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As the U.S. population ages, millions of people face almost certain blinding disease because progress on treating the dry form of macular degeneration is inching rather than rushing along. New theories of pathogenesis, and new therapeutic targets that result, may sharpen the outcomes and pump up the pace of research.
The Centers for Disease Control reports that over a million Americans now have geographic atrophy, and another 7.3 million have large drusen and are at serious risk for degenerating macular vision. The human, social and economic implications of those numbers are enormous, so there must be a grand campaign afoot to save the vision of so many people, right?
For years, an alphabet soup of agents has lingered in preclinical or early-phase trials: ACU-4429, POT-4, NT-501, OT-551, RT-101. The biggest drag on this research seems to be that these agents are scattershot, and not based on a thorough understanding of the pathogenesis of dry AMD. “Drug development follows breakthroughs in understanding the cause of a disease. And we haven’t had that breakthrough,” said Paul Sternberg Jr., MD. “We haven’t found a significant enough defined cause such that blocking at that point has a dramatic impact.” Dr. Sternberg is professor and chairman of ophthalmology at Vanderbilt University in Nashville.
Waiting for such a breakthrough effectively means saying good-bye to functional vision for many people, even though some could benefit from drugs now available only in small clinical trials. Below is a discussion of the problems holding research back, new theories of pathology focusing on inflammation and the complement cascade, and reasons why industry would be well-advised to invest more time and money in treating this disease.
DRY RESEARCH STYMIED BY COMPLEXITY
The cause of dry AMD has eluded researchers for a number of reasons, from a lack of animal models to finding a suitable clinical endpoint to the cost of bringing a product to market. And for years, dry AMD took a backseat to wet, which poses a more immediate risk of devastating visual loss, though dry affects anywhere from 10- to 20-fold the number of people who have the neovascular disease. The advanced form of dry AMD is present in 3.5 percent of people aged 75 and older; its prevalence rises to 22 percent in people older than 90 in the United States.1
The disease advances slowly, but, alas, so has the progress of research. “Other than vitamins, there’s nothing out there that we know works,” said Nancy M. Holekamp, MD, adding that the retina community has been lulled a bit by the recent lineup of successful treatments for wet AMD. Dr. Holekamp is professor of clinical ophthalmology at Washington University in St. Louis.
Geographic atrophy not even codable? Unlike CNV, dry AMD tends to spare the fovea until the disease is advanced. And since it isn’t triggered by a sudden event, there’s no acute loss of vision. “When people talk about dry AMD, it includes everything from drusen to geographic atrophy (GA),” said Janet S. Sunness, MD. “Still, to this day, there is no ICD-9 diagnosis code specific for GA. It’s all called ‘362.51,’ the code for dry,” she said. “But you’re not looking at one entity. You’re looking at a spectrum from people with normal vision to those with legal blindness.” Dr. Sunness is medical director of low vision rehabilitation services at the Greater Baltimore Medical Center.
Wet’s been hogging the stage. Where along that spectrum do you attack the disease? CNV was so much simpler. “What allowed us to treat wet AMD was the fundamental understanding that VEGF was a critical element to its development,” Dr. Sternberg said.
Once VEGF was implicated in the pathogenesis of CNV, safe and effective treatments followed—Macugen, Avastin and Lucentis. It was the same story with AIDS, Dr. Sternberg said. “We had that breakthrough when we identified that it was caused by a virus, then we identified the virus, and then we could treat it.”
Dr. Sunness agreed. “The reason the anti-VEGF was so successful is there’s hard science behind it. They found something to fight against. There’s not that kind of argument to make with geographic atrophy.” CNV presents as a treatable event, whereas GA is chronic and degenerative, she continued. “In other areas of disease, there aren’t good treatments for degeneration of cells.”
“We’ve been spoiled by wet AMD. Nobody believed a single pathway, such as VEGF, would have had such a positive effect. We’re looking for a similar home run for dry, and it may not exist,” said Philip J. Rosenfeld, MD, PhD. “Dry is a tougher nut to crack.” Dr. Rosenfeld, who is professor of ophthalmology at Bascom Palmer Eye Institute, likened the disease to glaucoma. “It’s a slowly degenerative condition, in which you don’t have an easy signal that you can observe over the short term to establish a dosing interval.” And, as in glaucoma, patients may suffer irreparable damage before knowing they have a disease. “Wet got a lot more attention. It was rapid vision loss and it did cause the lion’s share of vision loss,” said Dr. Sternberg, who has been working on dry AMD since the 1980s. “It was pretty lonely for a while.”
Après le déluge: dry replaces wet. Now that there are safe and effective treatments for wet AMD, researchers are turning their attention to dry. “We’re drying up the wet,” said Dr. Holekamp, “but people are still losing vision from dry.”
NEW THEORIES BOOST RESEARCH, BUT LACK OF CADAVER EYES SLOWS IT
Today, more than a dozen trials, from preclinical to phase 3, are investigating different drugs with different mechanisms that attack the disease along various pathways. Hypotheses behind these drugs abound, from chronic inflammation to mutations along the complement pathway to lipofuscin accumulation and oxidative stress.
Dr. Rosenfeld said that the most compelling evidence of causation comes from genetic research along the complement pathway. Since complement genes have been associated with AMD and complement proteins are known to cause tissue damage, one theory purports that blocking complement activation prevents disease progression. “There are arguments in favor of blocking complement C3 or C5, though nobody knows where to block.”
Currently, Dr. Rosenfeld is enrolling patients in a phase 2 trial to test eculizumab (Soliris), which is already FDA-approved for treating another complement- mediated disease, paroxysmal nocturnal hemoglobinuria. The humanized monoclonal antibody binds to complement protein C5, inhibiting its role in complement activation, and blocking the formation of membrane attack complex. Or at least that’s the theory. “But a lifetime of complement activation may have nothing to do with disease progression,” Dr. Rosenfeld admitted. “It could be that complement activation is an essential step to the underlying disease process, but it may be too late to block complement once we see the disease. We don’t know. It’s a matter of experimentation.”
Dr. Sternberg put it similarly: “Are the horses out of the barn? By the time someone develops GA and a drug is not effective in preventing the progression of the atrophy, is it because the drug has no efficacy in dry AMD, or is the disease too far along for any benefit to be demonstrable?”
Wanted: diseased donor eyes. Like any disease, any useful understanding of dry AMD requires an examination of how it has affected diseased tissue. But since it is a disease of the macula, and only primates have maculas, researchers need a ready supply of human cadaver eyes from patients who suffered from geographic atrophy, said Jayakrishna Ambati, MD. “Now we have hit-or-miss access.” Dr. Ambati’s laboratory is studying a pseudomicrobial substance for use in the treatment of dry AMD. He is professor of physiology and professor and vice chairman of ophthalmology and visual sciences at the University of Kentucky in Lexington.
“The mice used in research are imperfect models of chronic aging conditions,” he explained. “It’s not clear that what we see in those mice is what we see in human settings. So if there’s one thing that can catalyze and catapult GA research, it will be if the community of researchers had wide access to existing libraries of human eyes, and if clearinghouses of good quality human eyes were made widely available. The importance of that cannot be overemphasized.”
Dr. Ambati predicts that easy access to human donor eyes would accelerate progress since much about the disease is already known. For example, the molecular and biochemical techniques are already available to help find the actual triggering mechanism. “We know that in GA the RPE cells die. There’s a lot of research on why cells die,” he said. And a number of cell-death pathways have been extremely well worked out. He said that with 50 or 100 eyes, a researcher could test these pathways and observe which ones appear to be involved in the human eye specimens.
Blocking cascades. The next step, he said, would be to try to perturb that pathway in human cells or organ cultures and animal models and test a way to block the cascade. Within a year, a researcher could find a good measure of what is needed to develop potential drug candidates.
This method worked for CNV research, and today physicians have VEGF antibodies to treat the condition, said Dr. Ambati, recalling that in 1996 researchers had access to submacular CNV specimens, when “the rage was submacular surgery.” They examined those eyes for various factors known to promote blood vessel growth and consistently found VEGF. Simultaneously, Genentech was pursuing drugs to inhibit VEGF. But such a defining moment may never occur with dry AMD. And not simply for lack of donor eyes. “The state of affairs is that we have lots of theories and hypotheses. And until we get a good molecular understanding, such a breakthrough is not going to happen,” Dr. Ambati said.
