ARVO 2012 Gives Florida Our Best

This year’s ARVO meeting in Fort Lauderdale marked the end of an era, as a fixture on the Florida convention calendar begins its nomadic cycle of west coast to east, beginning with next year’s meeting in Seattle. As we bid adieu to the Sunshine State, we look forward to new adventures across the country. Before we go though, here’s a look at some of the best research from this year’s meeting.

Retina Update

Last year saw the release of interim findings from the Comparison of Age-related macular degeneration Treatments Trials, the head-to-head comparison of Avastin and Lucentis for treatment of wet AMD. This year’s meeting opened with a twin bill that included both results from the completed CATT and an interim analysis of results from the alternative treatments to Inhibit VEGF in Agerelated choroidal Neovascularization study.Martin DF, Maguire MG, Fine SL, et al. Ranibizumab and Bevacizumab for Treatment of Neovascular Age-Related Macular Degeneration: Two-Year Results. Ophthalmology May 1, 2012. [epub ahead of print] ,Chakravarthy U, Harding SP, Rogers CA, et al. Ranibizumab versus Bevacizumab to Treat Neovascular Age-related Macular Degeneration: One-Year Findings from the IVAN Randomized Trial. Ophthalmology May 10, 2012 [epub ahead of print] The latter was a head-to-head comparison of the two VEGF monoclonal antibody therapies that employed a four-treatment-arm protocol similar to the one used in the CATT study. Monthly injections of each drug were compared to each other, and to “as needed” treatments arms. The p.r.n. criteria in both studies were the same: Any evidence of fluid, either intraretinal, subretinal or below the retinal pigment epithelium (assessed by optical coherence tomography) was an indication for treatment. As with the interim results from the CATT study, improvement in best-corrected vision was the primary endpoint for the IVAN trial.

Results of the IVAN study mirrored those from the CATT: Acuity changes were comparable for Avastin and Lucentis, and while monthly injections were numerically superior to p.r.n. therapy, the difference wasn’t significant. The IVAN study group also conducted a meta analysis by including one-year data from CATT, again with similar results.

In the second year of the CATT study, a group of subjects receiving monthly treatments were randomized to the p.r.n. regimen, allowing investigators to assess potential effects of switching patients from one injection schedule to another; this protocol design demonstrated that the small benefit accompanying monthly injections is lost when patients transition to p.r.n. dosing. Analysis of secondary endpoints reinforced the notion that there are differences between the two drugs: While the monthly Lucentis group showed the highest percentage of patients without retinal fluid as measured by OCT, this same group also exhibited the highest rates of geographic atrophy.

Ocular Imaging

As in years past, imaging technologies and their applications were ubiquitous at this year’s ARVO meeting, with applications that cover the eye from front to back all on display.

Significant progress has continued in the development of technologies and protocols for ocular surface imaging, and these advances were wellrepresented at this year’s meeting. A major focus was in vivo confocal microscopy, with several poster sessions focusing particularly on corneal imaging methods. One study correlated the density of Langerhans’ cells, an indicator of inflammation, with a course of cyclosporine A in patients with severe keratoconjunctivitis sicca. HRT imaging of the central cornea showed a significant decrease in Langerhans’ cell density following treatment, and this was correlated with tear-film breakup time increases (but not with tear osmolarity or Schirmer’s tests). (Jacobi C, et al. IOVS 2012;53:ARVO E-Abstract 2355) Another group described their use of confocal imaging to assess agerelated changes in normal meibomian glands. They noted two major changes in the glands over time: a decrease in gland density and a decrease in homogeneity of acinar structures and secretions. (Canton V, et al. IOVS 2012;53:ARVO E-Abstract 86) Studies such as these should be useful in distinguishing the natural aging process from pathological conditions associated with meibomian gland dysfunction.

Improvement in imaging technologies has also made its way to the posterior segment, with the use of adaptive optics in combination with other technologies. These technologies are helping us correlate structural changes with visual function, a key step in advancing our understanding of degenerative retinal diseases. New surrogate endpoints for visual acuity based on enhanced imaging should aid in future clinical development programs. For example, adaptive optics scanning laser ophthalmoscopy provides high-resolution images for clear visualization of individual photoreceptor cells, and the high number of retinal imaging abstracts at the 2012 ARVO meeting evidenced the burgeoning interest in this technology. Imaging the retina in real time, AOSLO utilizes adaptive optics to remove optical aberrations from images.

In vivo confocal microscopy of the ocular surface is becoming increasingly popular for following the course of diseases and monitoring treatment. For example, in this image the normal conjunctival vasculature appears on the left. At right, confocal microscopy shows infiltrating white cells in the vasculature following allergen exposure.

