Laser-sealing eye blood vessels can save central vision, but this often sacrifices peripheral and night vision, according to Akrit Sodhi, MD, PhD, an assistant professor of ophthalmology at the Johns Hopkins University School of Medicine. Bevacizumab, ranibizumab and aflibercept can help treat these blood vessels by blocking the action of VEGF, the growth factor released as part of a chain of signals in response to low oxygen levels, which stimulates the growth of new, often abnormal, blood vessels. But studies have shown that although these drugs slow progression to proliferative diabetic retinopathy, they do not reliably prevent it.
Looking for an explanation, postdoctoral fellow Savalan Babapoor-Farrokhran, MD, and Kathleen Jee, a student at the school of medicine who will begin her residency in ophthalmology at the Wilmer Eye Institute at Johns Hopkins next year, tested levels of VEGF in samples of fluid from the eye taken from healthy people, people with diabetes who did not have diabetic retinopathy and people with diabetic retinopathy of varying severity.
While levels of VEGF tended to be higher in those with proliferative diabetic retinopathy, some of their fluid had less VEGF than did the healthy participants. But even the low-VEGF fluid from patients with proliferative diabetic retinopathy stimulated blood vessel growth in lab-grown cells.
“The results suggested to us that although VEGF clearly plays an important role in blood vessel growth, it’s not the only factor,” Dr. Sodhi says.
A series of experiments in lab-grown human cells and mice revealed a second culprit, a protein called angiopoietin-like 4. When the researchers blocked the action of both VEGF and angiopoietin-like 4 in fluid from the eyes of people with proliferative diabetic retinopathy, it markedly reduced blood vessel growth in lab-grown cells.
If a drug can be found that safely blocks the second protein’s action in patients’ eyes, it might be combined with the anti-VEGF drugs to prevent many cases of proliferative diabetic retinopathy, Dr. Sodhi suggests.
The team is now investigating whether angiopoietin-like 4 might also play a role in other eye diseases, such as macular degeneration.
A summary of the study appeared online May 25 in Proceedings of the National Academy of Sciences.
FDA Allows Aerie Endpoint Change
Aerie Pharmaceuticals reported that the Food and Drug Administration has agreed that Aerie may change the primary endpoint range of its second Phase III registration trial of Rhopressa, named Rocket 2. With this agreement, Aerie is changing the primary endpoint range to include patients with baseline intraocular pressures ranging from above 20 mmHg to below 25 mmHg. The former range for the primary endpoint of above 20 mmHg to below 27 mmHg will now represent a secondary endpoint range for Rocket 2.
The Rocket 2 primary endpoint range is now changed to the same range where the Phase III registration trial results of Rocket 1 demonstrated success. In the Rocket 1 trial, in this range, Rhopressa demonstrated non-inferiority to timolol, and numerical superiority over timolol at the majority of time points. According to the Baltimore Eye Survey, nearly 80 percent of newly diagnosed glaucoma patients have unmedicated baseline IOPs below 26 mmHg.
The FDA also agreed that Aerie may use a hierarchically based statistical approach in determining whether this three-arm trial is adequately powered at the revised primary endpoint range. Using this methodology, Aerie believes that the new primary endpoint range is adequately powered, and there is no need to recruit additional patients into Rocket 2. Three-month efficacy results for Rocket 2 are expected by the end of the third quarter of 2015. An additional Rhopressa Phase III registration trial, named Rocket 4, is expected to commence in the third quarter of 2015.
“We are extremely pleased with the outcome of our communications with the FDA,” said Vicente Anido Jr., PhD, Aerie’s chairman and CEO. “If Rocket 2 results resemble those of Rocket 1, we believe we may have a much greater opportunity for success in meeting the clinical endpoint of non-inferiority to timolol. We are also very appreciative of the thoughtful guidance provided by the FDA, and believe their feedback will prove very useful as our programs progress.” Rocket 4 is expected to be established with a primary endpoint range of above 20 mmHg to below 25 mmHg.
