongoingKEY

UPCOMING

MILESTONES

U.S. PATIENTS

NEEDING

TREATMENT


51



Expand Rare Disease

Portfolio


Diseases


with PNH



• Develop siRNA +

EMPAVELI


pathway inhibitor


& New Indications


Launch Enable Device

Victoria Brown

Senior Vice President, Rare Disease Program Executive



• Develop siRNA +

EMPAVELI


pathway inhibitor


& New Indications


53

Advancing Patient-Centered Device Innovation for 2022

Source: Consultant analysis of PNH focus groups unique

PAT I E N T S R E S P O N D E D P O S I T I V E LY T O A N E X T - G E N E R AT I O N D E V I C E :

Administers with a few simple steps

Allows discreet self-administration

Alleviates needle fear

Increases mobility and independence


Develop siRNA + EMPAVELI

for Less-Frequent Dosing

Lukas Scheibler, Ph.D.

Chief Innovation Officer



• Develop siRNA +

EMPAVELI


pathway inhibitor


& New Indications


55

C3

Receptor-mediated

endocytosis

RISC

loadingPassenger

strand

degradation

C3 mRNA target

recognition

AGO2 cleavage

of C3 mRNA

Ribosome/

tRNA protein

synthesis

Endosomal

escape

Receptor

recycling

Endosomal

trafficking

• EMPAVELI dose and posology is driven

by high C3 concentration in blood

• Silencing C3 expression in the liver with

siRNA reduces circulating C3

concentration

• GalNAc-conjugated siRNAs have been

shown to target the liver and are

approved in variety of indications

– Patisiran, givosiran, inclisiran are

approved

– 19 GalNAc-siRNA development

programs exist

Silencing C3 Expression Could Reduce EMPAVELI Posology


56

Apellis siRNA Silenced 90% of C3

3 mg/kg 10 mg/kg 30 mg/kg

mRNA Day 15 KD 89% 97% 99%

Protein max KD 77% 85% 94%

15 46 79 113 156 1900.0

0.5

1.0

1.5

2.0

Days post-dose

NHP Liver Biopsy C3 mRNA

0 50 100 150 2000

50

100

150

Days post-dose

NHP Serum C3 Protein to Day 172

Vehicle 3 mg/kg 10 mg/kg 30 mg/kg

Rela

tive

C3 g

en

e e

xp

res

sio

n

Vehicle 3 mg/kg 10 mg/kg 30 mg/kg

C3 %

of

ba

se

lin

e

0 – 10%


57

Complement Targets Require Silencing & Inhibition

C5 siRNA in monotherapy

does not control PNH in

Phase 1 study

• “Maximal reductions in LDH, an

exploratory objective, of 37-50%

were observed in eculizumab-

naïve patients, and LDH levels

remained above the goal of

<1.5xULN.” – Badri et al 2020

• “... residual levels of C5 … were

sufficient to cause intravascular

hemolysis.” - Harris et al 2018

C5 siRNA in combination with eculizumab controls PNH with less-frequent dosing in Phase

1 study

• “All patients receiving cemdisiranachieved LDH <1.5xULN on reduced doses and/or frequency of eculizumab.” – Badri et al 2020

siRNA enables less frequent dosing:

• “In combination with Cemdisiran, the total cumulative yearly maintenance dose of eculizumab can potentially be reduced to approximately 70%.” – Badri et al 2020

Single dose ALN-CC5 reduced classical pathway

hemolytic activity by 65-70% to day 71 in nonhuman

primates. – Badri et al 2020; Kusner et al 2019


58

Apellis siRNA + EMPAVELI: Improving Treatment Experience

with Less-Frequent Dosing

Silencing C3 expression in the liver may reduce treatment frequency of EMPAVELI

Apellis siRNA silenced C3 expression >90% over 3+ months in NHP and significantly

reduced complement activity

IND for siRNA program anticipated in 2022

Results support potential to reduce dosing frequency of EMPAVELI


Oral Alternative Pathway

Inhibitor





• Develop siRNA +

EMPAVELI


pathway inhibitor


& New Indications


60

Alternative Pathway Inhibitor Where Comprehensive Control of

Complement Is Not Needed and/or Classical Pathway Is Not Involved

R AT P K

A LT E R N AT I V E PAT H W AY I N H I B I T I O N

IC50

Apellis 29 nM

LNP023 (Iptacopan) 162 nM

C3

Alternative

Pathway

Classical

Pathway

Lectin

Pathway

C3a C3b

C5a C5b

C5

10000

1000

100

10

1

0.1

Co

nc

en

tra

tio

n (

ng

/mL

)

Time (h)

0 5 10 15 20 25

IV

PO

STOP


61

Oral Alternative Pathway Inhibitor for Indications Where

Comprehensive Control of Complement Is Not Needed

C 3 G

S E V E R EP O S T- T R AN S P L AN T

R E C U R R E N C E

EMPAVELI

targetEMPAVELI

target

E S R D & K I D N E Y

T R AN S P L AN TM I L D

Oral

alternative

pathway

inhibitor

target


62

Transforming Treatment Across Rare,

Complement-Driven Diseases


APELLISR&D DAY

A N D T H E Y ’ R E O F F ! Rare Disease Q&A


APELLISR&D DAY

A N D T H E Y ’ R E O F F ! Lunch Break

Boxed lunches are in the lobby. The presentation

will resume in 20 minutes.


