While treatments for neovascular AMD have advanced, effective therapies for geographic atrophy (GA) have remained limited. Katherine Talcott, MD, at the OSN New York 2024 conference, highlighted several potential therapies under evaluation in clinical trials, offering hope for reducing the individual and societal burdens of GA secondary to age-related macular degeneration (AMD).
Complement Pathway Modulation
ANX007 (Annexon) is an antibody that inhibits C1q, a component accumulating on drusen in aging eyes with GA, initiating the classical complement cascade in AMD. Intravitreal administration of ANX007 blocks downstream activation of this cascade. In the Phase 2 ARCHER trial, monthly or every-other-month dosing of ANX007 was compared to sham. After 12 months, monthly dosing showed a 72% reduction in the risk of a 15-letter or greater BCVA loss, while every-other-month dosing showed a 48% reduction, compared to sham. The safety profile was favorable, with few incidences of choroidal neovascular conversion, endophthalmitis, intraocular inflammation, or retinal artery occlusion.
Danicopan ALXN 2040 (Voydeya, Alexion Pharmaceuticals, Inc.) is an oral agent inhibiting complement factor D, preventing activation of the alternative pathway and blocking inflammatory response and cell lysis. An ongoing Phase 2 dose-finding study (NCT05019521) is testing three doses (100 and 200 mg twice daily and 400 mg once daily) against placebo in approximately 332 patients without foveal involvement.
AVD-104 (Aviceda Therapeutics) is a sialic acid-coated nanoparticle binding to specific sialic acid-binding immunoglobulin-type lectin receptors. This action repolarizes overactivated macrophages into their resolution phenotype and up-regulates complement factor H. The Phase 2/3 SIGLEC study is evaluating a single intravitreal injection of AVD-104. Part 1 results showed that 80% of the initial patients reaching the 3-month endpoint experienced visual acuity gains. Part 2 will include 290 patients.
Gene and Cell-Based Therapies
JNJ-1887 (Johnson & Johnson), assessed in the Phase 2b Parasol Geographic Atrophy Study, involves a one-time intravitreal injection (AAVCAGsCD59). This treatment aims to increase expression of a soluble recombinant version of CD59, inhibiting membrane attack complex formation, the terminal step in complement-mediated cell lysis, thereby protecting retinal cells. The Phase 1 study demonstrated that three doses met the primary safety endpoint over a 2-year follow-up, with promising efficacy measures in the high-dose cohort, showing a continual decline in lesion growth over 6-month intervals.
ASP7317 (Astellas) is a subretinal therapy derived from human embryonic stem cell-derived retinal pigment epithelial (RPE) cells. The Phase 1b trial, involving 18 patients, is evaluating three doses of ASP7317 via vitrectomy with subretinal injection, alongside immunosuppressive therapy. Primary outcomes focus on safety/tolerability at 52 weeks, while secondary endpoints include changes in GA lesion area and BCVA at week 52 compared to baseline.
RG6501 (OpRegen, Lineage Cell Therapeutics, Genentech) is a suspension of human allogeneic RPE cells delivered subretinally. A Phase 1 study showed improved outer retinal structure in 5 patients, with a 1-year mean gain in BCVA of 12.8 letters. Phase 2 is currently enrolling patients.
Additional Therapeutic Approaches
Elamipretide (Stealth BioTherapeutics) is a tetrapeptide targeting cardiolipin in mitochondria, reducing reactive oxygen species production. The Phase 1 ReCLAIM study evaluated subcutaneous delivery of elamipretide for 24 weeks in dry AMD with non-central GA, suggesting possible positive effects on visual function. ReCLAIM-2 achieved a 43% reduction in the progression of the ellipsoidal zone (EZ) total attenuation versus placebo (p=0.003) and a 47% reduction in the progression of partial EZ attenuation (p=0.004), along with improved low-light visual function. Phase 3 ReNEW and ReGAIN will evaluate once-daily subcutaneous injections of elamipretide.
Glideuretinal (ALK-001) and AREDS/AREDS2 are antioxidants. Glideuretinal, an oral form of vitamin A, is being evaluated in the ongoing Phase 3 SAGA trial to determine efficacy and safety in approximately 300 patients with GA secondary to dry AMD. AREDS/AREDS2, a vitamin and mineral supplement, showed a greater than 33% reduced odds of developing advanced AMD in high-risk patients. AREDS2, replacing beta-carotene with lutein/zeaxanthin, was associated with a similar reduced risk of advanced AMD and eliminated the increased lung cancer risk associated with beta-carotene.
ONL1204 (ONL Therapeutics) is a Fas inhibitor reducing Fas-mediated retinal cell apoptosis and inflammatory cytokines. A Phase 1b part 1 safety assessment of a single intravitreal injection showed early efficacy with an average reduction in GA lesion growth of 42% at 6 months. Part 2, involving two injections administered 3 months apart, resulted in reduced lesion growth by approximately 50%. A Phase 2 study is commencing.
