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Clinical

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To maintain treatment quality and patient and staff safety in the SARS-CoV-2 era, it is important to minimize clinic visits and maximize the use of imaging modalities. In addition, extending treatment intervals with longer-acting agents is key to maximizing safety and patients’ vision outcomes.

Pearls for maintaining quality, safety in retina clinics amid a pandemic

Treatment with a subretinal injection of voretigene neparvovec (Luxturna, Spark Therapeutics) resulted in a significant increase in visual function at the 12 months evaluation in most treated pediatric patients with 

mediated inherited retinal dystrophy (IRD),

 according to first author Alejandra Daruich, MD, PhD. She is from the Ophthalmology Department, Necker-Enfants Malades University Hospital, Paris Cité University, and INSERM, UMRS1138, Team 17, Sorbonne Paris Cité University, Centre de Recherche des Cordeliers, both in Paris.

Previous research has shown that voretigene neparvovec administered subretinally early in childhood for 

-mediated inherited retinal dystrophy achieved encouraging efficacious results,

 the authors explained. However, perifoveal chorioretinal atrophy developed in children who underwent post-market treatment.

Daruich and colleagues conducted a retrospective study to determine the main outcomes and complications in pediatric patients after treatment with voretigene neparvovec. They reviewed the records of patients younger than 17 years who had undergone subretinal administration of voretigene neparvovec for confirmed biallelic 

-mediated IRD. Twelve months after treatment, the best-corrected visual acuity (BCVA) was measured, spectral-domain optical coherence tomography (SD-OCT) and ultra-wide-field fundus images were reviewed, and the Goldmann visual fields were analyzed.

The study included 12 eyes (6 patients; mean age, 7.8 years). The investigators reported, “No intraoperative complications occurred. The BCVA significantly improved at the 12-month follow-up (mean logarithm of the minimal angle of resolution BCVA, 1.0±0.8 at baseline vs. 0.6±0.3 at 12 months, p=0.001). The mean central macular thickness and central outer nuclear layer thickness did not change at 12 months follow-up. The visual field V4e isopter did not show significant changes.”

Regarding complications, 1 patient had elevated intraocular pressure bilaterally. The most common complication was atrophy on the injection site. The atrophy on the injection site was limited in all patients except 1, in whom the atrophy increased considerably.

Daruich and colleagues concluded, “…the majority of pediatric patients treated with voretigene neparvovec exhibited a significant increase in visual function at the 12-month follow-up. This improvement was not associated with structural changes in SD-OCT or intraoperative foveal detachment. The most common complication was atrophy at the injection site. None of the observed postoperative complications prevented gains in visual function. Long-term studies are expected to evaluate the evolution of retinal thickness and chorioretinal atrophy.”

The investigators also pointed out that no consensus has yet been reached regarding the indications for treatment with voretigene neparvovec in children. Long-term studies are expected to evaluate the evolution of VA and chorioretinal atrophy in these patients.

Daruich A, Rateaux M, Batté E, et al. 12-Month outcomes after voretigene neparvovec gene therapy in paediatric patients with 

HauswirthWW, AlemanTS, KaushalS, et al. Treatment of Leber congenital amaurosis due to RPE65 mutations by ocular subretinal injection of adeno-associated virus gene vector: short-term results of a phase I trial.Hum Gene Ther. 2008;19:979–90. 

MaguireAM,SimonelliF, PierceEA, et al. Safety and efficacy of gene transfer for Leber’s congenital amaurosis.N Engl J Med. 2008;358:2240–8. 

BennettJ, WellmanJ, MarshallKA, et al. Safety and durability of effect of contralateral-eye administration of AAV2 gene therapy in patients with childhood-onset blindness caused by RPE65 mutations: a follow-on phase 1 trial.Lancet. 2016;388:661–72. 

Le MeurG, LebranchuP, BillaudF, et al. Safety and long-term efficacy of AAV4 gene therapy in patients with RPE65 Leber congenital amaurosis.Mol Ther. 2018;26:256–68. 

BainbridgeJWB, SmithAJ, BarkerSS, et al. Effect of gene therapy on visual function in Leber’s congenital amaurosis. N Engl J Med. 2008;358:2231–9. 

. Perifoveal chorioretinal atrophy after subretinal voretigene neparvovec-rzyl for RPE65-mediated leber congenital amaurosis.Ophthalmol Retina. 2022;6:58–64. 

Previous research has shown that voretigene neparvovec administered subretinally early in childhood for RPE65-mediated inherited retinal dystrophy achieved encouraging efficacious results.

clinical

Successful treatment of RPE65-mediated inherited retinal dystrophy with voretigene neparvovec

Considerations for surgical implant of the port delivery device and refill process

Video content above is prompted by the following:

What are the key considerations for the surgical implantation of the PDS?

Can you explain the refill process for the PDS and how it differs from standard intravitreal injections in terms of procedure and patient experience?

Panelists discuss how successful implementation of the port delivery system requires careful attention to surgical technique during both initial implantation and subsequent refill procedures, with specialized training and protocols that differ significantly from standard intravitreal injections in terms of procedural steps, sterility requirements, and patient preparation.

Video Series

Retinal Disease 

Considerations for Surgical Implant of the Port Delivery System and Refill Process

Panelists discuss how patients experiencing a high treatment burden with frequent anti-VEGF injections every 4-8 weeks are optimal candidates for the port delivery system, which can help reduce their number of clinic visits while maintaining therapeutic effectiveness.

Patient Selection For Port Delivery Device

Video content above is prompted by the following: 

Which patients are ideal candidates for this anti-VEGF delivery method?

Patients with frequent anti-VEGF treatment burden (4-8 weeks)

Patient Selection For Port Delivery System

Panelists discuss how the port delivery system (PDS) with ranibizumab represents a paradigm shift in neovascular AMD treatment by utilizing a surgically implanted refillable device that provides continuous medication delivery for 6 months, offering patients a preferred alternative to frequent intravitreal injections while ensuring consistent therapeutic levels.

Overview and Benefits of Port Delivery Device with Ranibizumab

Can you provide an overview of the port delivery system with ranibizumab approved for treating neovascular AMD?

What are the benefits of using the port delivery system with ranibizumab?

Certainty of 6 months of continuous anti-VEGF delivery

Patients in clinical trials prefer PDS over intravitreal injections

Overview and Benefits of Port Delivery System with Ranibizumab

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.

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.

Marc de Smet, MD, PhD

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