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Evaluation of Baseline Risk Factors on Progression in Geographic AtrophyPost-hoc Analysis from the FILLY Study
Nathan Steinle, MD1, Mohamed Hamdani2
1California Retina Consultants2Apellis Pharmaceuticals
Consultant: Apellis Pharmaceuticals, Alimera Sciences; Regeneron Pharmaceuticals, Genentech; Regenxbio; Carl Zeiss Meditec; Regenerative Patch Technologies; Novartis; and Vortex Surgery
Speaker’s Bureau: Alimera Sciences; Genentech; Regeneron Pharmaceuticals; Notal Vision; and Novartis
Research Support: Carl Zeiss Meditec; Genentech; and Regeneron Pharmaceuticals
2
Financial Disclosures
Cell death, secretion, lysis, or
proliferationInflammation
Inflammation Cell removal, Antigen uptake by APCsC3a
C5a MACC5b
C3
C3b
C5
Lectin Pathway Classical Pathway Alternative Pathway
APL-2 Complete Inhibition of the Complement Pathway
The Complement Pathway and C3 Inhibition
Phase 2 Study Design
(SEOM)N=40
ShamEvery Other Month
APL-2 15 mgEvery Other Month
(AEOM)N=79
Sham Monthly
(SM)N=41
APL-2 15 mgMonthly
(AM)N=86
Eligible Patients with Geographic Atrophy*246 subjects in 43 sites†
Randomized 2:2:1:1
Treatment Period ǂ Follow up
AM (n=86]
AEOM (n=79)
SM (n=41)
SEOM (n=40)
D0 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
*Confirmed by the central reading center using FAF images, † Not counting the 3 satellite sites. ǂ Subjects also had a safety visit at Day 7
Single Masked
Primary efficacy endpointChange in square root geographic atrophy (GA) lesion size from baseline to month 12
Primary safety endpointNumber and severity oflocal and systemic treatment emergent adverse events (TEAEs)
Endpoints
treatment period
no injections
0 6months
12months
18months
2months
images taken at
APL-2 Slows GA Lesion* Growth at 12 Months
Modified Intent to Treat population (mITT), Observed, Mixed-Effect Model
6 months2 months 12 months
Cha
nge
from
bas
elin
e in
squ
are
root
G
A le
sion
grow
th (m
m)
0.250.28
0.35APL-2 EOM 20%lesion growth difference p=0.067vs Sham
APL-2 Monthly 29% lesion growth difference p=0.008vs Sham
0.4
0.3
0.2
0.1
0.5
0
Sham Injections APL-2 EOM APL-2 Monthly
*Square root
Post-hoc Analysis
• Baseline GA lesion size1,2
• Focality2-5
o Multifocal vs Unifocal
• GA lesion location4,5
o Extrafoveal vs Foveal• Low luminance deficit2,6
• GA junction patterns7
• Presence of reticular pseudo-drusen2
Risk Factors for GA Progression
1. Keenan et al. 2018, 2. Rosenfeld et al. 2018, 3. Klein et al. 2008, 4. Schmitz-Valckenberg et al. 2016, 5. Keenan et al. 2018, 6. Yehoshua et al. 2014, 7. Lindner et al. 2018
Post-hoc analysis to identify risk factors that
predict GA progression at month 12
Purpose
• N=176 subjects
o Included subjects who completed month 12 with no missing data
• Univariate analysis performed for categorical and quantitative predictors
• Multivariable analyses performed to evaluate
o Risk factors for predicting GA progression, excluding treatment designationo Relationship between treatment and GA progression after controlling for
identified risk factors
• The final model was fit by using a significance level of 0.05
Methodology
Change in GA Lesion Size at Month 12 Overall
Change in GA Lesion Size at Month 12Baseline GA Size
Change in GA Lesion Size at Month 12Baseline GA Lesion Characteristics
Change in GA Lesion Size at Month 12Pseudodrusen Status
Change in GA Lesion Size at Month 12Baseline BCVA
Change in GA Lesion Size at Month 12Baseline Low Luminance Deficit
Univariate Analysis
Risk Factors Estimate (SE) P-value
Age -0.0015 (0.002) 0.480
SexMale vs female -0.025 (0.033) 0.449
GA lesion locationFoveal vs extrafoveal -0.126 (0.031) <0.001
Baseline GA lesion size -0.022 (0.022) 0.315
Low-luminance deficit 0.003 (0.001) 0.002
BCVABCVA≥20/60 vs <20/60 0.100 (0.031) 0.001
Multivariable Analysis
Intercept = 0.447 (0.17)
Multivariable Linear RegressionNot Adjusting for Treatment
Risk Factors Estimate (SE) P-value
Age -0.001 (0.17) 0.42
SexMale vs female -0.011 (0.002) 0.71
GA lesion locationFoveal vs extrafoveal -0.090 (0.03) 0.01
Baseline GA lesion size -0.011 (0.02) 0.62
Low-luminance deficit 0.002 (0.001) 0.04
BCVABCVA≥20/60 vs <20/60 0.027 (0.03) 0.46
Final Multivariable AnalysisNot Adjusting for Treatment
Risk Factors Estimate (SE) P-value
GA lesion locationFoveal vs extrafoveal -0.106 (0.03) 0.01
Low-luminance deficit 0.002 (0.001) 0.02
Intercept = 0.30 (0.03)
Multivariable Analysis Adjusting for Treatment
Risk Factors Estimate (SE) P-value
APL-2 Monthly -0.073 (0.03) 0.04
APL-2 EOM -0.076 (0.03) 0.04
Age -0.001 (0.17) 0.42
SexMale vs female -0.011 (0.002) 0.71
GA lesion locationFoveal vs extrafoveal -0.090 (0.03) 0.01
Baseline GA lesion size -0.011 (0.02) 0.62
Low-luminance deficit 0.002 (0.001) 0.04
BCVABCVA≥20/60 vs <20/60 0.027 (0.038) 0.46
Intercept = 0.44 (0.17)
Final Multivariable AnalysisAdjusting for Treatment
Risk Factors Estimate (SE) P-value
APL-2 Monthly -0.076 (0.036) 0.03
APL-2 EOM -0.08 (0.037) 0.03
GA lesion locationFoveal vs extrafoveal -0.0967 (0.031) 0.02
Low-luminance deficit 0.0021 (0.001) 0.04
Intercept = 0.35 (0.04)
• Strengths –
o Data from large prospective Phase 2 studyo Independent masked reading center evaluations
o Masked visual acuity examiners
• Limitations –
o Post-hoc analysiso Small sample sizes in the subgroups
Strengths and Limitations
• Benefit of treatment with APL-2 compared to sham was observed across analyses
• Risk factors that are predictors of GA progression in the FILLY study population were in line with previously described in the literature
• Treatment effect with APL-2 remained statistically significant when population was controlled for two key risk factors:
a) Lesion locationb) Low-luminance deficit
Summary
Phase 3 Overview
26
2 Global Studies
Population Patients with Geographic Atrophy secondaryto AMD
1o
EndpointChange in total area of GA lesion(s) based on FAF at Month 12
Design Double Masked, Randomized 2:1:2:1
Treatment 15 mg/0.1 mL Intravitreal Injection vs. Sham Injection
Sample size
600 Subjects from approx. 100 multinational sites per study
APL-2 Monthly N = 200
Screening - R:2:1:2:1
APL-2 EOM N = 200
Sham Monthly N = 100
Sham EOM N = 100
2 years
Each study will have the following design: