By Suzanne Oliver

Scientists may be just a few years away from delivering new treatments for age-related macular degeneration (AMD), the leading cause of irreversible vision loss in people more than 50 years old.

Over the past 15 years there has been only one class of successful AMD drugs, known as anti-VEGF agents, and they have worked for a minority of AMD sufferers. Now researchers are having success fighting AMD from new directions. They include an immune-system inhibitor and stem-cell therapy, which show promise for treating the dry form of AMD in its advanced stage, for which there is currently no treatment approved by the U.S. Food and Drug Administration.

"I'm cautiously optimistic that we will have markedly improved treatments for both wet and dry AMD within two to three years," says Joshua Dunaief, professor of ophthalmology at the Scheie Eye Institute at the University of Pennsylvania.

Therapies showing success in trials for the wet form of AMD, which is less common but leads to more-rapid vision loss, aim to replace the current treatment regimen of monthly eye injections with alternative approaches that may last from six months to, in the case of gene therapy, as much as a lifetime.

As many as 11 million people in the U.S. have AMD, according to the BrightFocus Foundation, a nonprofit that funds research into macular degeneration, glaucoma and Alzheimer's disease. As the population ages, the prevalence of AMD is rising, and the foundation estimates 22 million Americans will have the disease by 2050.

Promising trials

Dry AMD occurs when parts of the eye's macula -- which is the part of the retina responsible for central, rather than peripheral, vision -- thin with age and protein deposits known as drusen accumulate in the retina. This leads to the death of photoreceptors and causes a gradual loss of central vision. People with advanced dry AMD cannot do things like read a book, recognize faces or drive a car.

The wet form of AMD, which is usually preceded by the dry form, is less common but more serious. In wet AMD abnormal blood vessels leak blood and fluid into the macula, causing scarring, the death of photoreceptors and eventually total blindness.

Scientists are uncertain of the initial causes of AMD but have recently discovered an association between AMD and hyperactivity in a part of the immune system known as the complement system. Apellis Pharmaceuticals is testing pegcetacoplan, a complement-inhibiting peptide that in Phase 2 trials of 246 participants was injected into the eye monthly or every other month. The drug significantly slowed the progression of the advanced stage of dry AMD, which is also referred to as geographic atrophy.

"Pegcetacoplan has been a very exciting result in the field," says Catherine Cukras, director of the Medical Retina Fellowship Program at the National Eye Institute, a division of the National Institutes of Health. Dr. Cukras wasn't involved in the pegcetacoplan studies. "It really has been the first trial to meet that primary endpoint of reducing the growth of geographic atrophy," she says. Apellis is now enrolling patients for a Phase 3 trial for pegcetacoplan.

Iveric Bio has completed a pivotal trial with its own complement-inhibiting drug, Zimura, which also demonstrated success in slowing the growth of geographic atrophy. A Phase 3 trial is planned.

Stem-cell studies

Other researchers have been experimenting with stem-cell therapies for AMD for close to a decade. Challenges include getting the implanted or injected cells to organize themselves properly in the eye, overcoming the immune response to foreign cells, eliminating the risk of a cancerous cell mutation and developing a manufacturing process that can work on a large scale. There is no FDA-approved stem-cell treatment for AMD.

Now, researchers at the National Eye Institute are preparing to test a stem-cell therapy in humans that marks a new approach to those challenges. It will be the first clinical trial in the U.S. to generate retinal cells from a patient's own cells rather than from embryonic stem cells, which bring ethical complications and an increased risk of tissue rejection.

It will also be the first to grow those cells on a biodegradable scaffold that enables the cells to grow in a single layer, which replicates their natural formation in the back of the eye. It is believed that this single-layer form, which will be transplanted into the eye, will be more successfully integrated into the eye than cells that are simply injected and must figure out where and how to arrange themselves. The scaffold will disappear after the transplant.

"We start with a patient's own blood cells," which are used to create so-called pluripotent stem cells, says lead researcher Kapil Bharti. Pluripotent stem cells can be converted into various types of cells, in this case retinal cells.

In preclinical trials, the therapy restored vision in pigs and rats.

"People will be watching this trial very carefully and with great excitement," says Peter McDonnell, director of the Wilmer Eye Institute at Johns Hopkins University. Dr. McDonnell isn't involved in the trial.

Dr. Bharti's team will be growing and transplanting a patch of retinal pigment epithelial cells. RPE cells nurture the eye's photoreceptors. Ultimately, researchers hope that the new RPE cells will rejuvenate dying photoreceptors. But this clinical trial will primarily be a test of the safety and integration of the patch. Efficacy may be difficult to ascertain, because the 12 patients in the trial will have very advanced forms of dry AMD, so they may not have any photoreceptors left to revive. "If the patch does change something in the vision, that would be a home run," says Dr. Bharti.

"This is not going to be a fast thing, but we are certainly moving in the right direction," says Dr. McDonnell.

Currently it takes six months to make one patient's retinal patch, but Dr. Bharti's team is hoping to shorten that time by automating cell production in new ways. They have developed an artificial-intelligence-based method of testing the integrity of the cells in the retinal patch that measures things like the shape and light absorbency of its cells to confirm that the stem-cell-derived tissue functions similarly to the patient's native tissue and will likely be a successful transplant. They are also planning robotic production that would enable one technician to make patches for as many as 20 patients simultaneously, rather than the current one at a time.

Ultimately, universal pluripotent-stem-cell derived cell types that aren't rejected by patients' immune systems might eliminate the need to make a unique patch for each patient, but the potential for that isn't clear. Pluripotent stem cells that could be tested for this purpose are currently being produced through genetic engineering of existing pluripotent stem cells by private companies. Dr. Bharti suspects that within six years we will have some evidence from early-phase human studies of whether universal pluripotent-stem-cell lines would provide an "off-the-shelf" RPE patch that works in every patient.

Injections and genes

New approaches are also being explored to improve on the existing treatment for wet AMD. For more than a decade, patients with wet AMD have been treated successfully with eye injections that block the development of leaky, abnormal blood vessels. The trouble is that most patients need the injections monthly, which is costly and can be difficult for aging patients, who often can't drive and may have other health complications that can throw them off schedule. "When they miss appointments, the disease reactivates," says Peter Campochiaro, professor of ophthalmology at the Wilmer Eye Institute.

The inconvenience and cost of monthly injections has motivated researchers to look for treatments that provide longer-term relief. One new injectable therapy, Beovu from Novartis, lasts as long as 12 weeks in some patients following three months of monthly injections. Like current therapies, it works by blocking VEGF, a protein that promotes the creation of new blood vessels.

Genentech has completed a Phase 3 clinical trial with an even longer-term solution. It's a tiny device known as a port delivery system, or PDS, that is surgically implanted into the wall of the eye and slowly releases the anti-VEGF medication into the eye. Like a gas tank, the PDS can be refilled when it is nearly empty of medicine. In the Phase 3 clinical trial with a customized formulation of Genentech's anti-VEGF medication Lucentis, patients were able to go six months without needing a refill.

Meanwhile, gene therapy offers the possibility of a lifelong solution. "Retinal gene therapy looks very promising right now," says Dr. Dunaief. At least two groups of U.S. researchers have completed Phase 1 gene-therapy trials for wet AMD using a harmless virus called adeno-associated virus to deliver genes into the eye that encode VEGF antibodies.

The Phase 1-2 trial (a single trial gathering data relevant to both safety and efficacy) for Regenxbio's RGX-314 showed particularly strong results. The trial included 42 patients receiving a variety of doses administered through a surgical procedure. "At the highest dose cohort, eight out of 11 patients no longer needed any injections," says Dr. Campochiaro, a researcher on the trial. Two years after the injection, levels of the VEGF antibody produced by the gene hadn't diminished, and patients at the highest dose cohort have experienced an improvement in their vision in six months. Regenxbio plans to begin Phase 3 trials of RGX-314 this year.

Patients and their doctors are eager for new solutions for AMD. "Cataracts we can fix," says Dr. McDonnell. "Seeing people develop AMD just when they've retired and are ready to enjoy life is heartbreaking for ophthalmologists and devastating for patients."

Ms. Oliver is a writer in New York. She can be reached at reports@wsj.com. 



  Corrections & Amplifications


  This item was corrected at June 10, 2020 to show that a Phase 1-2 trial of Regenxbio's RGX-314 gene therapy for age-related macular degeneration, levels of an antibody produced by the treatment, which blocks a protein that causes AMD, hadn't diminished in one patient group two years after injection of the drug, and patients at the highest dose cohort experienced an improvement in their vision six months after injection. Also, Regenxbio now plans to begin Phase 3 trials of RGX-314 this year. An earlier version misstated the time frame as 18 months, omitted that the time frame for improved vision in the highest dose cohort, and incorrectly said that the company planned to start Phase 3 trials by early next year.