In the future, the number of patients with diabetes mellitus will dramatically increase, and approximately one-third of them will have DR.¹ Although improved blood glucose control can reduce the incidence of DR progression, maintaining such control for extended periods of time is difficult for most diabetics. Additionally, many patients develop clinically significant loss of VA due to proliferative DR (PDR) or DME despite tight control of glycated hemoglobin (HbA₁c).^2-4 This is very relevant as many diabetic patients fear visual loss and consider it the worst complication of diabetes regardless of whether they have personally experienced it.^5,6

Diabetic retinopathy is the leading cause of blindness in working-age patients. Prevention of the sight-threatening sequelae of DR would have a significant global impact on day-to-day functioning of individuals with diabetes as well as on the societal and economic burden of diabetes.

AVAILABLE TREATMENTS FOR DIABETIC EYE DISEASE

Treatment of diabetic eye disease is generally restricted to eyes demonstrating DME or PDR. For center-involved (CI)DME, intravitreal therapy (IVT) with anti-VEGF therapies or corticosteroids has replaced laser therapy as the standard of care. Although these therapies usually provide clinically significant improvement in BCVA, many patients continue to experience residual visual loss, with approximately 40% of patients not achieving BCVA of 20/40 or better.⁷ Frequent injections also result in a significant treatment burden, and IVT can result in rare but potentially vision threatening adverse events such as endophthalmitis, RD, and vitreous hemorrhage.⁸

Although the standard treatment for PDR, panretinal photocoagulation (PRP), effectively manages progression of vision loss, VA is stabilized rather than improved, and side effects such as reduced peripheral vision, dark adaptation, and color vision can occur.⁹ The recently completed DRCR.net Protocol S, a randomized controlled study comparing PRP to anti-VEGF therapy for PDR, found that the 2 therapies were similar, without significant increase in BCVA after 2 years of therapy with either treatment.¹⁰

There is clearly a need for treatment options that prevent the progression of DR, which is directly associated with increased risk of vision loss due to PDR^11,12 or DME,¹³ as well as a decreased quality of life.^14,15 Regression of DR severity should result in decreased incidence of visual loss. In pivotal phase 3 clinical trials of anti-VEGF agents (ranibizumab [Lucentis]; Genentech/Roche and aflibercept [Eylea]; Regeneron) for the treatment of DME, treatment showed beneficial effects on DR severity.^16,17 Based on these data, Lucentis and Eylea have been approved for the treatment of DR in patients with DME. Lucentis also recently received FDA approval for treatment of DR based on the results of the RISE/RIDE clinical trials as well as DRCR.net Protocol S in patients with PDR.¹⁸ Two trials are currently under way to test the efficacy of Eylea in patients with moderately severe to severe DR without DME (the PANORAMA study, NCT02718326, sponsored by Regeneron; and Protocol W, NCT02634333, sponsored by DRCR.net ). However, to date, there are no clinical trial data on the efficacy of anti-VEGF therapy in the treatment of nonproliferative DR (NPDR) in patients prior to the development of DME or PDR.

MOVING BEYOND ANTI-VEGF: THE TIE2 PATHWAY

There has been a great deal of activity to identify targets other than VEGF to treat diabetic eye disease. The Tie2 pathway has generated a great deal of attention in the treatment of various vasculopathies, including DR.^19,20 Over the last decade, this pathway has been identified as a key modulator of endothelial function and vascular stability.^21,22

Tie2 is a transmembrane receptor expressed principally in vascular endothelial cells and serves as the receptor for the angiopoietin family of secreted polypeptides. The members of the angiopoietin family that are ligands for Tie2 are angiopoietin-1 (Ang1), which is a Tie2 receptor agonist, and angiopoietin-2 (Ang2), which functions as a context-dependent Tie2 receptor antagonist.^23,24 In addition to these ligands, vascular endothelial protein tyrosine phosphatase (VE-PTP), a membrane-bound phosphatase found exclusively in endothelial cells, is a downstream intracellular inhibitor of Tie2 activity which can override the effects of the angiopoietins on Tie2. The bulk of evidence indicates that Ang1 signaling promotes normal vascular integrity. Conversely, in settings where VE-PTP and Ang2 are upregulated, Tie2 signaling is blunted and the vasculature is destabilized, thereby promoting vascular leak and enabling pathologic angiogenesis (Figure 1). Reduction of Tie2 activity has been implicated in vascular destabilization that precedes ischemia in diabetic eye disease.^25-27

TARGETING THE TIE2 PATHWAY

Restoration of Tie2 activity (Figure 2) could directly address the pathophysiology of DR by enhancing endothelial survival and function and improving vascular stability.²⁸

