Subspecialty News

Danger of driving with blind spots; Pill for dry AMD advances; What’s next in wet AMD therapy? And more.


What’s Next in Wet AMD Therapy?

Combination drugs show great promise.


■ For most of the past decade, anti-VEGF therapies for treating wet AMD and other retinal diseases have held center stage, hailed as great advances and far more effective than any drug or procedure previously available.

But now, a growing opinion suggests that anti-VEGF monotherapy — as important as it has proven to be — will eventually be viewed as only an intermediate step in the ongoing fight to combat retinal disease.

While anti-VEGF drugs have improved the vision and quality of life for hundreds of thousands of patients with retinal disease, these drugs do have some shortcomings. Patients and retinal specialists understandably chafe under the treatment burden that regular anti-VEGF intravitreal injections entail. In addition, some patients are not responsive to anti-VEGF therapy.

Given that opportunities exist to improve upon anti-VEGF monotherapy, numerous efforts are under way to find better drugs or less-invasive delivery systems. In the investigational pipeline for wet AMD are such concepts as pills, eye drops, sustained-release delivery systems, radiation treatments (NeoVista and Oraya) and other innovative drug-development efforts too numerous to mention here.

But in terms of what new therapies are deemed most promising, early-stage clinical trials have shown that combination drugs may have the best chance of early approval. Three combinations worth mentioning are:

► Ophthotech’s anti-platelet-derived growth factor (pdgf) drug Fovista in combination with ranibizumab has shown excellent results in a phase 1/2a clinical trial of 22 patients who were not responsive to anti-VEGF monotherapy. In a large phase 2 study encompassing 449 patients, investigator Pravin Dugel, MD, reported a combination of Fovista and ranibizumab was 62% more efficacious than ranibizumab monotherapy.

► Allergan’s DARPin (designed ankyrin repeat proteins) drug, developed along with partner Molecular Partners, showed efficacy in treating wet AMD as monotherapy in a phase 2a study. The priority now is to combine the DARPin with an anti-pdgf developed by Molecular Partners in a dual-acting combination therapy. The DARPin is also being tested in combination with ranibizumab.

► Allegro Ophthalmics’ integrin peptide (ALG-1001) is designed to shut off VEGF production at its source. The drug showed good efficacy in a small study of DME patients and will be used in a phase 1b/2a trial as monotherapy to treat wet AMD.

The excellent results demonstrated thus far by Fovista, the DARPin and ALG-1001 appear to indicate that a next-generation of combination drugs to combat retinal disease may be just over the horizon.


■ Stem cells for myopic macular degeneration. The University of California, Los Angeles (UCLA) Geffen School of Medicine has received FDA approval of its Investigator Investigational New Drug Application to initiate a phase 1/2 study using Advanced Cell Technology’s retinal pigment epithelial (RPE) cells derived from human embryonic stem cells to treat myopic macular degeneration.

The trial, led by Steven Schwartz, MD, will enroll a total of 12 patients, with cohorts of three patients in an ascending dosage format. The trial is a prospective, open-label study designed to determine the safety and tolerability of human embryonic stem cell-derived RPE cells following subretinal transplantation into patients with myopia at 12 months, the study’s primary endpoint.

Study of Stargardt Disease planned. The Foundation Fighting Blindness Clinical Research Institute is launching a natural history study of people affected by Stargardt Disease, which includes approximately 30,000 people in the United States. Known as ProgStar, the study has three primary goals: determine the best outcome measures to accelerate evaluation of emerging treatments; better understand disease progression for selecting future clinical trial participants; and identify potential participants for forthcoming clinical trials.

The study, taking place in nine locations worldwide, will combine both prospective and retrospective analyses. The prospective portion, for which physicians will track the progression of disease in participants, will last two years. Physicians will also retrospectively analyze disease progression by reviewing the participants’ past medical records.

Pill for Dry AMD Advances

Emixustat enters large phase 2/3 study.