APELLISR&D DAY


Building a Portfolio of

Brain-Active

Complement Therapies





66

The Retina as a Window to the Brain

Picture: discoveryeye.org


67

C3 Therapy for Neurodegeneration Is an Extension of the

Neuroprotective Effects of Pegcetacoplan in the Retina

Geographic Atrophy Is a

C3-Dependent Neuropathology

Phase 2 FILLY Study:

Pegcetacoplan Reduced GA Lesion Growth

*,†Square root. Modified intention-to-treat (mITT) population was used for the efficacy analysis; defined as all patients who received at least 1 injection and underwent at least 1 follow-up examination at month 2 or

later at which primary efficacy data were collected. 2-sided t tests at the alpha = 0.1 level

Liao DS, et al. Ophthalmology. 2020;127:186-95. Holz et al. JAMA Ophthalmol. 2018


Role of C3 in

Neurodegeneration

Angela Genge, M.D., FRCP(C)

Executive Director, Clinical Research Unit & Director of ALS Center of Excellence

Montreal Neurological Institute


69

Multiple Preclinical Studies Demonstrate that C3 Inhibition Is

Neuroprotective in Aging and Neurodegenerative Diseases


70

Aberrant C3-Mediated Pruning Leads to Synaptic and

Cognitive Dysfunction in Multiple Neurologic Diseases

Stephen, Barres and Stevens, Annu Rev Neurosci 2012 https://joannamoncrieff.com/2017/11/27/philosophy-part-6-are-mental-

disorders-brain-diseases-in-waiting/


71

C3 Protein Is Elevated in Alzheimer’s Disease Patient CSF;

C3 Knockout Is Synaptoprotective in AD Animal Models

C3 and Processed C3 Protein (C3b, iC3b and C3c)

Is Increased in AD Patient CSF

M O U S E M O D E L O F A DA D PAT I E N T S

C3 Knockout Is Protective of Synapses

in an Amyloid Mouse Model

Wu, 2019 Wu, et al 2019


72

C3 Is Upregulated in Rapidly Progressing Tauopathies

such as PSP, CBD and FTD

C3 KO Prevents Cortical Atrophy in a

Mouse Tauopathy Model

C3 mRNA Is Elevated in CBD

and PSP Patient Brains

Litvinchuk et al., 2018

CBD – Corticobasal Degeneration

PSP – Progressive Supranuclear Palsy

FTD – Frontotemporal Dementia

Wu et al., 2019

6

5

4

3

2

1

0

Rela

tive C

3 m

RN

A l

evel

NCI CBD Pick PSP

n.s.

**

*


73

C3 Protein Is Correlated with Cognitive Decline in Patients

with Demyelinating Disease

C3 Is Increased in MS Patient

Brain and CSF

Neuroinflammation Leads to Cortical

Atrophy and Cognitive Decline in MS

Aeinehband et al., 2017; Xin & Chan 2020 Damjanovic et al., 2017


74

Rationale for C3 Inhibition as a Treatment for

Neurodegenerative Diseases

C3 regulation is required for synaptic refinement, learning, and memory in neural

development and throughout life

C3 dysregulation results in synaptic loss and dysfunction, a primary cause of

cognitive decline in aging and many neurologic diseases including ALS, Alzheimer’s

disease, multiple sclerosis, and tauopathies.

Restoring C3 regulation with Apellis’ proprietary molecules aims to improve cognitive

function in multiple neurodegenerative diseases


Pioneering C3 in

Neurodegeneration

David Eyerman, Ph.D.

Vice President, Translational Neurology



76

A Large Challenge in Treating CNS Diseases Is Getting

Pharmacologic Treatment Across the Blood Brain Barrier

Zhou et al., 2017


77

• Brain-shuttle enabled

biologic inhibitors

Next-Gen Brain-Active

C3 Inhibitors • Brain-delivered

APL-1030 secretors

• Brain-delivered C3 gene

knockdown

Gene Therapies

• Intrathecal APL-1030

First-in-Class Brain-Active

C3 Inhibitor

Building a Portfolio of Brain-Active Complement Therapies


78


biologic inhibitors



APL-1030 secretors


knockdown

Gene Therapies



C3 Inhibitor



79

APL-1030: A Novel Molecular Entity C3 Inhibitor

• 64 amino acids, highly water soluble

• Binds to same epitope of C3/C3b as

pegcetacoplan

• Binding affinity and inhibition equal to

pegcetacoplan

• High thermal stability

• Recombinant and synthetic manufacture is

feasible

• C- and/or N-terminus accessible to

modification without impact on function

C3

Alternative

Pathway

Classical

Pathway

Lectin

Pathway

C3a

MAC

C3b

C5a C5b

C5

STOP STOP

STOP STOP

Co

ntro

ls a

ll do

wn

stre

am

effe

cts

A P L - 1 0 3 0

Neuroinflammation

Neurodegeneration


80

APL-1030 Is a Novel C3 & C3b Inhibitor for Intrathecal

Delivery to the Brain

• Good tolerability and high

brain concentrations

following 5-day intrathecal

pump infusion in rats

• Enters brain interstitial fluid

in rats

• Enters brain and inhibits C3

in human primates (NHPs)

