Presentation by Aerpio Therapeutics at OIS@ASRS 2016.
Participant:
Joseph Gardner, President & CEO - Aerpio Therapeutics
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EMERGING APPROACHES TO COMBINATION THERAPIES IN AMD & DME - Aerpio Therapeutics
1.
2. 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
3. VE-PTP is a critical down regulator of Tie2 activity
Blood vessel lumen
Intracellular Space
4. AKB-9778 mechanism of action
• Small molecule
inhibitor of VE-PTP
• Activates Tie2
• Administered via
subcutaneous
injection
10. TIME-2 DRSS analysis
• Pre-specified, planned analysis comparing:
– Study eyes: Treatment groups
Campochiaro P, et al. Ophthalmology. 2016; 123: 1722-1730,
11. 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,
12. 10 8.8
11.4
0
5
10
15
Study Eye
%ofpatients
AKB-9778 (N=40)
RBZ (N=34)
AKB-9778 + RBZ (N=44)
Percentage of Patients with a ≥ 2-Step Improvement in DRSS from Baseline
4.2
11.4
Fellow Eye
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,
13. 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 48
Subjects w/ Ocular AEs, n (%) 10 (20.8) 19 (40.4) 23 (46.9)
Number of Non-Ocular AEs 76 89 108
Subjects w/ Non-Ocular AEs, n (%) 28 (58.3) 30 (63.8) 33 (67.3)
Number of Serious AEs 2 0 2
Subjects w/ Serious AEs, n (%) 2 (4.2) 0 2 (4.1)
Number of Severe AEs 1 10 4
Subjects w/ Severe AEs 1 (2.1) 5 (10.6) 3 (6.1)
Campochiaro P, et al. Ophthalmology. 2016; 123: 1722-1730,
14. 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
15. 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
16. • 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
17. • 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
Tie2 is a transmembrane receptor found on endothelial cells
Under physiologic conditions the Tie2 receptor is in the activated state and maintains stable, quiescent vasculature
One of the most profound down regulators of Tie2 activity is a phosphatase called VE-PTP
VE-PTP is a transmembrane phosphatase which, similar to Tie2, is almost exclusively found in endothelial cells.
It’s only know function is to deactivate Tie2 by cleaving phosphate groups off an active Tie2 receptor.
AKB-9778 is a subcutaneously administered small molecule that inhibits VE-PTP
Once injected subcutaneously AKB-9778 it taken up into the bloodstream and works by selectively binding the catalytic domain of VE-PTP, inhibiting its ability to deactivate Tie-2
Essentially, inhibiting the inhibitor
Pre-clinical experiments have shown that targeting this enzyme may be the most effective approach to regulating Tie-2 activity.
This western blot shows Tie-2 activation, black, in cultured endothelial cells.
Of note, Tie-2 activation is most profound in the lanes where AKB-9778 is present and inhibiting VE-PTP, colored lanes
To date AKB-9778 is the only Tie2-focused therapeutic that has published data on the ability to directly activate the Tie2 receptor.
TIME-2 was a proof-of-concept, phase 2a study that studied AKB-9778 alone, AKB-9778 plus ranibizumab and ranibizumab alone in patients with DME.
144 patients were randomized equally to these three arms with active treatment for three months
The change in central subfield thickness at three months showed a 42% improvement for the combination of AKB-9778 and ranibizumab compared to the ranibizumab alone
This result was statistically significant and continued to improve at the 2- and 3-month time points.
Although the 15 mg BID dose of AKB-9778 did enhance the effect of anti-VEGF therapy, this dose did not have significant effects on CST as monotherapy in this cohort of DME patients.
In this graph each bar represents an individual patient and the length of the bar represents magnitude of a response to therapy in terms of reduction in microns
This waterfall plot shows the profound difference in anatomic response at 3 months between patients in the AKB-9778 plus ranibizumab group, shown in orange, compared to the ranibizumab alone group (blue).
In a study with a small number of patients and a short duration of active treatment a statistically significant change is visual acuity was not expected. However we did want to see a trend in the right direction
Change from baseline in visual acuity parameters such as mean VA, and the percentage of 2- and 3-line gainers were secondary endpoints and are shown here.
In larger, longer studies we would expect that a visual acuity benefit would follow this rapid decrease in CST.
One of the more interesting analyses was the change in DRSS from TIME-2
All of these analyses were pre-specified
In the study eye analysis each group was evaluated individually
The fellow eye analysis grouped patients that were exposed to subcutaneous AKB-9778 and compared those to patients were given subcutaneous placebo.
The analysis showed that in this study AKB-9778 was able to improve the proportion of patients improving 2- or more DRSS steps as well as anti-VEGF in the study eye
The proportion of patients achieving an improvement of 2- or more DRSS steps in the fellow eye was equivalent to the results seen in the study eye.
In terms of safety there were no major differences between the AKB-9778 + Lucentis group and the Lucentis monotherapy group in terms of ocular or non-ocular adverse events with the majority of AEs being mild/moderate in severity
In conclusion, the TIME-2 study provided proof-of-concept for activating Tie2 in the treatment diabetic eye disease
AKB-9778 was well-tolerated
Future clinical trials will study
The combination of AKB-9778 + anti-VEGF therapy in DME and
AKB-9778 monotherapy in patients with diabetic retinopathy
In conclusion, the TIME-2 study provided proof-of-concept for activating Tie2 in the treatment diabetic eye disease
AKB-9778 was well-tolerated
Future clinical trials will study
The combination of AKB-9778 + anti-VEGF therapy in DME and
AKB-9778 monotherapy in patients with diabetic retinopathy