Latest data show progress of GA therapies in the pipeline
The current state of treatment for geographic atrophy is marked by two approved therapies that slow GA progression: pegcetacoplan, or Syfovre, from Apellis Pharmaceuticals and avacincaptad pegol, or Izervay, from Astellas.
The approvals of these first treatments for GA were an important step in addressing the dearth of options to treat this disease, which is newly diagnosed in 160,000 Americans annually (Rudnicka and colleagues). Although these drugs allow us to treat patients with something rather than nothing, they insufficiently preserve vision in many patients, and data have not shown that they improve vision.
Several pipeline drug candidates, if proven safe and effective in clinical trials, could surpass current treatments in efficacy by not just slowing the progression of the disease but also (in some instances) improving vision. Among the treatments in late-stage clinical trials that have shown demonstrable promise in improving vision are AVD-104 (Aviceda Therapeutics), ANX007 (Annexon) and elamipretide (Stealth BioTherapeutics). Each molecule leverages a unique mechanism of action targeting the drivers GA growth; they all recently shared findings from phase 2 trials and will conclude phase 3 trials within the next 12 to 24 months.
AVD-104 and the SIGLEC study
AVD-104 is a novel glycan (sialic acid)-coated nanoparticle characterized by a unique dual mechanism of action. It binds to Siglecs, which are sialic acid-binding immunoglobulin-like lectin receptors, to repolarize inflammatory macrophages and microglia into a neuroprotective state. AVD-104 also binds directly to complement factor H, enhancing the effects of complement factor H and thereby downregulating complement amplification. It is administered via intravitreal injection.
At this year’s Macula Society meeting, Robert L. Avery, MD, presented the latest efficacy and safety findings from part 1 of the phase 2/3 SIGLEC study. In a multicenter, open-label, single-dose study of 30 patients, AVD-104 demonstrated an excellent safety profile with no dose-limiting toxicity at 3 months following a single injection of AVD-104 at any of four doses (0.1 mg, 0.5 mg, 1 mg and 3 mg); 1 mg and 3 mg were considered clinical dose levels.
Compared with baseline at 3 months after a single injection, patients gained 4.8 letters in the AVD-104 1 mg arm and 6.5 letters in the AVD-104 3 mg arm. Patients in the clinical dose cohorts experienced a 48% reduction in GA lesion growth rate compared with untreated fellow eyes. Researchers used change in hyperautofluorescence from baseline to assess disease activity in the junctional zone (ie, the area immediately outside of a GA lesion), with a reduction in hyperautofluorescence activity indicating a therapeutic effect. Among clinical dose cohorts, 67% of patients experienced a decrease in junctional zone hyperautofluorescence (Avery).
Part 2 of the SIGLEC study, which will compare AVD-104 against avacincaptad pegol in a head-to-head fashion, is fully enrolled at 300 patients. Topline data are expected in the fourth quarter.
ANX007 and the ARCHER study
ANX007 is a non-pegylated antigen-binding fragment (Fab) antibody that selectively inhibits C1q, thereby preventing activation of the classical complement pathway. ANX007 aims to minimize inflammation, synapse loss and neuronal damage that lead to vision loss in patients with GA. It is delivered via intravitreal injection.
In 2023, topline data from the phase 2 ARCHER trial, a randomized, double-masked, sham-controlled 12-month study, showed the primary endpoint (mean rate of change [slope] in GA) did not reach statistical significance, but ANX007 was well tolerated (Annexon).
Updated visual data from the phase 2 ARCHER trial shared in 2024 were encouraging. Rates of 15 letter or more loss at month 12 were statistically significant and dose dependent, with 21.3% of sham patients losing 15 letters or more at 12 months compared with 5.6% of patients dosed with ANX007 monthly (P = .0021). A similar statistically significant finding was seen for low luminance visual acuity (LLVA). At month 12, rates of LLVA 15 letter or more loss were 20.3% in the sham group and 7.6% in the ANX007 monthly treatment group (P = .022). ANX007 also demonstrated better protection compared with sham in key regions of the retina through 12 months, providing up to 60% protection of photoreceptors within the central 1.5 mm of the fovea (nominal P = .0319) and 29% protection of photoreceptors across the full retinal field (nominal P = .017) (Annexon).
