The treatment of diabetic macular edema (DME) was revolutionized with the advent of anti-VEGF therapy. The initial clinical trials RISE and RIDE for DME demonstrated the utility of monthly ranibizumab therapy.¹ Subsequently, VIVID and VISTA, the clinical trials resulting in the approval of aflibercept for DME, demonstrated similar efficacy of every eight-week aflibercept therapy.² While these treatments are remarkably effective, the response to treatment in some individuals may be suboptimal, with a proportion of patients demonstrating persistent DME despite monthly therapy.

To address these unmet needs, a plethora of medications and treatments have emerged and are currently in various stages of clinical trials. This article highlights the salient features of some of these molecules and some of the newer laser strategies.

ANTI-VEGF AGENTS

Brolucizumab

Brolucizumab (Novartis) is a humanized single chain antibody (26 kilodaltons) that inhibits all forms of VEGF-A. The small molecular weight relative to other available anti-VEGF therapies allows it to be concentrated to 22 times the dose of ranibizumab (Lucentis, Genentech) and 11 times the dose of aflibercept (Eylea, Regeneron) in a single 0.05 ml injection.

Phase 3 clinical trials have already demonstrated positive results in AMD. The paired Phase 3 AMD clinical trials (HAWK and HARRIER) demonstrated noninferiority of brolucizumab dosed every 12 weeks after loading doses vs. aflibercept dosed every eight weeks after loading doses.³ Additionally, in the HAWK and HARRIER trials, 56% and 51% of patients were maintained at a 12-week dosing interval at week 48. These results were maintained at two years.⁴

Given the positive results in this trial, Phase 3 clinical trials evaluating brolucizumab for DME (KESTREL and KITE) are underway.

Abicipar pegol

Abicipar pegol (Allergan) belongs to a novel class of protein-binding molecules called “designed ankyrin repeat proteins (DARPins),” which bind to all isoforms of VEGF-A. The DARPin platform holds promise as this scaffold technology can theoretically be applied to other protein targets. Abicipar, a first-in-class DARPin in the ophthalmology space, has a higher binding affinity and longer half-life than ranibizumab. This may translate to increased durability and extension between treatment intervals.⁵

This drug has already yielded positive Phase 3 efficacy results in neovascular AMD (CEDAR and SEQUOIA) with every eight and 12-week dosing arms demonstrating similar efficacy to every four-week ranibizumab.⁶ The rates of intraocular inflammation, however, were approximately 15% in the abicipar arms compared to 0% to 0.6% in the ranibizumab arms. An optimized manufacturing version of abicipar was studied in a 28-week, open-label MAPLE study in exudative AMD with the goal of specifically evaluating inflammatory events. Top-line data showed a reduction of intraocular inflammation to 8.9% and severe intraocular inflammation occurring in 1.6% of patients.

Pertaining to DME, interim results of the PALM Phase 2 study, presented in 2016 at the AAO annual meeting, demonstrated efficacy of 2 mg abicipar dosed every eight and 12 weeks relative to ranibizumab dosed every four weeks.⁷ Final results of the PALM Phase 2 study are concluding, and a decision to proceed to Phase 3 for DME is pending.

Conbercept

Conbercept (Chengdu Kanghong Biological Science & Technology) is a recombinant fusion protein-inhibiting VEGF-A, VEGF-B and placental growth factor. The Phase 3 trial for the drug’s use in neovascular AMD (PHOENIX trial) showed that the drug was effective compared to sham treatment for neovascular AMD. The China Food and Drug Administration approved the drug in December 2013 for the treatment of neovascular AMD. The drug was also examined in a small retrospective study for DME and showed that it was non-inferior to ranibizumab.⁸

The drug is currently undergoing Phase 3 trials (FRONTIER-1 and SAILING) comparing the drug to laser treatment.^9,10

