Uncontrolled Wet AMD: Switch to Brolucizumab Can Restore Disease Inactivity

Caroline Helwick

April 25, 2023

Some patients with uncontrolled neovascular age-related macular degeneration (nAMD) achieved a reduction in disease activity and gains in visual acuity after switching to the biologic agent brolucizumab, according to a new study presented at the 2023 annual meeting of the Association for Research in Vision and Ophthalmology.

Patients involved in the phase 3b trial qualified for the study if they experienced suboptimal responses to first-line agents, and 40% of participants had no disease activity at 16 weeks.

Study leader Ramin Tadayoni, MD, PhD, a professor and head of the department of ophthalmology at Lariboisière and Saint-Louis University Hospitals in Paris, France, said the study, SWIFT, is the first of its kind to examine the efficacy of the drug in this population of patients who had been pretreated.

"The study shows there's a benefit; I can recommend this treatment," said Tadayoni, who also is a professor at the University of Paris.  

Other findings from the Australian "Fight Retinal Blindness!" real-world registry presented at the conference reached the same conclusion as the new phase 3b "treat and extend" observational trial.

SriniVas R. Sadda, MD, director of artificial intelligence and imaging research at Doheny Eye Institute and professor of ophthalmology at the University of California Los Angeles David Geffen School of Medicine, said patients should be closely monitored to ensure safety.

"If we can get the patient's exudation under control, as the investigators have nicely demonstrated, there can be an improvement in vision," Sadda said. "It would be wrong to leave this patient uncontrolled."

Brolucizumab (Beovu) was approved by the US Food and Drug Administration in October 2019, after showing outcomes similar to aflibercept (Eylea), but with longer dosing intervals.  

The drug works against vascular endothelial growth factor (VEGF) attached to a human single-chain antibody fragment, allowing for greater dosing of anti-VEGF per volume. Since its release, brolucizumab has come under scrutiny following reports of vision loss largely attributed to intraocular inflammation.  

SWIFT Details

SWIFT is an ongoing 48-week, single-arm, open-label study conducted across 52 sites in France. All patients in the trial had active choroidal neovascularization (CNV) lesions diagnosed within the previous 18 months while undergoing treatment every 4 or 8 weeks. Patients with best corrected visual acuity (BCVA) of 83 or lower and at least 38 ETDRS letters were included in the study.  

After switching from their initial anti-VEGF agent, patients received 6-mg injections of brolucizumab at week 0 and week 8, then entered a treat-to-control maintenance phase with interval adjustments. Treatment interval were extended by 4 weeks if patients did not experience changes in visual acuity or other signs of disease.

If symptoms were present at any visit, the frequency of administration was shortened by 4 weeks at a time or to a minimum interval of 8 weeks.  Patients who required injections every 4 weeks after the loading phase were discontinued and moved to a standard-of-care treatment. The primary endpoint was the proportion of patients with no disease activity by investigator assessment at Week 16.

For the 295 enrolled patients, mean age was 76 years and 62% were female. Previous treatment was a mean of 7.2 injections over 9.2 months. At baseline, the BCVA was no more than 70 letters for 38% and at least 71 letters for 52%. The mean central subfield thickness (CSFT) was 417µm. At baseline, 84% had subretinal fluid (SRF) and 36% had intraretinal fluid (IRF).

The proportion of patients with no disease activity at week 16 was 40.4%, with consistent benefit across subgroups. A mean increase from baseline in BCVA of 4.1 letters was also observed as was a mean decrease in CSFT of −51 µm, according to the researchers. While 85% of patients had SRF fluid at baseline, this figure dropped to 53% at week 16; the incidence of dry retina improved from 1.4% at baseline to 31.3% after treatment, Tadayoni's group reported.

"Better disease control translated into improvements in visual acuity," Tadayoni said.  "The CNV lesion area also showed a small decrease in size [-0.24 mm2] in parallel to the better control of the disease."

Similar Outcomes in "Fight Retinal Disease!"

The Australian patient registry included 66 eyes in patients who on average had received 16 injections before switching to brolucizumab. At baseline, only 5% of patients had inactive disease — a proportion that improved to 39% at 12 months after the switch. In this series, the improvement in disease activity was not accompanied by a significant improvement in BCVA.

"Brolucizumab inactivated most lesions that were previously active," said Mark Gillies, MD, professor of ophthalmology and director of the Macula Research Group at The University of Sydney Save Sight Institute. "In fact, we got to that level [of inactivity] after 3 months."

"These findings suggest brolucizumab can be considered for eyes on maximal therapy with other VEGF inhibitors, where the benefit of longer treatment interval outweighs the increased risk of intraocular inflammation, Gillies added.

Two cases of occlusive vasculitis occurred in the study, one of which resulted in vision loss.

"You have to look out for this very carefully," Gillies said. "All these patients were immediately switched back to their original agent and treated aggressively."

Safety Profile

Overall ocular-related adverse events were observed in 33.9% of the SWIFT population, and complications such as retinal vasculitis and endophthalmitis occurred in 12.9% of participants. Of those, 28 were confirmed by the study review committee and 9 were subsequently considered noninflammatory, Tadayoni said.

The committee confirmed intraocular inflammation-only in 20 (7%) patients, inflammation plus retinal vasculitis in six (2%), and inflammation plus retinal vascular occlusion in two (0.7%). One patient (0.3%) had inflammation plus both retinal vasculitis and retinal vascular occlusion. For these events, the incident rate per 1000 injections was, respectively, 12.50, 3.75, 1.25, and 0.63, Tadayoni reported.

"Brolucizumab has a favorable safety profile in these patients who are not otherwise controlled by other drugs," Tadayoni said, while acknowledging outcomes from follow-up is being analyzed.

Sadda predicted that brolucizumab likely will be incorporated into treatment of nAMD beyond the second or third line, as clinicians remain concerned about safety. But he said he was "impressed" that virtually all patients had good recovery of vision.

"You just have to be careful with this drug," and perhaps have staff check up on patients between injections, he told Medscape.

Tadayoni reports financial ties with Novartis, AbbVie, Allergan, Bayer, Alcon, Genentech, Roche, Thea, KHB, Apellis, Iveric Bio, and Oculis.  Gillies reports no relevant financial relationships.

Association for Research and Vision in Ophthalmology 2023 Annual Meeting. Abstracts 465 and 466. Presented April 23, 2027.

Caroline Helwick is a medical journalist in New Orleans with more than 25 years of experience reporting from medical conferences around the world.

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