AAO RESEARCH

AAO Retina Subspecialty Days Detail Up-to-the-Minute Findings

ANDREW E. MATHIS, PhD, MEDICAL EDITOR

The retina subspecialty days at this year’s AAO annual meeting, dubbed “Retina 2013: Let the Good Times Roll,” featured two sessions in which the nation’s leading retinal specialists presented clinical trials data on a number of established and emerging treatments.

In the sessions on both days, the majority of the presentations focused on treatment of wet AMD and the use of anti-VEGF drugs. Some of the key findings are presented here.

ONE-YEAR LUCAS RESULTS

Karina Berg, MD, of Oslo University in Norway, presented the one-year results from her country’s LUCAS trial, in which nine centers are treating patients with treat-and-extend protocols of either ranibizumab (Lucentis, Genentech, South San Francisco, CA) or bevacizumab (Avastin, Genentech).

According to the protocol, patients received injections beginning at four-week intervals, with the interval extended to up to 12 weeks based on response. If shortening a patient’s interval became necessary, when increased again, the new interval could not be longer than the time to recurrence.

Both groups experienced significantly increased VA, with mean changes of 8.2 and 8.0 ETDRS letters in the ranibizumab and bevacizumab groups, respectively. The mean numbers of injections were 8.0 for ranibizumab and 8.8 for bevacizumab, and this difference was statistically significant. Central retinal thickness also decreased in both groups.

Serious medical conditions occurred in both groups. Dr. Berg noted this was to be expected in an elderly population. However, the numbers of thromboembolic and less serious adverse events were low in both groups.

Dr. Berg concluded noting that the one-year results confirmed equivalent effects of both drugs in improving VA. The study is set to continue for another year.

HEAD-TO-HEAD AMD TRIALS

LUCAS is not the only trial comparing these drugs, however. Daniel F. Martin, MD, chair of the Cole Eye Institute of the Cleveland Clinic and principal investigator on the CATT trial, discussed results from these and four other head-to-head trials (IVAN, MANTA, GEAFAL and BRAMD).

Dr. Martin noted his “top five” findings of these trials. First, ranibizumab and bevacizumab have shown no difference in improvement in VA. The two-year results confirm this finding.

Second, PRN dosing has provided excellent visual results. While some of the trials (eg, CATT) have shown statistically significant differences in VA, others (eg, IVAN) have not.

As his third point, Dr. Martin reported that both drugs produced “immediate and dramatic improvement” in resolving subretinal fluid, but ranibizumab produces better results.

Fourth, on a bit of bad news, both drugs produce geographic atrophy, with monthly dosing producing higher rates than PRN dosing. Again, the results from individual trials varied. IVAN, for instance, showed no difference between the drugs regarding GA rates, but it did show a significant difference between its monthly and PRN arms.

Finally, Dr. Martin reported, the drugs have not produced different rates of adverse events. Despite bevacizumab causing some concern in the CATT trial due to increased thromboembolic events, the other trials have not borne this finding out.

Dr. Martin was adamant in stating that despite continued interest in possible differences between the two drugs, these differences are nothing but statistical “noise.”

ASSESSING AFLIBERCEPT

Dr. Martin’s Cole Eye colleague Rishi P. Singh, MD, presented six-month interim results from the ASSESS study, which treated non-naïve wet AMD patients, previously treated with ranibizumab, bevacizumab or both, with aflibercept (Eylea, Regeneron, Tarrytown, NY). These patients were not non-responders; rather, they were normal patients.

The study investigators treated 26 patients monthly with 2 mg aflibercept. At six months, they measured absolute change in central subfield retinal thickness on OCT, mean change from baseline BCVA, 15-letter gains, 15-letter losses, and VA results better than 20/40 and worse than 20/200.

At six months, the patients showed a mean decrease in retinal thickness of 38.6 μm and a mean gain of 5.9 letters. The investigators also observed decreases in macular volume.

In addition, 46.15% of the patients gained more than 15 letters, and 42.31% had VA of 20/40 or better at six months; 15.38% had VA of 20/200 or worse. No significant adverse events occurred.

Dr. Singh concluded that the gains seen in this study were comparable to those seen in treatment-näive patients. It remains uncertain whether the improvements were the results of the combination of drugs or the fixed dosing regimen used in ASSESS.

BEYOND ANTI-VEGF

Because vitreomacular adhesion (VMA) is a not uncommon complication of wet AMD, Roger Novack, MD, PhD, of the Pacific Eye Institute in Upland, CA, reported on the use of ocriplasmin (Jetrea, ThromboGenics, Iselin, NJ), which is FDA-approved for VMA.