I N V I V O P K / P DDrug

Delivery

Pump

APL-1030 Delivery to

CSF and Brain


81

High CSF Concentrations and Good Tolerability in NHPs

Following Intrathecal Administration of APL-1030

CSF Levels of APL-1030

0 24 48 72 96 120 1440.1

1

10

100

1000

Hours of Infusion

Pump

Shutoff

Plasma Levels of APL-1030

0 24 48 72 96 120 1440.01

0.1

1

10

100

1000

Hours of Infusion

CSF 0.8 mg/day CSF 2.0 mg/day

CSF 8 mg/day CSF 20 mg/day

CS

F [

AP

L-1

03

0]

µg

/mL

Pla

sm

a [

AP

L-1

03

0]

µg

/mL

Pump

Shutoff

Plasma 0.8 mg/day Plasma 2.0 mg/day

Plasma 8 mg/day Plasma 20 mg/day

20-NPK-001

• Dose escalating exposure in CSF up to ~500ug/mL

• SS CSF achieved within 8-24 hours of infusion

• T1/2 of APL-1030 post-pump shutoff = 3-6h in CSF and ~20h in plasma

• Plasma concentrations are 10-15X lower than CSF


82

APL-1030 Distributes Across the Brain of NHPs Following

5 Days of Intrathecal Administration

Pre

fronta

l Cort

ex

Occ

ipita

l Cort

ex

Ento

rhin

al C

ortex

Par

ieta

l Cort

ex

Hip

pocam

pus CA1

Hip

pocam

pus CA2

Hip

pocam

pus CA3

Cau

date

Puta

men

Subst

antia

Nig

ra

Glo

bus Pal

lidus

Am

ygdal

a

Thalam

us

Cer

ebel

lum

0.1

1

10

100

1000

AP

L-1

030 (

ug

/g)

APL-1030 (2 mg/day)

Cortex Hippocampus Basal Ganglia Other

Pre

fronta

l Cort

ex

Occ

ipita

l Cort

ex

Ento

rhin

al C

ortex

Par

ieta

l Cort

ex

Hip

pocam

pus CA1

Hip

pocam

pus CA2

Hip

pocam

pus CA3

Cau

date

Puta

men

Subst

antia

Nig

ra

Glo

bus Pal

lidus

Am

ygdal

a

Thalam

us

Cer

ebel

lum

0.1

1

10

100

1000

APL-1030 (20 mg/day)

AP

L-1

030 (

ug

/g)

Cortex Hippocampus Basal Ganglia Other

Brain Tissue Concentrations of APL-1030

Target Tissue

Concentration

20-NPK-001


83

PFC EC CA1 CA3

0

1

2

3

4

5

6

C3a n

g/g

, B

rain

Tis

su

e Vehicle

APL-1030 (20 mg/day)

APL-1030 (2 mg/day)

Functional Inhibition of C3 Breakdown in Cognition-Relevant

Brain Regions of NHPs Treated with APL-1030

Brain Tissue Levels of the C3 Breakdown Product C3a Following

Intrathecal Infusion with APL-1030 for 5 Days

Prefrontal

CortexHippocampus

CA1

Hippocampus

CA3 20-NPK-001

Entorhinal

Cortex

LOD

(0.12 ng/mL)


84

APL-1030: Advancing First-in-Class, Brain-Active C3 Inhibitor

IND planned in H1 2022

Potential to treat multiple neurodegenerative disorders

Inhibits C3 breakdown in brain of nonhuman primates

Distributes throughout the brain


85


biologic inhibitors



APL-1030 secretors


knockdown

Gene Therapies



C3 Inhibitor



86

Small Biological Building Blocks Replicating Pegcetacoplan

Pharmacology Will Yield New Therapies for Neurologic Diseases

Salvia et al., 2016

Brain Shuttle Mediated Delivery

via Systemic ROA

C3/C3b Complement Inhibitors

and Bifunctional NBEs

Gene Therapy Secretion in Brain

with Long Durability of Effect

LNP / AAV

https://engage.utsouthwestern.edu/pages/stories/donor-

story-gene-therapy


https://engage.utsouthwestern.edu/pages/stories/donor-story-gene-therapy

87

Hal

f Bra

in

Stria

tum

Cer

ebel

lum

Hip

pocam

pus

Cort

ex

0.0

0.5

1.0

1.5

2.0

Test A

rtic

le u

g/g

Brain-Shuttle Enabled C3 Inhibitor to Treat CNS Indications

C3/C3bPharmacologically-

active moiety

Brain

Shuttle

Brain ShuttleBrain delivery via

trojan horse

Brain-Shuttle Enabled C3 Inhibitor in Rat Brain

Following a Single IV Administration

Target

Concentration

10mg/kg; IV route of administration;

