Published in Retina

New Developments in Retina Drug Delivery

This is editorially independent content
10 min read

In this session from Eyes On 2023, Michael Singer, MD, reviews clinical trials and recent advances in therapies to treat retinal diseases.

New Developments in Retina Drug Delivery

From November 18 to 20, 2022, eyecare practitioners from around the world gathered online for Eyes On 2023, a 3 day educational summit offering up to 9 hours of COPE-accredited CE and CME providing the latest innovations in the ophthalmic industry.

Enjoy this presentation from Michael Singer, MD, and don't forget to check out our list of future events!

Please note these videos are provided for review only.

From 2000 to 2010, the number of cases of diabetic retinopathy increased by 89%, from 4.06 million to 7.69 million. However, in 2011, only 57% of diabetics had the recommended eye examination performed. This is cause for concern, as it leaves many diabetic patients vulnerable, missing the necessary diagnosis and treatment to address their symptoms.
When approaching the importance of eyecare for our patients with diabetes, consider the one-third rule: approximately ⅓ of people with diabetes have diabetic retinopathy, about ⅓ of people with diabetic retinopathy have diabetic macular edema (DME), and further, ⅓ of these patients have clinically significant macular edema.
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Treatments for diabetic macular edema

Diabetic macular edema is treated with laser photocoagulation, anti-vascular endothelial growth factor (VEGF) agents, corticosteroid injections/implants, and vitrectomy.

Laser photocoagulation to treat DME

In this procedure, high-energy light is applied to the retina to cause burning that coagulates blood vessels. This also causes tissue destruction, which decreases the metabolic load and destroys cells that produce angiogenic factors. Laser photocoagulation decreases the prevalence of severe retinopathy when used over the course of a series of treatments.

Anti-VEGF treatments for diabetic macular edema

There has been a shift to using anti-VEGF treatments more when managing diabetic eye diseases. These work by blocking leakages of nearby capillaries that lead to macular edema. There are currently four anti-VEGF medications used for DME patients.
  1. Bevacizumab (Avastin): A full-length humanized monoclonal antibody against VEGF that binds and inhibits VEGF. This is an off-label treatment for DME.
  2. Ranibizumab (Lucentis): An antibody fragment to VEGF from the same parent mouse antibody as bevacizumab. This is FDA-approved for DME.
  3. Aflibercept (Eylea): Acts as a decoy VEGF receptor, binding to VEGF/placental growth factor (PlGF) to prevent binding to VEGF receptors. This is FDA-approved for DME.
  4. Faricimab (Vabysmo): Bi-specific treatment with anti-VEGF and anti-angiopoietin-2 (Ang2) that stabilizes vessels and reduces vascular leakage growth, vessel growth, and inflammation. This is FDA-approved for DME.

Protol-T comparing three anti-VEGF treatments for DME

The first comparative trial of available anti-VEGF agents in the treatment of diabetic retinopathy was conducted by the Diabetic Retinopathy Clinical Research (DRCR) Retina Network. The 2-year data from Protocol-T, an interventional, randomized, multicenter, parallel, single-masked clinical trial comparing intravitreal aflibercept, bevacizumab, and ranibizumab as treatment options for eyes with center-involved DME with decreased visual acuity.

In the study, participants received either 2.0mg aflibercept, 1.25mg bevacizumab, or 0.3mg ranibizumab every 4 weeks. The safety and efficacy of these therapies were compared over the course of 1 year. Vision gains from baseline were seen with all three drugs at year 2. However, differences existed regarding the need for a rescue focal laser.

