Clockwise: Figure A. Fundus photograph of an eye with geographic atrophy (GA). There is loss of the outer retina and choriocapillaris with prominent underlying larger choroidal vessels. Figure B. Corresponding fundus autofluorescence demonstrating large areas of hypo-autofluorescence or retinal pigment epithelium atrophy. There is a ring of hyper-autofluorescence on the outer border of GA showing progressive RPE dysfunction. Figure C. Optical coherence tomography through the fovea showing preserved photoreceptor layer in the fovea extending temporally. There is marked hyper-transmission (arrowheads) in the area of outer retinal and RPE atrophy.
In the treatment of age-related macular degeneration (AMD), researchers have developed significant breakthroughs and continued improvements in therapies for neovascular AMD (nAMD). Since the advent of anti-vascular endothelial growth factor (VEGF) therapy for nAMD, we can now preserve and, in many cases, improve vision. There are now 4 different anti-VEGF products on the market that are administered intravitreally in the outpatient clinic setting. In addition, the US Food & Drug Administration (FDA) recently approved a surgical implant with a refillable reservoir of ranibizumab that effectively reduces the treatment burden in patients with nAMD.1 Furthermore, multiple ongoing clinical trials of potentially more durable treatments are ongoing.2-5
Despite these advances in the treatment of nAMD, treatment for geographic atrophy (GA) — an advanced form of dry AMD characterized by the loss of photoreceptors and retinal pigment epithelial (RPE) cells in the macula — remains elusive.6 However, several potential treatments are currently under investigation and can be categorized based on their therapeutic targets or mechanism: complement inhibition, antioxidative stress, anti-inflammatory, visual cycle modulation, gene therapy, and cell-based therapy. In this article, we look at the current state of the GA therapeutic pipeline and provide a brief overview.
Studies into the molecular makeup of drusen had suggested that AMD may have an immunological component. The complement system is implicated in GA by human genetics, where variants in complement-related genes are associated with GA. These include variants such as CFH, CHFR1/3, C2/CFB, C3, CFI, and C9. The complement system is a key component of both innate and adaptive immunity. It can be activated via 3 separate pathways: antigen-antibody complexes (classical), microbial polysaccharides (lectin), and pathogen cell surfaces (alternative). All 3 pathways converge with the activation of complement C3, which can lead to inflammation, cell phagocytosis and membrane attack complex activation.
Complement inhibition has been the focus of several recent clinical trials. Lampalizumab, a complement factor D inhibitor, failed to demonstrate efficacy in 2 side-by-side phase 3 trials.7 Patients were treated with intravitreal lampalizumab 10 mg either every 4 weeks or every 6 weeks, or with sham. At the end of 48 weeks, no benefit in GA size reduction was seen in the treatment arms compared with sham treatment.7
Pegcetacoplan (APL-2, Apellis Pharmaceuticals) is a pegylated cyclic peptide inhibitor of complement C3. Due to complement C3’s central role in the regulation of the complement cascade, it is an attractive therapeutic target for altering the progression of AMD. The FILLY phase 2 trial randomized subjects with GA to receive either intravitreal APL-2 monthly or every other month (EOM), or sham injections monthly or EOM, for 12 months followed by a 6-month follow-up period. Area and growth of GA were measured using fundus autofluorescence imaging. Growth rate of GA was reduced by 29% and 20% in the APL-2 monthly and EOM groups, respectively, compared to the sham-treated control groups at 12 months.8 A higher rate of new-onset exudative AMD was identified in patients receiving APL-2 compared to the control group (20.9% in monthly APL-2, 8.9% in EOM APL-2, and 1.2% in sham-treated control). The rate of exudation was highest when the fellow eye had neovascular AMD.