24 hours post dose

Data on file


88


biologic inhibitors



APL-1030 secretors


knockdown

Gene Therapies



C3 Inhibitor



89Salvia et al., 2016

Brain Shuttle Mediated Delivery

via Systemic ROA

C3/C3b Complement Inhibitors

and Bifunctional NBEs

Gene Therapy Secretion in Brain

with Long Durability of Effect

LNP / AAV

https://engage.utsouthwestern.edu/pages/stories/donor-

story-gene-therapy

Small Biological Building Blocks Replicating Pegcetacoplan

Pharmacology Will Yield New Therapies for Neurologic Diseases


https://engage.utsouthwestern.edu/pages/stories/donor-story-gene-therapy

90

Lipid Nanoparticles and APL-1030 Plasmids Distribute to

Brain and Secrete Protein In Vitro and In Vivo

Protein in Rat Brain

28-Days Post Single ICM Dose

APL-1030 Secretion in

hIPSC Derived Brain Cells

Sham

Injection

Lumbar

Intrathecal

(IT)

Cisternal

Intrathecal

(ICM)

Reporter Brain Distribution

Following Different Intrathecal ROAs

Active

PBS

10X 20X

0

100

200

300

400 3022

3027

Time point

AP

L-1

03

0 (

ng

/mL

)

91


TECHNOLOGYDRUG

CANDIDATEDISCOVERY

IND

ENABLING

EARLY

CLINICAL

Biologic

APL-1030 - IT

C3/C3b

Brain Shuttle

Gene

therapy

C3/C3b

Secretor

• Potential to treat multiple

neurodegenerative diseases by

targeting C3

• APL-1030 is a first-in-class, brain-

active C3 inhibitor

– Preclinical pharmacodynamic

response at dose levels expected

to translate to humans

– IND submission in H1 2022


APELLISR&D DAY

A N D T H E Y ’ R E O F F ! Be #1 in the Retina





93

• Pegcetacoplan

• APL-2006: anti-VEGF

plus anti-C3

Next-Gen Wet AMD

Apellis: Be #1 in the Retina

• Gene therapies for all

forms of AMD

Gene Therapy

Geographic Atrophy and

Intermediate AMD


94

• Pegcetacoplan


plus anti-C3

Next-Gen Wet AMD



forms of AMD

Gene Therapy


Intermediate AMD


95

We believe that GA is the consequence of a failure to clean up C3 deposition in the retina.

Single pathway inhibitors are insufficient to correct this failure .

Pegcetacoplan, a targeted C3 therapy, has the potential to accomplish this with its broad,

multi-point control of complement across all three pathways.

“Other complement

inhibitors have failed.

Why should

pegcetacoplan work?”

• Visual acuity charts don't reflect the real impact of GA in vision due to foveal sparing.

• GA is a relentless, progressive disease that severely impairs patients’ visual function and quality

of life.

• A leading cause of blindness, GA has no approved treatments and remains the most significant

unmet need in the retina.

• The need and desire for treatment was reflected in the speed of enrollment in DERBY and

OAKS.

“Pegcetacoplan has no

impact on visual acuity. It

will take years to notice a

difference. Why would

people take this drug?”

Key Misconceptions Dispelled


96

• The FILLY study met its primary endpoint, demonstrated a dose response, and the sham group

progressed at the expected rate.

• Dropouts were in line with other GA trials. 242 out of 246 patients (modified intent-to-

treat: mITT) were included in the primary analysis population, which accounted for missing data with

the well-established mixed-effect model for repeated measures (MMRM).

• All sensitivity analyses confirmed the efficacy results.

• Post hoc analyses also showed that lesion growth slowed in treated eyes vs. contralateral eyes in

patients with bilateral GA and that pegcetacoplan slowed progression from intermediate AMD to GA.

“How can we trust the

FILLY data?”

• The FILLY trial had no safety findings that limited DERBY and OAKS, which studies the same

broad patient population.

• Exudations are an expected occurrence in GA. No classical CNV was detected and there was

no clinically significant impact on vision.

• FILLY was single-masked, which may have led to greater reporting of exudations in subjects

randomized to pegcetacoplan than in subjects randomized to sham. DERBY and OAKS are

double masked to further minimize potential bias.

• Two cases of infectious endophthalmitis out of ~1,500 intravitreal injections are consistent with

reported incidence rates in published studies involving intravitreal injection.

“FILLY had safety issues.

Pegcetacoplan causes

‘wet AMD' and had two

cases of infectious

endophthalmitis.”

Key Misconceptions Dispelled


97

Geographic Atrophy Is a Leading Cause of Blindness

Impacting 5M Patients Worldwide

2,741,000

2,035,000

588,000

1,296,000

907,000

257,000

4,037,000

2,942,000

845,000

Prevalent Patients Diagnosed Patients Treated by any DMT

US

Europe

Estimated future commercial opportunity across US and Europe

Global Prevalence

5,000,000

1.Boyer DS et al., Retina 2017 2 2. Wong WL, et al. Lancet Glob Health. 2014;2:e106-16; 3. Global Data AMD Global Drug Forecast and Market Analysis, JAMA Ophthalmology, Gibson 2012 American Journal of

Preventative Medicine, ZS Associates Demand Forecast Market Research, APLS internal analysis and assumptions

Current global prevalence

Europe includes 31 countries in southern, northern, and western Europe. US and EU figures represent future years. DMT: Disease Modifying Therapies


What Is the Unmet Need in

Geographic Atrophy?

