EMERGING APPROACHES TO COMBINATION THERAPIES IN AMD & DME - Regeneron
Transcript of EMERGING APPROACHES TO COMBINATION THERAPIES IN AMD & DME - Regeneron
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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