Rishi P. Singh, MD

Staff Surgeon, Cole Eye Institute, Cleveland Clinic

Associate Professor of Ophthalmology, Case Western Reserve University

Medical Director, Clinical Systems Office

APL-2 (pegcetacoplan)

Geographic atrophy Preliminary 18-month results

The Macula Society

February 22, 2018

Financial disclosures

• Consultant – Genentech, Regeneron, Novartis/Alcon, Optos, Zeiss

• Sponsored research support – Apellis, Genentech, Regeneron , Alcon/Novartis, Clearside

2

The Complement Pathway and Geographic Atrophy

Cell death,

secretion, lysis,

or proliferationInflammation

InflammationCell removal,

Antigen uptake by APCsC3a

C5a MACC5b

C3

C3b

C5

Lectin Pathway Classical Pathway Alternative Pathway

APL-2

3

FILLY - Phase 2 study of APL-2 in Geographic Atrophy

Active group 2, n=86Active group 1, n=79Sham group, n=81

APL-2 injections every monthAPL-2 injections every other monthSham injections

APL-2

15 mg

APL-2

15 mg

APL-2

0 mg

4

treatment

period

no

injections

FILLY – timeline and endpoints

0 6

months

12

months

18

months

2

months

images

taken at

Primary efficacy

endpoint is the primary

registration endpoint

Change in geographic

atrophy (GA) lesion size

from baseline to month 12.

Primary safety

endpoint

Number and severity of

local and systemic treatment

emergent adverse events

(TEAEs).

5

Baseline Characteristics

• Groups were well balanced as to age, gender and race

APL-2 Monthly

N=86

APL-2 Every Other

MonthN=79

Sham Pooled

N=81

Bilateral GA, n (%) 71 (85.5%) 64 (82.1%) 72 (90.0%)

History of CNV in Fellow Eye, n (%) 36 (41.9%) 28 (35.4%) 29 (35.8%)

GA lesion size, mean, mm2 (SD) 8.0 (3.8) 8.9 (4.5) 8.2 (4.1)

BCVA score, mean letters (SD) 59.8 (15.7) 58.4 (16.0) 59.8 (17.2)

BCVA score (Snellen equivalent) 20/63 20/80 20/63

LL-BCVA score, mean letters (SD) 36.3 (16.6) 31.4 (17.1) 33.6 (17.8)

6

Primary Endpoint: GA Lesion Growth

Modified Intent to Treat population (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.mITT = All subjects receiving at least one injection and having at least one FAF image after day 1

0.35

0

0.1

0.2

0.3

0.4

0 6 12

LS M

ean

(±S

E) C

han

ge f

rom

Bas

elin

e in

Sq

uar

e R

oo

t G

A L

esi

on

(m

m)

Month

2

Sham Control (n=80)

7

0.25

0.35

0

0.1

0.2

0.3

0.4

0 6 12

LS M

ean

(±S

E) C

han

ge f

rom

Bas

elin

e in

Sq

uar

e R

oo

t G

A L

esi

on

(m

m)

Month

APL-2 Monthly (n=84) Sham Pooled (n=80)

2

†p=0.008 vs Sham

† 28.6%

Modified Intent to Treat population (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.mITT = All subjects receiving at least one injection and having at least one FAF image after day 1

Primary Endpoint: GA Lesion Growth

8

Modified Intent to Treat population (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.mITT = All subjects receiving at least one injection and having at least one FAF image after day 1

0.25

0.28

0.35

0

0.1

0.2

0.3

0.4

0 6 12

LS M

ean

(±S

E) C

han

ge f

rom

Bas

elin

e in

Sq

uar

e R

oo

t G

A L

esi

on

(m

m)

Month

APL-2 Monthly (n=84)

APL-2 Every Other Month (n=78)

Sham Pooled (n=80)

2

20.0%*

† 28.6%

* p=0.067 vs Sham†p=0.008 vs Sham

Primary Endpoint: GA Lesion Growth

9

Post hoc analysis: greater reduction in GA lesion growth from month 6 to 12

0.174

0.117

0.093

0.00

0.05

0.10

0.15

0.20

Sham Pooled (n=61) APL-2 EOM (n=54) APL-2 Monthly (n=58)

Leas

t Sq

uar

es

Me

an (

±SE)

Ch

ange

fro

m

mo

nth

6 t

o 1

2 i

n S

qu

are

Ro

ot

GA

Le

sio

n (

mm

)

32.8%

46.6%

Data from subjects with a measurable GA lesion size at both Months 6 & 12. Data as of August 24, 2017

p = 0.010 vs Sham

p < 0.001 vs Sham

10

Post hoc analysis: in bilateral GA, monthly APL-2 reduced GA growth compared to contralateral eye

