Compiled by Dan Roberts
What Is Geographic Atrophy?
Geographic atrophy (GA) is a late stage of “dry” age-related macular degeneration (AMD) presenting with gradual deterioration of the photoreceptor and retinal pigment epithelium (RPE) layers of the retina. The main symptom is the absence of vision in one or more areas of the central vision, beginning with small areas that eventually coalesce. The very center of the macula, the fovea, is often spared until much later in the disease, so detail vision may not be immediately impacted. With a prevalence slightly lower than wet (neovascular) AMD, approximately four million Americans and Europeans are affected by GA.
This is a guide to all leading research to date in the field of dry age-related macular degeneration (AMD). It is divided into three categories:
Most headings contain links to further information. Hopefully, this document will help to identify information of interest specifically to those who are still, and hope to remain, in the early and intermediate stages of AMD.
Pegcetacoplan (originally POT-4 and APL-2)
Potentia Pharmaceuticals, Inc. announced on March 20, 2007 that it was entering the clinical phase of development of POT-4 for treatment of age-related macular degeneration (AMD). According to the researchers, POT-4, a synthetic peptide, shuts down the complement activation system that can lead to local inflammation, tissue damage (as in dry AMD) and the resulting blood vessel growth (angiogenesis in wet AMD). Discovered by Professor John Lambris, University of Pennsylvania, POT-4 is the first complement inhibitor tested in patients with AMD.
In 2014, Apellis Pharmaceuticals acquired Potentia Pharmaceuticals and obtained the rights to develop POT-4, which they renamed APL-2. APL-2 has the same mechanism of action as Potentia’s original drug compound but has a significantly improved half-life in the eye.
On Feb. 10, 2015, Apellis announced the beginning of Phase I clinical trial of APL-2. The multi-center trials, labeled ASAP II, focused on establishing safety of intravitreal injections of APL-2. Then, in the late spring of 2015, Apellis began a larger Phase II trial called FILLY. The company reported in August 2017 that APL-2 demonstrated a statistically significant slowing of dry AMD over 12 months, while appearing to increase in the second 6 months of the study. This represented a slowing down of the rate of degeneration by almost half, according to Apellis founder and CEO Cedric Francois, MD, PhD.
In October 2020, Apellis announced its analysis of the Phase 2 FILLY study. The post hoc analysis found that the monthly treatment reduced the rate of progression to GA by 39 percent in areas of the retina outside of existing GA lesions.
In July 2020, Apellis completed enrollment of a total of 1,259 patients in its Phase 3 DERBY and OAKS studies. At that time, the name of the medication was changed to pegcetacoplan. These identical, prospective, multicenter, randomized, double-masked, sham-injection controlled studies are designed to assess the efficacy and safety of multiple IVT injections of pegcetacoplan in patients with GA secondary to AMD.
In April 2022, Apellis announced longer-term results from the Phase 3 DERBY and OAKS clinical studies. In an analysis conducted at month 18 of the clinical studies, treatment with both monthly and every-other-month pegcetacoplan reduced GA lesion growth compared to sham injections (no treatment). Pegcetacoplan continued to demonstrate a favorable safety profile in both studies. Overall, these longer-term results provide further evidence that pegcetacoplan meaningfully slows disease progression and has the potential to preserve vision longer.
On February 18, 2023, Apellis announced that the U.S. Food and Drug Administration (FDA) had approved SYFOVRE™ (pegcetacoplan injection) 15mg/0.1mL, treatment for geographic atrophy (GA) secondary to age-related macular degeneration (AMD). SYFOVRE™ is a synthetic peptide (a protein consisting of a compound of amino acids) that shuts down the body’s complement activation system (aka complement cascade). This system normally helps to clear harmful microbes and damaged cells, but over-activation of the system can lead to tissue damage (as in GA). More information.