OPT-302

OPT-302 (Ophthea) is a VEGF C/D trap molecule that is currently being studied in conjunction with anti-VEGF A (aflibercept). The drug showed promise in Phase 1 trials when used in combination with aflibercept. The drug is undergoing a Phase 2A DME trial for patients who demonstrate a refractory response to anti-VEGF therapy. The trial will look at combination OPT-302 and aflibercept vs. aflibercept monotherapy.¹¹

COMBINATION ANGIOPOIETIN DRUGS

Angiopoietin-2 (Ang2)

Ang2 is believed to play a role in the breakdown of the blood retinal barrier, causing endothelial destabilization and, ultimately, increased vascular permeability in conjunction with VEGF. Nevascumab (Regeneron) was an Ang2 molecule studied in the Phase 2 RUBY trial comparing combination nevascumab and aflibercept vs. aflibercept.¹² While the combination therapy did not demonstrate a positive signal, it was deemed to be insufficient to warrant further development for strategic reasons.

Faricimab

Faricimab (Genentech/Roche) is a bispecific molecule that simultaneously targets and blocks VEGF-A and Ang2 in one injection, with a single clearance rate. The drug was studied in a Phase 2 clinical trial (BOULEVARD trial) where patients were treated with 1 or 6 mg of faricimab monthly or 0.3 mg ranibizumab monthly for 20 weeks, then monitored without treatment for up to 36 weeks. Data from the study shows improved visual outcomes four weeks from last treatment (week 24), and early follow-up data shows improved visual outcomes at 12 weeks from last treatment (week 36).¹³

Given these encouraging results, recruitment for Phase 3 trials studying faricimab in DME (YOSEMITE and RHINE) are underway. Perhaps most encouraging was that the greatest benefit tended to occur towards the end of the study, suggesting that a longer study would be more likely to show the full benefits of Ang2 suppression.

OTHER DRUG PATHWAYS

Fasudil combination therapy

Fasudil is a Rho-kinase inhibitor and is believed to exert its therapeutic effect by blocking leukocyte adhesion endothelial damage in diabetes. Recently, Ahmadieh et al. evaluated the use of fasudil in combination with bevacizumab vs. bevacizumab monotherapy in DME. Each arm received injections monthly for the first three months followed by an observation window out to six months. While both groups demonstrated improvements in visual acuity and macular edema through three months, the effects were sustained only in the combination therapy arm.^14,15

Risuteganib

Risuteganib (Allegro) is a synthetic molecule that blocks three different integrin receptors implicated in retinal disease. The ultimate goal is reducing oxidative stress that has been implicated in inflammation and angiogenesis upregulation. The Phase 2 data (DEL MAR study) comparing risuteganib to bevacizumab showed that it was non-inferior and may be efficacious at q12 week dosing.¹⁶ The drug is currently in Phase 3 trials.

ALTERNATE DELIVERY APPROACHES

Steroid therapy

Steroid therapy is critical in DME management. Currently approved treatments include the dexamethasone steroid implant (Ozurdex, Allergan) and the longer-acting fluocinolone steroid implant (Iluvien, Alimera). The potential tradeoff, however, is cataract and ocular hypertension.^17,18

Alternative steroid delivery into the suprachoroidal space is currently being studied. The intended goal is to maintain efficacy but decrease cataract and ocular hypertension complications by minimizing steroid exposure to the anterior segment.

Suprachoroidal delivery

CLS-TA (Clearside Biomedical) is a suprachoroidal delivery of triamcinolone (4 mg/0.1 ml). Six-month results of the combination CLS-TA with aflibercept vs. aflibercept monotherapy were recently reported at the 2019 Macula Society (TYBEE study). Patients were randomized to either combination suprachoroidal triamcinolone + aflibercept every three months for two doses, or monthly aflibercept injections for four months. The patients in both treatment arms were followed monthly and received aflibercept injections as needed. Combination therapy was non-inferior to aflibercept with fewer treatments in the combination arm of the trial. In the combination arm, 13.9% of patients had IOP elevation of greater than 10 mm Hg at any visit over baseline compared to 0% in the aflibercept only arm.¹⁹

UPDATES IN LASER TECHNOLOGY

Focal laser

While focal laser has fallen out of favor in the management of center-involving DME, it may still play a role in the treatment of extramacular edema resulting from focal microaneurysms. Additionally, focal laser technology has considerably advanced since the Early Treatment of Diabetic Retinopathy Study (ETDRS) that solidified the role of laser as a treatment for DME.

Guided laser treatment

Treatment of edema close to the fovea requires increased precision. This undue risk may certainly play a role in its limited use in these circumstances. Navilas (OD-OS) is a navigated laser that combines retinal eye-tracking with fundus images to accurately track and deliver laser (532 nm or 577 nm) to the microaneurysms.²⁰ In 2014, Liegl et al. compared Navilas laser combined with intravitreal ranibizumab vs. ranibizumab monotherapy. At 12 months, both groups demonstrated similar visual acuity improvement but the combination group received three fewer injections at one year.²¹ The laser tracking device received FDA approval for focal and grid laser for DME.

Micropulse laser

Micropulse laser delivers short, repetitive, low-energy pulses to heat the RPE but avoid laser scarring. While the wavelength and duty cycles vary between lasers and the settings lack standardization, studies suggest it may decrease the overall treatment burden in early stage disease when used in combination with anti-VEGF.²² Further randomized trials may be required to delineate the clinical scenario where micropulse laser is most valuable.

CONCLUSION

Anti-VEGF therapy has revolutionized the landscape of DME treatment. The search for continued pharmacologic targets is ongoing to achieve higher potency and more durable treatment options for patients with suboptimal response.

With additional agents in the DME armamentarium on the horizon, now is an incredibly exciting time to be a retina specialist. OM

