ARVO 2013: Sight set on world-class science

Take-home

No matter the setting, world-class science continues to be the focus at the annual meeting of the Association for Research in Vision and Ophthalmology (ARVO).

Seattle-Though the scenic backdrop of the Pacific Northwest at this year’s meeting of the Association for Research in Vision and Ophthalmology (ARVO) may have been different from the traditional Floridian seascape, the meeting’s world-class science continues to be at the forefront.

Much like the anticipated Comparison of Age-related Macular Degeneration Treatments Trials last year, the scientific attraction of this year’s meeting was the results of the Age-Related Eye Disease Study 2 (AREDS2) trial.¹ This 5-year study examining modifications to the original AREDS formulation included more than 4,000 participants, ages 50 to 85 years, who were at risk for advanced age-related macular degeneration (AMD). Although there was no overall benefit from adding omega-3 fatty acids or the antioxidants lutein and zeaxanthin to the original formulation, participants who were treated with both antioxidants without beta-carotene reduced their risk of AMD by approximately 18%.²

Editor’s Note: For further information about AREDS2, see “AREDS gets another look,” Ophthalmology Times, June 1, 2013, Page 1).

Refining methods and best practices

Novel data were presented on the use of software analysis for the evaluation of corneal superficial punctuate keratitis (SPK), an important primary endpoint for dry eye trials (Rodriguez J et al. IOVS 2013;54: ARVO-E Abstract 4341). Although an automated approach is useful in standardizing the SPK evaluation process, it is not necessarily applicable in every situation, or for every disease. In a separate study, a software-based analysis of hyperemia grading showed that confounding factors in allergic hyperemia, such as chemosis, prevent the use of automated redness analyzers (Raval Y et al. IOVS 2013;54: ARVO E-Abstract 2553).

As ophthalmologists and vision scientists learn more and more about the diseases for which they spend their days developing drugs, they also know that refining and enhancing their methods for patient inclusion and disease assessment is an ongoing process. In the allergy arena, modifications to the traditional conjunctival allergen challenge protocol were used to elicit a more chronic, inflammatory conjunctivitis (Gomes Pet al. IOVS 2013;54: ARVO E-Abstract 2555). Other improvements included updated protocols for fluorophotometry (Heckley C et al. IOVS 2013;54: ARVO E-Abstract 6043) and conjunctival staining (Lane K et al. IOVS 2013;54: ARVO E-Abstract 6045).

Additionally, presentation topics ranged from best practices when deciding between blink rate and interblink interval (Johnston P et al. IOVS 2013;54: ARVO E-Abstract967) and the importance of considering lid contact time to differentiate dry eye and normal subjects (Lafond A et al. IOVS 2013;54: ARVO E-Abstract 962). Other presenters examined the relationship between tear meniscus dimensions and other disease measures in subcategories of dry eye and found that in patients with aqueous tear-deficient dry eye and autoimmune disease, lower tear volume is associated with worse corneal epithelial disease (Tung CI et al. IOVS 2013;54: ARVO E-Abstract 970.

The topic of advances in ocular surface microscopy was dominant as well. Studies of corneal nerve morphology (Sanchez Dalmau BF et al. IOVS 2013;54: ARVO E-Abstract 530; You JY et al. IOVS 2013;54: ARVO E-Abstract 531) by in vivo confocal microscopy (IVCM) demonstrated the utility of enhanced ocular-surface imaging. Other presentations focused on IVCM-based advances in limbal morphology (Baclagon ER et al. IOVS 2013;54: ARVO E-Abstract 537) and on inflammatory cell infiltration of the conjunctival vasculature (Angeli E et al. IOVS 2013;54: ARVO E-Abstract 2557).

Emerging treatments for retinal disease

A meta-analysis of ranibizumab safety data in patients with AMD, retinal vein occlusion (RVO), or diabetic macular edema (DME) was also presented (Avery RL et al. IOVS 2013;54: ARVO E-Abstract 1535). The analysis comprised 22 phase II, III, and IIIb studies and included 10,300 patients. After a mean follow-up time of 15.9 months, patients with DME showed higher mortality rates and greater rate of wound-healing complications than those with either AMD or RVO.

A phase III study sub-analysis examined the efficacy of ocriplasmin (Jetrea, Thrombogenics NV) in traditional vitrectomy candidates (Kuppermann BD. IOVS 2013;54: ARVO E-Abstract 1942). Overall, 33.2% of eyes treated with ocriplasmin achieved vitreomacular adhesion (VMA) resolution as compared with 11.5% of those treated with placebo.

In vitro and in vivo data presented on AKB-9778 (Aerpio Therapeutics) confirmed its bioactivity as a potent and selective small-molecule inhibitor of vascular endothelial-protein tyrosine phosphtase (VE-PTP)(Shen J et al. IOVS 2013;54: ARVO E-Abstract 6094). Although the drug is initially being developed for DME, vascular stabilization may also provide benefits for a number of diseases.

