Diabetic retinopathy (DR) is a leading cause of vision loss worldwide, with an ever-increasing prevalence.^1,2 Anti-vascular endothelial growth factor (Anti-VEGF) agents have revolutionized the treatment of diabetic macular edema (DME) after several large-scale studies reported significant efficacy at reducing DME and improving vision. However, anti-VEGF treatment requires long-term therapy with frequent intravitreal injections — and, even with good compliance, many patients are incomplete responders.

Another major area of interest is the use of anti-VEGF agents in the management of DR in the absence of macular edema. The PANORAMA study and the Diabetic Retinopathy Clinical Research Retina Network’s Protocol W reported that anti-VEGF injections can improve DR severity scores and lower the likelihood of developing sight-threatening complications such as proliferative diabetic retinopathy (PDR) and DME.^3,4 However, there was no difference in mean visual acuity between anti-VEGF and sham at 2 years.

Perhaps this is the reason that, despite both ranibizumab and aflibercept being approved for this indication, most retina specialists defer initiation of anti-VEGF injections until patients develop center-involving DME or PDR. Results of the 2020-2022 American Society of Retina Specialists Preference and Trends Survey demonstrate that the majority of US retina specialists choose to monitor their patients with severe non-proliferative diabetic retinopathy (NPDR) without DME.⁵ This practice pattern, while avoiding the costs and risks associated with repeated anti-VEGF injections, is not optimal for these patients, as it is likely that DR will progress.

Thus, we have an unmet need for early, non-invasive treatment options that can prevent the progression of DR. Here, we provide a brief review on five emerging therapies for the management of DR that offer potential alternatives to intravitreal anti-VEGF injections (Table).

OCULIS OCS-01

OCS-01 is a topical formulation of dexamethasone. Corticosteroids have both anti-inflammatory and anti-angiogenic effects, and they offer the only approved pharmaceutical treatment for DME other than anti-VEGF. With its topical formulation, OCS-01 avoids the risks of intravitreal steroid injection. Studies in rabbit and human eyes demonstrated that the drug-delivery technology utilized by OCS-01 delivers a clinically significant amount of drug to both the anterior and posterior segment of the eye.^6,7

In a completed Phase 2, multi-center, randomized, double-masked, vehicle-control trial, patients with DME were randomized to receive either OCS-01 (n=99) or vehicle (n=45) t.i.d. for 12 weeks, followed by 4 weeks of no treatment. At 12 weeks, there was a greater reduction in central macular thickness (CMT) in the OCS-01 group (difference of -36.81 um). The OCS-01 group had more patients with both 10 letter gains (14.1% with OCS-01, 8.9% with placebo) and 15 letter gains (5.1% with OCS-01, 0% with placebo).

It has a favorable safety profile, with the most notable adverse event of increased IOP in 21.2% of patients receiving OCS-01 compared to 0% in patients receiving placebo. The increase in IOP was never greater than 5 mm Hg, and IOP rapidly returned to baseline upon cessation of the drug at 12 weeks.⁸

A Phase 3, multi-center, randomized, double-masked, vehicle-controlled study is currently underway to evaluate OCS-01 in the treatment of DME. In Stage 1, investigators randomized 148 patients 2:1 to receive OCS-01 or vehicle six times a day for 6 weeks followed by three times a day for an additional 6 weeks. According to recently released topline results, the primary endpoint of statistically significant improvement in mean BCVA from baseline to week 6 was met; in the OCS-01 group, patients showed an improvement of 7.2 letters and 3.1 letters in the vehicle group, which was continued to week 12.⁹ Additionally, a higher percentage of patients in the treatment group achieved a 15 or more letter improvement in BCVA from baseline at week 6 than those in the vehicle group. The treatment was well tolerated with no unexpected adverse events.⁹

In the second half of this year, the company will move onto Stage 2 of the study. Stage 2 will enroll approximately 800 patients in to confirm the efficacy and safety of the selected dosing regimen, and patients will administer the selected dose regimen determined in Stage 1 for 52 weeks.¹⁰

OCUPHIRE APX3330

APX3330 is an oral inhibitor of reduction-oxidation effector factor-1 (Ref-1), which is a transcription factor regulator that is upstream in the pathway of VEGF and other growth factors. Its inhibition blocks multiple signaling cascades reducing both neovascularization and inflammation.¹¹

