This month, we’ll review the highlights of the meeting in various areas of vision research. (Unless otherwise specified, all of the abstract citations are from this year: IOVS 2013;54.)
The scientific headliner of this year’s meeting was the AREDS2 trial,1 the second part of the Age-related Eye Disease Study. AREDS2 examined modifications to the vitamin formulation that AREDS had established as a valuable preventative approach for patients at risk for age-related macular degeneration. This five-year study included 4,203 participants randomized to receive: 1) 10 mg lutein + 2 mg zeaxanthin; 2) 350 mg DHA + 650 mg EPA; 3) lutein + zeaxanthin and DHA + EPA or 4) placebo. All participants also took either the original AREDS formulation or were randomized to AREDS variations (no beta carotene, reduced zinc or both).
There were no significant differences in disease progression in the four major treatment groups. The probability of progression to advanced AMD was 31 percent in the placebo group, 29 percent in the lutein + zeaxanthin group, 31 percent in the DHA + EPA group and 30 percent in the lutein + zeaxanthin and DHA + EPA group. There was also no significant difference between the two zinc concentrations tested. One subgroup, consisting of patients receiving lutein + zeaxanthin and no beta-carotene, saw an 18-percent reduction in the risk of progression to advanced AMD when compared to those who took AREDS with beta-carotene (and no lutein + zeaxanthin). Study authors also noted that this replacement of beta carotene in the original formulation with lutein + zeaxanthin reduced the risk for lung cancer in ex-smokers.
Models, Methods, Endpoints
A key aspect of therapeutic development is the refinement and optimization of methods for patient inclusion in studies and disease assessment. Ocular inflammation is an area of active effort, and many presenters reported on their attempts to improve protocol design, symptom evaluation or both.
Investigators from our research firm, Ora, used modifications to the traditional conjunctival allergen challenge protocol to elicit a more chronic, inflammatory conjunctivitis that may be a means for developing treatments for chronic allergy. (Gomes P, et al. ARVO E-Abstract 2555) Other refinements included updated protocols for fluorophotometry and conjunctival staining. (Heckley C, et al. ARVO E-Abstract 6043; Lane K, et al. ARVO E-Abstract 6045) The optimization of fluorometric measures of tear turnover was particularly intriguing, because the authors were able to show a significant correlation between this sign of dry-eye disease and the Ocular Surface Disease Index symptomatology scale, a noteworthy accomplishment for clinical studies of this disease.
Advances in ocular surface microscopy was a dominant topic, as well. Studies of corneal nerve morphology by in vivo confocal microscopy demonstrated the utility of enhanced ocular surface imaging, both as a potential diagnostic tool and as a potential therapeutic endpoint. (Sanchez Dalmau BF, et al. ARVO E-Abstract 530; You JY, et al. ARVO E-Abstract 531) Other presentations focused on IVCM-based advances in limbal morphology and on inflammatory cell infiltration of the conjunctival vasculature. (Baclagon ER, et al. ARVO E-Abstract 537; Angeli E, et al. ARVO E-Abstract 2557)
A big topic in clinical methodology for ocular inflammation was the measurement of biomarkers of disease with a focus on those found in tears. A number of groups reported efforts to identify both normal and pathological values for cytokines in tears. (Hagan S, et al. ARVO E-Abstract 955; Enriquez-De-Salamanca A, et al. ARVO E-Abstract 2072; Dionne K et al. ARVO E-Abstract 4324; Lakshman N et al. ARVO E-Abstract 4325) While there were some disagreements on the quantitative aspects of these studies, it’s clear that the technology to accurately measure picogram quantities of signaling molecules including IL-2, IL-6 and IL-8 is here, and such measurements will become an increasingly important aspect of diagnosis going forward.
