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Retinal Physician

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The Latest Research Into Novel Therapies for Diabetic Macular Edema

New delivery methods could decrease treatment burden and improve disease control.

By: Abrahim A. Ahmed, BS, Hannah Khan, MPH, Tyler M. Ewing, MS, Arshad M. Khanani, MD, MA, FASRS
Retinal Physician September 1, 2022 Vol 19, Issue September 2022 Page(s): 24-26

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Diabetic macular edema (DME) remains a leading cause of central vision loss in patients with diabetes mellitus (DM) worldwide, and as diabetes prevalence increases with the aging population, DME diagnoses are also expected to increase.1 Current gold-standard DME treatments target vascular endothelial growth factor A (VEGF-A).2 Anti-VEGF therapy is delivered via intravitreal injection (IVI), and include ranibizumab (Lucentis; Genentech), aflibercept (Eylea; Regeneron), and the off-label use of bevacizumab (Avastin; Genentech). Secondline DME treatment includes corticosteroids delivered via dexamethasone intravitreal implants (Ozurdex; Allergan) or fluocinolone acetonide (FAc) intravitreal implants (Iluvien; Alimera Sciences).2

Due to the high treatment burden associated with frequent anti-VEGF injections, real-world studies have highlighted undertreatment of DME patients, leading to significantly inferior visual acuity (VA) outcomes in comparison to landmark clinical trials.3,4 In addition, a subset of DME patients do not respond to current anti-VEGF treatment.5,6 Novel agents in the pipeline aim to extend treatment intervals, provide broad-spectrum VEGF inhibition, and target new pathways to decrease treatment burden and increase treatment efficacy.

RECENT FDA APPROVALS

Treatment agents for DME recently approved by the US Food and Drug Administration (FDA), such as brolucizumab (Beovu; Novartis) and faricimab (Vabysmo; Genentech), have the potential to mitigate treatment burden by extending injection intervals compared to prior treatments. Faricimab is a bispecific antibody that targets Ang-2 and VEGF-A that was FDA approved for the treatment of DME and neovascular age-related macular degeneration (nAMD) in January 2022. The Ang/Tie2 axis involves a tyrosine kinase receptor that, when dephosphorylated by Ang-2, upregulates proinflammatory cytokines, vascular permeability, and neovascularization.7 In the phase 3 YOSEMITE and RHINE studies, nearly three-quarters of patients that received faricimab had treatment interval for 3 months and half were extended to 4 months.8,9 There were no new safety signals noticed in these trials. Faricimab’s long-term efficacy and safety is being evaluated in the RHONE-X extension study, with results expected in August 2023.10

Brolucizumab is a novel antibody delivered via IVI that binds and inhibits VEGF-A with high tissue penetration. Brolucizumab was FDA approved for DME treatment in June 2022 following favorable results from phase 3 trials KESTREL and KITE. Brolucizumab demonstrated noninferiority to aflibercept at 52 weeks and maintenance of VA gains on 12-week dosing regimens.11,12 In KESTREL, intraocular inflammation (IOI) was observed in 3.7% of subjects in the brolucizumab 6 mg arm, 4.7% in the brolucizumab 3 mg arm, and 0.5% in the aflibercept arm. Additionally, retinal vasucilitis was reported in one patient (0.5%) in the brolucizumab 6 mg arm and in 3 patients (1.6%) in the brolucizumab 3 mg arm. Only one patient experienced retinal artery occlusion.11 In comparision, KITE observed IOI in 1.7% of patients in both the brolucizumab 6 mg arm and in the aflibercept arm, no instances of retinal vasculitis, and one instance of retinal artery occlusion in both the brolucizumab 6 mg arm and aflibercept arm.11

However, nAMD studies of brolucizumab have reported intraocular inflammation, retinal vasculitis, and retinal artery occlusions. A post hoc safety analysis of the HAWK and HARRIER studies revealed brolucizumab was associated with an increased risk of IOI endophthalmitis, and retinal arterial occlusion, with an IOI incidence rate of 4.6% compared to 1.1% when treated with aflibercept.13 A recent real-world study has shown a smaller, yet significant incidence rate of any form of IOI or retinal vascular occlusion of 2.4% in 21,851 eyes with nAMD treated with brolucizumab.14

DURABLE ANTI-VEGF TREATMENTS IN DME

Novel applications of anti-VEGF therapy, such as biopolymer conjugates and the Port Delivery System with ranibizumab (PDS; distributed by Genentech under the brand name Susvimo), seek to reduce the treatment burden by greatly decreasing the frequency of medication administration or injection.

