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Clinical

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Closing out his discussion on the port delivery system in retinal diseases, Chirag Jhaveri, MD, considers how this approach has impacted the treatment landscape. 

Clinical Implications of Port Delivery System in Retinal Diseases

Concise insight on education and training strategies that will optimize use of the port delivery system in retinal diseases.

PDS in Retinal Diseases: Practical Advice on Education and Training 

Chirag Jhaveri, MD, reviews the trial design and results of the LADDER and ARCHWAY studies, which tested the port delivery system in neovascular AMD. 

PDS in Retinal Diseases: Interpreting the LADDER and ARCHWAY Studies

Expert insight on the history of the port delivery system in neovascular AMD and how it has impacted patient experience and outcomes.

The Development and Safety of Port Delivery System in Retinal Diseases 

The 1-year results from the HELIOS Trial that evaluated the investigational intravitreal AXPAXLI implant (OTX-TKI, Ocular Therapeutix) for the treatment of non-proliferative diabetic retinopathy (NPDR) are in. The treatment showed stability or improvement in the Diabetic Retinopathy Severity Scale (DRSS) and that generally the drug was well tolerated.

Diana V. Do, MD, Professor of Ophthalmology and Vice Chair for Clinical Affairs at the Byers Eye Institute, Stanford University, Los Altos, CA, and Clinic Chief of Ophthalmology at Stanford Health Care, Stanford, CA, spoke on behalf of the HELIOS investigators at the Hawaiian Eye and Retina 2025 Meeting, in Kauai, HI.

OTX-TKI is a sustained-release drug in hydrogel that was evaluated in a multicenter, double-masked, randomized parallel group study of patients with moderately severe to severe NPDR without center-involved diabetic macular edema (CI-DME). One intravitreal bioresorbable hydrogel injection allows sustained release of the drug for 6 to 12 months.

She enumerated the key takeaways from the phase 1 trial:

OTX-TKI showed DRSS stability or improvement with durability through 48 weeks; 23.1% of patients in the OTX-TKI arm had a 2-step or greater DRSS improvement, and 46.2% of patients had a 1- or 2-step or greater DRSS improvement at 48 weeks. The DRSS did not worsen at 48 weeks in any patients in the OTX-TKI arm;

No patients in the OTX-TKI arm developed PDR or CI-DME)through week 48; in contrast in the sham control arm, 37.5% developed PDR or CI-DME through week 48;

A single OTX-TKI injection showed durable fluid suppression and more stable fluid control through week 48;

OTX-TKI was generally well tolerated with no incidence of treatment or injection procedure-related intraocular inflammation, iritis, vitritis, or vasculitis.

DR is a chronic, progressive, and burdensome disease for which earlier treatment is needed to prevent progression, Do pointed out. While the efficacy of anti-vascular endothelial growth factor (VEGF) therapy and need for proactive treatment of NPDR has been established in the PANORAMA and Protocol W studies,

 less than 1% of patients with NPDR received anti-VEGF therapy and most retina specialists (62.7%) do not recommend treating patients with NPDR who do not have DME.

This has resulted in what Do described as an unsustainable treatment burden of frequent injections and worse outcomes in eyes that had interrupted or reduced treatment compared to those never treated at all.

“There is an unmet need for early intervention with a longer lasting treatment option,” she emphasized.

AXPAXLI’s efficacy and safety profiles have not been established, and it has not been approved by the FDA or any other health agency.

1. Maturi RK, Glassman AR, Josic K, et al

 Four-year visual outcomes in the protocol w randomized trial of intravitreous aflibercept for prevention of vision-threatening complications of diabetic retinopathy. JAMA. 2023;329:376-385.

2. Brown DM, Wykoff CC, Boyer D, et al. Evaluation of intravitreal aflibercept for the treatment of severe nonproliferative diabetic retinopathyresults from the PANORAMA randomized clinical trial. 

3. Market Scope. 2022 Retinal Pharmaceuticals Market Report: Global analysis for 2021 to 2027. Published August 2022.

4. Market Scope. US Retina Quarterly Update: O2 2022 analysis of historical trends and latest developments. Published August 2022

5. Hahn P, Garg SJ, eds. 2023 Global trends in retina survey. Chicago, IL. American Society of Retina Specialists; 2023.

6. Goldberg RA, Hill L, Davis T, Stoilov I. Effect of less aggressive treatment on diabetic retinopathy severity scale scores: analyses of the RIDE and RISE open-label extension. 

