Clinical Trials Provide Guidance in Therapeutic Decision Making for DME

Research helps answer real-world patient management questions.

BY DESIREÉ IFFT, CONTRIBUTING EDITOR

A flurry of research in recent years has served to validate several new treatment options for diabetic macular edema (DME). The RISE/RIDE and VIVID/VISTA Phase III clinical trials demonstrated the safety, effectiveness and superiority over laser treatment of the anti-VEGF drugs ranibizumab (Lucentis 0.3 mg, Genentech) and aflibercept (Eylea 2 mg, Regeneron). Three-year data from RISE/RIDE and 2-year data from VIVID/VISTA have shown that with frequent injections (Lucentis monthly and Eylea every 8 weeks after five monthly injections), the favorable anatomic and visual acuity (VA) results achieved can be maintained.^1,2

While the most robust results have been achieved with the consistent dosing frequencies described above, as-needed treatment protocols utilizing Lucentis, such as those followed in the RESTORE, DRCR.net Protocol I and RISE/RIDE extension studies, have also been shown to effectively reduce retinal thickness and improve VA.^3-5 In addition, in these three studies, results were maintained with decreasing numbers of injections per year.

The only large-scale direct comparison of three anti-VEGF agents for the treatment of DME, the Protocol T trial,⁶ was conducted by the Diabetic Retinopathy Clinical Research Network (DRCR.net). The trial showed that all three drugs — Lucentis, Eylea and bevacizumab (Avastin, Genentech) — are safe, effective treatments for DME, though Avastin in this setting is off label. In addition, the outcome of a pre-specified subgroup analysis based on visual acuity emerged as a key finding. In eyes with baseline visual acuity of 20/50 or worse, Eylea outperformed the other two drugs (Figure 1). In that group of patients, the mean improvement in VA letter score (range 0 to 100) was 18.9 with Eylea, 14.2 with Lucentis and 11.8 with Avastin.

FIGURE 1. In the DRCR.net Protocol T trial, in eyes with baseline visual acuity of 20/50 or worse, Eylea outperformed Lucentis and Avastin.
Slide courtesy of John A. Wells, MD

Although mean improvement in VA letter score for the entire study population was also greater with Eylea than with the other two drugs, the authors of the study reported that advantage as not clinically meaningful. John A. Wells, MD, lead author, explains: “The overall result, while favoring Eylea, has limited clinical utility because that was not the case for eyes with better baseline vision. All three agents gave equal improvement in that subgroup. In other words, the overall result has limited clinical utility because it can’t be applied to all eyes; the difference was driven by the eyes with worse visual acuity at baseline. Statistically speaking, when there is a strong interaction with a prespecified subgroup analysis, in this case the interaction between treatment and baseline visual acuity, the overall result has limited meaning.”

Dr. Wells says a better way to apply the Protocol T study results to an individual patient is based on the percentages of patients who gained three or more Snellen lines of vision. In the worse baseline vision group, this was seen in 63% more Eylea-treated eyes than Avastin-treated eyes (67% vs. 41%) and in 34% more Eylea-treated eyes than Lucentis-treated eyes (67% vs. 50%). “That is a compelling reason to use Eylea for patients with worse baseline vision. It gives them a significantly better chance to have improved vision,” he says.

Intravitreal steroids are another option for achieving vision gains in eyes with DME, as evidenced by the pivotal trials that led to FDA approval of two sustained-release implants, dexamethasone 0.7 mg (Ozurdex, Allergan) and fluocinolone acetonide 0.19 mg (Iluvien, Alimera Sciences). Although the percentages of patients who achieved a ≥15-letter VA improvement in the 3-year MEAD trial of Ozurdex (22.2%) and the 3-year FAME trial of Iluvien (28.7%) weren’t as high as were seen in the anti-VEGF trials, they were achieved with fewer treatments: an average of one implant over 3 years in FAME and 4.1 implants over 3 years in MEAD.^7,8 (See “Additional Notable Findings in DME” for more anti-VEGF and steroid implant study take-home points.)

ANTICIPATING POTENTIAL COMPLICATIONS

The randomized, controlled Phase III clinical trials have also elucidated what side effects may occur with the FDA-approved DME treatment options. The Lucentis and Eylea labels note the possibility of mild injection-related side effects as well as the potential for endophthalmitis and retinal detachment. Notably, in particular for patients with diabetes, the potential risk of arterial thromboembolic events with systemic exposure to VEGF inhibitors delivered intraocularly did not materialize in the Lucentis or Eylea trials with any significance.

In both the MEAD and FAME trials, the most common adverse events associated with the sustained-release steroid implants were increased IOP and cataract. In MEAD, IOP peaked at week 6 following Ozurdex implantation, and IOP increases were controllable with medication in most cases. IOP increases mostly occurred following the first or second implantation, and if a significant increase didn’t occur with a patient’s first, second or third implant it was unlikely to occur with subsequent implants.⁹ A higher number of implants was not related to a higher risk of developing increased IOP. Trabeculectomy was required in 0.6% of patients. Cataract surgery was successful in patients who developed cataract, and their vision improved postoperatively to levels on par with pseudophakic patients.

Similarly, the phakic patients who developed cataract and had surgery during the FAME trial of Iluvien achieved a visual benefit comparable to that of pseudophakic patients. It’s not yet clear how predictable IOP increases may or may not be with Iluvien. Data from the prospective FAMOUS pharmacokinetics study suggest that IOP increases could be more likely during the first several months after implantation and less likely after that time because levels of fluocinolone in the aqueous reached a steady state by roughly 6 months and then were stable out to 3 years.¹⁰ In FAME, 4.8% of patients who received Iluvien required incisional glaucoma surgery.

MORE RESULTS TO COME

Although the knowledge base surrounding DME has been growing, much remains to be learned. Future studies will explore new treatment options and help determine the best ways to utilize all available therapies to achieve optimal results with the least treatment burden. Dr. Wells says the 2-year results from the Protocol T study will be of great interest to retinal physicians as will results from the DRCR.net’s Protocol V trial, which is nearly fully enrolled and will evaluate whether observation, laser plus deferred anti-VEGF, or prompt anti-VEGF is best for patients with center-involving DME but 20/25 or better vision. ❖

REFERENCES