The PDS is a surgically implanted device that provides sustained release of ranibizumab into the vitreous, requiring refill-exchange procedures every 6 months (Q6M). The FDA approved PDS for nAMD in October 2021 following favorable phase 3 ARCHWAY results.15 The efficacy and safety of PDS with in-clinic refill exchange procedures Q6M compared to monthly intravitreal ranibizumab injections in DME patients is being evaluated in PAGODA, a randomized, multicenter, active comparator phase 3 study.16 Results from PAGODA are expected in the first half of 2022.

KSI-301 (Kodiak Sciences) utilizes an anti-VEGF antibody conjugated to a high-molecular weight biopolymer, allowing for increased treatment intervals, and is delivered via intravitreal injection.17 A pair of ongoing randomized, multicenter, non-inferiority phase 3 clinical trials, GLIMMER and GLEAM, seek to evaluate the safety, efficacy, durability, and mean changes in best corrected visual acuity (BCVA) of KSI-301 given every 8 to 24 weeks via an individualized dosing regimen following 3 monthly loading doses in comparison with intravitreal aflibercept injections every 8 weeks following 5 monthly loading doses.18,19 Both studies are estimated to read out in 2023.

NOVEL MECHANISMS AND PATHWAYS IN DME

Although anti-VEGF therapy remains the gold standard in the treatment of retinal disease, several other pathways known to promote angiogenesis, vascular permeability, vascular stability or inflammation are being investigated in clinical trials. OPT-302 (Opthea) is an intravitreal agent that inhibits VEGF-C and VEGF-D. OPT-302 has been investigated in both DME and nAMD patients in combination with IVI anti-VEGF-A therapy. In Opthea’s randomized, double-masked, sham-controlled, phase 1b/2a trial, 153 patients with DME were treated with OPT-302 alone, in combination with intravitreal aflibercept injections, or with aflibercept alone. OPT-302 and aflibercept combination therapy yielded the largest proportion of DME patients who gained ≥10 ETDRS letters from baseline to week 12.20 Opthea has initiated phase 3 trials for OPT-302 in combination with and in comparison to ranibizumab and aflibercept for nAMD patients.21

Plasma kallikrein (PKal) is independent of the VEGF pathway and is also thought to promote vascular permeability and neovascularization.22 THR-149 (Oxurion NV) is bicyclic peptide PKal inhibitor delivered via intravitreal injection currently in clinical trials for DME patients who demonstrated suboptimal response to anti-VEGF therapy. KALAHARI is a 2-part, randomized, multicenter, phase 2 study that aims to assess the dosage levels of THR-149 intravitreal injection in addition to the efficacy and safety of THR-149 compared to aflibercept injections in 126 patients with DME.23 KALAHARI is expected to reach its primary endpoint in March 2023. Interim results presented in February 2022 revealed that over 80% of DME patients in the THR-149 high-dose arm gained ≥5 ETDRS letters and 50% of patients gained >10 ETDRS letters 4 months after the final THR-149 injection.24 Central subfield thickness (CST) also remained stable at the 6-month mark.

Integrins are transmembrane glycoprotein receptors that play a role in cell signaling, adhesion, migration, remodeling, and proliferation and are thought to contribute to retinal pathology via modulation and integration of the VEGF and Ang/Tie2 pathways.25,26 Clinical trials exploring the efficacy of anti-integrin therapy in DME are underway, including integrin inhibtors such as THR-687 (Oxurion NV).