ARC1905 (Anti-C5 Aptamer)
Ophthotec’s ARC1905 works selectively, blocking the complement factor (C5) that seems to contribute to dry AMD, while allowing other immuno-protective complement factors in the body to work. A Phase I clinical trial on patients with wet AMD showed the treatment to be safe, with almost 50% of participants gaining vision. The study was completed in November 2012, but no results have been posted. More about ARC1905.
Astellas Pharma Inc. announced on August 5, 2023 that the U.S. Food and Drug Administration (FDA) approved IZERVAY™ (avacincaptad pegol intravitreal solution) for the treatment of geographic atrophy (GA) secondary to age-related macular degeneration (AMD). IZERVAY, a new complement C5 inhibitor, is the only approved GA treatment with a statistically significant reduction in the rate of GA progression at the 12-month primary endpoint across two Phase 3 clinical trials.
This approval opened a second option for treatment of GA, the other being SYFOVRE™, available in clinics since February 2023.
Aspirin appears to be beneficial as a preventer of AMD, but the debate continues. Follow the research.
Brimonidine Tartrate Implant
Allergan is testing the effectiveness of injecting an implant into the vitreous of the eye containing brimonidine tartrate. Brimonidine is approved by the FDA for the treatment of glaucoma, but it shows potential for slowing vision loss from AMD. The trial ended in 2011, and patients were followed through 2013. A second trial was begun in March 2016 and was completed in April 2019. Results are pending.
A one-time subretinal administration of Human Umbilical Tissue-Derived Cells (CNTO 2476) in patients who are experiencing vision loss due to geographic atrophy from dry macular degeneration. Study sites include Arcadia, California and Philadelphia, Pennsylvania. Enrollment terminated. Results pending. More information
Gemini Therapeutics, announced in January 2020 that it initiated enrollment in its Phase 1 study of GEM103, a recombinant, native Complement Factor H (CFH) for the treatment of dry age-related macular degeneration. The study is a single ascending dose clinical study evaluating the safety, pharmacokinetics and pharmacodynamics of GEM103. The study targets enrollment of approximately 9 patients with dry AMD who have known CFH mutations.
In January 2021, Gemini announced that their ongoing ReGatta study, now in Phase 2a, has been granted Fast Track designation by the United States Food and Drug Administration (FDA).
Multi-center study in the United Kingdom “evaluating the safety, the dose response and efficacy (anatomical and functional visual outcomes) of two doses of GT005 administered as a single subretinal injection in genetically defined subjects with Macular Atrophy due to Age-related Macular Degeneration.” More information
Iluvian (fluocinolone acetonide)
Iluvian is a corticosteroid that has shown signs of preventing macular degeneration in animals. PSivida Ltd. has begun an early-stage clinical trial for testing a tiny implanted insert called Medidur for delivery of the drug to the retinas of patients with bilateral geographic atrophy (dry AMD). Iluvien is being evaluated in the MAP-GA trial, funded by Alimera Sciences, the developers of the delivery system. The trial is designed to assess whether low dose, sustained-release Iluvian can slow the progression of geographic atrophy in patients with dry AMD.
Citing concerns about safety and manufacturing standards, the U.S. Food and Drug Administration notified Alimera Sciences in October 2013 that it could not approve the company’s new drug application. The FDA indicated that results from a new clinical trial would need to be submitted, together with at least 12 months of follow-up for all enrolled patients.
Iluvien has been granted marketing authorization for treatment of diabetic macular edema in the Netherlands, Belgium, Luxembourg, Sweden, Denmark, Finland, Norway, Poland, the Czech Republic, Austria, Italy, the United Kingdom, Portugal, France, Germany, and Spain. It is commercially available in the United Kingdom and Germany.
A study by Ionis Pharmaceuticals to study the efficacy of multiple doses of Ionis FB-LRx in participants with geographic atrophy secondary to Age-Related Macular Degeneration (AMD). More information.
Novartis is studying this inhibitor against complement factor (C5), administered intravitreally. Trials are underway, but not recruiting. More information.
The National Eye Institute is looking to see if a common antibiotic, minocycline, will help those with geographic atrophy (GA). The objective of this study is to investigate the safety and possible efficacy of oral minocycline in patients with GA.
