Research on dry AMD therapies may give new hope for preserving vision

While there is no true therapeutic option for non-neovascular age-related macular degeneration, several lines of ongoing scientific research have retinal specialists cautiously optimistic for the future.

For patients with neovascularization secondary to AMD, anti-VEGF therapy is a mainstay. Questions still remain regarding its optimal use, but the therapy has proven both safe and effective.

Meanwhile, management of patients with dry AMD follows a far more uncertain path. A large clinical trial found that nutritional supplementation aids in preventing progression of the disease and staves off vision loss, but those results were modest.

According to some experts, the fact that no gold standard therapy exists may come from a lack of understanding of the actual dry AMD disease state. It is known, for example, that there is an inciting event that leads to formation of drusen, but whether that is due to ischemia, inflammation, genetic predisposition, or some other factor or combination of factors is unknown. Additionally, risk factors for progression, some modifiable, are known and appreciated; yet, the interplay between genetic abnormalities and phenotypic expression is only beginning to be understood.

According to Peter K. Kaiser, MD, dry AMD appears to be a uniquely human disorder, making it difficult to scientifically hypothesize how to treat it. Image: Nathan Steinle

“We don’t know why some patients who have a genetic predisposition don’t develop it. We don’t know why patients who don’t have a genetic predisposition do develop it, especially in the absence of smoking,” OSN Retina/Vitreous Board Member Peter K. Kaiser, MD, of Cole Eye Institute, said.

“There is no smoking gun like there is in wet AMD where we can go after VEGF,” he said.

Nutritional supplementation

Several candidate therapies currently being investigated may someday change how patients with dry AMD are managed, including potentially improving vision and causing regression of hallmark drusen and geographic atrophy.

Research into potential therapies, however, has followed a novel path within the realms of medical research. Unlike most candidate drugs or treatments that trickle through the clinical trial process, most dry AMD therapies have started investigation in human patients because of a lack of a good animal model for the pathology. According to Dr. Kaiser, dry AMD appears to be a uniquely human disorder.

“Oftentimes, new therapeutics go straight into humans, with minimal to no efficacy testing in animals to see if it works. This makes dry AMD a difficult disease to treat because it is even difficult to scientifically hypothesize how to treat it with a good drug,” Dr. Kaiser said.

The fortunate news for the retinal community is that a number of candidate drugs are currently in various stages of development. Moreover, numerous potential therapies with differing mechanisms of action are being investigated, a fact that increases the odds that a potential therapy will emerge.

According to Dr. Kaiser, research so far has fallen into four basic categories: neuroprotection, visual cycle modulation, immune system manipulation and anti-inflammatory. But the research is so nascent at this point that it is impossible to say if any one strategy is more beneficial than another.

And because the clinical potential of these candidates is unknown, it may turn out that the few options already in use — nutritional supplementation and risk factor reduction — may be the best options.

In the early 1990s, the beneficial effects of antioxidants, dietary lutein, zeaxanthin and omega-3 acids derived from fish and nuts were reported by Johanna M. Seddon, MD, ScM, of the New England Eye Center at Tufts Medical Center. Several other studies confirmed these associations.

Johanna M. Seddon

In 2001, the Age-Related Eye Disease Study (AREDS) reported results of a clinical trial sponsored by the National Eye Institute investigating the potential usefulness of nutritional supplementation for reducing the risk of AMD progression.

Since the release of the AREDS data, various formulations of vitamins and antioxidants have been suggested. But only one formulation of dietary supplementation has been put to the test in a large-scale clinical trial.

Any manipulation of the formulation has the potential to change efficacy and safety, according to Susan B. Bressler, MD, Julia G. Levy, PhD, Professor of Ophthalmology at Wilmer Eye Institute.

“The only formulation that we have good, solid evidence for is the one that was tested in AREDS, and that is 500 mg of vitamin C, 400 IU of vitamin E, 15 mg of beta-carotene, 80 mg of zinc oxide and 2 mg of copper,” she said.

The AREDS results were positive, but the treatment only appeared to work in select individuals, and there was still a significant amount of disease progression among participants in the study. According to Dr. Bressler, about 34% of patients had disease progression over the 10-year study period despite active treatment, and roughly 44% developed moderate vision loss.

Furthermore, Dr. Bressler said, the treatment was most beneficial among select patients: individuals older than age 50 years with extensive medium drusen (64 µm to 125 µm), at least one large drusen (greater than 125 µm) or geographic atrophy not affecting the foveal center.

