Diabetic Eye Disease: The Therapeutic Landscape

Of roughly 37 million Americans with diabetes, an estimated 9.6 million (26.4%) have diabetic retinopathy (DR) with 1.8 million (5%) of those cases considered vision-threatening.^1,2 Compared with data published in 2004, these numbers have more than doubled.³ Despite recent advances in the field of anti-VEGF therapy, many patients continue to suffer from treatment-resistant macular edema (Figure).

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Figure. OCT of the macula of a patient with persistent intraretinal fluid despite serial anti-VEGF treatment.

Recent DR clinical trials have sought to improve outcomes, prolong treatment duration, and mitigate the iatrogenic risks associated with treatment. Many phase 2 and 3 studies are underway for novel antibodies, small molecules, gene therapies, topicals, and oral options, as well as novel delivery mechanisms (Table). Here, we review the landscape of clinical trials for DR/diabetic macular edema (DME) management, highlighting select studies that may improve our ability to manage these conditions.

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INTRAVITREAL

RC28-E (RemeGen), a fusion protein targeting FGF2 and VEGF, has been shown to reduce vascular leakage and apoptosis in preclinical models.⁴ A phase 3 trial (NCT05885503) recruiting 316 patients with DME is comparing 2 mg RC28-E with aflibercept (Eylea, Regeneron), with each arm receiving the assigned agent every 4 weeks for five injections, then every 8 weeks through week 48. The primary outcome is change in BCVA.

UBX1325 (foselutoclax, Unity Biotechnology) reduces retinal vascular inflammation via inhibition of Bcl-xl, an apoptosis-regulating protein. The phase 2 BEHOLD study (NCT04857996) showed that, for 65 patients with DME resistant to anti-VEGF therapy, a single UBX1325 injection led to sustained BCVA improvement from baseline (+6.2 ETDRS letters) compared with sham at 48 weeks.⁵ The phase 2b ASPIRE study (NCT06011798) will include 40 patients with NPDR and persistent center-involving DME (CI-DME) despite three or more anti-VEGF injections in the prior 6 months. All patients will receive three monthly loading doses of aflibercept, then treatment (10 µg UBX1325 every 8 weeks) or control (aflibercept every 8 weeks). The primary outcome is mean change in BCVA at 24 weeks; secondary measures include central subfield thickness (CST) changes, ETDRS gains, and safety.

OPT-302 (Opthea) is an anti-VEGF therapy that blocks VEGF-C and VEGF-D and is designed to be used in combination with current anti-VEGF agents. In a phase 2 trial (NCT03397264) of patients with persistent DME, 52.8% of participants treated with OPT-302 in combination with aflibercept achieved a visual gain of ≥ 5 ETDRS letters at 12 weeks compared with baseline. The company has yet to announce further plans in the DME space.

THR-149 (Oxurion), a bicyclic peptide that selectively inhibits human plasma kallikrein, was under investigation for the treatment of DME. In November, the company announced that part B of the phase 2 KALAHARI trial (NCT04527107) did not meet the primary endpoint of improved vision at month 3 compared with aflibercept.⁶

AG-73305 (Allgenesis Biotherapeutics), a bispecific Fc-fusion protein, is in a phase 2a trial (NCT05301751) evaluating the drug’s safety and efficacy for the treatment of DME. Preliminary data for six patients treated with the 0.5 mg and 1 mg doses (n = 3 each) suggest that the drug is well-tolerated, and early improvements in BCVA at week 1 were maintained for 3 months.⁷

Vorolanib (EYP-1901, EyePoint Pharmaceuticals), a tyrosine kinase inhibitor, is a potential 9-month treatment option for moderately severe to severe NPDR. The ongoing phase 2 PAVIA trial (NCT05383209) enrolled 77 patients randomly assigned to 2 mg or 3 mg vorolanib or sham, and interim data show a positive safety profile at 3 months. The 12-month trial will evaluate the improvement of ≥ 2 Diabetic Retinopathy Severity Score (DRSS) steps at week 36.⁸

RO7200220 (Hoffmann-La Roche) is an interleukin-6 inhibitor in phase 2 (NCT05151731) for the treatment of DME. Patients will randomly receive 0.25 mg of the study drug every 8 weeks, 1.0 mg every 4 or 8 weeks, or ranibizumab (Lucentis, Genentech/Roche) every 4 weeks. The trial is evaluating safety and efficacy up to week 72. The company is also investigating RO7200220 in combination with ranibizumab (NCT05151744).

