It’s not your grandparents’ anti-VEGF therapy – Optometry Times

New DME treatments aim to extend time between intravitreal injections.

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

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 m 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 eventthough 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

Novartis is currently seeking approval for brolucizumab in patients with DME based on results from the KESTREL (NCT03481634) and KITE (NCT03481660) studies showing noninferiority compared with aflibercept.

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

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.

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 m 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 m). At 6 months, 50% of participants had a 2-line improvement in BCVA with no additional rescue therapy.

The study was small20 total participantsand only the highest dose affected acuity gains, but these findings offer additional hope of improved vision for patients who dont 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 m.

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

A phase 2 trial (NCT05063734) of THR-687 in treatment-nave 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

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 m, and best-corrected vision ranging from 20/30 to 20/200 showed a significant 59-m 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 placebolow energy, broad spectrum white lightwith 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 m/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 wavelengthsyellow, red, and near infraredfor 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 dont respond well to traditional therapies and may reduce the treatment and vision burden of these all-too-common disorders.

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It's not your grandparents' anti-VEGF therapy - Optometry Times