Preclinical data found that APX3330 can reduce VEGF expression, reduce pro-inflammatory cytokines and increase neuronal protection.¹² The novel drug has been studied in six completed Phase 1 trials and five completed Phase 2 trials in more than 300 total subjects, demonstrating a favorable ophthalmic and systemic safety profile. The most common related adverse events were mild diarrhea or soft stool (4% with APX3330, 2% with placebo) and mild rash or pruritus (4% with APX3330, 1% with placebo).¹³

ZETA-1, a Phase 2b randomized, placebo-controlled, double-masked, multi-center study, evaluated the efficacy and safety of APX3330 600-mg daily dose over 24 weeks in patients with moderately severe-to-severe NPDR or mild PDR. The study demonstrated a statistically significant reduction in the percentage of patients who lost three-steps or greater of binocular Diabetic Retinopathy Severity Scale (DRSS) after 24 weeks of treatment (0% of APX3330-treated patients vs 16% of placebo-treated patients). A three-step change is the DRSS level change in both eyes summed. This is the preferred outcome measure when testing a systemic product that acts on both eyes simultaneously. APX3330 demonstrated a favorable safety and tolerability profile, and no major organ toxicities or vital sign abnormalities were observed.¹⁴

OCUTERRA OTT166

OTT166 is a topically administered, integrin inhibitor that targets RGD-binding integrins. RGD-binding integrins are transmembrane receptors that modulate not only VEGF but other growth factors involved in the pathophysiology of DR as well. OTT166 is designed to reach the retina via the trans-scleral route. After penetrating the conjunctiva, it diffuses through the sclera, permeates the choroid and RPE and diffuses through all retinal layers.¹⁵

Pre-clinical studies demonstrated that OTT166 inhibits retinal vascular leakage in a dose-dependent manner in a rabbit retinal edema model.¹⁶ The first-in-human Phase 1b of OTT166 in DR patients with DME demonstrated safety and tolerability, with no drug-related SAEs in the 44 included patients. Thirty-five percent of patients demonstrated decreased central retinal thickness at 28 days, which was maintained at 56 days, suggesting that the drug achieves at least some level of biologic activity.¹⁷

A Phase 2b, multi-center, randomized, double-masked, vehicle-control trial is underway for OTT166 in patients with moderate-to-severe NPDR or mild PDR without center-involving DME. The study will evaluate the safety and efficacy of OTT166 and select an optimum dosing regimen for Phase 3 trials. It will enroll approximately 210 treatment naïve patients randomized into OTT166 low dose, OTT166 high dose or one of two control groups. All groups will receive treatment for 24 weeks.¹⁸

REZOLUTE BIO RZ402

RZ402 is an oral plasma kallikrein inhibitor in Phase 2 development for the treatment of DME.

Plasma kallikrein is a serine protease that, when activated, leads to bradykinin-mediated inflammation, vascular leakage and neovascularization. Elevated plasma kallikrein has been found to be present in the vitreous of patients with both DME and PDR and to be involved in DME pathogenesis in both VEGF-independent and VEGF-interdependent mechanisms, suggesting potential efficacy for anti-VEGF non- or incomplete responders.¹⁹

In preclinical trials, RZ402 is shown to be a selective plasma kallikrein inhibitor that can suppress retinal vascular leakage.²⁰

The first-in-human, Phase 1a study, single-ascending dose study demonstrated that RZ402 was safe and well-tolerated at 25-mg, 100-mg and 250-mg doses. Single doses resulted in dose-dependent increases in systemic concentration of RZ402, and all doses led to concentrations that exceeded the 3.5-ng/mL target shown to reduce retinal inflammation and vascular leakage in animal models.²¹

The Phase 1b, single-center, randomized, double-blind, placebo-controlled, multiple-ascending dose study showed that RZ402, when administered as a once-daily oral dose for 2 weeks, led to dose-dependent increases in systemic concentration surpassing the biologically active concentration shown in animal models. Importantly, RZ402 was found to inhibit plasma kallikrein activity in a dose and concentration-dependent manner. RZ402 was safe and well-tolerated, without any serious adverse events or drug reactions.²²