Forty participants who have GA in one or both eyes will be enrolled in the study. A 100 mg dose of minocycline will be taken twice daily for 36 months. More information
A medication that is to be given as a capsule daily for 24 months at a dose of 40 mg for treatment of geographic atrophy (GA). More information
Lineage Cell Therapeutics (originally BioTime, Inc.) has announced positive results with its experimental OpRegen® therapy for geographic atrophy (GA), the advanced stage of dry macular degeneration. In May 2020, researchers reported that positive results are continuing to come from the Phase 1/2 study, including gains in visual acuity, reduced geographic atrophy (GA) progression, and improved reading speed. In one patient of 17 so far enrolled, geographic atrophy was 25% smaller at 9 months than at baseline. In the next 6 months, the area grew approximately 50% slower than its historical rate. More information
On October 13, 2019, David Boyer, MD (Retina-Vitreous Associates Medical Group), presented results from a study of risuteganib intravitreal injection to members of the American Academy of Ophthalmology (AAO). He reported that the Phase 2 primary endpoint was met, with nearly half of those receiving the treatment achieving an increase of 8 or more letters of best-corrected visual acuity (BCVA) at 48 weeks.
A total of 45 patients were recruited for the study and 42 were included in the final analyses. A total of 25 patients were included in the risuteganib group while 14 were included in the sham group. Due to the successful results, all patients were allowed to switch over to risuteganib at week 16.
No serious systemic serious adverse events and no ocular serious events occurred as a result of risuteganib use. In addition to the study participants, 1200 injections have been given outside of the study.
The GALLEGO study (Genentech) will evaluate the safety, tolerability, and efficacy of intravitreal injections of RO7171009 administered every 4 weeks (Q4W) or every 8 weeks (Q8W) for approximately 76 weeks in participants with geographic atrophy (GA) secondary to age-related macular degeneration (AMD) compared with sham control. More information.
IVERIC bio, Inc. has announced positive Phase 3 results from its GATHER1 clinical trial with Zimura® (avacincaptad pegol). Zimura® met its pre-specified primary efficacy endpoint at 12 months and reached statistical significance.
Zimura® is an inhibitor of complement factor C5, a central component of the complement cascade believed to be involved in the development of AMD. More information
Restoring and regulating proteins which interact to initiate autophagy (the cleaning mechanism in the retina) can support and increase its effectiveness. This could lead to a new treatment protocol for AMD and other retinal degenerative diseases.
CD36 is a protein molecule (called an “integral membrane protein”) permanently attached to the surface of certain human cells. It plays a role in the inflammation process, but researchers have now discovered that a deficiency of the protein may cause the dry form of macular degeneration. Read the research.
CFH and CFB
Two genes have been shown to lead to age-related macular degeneration (AMD) in simultaneous studies. Called Complement Factor H (CFH) a potential cause of AMD in as many as 50% of cases, helps to control the body’s immune response and inflammation. CFH stops the immune response, while Factor B activates it. More about CFH and CFB.
C-reactive protein (CRP) levels in test subjects have displayed significant association with the presence of both intermediate and advanced stages of ARMD. A UC Berkeley study led by Gladys Block, PhD, suggests that 1,000 mg of daily supplemental vitamin C can lower concentrations of C-reactive protein (CRP), the marker associated with systemic inflammation. Read more.
Researchers have found that a variant of the C3 gene can more than double the risk of age-related macular degeneration (AMD). Read more.
A July 22, 2004 report announced that Fibulin 5 was the second gene to have been shown to be related to AMD (the first being HEMICENTIN-1 in 2003). More about Fibulin 5.
First Gene Therapy For Dry AMD
Researchers at the University of Oxford have carried out the world’s first gene therapy operation to tackle the root cause of age-related macular degeneration (AMD).
