Despite significant improvements in the treatment of exudative neovascular AMD in recent years, there is no approved treatment for geographic atrophy (GA). Geographic atrophy affects more than 5 million patients worldwide, and it can be attributed to approximately 20% of all cases of legal blindness in North America.¹ There are 30 registered GA trials at clinicaltrials.gov actively recruiting subjects. Because there is a lack of a good experimental model, and the exact etiology of GA is not known, studies have implemented a variety of different treatment modalities. Research has focused on strategies such as anti-inflammatory drugs, inhibition of complement activation, reduction of toxic byproducts, neuroprotection, mitochondrial enhancers, and the use of stem cells.

INFLAMMATION

Many studies deal with modification of the complement system. The complement system has been shown to be involved both in the genetics of AMD and in the deposition of complement activation products in pathology specimens of eyes with AMD. An ocular gene therapy trial using AAVCAGsCD59 (Hemera Biosciences) consists of an intravitreal injection resulting in an increase in the expression of a soluble form of CD59 (sCD59), which inhibits the formation of the membrane attack complex, the terminal step of complement-mediated cell lysis. An ongoing phase 1 trial has reportedly shown that the gene therapy to be safe.

Avacincaptad pegol (Zimura; Iveric bio, formerly Ophthotech), an anti-C5 aptamer, is currently in a phase 2b study (NCT02686658). Results are expected at the end of this 2019. Isis 696844 (IONIS-FB-LRx; Ionis Pharmaceuticals) is a subcutaneous injection of an antisense RNA against factor B that is currently in a phase 2 study (NCT03815825). The C3 inhibitor pegcetacoplan (APL-2; Apellis Pharmaceuticals) has shown a 29% decrease in progression of GA compared with sham in a phase 2 trial,² and a phase 3 trial is enrolling (see “Inhibiting Complement Factor C3 in Dry AMD” in this issue). A phase 2 trial of LFG316 (tesidolumab; Novartis, NCT01527500) showed no benefit in reducing the growth of GA lesions. LFG316 was also studied in combination with an inhibitor of properdin known as CLG561 (Alcon). Properdin stabilizes the alternative pathway C3 and C5 convertases by extending the half-lives of the C3 and C5 converting enzymes. A phase 2 study (NCT02515942) of 114 participants evaluated CLG561 as a monotherapy and in combination with LFG316 compared with sham in subjects with GA. Although official results are expected from the company shortly, initial reports are that the study failed.

Prior to these trials, there were several failures, including the phase 3 clinical trials of the anti-factor D lampalizumab (Chroma and Spectri, Genentech), as well as the phase 2 trial of systemic complement C5 inhibition with eculizumab (Soliris; Alexion Pharmaceuticals). Both studies failed to show a treatment benefit.^3,4

The antibiotic doxycycline has anti-inflammatory activities that appear to be beneficial for patients with GA. There is evidence that tetracyclines can target the low-grade inflammation and may slow the progression of GA. Doxycycline is a broad-spectrum antibiotic at a dose of 100 mg per day; however, at a lower dosage (20-40 mg/day), it acts as an anti-inflammatory. Low-dose oral doxycycline is currently approved for treating the inflammatory lesions of rosacea and is under investigation in a randomized, double-masked, placebo-controlled study (TOGA; NCT01782989) to determine its efficacy and safety in slowing the progression of GA in patients with AMD.

Statins are lipid-lowering agents with anti-inflammatory properties. Emerging evidence from a National Health and Nutrition Examination Survey suggests a possible role for statins in delaying the progression of AMD.⁵

Another class of drugs includes integrin inhibitors that target macrophages and decrease inflammasome activation. One integrin inhibitor known as risuteganib (Luminate; Allegro Ophthalmics) recently showed some promising results (see “Risuteganib for Intermediate Dry AMD” in this issue).

REDUCTION OF TOXIC BYPRODUCTS

Amyloid β, which has been found in drusen, was thought to promote complement activation by inhibiting complement factor I bioactivity. Three drugs have been evaluated that have shown to reduce extracellular amyloid deposits: glatiramer acetate (Copaxone; Teva Pharmaceuticals), and the anti-amyloid β monoclonal antibodies GSK933776 (GlaxoSmithKline) and RN6G (Pfizer). Copaxone is FDA approved to treat multiple sclerosis. It has been found to suppress T-cells and downregulate inflammatory cytokines. When the drug was evaluated for the treatment of Alzheimer disease, it was found to reduce drusen. Although drusen reduction has been seen following laser treatment, it was not associated with visual improvement. The hope was that glatiramer acetate would also decrease vision loss. RN6G was shown in a mouse model to reduce amyloid β deposits in the retina when administered systemically. The trial of RN6G (NCT01577381) was terminated for a lack of efficacy and the trial of GSK933776 failed to show a treatment benefit.⁶

The investigational compound MRZ-99030 (GAL-101; Galimedix Therapeutics), which causes sustained prevention of misfolded amyloid β molecules from aggregating into toxic forms in vitro, is proposed to neutralize their toxic effects in neural tissues. Galimedix Therapeutics is developing a phase 2 clinical trial of MRZ-99030 for the treatment of GA.

