ARVO 2017 showcases vision research advances

© Santibhavank P/Shutterstock.comWith the latest in basic and clinical vision science on display at this year’s meeting of the Association for Research in Vision and Ophthalmology (ARVO), a growing interest in presbyopia was apparent.

A mini-symposium on the aging eye discussed the optical and visual trade-offs of lenses and other approaches for presbyopia correction. Guiterrez-Contreras et al. (ARVO E-Abstract 1246) demonstrated the promise of IOLs for restoring accommodation levels of the crystalline lens. Work presented by de Gracia and Hartwig (ARVO E-Abstract 327) showed ways to optimize the optical design of a corneal inlay (Kamra, AcuFocus).

Pharmaceutical therapies for presbyopia were also described, including an eye drop (EV06, Encore Vision). In a phase I/II study, EV06 treatment resulted in significant improvements in distance-corrected near visual acuity when compared with placebo (Korenfeld et al. ARVO E-Abstract 331). A 7-month follow-up demonstrated that the gains in distance-corrected near visual acuity from EV06 persisted for at least an additional 210 days after final exposure to the drug (Stein et al. ARVO E-Abstract 330).

Dry eye products still an ARVO mainstay

One study described a new lubricant eye drop for patients with lipid-deficient tears (Hom et al. ARVO E-Abstract 2671). The eye drop contains lubricant polymers along with omega-3 fatty acids and trehalose. When compared with a marketed eye drop, the investigational drop proved noninferior for symptomatic dry eye relief. Further, subjects using the investigational drop saw significant improvement in corneal and conjunctival staining when compared with the control drops at all follow-up visits.

One exciting topic in the clinical dry eye community at this year’s ARVO was a novel intranasal tear neuro-stimulator (TrueTear, Allergan). This small, handheld device with two slim prongs delivers a small electrical current to sensory neurons in the nasal cavity. This stimulation induces the nasolacrimal reflex, resulting in tear formation. The device was shown to significantly increase tear production in dry eye patients when measured by Schirmer’s test and tear meniscus height measured by optical coherence tomography (OCT) (Orrick et al. ARVO E-Abstract 2692).

In the same study, it was shown that use of the device also significantly increased tear film lipid layer thickness--a finding that may have implications in tear film stability for patients with evaporative dry eye (Watson et al. ARVO E-Abstract 4387).

A separate study analyzed meibomian gland morphology before and after stimulation with the device in subjects with dry eye (Pondelis et al. ARVO E-Abstract 2235). The group used OCT to measure the size of the glands and found that the overall gland area and perimeter were significantly smaller after stimulation. The authors suggest this is due to expression of meibum from the glands--a finding that corroborates the results from the aforementioned Watson study.

Attendees also saw positive results presented from ReGenTree LLC’s ARISE-I phase IIa study evaluating RGN-259 (Thymosin β-4) ophthalmic solution for the treatment of dry eye (Ousler et al. ARVO E-Abstract 2668). This 5-week, multicenter study evaluating 317 subjects in three arms (placebo, 0.05%, and 0.10% RGN259) showed positive results for RGN-259 in ocular discomfort and ocular surface staining over placebo. The 0.05% and 0.10% solutions reduced ocular discomfort on day 28 both before and in patients more symptomatic at baseline, after exposure to a controlled adverse environment. Additionally, subjects in the 0.05% and 0.10% RGN-259 groups with worse tear-film break-up time at baseline saw improved corneal staining scores by the end of the study.

ARVO 2017 also hosted a special interest group where conclusions and recommendations from the Tear Film and Ocular Surface Society Dry Eye Workshop II were presented. The full workshop report should be published later this year.

Allergy and dry eye were also highlighted in a mini-symposium focused on the relation of these conditions to the ocular surface health. Among the presented topics, Andrea Leonardi, MD, of the University of Padua, Padua, Italy, (ARVO E-Abstract 1599) discussed how disruption of cell-cell junctions on the ocular surface is pivotal to the immune response. An analysis of patterns of tissue RNA from the conjunctival surface has provided clues to the underlying etiology of the severe allergic disorder vernal keratoconjunctivis.

Retina research

Retina research

Understanding the course and risk factors of age-related macular degeneration (AMD), as well as evaluating new imaging techniques and clinical endpoints, were hot topics. Drusen deposits and pigmentary changes in the macula-including drusen size-are risk factors for the progression of more advanced forms of AMD. However, the exact role of drusen in the pathogenesis of AMD is not fully understood.

One report (Baratsits et al. ARVO E-Abstract 1579) demonstrated that eyes from early AMD subjects showed a dynamic progression as well as regression of drusen volume, which, surprisingly, occurred simultaneously at different locations within the same retina.

Another group looked for molecular changes in drusen using fluorescence lifetime imaging ophthalmoscopy (FLIO) (Sauer et al. ARVO E-Abstract 3399). This technique distinguishes soft and hard drusen based upon autofluorescence. Using this method, it was possible to differentiate drusen types, distinguishing those in patients with AMD from those of a healthy retina-thus, giving FLIO the potential to provide information on individual risks for the progression to later stages of dry AMD.