Tarcocimab (KSI-301, Kodiak Sciences), an intravitreal anti-VEGF biologic that uses an antibody biopolymer conjugate platform, is dosed every 24 weeks. The phase 3 GLOW study (NCT05066230) met its primary endpoint with 41.1% of treated patients demonstrating at least a 2-step DRSS improvement versus 1.4% of patients in the sham group. Based on the positive findings, the company is reinitiating the program, having paused it after the phase 3 GLEAM and GLIMMER trials failed to meet their primary endpoints.⁹

GENE THERAPY

ABBV-RGX-314 (Regenxbio), a transgene encoding an anti-VEGF antibody fragment packaged in an AAV8 vector for one-time suprachoroidal injection, showed promising results in the ALTITUDE trial (NCT04567550) for NPDR and mild PDR without CI-DME. At 1 year, 70.8% of patients treated with 5x10¹¹ GC/eye of ABBV-RGX-314 experienced DRSS improvement compared with 25% of controls, and no patients worsened by 2 steps or more compared with 37.5% of the control group. Of the 50 patients treated with ABBV-RGX-314, three eyes (6%) experienced intraocular inflammation that resolved with topical steroids.¹⁰

4D-150 (4D Molecular Therapeutics) is an intravitreally injected gene therapy that expresses aflibercept and a micro-RNA targeted to VEGF-C. The phase 2 trial (NCT05930561) aims to enroll 72 patients with CI-DME and BCVA of 25 to 83 ETDRS letters, divided into dose-confirmation and dose-expansion groups using fixed-regimen aflibercept as a control over 52 weeks.¹¹ The primary outcome is the number of rescue injections, with secondary measures including change in BCVA, CST, DRSS, and adverse events through 104 weeks.

CORTICOSTEROIDS

OXU-001 (Oxular) is a suprachoroidal injection of dexamethasone microspheres delivered via the company’s Oxulumis microcatheter. The 52-week phase 2 OXEYE study (NCT05697809) for DME compares adverse events, BCVA, CST, and interval to recurrence between intravitreal dexamethasone (Ozurdex, Allergan/AbbVie) and suprachoroidal OXU-001. Preclinical studies show that therapeutic levels of OXU-001 were maintained in the retina for 12 months post-injection. The safety and tolerability of the Oxulumis microcatheter is also being tested in a separate 24-week study (NCT05512962) using triamcinolone acetonide.

IBE-814 IVT (Ripple Therapeutics) is an intravitreal dexamethasone implant in the phase 2 RIPPLE-1 trial (NCT04576689) for the treatment of DME and retinal vein occlusion. The 6-month data showed mean chances in CST of -68 µm and -94 µm in the low- and high-dose cohorts, respectively. Patients in the high-dose cohort experienced a mean BCVA gain of +8.7 letters (one patient required rescue), and patients in the low-dose cohort experienced a mean BCVA loss of -1.9 letters (eight required rescue).¹²

ORAL AND SUBCUTANEOUS

Studies show that fenofibrate, an oral medication used to manage dyslipidemia, reduced the frequency of laser treatment for DR and slowed DR progression.^13,14 The DRCR Retina Network Protocol AF (NCT04661358) is comparing DR progression over 4 years in patients with mild to moderate NPDR without CI-DME taking daily oral fenofibrate versus placebo.¹⁵

Tonabersat, an oral connexin43 inhibitor developed for use as an anticonvulsant and migraine preventative, is in a phase 2 trial (NCT05727891) for the treatment of DME. Connexin43, a gap junction hemichannel expressed in retinal cells, is upregulated in states of retinal damage.^16,17 In the trial, 128 patients with CI-DME and BCVA ≥ 20/25 will receive oral 80 mg tonabersat or placebo for 6 months.¹⁷ The primary outcome, mean change in CST, will be measured monthly through completion of the oral regimen and for 6 months of follow-up.¹⁷

D-4517.2 (Ashvattha Therapeutics is a nanoparticle that inhibits VEGF receptors 1 and 2 tyrosine kinases in the retinal pigment epithelium, microglia, and macrophages. In a rat model of choroidal neovascularization, one dose reduced vascular leakage and choroidal neovascularization area comparable with aflibercept.¹⁸ The phase 2 study (NCT05387837) compares three doses of subcutaneous D-4517.2 in patients with recurrent CI-DME. The trial is monitoring for adverse events, changes in CST and BCVA, and effect duration.