Figure 1 is a line graph comparing the mean change in visual acuity letter scores of the three anti-VEGF treatments, aflibercept, bevacizumab, and ranibizumab, per week over the course of the 104-week study period.
Figure 1: Courtesy of DRCR Retina Network

Corticosteroid implants

Corticosteroids are anti-inflammatory and may also inhibit the expression of the VEGF gene. Ozurdex and Iluvien are two current intraocular implants that use dexamethasone.
Table 1 shows inflammatory mediators in DME inhibited by corticosteroids compared to anti-VEGF agents.
FactorRole(s) in DMEInhibited by corticosteroidsInhibited by anti-VEGF agents
ICAM-1Facilitates leukocyte adhesion to endothelial cellsX
P-selectinFacilitates leukocyte adhesion to endothelial cellsX
VCAM-1Facilitates leukocyte adhesion to endothelial cellsX
IL-6Increases VEGF productionX
VEGFPromotes breakdown of the blood-retina barrier (BRB), promotes retinal neovascularization, stimulates leukostasis, increases vascular permeabilityXX
MCP-1Regulates migration and infiltration of monocytes/macrophagesXX
Ang-2Promotes breakdown of the BRB, sensitizes endothelial cells to TNF-⍺X
TNF-⍺Promotes breakdown of BRB, promotes ICAM-1 expressionX
CCL2Induces leukocyte recruitment and activationX
Table 1: Courtesy of Michael Singer, MD

Ozurdex intraocular implant

Ozurdex is a sustained-release dexamethasone biodegradable intraocular implant. It has anti-inflammatory and anti-angiogenic properties and is a solid polymer matrix with 0.7mg of dexamethasone. It biodegrades to lactic acid and glycolic acid over time and has a novel long-acting delivery system using Novadur technology that provides sustained and localized release of dexamethasone.

Iluvien intraocular implant

Iluvien is a non-erodible fluocinolone acetonide (FAc) implant that is FDA-approved for treating DME in patients who have been previously treated with a course of corticosteroids and did not have a clinically significant rise in intraocular pressure (IOP). It is a cylindrical polyamide tube containing 0.19mg of fluocinolone acetonide and is injected through a self-sealing wound via a 25-gauge proprietary inserter.

EARLY analysis comparing DME treatments

The EARLY analysis is a phase 3, randomized, multicenter clinical trial comparing various treatments for DME. These treatments included ranibizumab plus prompt or deferred laser, steroid plus prompt laser, and sham plus prompt laser. The study evaluated the outcomes of anti-VEGF treatment responses at week 12 and long-term best-corrected visual acuity (BCVA) in DME.

At week 12, the study showed that 39.7% of patients receiving ranibizumab had an early response of <5-letter gain, 23.2% of patients had a five to nine-letter gain to treatment, and 37.1% had an early response of ≥10-letter gain.

Significant improvements in BCVA were noted in patients implanted with corticosteroids compared to the sham group with relatively few injections. The treatment benefit of dexamethasone implant was observed with a mean of 4.1 injections over 3 years. Longer exposure to corticosteroid implants was associated with the formation or progression of cataracts, but vision improvement was restored following cataract surgery.

REINFORCE study analyzing steroid implants

The REINFORCE study assessed the effectiveness, safety, and real-world outcomes of the dexamethasone intravitreal implant (DEX) in clinical practice in patients with chronic DME. This was a prospective, multicenter, observational registry study with primary endpoints measuring the mean maximum BCVA change from baseline following each DEX injection, the percentage of patients with >15-letter improvement in BCVA, and an average improvement in BCVA.
In real-world clinical practice, DEX monotherapy and adjunctive therapy improved BCVA and CRT in patients with DME. An increase in IOP was the most common adverse event, with 22% of study eyes having an IOP greater than 25mmHG and 5% having an IOP higher than 35mmHg. No glaucoma surgeries were reported, and no new safety concerns were identified.

REINFORCE study outcome measures

  • 36% of study eyes had a >15-letter improvement in BCVA
  • Mean average improvement in BCVA from baseline of 3.6 letters
  • Mean maximum change in BCVA from baseline during the study was 11.7 letters
  • Mean maximum change in central retinal thickness (CRT) from baseline was -137.7μm
  • 19.4% of study eyes achieved BCVA of 20/40 or better and <300μm CRT at the same visit

PALADIN trial evaluating intravitreal implants

The phase 4 PALADIN study is a prospective, open-label observational study designed to evaluate the safety and efficacy of the 0.19mg fluocinolone acetonide intravitreal implants over 36 months for DME. In the study, 202 eyes received the 0.19mg FAc implant on-label to determine the incidence of IOP-lowering procedures and IOP-related signals. Three years before the implant, patients lost an average of 6.4 letters; after the implant, they gained 4.5 letters.

