Avacincaptad pegol (Zimura, IVERIC bio) slows the progression of geographic atrophy, results from a phase 3 clinical trial show, giving hope that there will soon be an approved treatment for one of the most common causes of vision loss.
"We are ecstatic," said Kourous Rezaei, MD, chief medical officer of IVERIC bio. "We are really excited about the data we have."
The experimental drug reduced the mean rate of geographic atrophy growth by 28% over 18 months. The study could not detect statistically significant benefits in visual acuity, Rezaei acknowledged, but he is hopeful that the drug can preserve vision with long-term use.
The results were presented during the virtual Association for Research in Vision and Ophthalmology 2020 Annual Meeting by coinvestigator Karl Csaky, MD, PhD, from Retina Foundation of the Southwest in Dallas.
Although anti-vascular endothelial growth factor (VEGF) drugs have dramatically improved the outlook for patients with wet age-related macular degeneration, no drug has yet been approved to treat the more common dry form of the disease, which can lead to geographic atrophy and severe vision loss.
Researchers have struggled to pinpoint the causes of geographic atrophy. Recently, they have begun to focus on complement factors, which are elements of the immune system that can become dysregulated and destroy healthy cells. Avacincaptad pegol specifically blocks complement factor 5 without interfering with complement factor 3, the target of some of the other drugs under investigation.
For their study, Rezaei, Csaky, and Keith Westby, chief operating officer at IVERIC bio, assessed avacincaptad in patients with nonfoveal geographic atrophy secondary to dry age-related macular degeneration.
All study participants had a multifocal geographic atrophy lesion between 2.5 mm² and 17.5 mm², part of which was 1500 μm from the foveal center, that could be photographed in its entirety. Best-corrected visual acuity in the study eye ranged from 20/25 to 20/320.
The 286 participants were randomly assigned to monthly avacincaptad or sham intravitreal injections. The size of geographic atrophy lesions were measured, with fundus autofluorescence, at baseline and at 6, 12, and 18 months.
Because the lesions were different sizes at baseline, the investigators compared change in the square root of the lesion area.
The first part of the study compared avacincaptad 1 mg or 2 mg with placebo in a cohort of 77 patients, but early on, it was determined that the 1 mg dose was not effective, so that dose was discontinued and the 26 patients in that group were dropped from the analysis.
The second part of the study compared avacincaptad 2 mg or 4 mg with placebo in a cohort of 209 patients. The final analysis combined those data with data from the original 25 patients in the 2 mg group and the 26 original sham patients.
From baseline to 18 months, lesion growth was 28% slower in the 67 patients in the 2 mg group than in the 110 patients in the sham group (0.430 mm vs 0.599 mm; P = .0014). It was 30% slower in the 83 patients in the 4 mg group than in the 84 in the sham group (P = .0021).
The difference in growth of geographic atrophy areas remained significant even after adjustment for missing data.
And the data suggest that the drug becomes more effective over time. From 12 months to 18 months, the difference between the avacincaptad and sham groups widened by about 1 percentage point for the 2 mg dose and 2 percentage points for the 4 mg dose.
"To be able to reduce the growth of this geographic atrophy is a major step forward for these patients," Rezaei said.
However, best-corrected visual acuity declined in all the groups.
| ETDRS Letters Lost at 12 Months | ||
| Dose | Avacincaptad Injection | Sham Injection |
|---|---|---|
| 2 mg | 7.90 | 9.29 |
| 4 mg | 3.79 | 3.51 |
The trial was not designed to measure differences in visual acuity because the US Food and Drug Administration (FDA) only requires evidence of a difference in lesion size to approve a drug for geographic atrophy, Rezaei reported.
There were no signs of inflammation, endophthalmitis, or other adverse events related to the drug, and no patients withdrew from the trial because of drug-related adverse events.
During the 18-month follow-up period, the incidence of choroidal neovascularization was 11.9% in the 2 mg group, 15.7% in the 4 mg group, 3.8% in the untreated fellow eyes, and 2.7% in the sham groups. The ocular adverse events most frequently reported were related to the injection procedure.
A second phase 3 trial is now being planned, and the hope is that avacincaptad pegol will garner FDA approval in a few years, said Rezaei.
Getting Buy-In From Patients
The progress on drugs to treat patients for geographic atrophy is heartening for retina specialists, said Ajay Kurian, MD, from Mid-Atlantic Retina and Thomas Jefferson University in Philadelphia.
"I can't say one drug is doing better than others, but it's exciting that this drug showed signs of slowing down geographic atrophy," he said.
Geographic atrophy progresses very slowly, he noted, so it is not surprising that differences in visual acuity did not reach statistical significance at 18 months.
If approved, avacincaptad pegol would likely be administered monthly for the first year and at longer intervals thereafter, Rezaei said.
However, clinicians might have a harder time convincing patients to show up for intraocular injections of avacincaptad than they do convincing patients with wet macular degeneration to show up for anti-VEGF injections.
"I don't think you're going to have the same 'wow' effect for the treatments of geographic atrophy," Rezaei said. "I think it would definitely entail a lot of education about the natural history of the disease in order to get buy-in from patients for something that would not necessarily improve their vision but seems to slow down the worsening of their vision."
Rezaei and Westby are employees of IVERIC bio. Csaky and Kurian have disclosed no relevant financial relationships.
Association for Research in Vision and Ophthalmology (ARVO) 2020 Annual Meeting.
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Cite this: Avacincaptad Results Promising for Geographic Atrophy - Medscape - Jun 29, 2020.
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