There were originally three Phase III registration trials for Rhopressa. Rocket 1 was a 90-day efficacy trial, with results reported in April 2015; Rocket 2 is a 12-month safety trial with a 90-day interim efficacy readout; and Rocket 3 is a safety-only study being conducted in Canada. In Rocket 1, for the primary endpoint range of above 20 mmHg to below 27 mmHg, Rhopressa did not demonstrate non-inferiority to timolol. However, Rhopressa did demonstrate non-inferiority to timolol at all ranges below 26 mmHg. As a result, Aerie plans to commence in the third quarter of 2015 an additional Phase III registration trial, named Rocket 4. Based on the current clinical trial status, Aerie may submit a New Drug Application filing in the second half of 2016.
Contact Lens Wear May Alter Microbiome
Using high-precision genetic tests to differentiate the thousands of bacteria that make up the human microbiome, researchers at NYU Langone Medical Center suggest that they have found a possible—and potentially surprising— root cause of the increased frequency of certain eye infections among contact lens wearers.
In a study report on their work presented at the annual meeting of the American Society for Microbiology on May 31 in New Orleans, NYU Langone researchers say they have identified a diverse set of microorganisms in the eyes of daily contact lens wearers that more closely resembles the group of microorganisms of their eyelid skin than the bacterial grouping typically found in the eyes of non-wearers.
Specifically, the NYU Langone team found that the conjunctiva has surprisingly higher bacterial diversity than the skin directly beneath the eye and three times the usual proportion of Methylobacterium, Lactobacillus, Acinetobacter and Pseudomonas bacteria in the eyes of the study’s nine contact lens wearers than is typically found on the surface of the eyeballs of 11 other men and women in the study who did not wear contact lenses. When measured and plotted on a graph, statistical germ diversity scores showed that the eye microbiome of contact lens wearers had a composition more similar to that of the wearer’s skin than the eye microbiome of non-lens wearers.
“Our research clearly shows that putting a foreign object, such as a contact lens, on the eye is not a neutral act,” says senior study investigator and NYU Langone microbiologist Maria Gloria Dominguez-Bello, PhD.
“What we hope our future experiments will show is whether these changes in the eye microbiome of lens wearers are due to fingers touching the eye, or from the lens’s direct pressure affecting and altering the immune system in the eye, and what bacteria are suppressed or are allowed to thrive,” says Dominguez-Bello, an associate professor at NYU Langone.
“These findings should help scientists better understand the longstanding problem of why contact-lens wearers are more prone to eye infections than non-lens wearers,” says Dr. Dominguez-Bello, whose research focuses on the different microbiomes of the gut and other body parts, how they interact and how contemporary lifestyle practices may affect the microbiome and increase disease risk. Such understanding, she says, should point to better means of preventing infections.
“There has been an increase in the prevalence of corneal ulcers following the introduction of soft contact lenses in the 1970s,” says study co-investigator Jack Dodick, MD, professor and chair of ophthalmology at NYU Langone. “A common pathogen implicated has been Pseudomonas. This study suggests that because the offending organisms seem to emanate from the skin, greater attention should be directed to eyelid and hand hygiene to decrease the incidence of this serious occurrence,” he says.
As part of the study, researchers took hundreds of swabs of various parts of the eye, including the conjunctiva, as well as along the skin directly beneath the eye. Both swabs and used contact lenses were then subjected to genetic analysis in the lab to determine which bacteria were present.
While the bacterial composition in the eye of contact lens wearers more closely resembled that of the skin, some 5,245 distinct bacterial strains and subtypes were identified in the eye conjunctiva of lens wearers, and 5,592 strains were identified in the eyes of non-lens wearers. A similar but different composition of 2,133 strains and subtypes was identified in the skin directly beneath the eye of those with contact lenses, while 3,849 distinct bacteria were identified in non-lens wearers.
Surprisingly, researchers say, more Staphylococcus bacteria, which are linked to eye infections and more prominent on the skin, were found in the eyes of non-lens wearers, and researchers do not yet have an explanation for the disparity. Estimates vary, but many cases of potentially scarring bacterial keratitis, as well as conjunctival infections, occur in contact lens wearers. REVIEW