apl-2 in geographic atrophy - apellis.com - apl-2 in... · 2020. 6. 1. · modified intent to treat...

CONFIDENTIAL AND PROPRIETARY – for discussion purposes only

APL-2 in Geographic Atrophy12-Month ResultsJeffrey S. Heier, MDCo-President & Medical DirectorOphthalmic Consultants of Boston


Central inhibition of complement

Cell death, secretion, lysis, or

proliferation

Inflammation

InflammationCell removal, Antigen uptake by APCsC3a

C5a MACC5b

C3

C3b

C5

Lectin Pathway Classical Pathway Alternative Pathway

2

APL-2

Lampalizumab (Factor D, Roche)

CLG561 (Properdin , Novartis)

LFG316 (C5, Novartis)

Eculizumab (C5, Alexion)Zimura (C5, Ophthotech)

CONFIDENTIAL AND PROPRIETARY – for discussion purposes only3

All pathways of complement converge on C3

7

Lectin Pathway

Classical Pathway

Alternative Pathway

C3


APL-2 targets C3 centrally in the complement cascade

8

Lectin Pathway

Classical Pathway

Alternative Pathway

C3Phagocytosis

Membrane attack

Inflammation

APL-2


Endpoints

Primary Efficacy• Mean change in square root GA area from baseline to

month 121,2

Primary Safety• Incidence and severity of ocular and systemic AEsKey Secondary Endpoints• Change in best corrected visual acuity• Incidence of new onset exudative AMD

1. Based on fundus autofluorescence photographs (FAF)2. Feuer WJ et al. Square root transformation of geographic atrophy area measurements to eliminate dependence of growth rates on baseline lesion measurements: a reanalysis of age-related eye disease study report

no. 26.; JAMA Ophthalmology. 2013 Jan.

5


(SEOM)N=40

ShamEvery Other

Month

APL-2 15 mgEvery Other Month

(AEOM)N=80

Sham Monthly

(SM)N=40

APL-2 15 mgMonthly

(AM)N=80

Safety, Tolerability and Evidence of Activity N=240*

Randomized 2:1:2:1

Phase 2 GA – FILLY design

Treatment Period Follow up

AM=2 D0

AEOM=2

SM=1

SEOM=1

M1 M2 M3 M4 M5 M6 M7 M8 M9 M10 M11 M12

D0 M1 M2 M3 M4 M5 M6 M7 M8 M9 M10 M11 M12

D0 M2 M4 M6 M8 M10 M12

D0 M2 M4 M6 M8 M10 M12

Randomization

M15 M18

M15 M18

M15 M18

M15 M18*Note: 246 total patients enrolled in the Phase 2 Filly Study. 240 patients were planned for enrollment

AM = APL-2 monthly; AEOM = APL-2 every other month


Primary Efficacy Endpoint = Primary Registration Endpoint� The primary endpoint is the change in square root of geographic

atrophy (GA) lesion size from baseline at month 12

Primary Safety Endpoint� Number and severity of local and systemic treatment emergent

adverse events (TEAE)

Phase 2 GA – FILLY endpoints

7

Areas of GA are measured using fundus autofluorescent imaging. Changes in growth of GA over time can thus be compared between SHAM and ACTIVE groups


FILLY phase II trial

No specific genotypedriving results

Increased effect size over time

Further confidence in results from intra-patient control

Notable response in patients that converted to wet AMD

Preventing complement activation by blocking C3

Statistically significant data in largest Phase II in GA (n=246)

Results correlated to treatment frequency

C3

Phase III design finalized


treatment period

no injections

FILLY - primary endpoint

0 6months

12months

18months

2months

images taken at

Primary efficacy endpoint is the primary registration endpointThe primary endpoint is the change in geographic atrophy (GA) lesion size from baselineat month 12.

Primary safety endpointNumber and severity oflocal and systemic treatment emergent adverse events (TEAE).

Data will be available

February 2018.


Baseline Characteristics

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

10

APL-2 Monthly

N=86

APL-2 Every Other

MonthN=79

Sham Pooled

N=81Bilateral 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 20/63LL-BCVA score, mean letters (SD) 36.3 (16.6) 31.4 (17.1) 33.6 (17.8)


Primary Endpoint: GA Lesion Growth

11

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

(±SE

) Cha

nge

from

Bas

elin

e in

Squ

are

Root

GA

Les

ion

(mm

)

Month

Sham Pooled (n=80)

2



12

0.25

0.35

0

0.1

0.2

0.3

0.4

0 6 12

LS

Me

an

(±

SE

) C

ha

ng

e f

rom

Ba

se

lin

e

in S

qu

are

Ro

ot

GA

Le

sio

n (

mm

)

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



13

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

0.250.28

0.35

0

0.1

0.2

0.3

0.4

0 6 12

LS M

ean

(±SE

) Cha

nge

from

Bas

elin

e in

Squ

are

Root

GA

Les

ion

(mm

)

Month


APL-2 Every Other Month (n=78)

Sham Pooled (n=80)

2

20.0%*

†

28.6%


Post hoc analysis: reduction in GA lesion growth was accelerated 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

uare

s M

ean

(±SE

) Cha

nge

from

m

onth

6 to

12

in S

quar

e Ro

ot G

A

Lesi

on (m

m) 32.8%

46.6%

14

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


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

15

0.262

0.3620.340

0.363

0

0.1

0.2

0.3

0.4

0 6 12

Mea

n (±

SE) C

hang

e fr

om B

asel

ine

in S

quar

e-ro

ot G

A Le

sion

(mm

)