DRSS stable/improved with OKT-TKI; drug well tolerated

clinical

HELIOS trial: Promising 1-Year results of phase I study for treating NPDR

EYLEA’s unique MoA: What is the rationale for the higher molar dose?

Hello and welcome to this video series sponsored by Bayer in which we are going to explore Eylea 8 mg for the treatment of age-related macular degeneration and diabetic macular edema. I am Professor Jean-Francois Korobelnik. I'm working in Bordeaux at the University Hospital in France. In this video I will be talking about Eylea's unique mechanism of action and the rational for the higher molar dose. Before we get started, I'd like to share my disclosures. I have been compensated by Bayer for my participation in this video. First, let's explore how Eylea targets disease pathogenesis.

To do that, let's have a look at the Eylea molecule. Eylea is a recombinant fusion protein consisting of portion of human VEGF receptors 1 and 2 domains fused to the Fc portion of human IgG1. So, it works as a decoy for multiple targets: VEGF-A, VEGF-B, placental growth factor, and galectin-1. This is a pioneer for the multi-targeted therapeutic approach.

In fact, Eylea is the only widely approved agent that blocks all VEGF receptor 1 ligands and the key VEGF receptor 2 ligands.

So, let's talk about the molar dose of Eylea 8 mg and why it is so significant. Eylea 8 mg has the highest reported potency. It demonstrates a stronger binding affinity for VGF-A and it targets a broader range of molecules including VEGF-A, VEGF-B, PLGF, and galectin-1. Additionally, Eylea 8 mg has a 34% slower ocular clearance compared to its 2 mg counterpart.

Now, let's take a look at the rational for increasing the molar dose of Eylea.

As I mentioned, 8 mg dose has a slower ocular clearance than the 2 mg dose. In fact, 8 mg is estimated to remain in the eye for 6 weeks longer, on average, than the Eylea 2 mg.

Why is this significant? Well, with its four-fold higher molar dose compared with the Eylea 2 mg, Eylea 8 mg aims to achieve sustained disease control for all eligible patient groups, potentially addressing key unmet needs in retinal care.

So what would shifting the curve mean for patients with neovascular AMD and DME who currently experience a higher treatment burden? What would this mean for clinic capacity? As you can see on this illustrative model, shifting the curve on the right could mean increasing the treatment intervals by four to eight weeks, from eight-week intervals to eight or 12-weeks intervals, thus lowering the treatment burden and reducing clinic capacity issues.

Another potential benefit of longer acting agents is that they may extend the time between injections compared to current treatment options. With Eylea 2 mg, approximately a third of the patients in ALTAIR and ARIES trials received injections every eight weeks or less at year two. On the other end, the percentage of patients receiving Eylea 8 mg that had last assigned treatment interval of 8 weeks at week 96 in PULSAR and PHOTON was between 5 and 13% only.

So now, let's return to our illustrative model and take a closer look at patients who are currently able to achieve extended treatment intervals on the right of your slide.

You can see the green line that represents the higher molar dose, so that the patients can, in fact, achieve those extended intervals as a result with lower treatment burden.

Let's now take a closer look about what longer interval means really. For Eylea 2 mg, one study found that 42 to 46% of patients were on 16-week intervals at year 2. Whereas another study found that 27 to 30% of patients were at 16-week or greater intervals at year 2. By contrast, between 78 and 88% of patients receiving Eylea 8 mg in PULSAR and PHOTON had a last treatment interval of 16-weeks or greater at week 96. So this data strongly suggests that longer acting agents may extend the time between injections compared with current treatment options.

Now, let's put together all the pieces and see what impact this could have for the patient. Based on everything we've explored in this video, Eylea 8 mg has the potential for greater and longer lasting control of disease activity through lasting vision gains, rapid and resilient fluid control, and extended treatment intervals. Additionally, Eylea 8 mg has the safety profile that is consistent with the Eylea 2 mg. With this in mind, let's take one last look at the mechanism of action of Eylea to support the rational for higher molar dose. Eylea's unique mechanism of action and molecular properties contribute to a sustained suppression of VEGF which is the master regulator of disease pathology. With its four-fold higher molar dose and 34% slower ocular clearance than Eylea 2 mg, Eylea 8 mg shifts the curve for all eligible patient groups. As a result, Eylea 8 mg has the potential for greater and longer lasting control of disease activity through sustained disease control compared to Eylea 2 mg for eligible patients groups with neovascular AMD and DME. Thank you very much for watching.