ANX007 is under investigation in the phase 3 ARCHER II trial, with topline data expected in 2026. ARCHER II will enroll 630 patients and initiated patient dosing in August 2024. The drug received priority medicine designation in the European Union and fast track designation from the FDA.
Elamipretide and the ReCLAIM-2 study
Elamipretide is a mitochondria-targeting peptide compound that binds reversibly to cardiolipin. In stabilizing mitochondrial function, the elamipretide-cardiolipin association may lead to improvement of ATP production and interruption and reversal of oxidative stress. The treatment is under investigation for several diseases linked to mitochondrial dysfunction, including GA.
In October, Ehlers and colleagues published results from the phase 2 ReCLAIM-2 clinical trial assessing safety and efficacy of elamipretide in patients with dry AMD and noncentral GA. In this prospective, randomized, placebo-controlled, double-masked, multicenter trial of 176 patients with dry AMD with GA, elamipretide (40 mg) was self-administered subcutaneously daily for 48 weeks.
Elamipretide treatment did not meet statistical significance for the primary endpoints (ie, change in LLVA and square root converted GA area from baseline, as seen on OCT). However, at week 48, elamipretide produced a 43% reduction in the mean progression from baseline in the macular percentage of total ellipsoid zone (EZ) attenuation/loss, defined as complete loss of EZ band (nominal P = .0034). At week 48, a 47% reduction in the mean progression of macular percentage of partial EZ attenuation/degradation (nominal P = .0040) vs. placebo was observed. The treatment group also demonstrated more patients experiencing a 10 letter or more gain in LLVA compared with the placebo group (14.6% vs. 2.1%; nominal P = .0404). Adverse events were reported in 86% of patients treated with elamipretide and 71% of the placebo group. Injection site reaction was the most common adverse event reported (Ehlers and colleagues).
Two phase 3 trials (ReNEW and ReGAIN) will evaluate daily subcutaneous elamipretide treatment in patients with dry AMD, with rate of change in the macular area of photoreceptor loss at week 48 serving as the efficacy endpoint (Stealth Biotherapeutics).
The future of GA therapy
The need for a safe and effective GA therapy that goes beyond C3 or C5 in the complement system is obvious. The fact that each of the drugs discussed herein target GA or dry AMD from different angles is a testament to innovators’ commitment to creative thinking. These novel therapies may, if they clear regulatory hurdles, result in viable treatments that go beyond our current treatment options, and could quality of life for the millions of Americans suffering from vision loss.
References:
- Annexon provides update on ARCHER II global registrational program in geographic atrophy. https://ir.annexonbio.com/news-releases/news-release-details/annexon-provides-update-archer-ii-global-registrational-program. Published Aug. 5, 2024. Accessed Feb. 4, 2025.
- Annexon topline data from ARCHER phase 2 trial of ANX007 in geographic atrophy demonstrated statistically significant, dose-dependent preservation of visual function. https://ir.annexonbio.com/news-releases/news-release-details/annexon-topline-data-archer-phase-2-trial-anx007-geographic. Published May 24, 2023. Accessed Feb. 4, 2025.
- Avery RL. AVD-104 for geographic atrophy secondary to age-related macular degeneration: A review of the phase 2a SIGLEC findings and an overview of the SIGLEC phase 2b study. Presented at: Macula Society meeting; Feb. 13, 2025; Charolette Harbor, Florida.
- Ehlers JP, et al. Ophthalmol Sci. 2024;doi:10.1016/j.xops.2024.100628.
- Rudnicka AR, et al. Am J Ophthalmol. 2015;doi:10.1016/j.ajo.2015.04.003.
- Stealth BioTherapeutics announces first patient enrolled in global phase 3 clinical program for elamipretide in patients with dry age-related macular degeneration. https://stealthbt.com/stealth-biotherapeutics-announces-first-patient-enrolled-in-global-phase-3-clinical-program-for-elamipretide-in-patients-with-dry-age-related-macular-degeneration/. Published June 5, 2024. Accessed Feb. 6, 2025.
For More Information:
Rishi P. Singh, MD, vice president and chief medical officer of Martin North and South Hospitals at Cleveland Clinic Martin Health in Stuart, Florida, professor of ophthalmology at Cleveland Clinic Lerner College of Medicine in Cleveland and Healio | OSN Associate Medical Editor, can be reached at singhr@ccf.org.
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