As well, individuals with advanced disease in one eye, in which the second eye was at highest risk of disease progression, also benefited from nutritional supplementation. “Fortunately, that risk is reduced for the second eye in those individuals using the supplement,” Dr. Bressler said.

Despite the demonstration of benefit, however, the results are from only one study. Additionally, in the decade since the publication of AREDS data, new information has come to light regarding the safety of some components of the AREDS formulation for some individuals and there have been several additional reports about the potential benefit of omega fatty acids.

“At the end of AREDS, we knew there was still a lot of room for improvement,” Dr. Bressler said. “The reduction in AMD progression and vision loss observed in AREDS was consistent with a modest treatment effect; however, with only one study to depend on, it is hard to say beyond a shadow of a doubt that these treatments are definitely doing something helpful.”

Susan B. Bressler

To answer some of those questions, as well as to attempt to improve the success of treatment, the NEI sponsored AREDS 2. According to Dr. Bressler, AREDS 2 intentionally enrolled patients at highest risk for disease progression, that is, persons with bilateral large drusen or those who have one eye already lost to advanced AMD and large drusen in the second healthier eye.

Patients were randomly assigned in a double-blind fashion to lutein and zeaxanthin in one group, omega-3 fatty acids DHA and EPA in a second group, lutein, zeaxanthin, and DHA and EPA in a third group and placebo in a fourth group. A second randomization will test various adjustments to the original AREDS formula. For instance, some patients will receive a supplement that does not contain any beta-carotene because there has been evidence that excessive beta-carotene exposure in individuals with a smoking history may be harmful. Reduced amounts of zinc are being tested in another variation of the original AREDS formula.

“AREDS 2 will be an opportunity to see whether the original formulation can be altered and still achieve the same benefit, while potentially providing a safer formulation for the long run,” Dr. Bressler said.

“It is very important,” Dr. Kaiser said, “because vitamins are the only approved treatment, and it could turn out that this study may be the only positive one.”

Complement inhibition

In terms of novel strategies to treat dry AMD, scientists are pursuing a line of research involving complement inhibition, which essentially seeks to reduce inflammation, a key component in dry AMD progression.

Upon activation, proteins in the complement system undergo a series of cleavages, terminating at a final common pathway known as complement factor 3, or C3. When C3 is activated to C3 convertase, it activates up to four effector molecules: C3a and C5a, which recruit inflammatory molecules to the cell; C3b, which coats an inciting pathogen in preparation for phagocytosis by a white blood cell; and/or membrane attack complex, which forms holes in the cell membrane of an inciting pathogen or host cell.

Several studies have reported complement deposits within drusen. As well, research has indicated that some patients with dry AMD have a single nucleotide polymorphism in the coding for complement factor H, an important inhibitor of complement activity, suggesting a dysfunction in the complement system.

However, the events that lead to complement initiation in dry AMD, as well as exactly how complement deposits come to reside within drusen, are unknown. Researchers speculate that if the complement cascade can be downregulated, positive benefits in terms of slower disease progression should follow.

“The current theory is that complement plays a role in drusen formation, and by blocking complement, we can prevent or reverse drusen. Complement may also play a role in killing retinal pigment epithelium and, therefore, may promote formation of geographic atrophy. By blocking complement, maybe we can prevent the enlargement of geographic atrophy,” Scott W. Cousins, MD, of Duke Eye Center, said.

While there is cautious optimism for the potential of complement inhibition, there are also numerous questions remaining. For example, the optimal target within the complement cascade is unknown because there may be benefits and disadvantages to upstream inhibition of C3 vs. downstream inhibition of C5. Whereas inhibition of C3 engenders blockade of all four effector molecules — C3a, C5a, C3b and membrane attack complex — it may yield too much of a good thing.

“By blocking C3, you are blocking all the effector pathways. By blocking C5, you are blocking the terminal effector pathways, preserving theoretical antibacterial protection but maybe allowing some proinflammatory activity to continue,” Dr. Cousins said.

The safety of early inhibition arose most prominently in relation to phase 1 studies conducted by Potentia on its candidate C3 inhibitor, known as POT-4, as therapy for wet AMD. The molecule has since been licensed to Alcon.

Although speculative, it is possible that inhibition of complement later in the cascade (ie, C5) may preserve beneficial byproducts of C3.