APX3330 (Ocuphire) is a twice-daily oral formulation that targets the Ref-1 protein. The phase 2 ZETA-1 trial (NCT04692688) for patients with DR did not meet its primary endpoint of ≥ 2-step improvement in DRSS from baseline.¹⁹ However, the trial did achieve statistical significance on the secondary endpoint of preventing clinically meaningful progression of DR (≥ 3-step DRSS worsening) at 24 weeks. The company is further analyzing the ZETA-1 data to gain potential phase 3 trial design insights.¹⁹

Runcaciguat (Bayer), a soluble guanylate cyclase activator, is an investigational oral therapy for the treatment of NPDR.²⁰ The phase 2 NEON-NPDR trial (NCT04722991) is evaluating the safety and efficacy of runcaciguat compared with placebo in 104 patients, with a primary endpoint of a DRSS improvement of ≥ 2 steps at 24 weeks.

RZ402 (Rezolute), a selective plasma kallikrein inhibitor, is being investigated for the treatment of CI-DME with once-daily oral dosing. The phase 2 trial (NCT05712720) will evaluate three doses of RZ402 compared with placebo in a total of 100 patients. The primary endpoints are number and severity of adverse events and change in CST from baseline.

OPL-0401 (Valo Health), an oral agent that inhibits Rho kinase signaling, is in a phase 2 trial (NCT05393284) for the treatment of NPDR and mild PDR. Approximately 90 patients will randomly receive either the study drug or placebo twice daily for 24 weeks. The primary endpoint is the proportion of patients with a ≥ 2-step DRSS improvement from baseline at 24 weeks.

CU06-1004 (Curacle) is a once-daily oral therapy that reduces vascular hyperpermeability induced by VEGF and angiopoietin-2. In a phase 2a study (NCT05573100), approximately 60 patients with DME were randomly assigned to one of three dosing regimens, with primary outcomes of change in CST at 12 weeks and determination of the optimal dose.

TOPICAL

OCS-01 (15 mg/mL dexamethasone, Oculis) eye drops met the primary and secondary endpoints in stage 1 of the phase 3 DIAMOND trial (NCT05066997). In the study, 148 patients with DME were randomly assigned to treatment with OCS-01 or vehicle, each six times daily for 6 weeks, followed by three times daily for 6 weeks. The primary endpoint was improvement in BCVA; at week 12, patients treated with OCS-01 achieved +7.7 ETDRS letters versus +3.7 ETDRS letters for those treated with vehicle. The treatment group achieved a higher percentage of patients with ≥ 15-letter BCVA improvement (27.4%) compared with vehicle (7.5%) at week 12.²¹

OTT166 (Ocuterra) topical drops target integrin, a cell adhesion molecule dysregulated in DR. Drop safety and biological activity were demonstrated in two phase 1b trials,²² and in August, the phase 2 DR:EAM trial (NCT05409235) of 210 treatment-naive participants with NPDR/mild PDR completed enrollment.

THE FUTURE OF DIABETIC EYE DISEASE CARE

Numerous therapies for the treatment of DR/DME are in the pipeline. Several intravitreal agents and gene therapies have demonstrated favorable results, while topical and oral treatments may benefit patients who are intolerant of intravitreal injections. We remain optimistic that additional treatments are on the horizon for diabetic ocular disease.

1. National Diabetes Statistics Report website, 2022. Accessed October 6, 2023. bit.ly/3PJN9Rw

2. Lundeen EA, Burke-Conte Z, Rein DB, et al. Prevalence of diabetic retinopathy in the US in 2021. JAMA Ophthalmol. 2023;141(8):747-754.

3. Kempen JH, O’Colmain BJ, Leske MC, et al. The prevalence of diabetic retinopathy among adults in the United States. Arch Ophthalmol. 2004;122(4):552-563.

4. Yang Q-H, Zhang Y, Jiang J, et al. Protective effects of a novel drug RC28-E blocking both VEGF and FGF2 on early diabetic rat retina. Int J Ophthalmol. 2018;11(6):935.