WELCOME: A NEW ENDPOINT AND FRESH INVESTMENT DOLLARS
Dry AMD studies got a shot in the arm in 2006, when the FDA agreed to a new endpoint: GA, with enlargement of the atrophied area as an outcome measure.
Visual acuity (VA), the standard endpoint in clinical trials, doesn’t adequately capture the vision loss experienced by dry AMD patients, said Dr. Sunness, whose research has demonstrated the need for a different endpoint for GA studies. VA is not a good endpoint, she said, because dry AMD often spares the fovea, something she calls “foveal resilience,” until late in its course. The fovea may hold on for years, yet a person may have huge areas of sight-robbing atrophy. “The area that’s spared gets smaller and smaller, but they still have good acuity,” she said. “You see someone with 20/40 or 20/50 and think they’re not bad off.” But they may have areas of atrophy surrounding the fovea, so that while reading, for example, a whole word of even just three or four letters may not fit within the spared visual area. In other words, patients with GA may have severe vision impairment that interferes with reading and other tasks, but they still have good VA. “So visual acuity is not capturing everything that’s going on with GA.”
Dr. Sunness’ work explained why VA is not a suitable endpoint. First, it could result in under-estimating disease progression. Second, because of the time it takes for dry AMD to affect VA, studies could take three to five years or more. Third, studies using VA as an endpoint require more patients.
But with the enlargement rate of GA as an endpoint, Dr. Sunness and colleagues found that it would take only 153 patients each in a control group and treatment group to detect a 25 percent reduction in enlargement rate from a systemic treatment, with a two-year follow-up period. Testing a uniocular treatment would require 38 patients with bilateral GA, using the untreated eye as a control.1
“GA is a very easy disease to do trials on,” Dr. Sunness said. “Unlike CNV, GA is a very orderly disease. It behaves in a very lawful fashion.”
Taking an investment risk. An easier endpoint will help lubricate research, but given the murkiness of its pathogenesis, why would anyone risk the bank to find a treatment for dry AMD? For Ted Danse, MBA, president and CEO of Neurotech Pharmaceuticals, the answer is as simple as the one a climber gives to explain why he scales mountains. “It’s like exploration,” he said. “There are a lot of unmet medical needs for which we’re not always fortunate enough to know the mechanism of action. GA is one good example. People don’t know the exact pathogenesis. How does it happen? We’re just seeing the tip of the iceberg.” But, Mr. Danse said, there are important facts that are established: as the area of RPE atrophy grows, photoreceptors die and GA advances.
Like Dr. Rosenfeld, Mr. Danse sees an analogy to glaucoma. While all the causes of that disease aren’t fully understood, it is generally agreed that lowering intraocular pressure is a good thing, he said. “We believe, similarly, that rescuing photoreceptors is a good thing because without photoreceptors vision is lost.” Neurotech is trying to save photoreceptors with ciliary neurotrophic factor (CNTF), a neurotrophic agent delivered by means of long-term encapsulated cellular implants. It has been effective in preserving photoreceptors in animal models of retinal degeneration and early clinical research.
Mr. Danse, who noted that the cost of bringing a treatment to market ranges in the hundreds of millions of dollars, acknowledged the challenges ahead. “This isn’t a quick fix. You’re not going to have a silver bullet for addressing GA that all of a sudden solves the whole problem like a VEGF antagonist for CNV. Hopefully we will eventually have a therapy to slow or halt photoreceptor degeneration to thereby preserve a patient’s vision.”
Big bucks might bring big return. For now, he said, there isn’t any experimental treatment that’s nearing the finish line. He predicted that therapeutic discovery would advance if big pharmaceutical companies more aggressively stepped up to support more research programs for GA. He added that the market for whatever treatment emerges is well over a billion dollars. “It’s a blockbuster opportunity.”
