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Retinal Physician

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Current Clinical Trials in Diabetic Macular Edema

Various therapies are in development.

By: Thomas A. Ciulla, MD, MBA, Raj Maturi, MD
Retinal Physician October 1, 2021 Vol 18, Issue October 2021 Page(s): 21, 22, 24, 25

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Diabetic macular edema (DME) represents a leading causes of irreversible legal blindness in the industrialized world. Therapeutically, corticosteroids were utilized early in the treatment of DME. Intravitreal (IVT) corticosteroids, which reduce inflammatory cytokines and act on several pathogenic pathways in DME, have proven effective for the management of DME, supplementing focal laser. For example, The National Institutes of Health-sponsored Diabetic Retinopathy Clinical Research Network (DRCR Retina Network) protocol I showed that, among pseudophakic eyes, off-label IVT triamcinolone acetonide was as effective at improving BCVA as ranibizumab early in treatment, though it was associated with more side effects.1 DRCR Protocol U, using a combination of dexamethasone implant and ranibizumab (Lucentis; Genentech) vs ranibizumab alone demonstrated similar visual acuity improvement between the 2 groups, although there were improved anatomic results in the combination treatment group.2

Vascular endothelial growth factor (VEGF) plays a central role in both angiogenesis and vascular permeability, which are key pathologic features in diabetic retinopathy (DR) and DME. The VEGF family of proteins includes VEGF-A, VEGF-B, VEGF-C, VEGF-D and VEGF-E, as well as placental growth factor. The activation of tyrosine kinase receptors mediates the actions of these VEGF ligands. Currently, Anti-VEGF-A IVT injection therapy is first-line treatment for DME associated with decreased visual acuity in the United States. In both the VISTA and VIVID DME registration trials for aflibercept, monthly loading followed by bimonthly aflibercept was associated with a mean 1-year gain in best corrected visual acuity (BCVA) of 10.7 letters.3 In the ranibizumab DME registration trials, monthly ranibizumab was associated with a mean 1-year BCVA gain of 12.5 letters (in RISE) and 10.9 letters (in RIDE).4

DRCR Retina Network has compared aflibercept (Eylea; Regeneron), ranibizumab, and off-label bevacizumab (Avastin; Genentech) for the treatment of DME, revealing similar BCVA gains after 2 years for all 3 anti-VEGF agents.5 The study found that in the prespecified group with poor vision (BCVA of 20/50 or worse), visual acuity gain was significantly greater in the aflibercept group at 1 year. The current DRCR AC study is examining if subjects with low initial vision (20/50 or worse) could be initiated with bevacizumab and only switched to aflibercept if found to have a poor response to bevacizumab initially. This could provide a lower cost but equally effective treatment. Overall, in protocol T, incomplete resolution of macular edema was noted in approximately one-third of participants receiving anti-VEGF therapy at 1 and 2 years. Furthermore, “real-world” studies from electronic medical records and claims data have demonstrated that DME patients are meaningfully undertreated, receiving as few as 2 to 6 treatments in the first year,6-10 with mean gain of only 5 letters on average.8,11 Consequently, there is a persistent unmet need to address limited visual outcomes, as well as treatment burden associated with intensive anti-VEGF IVT injection therapy. This review will cover some of the novel therapies for DME, organized by mechanism of action.

NOVEL ANTI-VEGF-A THERAPIES FOR INCREASED DURABILITY

Several anti-VEGF-A DME therapies with novel approaches to increase durability and address treatment burden have been studied recently. For example, ADVM-022 gene therapy utilizes a propriety vector capsid, AAV.7m8, carrying an optimized aflibercept coding sequence, administered as a one-time IVT therapy.

The phase 2 INFINITY trial of ADVM-022 in DME is a multicenter, randomized, double-masked, active comparator-controlled study that enrolled 36 patients. In April 2021, Adverum announced a Suspected Unexpected Serious Adverse Reaction (SUSAR) of hypotony in the eye treated with higher dose ADVM-022. They unmasked INFINITY, noting clinically relevant decreases in intraocular pressure refractory to steroids. Such hypotony has not been noted in DME patients treated with the low dose or in any neovascular age-related macular degeneration (AMD) patients in the OPTIC trial treated at either the high or low dose. In July 2021, Adverum announced that it no longer plans future development of ADVM-022 for DME.12

Brolucizumab (Beovu; Novartis) is a humanized single-chain antibody fragment that binds VEGF-A, with small size and high tissue penetration. It facilitates high-molar-concentration dosing.

In October 2019, the US FDA approved brolucizumab for the treatment of neovascular AMD. In December 2020, Novartis announced that the phase 3 KESTREL study of DME met its primary endpoint of noninferiority to aflibercept 2 mg in BCVA change at year 1, with more than half of patients in the 6 mg arm maintained on a 3-month dosing interval, following a loading phase.13 Novartis announced plans to submit the data from KESTREL, together with the data from the pivotal phase 3 KITE2 study in DME, to health authorities in the first half of 2021. However, due to events of severe vision loss related to retinal vascular occlusion and/or vasculitis in neovascular AMD patients treated with brolucizumab, its commercial update has been tempered.