Tie2 Activation Via VE-PTP Inhibition

AKB-9778 (Aerpio Therapeutics) is a small molecule that inhibits the intracellular catalytic domain of VE-PTP (Figure 2). It is being developed as a novel subcutaneous therapy for the treatment of DR. This approach is based on the discovery that inhibition of VE-PTP enhances Tie2 activation and signaling.^29-31 AKB-9778 has shown beneficial effects in multiple preclinical models of retinopathy.³⁰

In phase 1b and 2a clinical studies of AKB-9778 administered subcutaneously at 15 mg BID for up to 3 months, the drug has been well tolerated, and there were no serious adverse events attributable to the drug.^32,33 In the 3-month, phase 2a proof-of-concept study, TIME-2, the effect of AKB-9778 on DR was assessed in a prospective prespecified analysis in patients who had NPDR at baseline.³³ Eligible eyes for the analysis had 7-field fundus photographs at baseline and end of treatment, and were not rescued during the treatment period. Eligibility criteria were met for 118/144 study eyes and 94/144 fellow eyes. The results provided evidence that 15 mg AKB-9778 dosed subcutaneously BID may reduce the severity of NPDR (Figure 3). When eyes were treated with AKB-9778 as monotherapy or in combination with Lucentis, the percentage of patients with ≥2-step improvement in diabetic retinopathy severity scale (DRSS) in the study eye was similar to that for study eyes treated with Lucentis alone. In fellow eyes treated with AKB-9778 as monotherapy, the percentage of patients with a ≥2-step improvement in DRSS was greater than that obtained in untreated fellow eyes of patients treated with Lucentis in the study eye.

These results are noteworthy given that current treatment of DR is largely limited to patients who have already developed sight-threatening conditions. The invasive nature of repeated IVT in one or often both eyes, as well as the associated complications and treatment burden, has led to suboptimal compliance and fewer injections in the real-world treatment of DME.^34,35 These considerations make it unlikely that repeated IVT would be a sustainable treatment option in moderate/severe NPDR patients who generally have well-preserved VA and frequently have bilateral disease. Subcutaneous administration of AKB-9778 may afford the opportunity to address DR in both eyes without the need for an intravitreal injection and may be less of a treatment burden.

Tie2 Activation Via Ang2 Inhibition

Neutralization of Ang2 may also activate Tie2 by removing competition for Ang1 binding. There are currently 2 anti-Ang2 antibodies in clinical trials that are assessing the effect of combined suppression of VEGF and Ang2 vs suppression of VEGF alone in patients with DME. The BOULEVARD trial (clinicaltrials.gov ID NCT02699450) is examining the efficacy of IVT injections every 4 weeks of 1.5 mg or 6 mg of RO6867461 (Genentech/Roche), a bispecific antibody that blocks VEGF-A and Ang2, compared to 0.3 mg Lucentis every 4 weeks. In the RUBY study (clinicaltrials.gov ID NCT02712008), patients with DME are being randomized to receive 3 mg REGN910-3 (Regeneron), an anti-Ang2 antibody, combined with 2 mg Eylea, 6 mg REGN910-3 and 2 mg Eylea, or 2 mg Eylea. These studies will provide critical information about whether combined suppression of Ang2 and VEGF provides added benefits relative to suppression of VEGF alone in patients with DME.

VE-PTP Inhibition More Efficient Than Ang2 Neutralization in Activating Tie2

Current preclinical evidence suggests that VE-PTP inhibition might be a more efficient approach than Ang2 neutralization to restore Tie2 activation and vascular stability in the diabetic retina. AKB-9778 inhibition of VE-PTP is intracellular and its effects on Tie2 are downstream of the effects of Ang1 and Ang2 ligands. VE-PTP is upregulated under hypoxic conditions³⁰ and acts as a final brake on Tie2 activation. This upregulation of VE-PTP provides resistance to activation of Tie2 by Ang1. Thus, an effective anti-Ang2 antibody may not restore normal Tie2 activity in the context of active VE-PTP (Figure 4). AKB-9778, by inhibiting VE-PTP, may restore normal Tie2 activity independent of the presence of Ang1 or Ang2 (Figure 4).³⁰ Furthermore, VE-PTP inhibition enhances both Ang1-mediated Tie2 activation and the Tie2 agonist properties of Ang2.^30,36