Charles Wykoff, M.D., Ph.D.

Director of Research

Retina Consultants of Texas


99

• There are 5 million people living with GA

worldwide; 1 million are in the US1

• GA accounts for 20% of all legal blindness

attributed to AMD2, 3

• There is no approved treatment for GA1

1. Boyer DS et al., Retina 2017.

2. Ferris FL 3rd et al., Arch Ophthalmol. 1984

3. Klaver CC, et al., Arch Ophthalmol. 1998

Image from Holz FG et al., Ophthalmology 2014.

There Is No Treatment for GA, a Leading Cause of Blindness


100

V I S U A L

S Y M P T O M S 1

• Loss of ability to see

objects clearly

(especially in dim light

conditions)

• Straight lines appear

to be wavy or

distorted

• Loss of color vision

• Dark areas of gray

and white spots may

appear in the center

of vision

1. Boyer DS, et al. Retina. 2017;37(5):819-35; Holz FG, et al. Ophthalmology. 2014;121:1079-91; 2. Chakravarthy, U et al. Ophthalmology. 2018;125(6):842-849.

Images: NIH National Eye Institute video on AMD

In a natural history study, among

patients who had visual acuity

sufficient to drive at baseline, 2/3

…progressed to vision loss that

left them ineligible to drive over

a median time of 1.6 years2

70

60

50

40

30

20

10

0

Me

an

VA

(E

TD

RS

le

tte

rs)

0 12

Time since index (months)

24 36 48 60

Better-seeing eye:

Mean of 22.6 letters lost at 60 months

Worse-seeing eye:

Mean of 10.9 letters lost at 60 months

Progressive Decline of Visual Acuity in GA2

37.0

27.0

GA Causes Loss of Retinal Tissue and Progressive Vision Loss


101

Living with GA:

Q&A with Rob


Pegcetacoplan: Phase 2 FILLY Results

Charles Wykoff, M.D., Ph.D.

Director of Research

Retina Consultants of Texas


103

Phase 2 FILLY Study: Design

*Confirmed by the central reading center using fundus autofluorescence images. †Not counting the 3 satellite sites

Liao DS, et al. Ophthalmology. 2020;127

Sham groups were pooled

for all analyses

PEGCETACOPLAN

15 mg/0.1 mL

every other month (n=79)

PEGCETACOPLAN

15 mg/0.1 mL

monthly (n=86)Population: patients with

geographic atrophy*

secondary to AMD

Design: single masked,

randomized 2:1:2:1

Duration: 18 months

Randomized 2:2:1:1

ELIGIBLE PATIENTS

WITH GA*

246 subjects

in 43 sites†

SHAM


SHAM

monthly (n=41)

Single masked


104

Phase 2 FILLY Study: Timeline and Endpoints

Liao DS, et al. Ophthalmology. 2020;127

0 6

months

12months

18months

2

months

Images

taken at Primary safety endpoint

Number and severity of local and

systemic treatment emergent

adverse events (TEAEs)

Primary efficacy endpoint

Change in geographic

atrophy (GA) lesion size

from baseline at month 12

Treatment

period

No

injections


105

Chroma and Spectri Phase 3 Trials

Change from baseline in square

root of GA area at 48 wk, mm

Sham Pooled

(n=598)

Adjusted mean (SE) 0.342 (0.007)

*p=0.067 vs sham†p=0.008 vs sham

*

†

0.35

0.28

0.25

0

0.1

0.2

0.3

0.4

0 6 12

LS

Me

an

(±S

E)

Ch

an

ge f

rom

Bas

eli

ne

in

S

qu

are

Ro

ot

GA

Le

sio

n (

mm

)

Month

20%29%

Phase 2 FILLY Study: Pegcetacoplan Met Primary

Endpoint, Reducing GA Lesion Growth

*,†Square root. Modified intention-to-treat (mITT) population was used for the efficacy analysis; defined as all patients who received at least 1 injection and underwent at least 1 follow-up examination at month 2 or

later at which primary efficacy data were collected. 2-sided t tests at the alpha = 0.1 level

Liao DS, et al. Ophthalmology. 2020;127:186-95. Holz et al. JAMA Ophthalmol. 2018

Sham injections

(N=80)

Pegcetacoplan


Pegcetacoplan

monthly (N=84)

FOR APELLIS USE ONLYAPELLIS PROPRIETARY INFORMATION / FOR APELLIS USE ONLY

106

Phase 2 FILLY Study: Impact of Pegcetacoplan on Absolute

GA Lesion Growth Is Consistent with the Primary Endpoint

1.47

2.13

0

0.5

1

1.5

2

2.5

0 6 12

20%30%

*** p=0.068 vs sham

††† p=0.005 vs sham

†††

*Nominal p values

mITT, Observed, Mixed-Effect Model

A mixed effect model with main effects of treatment, visit and GA lesion at baseline, and interactions of treatment × visit, visit ×

baseline.