The trial, called MIVI-005, tested a single intravitreal injection of ocriplasmin in patients with AMD who had received between three and nine anti-VEGF injections. Dr. Novack characterized these patients as “stable but not recalcitrant.” The study followed up the patients for 12 months.

Reporting the 28-day data, Dr. Novack stated that 24% of the ocriplasmin-treated eyes achieved VMA resolution, compared to 12% of control eyes. The percentage of eyes achieving total posterior vitreous detachment was 16.2% of treated eyes versus 4% of control eyes. The mean number of anti-VEGF injections decreased by 28% in the treatment, and the VA results were similar to the pivotal trials of ocriplasmin.

Minor side effects, including floaters, occurred in approximately 40% of the ocriplasmin-treated eyes. Two cases of retinal detachment occurred, which did not coincide with ocriplasmin treatment. In addition, two cases of transient blindness due to elevated IOP also occurred, but they both resolved in less than one hour.

Dr. Novack was careful to note that the study was not sufficiently powered to demonstrate statistically significant differences. He noted that MIVI-005 was a phase 2, proof-of-concept/safety study, so any findings reported were secondary endpoints.

STEROID FOR DME

Laser remains the standard of care for DME, but other treatments are under investigation. Allergan’s (Irvine, Calif.) dexamethasone implant (Ozurdex), which is FDA-approved for macular edema due to RVO, is among these treatments. David S. Boyer, MD, of Retina-Vitreous Associates Medical Group in Los Angeles, reported three-year data from a phase 3 study.

Dr. Boyer began by noting the three-point rationale for treating DME with steroids, ie, that steroids target angiogenesis, vascular leakage, and inflammation. He then described the enrollment and inclusion criteria. The study excluded patients who had received anti-VEGF injections in the previous three months or steroid in the previous six months.

The trial enrolled more than 500 patients, 75% of whom were phakic and approximately one-quarter of whom were treatment-naïve. The investigators assigned the patients randomly to 700 μg dexamethasone, 350 μm dexamethasone or sham. The primary endpoint was a 3-line gain in vision.

At three years, the mean numbers of injections were 4.1 (750 μg) vs. 4.4 (350 μg) vs. 3.3 (sham). The study found meaningful improvement in vision, with nearly a quarter of treated patients gaining 3 lines and approximately 10% gaining 4 lines or more.

Not surprisingly, cataract was a common adverse event in phakic patients. No adverse systemic events occurred. Dr. Boyer ended by noting that these side-effects were as uncommon as those in other studies of the implant.

GENE THERAPIES IN AMD

Jeffrey S. Heier, MD, of Ophthalmic Consultants of Boston, gave the final presentation on the second subspecialty day. His talk was on genetic therapies for wet AMD using viral delivery vectors.

Dr. Heier began by singing the praises of anti-VEGF therapy, but he noted the difficulties with treatment burden. In addition, he noted, “long-term delivery has been more difficult to achieve than anticipated.”

Viral delivery vectors are an alternative that could perhaps minimize these issues. Summarizing the mechanisms at work, Dr. Heier described how gene therapies either compensate for abnormal genes or help to make beneficial proteins. Vectors are genetically engineered, modified viruses. Among them, the adeno-associated viruses (AAVs) have attracted considerable attention owing to their lack of pathogenicity.

More than 80 CTs are currently examining looking at AAVs. One of these AAVs, sFLT01, a naturally occurring VEGF inhibitor with an affinity similar to that of aflibercept, is under investigation in two trials.

Dr. Heier specifically addressed the phase 1/2 trial of subretinal sFLT01 under way by Avalanche Biotechnologies, Inc. (San Francisco). Under Avalanche’s formulation, doctors can administer sFLT01 extrafoveally, but the area of distribution broadens to penetrate subfoveally.

The trial investigators are testing low and high doses of sFLT01, given on the seventh day after treatment with ranibizumab. Although the results thus far are very preliminary, the investigators have reported no side effects, including vector-specific adverse events.

In addition, in certain cases, VA has improved against control arms. Noting that he places greater emphasis in early-phase trials on biological changes, Dr. Heier stated that central retinal thickness decreased in the treatment arms and was maintained over 12 months with very few retreatments.

In closing, Dr. Heier reminded the audience of the preliminary nature of the results. Nevertheless, he concluded that the trials of sFLT01 had entailed “small numbers but an exciting approach.”

LOOKING AHEAD

This year’s AAO annual meeting will be at Chicago’s McCormick Place October 18-21. The subspecialty days, including for retina, will be October 17 and 18. RP