With the release of topline results from the Phase III SEQUOIA and CEDAR trials of abicipar pegol just before the annual meeting of the American Society of Retina Specialists, Allergan and its collaborative partner, Molecular Partners, touted that the investigational agent showed noninferiority to ranibizumab (Lucentis, Roche/ Genentech) for treatment of neovascular age-related macular degeneration. However, some clinicians expressed concerns about the relatively high rates of inflammation reported in the abicipar treatment arms.

After 12 months of treatment, in both studies abicipar demonstrated similar efficacy after six or eight injections compared to 13 ranibizumab injections, and the overall rates of adverse events were similar among the three treatment arms.

In SEQUOIA, the proportion of patients with stable vision were 94.8 percent in the abicipar eight-week dosing arm; 91.3 percent in the abicipar 12-week arm; and 96 percent in the ranibizumab four-week arm. Treatment-emergent adverse event rates were 78.3 percent, 78 percent and 74 percent, respectively, across the three treatment arms.

In CEDAR, the proportion of patients with stable vision in the abicipar arms were 91.7 percent (eightweek dosing) and 91.2 percent (12-week dosing) vs. 95.5 percent for ranibizumab dosed every four weeks. Rates of treatment-emergent adverse events were 73.7 percent, 81.1 percent and 73.2 percent, respectively, across the
treatment arms.

However, the rates of intraocular inflammation events were significantly higher in the abicipar groups in both trials. In SEQUOIA, 15.7 percent and 15.3 percent of patients in the abicipar eightand 12-week arms reported inflammation vs. 0.6 percent in the ranibizumab arm. In CEDAR, those rates were 15.1 percent and 15.4 percent in the abicipar eightand 12-week arms and 0 percent in the ranibizumab arms.

Allergan’s official statement said the investigators are further analyzing these results as both trials continue on a masked basis for a second year. David Nicholson, PhD, Allergan’s chief officer for research and development, told analysts the company is addressing the inflammation concerns by modifying the formulation of abicipar. The reformulated agent will be the subject of the upcoming MAPLE trial.

Here, investigator Raj Maturi, MD, of Midwest Eye Institute and associate professor at Indiana University School of Medicine in Indianapolis, answers questions about SEQUOIA and CEDAR.

Q: What is the key findings of both the SEQUOIA and CEDAR trials?
A: The trials showed non-inferiority of abicipar at a fixed 12-week regimen. The studies also disclosed that 91 percent of patients on a fixed 12-week regimen maintained or improved vision. Clearly there are other important points that a retina specialist would look for, including change in visual acuity from baseline as well as proportion with 2- and 3-line improvements. I suspect that these results are anticipated to be presented at a major meeting in the near future.

Q: What about the design of SEQUOIA and CEDAR that makes the findings credible?
A: These two trials involved a fixed-dosing regimen without any individual alteration of the regimen based on individual responses. There were no subgroups that received treatment at different intervals based on individual response.

Q: What was the dosing regimen?
A: In both studies, there were three arms: abicipar Q8 weeks; abicipar Q12 weeks; and the control, ranibizumab Q4 weeks. The Q8-week arm received three monthly doses followed by the eight-week treatment interval, while the Q12 arm received only two monthly doses followed by Q12-week dosing.

Q: What do these trials reveal about the potential advantage of abicipar vs. existing intravitreal treatments for nAMD?
A: Having a dependable drug that is able to last for almost 12 weeks would be a relative advantage for this disease. The treatment burden for patients would be
reduced markedly.

Q: Where would abicipar fit in the retina specialists’ tool box—alongside existing therapies (and brolucizumab) or in place of them? Or for refractory cases?
A: A full evaluation of the results of both brolucizumab (Novartis) and abicipar would be necessary to make this judgment. A longer duration of action would generally imply one or more of the following: better drug affinity to vascular endothelial growth factor molecules; slower clearance from the retina/subretinal space; or slower breakdown of active components. Longer duration drugs could thus be considered more powerful.

For larger pigment epithelial detachments and more difficult-to-treat AMD lesions, I typically use aflibercept (Eylea, Regeneron). One of the longer-duration drugs would likely replace aflibercept in the near future.

For the less-active and responsive lesions, my first line choice continues to be bevacizumab (Avastin, Roche/Genentech). However, given a longer duration-of-drug effect, some patients may wish for one of these alternatives.

Q: There has been a lot of concern over the inflammation outcomes in the trials. How should clinicians interpret these findings?
A: The two Phase III studies were conducted with A a biological agent that has since been improved. Allergan is conducting a smaller study, MAPLE, with this improved drug product. Biologicals are generally produced using genetically modified bacteria. Companies typically improve the purification process as they
gain experience with this delicate extraction.

Q: Drilling down into the inflammation issue, did that have any impact on functional vision in study subjects?
A: Allergan has reported that inflammation rates were around 15 percent for both abicipar arms. The full dataset on inflammation-related visual loss has not been disclosed. I would anticipate that this would be presented at a future meeting or formal scientific publication.

Q: What is the next step in the evaluation and development of abicipar?
A: The company has stated that it wishes to file a Biologics License Application within the next six to nine months. Having dosed this drug in my patients over the last few years in multiple trials, I look forward to using this drug in my clinic in the very near future.