EMERGING APPROACHES TO COMBINATION THERAPIES IN AMD & DME - Aerpio Therapeutics
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Presentation by Aerpio Therapeutics at OIS@ASRS 2016. Participant: Joseph Gardner, President & CEO - Aerpio Therapeutics Powered by: Healthegy For more ophthalmology innovation Visit us at www.ois.net
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EMERGING APPROACHES TO COMBINATION THERAPIES IN AMD & DME - Aerpio Therapeutics
- 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
- 5. Targeting VE-PTP is the optimal approach to activating Tie2
- 6. TIME-2 study design Observation N=144 1:1:1 D84 D140D28 D56 D112D0 0.3 mg ranibizumab Placebo SC BID 15 mg AKB-9778 SC BID Sham injection Active Treatment Campochiaro P, et al. Ophthalmology. 2016; 123: 1722-1730,
- 7. Change in central subfield thickness -10 -8 6 0 -91 -102 -110 -106 -146 -164 -170 -120 -70 -20 Month 1 Month2 Month 3 ChangeinCST(µm) AKB-9778 (N=46) RBZ (N=47) AKB-9778 + RBZ (N=48) p = 0.008* p = 0.02* *ANCOVA w/ baseline CST as covariate Campochiaro P, et al. Ophthalmology. 2016; 123: 1722-1730,
- 8. -700 -600 -500 -400 -300 -200 -100 0 100 200 ChangeinCSTat3Months(µm) AKB-9778 + RBZ (N=48) RBZ (N=47) Per patient change in CST at 3 months
- 9. 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,
- 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
- 18. Thank You
Hinweis der Redaktion
- 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