In one proof-of-concept study designed to examine whether structural parameters derived from using AOSLO on AMD patients are related to the participants’ AMD disease severity, AOSLO was able to produce high-resolution images. In patients with early to intermediate AMD, the cone photoreceptors showed reduced reflectivity and moderately increased cell spacing, while in patients with an advanced stage of the disease the cone mosaic was severely disrupted, and cone density and reflectivity were significantly decreased compared to that of normal subjects. (Zhang Y, et al. IOVS 2012;53:ARVO E-Abstract 3174) This study opens the door for future research seeking to examine the relationship between the statistical structural parameters of the photoreceptors.

AOSLO was also used to characterize hallmark diabetic retinopathy lesions and then compare the findings with those from fundus photography and spectral domain optical coherence tomography. Microaneurysms were not clearly distinguished from small dot hemorrhages on ETDRS photos and SD-OCT, but some were identified using AOSLO by observing red blood count flow within feeding vessels, as well as by observing red blood count flow within the microaneurysms themselves. AOSLO technology allows for highly detailed in vivo imaging of diabetic retinopathy lesions at the cellular level and is useful for discovering new morphological characteristics of various hallmark pathologies. (Prager G, et al. IOVS 2012;53:ARVO E-Abstract 5654)

Dry Eye

Last year, we noted the growing interest in osmolarity as a test for dryeye disease, and the continued interest in this measure was reflected in many poster and slide presentations at ARVO 2012. Some of these studies were efforts to identify correlations between osmolarity measures and established dry-eye metrics such as corneal staining, Schirmer’s testing, tear-film breakup and information from patient questionnaires such as the Ocular Surface Disease Index or the five-item Dry Eye Questionnaire (DEQ-5). (Bhosai SJ, et al. IOVS 2012;53:ARVO E-Abstract 547; Yang Y, et al. IOVS 2012;53:ARVO E-Abstract 548; See CW, et al. IOVS 2012;53:ARVO E-Abstract 549; Messmer EM, et al. IOVS 2012; 53:ARVO E-Abstract 556; Willmann G, et al. IOVS 2012;53:ARVO E-Abstract 557; Torricelli AA, et al. IOVS 2012;53:ARVO E-Abstract 558) The goal of these efforts was to identify a test or combination of tests that can reliably predict or otherwise be used to diagnose dry eye. From this year’s presentations, it doesn’t seem as though current methods of osmolarity measurement can meet that goal at present. Several presentations reported statistically significant correlations between these measures, while others suggest that associations are insignificant, sporadic or both. The take-home message is a familiar one: As one presenter stated in his conclusion “the clinical presentation of dry-eye disease is multifactorial, thus correlation between different tests should not be expected.” (Sullivan BD, et al. IOVS 2012;53:ARVO E-Abstract 550)

Another study of dry-eye metrics examined diurnal variation in tear osmolarity, and showed that tears are significantly more dilute in the morning (mean 265 mOsms/L) when compared to tears from the same patients measured later in the day (mean 299 mOsms/L). (Niimi J, et al. IOVS 2012;53:ARVO E-Abstract 560) Such variations may contribute to the inability to correlate osmolarity with other dry-eye metrics. Several other presentations examined the potential impact of hyper-osmolarity on ocular surface health: One group reported an effect of hyper-osmolarity on cytokine production (Jeong S, et al. IOVS 2012;53:ARVO E-Abstract 563), while others concluded that although increasingly solute concentrations may alter frictional forces during blink, they don’t seem to have an “adverse effect on physical properties or stability of the tear film,” (Samsom M, et al. IOVS 2012;53:ARVO E-Abstract 551; Mudgil P, et al. IOVS 2012;53:ARVO E-Abstract 555), this suggests that hyper-osmolarity itself isn’t contributing to changes in tearfilm stability of dry-eye patients.

Meanwhile, the search for additional dry-eye therapies continues. Positive data surrounding MIM-D3 as a potential dry-eye therapy was presented by Mimetogen Pharmaceuticals’ Karen Meerovitch, PhD, and her colleagues. MIM-D3 is a proteolytically stable cyclic peptidomimetic identified as a selective TrkA receptor agonist. TrkA receptor agonists are a novel pharmacological class for ocular disease, as nerve growth factor signaling plays a critical role in regulating the proliferation, survival and differentiation of neurons and many other non-neuronal cell types, and is mediated via both the TrkA receptor and the p75NTR receptor. NGF has multiple activities that may be beneficial for dry eye, including neurotrophic effects, corneal healing and mucin secretion. MIM-D3 has demonstrated similar activities to NGF and is under investigation as a pharmacologic agent to stimulate mucin secretion for the treatment of dry eye. In a multicenter, randomized, double-masked, placebo-controlled study utilizing the Controlled Adverse Environment model to assess the safety and efficacy of 1% and 5% MIM-D3 compared to placebo for the treatment of signs and symptoms of dry eye, both doses appeared safe and well tolerated. The study achieved significant improvements in key approvable sign and symptom endpoints, as MIM-D3 minimized the exacerbation of staining post- CAE exposure compared to placebo, and significant improvements were observed for ocular dryness during the 28-day dosing period. A more symptomatic subgroup of patients showed even greater improvements in symptoms compared to placebo for both the 1% and 5% dose. Of the 150 subjects in the safety population, 56 reported a total of 87 treatment emergent adverse events, 26 of which were ocular TEAs; the majority of the ocular TEAs were mild to moderate in severity. (Meerovitch K, et al. IOVS 2012;53:ARVO E-Abstract 578)