5. Bhisitkul R. 48-Week end-of-study results and sub-analyses from BEHOLD phase 2 study of UBX1325 (Foselutoclax) in patients with DME. Paper presented at: The Retina Society; October 13, 2023; New York, NY. 

6. Oxurion to file for bankruptcy after failed DME trial [press release]. Oxurion.November 21, 2023. Accessed November 28, 2023. bit.ly/3R2Hhn6

7. Patel S, Cheetham JK, Nguyen T, et al. Open-label phase 2a study of AG-73305, a novel bi-specific Fc-fusion protein for the treatment of diabetic macular edema. Invest Ophthalmol Vis Sci. 2023;64:2642.

8. EyePoint Pharmaceuticals reports positive masked safety update for lead product candidate EYP-1901 in ongoing PAVIA and DAVIO 2 phase 2 clinical trials as of September 1, 2023 [press release]. EyePoint Pharmaceuticals. September 11, 2023. Accessed October 6, 2023. bit.ly/3Q6xZai

9. Kodiak reboots tarcocimab tedromer development program following strong positive results in phase 3 diabetic retinopathy GLOW study and following dialogue with US regulatory authorities on a regulatory pathway for BLA submission [press release]. Kodiak Sciences. November 6, 2023. Accessed November 6, 2023. bit.ly/3SuDMrP

10. Regenxbio presents positive one year data from phase II ALTITUDE trial of ABBV-RGX-314 for treatment of diabetic retinopathy using suprachoroidal delivery [press release]. Regenxbio. November 3, 2023. Accessed November 6, 2023. bit.ly/3MyIbGp

11. 4DMT announces first patient enrolled in 4D-150 phase 2 SPECTRA clinical trial in DME, and expansion of 4D-150 phase 2 stage in PRISM clinical trial in wet AMD [press release]. 4DMT. September 7, 2023. Accessed October 6, 2023. bit.ly/48TdoOg

12. Sharma S. Intravitreal sustained-release dexamethasone implant for diabetic macular edema and RVO: six-month results from the first-in-human phase 2 RIPPLE-1 trial. Presented at AAO. San Francisco, CA; November 4, 2023.

13. Keech AC, Mitchell P, Summanen P, et al. Effect of fenofibrate on the need for laser treatment for diabetic retinopathy (FIELD study): a randomized controlled trial. Lancet. 2007;370(9600):1687-1697.

14. Chew EY, Davis MD, Danis RP, et al. The effects of medical management on the progression of diabetic retinopathy in persons with type 2 diabetes: the Action to Control Cardiovascular Risk in Diabetes (ACCORD) Eye Study. Ophthalmology. 2014;121(12):2443-2451.

15. A randomized trial evaluating fenofibrate for prevention of diabetic retinopathy worsening. Accessed September 9, 2023. bit.ly/45xLcxd

16. Danesh-Meyer HV, Zhang J, Acosta ML, Rupenthal ID, Green CR. Connexin43 in retinal injury and disease. Prog Retinal Eye Res. 2016;51:41-68.

17. A phase 2 evaluation of tonabersat for diabetic macular edema (DME). Accessed September 9, 2023. bit.ly/45s7ksY

18. Wu S, Xu Z, Wu T, et al. Suppression of subretinal neovascularization in Vldlr knockout mice by systemic administration of a targeted VEGF-receptor inhibitor. Invest Ophthalmol Vis Sci. 2023;64(8):3900-3900.

19. ZETA-1 APX3330 Topline Results Investor Webcast. Ocuphire. January 25, 2023. Accessed October 6, 2023. bit.ly/46grEPp

20. Non-proliferative diabetic retinopathy treated with runcaciguat (NEON-NPDR). Bayer. Accessed October 6, 2023. bit.ly/3M4DrrY

21. Oculis announces positive topline results from DIAMOND stage 1 phase 3 trial in DME with OCS-01 eye drops [press release]. Oculis. May 22, 2023. Accessed October 6, 2023. bit.ly/3LOTgCS

22. Boyer DS, Kaiser PK, Magrath GN, et al. The safety and biological activity of OTT166, a novel topical selective integrin inhibitor for the treatment of diabetic eye disease: a Phase 1b study. Ophthalmic Surg Lasers Imaging Retina. 2022;53(10):553-560.