0.262

0.362

0.340

0.363

0

0.1

0.2

0.3

0.4

0 6 12

Mea

n (

±SE)

Ch

ange

fro

m B

asel

ine

in

Squ

are-

roo

t G

A L

esio

n (

mm

)

Month

APL-2 Monthly Study Sham Study

APL-2 Monthly Fellow Sham Fellow

2

mITT-Bilateral GA, Observed, ANOVA at Month 12. Data as of August 24, 2017

Pairwise Comparison p-value

AM-Study vs. Sham-Study 0.020

AM-Study vs AM-Fellow 0.083

AEOM-Study vs Sham-Study 0.079

All other pairs (except AM-S or AEOM-S vs Sham-F)

> 0.1

(n=69) (n=72)

27.6%

6.3%

11

GA Lesion Growth to 18 Months

Modified Intent to Treat population (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.mITT = All subjects receiving at least one injection and having at least one FAF image after day 1

0.26

0.39

0.28

0.410.35

0.49

0

0.1

0.2

0.3

0.4

0.5

0.6

0 6 12 18

LS M

ean

(±S

E) C

han

ge f

rom

Bas

elin

e in

Sq

uar

e R

oo

t G

A L

esi

on

(m

m)

Month

APL-2 Monthly (n=84) APL-2 EOM (n=78) Sham Pooled (n=80)

2

16.3%20.4%

*

* p=0.097 vs Sham†p=0.044 vs Sham

†

Off Treatment

12

Best Corrected Visual Acuity

No differences were observed in visual outcomes between groups

-3.3

-7.7-5.8

-8.8

-4.4

-6.4

-10

-5

0

5

10

0 2 4 6 8 10 12 14 16 18LS M

ean

(±S

E) C

han

ge f

rom

Bas

elin

e in

B

CV

A (

lett

ers)

Month

APL-2 Monthly (n=84)

APL-2 EOM (n=78)

Sham Pooled (n=81)

p = 0.203 for treatment effect

p = 0.278 for treatment × visit interaction

Off Treatment13

Modified Intent to Treat population (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.mITT = All subjects receiving at least one injection and having at least one FAF image after day 1

New Onset Exudation – 18 months

0%

10%

20%

30%

40%

50%

60%

70%

80%

90%

100%

All subjects

Sub

ject

sw

ith

new

on

set

exu

dat

ion

inst

ud

yey

e

Sham Pooled APL-2 Every Other Month APL-2 Monthly

1%(n=1)

21%(n=18)

9%(n=7)

14

Adverse Event Profile

Adverse Eventn (%) of subjects with events

APL-2 Monthly

N=86

APL-2 Every Other MonthN=79

Sham Pooled

N=81

Ocular SAEs in study eye* 4 (4.7%) 2 (2.5%) 1 (1.2%)

Systemic (non-ocular) SAEs 19 (22.1%) 24 (30.4%) 23 (28.4%)

Treatment related ocular AEs in the study eye 22 (25.6%) 11 (13.9%) 0

New onset exudation 18 (20.9%) 7 (8.9%) 1 (1.2%)

Treatment related systemic (non-ocular) AEs 0 0 0

Ocular SAEsAPL-2 Monthly

N=86APL-2 EOM

N=79Sham Pooled

N=81

Endophthalmitis* 2 (2.3%) 1 (1.3%) 0

IOP increased 1 (1.2%)† 1 (1.3%) 0

Retinal detachment 1 (1.2%) 0 0

Visual impairment 0 0 1 (1.2%)

*2 culture positive for coagulase-negative Staphylococcus. 1 culture negative in the monthly group.†2 events in a subject 15

Possible explanations for APL-2 associated exudation

• APL-2 induces vascular exudation in the absence of neovascularization (VEGF-Like effect)• FA was not required on conversion to

exudative AMD so no confirmation this was truly from CNV complex

• APL-2 induces neovascularization and exudation

• APL-2 induces exudation for pre-existing subclinical neovascularization• FA at baseline would have missed

subclinical lesions • ICG angiography and OCT angiography were

not performed in the study• Structural OCT was performed – double

layer sign16

Summary

• APL-2 inhibits C3 and the downstream effects of the complement cascade

• APL-2 when given monthly or every other month demonstrated statistically

significant differences in GA growth over 18 months as compared to placebo

patients despite no treatment for 6 months

• APL-2 slowed growth of GA independent of Complement Factor I genotype

• Upon discontinuation of APL-2 at month 12, the treatment effect declines

• The risk/benefit profile at 18 months supports the decision to move to Phase 3

testing

17