The results of the 2011 Antibiotic Resistance Monitoring in Ocular Microorganisms study found fluoroquinolones to be very effective against S. pneumoniae isolates.

Another potential treatment for dry eye includes the use of Thymosin Beta 4. Recent preclinical evaluations have demonstrated that Tb4 promotes improved corneal epithelial intercellular adhesions following injury in animal models of dry eye. (Allan CB, et al. IOVS 2011;52:ARVO E-Abstract 3782) Given that the results from these studies show that Tb4 reduced corneal staining more than positive controls and demonstrated a statistically significant decrease in staining compared to the vehicle group, it was anticipated that RegeneRx Biopharmaceuticals’ RGN- 259 (0.1% Tb4 ophthalmic solution) would be a novel, safe and effective therapeutic treatment for dry eye. In a Phase II study comprising six study visits and using the CAE to assess the safety and efficacy of RGN-259 compared to placebo, subjects receiving the drug saw statistically significant improvements in both the signs and symptoms. (The study was conducted by employees of RegeneRx and other researchers.) There was a statistically significant reduction in central corneal fluorescein staining at visit five from baseline compared to placebo and also a greater reduction in exacerbation of ocular discomfort at visit four during a 75-minute CAE challenge compared to the placebo group. (Sosne G, et al. IOVS 2012;53:ARVO EAbstract 577)

Staff and consultants of Novagali Pharma used a post hoc analysis to evaluate the efficacy of Novagali’s drug Cyclokat (0.1% cyclosporine cationic emulsion) in Sjögren’s syndrome and non-Sjögren’s syndrome patients with moderate to severe dry eye. Sjögren’s syndrome is an autoimmune disorder characterized by lacrimal gland destruction that leads to prominent clinical features of dry eye and dry mouth. The researchers administered the drug q.d. and compared it with its cationic emulsion vehicle. Of the 379 analyzed patients, the improvement in dry-eye symptoms in the Cyclokat group compared to vehicle was greater in both the Sjögren’s and non-Sjögren’s groups and was similar across all levels of dry-eye severity at baseline as defined by corneal fluorescein staining. That being said, non-Sjögren’s patients treated with Cyclokat showed greater improvement in dry-eye symptoms than those with Sjögren’s, supporting the clinical notion that dry eye in Sjögren’s patients is more difficult to treat. (Buggage R, et al. IOVS 2012;53:ARVO E-Abstract 576)

Contact Lenses and Drug Delivery

A topic that’s generating a lot of buzz in ophthalmic circles is that of drug delivery via contact lens wear. With continued growth in technologies of polymer chemistry and manufacture, the contact lens is poised for use in a host of new therapeutic ways. Studies employing lenses for therapeutic use in allergy and dry eye are ongoing, but cutting-edge polymers and other innovations have paved the way for their use in treatment areas such as glaucoma and anti-infectives. Combinations of drug delivery and lenses were a common thread among the presentations at this year’s meeting, including innovative studies such as the investigation of hydrogel lenses molecularly imprinted with hyaluronic acid and timolol maleate. (Guidi G, et al. IOVS 2012; 53:ARVO E-Abstract 458) Another example of novel lens use was a pre-clinical study using lenses as a vehicle for drug delivery of latanoprost for the treatment of glaucoma. Using this approach, researchers were able to show that the lens was more effective at delivery of drug to the anterior chamber over a 14-day period than the control drug, topical latanoprost. (Ciolino J, et al. IOVS 2012;53:ARVO E-Abstract 479) Other innovations in contact lens technology included a poster that described a new hydrogel lens material that was capable of providing a continuous, sustained release of antibiotics. A comparison performed by a researcher and employees of SEED Co., the lens’s maker, showed that lens drug delivery was superior to that of gatifloxacin 0.3% or moxifloxacin 0.5% delivered by drops. (Kobayakawa S, et al. IOVS 2012;53:ARVO E-Abstract 6102)