VISUAL CYCLE MODULATION

Modulating the visual cycle by disrupting the conversion of retinol to rhodopsin decreases toxic waste products, such as lipofuscin and A2E, in the retinal pigment epithelium. Studies of this pathway include those of emixustat hydrochloride (ACU-4429; Acucela) and fenretinide (Sirion Therapeutics). Although both drugs were found to be safe, they were found to be ineffective.^7,8 Also, although vitamin A is not a true visual cycle modulator, vitamin A dimers are toxic to the retina. ALK-001 (Alkeus Pharma) is a modified form of vitamin A that does not dimerize readily. A phase 3 trial is actively recruiting to study oral ALK-001 in GA.

NEUROPROTECTION

Neuroprotective agents, including ciliary neurotrophic factor, brimonidine tartrate, and tandosporine, have all been investigated. Although these have been shown to decrease photoreceptor cell death in animal models of retinal degeneration, only brimonidine has shown any benefit in a clinical trial.

Brimonidine tartrate, an alpha-2 adrenergic receptor agonist, has been shown to reduce apoptosis in animal models of retinal injury, including ischemia, ocular hypertension, phototoxicity, and partial optic nerve crush. The Brimonidine Drug Delivery System (Brimo DDS; Allergan), an intravitreally administered, sustained-release implant, has been developed and is in clinical trials for patients with bilateral GA (see “Brimonidine Drug Delivery System for Geographic Atrophy” in this issue).

MITOCHONDRIAL ENHANCER

A novel mitochondrial protective compound, MTP-131 (Ocuvia; Stealth BioTherapeutics), is a systemic investigational drug, delivered subcutaneously, that is being studied for the treatment of eyes with GA secondary to AMD (see “The ReCLAIM Phase 1 Clinical Trial of Elamipretide for Dry AMD” in this issue). It has shown promising results in cell culture in preventing damage. MTP-131 has a high affinity for cardiolipin. A phase 1/2 open-label dose-escalation study of MTP-131 is ongoing (NCT02314299). Another class of drug that is being evaluated, because of its anti-inflammatory properties, is the diabetes medication metformin.

EXPLORE NEW PATHWAYS IN THIS ISSUE

This “new pathways” section of Retinal Physician will address several promising new treatments being developed to combat dry AMD, specifically risuteganib, MTP-131, pegcetacoplan, and Brimo DDS. We invite you to learn more about these investigational therapies in the detailed articles in this issue. Given the extensive research efforts under way, retina specialists can be hopeful that in the next decade there will be new approved treatments for GA. RP

REFERENCES

1. Holz FG, Strauss EC, Schmitz-Valckenberg S, van Lookeren Campagne M. Geographic atrophy: clinical features and potential therapeutic approaches. Ophthalmology. 2014;1215:1079-1091.
2. Liao DS, Grossi FV, El Mehdi D, et al. Complement C3 inhibitor pegcetacoplan for geographic atrophy secondary to age-related macular degeneration: a randomized phase 2 trial. Ophthalmology. 2019. [In press]
3. Holz FG, Sadda SR, Busbee B, et al; Chroma and Spectri Study Investigators. Efficacy and safety of lampalizumab for geographic atrophy due to age-related macular degeneration: Chroma and Spectri phase 3 randomized clinical trials. JAMA Ophthalmol. 2018 Jun 1;136(6):666-677.
4. Yehoshua Z, de Amorim Garcia Filho CA, Nunes RP, et al. Systemic complement inhibition with eculizumab for geographic atrophy in age-related macular degeneration: the COMPLETE study. Ophthalmology. 2014;121(3):693-701.
5. Barbosa DT, Mendes TS, Cíntron-Colon HR, et al. Age-related macular degeneration and protective effect of HMG Co-A reductase inhibitors (statins): results from the National Health and Nutrition Examination Survey 2005-2008. Eye (Lond). 2014;28(4):472-480.
6. Rosenfeld PJ, Berger B, Reichel E, et al. A randomized phase 2 study of an anti-amyloid β monoclonal antibody in geographic atrophy secondary to age-related macular degeneration. Ophthalmol Retina. 2018;2(10):1028-1040.
7. Rosenfeld PJ, Dugel PU, Holz FG, et al. Emixustat hydrochloride for geographic atrophy secondary to age-related macular degeneration: a randomized clinical trial. Ophthalmology. 2018;125(10):1556-1567.
8. Mata NL, Lichter JB, Vogel R, Han Y, Bui TV, Singerman LJ. Investigation of oral fenretinide for treatment of geographic atrophy in age-related macular degeneration. Retina. 2013;33:498-507.