In patients with intermediate AMD, the risk and speed of progression to choroidal neovascularization (CNV) or geographic atrophy (GA) is highly variable. A study (Erfurth et al. ARVO E-Abstract 3398) showcased a fully automated machine learning method that was developed to predict individual progression to AMD based on retinal imaging and genetics. Fellow eyes with intermediate AMD from subjects enrolled in the HARBOR trial were used to demonstrate that an automated analysis of OCT biomarkers allowed for a personalized prediction of AMD progression.

A major limitation in the development of novel therapeutic options for AMD has been a lack of sensitive endpoints to evaluate their therapeutic efficacy.

Bagheri et al. (ARVO E-Abstract 3400) carried out a retrospective review of blue auto-fluorescence fundus images, OCT, and Snellen visual acuity in patients with GA due to AMD (18 subjects) in order to understand the relationship between total GA, foveal GA, and visual acuity in AMD. Results suggest the percentage of GA within the fovea may be more sensitive in predicting the degree of visual acuity impairment than the total GA area or foveal involvement. However, further validation is needed in larger cohorts.

Clinical endpoints

The theme of developing sensitive endpoints for the clinical study of retinal degeneration was demonstrated in a number of presentations.

Cocce et al. (ARVO E-Abstract 3765) examined the lack of reliable functional endpoints for proof-of-concept clinical trials in AMD through the evaluation of visual function metrics. This study demonstrated that low luminance visual acuity, mesopic microperimetry with eye tracking, cone contrast test, or dark adaptation may be used as potential functional measures in clinical trials involving patients with early and intermediate AMD.

Other studies explored the use of other visual tests, including critical flicker fusion (Slocum et al. ARVO E-Abstract 2347; Lane et al. ARVO E-Abstract 4714), photostress and photobleach (Rodriguez et al. ARVO E-Abstract 4715), or critical flicker fusion combined with photobleach (Sundstrom et al. ARVO E-Abstract 4713). Each of these methods has the potential to serve as sensitive endpoints for therapies directed at retinal degeneration.

Long-term effectiveness

Long-term effectiveness

While data from clinical trials of VEGF antagonists have demonstrated the effectiveness of these therapies for the treatment of wet AMD, “real-world” data on the long-term effects of treatment are lacking. Several studies at ARVO evaluated the effectives of aflibercept after 3 years of treatment. These studies demonstrated the long-term effectiveness of aflibercept in the treatment of wet AMD after 3 years of treatment (Babalola et al. ARVO E-Abstract 423). However, visual acuity was lower for subjects that did not complete 3 years of treatment (Vig et al. ARVO E-Abstract 411) and longer treatment was need for subjects with persistent disease activity (Eleftheriadou et al. ARVO E-Abstract 874).

A study by Queguiner et al. (ARVO E-Abstract 414) demonstrated that ranibizumab injections were effective for up to 5 years of treatment, raising the question of whether ranibizumab is a more effective treatment than aflibercept for wet AMD.

Interestingly, Gillies et al. (ARVO E-Abstract 896) did a 12-month, head-to-head comparison, looking at visual acuity changes in 394 eyes with wet AMD. There were no significant differences in visual acuity between patients treated with ranibizumab compared with aflibercept for 12 months, suggesting both drugs are effective for wet AMD in real-world clinical practice.

New delivery mechanisms

As current therapies for wet AMD require repeated intravitreal injections of anti-VEGF, numerous presentations at this year’s ARVO focused on new delivery mechanisms-many of which focused on extended-release formulations that would not only reduce patient burden, but also potentially provide improved clinical outcomes.

Owens et al. (ARVO E-Abstract 409) from Envisia Therapeutics demonstrated a proof-of-concept, multi-month release of anti-VEGF from a biodegradable hydrogel matrix (aflibercept) in vitro that was further supported by 3-month release data in non-human primates.

A bio-absorbable hydrogel depot delivery system was also described in a presentation by researchers (Jarett et al. ARVO E-Abstract 1956) from Ocular Therapeutics, but in this case, the device was used to deliver a tyrosine kinase inhibitor.

Parallel studies of this same delivery system demonstrated it could provide 6 months of therapeutic levels of drug treatment for wet AMD using a VEGF-induced retinal leakage model (Elhayek et al. ARVO E-Abstract 1968).

Detecting significant differences

Detecting significant differences

Current endpoints often are not sensitive enough to detect clinically meaningful changes in patient visual function with some retinal diseases, especially in early stages of the disease.

One presentation described development of a portable visual navigation challenge, a maze through which subjects must navigate a marked path with a series of obstacles under homogenous, modifiable lighting conditions (Shapiro et al. ARVO E-Abstract 3290). This device was able to detect significant differences between three cohorts of subjects: those with normal vision, and those with simulated mild or severe retinitis pigmentosa (RP).

Having a portable and effective test that is able to detect differences in visual function due to RP could decrease the cost and time restraints that are often barriers to trials.