Biomarker assessment was not limited to cytokine studies, and other presentations described quantification of other potential indicators or predictors of ocular disease. One study provided evidence that several micro RNAs associated with retinal degeneration can be detected in systemic circulation, and so may ultimately function as biomarkers for retinal disease. (Peng Q, et al. ARVO E-Abstract 1947) These short-chain nucleic acid molecules function as regulators of gene transcription in a tissue-specific manner. The potential importance of miRNAs (particularly miRNA-96 and miRNA-124) was confirmed in other presentations examining the role of these molecules in retinal degeneration. (Langmann T, et al. ARVO E-Abstract 4517)
There were a number of presentations that provided new insights on the measures used to assess blink rates and the importance of considering lid contact time to differentiate between normal and dry-eye subjects. (Johnston P, et al. ARVO E-Abstract 967; Lafond A, et al. 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. ARVO E-Abstract 970)
Mucin function in dry eye was also the subject of multiple presentations. One presentation found that as the signs of dry eye worsen, soluble MUC16 values increase. (Watson M, et al. ARVO E-Abstract 4309) Another study used a polymerase chain reaction-based measure of MUC5A expression to screen for goblet cells in patients with limbal cell deficiency. The goal of this study was to correlate loss of this key cell type with disease severity. (Suarez-Cortes TM, et al. ARVO E-Abstract 547)
Ora presented novel data on the use of software analysis for the evaluation of corneal superficial punctate keratitis, an important primary endpoint for dry-eye trials. (Rodriguez J, et al. ARVO-E Abstract 4341) Clinical grading, typically based on a 0-to-4 point scale, poses many challenges, such as inefficiencies in reproducibility, accuracy, subjectivity and sensitivity. In a population of 665 dry-eye subjects, the software-based approach generated accurate, efficient quantification of corneal desiccation. An automated approach is useful in standardizing the SPK evaluation process and allows for clear identification of improvement due to therapeutic intervention. Automation may not be applicable in every situation, however. In another study, comparison of software-based analysis of hyperemia grading showed that while this approach may be useful for dry-eye studies, confounding factors in allergic hyperemia (such as chemosis) preclude the use of automated redness analyzers. (Raval Y, et al. ARVO E-Abstract 2553)
Dry eye is a disease that involves a range of functional tests of tear film stability, but despite this it’s still not clear which tests are best. One group sought to address this topic by calculating the correlations of dry-eye signs to signs, symptoms to symptoms, and both signs and symptoms to objective tests of tear-film stability. Contrary to many other reports, the authors reported that many signs and symptoms correlate with quality-of-life variables. In addition, they found a stronger correlation between tear turnover rate and symptoms than that seen between Schirmer’s tests and symptomatology. Lid variables, however, correlated in unexpected ways, and the authors suggest that compensatory mechanisms may underlie these findings. (Saigal S, et al. ARVO E-Abstract 4361)
Retina, Glaucoma and Dry Eye
In addition to the preclinical presentations, ARVO always presents a good opportunity to see what may be in the pipeline of new therapeutics. We came across a number of interesting posters throughout the week, including some on Thursday, the last day of the meeting. Just in case you weren’t able to stick around through the end of the week, we’ll provide a recap here, as a number of the “best-in-show” posters were presented on ARVO’s final day.
A group of investigators, one of whom is an employee for Aerpio Therapeutics (Cincinnati, Ohio) provided in vitro and in vivo data on the company’s drug AKB-9778. (Shen J, et al. ARVO E-Abstract 6094) The researchers confirmed its bioactivity as a potent and selective small molecule inhibitor of vascular endothelial-protein tyrosine phosphatase. The VE-PTP enzyme, also known as human protein phosphatase β or HPTBβ, is a negative regulator of the Tie2 receptor, which is expressed on vascular endothelial cells and plays a key role in stabilizing blood vessels. Inhibition of VE-PTP restores Tie2 signaling, reducing vascular leak and pathologic neovascularization. In the study, the researchers note that, in vitro, “AKB-9778 promoted phosphorylation of Tie2, enhanced angiopoietin (Ang)-1 induced Tie2 phosphorylation, and stimulated phosphorylation of signaling molecules in the Tie2 pathway.” In vivo, AKB-9778 also induced phosphorylation of Tie2. While AKB-9778 is initially being developed for diabetic macular edema, vascular stabilization may also provide benefits for a wide variety of disease states. Aerpio initiated a Phase Ib/IIa trial of AKB-9778 for the treatment of DME in September 2012.2
The agent ALG-1001 is being investigated in several vascular eye diseases including wet AMD, DME and symptomatic vitreomacular adhesion. ALG-1001 is a new small-molecule oligopeptide that targets multiple integrin receptor sites that play key roles in cell signaling and regulating cellular shape, motility and the cell cycle. Interim data on the Phase Ib/IIa dose-ranging, monotherapy study of the drug in wet AMD was presented at this year’s ARVO.3 (Kaiser P, et al. ARVO-E Abstract 2177) In the first human study of the agent, the drug appeared safe and well-tolerated and a treatment effect lasted longer than four months off-treatment. There was also a robust response in the 3.2-mg dose group of at least three months off-treatment in all subjects. A demonstrated mean best-corrected acuity improvement of eight letters as measured by ETDRS in this group corresponded to a 30-percent decrease in central macular thickness and improvement in retinal architecture.
Monday’s retina posters included a meta analysis of ranibizumab safety data in patients with AMD, retinal vein occlusion or DME. (Avery RL, et al. ARVO E-Abstract 1535) The analysis pooled 22 Phase II, III and IIIb studies and included 10,300 patients with a mean follow-up time of 15.9 months. In the analysis, patients with DME showed higher mortality rates and a greater rate of wound healing complications than those with either AMD or RVO. No other patterns of systemic disease emerged from the study.
