September 2018

RETINA

Pharmaceutical focus
New non-bioerodible intravitreal implant


by Maxine Lipner EyeWorld Senior Contributing Writer


Eye of a diabetic macular edema patient upon first receiving the Iluvien implant in October 2016, with baseline vision of 20/50

The same eye in August 2017 without further treatment and vision now of 20/25
Source (all): Caesar Luo, MD

 

Elucidating Iluvien use

For patients with diabetic macular edema, one new treatment method gaining notice is Iluvien (fluocinolone acetonide intravitreal implant, Alimera Sciences, Alpharetta, Georgia). This non-bioerodible implant continuously elutes the steroid fluocinolone acetonide at a low dose for up to 3 years, according to Caesar Luo, MD, Bay Area Retina Associates, Walnut Creek, California.
This implant is capped at one end and has a polyvinyl alcohol matrix that dissolves over time, releasing a slow and steady therapeutic dose of fluocinolone acetonide for treating diabetic macular edema, Dr. Luo explained.

Integrating Iluvien

The Iluvien implant is one of two FDA-approved steroid devices used in the eye as a second-line therapy, Dr. Luo noted. “The standard of care for most retinal physicians is to start with an antivascular endothelial growth factor [anti-VEGF] medication,” he said, adding that unless the macular edema is well outside the center of vision, primary therapy is usually the anti-VEGF approach. “Then most of us are treating once a month to determine the responsiveness of the macular edema to anti-VEGF therapy,” Dr. Luo said. “If we think the patient is a suboptimal responder or failing anti-VEGF therapy, we consider use of steroid inside the eye.”
Glenn Stoller, MD, Ophthalmic Consultants of Long Island, Rockville Centre, New York, pointed out that the issue with first-line diabetic retinopathy treatment compounds such as Eylea (aflibercept, Regeneron, Tarrytown, New York), Lucentis (ranibizumab, Genentech, South San Francisco), or Avastin (bevacizumab, Genentech) is that they only block VEGF. “Exudative age-related macular degeneration is primarily a VEGF driven disease. However, the pathogenesis of diabetic macular edema can be much more complicated,” Dr. Stoller said. “There are different factors that cause swelling of the retina; it’s not only VEGF.” Some of these other factors are addressed by intravitreal steroids.
The second-line approach involves use of intravitreal steroids in the form of either Ozurdex (Allergan, Dublin, Ireland), which elutes dexamethasone, or the Iluvien implant. Aside from the different steroids, there are similarities between the two, such as that both implants come preloaded in a dispenser with a sharp needle. “You insert the needle into the eye and press an actuator that causes the implant to be delivered into the vitreous cavity,” Dr. Stoller said. One key difference between the two is that one implant is bioerodible while the other is not.
Initially, Dr. Stoller usually gives three to four injections of anti-VEGF to see how a diabetic macular edema patient is responding before considering moving on to an intravitreal steroid approach. Still, consideration of intravitreal steroid use may come down to patient selection and weighing risk factors. “There are a number of variables to consider, such as the patient’s lens status, history of glaucoma, history of a steroid response, the degree of residual swelling, the amount of associated vision loss, and what the vision in the patient’s fellow eye is,” Dr. Stoller said.
Dr. Luo also starts with anti- VEGF therapy. Determining how long to stick with this strategy can be a balancing act. Dr. Luo pointed out that in some instances even when it appears the medication isn’t working, it is just a question of time. “There is a subset of patients who will improve with a longer course of monthly injections,” Dr. Luo said. “They may not see a response for 6 months or even 1 year.” The problem is that there is also a subset of patients who don’t recover even with monthly injections of anti- VEGF therapy. “There’s the risk that you have left some of these patients undertreated for an extended period of time,” he said.
He relies on patient signs to determine the best course. If the macular edema is getting worse, Dr. Luo will quickly consider using an intravitreal steroid. He also examines the appearance of the fluid. “There are some patients who have diffuse and cystic fluid with a lot of outer retinal atrophy and loss,” he said. “I will start considering steroid use at a very early stage for those patients, especially if after initiation of anti-VEGF therapy, they have not shown a response.”
In cases where there is even a mild response either in terms of visual acuity or central foveal thickness or macular volume, Dr. Luo will continue patients on anti-VEGF therapy. “I want to see how much better the patient can get with a safer side effect profile than with steroids,” he said. “However, if there is no response or a worsening, I will consider a relatively early change.”
That said, however, based on the DRCR.net Protocol T recommendations,1 which compared three anti-VEGF agents for diabetic macular edema, he will choose the anti-VEGF to use, keeping patients’ acuity in mind. “I will start with Avastin in the majority of my patients who have good vision and diabetic macular edema,” Dr. Luo said. “However, if they have less than 20/50 vision, I will start with intravitreal Eylea.” If they do not improve, he moves quickly to a steroid. The one caveat is for those with better vision who he starts on Avastin. Even if the patient does not have much of a response, he will switch to a full three-course treatment of Eylea, which in some patients may have higher efficacy than Avastin. However, if this is not effective, he considers intravitreal steroid use.