POTENTIAL FUTURE TREATMENT PARADIGM FOR DIABETIC RETINOPATHY

The next breakthrough in the treatment of diabetic eye disease is likely to involve the prevention of DR progression, thereby reducing or eliminating the vision loss caused by DME and PDR. There is ample preclinical evidence that restoring Tie2 activation plays an important role in preventing vascular pathology in diabetic retinas prior to, as well as following, the onset of retinal ischemia. Clinical trials with anti-Ang2 antibodies in combination with VEGF inhibition in patients with DME are currently ongoing. Treatment with anti-Ang2 antibodies may prove to be sufficient to restore Tie2 activity and provide benefit in patients with DME. Unfortunately, like anti-VEGF monotherapy, their intravitreal mode of delivery is less suitable for the treatment of patients with NPDR without DME especially in the setting of good visual function and bilateral disease. The inhibition of VE-PTP by subcutaneous AKB-9778 may prove to be a more effective activator of Tie2, leading to improvement in DR. The subcutaneous route of administration treats both eyes and allows for patient self-administration at home, resulting in decreased treatment burden and a potentially more viable strategy for the treatment of NPDR. RP

REFERENCES

1. Yau JW, Rogers SL, Kawasaki R, et al; Meta-Analysis for Eye Disease (META-EYE) Study Group. Global prevalence and major risk factors of diabetic retinopathy. Diabetes Care. 2012;35(3):556-564.
2. The Diabetes Control and Complications Trial Research Group. The absence of a glycemic threshold for the development of long-term complications: the perspective of the diabetes control and complications trial. Diabetes. 1996;45(10):1289-1298.
3. Stratton IM, Kohner EM, Aldington SJ, et al. UKPDS 50: risk factors for incidence and progression of retinopathy in Type II diabetes over 6 years from diagnosis. Diabetologia. 2001;44(2):156-163.
4. Chew EY, Ambrosius WT, Davis MD, et al; ACCORD Study Group. Effects of medical therapies on retinopathy progression in type 2 diabetes. N Engl J Med. 2010;363(3):233-244.
5. Coyne KS, Margolis MK, Kennedy-Martin Tet al. The impact of diabetic retinopathy: perspectives from patient focus groups. Fam Pract. 2004;21(4):447-453.
6. Luckie R, Leese G, McAlpine R, et al; DARTS/MEMO Collaboration. Fear of visual loss in patients with diabetes: results of the prevalence of diabetic eye disease in Tayside, Scotland (P-DETS) study. Diabet Med. 2007;24(10):1086-1092.
7. Nguyen QD, Brown DM, Marcus DM, et al; RISE and RIDE Research Group. Ranibizumab for diabetic macular edema: results from 2 phase III randomized trials: RISE and RIDE. Ophthalmology. 2012;119(4):789-801.
8. Souied EH, Dugel PU, Ferreira A, Hashmonay R, Lu J, Kelly SP. Severe ocular inflammation following ranibizumab or aflibercept injections for age-related macular degeneration: a retrospective claims database analysis. Ophthalmic Epidemiol. 2016;23(2):71-79.
9. Muqit MM, Sanghvi C, McLauchlan R, et al. Study of clinical applications and safety for Pascal laser photocoagulation in retinal vascular disorders. Acta Ophthalmol. 2012;90(2):155-161.
10. Gross JG, Glassman AR, Jampol LM, et al. Panretinal photocoagulation vs intravitreous ranibizumab for proliferative diabetic retinopathy: a randomized clinical trial. JAMA. 2015;314(20):2137-2146.
11. Davis MD, Fisher MR, Gangnon RE, et al. Risk factors for high-risk proliferative diabetic retinopathy and severe visual loss: early treatment diabetic retinopathy study report #18. Invest Ophthalmol Vis Sci. 1998;39(2):233-252.
12. Ip MS, Domalpally A, Sun JK, Ehrlich JS. Long-term effects of therapy with ranibizumab on diabetic retinopathy severity and baseline risk factors for worsening retinopathy. Ophthalmology. 2015;122(2):367-374.
13. Klein R, Klein BE, Moss SE. How many steps of progression of diabetic retinopathy are meaningful? The Wisconsin epidemiologic study of diabetic retinopathy. Arch Ophthalmol. 2001;119(4):547-553.
14. Hariprasad SM, Mieler WF, Grassi M, Green JL, Jager RD, Miller L. Vision-related quality of life in patients with diabetic macular oedema. Br J Ophthalmol. 2008;92(1):89-92.