Anti-Infectives

Another aspect of contact lens use presented this year was a focus on the mechanisms underlying the linkage between poor compliance and the contamination of lenses and lensrelated materials. Classic examples of this association are the recent outbreaks of ocular infections attributed to dangerous pathogens such as Acanthamoeba or Fusarium. One study from AMO determined the comparative rates of Acanthamoeba trophozoite growth on contact lens storage cases by seeding gram-negative bacteria from contact lens cases and Escherichia coli on non-nutrient agar plates and inoculating with cysts of A. castellanii or A. polyphaga. Results showed that contact lens case bacterial contaminants may support the growth of Acanthamoeba and can provide a food source for the organism in the development of amoebic keratitis. (Lam A. IOVS 2012;53:ARVO E-Abstract 6172)

One study found that contact lens case bacterial contaminants may support the growh of Acanthamoeba and can provide a food source for the organism in the development of amoebic keratitis.

Other highlights from the antiinfective segment included many posters that discussed the increasing popularity of fluoroquinolone therapy due to concerns of antibiotic resistance. A poster presentation by employees of and consultants to Bausch + Lomb examined the antibiotic resistance profile of ocular pathogens, with an update from the Antibiotic Resistance Monitoring in Ocular Microorganisms 2011 surveillance study. The ARMOR study results displayed resistance trends among ocular bacterial pathogens such as S. pneumoniae at 32 sites using antibiotic susceptibility testing. The 2011 results showed that while almost 46 percent of S. pneumoniae isolates were resistant to azithromycin, all isolates were susceptible to fluoroquinolones. Among the fluoroquinolones, the researchers say besifloxacin had the lowest MIC90. (Haas W. IOVS 2012;53: ARVO EAbstract 6195)

In a survey designed to assess ocular pathogen prevalence and emerging antibiotic therapy, one study examined the in vitro activity of a novel isothiazoquinolone (ITQ), ACH-0139586, against common ocular pathogens (S. aureus, S. epidermidis, S. pneumoniae, H. influenza, M. catarrhalis and P. aeruginosa) compared with moxifloxacin and gatifloxacin. ITQs are a new class in the quinolone family that has been found to have good in vitro and in vivo activity against pathogens such as S. aureus, including MRSA isolates. Pucci MJ, Podos SD, Thanassi JA, Leggio MJ, Bradbury BJ, Deshpande M. In vitro and in vivo profiles of ACH-702, an isothiazoloquinolone, against bacterial pathogens. Antimicrob Agents Chemother 2011;55:6:2860-2871. Fluoroquinolones typically inhibit both DNA gyrase and topoisomerase IV, which are required for the DNA replication process, whereas ITQs add a third mechanism of action as potent DNA primase inhibitors.,Agarwal A, Louise-May S, Thanassi JA, et al. Small molecule inhibitors of E. coli primase, a novel bacterial target. Bioorg Med Chem Lett 2007;17:10:2807-2810. ,Cheng J, Thanassi JA, Thoma CL, Bradbury BJ, Deshpande M, Pucci MJ. Dual targeting of DNA gyrase and topoisomerase IV: target interactions of heteroaryl isothiazolones in Staphylococcus aureus. Antimicrob Agents Chemother 2007;51:7:2445-2453. ,Molina-Torres CA, Ocampo-Candiani J, Rendon A, Pucci MJ, Vera-Cabrera L. In vitro activity of a new isothiazoloquinolone, ACH-702, against Mycobacterium tuberculosis and other mycobacteria. Antimicrob Agents Chemother 2010;54:5:2188.,Vera-Cabrera L, Campos-Rivera MP, Escalante-Fuentes WG, Pucci MJ, Ocampo-Candiani J, Welsh O. In vitro activity of ACH- 702, a new isothiazoloquinolone, against Nocardia brasiliensis compared with econazole and the carbapenems imipenem and meropenem alone or in combination with clavulanic acid. Antimicrob Agents Chemother 2010;54:5:2191-2193.,Zhang MQ, Haemers A. Quinolone antimicrobial agents: Structure-activity relationships. Pharmazie 1991;46:10:687-700. Inhibition of DNA primase increases efficacy and decreases the chances for developing resistance compared with fluoroquinolones. The study demonstrated that ACH-0139586 was more potent relative to gatifloxacin and moxifloxacin, regardless of methicillin and fluoroquinolone resistance, and that this was most apparent against evaluated gram-positive pathogens. (Shapiro A. IOVS 2012;53 ARVO EAbstract 6259)

Though we had to bid a fond farewell to our sunny center of research in Ft. Lauderdale, we’re looking forward to greeting friends and colleagues at ARVO’s new venues, and we can’t wait to see what study results they’ll have in store next year. We’ll see you in Seattle!

Dr. Abelson is a clinical professor of ophthalmology at Harvard Medical School and senior clinical scientist at the Schepens Eye Research Institute.