Aflibercept Combination Therapies Rinucumab/Aflibercept

andNesvacumab/Aflibercept

David Boyer, MD

Why Do We Need Combination Therapy?

• Wet AMD (VIEW 1 & 2 @ Year 1)– Only 31-33% 3 line gainers– Only 66-71% dry on OCT

• DME (Protocol T @ Year 1)– Only 42% 3 line gainers– Only 62-70% CFT <250 microns

HOW CAN WE DO BETTER?

Rationale for New Targets

Platelet Derived Growth Factor Receptor (PDGFR)• PDGF up regulation leads to pericyte recruitment• Pericytes protect endothelial cells from VEGF withdrawal and

confer resistance to VEGF blockade

Angiopoeitin2 (Ang2)• Significant up-regulation of Ang2 may play a role in vessel

remodeling, sprouting, and regression as associated with ophthalmic vascular and inflammatory diseases

Rinucumab/Aflibercept in Neovascular AMD(Co-formulated Anti-PDGFRβ + Anti-VEGF)

• Rinucumab is a recombinant human antibody that binds to human platelet-derived growth factor receptor β (PDGFRβ)

• Co-formulated with aflibercept in the investigational product rinucumab/aflibercept in a single 50uL intravitreal injection

Anti-PDGF-Rβ + Aflibercept Combination Induced Both Mural Cell Stripping and Regression of Newly

Formed Vasculature

P4 P4-P6 anti-PDGF-R

NG2NG2

lectinlectin

P4-P6 Combo

NG2

lectinlectin

Phase 1 Study Design: Overview

Phase 1, Open Label, Dose-EscalationPatients with Neovascular AMD

Follow-up to Week 24

Cohort 2rinucumab/aflibercept

0.5 mg : 2mg

Cohort 3rinucumab/aflibercept

1 mg : 2mg

Cohort 4rinucumab/aflibercept

3 mg : 2mg

• 4 dose-escalating cohorts: 3 patients per cohort • Study drug administration at baseline and week 4

• Patients eligible for IAI monotherapy as needed, beginning at week 8

• Primary outcome: safety and tolerability through week 8

Cohort 1rinucumab/aflibercept

0.2 mg : 2mg

Phase 1 Study: Safety Summary

• No Dose Limiting Toxicities

• No Intraocular Inflammation

• No Serious Adverse Events

– One patient developed an RPE tear resulting in a loss of >20 letters not considered related to study treatment

Phase 2 Study Design: Overview

Multiple Dose, randomized, controlled

N = 500 patients

Primary Endpoint:Mean change in BCVA at Week 12

GROUP 3IVT aflibercept

2mg

GROUP 1rinucumab/aflibercept

Dosing Regimen 1

GROUP 2rinucumab/aflibercept

Dosing Regimen 2

Combined Anti-Ang2/Anti-VEGF Therapy in Neovascular AMD and DME

Nesvacumab/aflibercept is a co-formulated drug product consisting of the fully human mAb,

nesvacumab, and the fusion protein, aflibercept

Angiopoietin/Tie2 Signaling Pathway

ANGPT1 ANGPT2

TIE2

ANGPT2

TIE1 VEPTPIntegrin51

PIP2PIP3

PI3K

AKTSHP2

eNOS Survivin Caspase

ABIN2

IKK

NF-B

DOKR

Nck

PAK

Ras

RAF1

MEKFAK ERK1 and ERK2

GRB2

• ICAM1• VCAM1• E-selectin

InflammationEndothelial cell

survival interactionEndothelial cell proliferation

and migration

• Tie2 is an endothelial cell-specific tyrosine kinase receptor to which two ligands bind– Ang1 –

• Expressed in normal adult tissues to help maintain vascular integrity

– Ang2 –• Secreted by endothelial cells• Required for post-natal vascular

remodeling and is only expressed under pathological conditions

• Expressed in endothelial cells at – very low levels in quiescent

blood vessels– high levels in ‘angiogenic’

vesselsThurston and Daly. Cold Spring Harb Perspect Med 2012;2:a006650Jones et al. Nature Reviews Molecular Cell Biology 2, 257-267 (April 2001)Eklund, Lauri et al. "Angiopoietin signaling in the vasculature." Experimental cell research 319.9 (2013): 1271-1280