■ Acucela’s drug emixustat (formerly known as ACU-4427) has entered a phase 2/3 trial for the treatment of dry AMD. If successful, it will be the first drug so approved. Moreover, as a once-a-day pill with an excellent safety profile, it promises to be a convenient therapy with very high compliance.

The search for a medical treatment for dry AMD has been difficult, says trial investigator Philip J. Rosenfeld, MD, PhD, of Bascom Palmer Eye Institute in Miami, in part due to the complexity and slow progression of the disease, the absence of bone fide animal models, the lack of validated clinical trial endpoints, and the different treatment strategies that have arisen as a result of competing theories on etiology of the disease.

“There are many different scientific schools of thought when it comes to explaining the underlying cause of AMD,” Dr. Rosenfeld says. “There is irrefutable scientific evidence to support each of the different theories, yet there are gaps and inconsistencies in each of the disease-causing scenarios, which suggests that we don’t have a single disease mechanism that can be attacked. Rather, multiple mechanisms are likely involved, probably at different stages of the disease.”

While emixustat targets and modulates the visual cycle of rod photoreceptors by inhibiting the enzyme RPE65, which is responsible for the isomerization of all trans-retinyl esters to 11-cis-retinol, the end result is the downregulation of rod photoreceptor metabolic activity and the decreased accumulation of toxic byproducts within the RPE cells. These toxic fluorophores result from the retinyl esters trapped in the outer segments.

Moreover, the downregulation of photoreceptor metabolic activity should result in a reduction in energy and oxygen utilization, decreases in the turnover of rod outer segments and RPE phagocytosis of outer segments, a lower metabolic profile, and most likely, a lessening in the large amount of lipid trafficking required for the rapid turnover of these to cellular membranes.

“In essence, emixustat puts the retina and RPE in hibernation while still permitting the cone visual cycle to function so that good vision can be maintained,” Dr. Rosenfeld says. “Since most geographic atrophy arises in the region of the macula, where rod photoreceptors predominate, it stands to reason that emixustat could very well slow the progression of geographic atrophy and preserve central vision.”

In addition, Dr. Rosenfeld says if emixustat can downregulate these activities, potential exists for the use of the drug in wet AMD, as well as in preventing conversion of dry AMD into the wet form of the disease.


Allegro moves ahead on two studies. Allegro Ophthalmics says it has completed enrollment of its phase 1b/2a study in wet AMD in addition to beginning its second diabetic macular edema (DME) trial. This second DME study is masked and will determine the additional clinical benefit of therapy with ALG-1001 (Integrin Peptide Therapy) in combination with bevacizumab (Avastin) versus bevacizumab alone. The wet AMD trial is a dose-ranging, monotherapy study with a primary endpoint of safety and a secondary endpoint of improvement in both BCVA and OCT central macular thickness.

According to the DME Study design, 30 subjects will be divided into three groups. Two groups will receive four monthly intravitreal injections of Avastin plus ALG-1001 (at two different doses of ALG-1001). The third group will receive four monthly intravitreal injections of Avastin and a sham injection. After the four monthly injections, the subjects will be observed for 30 days off-treatment for a total 120 days of observation.

ALG-1001 is a small molecule and a crucial agent in Integrin Peptide Therapy, a newly developed approach to treating vascular eye diseases. Allegro says by utilizing a small molecule discovered by the company’s founders in collaboration with The California Institute of Technology, Integrin Peptide Therapy uniquely approaches these indications by collectively turning off the production of aberrant blood vessels, reduces the leakage of aberrant blood vessels and inhibits the growth of aberrant blood vessels. Allegro says this novel approach has the potential to be both an effective stand-alone treatment as well as a complement to existing standard of care due to its unique mechanism of action.

Danger of Driving With Blind Spots

AMD patients fail simulator test.