Eyes that received the FAc implant had a 25% chance of remaining treatment-free over 3 years and saw significant reductions in DME therapies needed.

Over 36 months, the 0.19mg FAc implant provided improved disease control over the standard of care with a significant increase in visual acuity and significant reductions in both needed DME therapies and macular edema. Additionally, the 0.19mg FAc implant is safe with high predictability of IOP response from a single steroid challenge. It provides a durable treatment option that reduces the burden of care for patients with DME.

Retinal vein occlusion

Retinal vein occlusion (RVO) can be categorized into either central retinal vein occlusion (CRVO), branch retinal vein occlusion (BRVO), or hemispheric retinal occlusion (HRVO). Risk factors for RVO include ocular diseases, systemic vascular disorders, hematological abnormalities, and inflammatory/autoimmune diseases.

Treatments for retinal vein occlusion

In the past, the standard treatment for CRVO was to wait and observe symptoms, and for BRVO was to treat patients with laser photocoagulation. However, with recent pharmaceutical treatment developments, VEGF inhibitors and corticosteroids are now more commonly used. VEGF inhibitors that are used to treat RVO include ranibizumab, aflibercept, and bevacizumab.
The GENEVA study compared two different doses of dexamethasone (350 and 700μg) in the intravitreal implant Ozurdex to treat RVO. The study was a 6-month masked study with an open-label six-month follow-up.

Clinical trials evaluating anti-VEGF agents

  • Ranibizumab: BRAVO and CRUISE
  • Aflibercept: VIBRANT, GALILEO, and COPERNICUS

Future retinal therapies

A new treatment option for retinal vein occlusion is KSI-301, an anti-VEGF antibody biopolymer conjugate (ABC) with enhanced ocular durability and improved bioavailability. This technology uses the stable linkage between an immunoglobulin G1 (IgG1) antibody and biopolymer to create ABC platform medicines.

BEACON trial evaluating tarcocimab

BEACON is a phase 3 noninferiority study looking at the ABC platform medication tarcocimab tedromer compared to aflibercept treatment. This trial met its primary endpoint of showing that the mean change in BCVA with tarcocimab Q8W was non-inferior to aflibercept Q4W in retinal vein occlusion.

The study showed that tarcocimab is the first anti-VEGF therapy to show comparable visual acuity outcomes to monthly aflibercept while doubling the treatment interval.

It also has a favorable safety profile with low rates of intraocular inflammation and no cases of intraocular inflammation with vasculitis or vascular occlusion. The successful outcomes from BEACON lend confidence to ongoing studies across indications.

Conclusion

Multiple pathways are being evaluated to improve retinal disease treatment options. These options include building a better anti-VEGF molecule, sustained delivery, inhibiting a new mechanism of action, and gene therapy. The future is bright for treating diabetic macular edema and retinal vein occlusion.
Michael Singer, MD
About Michael Singer, MD

Michael Singer, MD, is a clinical professor of ophthalmology at the University of Texas Health Science Center in San Antonio, Texas. He is also the Director of Clinical Research at Medical Center Ophthalmology. Dr. Singer is a member of the Retina Society, the Macula Society, Club Jules Gonin, the American Academy of Ophthalmology, and a Fellow of the American Society of Retina Specialists.

He is the recipient of many awards, including the American Society of Retina Specialists Honor and Senior Honor award, the Achievement award of the American Academy of Ophthalmology, The Gary Thomas Award, Faculty of the Year of the F1000 Foundation, OSN 150 Top Retina Specialists, and Two ASRS Rhet Buckler Awards. Dr. Singer has been involved in over 150 clinical trials, presented research, and taught courses nationally and internationally. He is written numerous journal articles on all the medicines approved for retinal indications. In 2018 he was inducted into the Retina Hall of fame.

Michael Singer, MD
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