The treatment landscape for vitreomacular adhesions changed when ocriplasmin (Jetrea; Thrombogenics NV, Leuven, Belgium) was approved by the FDA in 2012.3 This recombinant protease targets vitreous proteins, resulting in degradation and enzymatic vitrectomy. A Phase III study sub-analysis examined the efficacy of ocriplasmin in patients designated as clinical candidates for traditional vitrectomy. (Kuppermann BD. ARVO E-Abstract 1942) Patients were evaluated for VMA resolution 28 days after injection of either ocriplasmin or placebo. In patients with full-thickness macular hole, closure was also assessed at 28 days. Overall, 33.2 percent of eyes treated with ocriplasmin achieved VMA resolution as compared with 11.5 percent (p=0.001) of those treated with placebo; in patients with a baseline FTMH, these rates were 50 percent and 25.5 percent (p=0.006), respectively. In addition, the study doctors report that FTMH closures were seen in 40.6 percent of the ocriplasmin-treated group as compared to 10.1 percent in the placebo group.
Building off data presented at last year’s ARVO (Van de Velde S, et 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), Amakem Therapeutics (Diepenbeek, Belgium) presented new preclinical data on its lead drug candidate, 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. ARVO E-Abstract 5631) The data demonstrated that AMA0076 elicited a sustained, 24-hour effect on lowering intraocular pressure, an effect not seen with Y-39983. Additionally, hyperemia was observed with Y-39983 at all concentrations, whereas only mild hyperemia was observed with the highest concentration (0.4%) of AMA0076. Looking ahead, Amakem initiated a Phase IIa proof-of-concept, placebo-controlled, dose-escalation study of topical AMA0076 in September 2012.
Data implicating β-Amyloid in the pathology of glaucoma, as analyzed via levels of β-Amyloid in human glaucomatous retinas in comparison to healthy subjects, set the stage for MRZ-99030 (Merz Pharmaceuticals; Frankfurt, Germany), a β-Amyloid aggregation modulator. (von Thun und Hohenstein-Blaul N, et al. ARVO E-Abstract 1139) Merz researchers found that the topically administered drug significantly reduced retinal ganglion cell apoptosis in a rodent model of glaucoma compared to vehicle control in a dose-dependent manner. (Gravius A, et al. ARVO E-Abstract 2625)
Multiple abstracts from Japan’s Ono Pharmaceuticals highlighted ONO-9054, an isopropyl ester derivative of the free acid ONO-AG-367 classified as a dual FP/EP3 receptor agonist that may be effective in lowering intraocular pressure. (Tomohiro K, et al. ARVO E-Abstract 766; Karakawa T, et al. ARVO E-Abstract 1998) In dogs and monkeys, the IOP-lowering effects of ONO-9054 were more potent and longer-lasting than the effects produced by an FP receptor agonist (latanoprost), a beta-adrenergic receptor antagonist (timolol) and a fixed combination of the two. (Nagai K, et al. ARVO E-Abstract 1986) In a double-masked study of 48 healthy volunteers, ONO-9054 was well-tolerated and there were no apparent dose-related responses in any systemic or local tolerability parameters. (Rowe-Rendleman C, et al. ARVO E-Abstract 440)
Also targeted to treat ocular surface orders such as dry eye, EBI-005 is a potent IL-1R1 inhibitor. Eleven Biotherapeutics (Cambridge, Mass.) 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 when administered three times daily. (Goldstein M, et al. ARVO E-Abstract 4319) The positive results of the Phase 1a study prompted a Phase 1b study in patients with dry eye. Eleven also presented preclinical toxicology data demonstrating that EBI-005 was well-tolerated in both mouse and rabbit. (Furfine E, et al. ARVO E-Abstract 4320)
Preclinical 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 in a study from Ora. (Whitlock A, et al. ARVO E-Abstract 902) The same compound also showed promise in an Ora preclinical study of allergic conjunctivitis, so we’re likely to see additional studies of cis-UCA in the future. (McLaughlin J, et al. ARVO E-Abstract 2554)
An interesting wrinkle in the therapeutic development paradigm was described by two poster presentations on the efficacy of low-dose brimonidine as an eye-whitener. (Chapin MJ et al. ARVO E-Abstract 2556; Horn G et al. ARVO E-Abstract 5451) (One of the presenters is the patent holder for this use of brimonidine.) The re-purposing of this anti-glaucoma agent provides a great example of how clinicians may be the best untapped resource in the drug development landscape. It also reminds us why we like the ARVO meeting: It represents a unique opportunity for clinicians and scientists to rub elbows, share ideas and move ocular therapeutics forward. REVIEW
Dr. Abelson is a clinical professor of ophthalmology at Harvard Medical School.
1. Age-Related Eye Disease Study 2. Lutein + Zeaxanthin and Omega-3 Fatty Acids for Age-Related Macular Degeneration. JAMA 2013;309:19:2005-2015.
2. Safety and Pilot Efficacy of AKB-9778 in Subjects With Diabetic Macular Edema. http://clinicaltrials.gov/ct2/show/NCT01702441?term=AKB-9778&rank=1. Accessed May 29, 2013.
3. A Safety And Efficacy Study Of ALG-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.
4. Approval letter for Jetrea (ocriplasmin) Intravitreal Injection. http://www.accessdata.fda.gov/drugsatfda_docs/appletter/2012/125422Orig1s000ltr.pdf. Accessed May 29, 2013.