apl-2 (pegcetacoplan) geographic atrophy preliminary 18 ... - apl-2...post hoc analysis: in...
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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
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Financial disclosures
• Consultant – Genentech, Regeneron, Novartis/Alcon, Optos, Zeiss
• Sponsored research support – Apellis, Genentech, Regeneron , Alcon/Novartis, Clearside
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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
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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
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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).
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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)
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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)
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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
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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
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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
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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%
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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
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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
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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)
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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
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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
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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