Compiled by Dan Roberts
(Updated March 2017)
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.
Acucela (emixustat hydrochloride)
On June 4, 2008, Acucela Inc. announced that it had dosed the first subject in a Phase I trial for its lead compound ACU-4429 (now called emixustat hydrochloride), an orally available small molecule being developed for the treatment of dry AMD. ACU-4429 modulates the visual cycle by significantly reducing the accumulation of the retinal related toxic by-product A2E, believed to damage retinal cells.
Dr. Ryo Kubota, Acucela’s chairman and chief executive officer, says that, because the drug is a non-retinoid (not derived from vitamin A), it has the potential to be safe for a wide range of people, including young patients and women of child-bearing age. Stephen Rose, Ph.D., chief research officer, Foundation Fighting Blindness, says ACU-4429 may also be a beneficial treatment for people with Stargardt disease.
In January 2010, following the success of the Phase I clinical trial, Acucela began recruiting participants with dry AMD for Phase II
Known as the ENVISION Clarity Trial, the 90-day dose-escalation safety study offered 56 subjects with geographic atrophy either ACU-4429 or placebo once per day. Approximately four hours after subjects were given either ACU-4429 or placebo, and following pupil dilation and dark adaptation, electroretinogram (ERG) measurements were recorded at multiple time points after three minutes of exposure to a bright, bleaching light. The interim data was reported at the annual ARVO meeting in May 2012. It showed that subjects receiving ACU-4429 had a dose-dependent response and that rod visual cycle was modulated, as measured by ERG, for doses up to 10mg.
The results of Acucela’s Phase 2 trial were announced at the ARVO meeting in 2013. This proof of concept study demonstrated a dose-dependent biologic effect and ACU-4429’s ability to modulate the visual cycle. Systemic adverse events were minimal. Results suggest that ACU-4429 (now called Emixustat hydrochloride) may be a useful agent in the treatment of geographic atrophy. A long-term Phase 2b/3 study is now underway to evaluate the drug. For more information about the trial, contact Covance Clinical Research Unit in Dallas, Laura Lonsdale at (214) 920-9053, Covance Clinical Research Unit in Austin, David Carter at (512) 302-6519, or visit www.clinicaltrials.gov. More about Acucela.
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. 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. Plans to move forward with Phase III are underway.
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.
In August 2013, Roche Pharmaceutical announced positive phase II results from their MAHALO phase II study of lampalizumab (aka anti-factor D). The study showed a 20.4 percent reduction in progression of advanced dry macular degeneration (geographic atrophy) at 18 months. More about the MAHALO study.
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.
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.
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.
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.
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.
Summary of Early Stem Cell Research