Month

AM-Study Sham-Study

AM-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%


23%Differencep = 0.083

0.1 0.1

0.2 0.2

0.3 0.3

0.4 0.4N=72 N=69

Study

Fellow Fellow

Study

Lesi

ongr

owth

(mm

)

15

GA growth comparison: fellow eye vs study eye

Sham groupSham injections

Active group 1APL-2 injections every other month

Active group 2APL-2 injections every month

0 0

2months

6months

12months

2months

6months

12months

10%Difference

p > 0.1

0.1

0.2

0.3

0.4 N=63

Fellow

Study

0

2months

6months

12months


Higher incidence of wet AMD conversion in APL-2 patients with wet AMD in the fellow eye

*Source: “The Long-term Natural History of Geographic Atrophy from Age-Related Macular Degeneration” Sunness J et al, Ophthalmology, 2007 Feb; 114(2): 271-277**Note: Patient groups exclude patients with fellow-eye wet AMD in the analysis. Data as of August 24, 2017

18%

n=15 10%

n=5 4%n=2

APL-2 Monthly(no exclusions)

APL-2 Monthly(excluding

fellow-eye wet AMD**)

APL-2 EOM(excluding

fellow-eye wet AMD**)

Incidence of wet AMD in study eye for GA Phase 2 trial subjectsPercent

Eligible Market:

5%

10%

15%

20%

*According to the Sunness et al study, 27% of GA patients have fellow-eye wet

AMD

APL-2 EOM(no exclusions)

8%

n=6

73% 73%100%100%


Post hoc analysis of patients with wet AMD conversions

18

mITT, Observed Descriptive

0.361

0.157

0.274

0.355

-0.05

0

0.05

0.1

0.15

0.2

0.25

0.3

0.35

0.4

0 6 12

Mea

n (±

SE) C

hang

e fr

om B

asel

ine

in G

A

Lesi

on (m

m, s

quar

e-ro

ot)

Month

Sham-Total (n=80) AM-Wet (n=6)

AEOM-Wet (n=1) Sham-Wet (n=1)

2

Sample size for Sham-Dry includes all subjects who did not develop wet AMD from mITT population. Sample size for all other groups includes subjects who had all images up to 12 months (i.e. Baseline, month 2, month 6 and month 12). Data as of August24, 2017


0.3610.355

GA growth notably reduced in patients that converted to wet AMD

0 0 0

0.1

0.2

0.30.274

0.157

0.4

2months

2months

2months

6months

6months

6months

12months

12months

12months

0.1 0.1

0.2 0.2

0.3 0.3

0.4 0.4

Sham groupSham injections

Active group 1APL-2 injections every other month

N=1 N=80 N=1 N=6

Lesi

ongr

owth

(mm

)

Active group 2APL-2 injections every month


0.261

0.275

0.361

0

0.1

0.2

0.3

0.4

0 6 12

Mea

n (±

SE) C

hang

e fr

om B

asel

ine

in G

A

Lesi

on (m

m, s

quar

e-ro

ot)

Month

AM/ Dry AEOM/ Dry Sham/ Dry

2

23.8%

27.7%

* p=0.028 vs Sham† p=0.011 vs Sham

Group wAMD Converter Month 2 Month 6 Month 12

APL-2 Monthly (n=85) No (n=71) 67 59 58

APL-2 EOM (n=78) No (n=73) 70 64 56

Sham-Pooled (n=81) No (n=80) 76 71 65

When patients with wet AMD conversions were excluded, treatment effect persisted (post hoc)

20

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

†

*


Best Corrected Visual Acuity

-3.3

-5.8

-4.3

-10

-5

0

5

10

0 2 4 6 8 10 12LS M

ean

(±SE

) Cha

nge

from

Bas

elin

e in

BC

VA (l

ette

rs)

Month

APL-2 Monthly (n=84) APL-2 Every Other Month (n=78) Sham Pooled (n=81)

No differences were observed in visual outcomes between groups


New Onset Wet AMD

0%

10%

20%

30%

40%

50%

60%

70%

80%

90%

100%

All subjects

Subj

ects

with

new

ons

et e

xuda

tion

in st

udy

eye

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

16

1%(n=1)

18%(n=15)8%

(n=6)


New Onset Wet AMD

0%

10%

20%

30%

40%

50%

60%

70%

80%

90%

100%

History/Presence of CNV Fellow Eye No History/Presence of CNV Fellow Eye

Subj

ects

wit

h ne

w o

nset

exu

dati

on in

stu

dy e

ye

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

17

14%(n=4)

0%(n=0)

10%(n=5)

29%(n=10)

4%(n=2)

2%(n=1)


Adverse Event ProfileAdverse Eventn (%) of subjects with events

APL-2 Monthly

N=86

APL-2 EveryOther Month

N=79

Sham Pooled

N=81

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

Systemic (non-ocular) SAEs 11 (12.8%) 23 (29.1%) 16 (19.8%)

Treatment related ocular AEs in the study eye 21 (24.4%) 11 (13.9%) 0

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

Ocular SAEs APL-2 MonthlyN=86

APL-2 EOMN=79

Sham PooledN=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


Conclusions

• APL-2 slowed growth of GA, independent of genetics

• APL-2 appeared to increase risk of new onset wet AMD‒ No adverse impact on visual outcomes

• No safety issues preclude further development

25

0.250.28

0.35

0

0.1

0.2

0.3

0.4

0 6 12

LS M

ean

(±SE

) Cha

nge

from

Bas

elin

e in

Sq

uare

Roo

t GA

Lesi

on (m

m)

Month


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

2

* p=0.067 vs Sham† p=0.008 vs Sham

20.0%*†

28.6%

apl-2 in geographic atrophy - apellis.com - apl-2 in... · 2020. 6. 1. · modified intent to treat...

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