APL-2 in Geographic Atrophy - Apellis.com - APL-2 in... · 2020. 6. 1. · Modified Intent to Treat...
Transcript of 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
CONFIDENTIAL AND PROPRIETARY – for discussion purposes only
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
CONFIDENTIAL AND PROPRIETARY – for discussion purposes only4
APL-2 targets C3 centrally in the complement cascade
8
Lectin Pathway
Classical Pathway
Alternative Pathway
C3Phagocytosis
Membrane attack
Inflammation
APL-2
CONFIDENTIAL AND PROPRIETARY – for discussion purposes only
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
CONFIDENTIAL AND PROPRIETARY – for discussion purposes only6
(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
CONFIDENTIAL AND PROPRIETARY – for discussion purposes only
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
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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
CONFIDENTIAL AND PROPRIETARY – for discussion purposes only810
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
CONFIDENTIAL AND PROPRIETARY – for discussion purposes only912
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.
CONFIDENTIAL AND PROPRIETARY – for discussion purposes only
Baseline Characteristics
• Groups were well balanced as to age, gender and race
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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)
CONFIDENTIAL AND PROPRIETARY – for discussion purposes only
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
0.35
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
CONFIDENTIAL AND PROPRIETARY – for discussion purposes only
Primary Endpoint: GA Lesion Growth
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
CONFIDENTIAL AND PROPRIETARY – for discussion purposes only
Primary Endpoint: GA Lesion Growth
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 Monthly (n=84)
APL-2 Every Other Month (n=78)
Sham Pooled (n=80)
2
20.0%*
†
28.6%
CONFIDENTIAL AND PROPRIETARY – for discussion purposes only
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%
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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
CONFIDENTIAL AND PROPRIETARY – for discussion purposes only
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%
CONFIDENTIAL AND PROPRIETARY – for discussion purposes only16
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
CONFIDENTIAL AND PROPRIETARY – for discussion purposes only17
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%
CONFIDENTIAL AND PROPRIETARY – for discussion purposes only
Post hoc analysis of patients with wet AMD conversions
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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
CONFIDENTIAL AND PROPRIETARY – for discussion purposes only1917
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
CONFIDENTIAL AND PROPRIETARY – for discussion purposes only
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)
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mITT, Observed, ANOVA at Month 12. Data as of August 24, 2017
†
*
CONFIDENTIAL AND PROPRIETARY – for discussion purposes only21
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
CONFIDENTIAL AND PROPRIETARY – for discussion purposes only
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)
CONFIDENTIAL AND PROPRIETARY – for discussion purposes only
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
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14%(n=4)
0%(n=0)
10%(n=5)
29%(n=10)
4%(n=2)
2%(n=1)
CONFIDENTIAL AND PROPRIETARY – for discussion purposes only24
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
CONFIDENTIAL AND PROPRIETARY – for discussion purposes only
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 Monthly (n=84)
APL-2 EOM (n=78) Sham Pooled (n=80)
2
* p=0.067 vs Sham† p=0.008 vs Sham
20.0%*†
28.6%