Roche’s Port Delivery System (PDS) is a permanent continuous delivery eye implant that is placed in the operating suite and refilled with a proprietary formulation of ranibizumab in the office setting every 6 months. In May 2020, Roche announced positive phase 3 ARCHWAY clinical trial results in neovascular AMD, in which PDS was noninferior to monthly ranibizumab.14 For DME, the Phase 3 PAGODA study will evaluate PDS with ranibizumab in DME every 6 months compared with monthly ranibizumab.15

KSI-301 (Kodiak Sciences) involves an antibody biopolymer conjugate (ABC) platform that maintains IVT anti-VEGF-A levels for multiple months. In February 2021, Kodiak Sciences announced 1-year durability, efficacy, and safety data from its ongoing phase 1b study of KSI-301. Two-thirds of patients went 6 months or longer without need for retreatment, after 3 monthly loading doses. The GLEAM and GLIMMER phase 3 global, multicenter, randomized studies in patients with treatment-naïve DME, are under way.16

PAN-VEGF INHIBITION AIMED AT IMPROVED EFFICACY

Broad VEGF inhibition may have efficacy advantages over anti-VEGF-A inhibition by acting at a different level of the angiogenesis cascade and may benefit patients who suboptimally respond to current anti-VEGF-A inhibition. Multiple trials of tyrosine kinase inhibitors (TKIs) for the treatment of neovascular AMD are under way; by acting intracellularly across VEGF receptors 1, 2, and 3, TKIs could address upregulation of VEGF-C and VEGF-D that occur with inhibition of VEGF-A.17,18

GB-102 (Graybug) is a microparticle IVT sustained-release depot formulation of sunitinib malate, a TKI. The ADAGIO clinical trial was an open-label, single-dose escalation study with 32 treatment experienced neovascular AMD patients, and between 50% and 88% of subjects required no additional IVT injections of any anti-VEGF for 6 months after a single treatment with GB-102. In September 2019, Graybug announced initiation of a clinical trial in patients with macular edema, including DME, which ultimately enrolled 21 patients; the 2-mg dose was associated with medication present in the anterior chamber in 5 of 11 patients, while the 1 mg dose met its primary endpoint of safety and tolerability with 7 of 10 patients demonstrating no adverse events.19

OPT-302 (Opthea), an IVT administered biologic, blocks VEGF-C and VEGF-D, and has undergone clinical study in conjunction with IVT anti-VEGF-A therapy in neovascular AMD and DME. Opthea’s phase 2a DME clinical trial in treatment-experienced patients with persistent center-involved DME met the prespecified primary efficacy endpoint for the trial, and patients with a prior treatment history of aflibercept showed the greatest visual acuity gains.20

TARGETING TIE2 AND ANGIOPOIETIN FOR IMPROVED DURABILITY

In addition to the VEGF axis, vascular stability is mediated by tyrosine receptor kinase (Tie2). Angiopoietin-1 (Ang1) binds to the Tie2, activating vascular maturation, whereas angiopoietin-2 (Ang2) deactivates Tie2, causing vascular destabilization. Faricimab is an IVT-administered bispecific antibody for both VEGF-A and Ang2. In December 2020, Roche announced positive top-line results from 2 global phase 3 clinical trials, YOSEMITE and RHINE, in which faricimab was administered every 8 to 16 weeks, and was noninferior to aflibercept administered every 8 weeks. More than half of participants in the faricimab personalized dosing arms had extended time between treatments to 16 weeks by year 1.21

THE ALTERNATIVE PATHWAY OF PLASMA KALLIKREIN INHIBITION

Plasma kallikrein is also a mediator of vascular leakage and inflammation. Activation of plasma kallikrein can induce features of DME in preclinical models, and human vitreous shows elevated plasma kallikrein levels in patients with DME.

Several early studies in DME have been completed. KVD001 (KalVista Pharmaceuticals) has undergone phase 2 clinical trial in patients with continued DME despite anti-VEGF treatment. The 3 μg and 6 μg dose of KVD001 showed +1.5 and +2.6 letters improvement over the sham treatment, respectively, but the difference was not statistically significant. No significant differences were noted in the secondary endpoints of CST.22

THR-149 (Oxurion) is a bicyclic peptide plasma kallikrein inhibitor, which has undergone phase 1 study in 12 DME subjects. A single IVT injection was followed by improvement in mean BCVA (6.4 letters on day 90), but there was minimal change in CST; a phase 2 study is planned.23

THE NOVEL MECHANISM OF ANTI-INTEGRIN THERAPIES

Integrins are a family of multifunctional cell-adhesion molecules that connect actin in the cell cortex to extracellular matrix and, consequently, serve as cell-adhesion and cell-signaling receptors. Integrins are composed of α and β subunits and they regulate the shape, orientation, and movement of cells, controlling a variety of cellular interactions with their microenvironment, such as adhesion, spreading migration, proliferation, invasion, survival, and apoptosis. Consequently, they play a role in pathologic processes, such as inflammation, angiogenesis, and fibrosis.