“By blocking C5, you are still blocking C5a and the membrane attack complex, but leaving C3a and C3b intact, which are antibacterial,” Dr. Cousins said. “By blocking complement factor 3, you theoretically may increase the risk of infection. However, Potentia did not see any increased infection in their phase 1 trial of C3 inhibition in wet AMD. Nonetheless, infection is something that must be monitored.”

Downstream blockade of the complement cascade at C5 is also in clinical trials. ARC1905 (Ophthotech) is a synthetic RNA that blocks C5 in much the same way an antibody would, and Soliris (eculizumab, Alexion) is an intravenous monoclonal antibody to C5.

“The early results of the Ophthotech study suggest an unexpected byproduct. In some cases, the drusen appear to go away. So, although they are testing anti-C5 therapy in geographic atrophy, it may also have therapeutic impact on drusen disappearance,” Dr. Cousins said. But, he added, “This finding is only anecdotal from a small number of cases.”

Another form of complement inhibition, anti-factor D, is being studied by Genentech. Factor D is a known activator of the cascade.

“Genentech has tested an antibody to complement factor D in geographic atrophy. They think complement factor D is the most important upregulator of complement effector molecule production and that blocking factor D can be a very powerful therapy,” Dr. Cousins said.

Neuroprotection

A separate therapeutic option for dry AMD relies on stopping or reversing the photoreceptor cell death process. The strategy has been successful in animal models and in early clinical development.

Neurotech Pharmaceuticals has developed a sustained-release platform housing genetically altered cells that produce ciliary neurotrophic factor, or CNTF. In essence, when the platform (NT-501) is implanted to the back of the eye, it becomes an intraocular factory capable of producing the desired drug for a year or more.

The core belief behind the potential of CNTF in dry AMD is that preservation of photoreceptors and retinal pigment epithelium should also preserve vision, and early studies on the product suggest a beneficial effect. In a phase 2 study, 96.3% of patients treated with the candidate product lost fewer than three lines of vision at 12 months, compared with 75% treated with sham therapy.

Best corrected visual acuity did not increase in the study, and stabilization of BCVA was not statistically significant. However, increases in retinal thickness reaching the level of statistical significance were noted among patients taking a higher dose of the drug.

Additionally, the area of geographic atrophy was noted to have shrunk by an average of 1.3 mm² in the 27 patients in the high-dose group; macular volume increased by an average of 0.5 mm² and 0.3 mm² in the high- and low-dose treatment groups, respectively.

Visual cycle modulation

Another novel mechanism of action in treatment of dry AMD is to affect the tempo of the visual cycle to prevent accumulation of harmful deposits. It is thought that by slowing the visual cycle, accumulation of lipofuscin precursor and retinal fluorophore A3E may be slowed or obviated, thus preventing downstream retinal degeneration.

“The idea is that if we can somehow prevent the mediator toxic byproducts accumulation in the retina, we should prevent photoreceptor cell death and prevent geographic atrophy,” Dr. Kaiser said.

Candidate drugs are already in accelerated development in this sphere. Last year, the U.S. Food and Drug Administration granted fast-track approval to Acucela, which, in partnership with Otsuka Pharmaceuticals, is working on development of ACU-4429, which slows the rod visual cycle. In phase 1 studies, the drug was proven to be safe, and a phase 2 trial has been launched.

According to Dr. Kaiser, a similar mechanism of action is being explored with fenretinide, a drug that prevents binding of retinol to the retinal binding protein in the bloodstream, blocking its passage into the retinal pigment epithelium, thus slowing the visual cycle.

“We really didn’t see a huge difference in geographic atrophy progression, but it did show decreased risk of progression to CNV and the wet form of AMD,” Dr. Kaiser said. “We are scratching our heads about this result because theoretically it should work on geographic atrophy, which it did not, but it did work in preventing CNV. We have to study that a bit more.”

Increased industry interest

Across the range of clinical trials, there have been numerous encouraging signs that a treatment option may be near. But these research efforts are in the beginning stages, so no certain answers exist.

According to Dr. Seddon, dry AMD has been a difficult disease to treat in part because the pathology takes years to develop, and only a subset continues to progress to more severe vision-threatening forms.

“There is no acute event like in the wet form, which appears with a collection of fluid and blood. Dry AMD progresses over years, and until it develops into the wet form, there is so far no well-defined target to treat,” Dr. Seddon said.

One additional avenue of research worth watching, Dr. Seddon said, involves the use of stem cells. Recently, Advanced Cell Technology announced the filing of an investigational new application to begin a phase 1/2 multicenter trial of human embryonic stem cell-derived retinal pigment epithelium cells.