A pair of phase 3 trials — DERBY (ClinicalTrials.gov Identifier: NCT03525613) and OAKS (ClinicalTrials.gov Identifier: NCT03525600) evaluated APL-2 monthly or EOM. In the OAKS study, monthly (P =.0003) and EOM treatment (P =.0052) with APL-2 met the primary endpoint, reducing GA lesion growth compared with pooled sham at 12 months by 22% and 16%, respectively. The DERBY study narrowly missed the primary endpoint, showing a reduction in GA lesion growth with monthly (P =.0528) and EOM treatment (P =.0750) compared to pooled sham at 12 months. In a prespecified analysis of the combined studies, pegcetacoplan showed a reduction in lesion growth in patients with foveal and extrafoveal lesions, with a greater effect in patients with extrafoveal lesions at baseline. APL-2 was well tolerated in both phase 3 studies. The results from these studies demonstrate the potential for Pegcetacoplan to become the first approved treatment for GA.
Another therapeutic candidate with C3 inhibition as its target is NGM621 (NGM Biopharmaceuticals).9 It is a humanized IgG1 monoclonal antibody designed to inhibit C3. In an open-label single-dose and multiple-dose escalation phase 1 study, NGM621 was well tolerated with no serious adverse events or drug-related adverse events.9 A phase 2 study, CATALINA (ClinicalTrials.gov Identifier: NCT04465955) is currently underway.
A C5 inhibitor, avacincaptad pegol (Zimura, Iveric Bio), met its prespecified primary endpoint in reducing the rate of geographic atrophy in a randomized, controlled phase 2/3 clinical trial GATHER1 Study (ClinicalTrials.gov Identifier: NCT02686658). The reduction in GA growth for 12 months was 27.4% (P =.0072) for the avacincaptad pegol 2 mg cohort, and 27.8% (P =.0051) for the avacincaptad pegol 4 mg cohort compared with their corresponding sham cohorts.10 There were no adverse events. A second confirmatory phase 3 clinical trial, GATHER2 Study (ClinicalTrials.gov Identifier: NCT04435366) is under way to confirm the efficacy and safety of avacincaptad pegol in slowing the GA growth.
C1q is the initiating molecule of the classical complement cascade and has been implicated in neurodegenerative diseases, including GA. ANX007 (Annexon Biosciences) inhibits C1q early in the classical pathway and allows the beneficial immune functions of the lectin and alternative complement pathways to continue. In a phase 1B study, ANX007 was well tolerated in glaucoma patients and a single intravitreal injection of ANX007 was able to completely suppress C1q for at least 4 weeks. A phase 2 study, ARCHER (ClinicalTrials.gov Identifier: NCT04656561) evaluating the efficacy of ANX007 in GA is currently underway.
IONIS-FB-LRx (Ionis Pharmaceuticals) is a novel specific antisense oligonucleotide that targets the complement factor B gene. It is delivered subcutaneously and its phase 1 study shows it was able to reduce plasma factor B for 54 healthy volunteers.11 A phase 2 trial, the GOLDEN study (ClinicalTrials.gov Identifier: NCT03815825), is underway.
Emerging evidence suggests an important role for retinal mitochondrial dysfunction in AMD.12 Multiple risk factors associated with AMD such as cigarette smoke, lipofuscin accumulation within the RPE, and complement dysregulation have been identified as triggers of mitochondrial dysfunction. In addition, genetic mitochondrial disorders such as maternally inherited diabetes and deafness (MIDD) and mitochondrial encephalopathy, lactic acidosis, and stroke-like episodes (MELAS) often develop GA.12
Elamipretide (Stealth Biotherapeutics) is a tetrapeptide believed to target cardiolipin in mitochondria, thereby reducing reactive oxygen species production. A phase 1 open-label clinical trial, ReCLAIM, (ClinicalTrials.gov Identifier: NCT02848313) evaluated subcutaneous delivery of elamipretide for 24 weeks in patients with dry AMD with noncentral GA or high-risk drusen and showed a possible positive effect on visual function. A phase 2b trial (ClinicalTrials.gov Identifier: NCT03891875) is underway.
Risuteganib (Allegro Ophthalmics) is an anti-integrin small peptide molecule that downregulates oxidative stress. In a phase 2a clinical trial, patients with intermediate dry AMD were randomized to intravitreal risuteganib or sham injections. In the treatment arm, 20% of participants gained 15 letters or more at week 28.13 Although not a treatment specifically for GA, the ability to demonstrate improvement in visual function could translate to a delay in progression or even prevention of the development of GA. A phase 2b/3 clinical trial is planned.