■ A study using a simulator and testing the driving ability of AMD patients with central vision loss against individuals with normal vision showed that patients with blind spots can be a major danger on the roadways. The research, led by Matthew Bronstad, PhD, of the Harvard Medical School, appeared in the January 17 online edition of JAMA Ophthalmology.

The researchers set out to determine how central field loss (CFL) affects reaction time to pedestrians. They also wanted to test the hypothesis that scotomas lateral to the preferred retinal locus will delay detection of hazards approaching from that side. In the United States, individual states do not test drivers for central blind spots, although this type of testing is done in the United Kingdom and other countries in Europe.

Eleven participants with binocular CFL (scotoma diameter, 7°-25°; visual acuity, 0.3-1.0 logMAR) using lateral preferred retinal fixation loci and 11 matched controls with normal vision drove in a simulator for approximately 90 minutes per session for two sessions a week apart. Participants responded to frequent virtual pedestrians who appeared on either the left or right sides and approached the participant’s lane on a collision trajectory.

The CFL participants had more detection failures for pedestrians who appeared in areas of visual field loss than did the controls in corresponding areas (6.4% vs 0.2%). The CFL participants reacted more slowly to pedestrians in blind than non-scotomatous areas (4.28 vs 2.43 seconds) and had far more late and missed responses than controls (29% vs 3%). Scotoma size and contrast sensitivity predicted outcomes in blind and seeing areas, respectively. Visual acuity was not correlated with response measures.

The researchers concluded that in addition to causing visual acuity and contrast sensitivity loss, the central scotomas delayed hazard detection even though small eye movements could have potentially compensated for the loss. Responses in non-scotomatous areas were also delayed, although to a lesser extent, possibly because of the eccentricity of fixation.


Bronstad PM, Bowers AR, Albu A, Goldstein R, Peli E. Driving with central field loss I: effect of central scotomas on responses to hazards. JAMA Ophthalmol. 2013;131:303-309.


Oraya radiation treatment for wet AMD. Oraya Therapeutics’ Intrepid study has shown positive results in the first sham-controlled double-masked trial to evaluate the effectiveness and safety of a one-time radiation therapy in conjunction with as-needed anti-VEGF injections for wet AMD.

A total of 21 sites in five European countries participated in the trial with a total enrollment of 230 subjects. Timothy L. Jackson, PhD, FRCOphth, King’s College Hospital, London, lead investigator, reported the trial achieved its primary endpoint demonstrating a statistically significant reduction in as-needed injections after one year. The actively treated patients required approximately 35% fewer injections than the sham group with similar or in some cases, better visual acuity outcomes. No radiation-related adverse events were experienced at the one-year endpoint; including 60 subjects already at two-year follow up. In addition, a defined population subgroup comprised of roughly half of the study participants experienced even lower injection rates while exhibiting meaningful vision benefit compared to sham.

Noted British author Jonathan Gathorne, who participated in the Intrepid trial, reported that he has experienced sustained vision improvement for more than two years after being treated in his right eye without any additional anti-VEGF injections.

Jetrea is approved by the EU. ThromboGenics NV said the European Commission has approved Jetrea (ocriplasmin) in the European Union. Jetrea is approved for the treatment of vitreomacular traction, including when associated with macular hole of diameter less than or equal to 400 microns. Jetrea was approved by the FDA in October of 2012.

Novartis (Alcon) purchased the rights to market Jetrea internationally from ThromboGenics while ThromboGenics retained the US rights and has recently launched the drug in the United States.

Dr. Shields receives national honor. Jerry A. Shields, MD, director of the Wills Eye Ocular Oncology Service, has received The National Physician of the Year Award in Clinical Excellence for his contribution to ophthalmology.

For 40 years, Dr. Shields has diagnosed and treated countless patients with ocular tumors and has led clinical research to improve methods for the diagnosis and treatment of eye cancers, including tumors of the eyelids, conjunctiva, intraocular structures, and orbit. RP