Combination interventions. Dr. Rosenfeld predicted that dry AMD may require a combination approach, with a different therapeutic intervention for each step in the pathogenesis of the disease. One treatment may address oxidative damage (the AREDS approach), while another modulates the visual cycle to prevent accumulation of toxic lipofuscin in the RPE (fenretinide, also known as RT-101). Another treatment could reduce chronic inflammation in the region of the RPE, Bruch’s membrane and choroid, while yet another addresses mutations in the complement pathway. Neuroprotection is another strategy.
In the meantime, as Dr. Sternberg put it, the need continues for basic research that elucidates the pathogenesis of dry AMD. “We can’t stop looking. I think that even if any of these drugs out there are beneficial, my worry is they’ll be beneficial as PDT was beneficial. It was statistically significant, but functionally it was only marginally beneficial. I have not yet seen any drug out there that’s the home run, that’s going to make a dent in this disease. Because we really haven’t identified the critical junctures and pathways that put you down the road to vision loss from dry AMD.”
Almost 10 million people in the Unites States alone are hoping to take a different road.
1 Sunness, J. S. et al. Ophthalmology 2007;114(2):271–277.
studies seeking to VANQUISH DRY AMD
Virtually all clinical studies for treating drusen, geographic atrophy or the progression of dry AMD to wet are described in detail at www.clinicaltrials.gov. (Enter “dry AMD” in the search field.) Study design, criteria, recruitment status and locations are also provided. For treating dry AMD, the 13 therapies below are all investigational in the United States.
Developers : Acucela and Otsuka.
Administration and Action : Given orally, this small-molecule modulator of the rod visual cycle is intended to slow the regeneration of 11-cis-retinal and prevent the accumulation of retinoid-related toxic by-products, including precursors of lipofuscin, which may provoke inflammation.
Stage of Development : Now in phase 2 clinical trials, ACU-4429 received FDA fast-track designation in March 2010.
Developer : Under development as Retaane, by Alcon, to prevent the progression of dry AMD to wet. Alcon has also studied it for treating choroidal neovascularization and glaucoma.
Administration and Action : Administered in a slow-release, posterior juxtascleral depot suspension, anecortave acetate is an angiogenesis inhibitor that interferes with the proteolysis required for vascular endothelial cell migration.
Stage of Development : In a phase 3 study, anecortave acetate matched but did not improve upon the efficacy of photodynamic therapy. The next step is unclear.
Developer : Under development by Ophthotec and is also under study for the treatment of neovascular AMD.
Administration and Action : Administered by intravitreal injection, ARC1905 is a selective aptamer inhibitor of C5-mediated inflammation.
Stage of Development : In a phase 1 study.
Developer : Developed by Alexion Pharmaceuticals and marketed as Soliris to treat paroxysmal nocturnal hemoglobinuria.
Administration and Action : Administered by intravenous infusion, this monoclonal antibody is designed to bind to, and block cleavage of, complement protein C5, in order to thwart complement-mediated cell destruction.
Stage of Development : Earned FDA fast-track designation for dry AMD in 2009 and continues in phase 2 trials.
Developer : Developed by a series of companies over 25 years, most currently ReVision Therapeutics, fenretinide is also under study to treat CNV, cystic fibrosis, rheumatoid arthritis, neuroblastoma, certain rare childhood cancers and dermatologic disorders.
Administration and Action : Given orally, this synthetic retinoid agonist reduces the expression of vascular endothelial growth factors, reduces accumulations of toxins like lipofuscin, and upregulates expression of complement factor H, an inhibitor of inflammation.
Stage of Development : Phase 2 data were presented in October at the Academy’s Joint Meeting in Chicago.
Developer : Teva Pharmaceutical Industries, which also markets it as Copaxone to treat multiple sclerosis.
Administration and Action : Administered by subcutaneous injection, glatiramer is an immunomodulator that increases the proportion of anti-inflammatory T helper-2 lymphocytes.
It may also decrease amyloid deposits, which are associated with aging and cognitive decline and which may share an inflammatory pathway with drusen.
Stage of Development : The drug is now in phase 1 and 2 studies.
Developer : Under development by MacuClear, which says the agent is already marketed in another proprietary form as an antihypertensive glaucoma medication.
Administration and Action : Administered topically with a novel delivery dropper, MC-1101 is intended to improve choroidal blood flow and prevent the rupture of the Bruch’s membrane and the transition to neovascular AMD.
