Currently no pharmacologic therapy is approved by the US Food and Drug Administration (FDA) for treatment of diabetic macular edema (DME), an ocular complication of diabetes that results in significant visual disability for many of the 23 million people with diabetes in the United States.1
A fluocinolone acetonide intravitreal insert (Iluvien, Alimera Sciences) is currently being evaluated in a phase 3 clinical study (the FAME study) for treatment of DME. Preliminary results for the month-24 primary endpoint of this study were announced last year,2 and the study will conclude this year with final visits at the 3-year data point.
The interim analysis of 24-month FAME data announced last year concentrated on the primary efficacy endpoint of 15-letter (three-line) improvement in visual acuity at 24 months. This article reviews additional data on the safety of the intravitreal insert regarding the number of subsequent ocular procedures required by study participants.3
FAME STUDY
Iluvien is an intravitreal insert for the sustained delivery
of fluocinolone acetonide to the posterior segment.
It is designed to be injected with a 25-gauge needle
through the pars plana. The device is not secured to the
sclera but remains free-floating. The Iluvien contains
approximately 190 μg of fluocinolone acetonide.
Depending on its formulation, the insert can deliver a
low dose of approximately 0.2 μg per day, with a delivery
lifespan of more than 2 years, or a high dose of
approximately 0.5 μg per day, with a lifespan of approximately
18 months.
In the FAME study, a total of 956 participants at 101 sites were randomized 2:2:1 to low-dose insert, high-dose insert, or sham treatment. All patients had DME involving the fovea, with central retinal thickness of 250 μm or greater on optical coherence tomography (OCT). All patients had previous laser treatment, and visual acuity was between 19 and 68 letters, inclusive, on the ETDRS chart. If progression of edema occurred, patients were permitted to undergo laser treatment 6 weeks after enrollment and retreatment with an additional study insert after 1 year.
The 24-month data readout indicated that Iluvien was effective in the treatment of DME, with 29% of treated patients (both treatment groups) gaining 15 letters of visual acuity compared with 16% of subjects in the sham group.
The two primary side effects of intraocular corticosteroids are development of cataract and elevation of intraocular pressure (IOP). The FAME investigators wanted to know whether Iluvien would mitigate these side effects. We evaluated the relative risk of all procedures associated with the treatment of diabetic retinopathy and elevation of IOP in FAME study participants.
CATARACT
The insert caused acceleration of cataract formation.
By 24 months, approximately 75% of the patients who
were phakic at enrollment had undergone cataract
surgery. Cataract developed mostly between months
6 and 18.
In these patients, therefore, the visual benefit of the insert was delayed. Patients who entered the study pseudophakic (n=139) experienced rapid improvement in visual acuity that remained stable through 24 months. Patients who entered the study phakic and underwent cataract surgery during the course of the trial (n=154) ended up with modestly better visual acuity, on average, at 24 months than those who were pseudophakic at baseline. Those who remained phakic throughout the first 2 years (n=82) had the worst vision at 24 months (Figure 1).
Patients with DME are usually at risk for worsening of edema after cataract surgery, but that did not occur in patients in this study. Treated patients who underwent cataract surgery had rapid postoperative improvement by a mean of approximately 20 letters and were stable for 12 months. Those with sham implant who underwent cataract surgery had a mean decrease in visual acuity, perhaps because of a worsening of DME, followed by a gradual increase in vision (Figure 2).
INTRAOCULAR PRESSURE
Some patients experienced elevation of IOP. Elevation
of IOP to greater than 30 mm Hg at any time during the
study was recorded in 16.3% of patients in the low-dose
group, 21.6% in the high-dose group, and 2.7% in the
sham group. The need for surgical intervention to
address elevated IOP was low: in the low-dose group,
2.1% underwent trabeculectomy, 1.3% underwent trabeculoplasty,
and 1.3% had another glaucoma procedure.
In the high-dose group, 5.1% underwent trabeculectomy,
2.5% had trabeculoplasty, and 2.5% had
another glaucoma procedure. This profile represents at
least 24 months of follow-up on all patients, but also
includes 40% of patients for whom follow-up data was
available beyond the 24-month visit at the time the
database was locked.
ADDITIONAL TREATMENTS
Patients could receive additional laser treatment at
the physician's discretion after week 6 if progression of
edema occurred. A lower percentage of patients in the
low-dose treatment group required laser (36.7%) than
in the sham group (58.9%). The number of treatments
per patient was 0.74 in the low-dose group and 1.34 in
the sham group.
The need for additional intravitreal injections, either triamcinolone acetonide or antiangiogenic agents was also lower in treated patients. In the low-dose treatment group, 12.5% of patients received additional injections, and in the sham group 28.6%. The number of injections per patient was 0.19 in the low-dose group and 0.72 in the sham group.
CONCLUSIONS
Although the incidence of incisional IOP-lowering
procedures was higher in the treatment groups, the
overall incidence of ocular procedures per subject for
diabetic retinopathy, IOP elevation, and cataract was
lower in the treatment groups. Subjects in the sham
group underwent 50% more procedures than those in
the low-dose treatment group.
The month-24 results of the FAME study show that delivery of fluocinolone acetonide through the Iluvien intravitreal insert resulted in an overall reduction in the number of procedures needed for control of diabetic retinopathy and elevated IOP. Cataract formation was accelerated, but visual results after cataract surgery were good in treated patients.
This insert, delivering daily sub-microgram doses of fluocinolone acetonide, has the potential to become a long-duration treatment for DME. In June, Alimera Sciences submitted a New Drug Application to the FDA for consideration of the Iluvien for regulatory approval, and in August the FDA granted the company's request for priority review, which could result in an FDA action by the end of this year. We look forward to the widespread availability of this treatment modality for the ophthalmic community and our patients with DME.
P. Andrew Pearson, MD, is Chair of the Department of Ophthalmology and Visual Science at the University of Kentucky, in Lexington, KY. Dr. Pearson states that he is a consultant with Alimera and has received travel support from them. He has a financial interest in pSivida. He can be reached at +1 859 323 5867.
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