This article is more than 5 years old. Information may no longer be current.
Corticosteroid implant fills an unmet need in treatment of DME
It may be sensible to treat severe chronic diabetic macular edema with a broad-acting anti-inflammatory agent.
Click Here to Manage Email Alerts
The recent RIDE and RISE studies have unequivocally demonstrated the importance of anti-VEGF monotherapy in the treatment of diabetic macular edema. Interestingly, both studies have also demonstrated a relatively resistant patient population: patients with chronic diabetic macular edema. The explanation for this is quite simple and has been known in the general medical literature for over 2 decades. As diabetes evolves, the inflammatory component becomes increasingly important.
This has been demonstrated in the ophthalmic literature as well. For instance, a recent study from Austria demonstrated that the aqueous concentration of inflammatory cytokines was increased in patients with diabetic macular edema. A recent study from Japan demonstrated a similar increase in cytokine levels in the vitreous of patients with diabetic macular edema. Therefore, while it may make sense to treat patients with non-chronic diabetic macular edema with anti-VEGF monotherapy, it may be equally sensible to treat patients with chronic diffuse, severe diabetic macular edema with a broad-acting anti-inflammatory agent such as corticosteroids.
Iluvien (fluocinolone acetonide, Alimera Sciences) is a non-bioerodable micro-implant administered via a 25-gauge injector. It is capable of delivering the drug for 3 years. This article focuses on the implications of a pre-planned subgroup analysis of two large phase 3 trials, FAME A and FAME B.
FAME trials
Both FAME trials had a similar design. Patients who had had at least one prior macular laser photocoagulation treatment were randomized into one of three groups: 0.2-µg implant, 0.5-µg implant, and a control group. At various time points the patients were allowed rescue laser photocoagulation at the investigator’s discretion. An algorithm was used for a pre-planned subgroup analysis to determine the median duration of diabetic macular edema, which was 3 years.
Following completion of the study, patients were divided into chronic diabetic macular edema (duration of at least 3 years) and non-chronic diabetic macular edema (duration of less than 3 years) subgroups. Within these two subgroups, the median duration of diabetic macular edema was well-balanced in all three randomized treatment groups. Both the FAME A and FAME B studies met their primary endpoint at the 3-year mark. Alimera Sciences has elected to commercialize the lower-concentration 0.2-µg fluocinolone acetonide implant. Therefore, this article concentrates on the efficacy data of the lower-dose implant but provides the safety data of both the lower-dose as well as the higher-dose implant.
What was the effect of the 0.2-µg fluocinolone acetonide implant on patients with chronic vs. non-chronic diabetic macular edema? It is important to emphasize that this was a pre-planned and not an ad hoc post-study subgroup analysis. Among patients with chronic severe diabetic macular edema, those with the implant had a significantly better outcome than those without the implant. Interestingly, this was not reflected in the OCT results; there was an OCT visual acuity disconnect in patients with chronic diabetic macular edema that did not exist in patients with non-chronic diabetic macular edema. One may speculate, therefore, that while OCT is an excellent barometer for VEGF levels, it may not be a very good barometer for inflammation.
Fluorescein angiography of clinically significant diabetic macular edema.
Image: Heidelberg Engineering
The complete safety data showed a low rate of endophthalmitis at 0.2%. However, because it is a corticosteroid implant, the rate of cataract extraction and IOP-related events was increased. Cataract extraction was performed in 80% of phakic patients, which amounted to 50.1% of the entire patient population. Increased IOP, defined as IOP greater than 30 mm Hg, was seen in 18.4% of patients. IOP-lowering medication was required in 38.4% of the patients. Laser trabeculoplasty was required in 1.3% of patients. Finally, incisional IOP-lowering surgery was performed in 4.8% of patients. It is notable that having the implant in the eye while undergoing cataract surgery was not a disadvantage for the patient. In fact, the vision in these patients improved remarkably well following cataract surgery. It is also of note that 62% of patients with the implant did not require IOP-lowering therapy. The distillation of all the efficacy and safety data is that the benefit-to-risk ratio is doubled with the implant in patients with chronic diabetic macular edema.
Regulatory update
Alimera Sciences submitted the data dossier to the regulatory health authorities in Europe as well as in the U.S. in the middle of 2010. In early 2012, it received a positive opinion from all seven European health authorities. According to the currently approved indication for this implant in Europe, “Iluvien, the commercial name, is indicated for the treatment of vision impairment associated with chronic diabetic macular edema considered insufficiently responsive to available therapies.” Note that the word “chronic” is used and no disease duration is required.
Pravin U. Dugel
This indication is based on two important data points. The first, as mentioned, is that the benefit-to-risk ratio is doubled in patients with this implant who have chronic diabetic macular edema. Second, the consistency of the data is remarkable. FAME A and FAME B were entirely separate studies that were conducted in separate recruitment centers. Yet the data from both studies are remarkably consistent. In early 2013, Alimera Sciences plans to launch Iluvien commercially in Germany, the U.K. and France. In the near future, the company also plans to submit a response to the U.S. Food and Drug Administration’s complete response letter with a focus on the chronic diabetic macular edema data.
In conclusion, diabetic macular edema is a multifactorial disease known to be driven by different cytokines in various stages of the disease. There is a good scientific basis for classifying diabetic macular edema as chronic and non-chronic. The inflammatory component is important in chronic diabetic macular edema; therefore, anti-VEGF drugs may be more effective in non-chronic diabetic macular edema, whereas corticosteroids may be more effective in chronic diabetic macular edema. Both FAME studies were consistent in confirming the role for a slow-release corticosteroid device in patients with chronic diabetic macular edema.
At the end of the day, when this implant becomes available, in my clinic it will not be a first-line agent but will be valuable in filling an unmet need in treating patients with chronic, severe, blinding diabetic macular edema.