M12DBL Data

LS

Mean

(±S

E)

Ch

an

ge f

rom

Baselin

e in

Sq

uare

Ro

ot

GA

Lesio

n (

mm

)

LS

Mean

(±S

E)

Ch

an

ge f

rom

Baselin

e

in G

A L

esio

n (

mm

2)

Sham injections

(N=80)

Pegcetacoplan


Pegcetacoplan

monthly (N=84)

Month Month

0.25

0

0.1

0.2

0.3

0.4

0 6 12

20%29%

** p=0.067 vs sham

†† p=0.008 vs sham

††

P R I M A R Y E N D P O I N T

( S Q U A R E R O O T T R A N S F O R M E D

L E S I O N G R O W T H )

A B S O L U T E ( U N T R A N S F O R M E D )

L E S I O N S I Z E *

0.28**

0.35

1.70***


107

• Exudations at 12 Months (treatment period):

– 16% monthly, 6% every other month, 1% sham

– 0 cases of classical CNV

– No clinically significant impact on vision

– Patients discontinued pegcetacoplan; most treated with anti-VEGF therapy

• Safety in line with other studies of intravitreally administered agents

• Serious adverse events in the study eye were reported in 4 of 86 (4.7%)

(2 endophthalmitis, 1 IOP increase, 1 retinal detachment), 2 of 79 (2.5%)

(endophthalmitis, IOP increase), and 1 of 81 (1.2%) (dry AMD) of patients in the

pegcetacoplan monthly, pegcetacoplan every other month, and sham groups,

respectively

Liao DS, et al. Ophthalmology. 2020;127:186-95.

Wykoff CC, et al. Ophthalmology. 2021; in press.

GA

Phase 2 FILLY Study: Safety


108

• Intermediate AMD (iAMD) is characterized

by the presence of large drusen and

pigmentary abnormalities in the macula

• Associated with visual impairment,

especially in low-light condition

• Similar to GA, dysregulation of the

complement system is implicated in iAMD

• No approved therapy to prevent the

progression of iAMD to advanced AMD

Longitudinal Analysis of Structural and Functional Changes in Presence of Reticular Pseudodrusen Associated With Age -Related Macular Degeneration.

Intermediate AMD

Geographic Atrophy Wet AMD

A d v a n c e d A M D

Pegcetacoplan: Opportunity for Earlier Intervention in AMD


109

iRORA: incomplete RPE and outer retinal atrophy; cRORA: complete RPE and

outer retinal atrophy; RPE: retinal pigment epithelium

Sadda et al., EURETINA 2020 late-breaking presentation.

cRORAMonth 12

iRORAMonth 0

• Therapeutic trials for geographic atrophy are focused

on the end-stage (complete RPE and outer retinal

atrophy or cRORA); e.g., GA lesions

• Earlier endpoints in the atrophy pathway have been

defined: incomplete RPE and outer retinal atrophy

(iRORA); e.g., consistent with intermediate AMD

Earlier Endpoints for Retinal Atrophy


110

Pearson Chi-Square:

Month 6 - P=0.08 for PM; P=0.32 for PEOM;

*Month 12 - P=0.02 for PM; P=0.03 for PEOM

Relative risk:

Month 12 - 0.61 (0.37- 1.00) for PM; 0.70 (0.50 – 0.98) for PEOM

cRORA

iRORA

Residual

RPE

Phase 2 FILLY Post Hoc Analysis: Pegcetacoplan Slowed

Progression from Intermediate AMD to GA

Ip et al., Macula Society 2021.

All p-values are nominal.

P R O G R E S S I O N F R O M i R O R A T O c R O R A

27.8%

50.0%

40.6%

57.6%53.1%

81.8%

0%

10%

20%

30%

40%

50%

60%

70%

80%

90%

100%

Month 6 Month 12

Pegcetacoplan Monthly (n=18)

Pegcetacoplan Every Other Month (n=33)

Sham (33)

*P=0.02

*P=0.03


111

Key Takeaways

Pegcetacoplan met the primary endpoint in the Phase 2 FILLY study, reducing GA lesion

growth with benefit shown across GA phenotypes

Demonstrated a dose response with sham group progressing at expected rate

Phase 2 FILLY safety in line with other studies of intravitreally administered agents

Slowed progression from intermediate AMD to GA; potential for earlier intervention in

the course of GA

Urgent and significant need for treatments for GA, a disease that leads to blindness


Pegcetacoplan: Advancing the First

Potential Treatment for GA

Jeffrey Eisele, Ph.D.

Executive Vice President, Ophthalmology Program Lead



113

94% believe that GA poses a significant

burden to patients’ quality of life1*

84% believe that slowing lesion growth is the

most important goal for preserving vision in GA1*

“I think APL-2 is the most promising of any of the

agents in development so far.” – Retina KOL2

“All three complement pathways converge on C3,

which makes APL-2 much more promising than

lampalizumab’s factor D inhibitor.”– Retina Specialist2

“Apellis designed these trials really well. If it shows

benefit, I think APL-2 will get a lot of uptake pretty quickly.”

– Retina Specialist2

1BEESY Strategy Global GA ECP ATU (n=488) | *Rating 5, 6 and 7-point scale where 1= completely disagree and 7= completely agree2Health Advances Commercial Assessment & Analysis (n=31)

“Anything over 20% [reduction in lesion growth rate]

would be significant in my mind.” – Retina Specialist2

These statements include only the opinions of a limited sample of retina specialists and do not necessarily reflect the opinions of all retina specialists.