An 80-year-old woman with AMD is the first of ten people to receive the treatment. The procedure was carried out at the John Radcliffe Hospital by Professor Robert MacLaren, Professor of Ophthalmology, in a clinical trial (FOCUS) sponsored by Gyroscope Therapeutics. It is too early to know if the patient’s sight loss has been halted, but her vision and all that of all other subjects will be closely monitored. This first stage of the trial is primarily designed to check the safety of the procedure. Read more.
The first gene mutation found (2003) to be directly tied to AMD. Read more.
Interleukin-6 and Interleukin-8
Two different studies during 2008 reveal that at least some cases of age-related macular degeneration may stem from genetically driven production of inflammatory cytokines called interleukin-6 and interleukin-8. Read more.
An April 2007 study showed that common variants of CFH (above) and another gene, LOC387115, independently increased the risk of progression from early or intermediate stages to advanced stages of AMD. Read the research.
Japanese researchers reported in September 2003 that mutations in the RDH5 gene can cause macular dystrophy, fundus albipunctatus, and/or night blindness. Read more.
An article published in August 2002 reported that the gene RPGR (associated until now with retinitis pigmentosa) is also been found to be responsible for an X-linked form of early-onset MD. Read more.
In October 2008, British scientists announced discovery of six variants within the gene, Serping1, that are associated with dry AMD. The report was published by Sarah Ennis and Andrew Lotery in the Lancet journal of the University of Southampton. Read the research.
As reported in the Aug. 28, 2008 online edition of the New England Journal of Medicine, researchers have found a genetic link associated with dry AMD. That’s the good news. The bad news is that siRNA drug therapy may increase the risk for dry AMD in patients who have that genetic variant.
The research team found that the protein TLR3 helps fend off certain viral infections. However, it also increases the risk for dry AMD in subjects taking an experimental anti-VEGF drug called “small interference ribonucleic acid” (siRNA), which activates TLR3. In fending off viral infections, TLR3 also attacks infected retinal cells, resulting in “a 60 percent spike in retinal cell death among mice and humans genetically susceptible to developing dry AMD.”
Patients currently involved in the siRNA study (labeled Cand5) sponsored by Acuity Pharmaceuticals should contact their doctors for more information.
NIH researchers prevent blindness in animal models of dry AMD
Using a novel patient-specific stem cell-based therapy, researchers at the National Eye Institute (NEI) prevented blindness in animal models of geographic atrophy, the advanced “dry” form of age-related macular degeneration (AMD). The protocols established by the animal study set the stage for a first-in-human clinical trial testing the therapy in people with geographic atrophy, for which there is currently no treatment.
The planning of a Phase I clinical trial testing the safety of the therapy in humans is underway and will be initiated after FDA approval. Read more.
Pixium Vision has announced its first successful human implantation of a wireless sub-retinal implant in a patient with atrophic dry age-related macular degeneration (AMD). So far, three patients have been implanted with the device, and results are promising.
As reported here in October 2017, the implant, called PRIMA, acts like a tiny solar panel that is powered by pulsed near-infrared light through a miniaturized projector integrated along with a mini-camera into a pair of glasses. PRIMA is designed to initially treat atrophic dry AMD, and at a later stage, retinitis pigmentosa (RP).
The PRIMA Bionic Vision System’s successful activation “was achieved one-month post implantation as per the protocol,” stated Dr. Le Mer, principal investigator of the study. “Following activation, the patient reported a first perception of light from the central zone where there was none previously. The patient now proceeds to the important re-education phase to learn to interpret the elicited light signals and evaluate the performance of the PRIMA system.”
The researchers still face important challenges, most important of which is improving resolution from the current level of 20/200 to 20/40. The lab expects to publish a new design for achieving that resolution later in 2018.
The feasibility clinical study in France is being conducted at Fondation Ophtalmologique Rothschild and Hôpital des Quinze-Vingt in Paris. Institutions working in close collaboration are the Institut de la Vision in Paris, the Hansen Experimental Physics Laboratory at Stanford University, Moorfields Eye Hospital in London, and Institute of Ocular Microsurgery (IMO) in Barcelona. Pixium is looking forward to completing the first phase in France and starting an FDA approved feasibility study in the U.S.
