Brolucizumab Prevails in Treat-and-Extend Trial of Anti-VEGF Therapy for Eye DiseaseJuly 20, 2022
NEW YORK CITY — The monoclonal antibody brolucizumab (Beovu) significantly extended the treatment-free interval without disease activity for neovascular age-related macular degeneration (nAMD), with comparable visual acuity, as compared with aflibercept (Eylea), a randomized trial showed.
Almost twice as many patients in the brolucizumab arm had a 12-week treatment-free interval without active disease, 38.5% versus 19.8%. Improvement in best-corrected visual acuity (BCVA) at 28 and 32 weeks was almost the same in the two groups, 5.3 versus 5.0 letters with brolucizumab and aflibercept, respectively. Central subfield thickness (CST) also declined significantly more with brolucizumab, reported Carl Regillo, MD, of the Wills Eye Hospital and Thomas Jefferson University in Philadelphia.
Ocular adverse events (AEs) occurred more often with brolucizumab, and nonocular events occurred in a similar proportion of patients in the two study arms, Regillo said at the American Society of Retina Specialists (ASRS) meeting.
“We can see from the results of the study that brolucizumab does indeed last longer than aflibercept,” he said. “With regard to safety, there were imbalances, as we’ve seen before, and very comparable to the HAWK and HARRIER studies, and imbalances with regard to IOI [intraocular inflammation] and vascular events. Stay tuned for the 64-week end-of-study results sometime later this year, and that will give us a good feel for how these drugs can be extended over time, and how the distributions will change as we try to extend out to 16 weeks for both drugs.”
Anti-VEGF therapy has become the mainstay of treatment for nAMD, but standard treatment protocols often involve monthly intravitreal injections. Recent therapeutic development has focused on extending the treatment interval, resulting in various treat-and-extend strategies. Brolucizumab, a newer anti-VEGF agent, received FDA approval for nAMD in 2019; approved indications were expanded to include diabetic macular edema in June 2022.
The AMD indication was supported in large part by results of the phase III HAWK and HARRIER trials, which demonstrated comparable vision outcomes with fewer injections versus aflibercept. Regillo presented initial data from the TALON trial, which sought to show superiority for vision outcomes with brolucizumab at 32 weeks.
Design, Key Findings
Investigators in 20 countries enrolled and randomized 738 patients with untreated nAMD associated with a BCVA of 38-83 letters (Snellen equivalent of 20/25 to 20/200). Patients in both arms began treatment at 4-week intervals, with a goal of extending the treatment interval to a maximum of 16 weeks during a 64-week follow-up period. If nAMD disease activity recurred at any follow-up visit, the treatment interval was reduced by 4 weeks to a minimal interval of 8 weeks. Subsequently, all patients who required treatment at 4-week intervals discontinued the study and received standard of care.
The trial had co-primary endpoints. The first endpoint was the proportion of patients who achieved the longest treatment-free interval without recurrent disease activity. The second endpoint was the mean change in BCVA from baseline to weeks 28 and 32.
The study population had a mean age of 75-76, women accounted for 55%-60% of all patients, mean baseline BCVA was 63-64 letters, and mean baseline CST was 444-467 µm. A majority (53%) of patients in both arms had occult choroidal neovascularity.
The results showed that 40.2% of aflibercept-treated patients and 25.7% of those in the brolucizumab arm had a 4-week maximum interval without disease activity. The 8-week interval was similar (39.9% with aflibercept and 35.8% with brolucizumab). Significantly more patients in the brolucizumab arm remained disease activity-free with 12-week treatment intervals (P<0.0001).
Brolucizumab also met the co-primary endpoint by achieving BCVA at 28 and 32 weeks that was non-inferior to the aflibercept arm (P<0.0001 for non-inferiority).
Effect of treatment on CST was a secondary endpoint and also favored brolucizumab. The decline from baseline mean CST averaged 166.9 µm with brolucizumab versus 140.0 µm with aflibercept (P=0.007).
With respect to safety, ocular AEs occurred more often in the study eye with brolucizumab than with aflibercept (26.5% vs 21.5%). Nonocular AEs occurred in about 40% of both groups. Serious ocular AEs (2.2% vs 0.5%), ocular AEs leading to study drug discontinuation (4.4% vs 0.3%), and ocular AEs of special interest, primarily inflammation, (5.5% vs 1.1%) all occurred more often with brolucizumab.
Results in Perspective
During a post-presentation discussion, session moderator Anat Loewenstein, MD, MHA, of Sourasky Medical Center in Tel Aviv, Israel, delved into the safety aspects of the study, noting that “this is what we’re concerned about with this and every new long-acting drug.”
Regillo said the data resembled safety findings from the HAWK and HARRIER studies and suggested longer-term follow-up will provide more insights into safety.
“This was just top-line data, and we will have a lot more on safety, especially over time, when we get to the end of the study, the 64-week results,” he said. “There is an imbalance in IOI events rates. I’m aware of only one patient who actually lost vision in this study, but again, the analysis is incomplete. Right now, we’re not seeing that it really changed much and appears similar to what we already knew.”
Co-moderator Charles Wykoff, MD, PhD, of Retina Consultants of Texas in Houston, asked whether any consensus exists as to how clinical trial data for treat-and-extend strategies translate into clinical practice.
“This is the first major prospective treat-and-extend study that actually looked at more real-world ways of using treat and extent,” said Regillo. “The trial began in 2019, when we were pretty much still in the mode of treat to dry. Although we know some degree of fluctuation [in disease activity] is tolerated, we also know that repeated fluctuations over time can lead to decreased vision.”
“I still think that’s what we should do [strive for no disease activity], and that’s what was done in this study,” he stated. “That’s why the drugs may not look as durable as perhaps other studies, where you allow for some recurrence and activation before you re-treat, or before you adjust the treatment. As we get to the 64-week results, that’s going to be exciting, to see how both drugs can be durable out to 16 weeks, and even in an extension study where we can potentially push it to 20 weeks.”
The study was supported by Novartis.
Regillo disclosed relationships with Adverum, Allergan, Annexon, Apellis, Astellas, Chengdu Kanghong Biotechnology, Genentech, Iveric, Kodiac, Novartis, Opthea, Regeneron, Regenxbio, Aldeyra, Merck, NGM Biopharmaceuticals, Notal Vision, Stealth Biotherapeutics, Takeda, Thea, and ZEISS.