In both DR and AMD, the avβ3 and avβ5 integrins have been shown to play key pathogenic roles. Targeting neovascularization with anti-integrin agents may interfere with proteolytic degradation of extracellular matrix and tissue remodeling, involved in neovascularization in AMD and DR. Anti-integrin therapies that are undergoing early clinical study include risuteganib (Luminate; Allegro Ophthalmics), THR-687 (Oxurion), and OTT-166 (Scifluor Life Science, now Ocuterra Therapeutics).

Risuteganib is an integrin inhibitor that binds to multiple integrin sites. The phase 2 double-masked, placebo-controlled, randomized, multicenter dose-ranging study evaluated safety and noninferiority of 3 risuteganib arms. In stage 1, this study demonstrated promising visual acuity gains and reduction in central macular thickness that were equivalent to bevacizumab monotherapy, with no drug-related toxicity. In stage 2, the mean gain in BCVA was 7.5 letters in the risuteganib (1 mg) with bevacizumab pretreatment group compared to 5.2 letters in the bevacizumab control group.24

THR-687 is a pan-integrin receptor antagonist that binds the integrins avβ3, avβ5, and a5β1 at a nanomolar concentration. An open-label, multicenter, single-dose escalation phase 1 study in DME patients showed promising results, with rapid and significant effect (+11.2 letters at day 14, and +12.5 letters at month 3) observed at the highest dose (2.5 mg), along with decreases in central subfield thickness.25

OTT-166 is a small molecule inhibitor of integrin avβ3 formulated for topical administration. A clinical trial was performed in 40 subjects with DME and 53% of patients showed a reduction in retinal thickness with no significant decreases in visual acuity.26

AXT-107 (Asclepix Therapeutics) is a collagen IV-derived peptide that disrupts α5β1 integrins, activates Tie2, and inhibits VEGF-A and VEGF-C. With a long half-life and IVT gel depot formation, AXT107 could potentially be dosed yearly. In January 2021, Asclepix announced dosing of the first patient in its CONGO phase 1/2a study of AXT107 for DME.27

CONCLUSION

Although anti-VEGF-A agents have revolutionized treatment for DME, significant unmet need remains to address limited visual outcomes, continued macular thickening in a significant proportion of patients, and a multiyear treatment burden. Therapies to lower overall cost of treatment, innovative therapies with sustained durability, and novel mechanisms of actions are in development, including pan-VEGF Inhibitors, Ang2 inhibitors, plasma kallikrein inhibitors, and anti-integrin therapies. Given the promising results in early clinical trials, the future is bright for patients afflicted with DME, one of the leading causes of vision loss in the industrialized world. RP

Thomas A. Ciulla, MD, MBA, is chief medical officer at Clearside Biomedical, a volunteer clinical professor of ophthalmology at Indiana University School of Medicine, and a board member at Midwest Eye Institute in Indianapolis, Indiana. Dr. Ciulla reports equity holdings in Spark Therapeutics (previously) and Clearside Biomedical (currently). Raj Maturi, MD, is a vitreoretinal medicine and surgery specialist at the Midwest Eye Institute in Indianapolis, Indiana. Dr. Maturi reports research support from Alcon, Alimera Sciences, Allergan, Bayer, Eli Lilly, Eyegate, GlaxoSmithKline, Quark, and Santen, as well as consultancy to Allergan and Eli Lilly. Reach Dr. Maturi at rmaturi@gmail.com. Editor’s note: Listen to discussion of this article on the Retina Podcast at retinapodcast.com .

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  24. Allegro Ophthalmics. Allegro Ophthalmics announces positive topline results from DEL MAR phase 2b stage 2 trial evaluating Luminate in patients with diabetic macular edema. News release. Accessed August 27, 2021. https://www.allegroeye.com/allegro-ophthalmics-announces-positive-topline-results-from-del-mar-phase-2b-stage-2-trial-evaluating-luminate-in-patients-with-diabetic-macular-edema-2/
  25. Oxurion. Oxurion NV – expert presentation of positive topline data from a phase 1 study evaluating THR-687 for the treatment of DME, at angiogenesis, exudation, and degeneration 2020 conference. News release. Accessed August 27, 2021. https://www.oxurion.com/content/oxurion-nv-expert-presentation-positive-topline-data-phase-1-study-evaluating-thr-687
  26. SciFluor. SciFluor announces positive results of phase 1/2 study of SF0166 topical ophthalmic solution in diabetic macular edema patients. News release. Accessed August 27, 2021. https://www.businesswire.com/news/home/20170928005321/en/SciFluor-Announces-Positive-Results-of-Phase-12-Study-of-SF0166-Topical-Ophthalmic-Solution-in-Diabetic-Macular-Edema-Patients
  27. AsclepiX Therapeutics, Inc. AsclepiX Therapeutics, Inc. doses first patient in phase 1/2a trial of axt107 intravitreal self-forming gel depot peptide for diabetic macular edema (DME). News release. Accessed August 27, 2021. https://asclepix.com/asclepix-therapeutics-inc-doses-first-patient-in-phase-1-2a-trial-of-axt107-intravitreal-self-forming-gel-depot-peptide-for-diabetic-macular-edema-dme/

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