THR-687 in an integrin receptor antagonist that inhibits avβ3, avβ5, and a5β, and demonstrated significant and rapid visual acuity gains in a multicenter, single-dose escalation phase 1 study in DME patients.27 INTEGRAL, a randomized, multicenter, 2-part phase 2 study evaluated the efficacy and safety of THR-687 compared to aflibercept intravitreal injections in 303 DME patients.28 Although THR-687 met its safety and tolerability endpoints, INTEGRAL found no significant difference in BCVA or CST, leading to the discontinuation of part B of the INTEGRAL trial.29

OCS-01 1.5% ophthalmic suspension (Oculis) is a topical formulation of dexamethasone that utilizes novel solubilizing nanoparticle technology to enhance bioavailability and durability of the dexamethasone solution.30 DIAMOND is a 2-stage, double-masked, randomized, multicenter phase 3 trial that will evaluate the safety and efficacy of OCS-01 with 2 dosing regimens in comparision to vehicle alone in 482 DME patients for 52 weeks.31 Preliminary results from DIAMOND are expected in 2024.

UBX1325 is an inhibitor of Bcl-xl, a protein that senescent cells rely on for survival. UBX1325 demonstrated a favorable safety profile and sustained improvements in visual acuity through 24 weeks in a phase 1 study of patients with advanced vascular eye disease.32 UBX1325 is currently being studied in the phase 2 BEHOLD study, a multicenter, randomized, double-masked, prospective phase 2 trial that enrolled 62 patients to receive one 10 μg UBX1325 injection or sham IVI and evaluated at 12, 24, and 48 weeks to ensure safety, efficacy, and durability.33 Sixteen-week results of the BEHOLD study are expected in the second half of 2022.34

CONCLUSION

Although anti-VEGF-A therapy is the treatment of choice, a subset of DME patients respond suboptimally to anti-VEGF-A injections. Additionally, current treatments are associated with a high treatment burden due to the frequency of injections, leading to instances of real-world visual outcomes unable to match clinical trial outcomes. Novel delivery methods and agents aim to extend treatment intervals for anti-VEGF-A therapy, provide broad-spectrum VEGF inhibition, and target alternative pathways and mechanisms involved in the pathogenesis of DME. These treatment modalities ultimately aim to decrease treatment burden or improve disease control, aiming to improve real world outcomes for our patients with DME. RP

Abrahim A. Ahmed, BS, is a medical student in the Morsani College of Medicine at University of South Florida in Tampa, Florida. He reports no relevant disclosures. Hannah Khan, MPH, is a clinical research assistant at Sierra Eye Associates in Reno, Nevada. She reports no relevant disclosures. Tyler M. Ewing, MS, is a clinical research coordinator at Sierra Eye Associates. She reports no relevant disclosures. Arshad M. Khanani, MD, MA, FASRS, is a vitreoretinal surgeon, managing partner, director of clinical research, and director of fellowship at Sierra Eye Associates and a clinical associate professor at University of Nevada, Reno. He reports consultancy to and research funding from Genentech, Kodiak Sciences, Novartis, Opthea, Unity, Oculis, and Oxurion, and consultancy for Regeneron. Reach Dr. Khanani at arshad.khanani@gmail.com. Editor’s note: Hear discussion of this article on the Retina Podcast at www.retinapodcast.com .

