Activated Tie2 is essential for vascular stability

• Transmembrane tyrosine kinase receptor located almost exclusively on endothelial cells

• Active Tie2 is essential for vascular stability by inhibiting permeability, blood retinal barrier breakdown and inflammation

Blood vessel lumen

Intracellular Space

VE-PTP is a critical down regulator of Tie2 activity

Blood vessel lumen

Intracellular Space

AKB-9778 mechanism of action

• Small molecule inhibitor of VE-PTP

• Activates Tie2

• Administered via subcutaneous injection

Targeting VE-PTP is the optimal approach to activating Tie2

TIME-2 study design

Observation

N=1441:1:1

D84 D140D28 D56 D112D00.3 mg ranibizumab

Placebo SC BID

15 mg AKB-9778 SC BID

Sham injection

Active Treatment

Campochiaro P, et al. Ophthalmology. 2016; 123: 1722-1730,

Change in central subfield thickness

Month 1 Month2 Month 3

-170

-120

-70

-20-10 -8

60

-91 -102 -110-106

-146 -164

AKB-9778 (N=46) RBZ (N=47) AKB-9778 + RBZ (N=48)

Chan

ge in

CST

(µm

)

p = 0.008*p = 0.02*

*ANCOVA w/ baseline CST as covariate

Campochiaro P, et al. Ophthalmology. 2016; 123: 1722-1730,

Series1

-700

-600

-500

-400

-300

-200

-100

0

100

200

AKB-9778 + RBZ (N=48)

RBZ (N=47)

Chan

ge in

CST

at 3

Mon

ths (

µm)

Per patient change in CST at 3 months

Visual acuity at 3 months

AKB-9778 (N=46)

RBZ(N=47)

AKB-9778 + RBZ(N=48)

Mean Δ from BL, letters 1.5 5.7 6.3≥ 2-lines, % 8.7 29.8 35.4≥ 3-lines, % 4.3 17.0 20.8

Campochiaro P, et al. Ophthalmology. 2016; 123: 1722-1730,

TIME-2 DRSS analysis

• Pre-specified, planned analysis comparing:– Study eyes: Treatment groups

Campochiaro P, et al. Ophthalmology. 2016; 123: 1722-1730,

TIME-2 DRSS analysis

• Pre-specified, planned analysis comparing:– Study eyes: Treatment groups– Non-study fellow eyes: Subcutaneous AKB-9778 treated and

placebo treated

Campochiaro P, et al. Ophthalmology. 2016; 123: 1722-1730,

Study Eye 0

5

10

15

10 8.811.4

AKB-9778 (N=40) RBZ (N=34)

AKB-9778 + RBZ (N=44)

% o

f pati

ents

Percentage of Patients with a ≥ 2-Step Improvement in DRSS from Baseline

Fellow Eye

4.2

11.4

Placebo Arm (N=24)

AKB-9778 Arms (N=70)

AKB-9778 has the ability to impact diabetic retinopathy severity bilaterally, without anti-VEGF therapy

Campochiaro P, et al. Ophthalmology. 2016; 123: 1722-1730,

Ocular and non-ocular adverse events were similar between groups

AKB-9778 (N=48)

RBZ(N=47)

AKB-9778 + RBZ

(N=49)Number of Ocular AEs 17 45 48Subjects w/ Ocular AEs, n (%) 10 (20.8) 19 (40.4) 23 (46.9)Number of Non-Ocular AEs 76 89 108Subjects w/ Non-Ocular AEs, n (%) 28 (58.3) 30 (63.8) 33 (67.3)Number of Serious AEs 2 0 2Subjects w/ Serious AEs, n (%) 2 (4.2) 0 2 (4.1)Number of Severe AEs 1 10 4Subjects w/ Severe AEs 1 (2.1) 5 (10.6) 3 (6.1)

Campochiaro P, et al. Ophthalmology. 2016; 123: 1722-1730,

Summary

• TIME-2 provides proof-of-concept for treatment of diabetic eye disease, both DME and DR, by activation of Tie2 with AKB-9778

• AKB-9778 alone and in combination with an anti-VEGF agent was well tolerated

• TIME-2 results support future development of AKB-9778

‒ in combination with anti-VEGF therapy for the treatment of DME

Summary

• TIME-2 provides proof-of-concept for treatment of diabetic eye disease, both DME and DR, by activation of Tie2 with AKB-9778

• AKB-9778 alone and in combination with an anti-VEGF agent was well tolerated

• TIME-2 results support future development of AKB-9778

‒ in combination with anti-VEGF therapy for the treatment of DME

‒ as monotherapy for the treatment of DR

• No approved treatments

• Diabetic eye disease is a global epidemic

• Targets a profound vascular stabilization mechanism with proven POC

• SC injection format addresses sustainability and access to care issues

• Treats both eyes (70% of patients have bilateral DR)

• Less invasive mode of delivery more acceptable to less symptomatic patients

AKB-9778 is ideally positioned to be the market leader in the treatment of NPDR without DME

Confidential

• Targets the extracellular domain of VE-PTP

• Pre-clinical studies have established biologic activity similar to AKB-9778• Provides additional options: – Intravitreal dosing– Stand alone therapy– Single syringe in combo

with anti-VEGF therapy– Initial indications: wAMD

and DME

ARP-1536: An alternative approach to targeting VE-PTP

Thank You