Retinal Stem Cells from Bone Marrow
An April 2006 study reported early improvement in the vision of patients who received injections into the cornea of stem cells derived from bone marrow. Read more.
Since 2000, a team of doctors led by Norman D. Radtke, M.D. (University of Louisville) have been transplanting intact sheets of both immature (fetal) neural retina cells and retinal pigment epithelial (RPE) cells in the sub-retinal space of patients with dry AMD and other retinal dystrophies. Read more.
Stem Cell Replacement from Human Embryos
Advanced Cell Technology announced on September 23, 2004 that they had engineered human embryonic stem cells which could be used to repair a damaged retina. On Nov 30, 2010 the company announced that it had filed an Investigational New Drug (IND) Application with the FDA to initiate a Phase I/II multicenter study using hESC derived retinal pigment epithelial (RPE) cells to treat patients with dry AMD.
On January 23, 2012, ACT reported preliminary results from the study, which involved one elderly patient with AMD and one younger patient with Stargardt disease. The transplants appeared safe after four months, and both patients had some improvement in vision.
Under their new name, Acucela, the company is working toward the start of Phase 3 in 2015. Follow the research.
Stem Cells from the Iris
A December 2001 article reported that, with manipulation of the CRX gene, cells from the iris may be able to replace photoreceptor cells in the retina. Read more.
Brain Stem Cell Transplantation
StemCells, Inc. announced on February 2, 2012 that trials began to test how purified human neural stem cell (HuCNS-SC) transplants from the brain might significantly protect against degeneration of existing photoreceptors in humans. Read more.
Embryo-derived Stem Cell Transplantation
Acucela Therapeutics, Inc. (formerly Ocata) is conducting follow-up trials of two open-label phase 1/2 studies testing the effects of human embryonic stem cell-derived retinal pigment epithelium in patients with age-related macular degeneration and Stargardt’s macular dystrophy. Follow the research.
Implantation of Stem Cell-Derived RPE Cells
Two trials reported in 2018 positive results with replacing defective cells leading to vision loss from dry (geographic) macular degeneration. In London, implantation of a specially engineered patch of retinal pigment epithelium (RPE) cells derived from stem cells has restored some vision in two people with sight loss from wet age-related macular degeneration (AMD). In California, implanted cells derived from stem cells have been implanted into five patients by researchers from University of Southern California (USC) and the University of California, Santa Barbara. Results at one year have shown that one patient’s acuity improved by 17 letters and two patients demonstrated improved ability to fixate on a target. Significantly, no patients have demonstrated progressive vision loss during the trial.
Summary of Early Stem Cell Research
The First Seven Years: An Overview of Stem Cell Transplantation Research for Treatment of Retinal Disease
Trials to begin for stem cell-based therapy to treat geographic atrophy
As reported in December 2019, a National Eye Institute (NEI) study will test the safety of a stem cell treatment for the dry (atrophic) form of age-related macular degeneration (AMD).
Under the phase I/IIa clinical trial protocol 12 patients with advanced-stage geographic atrophy will receive the iPSC-derived RPE implant in one of their eyes and be closely monitored for a period of at least one year to confirm safety before moving into later phases. This is the first clinical trial in the U.S. to use replacement tissues from patient-derived iPS cells.
Photobiomodulation involves exposure of the retina to light from diodes emitting red, yellow, and infrared wavelengths. Researchers in Switzerland and Toronto recently found that treating eyes three times a week for three weeks improved best corrected visual acuity by a mean of six to 10 letters in 48%, and 11 to 15 letters in 12% of the 24 subjects enrolled in the trial.
Contrast sensitivity and number and thickness of drusen also improved, with the improvement lasting for three months. Additionally, no new development of geographic atrophy occurred during that period. The treatment utilizes the LT-300 instrument devised by LumiThera.
A follow-up clinical trial called LIGHTSITE III is currently enrolling. The study is partially funded by a NIH National Eye Institute grant. More information.