Retina Specialists Are Enthusiastic About the Prospect of

Pegcetacoplan as the First-Ever GA Therapy


114

DERBY and OAKS: Two Phase 3 Studies of

Pegcetacoplan in Patients with GA (n=1,258)

Same study population

and trial design as FILLY

Population: patients with

geographic atrophy*

secondary to AMD

Primary endpoint: change

in total area of GA lesion(s)

based on fundus

autofluorescence (FAF) at

month 12

Design: single masked,

randomized 2:1:2:1

Duration: 2 years

Randomized 2:1:2:1

ELIGIBLE PATIENTS

WITH GA*

>600 subjects

from approx. 100

multinational sites

per study

PEGCETACOPLAN

15 mg/0.1 mL

monthly (n=200)

PEGCETACOPLAN

15 mg/0.1 mL


SHAM INJECTIONS

pooled (n=200)

Double masked Primary endpoint

read out

1 year 1 year

NCT03525600, NCT03525613


115

DERBY and OAKS: Key Efficacy Endpoints

BCVA=best-corrected visual acuity; FAF=fundus autofluorescence; LL-BCVA=low-luminance BCVA.

NCT03525600, NCT03525613

P R I M A RY

• Change from baseline to Month 12 in total area of GA lesion(s) in the study eye

(in mm2) based on FAF

S E C O N D A RY

• BCVA, LL-BCVA

• Reading speed

• Microperimetry (OAKS study only) —

Macular Integrity Assessment

(MAIA) device

• National Eye Institute Visual

Functioning Questionnaire 25-Item

Version (NEI VFQ-25)

• Functional Reading Independence

Index (FRI) composite score


116

DERBY and OAKS: Top-Line Results Expected in September

P R I M A R Y E N D P O I N T

Change in lesion growthS A F E T Y

Monthly treatment

with pegcetacoplan

Every-other-month treatment

with pegcetacoplan

• Safety profile including rate

of exudations and

intraocular inflammation


117

Advancing Pegcetacoplan into Intermediate AMD for

Earlier Treatment of AMD

Source: American Academy of Ophthalmology; The Lancet; Ophthalmology; L.E.K. interviews and analysis1 Rofagha et al. Ophthalmology 2013

Intermediate AMDPresence of drusen

No therapy to prevent

progression to advanced AMD

Geographic Atrophy Wet AMD

A d v a n c e d A M D

• Positive post-hoc analysis from FILLY

showed a treatment effect on

biomarkers of intermediate AMD

• Pivotal study in intermediate AMD

planned for 2022 following a positive

GA readout

• Study to assess potential of

pegcetacoplan to delay or prevent

progression to advanced AMD


Next-Gen Wet AMD





119

• Pegcetacoplan


plus anti-C3

Next-Gen Wet AMD



forms of AMD

Gene Therapy


Intermediate AMD


120

US and Europe Prevalence of Patients with AMD

Source: Health Advances analysis, UN Population Projections, Friedman 2004, EUREYE 2006, Kang and Kim 2019, Song 2017, Mathenge 2013, Grunwald 2013 Ophthal,

Sadda 2018 Ophthal, Domalpally 2018 Ophthalmol Retina, Klein 2008 Am J Ophthalmal, Mitchell 2002 Ophthal, Wong 2014 Lancet Glob Health, Colijn 2017 Oph, Gibson

2012 Am J Prev Med, Wu 2014 Ophthalmology, Wu 2015 IOVS, Wu 2016 IOVS, Augood 2006 Arch Ophthalmol (EUREYE).

A D VA N C E D A M D

GA +

WET AMD

~1.3 million at

highest risk of

progression to GA~4 million ~6 million


121

Wet AMD patients treated with anti-

VEGF therapy develop GA

Complement levels increase after anti-

VEGF therapy in eyes with wet AMDVisual function outcome declines over

time despite anti-VEGF treatment

0

5

10

15

20

25

30

35

40

Baseline Month 24

Proportion of patients with GA (%)

Lucentis (n=141) Eylea (n= 137)

https://www.aaojournal.org/article/S0161-6420(19)31954-2/fulltext https://doi.org/10.1038/s41598-021-87340-6 https://www.aaojournal.org/article/S0161-6420(18)30947-3/fulltext

C3 + Anti-VEGF Therapy May Be Superior to Anti-VEGF Alone


122

Lower rate of GA leading to superior outcome to Eylea and/or

Lucentis in the long term

T R E AT M E N T G O A L S

Non-inferior BCVA outcome to Eylea® (aflibercept) and/or

Lucentis® (ranibizumab) in year one

Re-treatment interval > 3 months

Similar safety as established therapies

APL-2006: Potential to Be Best-in-Class Treatment for Patients

with Wet AMD


123

APL-2006: Next-Generation Wet AMD Therapy

• Potential to provide superior

treatment for patients with

wet AMD and GA

• Less frequent dosing

• IND anticipated late 2022

Ranibizumab – VEGF inhibitor

VH

CH

VL

CL

LA

1030

LA

1030

Long Acting – 2x half-life over

Lucentis in NHP

APL-1030 – C3 / C3b inhibitor


124

APL-2006: Potent Bispecific C3 and VEGF Inhibitor

Complement Inhibition Potency VEGF Inhibition vs. Lucentis

HUVEC Proliferation Assay

0.20

0.15

0.10

0.05

0

Ab

s.

