Compiled by Dan Roberts
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.
APL-2 (originally POT-4)
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 December 2017, Appelis announced that it had finalized the trial design for its planned Phase 3 program.
The Phase 3 program, planned to begin in the second half of 2018, will consist of two identical studies to assess the efficacy and safety of multiple injections of APL-2 in the eyes of patients with GA. The Phase 3 trials will be substantially similar in design to Apellis’ ongoing Phase 2 FILLY trial, which, at 12 months, showed a 29% reduction in the growth of GA lesions (damaged areas of the retina) in the monthly treatment group and a 20% reduction in the every other month treatment group.
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.
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 is ongoing, with results expected in 2018.
Eculizumab for Geographic Atrophy
Alexion Pharmaceuticals concluded The COMPLement Inhibition with Eculizumab for the Treatment of Non-Exudative Age-Related Macular Degeneration (COMPLETE) Study in June 2012. It was designed to prospectively evaluate the effect of eculizumab, a systemic inhibitor of complement component 5 (C5), on the development of geographic atrophy. Eculizumab was well tolerated through the first 6 months of the trial. The 6-month outcome data are currently being analyzed and will be presented.
FCFD45145 (mFab anti Factor D)
Genentech/Roche has developed this drug to be injected into the eye to block a rate-limiting enzyme called complement factor D. Factor D is thought to be associated with dry AMD by genetic association. Trials were completed in April 2013, but no study results have been posted.
Encapsulated Cell Technology (ECT)
ECT is a means of delivering drugs into the retina on a time release basis. Developed by Neurotech Pharmaceuticals, it is achieved by a device called Renexus (formerly NT-501) implanted into the vitreous of the patient’s eye. Renexus continuously produces and releases a drug called ciliary neurotrophic factor (CNTF) over a period of two years to preserve the health of the retinal photoreceptor cells. In 2012, retrospective study demonstrated that the implant has “a favorable pharmacokinetic profile for the treatment of chronic retinal degenerative diseases without systemic exposure”. Mofre information about the trials may be found at ClinicalTrials.gov by referencing numbers NCT00063765, NCT00447954, NCT00447980, and NCT00447993.
Fenretinide (RT-101), a drug that has been used to treat certain cancers, rheumatoid arthritis, acne, and psoriasis, has been found to also slow the production and accumulation of a toxin that leads to vision loss in Stargardt’s patients. The toxin, called A2E, is a byproduct of vitamin A, the formation of which encourages production of waste deposits called lipofuscin. These deposits accumulate in the retinal pigment epithelium (RPE), interfering with the RPE’s ability to nourish the photoreceptors. News of the drug was worth following, but the developer, Sirion Therapeutics, announced in February 2012 that the trials had been suspended. The FDA ruled that the Phase 2 results were flawed, and, for now, the high cost of continuing the trials has halted further research.
GSK933776 for Geographic Atrophy
This is a Phase 2a proof of concept study conducted by GlaxoSmithKline to evaluate the safety and efficacy of GSK933776 via intravenous infusion for the treatment of geographic atrophy. Trials are ongoing. 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.
Novartis is studying this inhibitor against complement factor (C5), administered intravitreally. Trials are underway, but not recruiting. More information.
MC-1101 is a proprietary, topically administered eye drop drug for treating and stopping the progression of AMD from the early-stage (Dry AMD) to the late-stage (Wet AMD) by increasing ocular blood flow in the choroidal vessels. It was developed by MacuCLEAR, Inc. (Plano, Texas) under the leadership of George Chiou, Ph.D.
MacuCLEAR has completed a successful Phase Ib/proof of concept human clinical trial for MC-1101 which showed that the drug is safe and well tolerated by study subjects.
The first stage of MacuCLEAR’s double-blinded Phase III study is examininge 60 patients, using improvements in visual function as the trial’s primary endpoint. In addition to the data from this Phase III trial, MacuCLEAR will submit results from non-clinical studies to the FDA before filing for a new drug application. More information.
BioTime, Inc. is expanding its ongoing Phase I/IIa clinical trial for OpRegen® for treatment of dry AMD. by naming the first two sites that will treat patients in the U.S.
