番茄社区

CHICAGO -- Two therapeutic candidates for geographic atrophy (GA) secondary to age-related macular degeneration ("dry" AMD) continued to show promise with extended follow-up in randomized trials.

The 24-month data from two randomized trials of the complement C3 inhibitor pegcetacoplan showed GA growth reductions of as much as 22% versus sham injections. Analysis of treatment effects by 6-month intervals suggested increased slowing of GA growth over time, reported Charles C. Wykoff, MD, PhD, of Retina Consultants of Texas in Houston, during the American Academy of Ophthalmology meeting.

A post-hoc analysis of perilesional microperimetry revealed a "signal" of functional preservation.

"Pegcetacoplan slowed geographic atrophy lesions growth with increasing effects over time, reaching 30% with monthly injections and 24% with every-other-month treatment in the overall population of patients with nonsubfoveal and subfoveal lesions over months 18 to 24," said Wykoff. "Post-hoc microperimetry results provided a signal of functional preservation, consistent with less photoreceptor loss over time."

Overall, both treatment schedules were well tolerated. However, about 10% of patients treated with pegcetacoplan in both trials developed new-onset exudative AMD in the treated eye. None of the cases were severe, and all patients were treated with standard anti-VEGF therapy, said Wykoff.

Meanwhile, the C5 inhibitor avacincaptad pegol reduced GA growth by 14.3% at 12 months versus sham injections, and the benefit was similar across all prespecified subgroups, reported Arshad Khanani, MD, of Sierra Eye Associates in Reno, Nevada. Two-year data will be available in 2023.

Currently, patients with dry AMD have no FDA-approved treatments. The pathophysiology of the disease, and specifically GA, has been linked to the , wherein multiple inflammatory pathways converge at C5 and then downstream to C5, making both proteins viable targets for treatment.

OAKS and DERBY

Wykoff summarized results of the phase III OAKS and DERBY trials comparing two dosing schedules of pegcetacoplan with sham injections. Investigators randomized 1,258 patients with untreated GA 2:2:1:1 to monthly or every-other-month dosing of pegcetacoplan or to the same two schedules for sham injections. The primary endpoint for both trials was change in GA at 12 months as assessed by fundus autofluorescence. Change in GA at 24 months was a key secondary endpoint.

Eligible patients were 60 and older and had best corrected visual acuity (BCVA) of at least 24 letters. GA lesion requirements included total lesion size between 2.5 and 17.5 mm².

Overall compliance with randomized treatment ranged between 85% and 90% in both trials. As , the 12-month results were mixed, as both arms of the OAKS trial met the primary endpoint of change in GA versus the sham arms (16-22%) but not in the DERBY trial (11-12%). A prespecified analysis of pooled data from the two trials showed significant slowing of GA growth with both pegcetacoplan dosing schedules for patients with extrafoveal lesions (23-26%).

The 24-month data showed that both pegcetacoplan groups met the secondary endpoint in each of the trials. In OAKS, monthly intravitreal injections reduced GA growth by 22% (P<0.0001), and dosing every other month reduced GA progression by 18% (P=0.0002), as compared with sham treatment. In DERBY, the differences versus sham were 19% with monthly pegcetacoplan (P=0.0004) and 16% (P=0.0030) with every-other-month treatment.

Analysis of GA lesion size by 6-month interval suggested increased growth inhibition with pegcetacoplan over time. During months 0-6, the difference with sham was 12-13%, increasing to 17-19% during months 6-12, 17-20% during months 12-18, and 24-30% for months 18-24. Treatment effect at 24 months was greater in extrafoveal lesions (22-28%) versus foveal lesions (16-19%), but the difference from sham achieved statistical significance for both types of lesions (P=0.0003 to P<0.0001).

Neither BCVA nor microperimetry endpoints differed significantly between pegcetacoplan and sham treatment. Investigators hypothesized that linear expansion of GA lesions of 100-150 microns/year indicates that preservation of retinal tissue with pegcetacoplan is reflected in preservation of photoreceptor function near lesion borders at baseline.

To examine the issue, investigators used fundus autofluorescence to create a perilesional area within 250 microns on each side of a lesion's borders. The post-hoc analysis produced a signal of functional preservation within the perilesional area, particularly during the last 6 months of treatment and follow-up, especially with every-other-month dosing, said Wykoff.

Ocular treatment-emergent adverse events (TEAEs) occurred more often with pegcetacoplan. However, serious ocular TEAEs were uncommon, occurring in 1-2% of the pegcetacoplan and sham treatment groups in both trials. The 24-month incidence of infectious endophthalmitis was less than 1% in both pegcetacoplan arms, with no cases during months 18-24. Intraocular inflammation occurred in 3.8% of patients who received monthly pegcetacoplan and 2.1% of those randomized to injections every other month.

Wykoff told 番茄社区 that pegcetacoplan has reached the final stages of the FDA approval process and could be approved before the end of the year. If so, it would become the first approved therapy for dry AMD.

GATHER2

Khanani reported 12-month results with avacincaptad pegol from the phase III GATHER2 trial. Eligible patients were ages 50 and older, had baseline BCVA of 20/25 to 20/320, a non-center-point-involving GA lesion or GA in part within 1,500 microns from the foveal center, and a total GA area of 2.5-17.5 mm².

The patients were randomized to monthly intravitreal injections of avacincaptad pegol or sham injections. The primary endpoint was the difference in GA growth at 12 months. Data analysis included 447 randomized patients, more than 90% of whom received planned treatment.

Mean age was 76-77, women accounted for 68-70% of the total, about 60% of patients were enrolled outside the U.S., and 47-48% were current smokers. Baseline mean GA was 7.48-7.81 mm², 94-95% of patients had bilateral GA, and GA was multifocal in about 80% of patients.

The trial met the primary endpoint, showing a mean GA of 0.392 mm² in the sham group versus 0.336 mm² in the avacincaptad pegol group, representing an absolute decrease in growth rate of 0.056 mm and a 14.3% difference from sham (P=0.0064). The results were consistent with the smaller , which showed a 0.110-mm reduction in growth rate at 12 months with avacincaptad pegol.

As in the OAKS and DERBY trials, the GATHER2 data suggested an increasing treatment effect over time, as the difference in GA growth more than doubled from the first 6 months to the second 6 months.

"Both GATHER1 and GATHER2 have shown us that we see a treatment effect early with avacincaptad pegol that increases over time," said Khanani. "Avacincaptad pegol is the first investigational therapy in GA to achieve the 12-month prespecified primary endpoint in two pivotal studies."

The safety analysis showed no intraocular inflammation, endophthalmitis, or ischemic optic neuropathy in eyes treated with avacincaptad pegol. The incidence of choroidal neovascularization was 6.7% with the C5 inhibitor and 4.1% with sham injections.