(69

0n

m –

57

0 n

m)

Lucentis

APL-2006

Pegcetacoplan

APL-2006


125

• Pegcetacoplan


plus anti-C3

Next-Gen Wet AMD



forms of AMD

Gene Therapy


Intermediate AMD


126

Goal: Develop Gene Therapy to Secrete APL-1030 or

APL-2006 in the Retina

In vivo / rabbit studyIn vitro data in ARPE19 cells

Plasmid copy number GC/ng DNAAPL-1030 protein in media

of transfected ARPE19 cells

1500

1000

500

0

AP

L-1

03

0 i

n m

ed

ia (

ng

/mL

)

0.02 0.06 0.20

Dose (µg)

Sham 0.1 10 30

Dose (µg)

1 100

4000

3000

0

GC

/ng

DN

A

2000

1000


127

Be #1 in the Retina

A D VA N C E D A M D

GA +

WET AMD

PegcetacoplanPegcetacoplan APL-2006

Gene therapy

Gene therapy


APELLISR&D DAY


Neurology/Ophthalmology

Q&A


APELLISR&D DAY






130

EXCLUSIVE RESEARCH COLLABORATIONto apply base editing to discover novel therapies for complement-driven diseases

131

P O S I T I O N S A P E L L I S F O R L O N G - T E R M L E A D E R S H I P I N C O M P L E M E N T

EXCLUSIVE RESEARCH COLLABORATION

6 research programs

over 5 years: vision for

one-time, curative

therapies

Base editing technology

to discover precision

medicines for diseases of

the eye, liver, and brain

Focused on C3

and other

complement targets

Modulating

a complex biological

system

132

BASE EDIT ING IS A NEW APPROACH TO GENE EDIT ING

Nuclease editingCreation of double-stranded breaks in DNA at a target

location to disrupt, delete, insert, or modify genes

Base editingDirect conversion of one base pair to another at a

target location, without double-stranded breaks

CRISPR → Guide RNA-driven targeting

• Leverages established DNA targeting ability of CRISPR

• Modified to not cause double-stranded breaks

Deaminase → Single base editing

• Completes predictable chemical modification at target DNA base

• Adenine Deaminase for A-to-G editor (“ABE”)

• Cytidine Deaminase for C-to-T editor (“CBE”)

Two components fused as a single protein:

A

A

T▲

APELLISR&D DAY

A N D T H E Y ’ R E O F F ! Beam Collaboration Q&A


134

• EMPAVELI launch off to strong start

• Platform potential for EMPAVELI with four new registrational programs

• New molecular entities in development to sustain long-term growth in existing and new indications

Global Leader in Complement, Today and Tomorrow

R A R E D I S E A S E

N E U R O L O G Y

O P H T H A L M O L O G Y

• C3 plays a key role in a wide range of neurodegenerative conditions

• Apellis to pioneer targeted C3 therapies in neurodegeneration

• Optimistic heading into DERBY and OAKS readout in September 2021

– Significant unmet need and blockbuster opportunity

• Data from monthly dosing believed to be sufficient for NDA submission

– Primary endpoint on monthly dosing minimally affected by missed visits due to COVID-19

– Primary endpoint on every-other-month dosing may be affected by missed visits due to COVID-19

• New molecular entities in development in GA, wet and intermediate AMD


135

PRODUCT DISEASE PRECLINICAL PHASE 1 PHASE 2 PHASE 3 LAUNCH

Rare Disease

EMPAVELI™ (systemic

pegcetacoplan)*

PNH

IC-MPGN / C3G

ALS

CAD

HSCT-TMA

siRNA + EMPAVELI** Existing + new indications

Ophthalmology

Intravitreal pegcetacoplanGA

Intermediate AMD***

APL-2006 GA & Wet AMD

Gene therapies Wet AMD, Intermediate AMD & GA

Neurology

APL-1030 Undisclosed

Brain shuttle Undisclosed

Gene therapies Undisclosed

Multiple

Therapeutic

Areas

APL-9 Control of host attack for gene therapies

Oral alternative pathway inhibitor Mild C3G and other indications

Gene-edited therapies (Beam) Undisclosed

*Sobi has global co-development and ex-U.S. commercialization rights for systemic pegcetacoplan **Initial IND for siRNA *** Pending regulatory feedback

Growing Pipeline in Rare Disease, Ophthalmology, and Neurology

Marketed in the US

IND in ‘22

IND in ‘22

IND in ‘22

Initiate Ph 3 in H2’21


Initiate Ph 3 in ’22


Potential to be registrational*

*

*


APELLISR&D DAY

A N D T H E Y ’ R E O F F ! THANK YOU!


APELLISR&D DAYJune 30, 2021



APELLIS R&D DAY

Documents

Transcript of APELLIS R&D DAY