Effect of IVT Administration of Nesvacumab, Alone OR in Combination with Aflibercept in a Retinal

Vascular Development Model

Area of the superficial retinal plexus

P4 (post natal day 4); P6 (post natal day 6)

Total length of vessels of superficial retinal plexus

Nesvacumab

Nesvacumab

Nesvacumab Increased Duration ofAnti-Leak Action of Aflibercept in Preclinical model

of Chronic Vascular LeakSingle IVT injection of Aflibercept or Nesvacumab or both co-formulated

Nesvacumab (500 mcg/eye)Aflibercept (125 mcg/eye)

Nesvacumab/Aflibercept (500:125 mcg/eye)

• 4 dose-escalating cohorts– 4 patients per cohort (2 AMD and 2 DME)

• Nesvacumab/aflibercept co-formulated drugand delivered in a single 50μL Intravitreal injection

• Study drug administration at baseline, week 4, and week 8• Patients eligible for monotherapy with initravitreal aflibercept injection (IAI)

as needed, beginning week 12

Phase 1 Study Design: OverviewNesvacumab/aflibercept is a co-formulated drug product consisting of the

fully human mAb, nesvacumab, and the fusion protein, aflibercept

Phase 1, Open-label, Dose Escalation Studyin patients with Neovascular AMD or DME

Follow-up to Week 24

Cohort 2nesvacumab/aflibercept

1 mg : 2mg

Cohort 3nesvacumab/aflibercept

3 mg : 2mg

Cohort 4nesvacumab/aflibercept

6 mg : 2mg

Cohort 1nevacumab/aflibercept

0.5 mg : 2mgCohort 5

nesvacumab6 mg

Phase 1 Study: Safety Summary

• No Dose Limiting Toxicities

• No Intraocular Inflammation

• No Serious Adverse Events in the combination cohorts – One SAE of acute MI in the nesvacumab monotherapy cohort in a patient with a contributory history of diabetes and high cholesterol

Time of Re-treatment with IAI following the Mandatory Week 8 Dose

8 12 16 20 24

Time of Re-treatment (Weeks)

AMD Pt. 2AMD Pt. 1DME Pt. 1DME Pt. 2

AMD Pt. 2AMD Pt. 1DME Pt. 1DME Pt. 2AMD Pt. 2AMD Pt. 1DME Pt. 1DME Pt. 2AMD Pt. 2AMD Pt. 1DME Pt. 1DME Pt. 2AMD Pt. 2AMD Pt. 1DME Pt. 2DME Pt. 1

Coh

ort 5

(Nes

vacu

mab

6 m

g)C

ohor

t 1(0

.5 m

g:2

mg)

Coh

ort 2

(1 m

g:2

mg)

Coh

ort 3

(3 m

g:2

mg)

Coh

ort 4

(6 m

g:2

mg)

Combination therapy may prolong the effect of Aflibercept alone

Multiple Dose, randomized, controlled

Week 12 Primary Endpoint: Mean change in BCVA

GROUP 3IVT aflibercept

2mg

GROUP 1nesvacumab/aflibercept

Dose 1

GROUP 2nesvacumab/aflibercept

Dose 2

Key Secondary Objectives• If nesvacumab/aflibercept demonstrates an anatomical benefit compared to

IVT aflibercept alone• Duration of effect of nesvacumab/aflibercept• Safety and tolerability of nesvacumab/aflibercept

Total Study Duration: 36 Weeks

Study DesignN=360 patients N=300 patients

• Combination therapies may synergistically target different pathways and lead to increased efficacy and/or durability

• IVT aflibercept co-formulated with anti-PDGF (rinucumab) was demonstrated to be safe in a Phase 1 study of AMD patients; Phase 2 study underway– Primary results expected in H2’16

• IVT aflibercept co-formulated with anti-Ang2 (nesvacumab) was well tolerated in a Phase 1 study of AMD and DME patients; Phase 2 studies are under design

Summary

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