In December 2022, Rezolute Inc. announced the initiation of a Phase 2 multicenter, randomized, double-masked, placebo-controlled, parallel-arm study to evaluate the safety, efficacy and pharmacokinetics of RZ402 as monotherapy over a 12-week treatment period in participants with NPDR and DME who are naïve to or have received limited anti-VEGF injections.²³

YD LIFE SCIENCE YD-312

YD-312 is an oral formulation of imatinib, an ABL1 tyrosine-kinase inhibitor that was initially developed for the treatment of chronic myeloid leukemia. Imatinib has been shown in preclinical studies to inhibit angiogenesis in the retina, independent of the VEGF pathway.²⁴

A completed Phase 2a multi-center, randomized, double-blind, dose-finding trial compared once-daily dosing for 12 weeks of YD-312 50 mg, 150 mg and 350 mg, as well as placebo, in patients with DME. The study showed an improvement of vision in all YD-312 dose groups compared to placebo. No serious adverse events or drug reactions were reported.²⁵

CONCLUSION

Currently, the FDA has approved anti-VEGF injections at fixed intervals for the treatment of DR. Despite these approvals, most retina specialists do not routinely use anti-VEGF injections in the absence of DME or PDR. This review has focused on five novel non-injectable pharmaceutical agents in the pipeline for the management of DR.

Notably, we did not review the numerous intravitreally injected anti-VEGF medications with varying mechanisms of action that are concurrently undergoing investigation. There is no denying that intravitreal anti-VEGF agents are the current standard of care for DME, as well as for DR in appropriate cases. However, the development of therapies that could decrease the risks and burden of intravitreal injections is extremely compelling. Effective treatment via oral or topical administration could lead to increased compliance and improved visual outcomes for patients with sight-threatening complications of diabetes.

It is too early to know which of these treatments will cross the finish line in their pivotal clinical trials, but the future looks promising for our patients with DR. OM