Tetracyclines are a class of broad-spectrum antibiotics that also exhibit anti-inflammatory properties. Low-dose oral doxycycline (Oracea, Galderma Laboratories) is being investigated in an ongoing phase 3 clinical trial, TOGA (ClinicalTrials.gov Identifier: NCT01782989) to determine its efficacy and safety in slowing the progression of GA. Participants of that investigation are randomized to receive either 40 mg of oral doxycycline or placebo to be taken daily for 24 hours.
FHTR2163 (Genentech/Roche) is a novel antibody directed against high-temperature requirement protein A1 (HtrA1).14 Delivered by intravitreal injection, HTRA1 inhibition may preserve retinal integrity and slow disease progression in GA. A phase 2 clinical trial, GALLEGO (ClinicalTrials.gov Identifier: NCT03972709) is currently ongoing.
Visual Cycle Modulator
Visual cycle modulators are designed specifically to target enzymes of the visual cycle. A prominent early feature of GA is the aberrant accumulation of cellular debris or lipofuscin within the retinal pigment epithelium. By modulating the visual cycle, these novel drugs aim to reduce accumulation of these cytotoxic byproducts.
Toxic vitamin A aggregates have been implicated in the pathophysiology of GA. Vitamin A dimers form when 2 molecules of vitamin A are combined. ALK-001 (Alkeus Pharmaceuticals) is a chemically modified vitamin A to slow the formation of toxic vitamin A dimers. ALK-001 is taken orally once a day. A phase 2 clinical trial of ALK-001 in patients with Stargardt disease has shown clinically significant efficacy (ClinicalTrials.gov Identifier: NCT02402660). A phase 3 clinical trial, SAGA (ClinicalTrials.gov Identifier: NCT03845582) is underway.
GT005 (Gyroscope Therapeutics) is a 1-time AAV-based gene therapy designed to rebalance an overactive complement system by expressing the complement factor I (CFI), a natural inhibitor of the complement system. The FOCUS phase 1/2 (ClinicalTrials.gov Identifier: NCT03846193) open-label study is investigating safety, tolerability and dose response of 3 doses of GT005 administered as a single subretinal injection. Interim results demonstrated expression of the CFI protein, and evidence of its down-regulating effect has been confirmed by 41% and 42% decrease in levels of the Ba and C3 proteins in the vitreous, respectively. These results are sustained at 1 year after administration, and data in 2 patients have suggested sustained expression to more than 18 months. GT005 is being evaluated in phase 2 trials, EXPLORE (ClinicalTrials.gov Identifier: NCT04437368), and HORIZON (ClinicalTrials.gov Identifier: NCT04566445).
Stem cell transplantation to replace the diseased retina is another potential treatment avenue still in the early stages of development. OpRegen (Lineage Cell Therapeutics) is currently being evaluated in a phase 1/2a open-label, dose escalation safety and efficacy study of a single injection of human RPE cells derived from an established pluripotent cell line and transplanted subretinally in patients with GA.15 So far, 24 patients have been treated, 12 of which were not legally blind at baseline.
In addition, 4 patients within this subgroup received thorough coverage of OpRegen cells across the majority of the atrophic area and experienced a cessation or reversal of the size of GA at 12 months. These patients also experienced an increase in their visual acuities. In contrast to other existing GA trials, whose main outcome measure is a reduction in the progression of GA size, stem cell transplantation may potentially reduce the size of GA and improve vision.16
Where There’s a Will…
Geographic atrophy secondary to AMD is a devastating disease that can result in irreversible vision loss. With an aging population and an increasing prevalence of disease, an effective treatment is desperately needed to reduce both individual and societal burdens. Although there have been some recent failures, there are many ongoing studies with potential therapeutic options. As a field, we may be close to finally finding a treatment for GA. It is an exciting time for the field of retina and an approved treatment for GA could again transform the way we treat AMD, much like anti-VEGF therapy did 2 decades ago.
Dr Boyer and Dr Su are retinal surgeons at Retina-Vitreous Associates Medical Group in Los Angeles.
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