REFERENCES

  1. Lee R, Wong TY, Sabanayagam C. Epidemiology of diabetic retinopathy, diabetic macular edema, and related vision loss. Eye Vis (Lond). 2015;2:17. doi:10.1186/s40662-015-0026-2
  2. Udaondo P, Parravano M, Vujosevic S, Zur D, Chakravarthy U. Update on current and future management for diabetic maculopathy. Ophthalmol Ther. 2022;11(2):489-502. doi:10.1007/s40123-022-00460-8
  3. Holekamp NM, Campbell J, Almony A, et al. Vision outcomes following anti-vascular endothelial growth factor treatment of diabetic macular edema in clinical practice. Am J Ophthalmol. 2018;191(7):83-91. doi:10.1016/j.ajo.2018.04.010
  4. Ciulla TA, Pollack JS, Williams DF. Visual acuity outcomes and anti-VEGF therapy intensity in diabetic macular oedema: a real-world analysis of 28,658 patient eyes. Br J Ophthalmol. 2021;105(2):216-221. doi:10.1136/bjophthalmol-2020-315933
  5. Bressler NM, Beaulieu WT, Maguire MG, et al. Early response to anti-vascular endothelial growth factor and two-year outcomes among eyes with diabetic macular edema in protocol T. Am J Ophthalmol. 2018;195:93-100. doi:10.1016/j.ajo.2018.07.030
  6. Gonzalez VH, Campbell J, Holekamp NM, et al. Early and long-term responses to anti-vascular endothelial growth factor therapy in diabetic macular edema: analysis of protocol I data. Am J Ophthalmol. 2016;172:72-79. doi:10.1016/j.ajo.2016.09.012
  7. Khanani AM, Russell MW, Aziz AA, et al. Angiopoietins as potential targets in management of retinal disease. Clin Ophthalmol. 2021;15:3747-3755. doi:10.2147/OPTH.S231801
  8. Wykoff CC, Abreu F, Adamis AP, et al. Efficacy, durability, and safety of intravitreal faricimab with extended dosing up to every 16 weeks in patients with diabetic macular oedema (YOSEMITE and RHINE): two randomised, double-masked, phase 3 trials. Lancet. 2022;399(10326):741-755. doi:10.1016/S0140-6736(22)00018-6
  9. Heier JS, Khanani AM, Quezada Ruiz C, et al. Efficacy, durability, and safety of intravitreal faricimab up to every 16 weeks for neovascular age-related macular degeneration (TENAYA and LUCERNE): two randomised, double-masked, phase 3, non-inferiority trials. Lancet. 2022;399(10326):729-740. doi:10.1016/S0140-6736(22)00010-1
  10. A study to evaluate the long-term safety and tolerability of faricimab in participants with diabetic macular edema (RHONE-X). ClinicalTrials.gov Identifier: NCT04432831. Updated June 8, 2022. Accessed June 20, 2022.
  11. Brown DM, Emanuelli A, Bandello F, et al. KESTREL and KITE: 52-week results from two phase 3 pivotal trials of brolucizumab for diabetic macular edema. Am J Ophthalmol. 2022;238(6):157-172. doi:10.1016/j.ajo.2022.01.004
  12. Novartis. Novartis announces FDA approval of BEOVU for the treatment of diabetic macular edema. Press release. June 1, 2022. https://www.novartis.us/news/media-releases/novartis-announces-fda-approval-beovu-treatment-diabetic-macular-edema .
  13. Mones J, Srivastava SK, Jaffe GJ, et al. Risk of inflammation, retinal vasculitis, and retinal occlusion-related events with brolucizumab: post hoc review of HAWK and HARRIER. Ophthalmology. 2021;128(7):1050-1059. doi:10.1016/j.ophtha.2020.11.011
  14. Khanani AM, Zarbin MA, Barakat MR, et al. Safety outcomes of brolucizumab in neovascular age-related macular degeneration: results from the IRIS Registry and Komodo Healthcare map. JAMA Ophthalmol. 2022;140(1):20-28. doi:10.1001/jamaophthalmol.2021.4585
  15. Genentech. FDA approves Genentech’s Susvimo, a first-of-its-kind therapeutic approach for wet age-related macular degeneration (AMD). Press release. October 2021. https://www.gene.com/media/press-releases/14935/2021-10-22/fda-approves-genentechs-susvimo-a-first-
  16. This study will evaluate the efficacy, safety, and pharmacokinetics of the Port Delivery System with ranibizumab in participants with diabetic macular edema compared with intravitreal ranibizumab (PAGODA). ClinicalTrials.gov Identifier: NCT04108156. Updated April 12, 2022. Accessed June 20, 2022.
