SUBSPECIALTY NEWS

What’s Next in Wet AMD Therapy?

Combination drugs show great promise.

BY JERRY HELZNER, SENIOR EDITOR

■ 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.

Pill for Dry AMD Advances

Emixustat enters large phase 2/3 study.

BY ANDREW MATHIS, PHD, MEDICAL EDITOR

■ 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.

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.

REFERENCE:

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.