ALG-1001, a new small-molecule oligopeptide, is being investigated in a number of vascular eye diseases, including wet AMD, DME, and symptomatic VMA. Interim data on the phase Ib/IIa dose-ranging, monotherapy study targeting wet AMD were presented at this year’s ARVO.^3,4 In this first-in-human study, the drug appeared safe and well tolerated, and a treatment effect was seen to last more than 4 months off-treatment. There was also a robust response in the 3.2-mg dose group of at least 3 months off-treatment in all subjects. A demonstrated mean best-corrected visual acuity improvement of +8 letters as measured by ETDRS in this group corresponded to a 30% decrease in central macular thickness and improvement in retinal architecture.

A look at glaucoma therapies

Amakem Therapeutics presented new preclinical data on its front-runner, the locally acting Rho-kinase (ROCK) inhibitor, AMA0076. In Dutch Belted rabbits, once-daily treatment with AMA0076 resulted in IOP reduction that was more sustained than Y-39983, a non-local ROCK inhibitor (Van de Velde S et al. IOVS 2013;54: ARVO E-Abstract 5631). This data was much anticipated after an abundance of presentations on the drug at last year’s ARVO (Van de Velde Set al. IOVS 2012;53: ARVO E-Abstract 1977; Sijnave D et al. IOVS 2012;53: ARVO E-Abstract 2522; Hollanders K et al. IOVS 2012;53: ARVO E-Abstract 1974).

Data implicating β-Amyloid in the pathology of glaucoma in human glaucomatous retinae in comparison with healthy subjects (von Thun und Hohenstein-Blaul N et al. IOVS 2013;54: ARVO E-Abstract 1139) puts MRZ-99030, a β-Amyloid aggregation modulator, at the forefront of potential glaucoma therapies. In a rodent model of glaucoma, the topically administered drug dose-dependently and significantly reduced retinal ganglion cell apoptosis compared with vehicle control (Gravius A et al. IOVS 2013;54: ARVO E-Abstract 2625).

ONO-9054, an isopropyl ester derivative of the free acid ONO-AG-367, was the focus of several abstracts. The dual FP/EP3 receptor agonist may be effective in lowering IOP (Yamane S et al. IOVS 2013;54: ARVO E-Abstract 766; Karakawa T et al. IOVS 2013;54: ARVO E-Abstract 1998). In a double-masked study of healthy volunteers, ONO-9054 was well tolerated and there was no apparent dose-related responses in any of the tolerability parameters (Rower-Rendleman C et al. IOVS 2013;54: ARVO E-Abstract 440).

Tear film stability and ocular surface disorders

Although there are a variety of assessments for assessing tear film stability, there has been no consensus on which combination of tests should be used to define the dry eye. Saigal et al. presented data on the correlations of dry eye signs to signs, symptoms to symptoms, and both to objective tests of tear film stability. The authors reported the correlation of many signs and symptoms and quality-of-life variables, contrary to many reports that suggest otherwise (Saigal S et al. IOVS 2013;54: ARVO E-Abstract 4361).

Mimetogen presented post-hoc data from a completed trial of MIM-D3 ophthalmic solution, which targets mucin-protective compensatory mechanisms. Patients with greater or more rapid exacerbation of signs and symptoms from the controlled adverse environment were more responsive to MIM-D3 (Ousler G et al. IOVS 2013;54: ARVO E-Abstract 4343). Additional post-hoc analyses support an association between the duration of dry eye and the response to treatment for the reduction in both signs and symptoms (Meerovich K et al. IOVS 2013;54:ARVO E-Abstract 4340).

Eleven Biotherapeutics presented clinical data from a phase I safety study demonstrating that EBI-005 was safe and well-tolerated in normal volunteers at two dose levels (Goldstein M et al. IOVS 2013;54: ARVO E-Abstract 4319). EBI-005 is a potent IL-1R1 inhibitor. Preclinical toxicology data set the stage for success, as it demonstrated that EBI-005 was well tolerated in both mouse and rabbit models (Furfine E et al. IOVS 2013;54: ARVO E-Abstract 4320).

Shifting gears to the up-and-coming notion of re-purposing agents, two poster presentations highlighted the use of low-dose brimonidine as an eye whitener (Chapin MJet al. IOVS 2013;54: ARVO E-Abstract 2556; Horn G et al. IOVS 2013;54: ARVO E-Abstract 5451).

Last, but not least, pre-clinical data on a new topically administered anti-inflammatory, cis-urocanic acid, demonstrated a significant reduction in corneal staining using a murine model of dry eye (Whitlock A et al. IOVS 2013;54: ARVO E-Abstract 902). It also showed promise in a preclinical study of allergic conjunctivitis (McLaughlin J et al. IOVS 2013;54: ARVO E-Abstract 2554).

References

Age-Related Eye Disease Study 2. Lutein + zeaxanthin and omega-3 fatty acids for age-related macular degeneration. JAMA. 2013;309:2005-2015.

NIH study provides clarity on supplements for protection against blinding eye disease. https://web.emmes.com/study/areds2/resources/areds2_press_release_050513.pdf. Accessed May 22, 2013.

A safety and efficacy study of ALF-1001 in human subjects with wet age-related macular degeneration. http://clinicaltrials.gov/ct2/show/NCT01749891?term=ALG-1001&rank=1. Accessed May 15, 2013.

Kaiser P. Integrin peptide therapy: The first wet AMD experience. Paper presented at ARVO 2013; Seattle.

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