At the 2018 meeting of the American Academy of Ophthalmology, phase 3 safety and efficacy data were presented on the SEQUOIA and CEDAR studies of the Molecular Partners/Allergan DARPin technology called abicipar. The data showed that both 8-week and 12-week abicipar regimens met the prespecified criteria for noninferiority to monthly ranibizumab (Lucentis; Genentech) for the primary endpoint, defined as stable vision at week 52, in both studies. Initial vision gains for abicipar were maintained throughout week 52.
The overall incidence of treatment-emergent adverse events was comparable among all 3 treatment groups. However, abicipar-treated patients had a higher risk of developing intraocular inflammation (IOI) compared to ranibizumab-treated patients. Allergan undertook the MAPLE study, a 28-week open-label study that enrolled 123 neovascular age-related macular degeneration (nAMD) patients and evaluated the safety of abicipar produced via a modified manufacturing process.
As a result of the improvements in the manufacturing process, the incidence of IOI was 8.9% in the MAPLE study. This was lower than the rate observed in the SEQUOIA and CEDAR studies. Most IOI events were assessed as mild to moderate in severity. The incidence of severe IOI was 1.6%, with 1 reported case of iritis and 1 reported case of uveitis. There were no reported cases of endophthalmitis or retinal vasculitis in this study. Here we ask leaders in the retina field for their impressions of the data from the MAPLE study.
David S. Boyer, MD
Retina-Vitreous Associates Medical Group, California
The results of the MAPLE trial are very encouraging. It appears that with a change in manufacturing the incidence of IOI for abicipar has decreased by 40%. The press release indicates that the inflammation was mainly mild to moderate, which is also an improvement. The incidence of inflammation will still mean an increase in patient visits to treat the inflammation for these patients. This increase in visits to treat the inflammation has to be considered in view of the potential for 12-week treatment intervals. Other anti-VEGF agents have also shown 12-week interval for treatment in 50% of patients without the high incidence of inflammation. I hope that with further changes in manufacturing the incidence of inflammation can be significantly reduced.
Yoshihiro Yonekawa, MD
Mass Eye & Ear and Harvard Medical School, Boston, Massachusetts
Earlier this year we discussed our initial, unfiltered thoughts on the SEQUOIA and CEDAR study results. I had a few minor qualms about the efficacy and durability data, but overall, the studies demonstrated the effectiveness of abicipar and presented the much-needed opportunity for 12-week fixed-interval dosing for treating nAMD. The overshadowing concern was the 15% rate of IOI, which would likely not be acceptable as primary treatment. Allergan updated the manufacturing process of abicipar to address this issue and examined the new formulation in the MAPLE study.
The inflammation rate fortunately decreased to 8.9%. But that’s still quite a difference from the near-zero rates that we are accustomed to. Severe inflammation was seen in 1.6% of patients, which represented 2 subjects: 1 with iritis and 1 with uveitis. I’d like to know more about these patients, and I’d like to see a detailed look at the other 9 subjects with “mild to moderate” inflammation, how they were managed, and how visually significant these events were. Thankfully, Allergan reported that there were no cases of vasculitis as there were in SEQUOIA and CEDAR, but was widefield fluorescein angiography regularly performed to detect vasculitis in the most sensitive manner? MAPLE was also a smaller study with a presumably improved formulation of abicipar, so chances are, it was underpowered to provide a comprehensive understanding of the inflammatory issue — although we know it’s a safer formulation. Also note that there was no comparative arm.
I believe that if abicipar is approved, it will potentially become a second-line treatment for eyes with unresponsive or recurring activity and for retina specialists who feel comfortable with the small risk for IOI. My hope is that more detailed information will be provided in the upcoming months to better prepare us, and that Allergan will continue to improve the extraction process to further decrease the risk of this complication. I also hope that more granular studies will elucidate this complication in more detail.
Yehia Hashad, MD
Senior Vice President, Head of Global Clinical Development, Allergan
In April, Allergan and Molecular Partners announced topline safety results from the MAPLE study. In this single-arm study, treatment naïve or prior anti-VEGF treated patients received 3 monthly 2 mg abicipar injections followed by 2 mg injections every 8 weeks for up to a total of 5 injections through week 28. In our commitment to continuous improvement of abicipar, we have advanced our analytical methods and manufacturing processes. As a result, the 8.9% incidence of IOI in the MAPLE study was lower than the rate observed in prior phase 3 studies.
As demonstrated in our prior studies, CEDAR and SEQUOIA, abicipar is the first anti-VEGF to successfully maintain initial vision gains with a 12-week fixed treatment regimen in all patients compared to monthly ranibizumab. The safety profile results of MAPLE give us confidence to proceed with scale up manufacturing activities, and this scaled up product will be used in the upcoming larger study — Phase 3 DME — as we seek additional indications. RP