New Strategies for Geographic Atrophy Show Early Promise

CHICAGO — An investigational dual-action inhibitor for geographic atrophy (GA) significantly slowed disease progression and improved visual acuity after 3 months of treatment, a small preliminary study showed.

GA growth rate in treated eyes decreased by 48% from baseline versus untreated fellow eyes, and activity in the junctional zone of the retina was slowed or stabilized in 14 of 18 patients treated with AVD-104. Best corrected visual acuity (BCVA) improved by an average of 5.2 letters in treated eyes as compared with 1.7 letters in untreated eyes.

The findings provided the basis for a phase IIb/III randomized comparison of AVD-104 and avacincaptad pegol (Izervay) in 300 patients with GA, reported Rishi P. Singh, MD, of the Cleveland Clinic, at the American Academy of Ophthalmology (AAO) meeting.

“The SIGLEC IIa study U.S. clinical trial showed excellent safety with no dose-limiting toxicity out to 3 months after a single injection,” said Singh. Patients who received AVD-104 1 mg and 3 mg experienced gains of 4.8 and 6.5 letters, respectively, at month 3 after a single injection. The patients in this higher-dose cohort also demonstrated a 48% reduction in lesion growth compared with fellow eyes at month 3, and 78% of these patients also experienced a junctional change in the autofluorescence profile.”

“Seeing these functional benefits and efficacy in geographic atrophy is very promising, and the SIGLEC phase IIb/III trial is fully enrolled and active,” he added.

An investigational oral agent for GA also demonstrated preliminary activity. Patients treated with gildeuretinol had a 13.4% reduction in GA growth rate at 24 months versus a placebo control group, reported Alexander Melamud, MD, of the Retina Group of Washington in Fairfax, Virginia. Treatment with the deuterated vitamin A agent also slowed the loss of low luminance visual acuity (LLVA).

“Gildeuretinol is the first oral therapy to demonstrate a statistically significant functional benefit in low luminance visual acuity at month 24,” said Melamud.

The results support the concept that decreasing vitamin A dimerization is a potential mechanistic strategy to treat GA, he added.

Targeting the Junctional Zone

GA development and progression are driven by complement dysregulation and macrophage overactivation, Singh noted in his introduction. AVD-104 addresses both of those by inhibiting macrophages and binding to complement factor H to inhibit C3 amplification and stabilize junctional zone pathology.

“The junctional zone has become important in geographic atrophy, as we’ve learned from recent studies,” said Singh. “In the junctional zone, we know there are inflammatory microglial cells, activated macrophages, and MAC [membrane attack complex]. These cells are injured but not necessarily dead. Potentially, stabilization of the structure as well as rescuing these damaged cells might lead to functional improvement.”

The multicenter phase IIa SIGLEC trial was a first-in-human study evaluating single-dose AVD-104 at four dose levels. Eligible patients had bilateral foveal GA, BCVA of 20/80 to 20/800, and lesion size >1.25 mm². The primary endpoint was safety and tolerability at 3 months and dose-limiting toxicity. Secondary endpoints included changes in BCVA and GA and imaging biomarkers.

The study included a total of 30 patients across the four dose levels. One drug-related ocular adverse event (AE) occurred in the highest-dose cohort. No ocular serious AEs or dose-limiting toxicity occurred.

As compared with untreated fellow eyes, all dose levels of AVD-104 slowed GA progression. The largest reduction in GA growth (48% versus fellow eyes) occurred in the 18 patients who received the two highest doses.

The junctional zone may offer the greatest potential to stabilize or improve visual function, said Singh. As measured by hyper-autofluorescence (AF), 12 of the 18 patients had improvement in hyper-AF status and two others had no change representing 78% of the patients treated with the two highest doses of AVD-104. The 3-month change in hyper-AF activity averaged -0.075 mm² in eyes treated at the two highest doses versus -0.03 mm² in the untreated eyes.

With respect to BCVA status, 40% of all patients treated with AVD-104 had at least a 5-letter gain at 3 months. Four patients had gains of ≥15 letters.

The junctional zone comprises three distinct structural entities as defined by retinal pigment epithelium (RPE) defects, noted Odette Houghton, MD, of the Mayo Clinic in Rochester, Minnesota, addressing the rationale for targeting with therapy for GA.

“This most interesting one is where there is actual preservation of the photoreceptors, which is type 3,” she said. “Preservation of photoreceptors extends beyond where the RPE defect is, so that raises the possibility of us being able to look for cell-based therapies for geographic atrophy.

Vitamin A Replacement

GA, neovascular age-related macular degeneration, and Stargardt disease share a common disease pathophysiology that involves accumulation of vitamin A dimers early in the injury cascade, said Melamud. Gildeuretinol was designed to replace vitamin A loss in the visual cycle by slowing vitamin A dimerization.

Investigators in the multicenter SAGA trial evaluated gildeuretinol in patients 60 or older with well-demarcated GA lesions in at least one eye and BCVA ≥33 letters. Eyes with and without subfoveal involvement were allowed. Study participants were randomized 2:1 to gildeuretinol or placebo, and the primary endpoint was GA lesion growth at 24 months.

The 13.4% difference in lesion growth favoring gildeuretinol did not achieve statistical significance (P=0.075). However, a prespecified sensitivity analysis showed that the rate of growth from 6 to 24 months was significantly lower in patients who received active treatment versus placebo (15.3%, P=0.047).

Gildeuretinol reduced BCVA letter loss compared with placebo, but the difference did not achieve statistical significance (3.3, P=0.099). An analysis of LLVA at 24 months did show evidence of functional benefit (4.4 fewer letters lost, P=0.031).

Gildeuretinol had a safety profile similar to placebo, including any-grade treatment-emergent adverse events (TEAEs), severe TEAEs, serious TEAEs, and TEAEs related to the study drug. No patient treated with gildeuretinol had delayed dark adaptation or chromatopsia, vasculitis, intraocular inflammation, endophthalmitis, or symptoms of hyper-/hypovitaminosis A, said Melamud.

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