Evaluation of Baseline Risk Factors on Progression in ... Evaluation of Impact of... · Evaluation of Baseline Risk Factors on Progression in Geographic Atrophy Post-hoc Analysis

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

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bas

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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: