It’s not your grandparents’ anti-VEGF therapy

Therapies that block VEGF have become the mainstay of interventional treatment for retinal vascular disorders including neovascular age-related macular degeneration (nvAMD), diabetic macular edema (DME), and retinal venous occlusive disease.¹

Over the past few years, intravitreal anti-VEGF therapy (AVT) has been shown to be very effective for patients with diabetic retinopathy (DR), reducing its severity and subsequent vision-threatening complications such as proliferative diabetic retinopathy (PDR) and anterior segment neovascularization in patients with nonproliferative DR,² as well as center-involved diabetic macular edema (CI-DME).³

Clinical trials

In January, the FDA approved faricimab (Vabysmo, Genentech) to treat DME and nvAMD.⁴ It joins ranibizumab (Lucentis, Genentech) and aflibercept (Eylea, Regeneron) for this indication, although it is not yet approved for treating DR in isolation.

Faricimab is a bispecific monoclonal antibody targeted against both VEGF-A and angiopoietin-2 receptors. In the RHINE (NCT03622593) and YOSEMITE (NCT03622580) trials, faricimab demonstrated noninferiority compared with aflibercept against CI-DME in terms of vision gained and reduction in central retinal thickness.

Trial participants randomly assigned to take faricimab gained 1 ETDRS letter and 20 to 30 µm additional reduction in optical coherence tomography (OCT), central subfield thickness (CST) at 1 year, and these gains were sustained at 2 years.⁴

Moreover, 70% of participants taking faricimab were able to extend the time between injections to 12 or more weeks (50% were able to extend to 16 weeks), compared with 30% of participants taking aflibercept, thus reducing the burden of treatment.

In year 2, 80% of eyes were able to extend treatment intervals to 12 or more weeks with faricimab.⁵ No new safety signals were seen in roughly 900 participants in each arm, but it is worth noting that 5 eyes in the faricimab group versus 1 eye in the aflibercept group experienced a retinal artery occlusion, vein occlusion, or other retinal embolic event—though none of these were associated with inflammation/vasculitis.

Brolucizumab (Beovu, Novartis) is another AVT monoclonal antibody previously approved for nvAMD. Unfortunately, postapproval analysis showed a small but definite increased risk of intraocular inflammation (IOI) and/or retinal vascular occlusion (RO), with an overall incidence of 2.4%. Risk was substantially higher in patients who had IOI/RO within 12 months of drug initiation._⁶

More than 50% of participants achieved every 12-week dosing. Further, the incidence of IOI/RO was lower than what was seen in patients with nvAMD, but was still higher than those with aflibercept (4.1% for brolucizumab versus 1% aflibercept).⁷

AVTs/AAVs

One goal of these newer therapies is extending the time between intravitreal injections required to maintain both absence of disease activity and vision gains, given the relatively short half-life of current AVT. Gene therapy introduces genetic material into patients’ cells to compensate for faulty genes or deliver therapeutic transgenes capable of producing therapeutic molecules.⁸

In diabetic retinal disease, adenovirus-associated vectors (AAVs) modified to produce anti-VEGF and other antiangiogenic or neurovascular-protective molecules are implanted within the vitreous, sub-retinal pigment epithelium (RPE), or suprachoroidal space.

Animal trials have shown success, and results from a 1 phase II human trial showed improvement in DR severity sans DME at 6 months,⁹ whereas another trial in participants with CI-DME was terminated early due to safety concerns that included hypotony, inflammation, and vision loss.¹⁰ Retina specialists are optimistic that AAVs hold great promise for both DR/DME and AMD.

Beyond VEGF

Another pathway distinct from VEGF, but directly implicated in the pathogenesis of DME, is plasma kallikrein (PKal), a protein synthesized in the liver that mediates vascular leakage and inflammation, levels of which are elevated in the vitreous of patients with diabetic retinopathy.¹¹

Results from KALAHARI (NCT04527107), a phase II study of PKal inhibitor THR-149 (Oxurion), showed 6.1 letters of visual acuity improvement and CST reduction of 100 µm after 3 monthly injections in participants with DME suboptimally responsive to a minimum of 5 prior anti-VEGF injections (baseline BCVA ranging from 20/40 to 20/160, with baseline CST averaging 421 µm). At 6 months, 50% of participants had a 2-line improvement in BCVA with no additional rescue therapy.

The study was small—20 total participants—and only the highest dose affected acuity gains, but these findings offer additional hope of improved vision for patients who don’t respond adequately to AVT.¹²

Integrins are transmembrane receptors that allow cell-to-cell and cell-to-extracellular matrix adhesion and biochemical signal transduction. They have been implicated in DR and DME by activating growth factor receptors both upstream and downstream from VEGF.¹³

The integrin antagonist THR-687 (Oxurion) was assessed in a phase 1 trial (NCT03666923) at 3 doses in 12 participants with DME previously treated with AVT, mean visual acuity of 20/80 and mean CST of 542 µm.

Mean improvement of 7.2 letters was seen at 1 week and 9.2 letters at 1 month, as well as a 106-µm decrease in CST at 2 weeks that waned to a 37-µm reduction by month 3.

A phase 2 trial (NCT05063734) of THR-687 in treatment-naïve participants with DME is due for completion in August 2023. Several other anti-integrin therapies are in clinical trials, including at least 1 self-administered eye drop that reaches the posterior segment.^14,15

More DME treatments

Another possible treatment for DME is photobiomodulation (PBM), an LED or LASER application of visible light (typically 670 nm) that activates cytochrome-C oxidase within retinal mitochondria, enhancing cellular metabolism (ATP production) and reducing reactive oxygen species that play a critical role in diabetic eye disease.

Results of a study of patients with CI-DME, CST greater than 300 µm, and best-corrected vision ranging from 20/30 to 20/200 showed a significant 59-µm reduction at 2 months (p = 0.03), though acuity results were not reported.¹⁶

Investigators in a recent clinical trial from the DRCR Retina Network (Protocol AE) compared placebo—low energy, broad spectrum white light—with PBM for 90 seconds, twice daily for 4 months in 135 participants with center-involved DME and good vision (> 20/25).15 Unfortunately, both mean CST and vision in the treated group worsened only 2 µm/0.4 letters less in the PBM group versus placebo (both insignificant).¹⁷ This suggests PBM may be most effective for those with more substantial DME.

Of note, top-line data from the LightSite III trial (NCT04065490) showed that using PBM at 3 wavelengths—yellow, red, and near infrared—for intermediate dry AMD yielded a 5.5-letter improvement in the treatment (n = 91 eyes) versus sham treatment (n = 54 eyes) arms at 13 months.¹⁸ The investigation of PBM for both AMD and DME continues.

There now are multiple therapies for treating both DME and DR, with more on the horizon. This is particularly good news for those patients who don’t respond well to traditional therapies and may reduce the treatment and vision burden of these all-too-common disorders.

References

1. Yorston D. Anti-VEGF drugs in the prevention of blindness. Community Eye Health. 2014;27(87):44-46.

2. 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(9):946-955. doi:10.1001/jamaophthalmol.2021.2809

3. Sharma T. Evolving role of anti-VEGF for diabetic macular oedema: from clinical trials to real life. Eye (Lond). 2020;34(3):415-417. doi:10.1038/s41433-019-0590-0

4. FDA approves faricimab for neovascular age-related macular degeneration and diabetic macular edema. Medscape. January 28, 2022. Accessed January 28, 2022. https://www.medscape.com/viewarticle/967524?uac=373761SJ&faf=1&sso=true&impID=
3981173&src=wnl_newsalrt_220128_MSCPEDIT_faricimab

5. Wells JA. Presented at Angiogenesis, Exudation, and Degeneration Meeting 2022; February 11-12, 2022; virtual.

6. 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

7. Brown DM, Emanuelli A, Bandello F, et al. KESTREL and KITE: 52-week results from two phase III pivotal trials of brolucizumab for diabetic macular edema. Am J Ophthalmol. 2022;238:157-172. doi:10.1016/j.ajo.2022.01.004

8. Wang JH, Roberts GE, Liu GS. Updates on gene therapy for diabetic retinopathy. Curr Diab Rep. 2020;20(7):22. doi:10.1007/s11892-020-01308-w

9. REGENXBIO presents positive interim data from phase II ALTITUDE trial of RGX-314 for the treatment of diabetic retinopathy using suprachoroidal delivery. February 12, 2022. Accessed April 6, 2022. https://regenxbio.gcs-web.com/news-releases/news-release-details/regenxbio-presents-positive-interim-data-phase-ii-altitudetm

10. Bankhead C. Adverse events halt gene therapy trial for diabetic macular edema. Medpage Today. October 12, 2021. Accessed April 6, 2022. https://www.medpagetoday.com/meetingcoverage/asrs/94976

11. 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(3):237-244. doi:10.1080/13543784.2020.1723078

12. Khanani AM. Phase 2 Results of THR-149 in Patients with DME: KALAHARI Study Part A. Presented at Angiogenesis, Exudation, and Degeneration Meeting 2022; February 11-12, 2022; virtual.

13. 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. doi:10.1016/j.preteyeres.2021.100966

14. Slack RJ, Macdonald SJF, Roper JA, Jenkins RG, Hatley RJD. Emerging therapeutic opportunities for integrin inhibitors. Nat Rev Drug Discov. 2022;21(1):60-78. doi:10.1038/s41573-021-00284-4

15. 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(2):244-250. doi:10.1124/jpet.118.248427

16. Shen W, Teo KYC, Wood JPM, et al. Preclinical and clinical studies of photobiomodulation therapy for macular oedema. Diabetologia. 2020;63(9):1900-1915. doi:10.1007/s00125-020-05189-2

17. Kim JE, Glassman AR, Josic K, et al; DRCR Retina Network. A randomized trial of photobiomodulation therapy for center-involved diabetic macular edema with good visual acuity (Protocol AE). Ophthalmol Retina. 2022;6(4):298-307. doi:10.1016/j.oret.2021.10.003

18. Hutton D. LumiThera unveils LIGHTSITE III clinical trial data for improving vision in patients with dry age-related macular degeneration. Ophthalmology Times®. March 22, 2022. Accessed April 6, 2022. https://www.ophthalmologytimes.com/view/lumithera-unveils-lightsite-iii-clinical-trial-data-for-improving-vision-in-patients-with-dry-age-related-macular-degeneration