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Geographic atrophy

Dry age-related macular degeneration (AMD) accounts for 90 % of all AMD.  Geographic Atrophy (GA) is the most severe form of dry macular degeneration and accounts for 20 % of all AMD.  Atrophy means the cells and tissue of the retina are dying or have died from the changes of aging.  The macula in GA has basically “evaporated”.   The term Geographic refers to the shape of the atrophied (thin or dead) portion of the macula/retina, which resembles the irregular outline of map like in geography class.  Geographic atrophy starts typically in the central macula and expands over time to involve the fovea (center vision area of macula) leading to permanent loss of visual acuity. 

In geographic atrophy cells in the central macula area are losing their function (degenerating) due to aging.  As the degeneration continues there is cell death called atrophy.  The first cells to die are the retinal pigment epithelium (RPE).  The RPE helps to maintain the health of the retinal photoreceptor (rods and cones….the cells that do the light transduction). The photoreceptors are the most metabolically active cells in the body and produce lots of metabolic waste products which is cleaned up by the RPE cells.  When the RPE cells become dysfunctional and/or die, metabolic waste products build up causing low grade inflammation which in turn leads to damage to the photoreceptors and eventual death of these cells and subsequent loss of vision. 

Normal macula
Geographic atrophy

In geographic atrophy cells in the central macula area are losing their function (degenerating) due to aging.  As the degeneration continues there is cell death called atrophy.  The first cells to die are the retinal pigment epithelium (RPE).  The RPE helps to maintain the health of the retinal photoreceptor (rods and cones….the cells that do the light transduction). The photoreceptors are the most metabolically active cells in the body and produce lots of metabolic waste products which is cleaned up by the RPE cells.  When the RPE cells become dysfunctional and/or die, metabolic waste products build up causing low grade inflammation which in turn leads to damage to the photoreceptors and eventual death of these cells and subsequent loss of vision. 

The exact mechanism of how GA occurs is not fully known. Genetic and environmental factors seem to contribute substantially. Part of the process involves the development of inflammation from the body’s own immune system.  There are many ways the body tries to defend itself against infections.  One of these immune system pathways is called the complement system.  The complement system is a biochemical cascades which destroy microbes.  However, in AMD the process occurs toward the retina itself. The complement pathway involved is called the is alternative pathway of the complement system. Aging changes occurring within the bottom layer (one of 10 layers) called the retinal pigment epithelium seems to activate this pathway by a protein called C3b.  This protein binds directly to the age-damaged retinal pigment epithelium cells and initiates  the inflammatory process which leads to further damage to the retina including causing the cells to die.  Certain genes influence how strongly these inflammatory pathways manifest themselves.  The genes called Complement factor H variant Y402H and ARMS2 have been associated with increased risk of GA development.  Therefore, the low grade inflammation plus the oxidative stress of normal cellular metabolism play a role in the development of AMD.  In eyes studied at autopsy with GA show choroidal T-lymphocytes and macrophages which are inflammatory white blood cells which produce pro-inflammatory proteins called cytokines.  The low grade inflammation then combined with oxidative stress of cellular metabolism causes the AMD degeneration.

Park et. al., Front. Immunol 15 May 2019

“The complement factor D inhibitor, lampalizumab, failed to halt geographic atrophy (GA) progression in phase 3 studies. The complement factor 3 (C3) inhibitor, APL-2, has shown potential to reduce GA growth in a phase 2 trial, supporting advancement to phase 3 trials. The intravenous complement factor 5 (C5) inhibitor, eculizumab, failed to halt GA progression in a phase 2 study. Another C5 inhibitor, avacincaptad pegol, is delivered by intravitreal injection, and will be studied for safety and preliminary signs of efficacy for AMD and STGD1 patients in phase 2 trials. LFG316 (C5 inhibitor) and CLG561 (properdin inhibitor) failed to halt GA progression in phase 2 studies. A phase 1 trial is evaluating the effects of combining LFG316 and CL561. Complement inhibition by gene therapy will be explored in the phase 1 trial of HMR59 in AMD patients.”

Sixty billion dollars a year is spent on the research to find a cure for macular degeneration.  At present. there is no approved treatment for Geographic Atrophy (GA). The drug which is closest to approval is called APL-2 (complement 3 inhibitor. made by Apellis Pharmaceuticals.  This drug has entered its stage III trials and maybe available later this year (2020) if the drug passes its trial.  The FDA has fast tracked this drug. ClinicalTrials.gov Identifier: NCT03500549

Gyroscope Therapeutics initiates phase 2 trial of GT005 in geographic atrophy

Gyroscope Therapeutics has begun a phase 2 program to evaluate GT005, an investigational gene therapy for the treatment of geographic atrophy secondary to dry age-related macular degeneration.  Patients aged 55 years or older with a clinical diagnosis of geographic atrophy and a mutation of the CFI gene are being enrolled in the study.   GT005 works to balance an overactive complement system by increasing production of complement factor I protein, the release said. An overactive complement system may play a role AMD development

Second phase 3 trial of Zimura underway

Zimura (avacincaptad pegol), a novel complement C5 inhibitor, reached its primary efficacy endpoint in GATHER1, the first phase 3 trial.

In GATHER2, about 400 patients will be randomly assigned to receive monthly administration of either Zimura 2 mg or sham for 12 months. A primary efficacy analysis of the mean rate of change of geographic atrophy growth will occur at 12 months, and if the findings are positive,

Kassa, E et. al., Expert Opin Biol Ther. 12019 April 19