Steroid challenge requirement

Practitioners cannot move directly to Iluvien use without trying another steroid first, Dr. Luo pointed out. “Because of the way the FDA worded the label, there’s no requirement for what type of steroid to use in the eye,” he said. “You can use drops, you can use intravitreal Ozurdex, you can use intravitreal triamcinolone, as long as it is given to ensure that patients have a lessened risk of a steroid responsive intraocular pressure rise.” He prefers a course of intravitreal Ozurdex because he thinks this has the most comparable mechanism of action to Iluvien. By contrast, with triamcinolone, the side effect and therapeutic profile is more variable. “With Ozurdex, it is a controlled 3-month response, and if they’re going to have a pressure rise I expect to see that about 6 weeks after implantation.”
Likewise, Dr. Stoller prescribes Ozurdex first for patients since this implant lasts for up to 6 months. “If you’re going to have a steroid-induced glaucoma, better it be from something that goes away quicker than something that lasts for 3 years,” he said.
He views those who have had a positive response to Ozurdex or intravitreal triamcinolone without a steroid-induced elevation in IOP to be excellent candidates for Iluvien.
Dr. Luo will likewise consider switching a patient to Iluvien if the fluid melts away without any side effects after Ozurdex. “I will have that discussion with them at the 6-week follow-up when I see their OCT,” Dr. Luo said. He tells patients that there’s another implant option that has a longer duration of action, which may be able to reduce their overall treatment burden.
He usually starts considering Iluvien after one Ozurdex insertion. However, there are some additional patient factors to take into account. For instance, since the Iluvien implant lasts for so long, it’s vital that the patient return to check for pressure rises. Dr. Luo also stressed that it’s important to weigh the patient’s overall health. “If they have a lot of other doctors to see and their caregivers have difficulty getting them in, I sometimes give Iluvien sooner because it may be able to reduce their overall treatment burden if I can follow them every 3–4 months instead of every month,” he said. He finds that it’s important to still monitor those on Iluvien quarterly since the FAME trials2,3 indicated that their pressure might rise up to 1 year after implantation. He continues to check for a pressure rise as well as to see if they have any new fluid that needs to be addressed.
Dr. Luo finds that many patients do well with Iluvien alone. “I see about 60% of patients who have a single injection of Iluvien and have not needed another treatment,” he said. “About 40% in my data set have needed a supplemental therapy.” Dr. Luo keeps this in mind when he speaks to patients. “What I tell my patients now is that the expectation is to be able to reduce the overall treatment burden,” Dr. Luo said. “So instead of getting a monthly anti-VEGF treatment, they may need one every 6 months or every year.”
For example, Dr. Luo has a patient who failed anti-VEGF therapy for 1 year before coming to him. She did well on the Ozurdex he gave her, as well as on the subsequent Iluvien implant for about 3 months. When she had some fluid recurrence, he gave her two Eylea injections to supplement the Iluvien. In the more than 6 months since, she has not needed another anti-VEGF shot.
Dr. Stoller also finds that the Iluvien monotherapy suffices for some and that for others this can decrease the need for further anti-VEGF therapy. There is also likely a subset of patients who require the anti-VEGF to be given with the same frequency to supplement the Iluvien to get better control of the edema than could be obtained with anti-VEGF monotherapy.
Dr. Stoller and Dr. Luo have not had to remove an Iluvien implant. Dr. Luo noted that there are two situations that might necessitate removal. The first would be a patient who experiences an uncontrolled pressure rise even after receiving all of the pressure-lowering drops they can, as well as undergoing laser trabeculoplasty and surgery. The second would be if the implant ended up in the front of the eye and started causing corneal change. “I have a patient that has an implant that migrated forward,” Dr. Luo said. “But she has no corneal sequelae and her vision is excellent, so we left the implant.”
Overall, Dr. Stoller considers the advent of sustained delivery devices such as the Iluvien implant as a real advance in the ability to treat diabetic macular edema. “Not everyone responds to anti-VEGF therapy, so it enhances our ability to take care of patients and may reduce treatment burden for both the patient and the doctor,” Dr. Stoller said.

References

1. Cai S, Bressler NM. Aflibercept, bevacizumab or ranibizumab for diabetic macular oedema: recent clinically relevant findings from DRCR.net Protocol T. Curr Opin Ophthalmol. 2017;28:636–643.
2. Campochiaro PA, et al. Sustained delivery fluocinolone acetonide vitreous inserts provide benefit for at least 3 years in patients with diabetic macular edema. Ophthalmology. 2012;119:2125–32.
3. Parrish RK 2nd, et al. Quantitative assessment of optic nerve changes in patients with diabetic macular edema treated with fluocinolone acetonide vitreous implants. Ophthalmic Surg Lasers Imaging Retina. 2016;47:418–25.

Editors’ note: Dr. Luo has financial interests with Alimera Sciences, Allergan, Genentech, Iridex (Mountain View California), and Lumenis (Yokneam, Israel). Dr. Stoller has financial interests with Genentech, Roche (Basel, Switzerland), Allergan, and KalVista Pharmaceuticals (Cambridge, Massachusetts).

Contact information

Luo
: caesarluomd@gmail.com
Stoller: glstoller@gmail.com

New non-bioerodible intravitreal implant New non-bioerodible intravitreal implant
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