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. Eighteen months 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. Regenxbio plans to begin Phase 3 trials of
RGX-314 by early next 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.”
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