Retina Society Roundup

The Retina Society annual meeting was held in London, England from Sept 11 the 15th with a variety of first time and encore presentations. Here is a summary of the most impactful and noteworthy studies from the meeting.

Interim 24-week Cohort 1 data from the OPTIC trial –Intravitreal gene therapy with ADVM-022 (AAV.7m8-aflibercept) for neovascular age-related macular degeneration.

Dr. Szilard Kiss presented the 24-week outcomes of gene therapy for the treatment of exudative age-related macular degeneration. ADVM-022 is a viral vector encoded with the protein for aflibercept delivered as a single intravitreal injection. Preclinical models show the expression of atleast 30 months of continual aflibercept protein expression. The purpose of the OPTIC study was to assess the safety and tolerability of a single IVT injection of ADVM-022. Patients with previously treated neovascular AMD were treated with a single injection of alibercept following by a single injection of ADVM-022. There was rescue criteria with both anatomic and visual endpoints that was applied during the course of the study. With regards to safety, there were no serious adverse events experienced. All patients within the study experienced intraocular inflammation which was graded as mild or moderate. During the course of the study patients were allowed to be treated with topical steroids. Overall the patients lost on average 2 letters of vision while experiencing a reduction in retinal thickness of 52.7 microns. No patient was rescued due to a drop in vision or anatomical change during the course of the study.

The bottom line: While the inflammation is notable, these cases appears to be mild and not visually limiting. The company is investigating a lower protein producing vector which might
improve the inflammatory issues seen. The population of patients tested within the study was previously treated so a visual gain is not expected and six patients is just too small to make inferences on the success of this program.

Dorzolamide-Timolol vs Placebo Drops as an Adjunct to Intravitreal Anti-Vascular Endothelial
Growth Factor Injections for Incomplete Responders with Neovascular Age-related Macular Degeneration

Dr. Jason Hsu presented his study conducted at Wills Eye Hospital in which incomplete responders to anti-VEGF treatment were randomized to receive either topical aqueous suppressants or placebo to see if there was an increased effectiveness of the anti-VEGF in these patients. At each visit, anti-VEGF injections were continued with the same fixed interval as before the patients were randomized to drops. Forty six patients were randomized in the study with patients receiving a mean of 20.5 anti-VEGF prior to topical treatment. At the final follow up, the mean improvement of CST from baseline was -33.6 compared to +1.7 microns in the placebo group (p=0.02). There was no significant change in visual acuity between the two groups.

There are a variety of theories while dorzolamide and timolol might have had this outcome. Beta-blockade in animal models shows a decreased in VEGF production and other angiogenic factors. The aqueous suppression might prevent aqueous clearance and therefore the anti-angiogenic has less clearance and greater bioavailability.

The bottom line: While impressive results, there are significant study limitations. The study continued patients on non-standardized intervals prior to randomization. In addition, patients were on either aflibercept or ranbizumab and not on a single drug so it is difficult to compare these arms head to head. Nonetheless, the results show a statistically significant improvement in anatomy on the dual topical regimen. A larger prospective study with a single anti-VEGF given in more real world patients might yield better results.

APEX: A Phase II Clinical Trial Evaluating the Safety and Preliminary Efficacy of X-82 Administered Orally in the Treatment of Exudative Macular Degeneration

Dr. Michael Cohen presented the results from the APEX trial evaluating an oral multi-kinase VEGF and PDGF inhibitor. It is currently being tested for solid tumors such as in Von Hippel
Lindau and exudative AMD in a phase 2 study. In this phase 2 study, patients were randomized to three different oral doses of X-82 compared to oral placebo with anti-VEGF treatment. There
was a dose dependent decrease in anti-VEGF injections observed in the treatment group with X-82 from 7.5 injections over 52 weeks in the lowest dosage group. The highest dosage group
saw only 4.3 injections over 52 weeks while the placebo saw 7.9 injections of anti-VEGF.

Unfortunately, there were also significant systemic side effects with the oral treatment including diarrhea, vomiting and fatigue. Most important was the increase in ALT/AST elevations with approximately 20-28% of patients experiencing this versus 5.1% in the placebo group. Because of the liver enzyme rises, 17.9% of patients required early termination in the highest dosage group.

The bottom line: While the promise of oral therapy sounds intriguing and potentially would have better compliance, x-82 side effects are too significant to consider for future treatment. There was no assessment if BMI related to the level of toxicity and thus there might be a sweet spot for dosing. An agent with less systemic side effect profile would be a more ideal candidate.

Evaluation of iris and intraocular lens mobility in eyes with scleral-fixated IOLs

Dr. Jeremy Wolfe reported on his retrospective evaluated consecutive case series on the mobility of both the iris and scleral fixated IOLs versus traditional IOL cases. There has been some thought previously that these lenses do move significantly after implantation thus making the refractive error difficult to correct. Ultrasound biomicroscopy (UBM) was used to assess mobility in all cases. 36 eyes were included within the study. The lens position with relationship to either sitting upright or supine did not change significantly. Scleral fixated lenses were located more posteriorly than traditional bag placed PCIOLs (4.87 mm versus 4.11, respectively). The iris mobility was graded by two independent graders on a scale of 1-4 with 4 being the most mobile. It did appear that scleral fixated lenses had a more mobile iris compared to traditional bag placed PCIOLs.

The bottom line: While scleral fixated lenses are placed slightly more posterior, none of these parameters evaluated including the change in depth with head position nor iris position seems to change to the point where these are clinically significant. This gives some assurance to using this procedure in patients with floppy iris sydromes due to either systemic medications or systemic disease like Marfan’s.

Injection intervals in treatment naïve neovascular AMD patients who received anti-VEGF: Data from the IRIS registry

Dr. Matt MacCumber presented his study evaluating the treatment intervals of naïve nAMD eyes treated with anti-VEGF within the IRIS registry system. Recent studies have demonstrated that some drugs such as brolucizumab and aflibercept can go 12 weeks or longer for retreatment. The purpose of this study was to evaluate the real world injection intervals in nAMD eyes treated with anti-VEGF within the United States population. A total of 31,292 unique patients were identified with a mean age of 80 years. Patient’s interval of treatment was determined by their last two visit intervals within a 12 month period. The results from the study demonstrated that approximately 40% of patients were treated less than a q8 week interval, 30% were treated from q8 week to a less than q12 week interval, and 30% achieved a greater than q12 week interval. The study concluded that the majority of patients in a real world setting demonstrated less than a q12 week pattern of treatment with current FDA approved regimens.

The bottom line: While interesting, the study has significant limitations that impact the conclusions. Patients on bevacizumab were not evaluated in this analysis because they specifically evaluated for FDA approved medications only. In addition, treatment intervals can change during the course of therapy even after 1 year so it is not clear to see that patients don’t meet a lengthy interval in this period of time. In addition, the visual acuity and OCT relationship to the treatment interval was not elucidated within this study. Therefore it is possible for patients to achieve a less frequent interval at the detriment of vision and anatomy. More real-world studies evaluating this relationship would be helpful. Nonetheless, it does appear that few patients in clinical practice achieve a q12 week and beyond interval of retreatment.

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