The company anticipate enrolling and treating U.S.-based patients by the end of the second quarter of 2017 under David S. Boyer, M.D. (Retina-Vitreous Associates Medical Group, Los Angeles) and H. Richard McDonald, M.D., (West Coast Retina Medical Group, San Francisco).
OpRegen® is an investigational therapy in which retinal pigment epithelial (RPE) cells are introduced into the subretinal space where they are intended to replace missing RPE cells. As reported at the International Symposium on Ocular Pharmacology and Therapeutics (ISOPT) in Rome on December 2, 2016 and at the Angiogenesis meeting in Miami on February 11, 2017, OpRegen® caused no serious adverse events, and retinal imaging suggests the presence and survival of transplanted cells in the subretinal space for up to one year.
On February 26, 2007, Othera Pharmaceuticals presented new preclinical data demonstrating the safety and effectiveness of OT-551, an experimental drug in eye drop form for treatment of geographic atrophy (end stage dry AMD). Results from the Phase I trials demonstrated that when the compound is added to either Lucentis or Avastin treatment there is a synergistic effect versus either treatment alone. According to Dr. Len Parver, Othera’s Medical Director, “OT-551 could potentially improve the outcome of patients already on Lucentis by treating the underlying macular degeneration and decreasing the need for frequent Lucentis injections.”
On April 8, 2009, Othera announced positive interim data results from its Phase 2 trial of OT-551. The 12-month findings from the 2-year trial suggest an emerging trend for reducing moderate vision loss (i.e. 15 letters or more on the ETDRS chart) in treated patients compared to the placebo group.
In 2012, Colby Pharmaceutical Co. acquired Othera Pharmaceuticals Inc., saying that they would continue clinical development of OT-551. Trials, meanwhile, have been terminated.
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.
In the October 2008 Journal of Biological Chemistry, researchers at the Case Western Reserve University School of Medicine reported on a new study in mice showing that retinylamine markedly slows the progression of AMD. The study, led by Akiko Maeda, provides insight into the biochemical trigger for genetic changes leading to the disease. Research continues with hope of the drug someday showing efficacy in humans.
Researchers at Massachusetts Eye and Ear/Harvard Medical School and the University of Crete have found that high doses of statins (cholesterol-lowering medications) can effectively reduce the number of soft drusen deposits in retinas of people with dry age-related macular degeneration (dAMD). The findings from their phase I/II clinical trial were published in EBioMedicine. Their hope is that this research will provide a foundation for an effective means of preventing progression to the advanced stages of a disease which currently has no effective treatment.
Drusen in the retina are similar to cholesterol deposits in the blood vessels, which has led scientists to look at cholesterol-lowering drugs for AMD patients. Previous studies, however, have not shown a significant effect of cholesterol medications on drusen. The possible answer, according to these researchers, is to increase the dosages beyond the normal amount.
Twenty-three patients with dry AMD marked by soft lipid deposits in the outer retina were prescribed a high dose (80mg) of atorvastatin, the generic name of the statin marketed as Lipitor® and several generic equivalents. Of the 23 patients, 10 experienced an elimination of the deposits under the retina and mild improvement in visual acuity.
As the next step for this line of research, the investigators plan to expand to a larger prospective multicenter trial to further investigate the efficacy of the treatment in a larger sample of patients with dry AMD.
Ophthotech Corporation has announced that the first patient has been dosed in a Phase 2/3 clinical study of Zimura® (avacincaptad pegol sodium) for treatment of advanced dry macular degeneration (MD). Zimura® is an inhibitor of complement factor C5, a central component of the complement cascade believed to be involved in the development of AMD. The Company has also recently initiated a Phase 2 study of Zimura® in combination with anti-VEGF therapy for wet MD patients.
This is the company’s second drug under study for people with MD. The other is Fovista, designed for use in combination with anti-VEGF injections for treatment of the wet form of the disease.
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. Read the full report.
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
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 I is fully enrolled and targeted to complete in 2018. The study is partially funded by a NIH National Eye Institute grant.
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