REFERENCES

1. Nguyen QD, Brown DM, Marcus DM, et al. Ranibizumab for diabetic macular edema: results from 2 phase III randomized trials: RISE and RIDE. Ophthalmology. 2012;119:789-801.
2. Heier JS, Korobelnik JF, Brown DM, et al. Intravitreal aflibercept for diabetic macular edema: 148-week results from the VISTA and VIVID studies. Ophthalmology. 2016;123:2376-2385.
3. Dugel PU, Jaffe GJ, Sallstig P, et al. Brolucizumab versus aflibercept in participants with neovascular age-related macular degeneration: A randomized trial. Ophthalmology. 2017;124:1296-1304.
4. Dugel PU, Koh A, Ogura Y, et al. HAWK and HARRIER: phase 3, multicenter, randomized, double-masked trials of brolucizumab for neovascular age-related macular degeneration. Ophthalmology. 2019. Epub ahead of print.
5. Campochiaro PA, Channa R, Berger BB, et al. Treatment of diabetic macular edema with a designed ankyrin repeat protein that binds vascular endothelial growth factor: a phase I/II study. Am J Ophthalmol. 2013;155:697-704,704, e1-2.
6. Callanan D, Kunimoto D, Maturi RK, et al. Double-masked, randomized, Phase 2 evaluation of abicipar pegol (an Anti-VEGF DARPin therapeutic) in neovascular age-related macular degeneration. J Ocul Pharmacol Ther. 2018.
7. TS H. A multicenter, double masked phase 2 clinical trial evaluating abicipar pegol for diabetic macular edema. American Academy of Ophthalmology Annual Meeting; October 14-18, 2016.
8. Xu Y, Rong A, Xu W, Niu Y, Wang Z. Comparison of 12-month therapeutic effect of conbercept and ranibizumab for diabetic macular edema: a real-life clinical practice study. BMC Ophthalmol. 2017;17:158.
9. Safety and efficacy study of conbercept in diabetic macular edema (DME) (Sailing). ClinicalTrials.Gov. https://clinicaltrials.gov/ct2/show/NCT02194634 . Accessed April 29, 2019.
10. Safety and efficacy by multiple injection of KH902 in patients with diabetic macular edema (DME) (FRONTIER-1). Clinical Trials.Gov. https://clinicaltrials.gov/ct2/show/NCT01324869 . Accessed April 29, 2019.
11. A Dose Ranging Study of OPT-302 With Aflibercept for Persistent Diabetic Macular Edema. ClinicalTrials.Gov. https://clinicaltrials.gov/ct2/show/NCT03397264 . Accessed April 29, 2019.
12. Regeneron provides update on Eylea (AFLIBERCEPT) injection and nesvacumab (Ang2 antibody) combination program. Regeneron. 2017. https://investor.regeneron.com/news-releases/news-release-details/regeneron-provides-update-eylear-aflibercept-injection-and . Accessed April 29, 2019.
13. Sahni J, Patel SS, Dugel PU, et al. Simultaneous inhibition of angiopoietin-2 and vascular endothelial growth factor-A with faricimab in diabetic macular edema: BOULEVARD Phase 2 randomized trial. Ophthalmology. 2019.
14. Nourinia R, Ahmadieh H, Shahheidari MH, et al. Intravitreal fasudil combined with bevacizumab for treatment of refractory diabetic macular edema; a pilot study. J Ophthalmic Vis Res. 2013;8:337-340.
15. Ahmadieh H, Nourinia R, Hafezi-Moghadam A, et al. Intravitreal injection of a Rho-kinase inhibitor (fasudil) combined with bevacizumab versus bevacizumab monotherapy for diabetic macular oedema: a pilot randomised clinical trial. Br J Ophthalmol. 2018. Epub ahead of print.
16. Kaiser PK. DEL MAR: Phase 2, Stage 2. Paper presented at: ASRS; July 21, 2018, 2018; Vancouver, BC, CA.
17. Boyer DS, Yoon YH, Belfort R Jr, et al. Three-year, randomized, sham-controlled trial of dexamethasone intravitreal implant in patients with diabetic macular edema. Ophthalmology. 2014;121:1904-1914.
18. Syed YY. Fluocinolone acetonide intravitreal implant 0.19 mg (ILUVIEN): A review in diabetic macular edema. Drugs. 2017;77:575-583.
19. Lampen SIR, Khurana RN, Noronha G, Brown DM, Wykoff CC. Suprachoroidal Space Alterations Following Delivery of Triamcinolone Acetonide: Post-Hoc Analysis of the Phase 1/2 HULK Study of Patients With Diabetic Macular Edema. Ophthalmic Surg Lasers Imaging Retina. 2018;49:692-697.
20. Jung JJ, Gallego-Pinazo R, Lleo-Perez A, Huz JI, Barbazetto IA. NAVILAS Laser System Focal Laser Treatment for Diabetic Macular Edema - One Year Results of a Case Series. Open Ophthalmol J. 2013;7:48-53.
21. Herold TR, Langer J, Vounotrypidis E, et al. 3-year-data of combined navigated laser photocoagulation (Navilas) and intravitreal ranibizumab compared to ranibizumab monotherapy in DME patients. PLoS One. 2018;13:e0202483.
22. Moisseiev E, Abbassi S, Thinda S, et al. Subthreshold micropulse laser reduces anti-VEGF injection burden in patients with diabetic macular edema. Eur J Ophthalmol. 2018;28:68-73.

About the Authors

 

Archana Nair, MD, is an ophthalmology resident at NYU Langone Medical Center in New York.

 

 

Yasha Modi, MD, is an assistant professor of retinal diseases, uveitis and vitreoretinal surgery, director of uveitis, and director of tele-retina at NYU Langone Medical Center in New York.

 

Disclosures: Dr. Modi is a consultant for Alimera Sciences, Allergan, Genentech and Novartis.