Stage of Development : MacuClear has acquired FDA fast-track status for MC-1101 and has completed phase 1 trials.
Developer : Neurotech.
Administration and Action : Administered by way of an intraocular implant, these human retinal epithelial cells are modified genetically to secrete ciliary neurotrophic factor, then encapsulated in a polymer and implanted intraocularly into the posterior segment to deliver continuous, low doses of CNTF.
Stage of Development : Phase 2 trials are completed.
Developer : Othera Pharmaceuticals.
Administration and Action : Administered topically, this small novel molecule is thought to protect retinal pigment epithelium against light-induced degeneration, probably through activation of the transcription element Nrf2 and reduction of inflammation and oxidative stress.
Stage of Development : Now in phase 2 trials.
Developer : Potentia Pharmaceuticals.
Administration and Action : Administered intravitreally, this derivative of the cyclic peptide compstatin is capable of binding to, and preventing activation of, human complement factor C3, resulting in broad inhibition of the complement cascade, inflammation and angiogenic factors, including VEGF.
Stage of Development : Phase 1 trials are completed.
RETINAL PIGMENT EPITHELIUM TRANSPLANTATION
Developer : Pioneered by researchers at the University of Louisville in Kentucky and funded privately and anonymously, RPE transplantation has also been studied for the treatment of retinitis pigmentosa.
Administration and Action : Transplanted surgically, these neural retinal progenitor cell layers are harvested in sheets from human fetal donor retina and transplanted into the subretinal space near the recipient’s fovea to create newly functional RPE.
Stage of Development : A nonrandomized interventional trial is completed; further trials are stalled by lack of funding.
Developer : Also known as rapamycin and marketed by Pfizer to prevent organ transplant rejection, sirolimus is under development as Perceiva by Macu-Sight and is also under study to treat wet AMD, DME, anterior uveitis and polycystic kidney disease.
Administration and Action : Administered by subconjunctival injection, sirolimus is an immunosuppressive agent that inhibits mTOR, a protein involved in cell motility and proliferation.
Stage of Development : Phase 2 clinical trials are ongoing.
STEM CELL-DERIVED RPE
Developer : Advanced Cell Technology.
Administration and Action : Human embryonic stem cell-derived retinal pigment epithelial cells could functionally replace retina lost to GA; they are already under study to treat Stargardt disease. Similar in effect to RPE transplantation, this therapy originates with pre-differentiated rather than mature RPE cells.
Stage of Development : An IND was filed with the FDA in November for initiating a phase 1/2 multicenter study.
Meet the Experts
JAYAKRISHNA AMBATI, MD Professor of physiology and professor and vice chairman of ophthalmology and visual sciences at the University of Kentucky in Lexington. Financial disclosure: He and his lab members are co-inventors in patent applications filed by the University of Kentucky on technologies related to discoveries in geographic atrophy.
TED DANSE, MBA President and CEO, Neurotech Pharmaceuticals, Lincoln, R.I.
NANCY M. HOLEKAMP, MD Partner, Barnes Retina Institute and professor of clinical ophthalmology at Washington University in St. Louis. Financial disclosure: Consultant to Allergan and Genentech. Clinical research grants from Alimera, DRCR Network, Genentech, the NIH, Novartis, QLT and Regeneron.
PHILIP J. ROSENFELD, MD, PHD Professor of ophthalmology at Bascom Palmer Eye Institute. Financial disclosure: Clinical research grants from Alexion and Potentia; on advisory board for Potentia.
PAUL STERNBERG JR, MD Professor and chairman of ophthalmology at Vanderbilt Eye Institute, Vanderbilt University, in Nashville. Financial disclosure: None.
JANET S. SUNNESS, MD Medical director, Richard E. Hoover Low Vision Rehabilitation Services at the Greater Baltimore Medical Center. Financial disclosure: Consultant for Acucela, Advanced Vision Therapies, Alcon, Cell Cure, Genentech, GSK, Health Advances, Johnson & Johnson, Neurotech, Novartis, Ophthotech, Othera, Pfizer, Potentia, Shire, Sirion, Sucampo and Taligen. Advisory boards: Acucela, Potentia.