A Guide to Research in Dry AMD
Compiled by Dan Roberts
Updated April 25, 2013
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:
All headings contain links to further information, which will open in new windows. 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.
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 (formerly ACU-02), 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 HCl) 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 and search for "Acucela."
More about Acucela.
AL-8309B, a selective serotonin 1A agonist, is under evaluation by Alcon for dry AMD. Applied as an eyedrop, it is expected to slow atrophic lesion growth and improve visual acuity. Results are expected in 2012.
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. An additional Phase I study is now underway in patients with dry AMD.More about ARC1905.
Aspirin appears to be beneficial as a preventer of AMD. More about aspirin and AMD.
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 are being followed through 2013.
AMD patients are benefitting from a new drug therapy involving a combination of medicines which includes carbon dioxide. More about carbon dioxide therapy.
Copaxone (glatiramer acetate) injections are given in Alzheimer's disease to decrease destructive beta-amyloid deposits. These deposits are similar to the proteins seen in drusen found in dry AMD, so researchers are trying copaxone for treatment of dry AMD. In week 12 of a small preliminary study, 4 eyes (3 patients) treated with copaxone showed a total reduction of drusen area from baseline of 66%. Two eyes receiving sham injection had essentially no significant change in drusen area.
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.
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 are underway.
Encapsulated Cell Technology (ECT
ECT is a means of delivering drugs into the retina on a time release basis. 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 May 2011, results from Phase 3 clinical trials showed continued promise. More about ECT.
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.
More about fenretinide.
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. Estimated trial completion date is March 2014.
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.
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 will examine 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.
A study by Pfizer beginning in June 2012 and ending in June 2014 to test the safety and efficacy of intravenous RN6G on development of geographic atrophy.
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.
Phototrop (a combination of compounds which affect mitochondrial lipid metabolism) is now available in the United States. In the year-long study ending in May 2005, of 106 patients with early AMD, improvement was noted in visual field mean defect (VFMD), visual acuity, foveal sensitivity, and fundus alterations. In addition, in the treated group only 1 out of 48 cases (2%) showed worsening of VFMD, while in the placebo group 9 out of 53 (17%) showed worsening in VFMD. There was also a significant decrease in drusen-covered area of the treated eyes. More about Phototrop.
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. More about POT-4.
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.
Zinc has been shown to be an effective antioxidant, which is beneficial to the retina. In July 2008, researchers at Pipex Pharmaceuticals announced success with a complex that evidently results in a more potent antioxidant than zinc alone. This "zinc-monocysteine" molecule was developed by combining L-cysteine and zinc in a ratio of 1:1.
Under the commercial name Zinthionein, it was then administered as a 25 mg oral capsule twice a day to 80 test subjects for a period of six months. According to the phase 2 study results (David Newsome, primary investigator), these patients demonstrated a highly statistically significant improvement in visual acuity, contrast sensitivity and photorecovery time. Continued success in the trials could lead to a new and effective therapy for dry AMD. More about Zinthionein.
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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. More about CD36.
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. More about CRP levels.
Researchers have found that a variant of the C3 gene can more than double the risk of age-related macular degeneration (AMD). More about C3.
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. More about Hemicentin-1.
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.More about 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. More about LOC387115.
Japanese researchers reported in September 2003 that mutations in the RDH5 gene can cause macular dystrophy, fundus albipunctatus, and/or night blindness. More about RDH5.
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. More about RPGR.
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.
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.
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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. More about stem cell transplantation in mice.
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. More about retinal transplantation.
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.More about embryonic stem cell 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. More about stem cells from the iris.
Stem Cells from Umbilical Tissue
Centocor, Inc. is studying a single injection of human umbilical tissue derived cells (CNTO 2476) into the retina for treatment of dry AMD. The trial is expected to end in April 2013.
Stem Cell Transplantation in Mice
Scientists reported in November 2004 that they have improved the vision of mice with transplanted stem cells. More about stem cell transplantation in mice.
Stem Cell Transplants Protect Against Degeneration
StemCells, Inc. announced on February 2, 2012 that trials will begin to test how purified human neural stem cell (HuCNS-SC) transplants from the brain might significantly protect against degeneration of existing photoreceptors in humans. More about HuCNS-SC. . .
Summary of Early Stem Cell Research
The First Seven Years: An Overview of Stem Cell Transplantation Research
for Treatment of Retinal Disease
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