15. Mazhar K, Varma R, Choudhury F, McKean-Cowdin R, Shtir CJ, Azen SP. Los Angeles Latino Eye Study Group. Severity of diabetic retinopathy and health-related quality of life: the Los Angeles Latino Eye Study. Ophthalmology. 2011;118(4):649-655.
16. Ip MS, Domalpally A, Hopkins JJ, Wong P, Ehrlich JS. Long-term effects of ranibizumab on diabetic retinopathy severity and progression. Arch Ophthalmol. 2012;130(9):1145-1152.
17. Korobelnik JF, Do DV, Schmidt-Erfurth U, et al. Intravitreal aflibercept for diabetic macular edema. Ophthalmology. 2014;121(11):2247-2254.
18. Writing Committee for the Diabetic Retinopathy Clinical Research Network, Gross JG, Glassman AR, et al. Panretinal photocoagulation vs intravitreous ranibizumab for proliferative diabetic retinopathy: a randomized clinical trial. JAMA. 2015;314(20):2137-2146.
19. Han S, Lee SJ, Kim KE, et al. Amelioration of sepsis by TIE2 activation-induced vascular protection. Sci Transl Med. 2016;8(335):335ra55.
20. Campochiaro PA, Peters KG. Targeting Tie2 for treatment of diabetic retinopathy and diabetic macular edema. Curr Diab Rep. 2016;16(12):126-146.
21. Peters KG, Kontos CD, Lin PC, et al. Functional significance of Tie2 signaling in the adult vasculature. Recent Prog Horm Res. 2004;59:51-71.
22. Augustin HG, Koh GY, Thurston G, Alitalo K. Control of vascular morphogenesis and homeostasis through the angiopoietin-Tie system. Nat Rev Mol Cell Biol. 2009;10(3):165-177.
23. Gale NW, Thurston G, Hackett SF, et al. Angiopoietin-2 is required for postnatal angiogenesis and lymphatic patterning, and only the latter role is rescued by angiopoietin-1. Dev Cell. 2002;3(3):411-423.
24. Lobov IB, Brooks PC, Lang RA. Angiopoietin-2 displays VEGF-dependent modulation of capillary structure and endothelial cell survival in vivo. Proc Natl Acad Sci USA. 2002;99(17):11205-11210.
25. Hammes HP, Lin J, Wagner P, Feng Y, et al. Angiopoietin-2 causes pericyte dropout in the normal retina: evidence for involvement in diabetic retinopathy. Diabetes. 2004;53(4):1104-1110.
26. Yao D, Taguchi T, Matsumura T, et al. High glucose increases angiopoietin-2 transcription in microvascular endothelial cells through methylglyoxal modification of mSin3A. J Biol Chem. 2007;282(42):31038-31045.
27. Pfister F, Feng Y, vom Hagen F, et al. Pericyte migration: a novel mechanism of pericyte loss in experimental diabetic retinopathy. Diabetes. 2008;57(9):2495-2502.
28. Hammes HP, Feng Y, Pfister F, Brownlee M. Diabetic retinopathy: targeting vasoregression. Diabetes. 2011;60(1):9-16.
29. Winderlich M, Keller L, Cagna G, et al. VE-PTP controls blood vessel development by balancing Tie-2 activity. J Cell Biol. 2009;185(4):657-671.
30. Shen J, Frye M, Lee BL, et al. Targeting VE-PTP activates Tie2 and stabilizes the ocular vasculature. J Clin Invest. 2014;124(10):4564-4576.
31. Frye M, Dierkes M, Küppers V, et al. Interfering with VE-PTP stabilizes endothelial junctions in vivo via Tie-2 in the absence of VE-cadherin. J Exp Med. 2015;212(13):2267-2287.
32. Campochiaro PA, Sophie R, Tolentino M, et al. Treatment of diabetic macular edema with an inhibitor of vascular endothelial-protein tyrosine phosphatase that activates Tie2. Ophthalmology. 2015;122(3):545-554.
33. Campochiaro PA, Khanani A, Singer M, et al; TIME-2 Study Group. Enhanced benefit in diabetic macular edema from AKB-9778 Tie2 activation combined with vascular endothelial growth factor suppression. Ophthalmology. 2016;123(8):1722-1730.
34. Kiss S, Liu Y, Brown J, et al. Clinical utilization of anti-vascular endothelial growth-factor agents and patient monitoring in retinal vein occlusion and diabetic macular edema. Clin Ophthalmol. 2014;8:1611-1621.
35. Sivaprasad S, Oyetunde S. Impact of injection therapy on retinal patients with diabetic macular edema or retinal vein occlusion. Clin Ophthalmol. 2016;10:939-946.
36. Yuan HT, Khankin EV, Karumanchi SA, Parikh SM. Angiopoietin 2 is a partial agonist/antagonist of Tie2 signaling in the endothelium. Mol Cell Biol. 2009;29(8):2011-2022.