REFERENCES

1. Cheung N, Mitchell P, Wong TY. Diabetic retinopathy. Lancet. 2010;376(9735):124-136.
2. Zheng Y, He M, Congdon N. The worldwide epidemic of diabetic retinopathy. Indian J Ophthalmol. 2012 Sep-Oct; 60: 428–431.
3. Brown DM, Wykoff CC, Boyer D, et al. Evaluation of intravitreal aflibercept for the treatment of severe nonproliferative diabetic retinopathy: Results From the PANORAMA randomized clinical trial. JAMA Ophthalmol. 2021;139:946-955.
4. Maturi RK, Glassman AR, Josic K, et al. Effect of intravitreous anti–vascular endothelial growth factor vs sham treatment for prevention of vision-threatening complications of diabetic retinopathy. The Protocol W Randomized Clinical Trial. JAMA Ophthalmol. 2021;139:701-712.
5. Hahn P, ed. ASRS Preferences and Trends Membership Survey. Chicago, IL. American Society of Retina Specialists; 2022
6. Loftsson T, Stefánsson E. Cyclodextrins and topical drug delivery to the anterior and posterior segments of the eye. Int J Pharm. 2017;531:413-423.
7. Loftsson T, Jansook P, Stefánsson E. Topical drug delivery to the eye: dorzolamide. Acta Ophthalmol. 2012;90:603-608.
8. Stefansson E, Loftsson T, Larsen M, et al. Topical treatment of diabetic macular edema using dexamethasone ophthalmic suspension: A randomized, double-masked, vehicle-controlled study. Acta Ophthalmol. 2023;101:22-33.
9. Oculis Holding AG. Press release, May 22, 2023. https://investors.oculis.com/news-releases/news-release-details/oculis-announces-positive-top-line-results-diamond-stage-1-phase . Accessed May 31, 2023.
10. ClinicalTrials.gov . Multicenter study on the efficacy and safety of OCS-01 in subjects with diabetic macular edema. https://clinicaltrials.gov/ct2/show/NCT05066997 . Accessed May 9, 2023.
11. Logsdon DP, Shah F, Carta F, et al. Blocking HIF signaling via novel inhibitors of CA9 and APE1/Ref-1 dramatically affects pancreatic cancer cell survival. Sci Rep. 2018;8:13759.
12. Jiang A, Gao H, Kelley MR, Qiao X. Inhibition of APE1/Ref-1 redox activity with APX3330 blocks retinal angiogenesis in vitro and in vivo. Vision Res. 2011;51:93-100.
13. Logsdon DP, Shah F, Carta F, et al. Blocking HIF signaling via novel inhibitors of CA9 and APE1/Ref-1 dramatically affects pancreatic cancer cell survival. Sci Rep. 2018;8:13759.
14. Jiang A, Gao H, Kelley MR, Qiao X. Inhibition of APE1/Ref-1 redox activity with APX3330 blocks retinal angiogenesis in vitro and in vivo. Vision Res. 2011;51:93-100.
15. Van Hove I, Hu TT, Beets K, et al. Targeting RGD-binding integrins as an integrative therapy for diabetic retinopathy and neovascular age-related macular degeneration. Prog Retin Eye Res. 2021;85:100966.
16. Askew BC, Furuya T, Edwards DS. Ocular distribution and pharmacodynamics of SF0166, a topically administered αvβ3 integrin antagonist, for the treatment of retinal diseases. J Pharmacol Exp Ther. 2018;366:244-250.
17. Edwards D, Boyer DS, Kaiser PK, et al. First in-human study of SFO166 topical ophthalmic solution in patients with diabetic macular edema. Invest Ophthalmol Vis Sci. 2018;59:1961. ARVO E-Abstract 1961. https://iovs.arvojournals.org/article.aspx?articleid=2690249 . Accessed May 9, 2023.
18. ClinicalTrials.gov . OTT166 in diabetic retinopathy (DR). https://www.clinicaltrials.gov/ct2/show/NCT05409235 . Accessed March 28, 2023.
19. Bhatwadekar AD, Kansara VS, Ciulla TA. Investigational plasma kallikrein inhibitors for the treatment of diabetic macular edema: an expert assessment. Expert Opin Investig Drugs. 2020;29:237-244.
20. Phipps JA, Clermont AC, Sinha S, et al. Plasma kallikrein mediates angiotensin II Type 1 receptor–stimulated retinal vascular permeability. Hypertension. 2009;53:175-181.
21. Rezolute press release, May 4, 2021. Rezolute announces positive RZ402 study results demonstrating potential for once daily dosing of an Oral Plasma Kallikrein Inhibitor for Diabetic Macular Edema. https://ir.rezolutebio.com/news-events/press-releases/detail/278/rezolute-announces-positive-rz402-study-results . Accessed May 9, 2023.
22. Rezolute press release, Feb. 22, 2022. https://ir.rezolutebio.com/news-events/press-releases/detail/295/rezolute-announces-positive-study-results-for-rz402-an . Accessed May 22, 2023.
23. ClinicalTrials.gov . Study to evaluate the efficacy and safety of RZ402 in diabetic macular edema edema (DME). https://clinicaltrials.gov/ct2/show/NCT05712720 . Accesssed May 9, 2023.
24. Striglia E, Caccioppo A, Castellino N, et al. Emerging drugs for the treatment of diabetic retinopathy. Expert Opin Emerg Drugs. 2020;25:261-271.
25. ClinicalTrials.gov . The study to YD312 tablet in patients with diabetic macular edema. https://clinicaltrials.gov/ct2/show/NCT03635814 . Accessed May 9, 2023.

Caroline C. Awh, MD, is an ophthalmology resident at Cole Eye Institute, Cleveland. Dr. Awh has no relevant financial disclosures.

Peter K. Kaiser, MD, Cole Eye Institute, Cleveland. Dr. Kaiser is actively involved in clinical research having served as study chairman for numerous major, multi-center, international clinical trials, and principal investigator in over 60 trials evaluating new treatments for AMD, DR, and other retinal disorders. He is the director of Center for Ocular Research and Evaluation (CORE). Financial disclosures: Dr. Kaiser is a consultant to Allergan, AsclepiX, Bayer, Bausch + Lomb, Biogen Idec, Boehringer Ingelheim, Carl Zeiss Meditec, Clearside Biomedical, Coherus, Kanghong, Novartis, Ocular Therapeutix, Oculis, Ocuphire, OcuTerra Therapeutics, Oxurion, Palatin, Regeneron, RegenxBio and Samsung Bioepis.