  17. Chandrasekaran PR, Madanagopalan VG. KSI-301: antibody biopolymer conjugate in retinal disorders. Ther Adv Ophthalmol. 2021;13:25158414211027708.doi:10.1177/25158414211027708
  18. A study to evaluate the efficacy, durability, and safety of KSI-301 compared to aflibercept in participants with diabetic macular edema (DME) (GLIMMER). ClinicalTrials.gov Identifier: NCT04603937. Updated June 6, 2022. Accessed June 20, 2022.
  19. A trial to evaluate the efficacy, durability, and safety of KSI-301 compared to aflibercept in participants with diabetic macular edema (DME) (GLEAM). ClinicalTrials.gov Identifier: NCT04611152. Updated June 6, 2022. Accessed June 20, 2022.
  20. Ophthea Ltd. Opthea reports positive phase 2a trial results of OPT-302 in diabetic macular edema. Press Release. June 9, 2020. https://www.biospace.com/article/releases/opthea-reports-positive-phase-2a-trial-results-of-opt-302-in-diabetic-macular-edema/
  21. OPT-302 with ranibizumab in neovascular age-related macular degeneration (nAMD) (ShORe). ClinicalTrials.gov Identifier: NCT04757610. Updated June 20, 2022. Accessed June 20, 2022.
  22. Bhatwadekar AD, Kansara VS, Ciulla TA. Investigational plasma kallikrein inhibitors for the treatment of diabetic macular edema: an expert assessment. Expert Opin Investig Drugs. Mar 2020;29(3):237-244. doi:10.1080/13543784.2020.1723078
  23. A study to evaluate THR-149 treatment for diabetic macular oedema (KALAHARI). ClinicalTrials.gov Identifier: NCT04527107. Updated June 10, 2022. Accessed June 20, 2022.
  24. Oxurion. Oxurion announces new data on THR-149 phase 2 clinical trial (“KALAHARI”) in DME at the Angiogenesis, Exudation, and Degeneration 2022 Conference. Press release. February 14, 2022. https://www.oxurion.com/content/oxurion-announces-new-data-thr-149-phase-2-clinical-trial-kalahari-dme-angiogenesis
  25. Slack RJ, Macdonald SJF, Roper JA, Jenkins RG, Hatley RJD. Emerging therapeutic opportunities for integrin inhibitors. Nat Rev Drug Discov. Jan 2022;21(1):60-78. doi:10.1038/s41573-021-00284-4
  26. 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. Nov 2021;85:100966. doi:10.1016/j.preteyeres.2021.100966
  27. Khanani AM, Patel SS, Gonzalez VH, et al. Phase 1 study of THR-687, a novel, highly potent integrin antagonist for the treatment of diabetic macular edema. Ophthalmology Science. 2021;1(3). doi:10.1016/j.xops.2021.100040
  28. A study to evaluate THR-687 treatment for diabetic macular oedema. (INTEGRAL). ClinicalTrials.gov Identifier: NCT05063734. Updated October 1, 2021. Accessed June 20, 2022
  29. Oxurion. Oxurion announces top-line results from Part A of phase 2 INTEGRAL trial evaluating THR-687 for treatment of DME. Press release. May 9, 2022. https://www.ophthalmologytimes.com/view/oxurion-announces-top-line-results-from-part-a-of-phase-2-integral-trial-evaluating-thr-687-for-treatment-of-dme
  30. Oculis. OCS-01: a potential paradigm shift in treatment of diabetic macular edema. Accessed June 20, 2022. https://oculis.com/ocs-01-diabetic-macular-edema/
  31. Multicenter study on the efficacy and safety of OCS-01 in subjects with diabetic macular edema. ClinicalTrials.gov Identifier: NCT05066997. Updated December 2, 2021. Accessed June 20, 2022
  32. Zhang X, Zeng H, Bao S, Wang N, Gillies MC. Diabetic macular edema: new concepts in patho-physiology and treatment. Cell Biosci. 2014;4:27. doi:10.1186/2045-3701-4-27
  33. Safety, tolerability, and evidence of activity study of UBX1325 in patients with diabetic macular edema (BEHOLD). ClinicalTrials.gov Identifier: NCT04857996. Updated April 28, 2022. Accessed June 20, 2022
  34. Unity Biotechnology. Unity Biotechnology completes enrollment in BEHOLD, the phase 2 study of senolytic candidate UBX1325 in diabetic macular edema. Press release. April 12, 2022. https://ir.unitybiotechnology.com/news-releases/news-release-details/unity-biotechnology-completes-enrollment-behold-phase-2-study

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