Significance of the Higher Molar Dose of Aflibercept 8 mg

Video content above is prompted by the following: 

Aflibercept 8 mg was recently approved for treating age-related macular degeneration and diabetic macular edema. Could you discuss the significance of the higher molar dose?

Panelists discuss how the aflibercept 8 mg higher molecular concentration enables extended durability through increased VEGF binding capacity and longer intraocular drug levels, potentially allowing for less frequent dosing while maintaining efficacy.

Video Series

A European study found that temperature changes have the potential to adversely affect anti-vascular endothelial growth factor (VEGF) drugs when patients store them in their homes. These changes can result in bacterial contamination, loss of drug activity, and inflammation,1 according to first author Inès Ben Ghezala, MD, PhD. She is from the Ophthalmology Department, Dijon University Hospital, and Inserm, CIC 1432, Clinical Investigation Center, Clinical Epidemiology/Clinical Trials Unit, Dijon University Hospital, both in Dijon, France.

Increasing numbers of patients are being treated with anti-VEGF drugs worldwide. In some cases, according to the investigators, patients are instructed to obtain the drugs from a pharmacy, store them in their homes, and then bring them to their physicians for intravitreal injection.

Because of this step in the treatment process, the researchers conducted a quality improvement study to determine both if patients were adhering to the drugs’ storage guidelines and the effectson the drugs if they were not adhering to the storage guidelines. The study included all consecutive patients with new or renewed prescriptions for intravitreal anti-VEGF agents prescribed to treat any macular disease.

The investigators gave the participants a time-temperature indicator that changed color according to brief (2-12 hours), moderate (12-48 hours), and prolonged (≥48 hours) exposure over 8 °C. The indicator was activated at the time of the anti-VEGF agent delivery to the participant in community pharmacies, they explained.

During the study period that ranged from May 27 to June 7, 2024, 50 participants who were treated with intravitreal anti-VEGF agents received a time-temperature indicator. Of those, 38 participants (24 [63.2%] women; median age, 79.3 years) returned with their drugs to undergo an intravitreal injection with an analyzable indicator.

The authors reported, “Of the 38 analyzable indicators, all showed temperature excursions above the threshold of 8 °C, including 26 (68.4%) for 12 to 48 hours and 11 (28.9%) for 48 hours or longer.”

After the injection of the anti-VEGF drugs, no ocular adverse effect developed that might be associated with development of severe intraocular inflammation.

In commenting on their findings, the authors pointed that the anti-VEGF agents were exposed to temperatures above 8 °C for 48 hours or longer in 28.9% of participants while the drugs were stored in their homes.

“While it is unknown how these 38 participants relate to other patients worldwide who are required to obtain their own anti-VEGF agents, these findings suggest that patients need to be educated about the importance of rigorous maintenance of cold storage of their anti-VEGF agents,” Dr. Ben Ghezala and colleagues concluded.

1. Ben Ghezala I, Steinberg L-A, Sibert M, et al. Temperature excursion of intravitreal anti-VEGF agents during home storage. JAMA Ophthalmol. 2025; published online January 16. doi:10.1001/jamaophthalmol.2024.5884

Home-stored anti-VEGF drugs face risks from temperature changes, pointing to a need to protect efficacy and avoid dangerous contamination.

Potential effect of temperature changes on anti-VEGF drugs

Overview of Novel Treatments for Retinal Vascular Diseases

Video content above is prompted by the following: 


Could you briefly provide an overview of the new treatments available for retinal vascular diseases?

A panelist discusses novel treatments for retinal vascular diseases, including faricimab, aflibercept, and port delivery system with ranibizumab.

Retinal Disease 

Advantages of the molecular structure of aflibercept

Aflibercept 2 mg is considered the standard of care for retinal vascular diseases. Can you briefly explain the structure of the aflibercept molecule and its significance?

Panelists discuss how aflibercept’s molecular structure contributes to its clinical efficacy as a standard treatment for retinal vascular diseases.

Chirag Jhaveri, MD

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