From a market perspective, the level of dry AMD research suggests that industry recognizes the potential for a blockbuster treatment in the face of the rapidly expanding community of older adults. According to data extracted from AREDS, as much as 1% of the U.S. population may be affected by geographic atrophy secondary to AMD in 2020.

In addition, the burst of clinical trials and candidate therapies suggests the importance of the non-neovascular stages of macular degeneration. Not only are the predominant cases of macular degeneration non-neovascular in nature, but treatment of the wet form may also revert patients back to an anatomical state similar to the early stages of the disease. The question becomes, then, what to offer these patients?

“We have gone full circle now to looking back to the early stages with drusen to find out why and how they develop and progress,” Dr. Seddon said. – by Bryan Bechtel

After successful treatment of wet AMD, in what patients would retina specialists continue to treat dry AMD and what treatment should be used?

References:

• Age-Related Eye Disease Study Research Group. A randomized, placebo-controlled, clinical trial of high-dose supplementation with vitamins C and E, beta-carotene, and zinc for age-related macular degeneration and vision loss: AREDS report No. 8. Arch Ophthalmol. 2001;119(10):1417-1436.
• Anti-factor D. Genentech website. http://www.gene.com/gene/pipeline/status/neuroscience/anti-factord/. Accessed Dec. 9, 2010.
• ARC1905 – anti-C5 aptamer. Ophthotech website. http://www.ophthotech.com/products/arc1905/. Accessed Dec. 9, 2010.
• The AREDS formulation and age-related macular degeneration. National Eye Institute website. http://www.nei.nih.gov/amd/summary.asp. Accessed Dec. 9, 2010.
• Complement platform. Alexion website. http://www.alxn.com/RandD/Complement%20Platform/Default.aspx. Accessed Dec. 9, 2010.
• Emerich DF, Thanos CG. NT-501: an ophthalmic implant of polymer-encapsulated ciliary neurotrophic factor-producing cells. Curr Opin Mol Ther. 2008;10(5):506-515.
• Lindblad AS, Clemons TE. Responsiveness of the National Eye Institute Visual Function Questionnaire to progression to advanced age-related macular degeneration, vision loss and lens opacity. AREDS Report No. 14. Arch Ophthalmol. 2005;123(9):1207-1214.
• NT-501. Neurotech website. http://www.neurotechusa.com/ect/nt-501.asp. Accessed Dec. 9, 2010.
• POT-4. Potentia website. http://www.potentiapharma.com/products/pot4.htm. Accessed Dec. 9, 2010.
• Product candidates. Acucela website. http://www.acucela.com/pipeline-candidates.html. Accessed Dec. 9, 2010.
• Retinal pigmented epithelial cell program. Advanced Cell Technology website.http://www.advancedcell.com/act-stem-cell-related-research-pipeline/retinal-pigment-epithelial-cell-program/. Accessed Dec, 9, 2010.
• Thanos CG, Bell WJ, O’Rourke P, et al. Sustained secretion of ciliary neurotrophic factor to the vitreous, using the encapsulated cell therapy-based NT-501 intraocular device. Tissue Eng. 2004;10(11-12):1617-1622.

• Susan B. Bressler, MD, can be reached at Wilmer Eye Institute, Johns Hopkins Hospital, Maumenee 706, 600 North Wolfe St., Baltimore, MD 21287; 410-955-3648; e-mail: sbressler@jhmi.edu.
• Scott. W. Cousins, MD, can be reached at Duke University Eye Center, DUMC Box 3802, Durham, NC 27710; 919-684-3090; e-mail: scott.cousins@duke.edu.
• Peter K. Kaiser, MD, can be reached at Cole Eye Institute, Division of Ophthalmology, A31, 9500 Euclid Ave., Cleveland, OH 44195; 216-444-6702; e-mail: pkkaiser@aol.com.
• Johanna M. Seddon, MD, ScM, can be reached at Department of Ophthalmology, Tufts Medical Center, 800 Washington St. #450, Boston, MA 02111; 617-636-9000; e-mail: jseddon@tuftsmedicalcenter.org.
• Disclosures: Dr. Bressler’s institution has received research grants from Genentech. Dr. Cousins is a paid consultant for Alcon, Genentech and Ophthotec. Dr. Kaiser is a consultant to Genentech and Alcon. He has equity in SKS Ocular. Dr. Seddon has no direct financial interest in any of the products, nor is she a paid consultant for any companies mentioned.