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CLINICAL TRIAL DOWNLOAD: Safety and Efficacy Data for Abicipar

Questions remain regarding inflammation rates.

EDITED BY PRAVIN U. DUGEL, MD

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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. Additionally, initial vision gains for abicipar were maintained through week 52.

The anatomical data (OCT) on abicipar-treated patients showed reductions of central retinal thickness (CRT) in all arms in both studies in the same range as for ranibizumab. Overall, the efficacy endpoints at week 52 showed comparable efficacy with 6-8 injections of abicipar vs 13 injections of ranibizumab.

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 than did ranibizumab-treated patients. According to the company, the majority of inflammation cases were mild to moderate and were treated with topical corticosteroids. Here we ask several leaders in retina for their impressions of the recent data.

David S. Boyer, MD, Retina-Vitreous Associates Medical Group, California

I was anxiously awaiting the results of the CEDAR and SEQUOIA phase 3 trials studying the DARPin technology. Because of the unique nature of DARPins, I was hoping that the drug would last 12 weeks. Unfortunately, the press release and the podium presentations leave many unanswered questions. A 15% incidence of inflammation is unfortunately unacceptable compared to the other treatments that are currently available. I would not put patients at risk by using this drug if other anti-VEGF treatments do not result in a 15% increase in follow-up and treatment of uveitis. I also find it to be very unusual that the results were described in terms of not losing 3 lines of vision rather than in terms of mean vision gained, 3-line vision gain, or dryness as seen on OCT, as most neovascular AMD trial results are described today. I question why there was a lack of transparency concerning the degree of inflammation and visual results. The fact that the MAPLE study is being conducted to study a new formulation seems to show that the complication rate continues to be too high for the drug used in the SEQUOIA and CEDAR trial. I hope I am wrong. The lack of a control group in the MAPLE trial will only give us safety information.

Allen C. Ho, MD, FACS, Wills Eye Hospital, Thomas Jefferson University, and Mid Atlantic Retina, Philadelphia, Pennsylvania

Abicipar may soon be another anti-VEGF biologic therapy in the retina specialist’s tool box for the management of neovascular AMD with extended durability. The ongoing MAPLE study, a follow-up to CEDAR and SEQUOIA, will provide key information on whether the 15% intraocular inflammation rates can be reduced with adjustments to its biologic formulation. We’ve seen intraocular inflammation in the evolution of other approved biologics and two things are clear: first, these rates can be improved with formulation adjustments, and second, retina specialists avoid agents with higher rates of intraocular inflammation when other options are available. Time will tell, and we will learn more from the MAPLE trial in 2019.

Yoshihiro Yonekawa, MD Mass Eye & Ear and Harvard Medical School, Boston, Massachusetts

We were all excited to hear the details of the SEQUOIA and CEDAR studies, after the sneak preview of the top-line results announced last summer suggesting that abicipar q8 and q12 dosing were comparable to ranibizumab monthly dosing, with some uneasiness surrounding inflammation rates. Here are my initial gut reactions:

The primary endpoint was percentage of patients with “stable” vision, defined as worse than 3 lines or more of vision loss. It’s standard in clinical trials, but not a high bar in the anti-VEGF era. While not statistically significant, the numbers seemed to slightly favor monthly ranibizumab (91.3% and 91.2% for abicipar q12 in SEQUOIA and CEDAR, respectively, vs 96.0% and 95.5% for ranibizumab q4). Monthly ranibizumab seemed to have an edge in the number of letters gained also, especially in CEDAR (+5.6 vs +8.5). This also did not reach statistical significance but is worth noting.

Vision is what ultimately matters, but we do tend to rely on the OCT in neovascular AMD more than in other macular disorders. I noticed that the abicipar arms had a saw-toothed pattern compared to monthly ranibizumab in the CRT graphs. It would be interesting to measure the areas under the curves. This tells me that abicipar dosed at q12 or even q8 might result in some up and down of the CRT, which we tend to want to avoid in neovascular AMD.

These are my subjective reactions, and not scientifically validated. If the differences are negligible, which is what the statisticians indicate, I would prefer q8 or q12 dosing to reduce treatment burden. As long as all other factors are more or less equal. The tiebreaker in our minds now is the inflammation piece. Fifteen percent is not negligible, and while the “majority” were “mild or moderate,” there were cases of vitritis and vasculitis. I’d like to know more about these eyes.

That said, Allergan is addressing this issue with a new formulation being examined in the MAPLE study. Personally, I really want the DARPin platform to work. Of course, it would be great having another mechanism to pound on VEGF, but what’s most exciting is in the future. The DARPin platform allows the installation of multiple units to target more than one ligand. As we uncover more potential targets to control retinal vascular diseases, DARPin can serve as a versatile platform.

I have 2 final points that I still need to think more about. First, how will we incorporate abicipar into our treatment paradigms? This will depend on the labeling and comparisons to treat-and-extend regimens. Second, how will abicipar compare to brolucizumab? These questions would be for a different editorial as we gain more insights.

Yehia Hashad, MD Vice president and global head of clinical development for ophthalmology at Allergan

The abicipar phase 3 results presented at the 2018 meeting of the American Academy of Ophthalmology showed mean changes in visual acuity from baseline and 3-line vision gains. The data demonstrated that initial vision gains were maintained through week 52 on both treatment regimens. The fact that patients can be effectively maintained on a fixed 12-week treatment regimen without having been selected for an expected favorable response should be considered sufficient evidence for a drug effect that lasts (at least) 12 weeks. The long duration of effect was confirmed by the OCT data — also presented at the meeting — that showed reductions in CRT following 6 abicipar injections that were virtually identical to those achieved with 13 injections of ranibizumab.

A thorough and comprehensive analysis of the inflammation risk has to take into consideration not only the overall incidence but also such important aspects as severity, outcome, and manageability of inflammation episodes. As demonstrated with other biologic agents and specifically anti-VEGFs, Allergan will continue to improve the manufacturing process to reduce the incidence of intraocular inflammation.

We believe that this comprehensive analysis, together with the indisputable evidence of a reduced treatment burden compared with the current standard of care, will show a favorable benefit–risk profile for abicipar. We plan to present further data on efficacy and a comprehensive review of inflammation at future scientific meetings. RP