Mark B. Abelson, MD, CM, FRCSC and the Ora Staff
Researchers convened in
Age-Related Macular Degeneration
In the vast landscape of AMD research at ARVO, some of the posters stood out for highlighting potentially viable future treatments. In particular, there were several Phase I clinical results with promising agents moving further in the development process.
A Phase I study of a complement factor 5 inhibitor (ARC1905) in combination with ranibizumab for the treatment of neovascular AMD found the therapy to be safe and well-tolerated in all 58 subjects, with nearly 60 percent among the high-dose group (2 mg ARC1905) exhibiting at least a three-line ETDRS visual acuity gain at week eight. Based on these results, another Phase 1 study examining the effects of ARC1905 monotherapy on geographic atrophy area and drusen volume is planned. (Cousins SW, et. al. IOVS 2010;51:ARVO E-Abstract 1251)
In another Phase I study, the alpha5beta1 integrin antagonist volociximab also exhibited efficacy in the treatment of neovascular AMD when administered intravitreally in combination with ranibizumab. Thirty-seven treatment-naïve eyes with wet AMD were treated with two doses of volociximab (either 0.5, 1.25 or 2.5 mg) and 0.5 mg ranibizumab. At week 12, 35 percent of subjects gained at least three or more lines of ETDRS and the medication was safe and well-tolerated by all subjects. (Kuppermann BD, et. al. IOVS 2010;51:ARVO E-abstract 1252)
Stemming from preclinical data showing that sphinogosine-1-phosphate (S1P) may play a role in the regulation of fibrosis, inflammation and choroidal neovascularization, a Phase I study was conducted investigating the tolerability of intravitreal injections of iSONEP, an anti-S1P monoclonal antibody. The open-label dose-escalating study enrolled 15 patients, and while the maximum tolerated dose was not reached, single doses up to 1.8 mg were well tolerated. Although not powered to show significance, the results also suggested positive biological activity of iSONEP with reductions in CNV lesion size and decreases in central retinal thickness noted in some patients. (Stoller G, et. al. IOVS 2010;51:ARVO E-abstract 1253)
Also noteworthy was a preclinical study evaluating the effect of the histone deacetylase (HDAC) inhibitors valporic acid (VPA), 4-phenylbutyrate (PBA) and the VPA analog valpromide (VPD) on the survival and function of retinal pigment epithelium cells in response to oxidative stress and complement attack. VPA and VPD both increased cell viability following challenge with the oxidative agent hydroquinone and protected against complement mediated cell death in vitro. VPA also protected against oxidative stress induced by intravitreal paraquat injection in mice, suggesting it may be a worthwhile agent for future clinical studies. (Upadhyay SJ, et. al. IOVS 2010;51:ARVO E-Abstract 496)
Once again, there was also no shortage of exciting research on diabetic retinopathy presented this year. Much of this work focused on VEGF-inhibitors, which continue to show promising results both in monotherapy and in conjunction with laser photocoagulation. The stage was set just prior to the meeting when the latest data from the Diabetic Retinopathy Clinical Research Net-work's (DRCRnet) trial examining the anti-VEGF antibody ranibizumab (Lucentis, Roche/Genentech) in combination with laser treatment were announced. Overall, the DRCRnet results support the use of intravitreal anti-VEGF therapy as the first-line treatment for diabetic macular edema, with ranibizumab expected to be the first anti-VEGF agent approved for this indication, with other anti-VEGF drugs to follow.
Aside from ranibizumab and its sister compound bevacizumab (Avastin, Roche/Genentech), pegaptanib sodium is also being investigated as an anti-VEGF agent for DME. In a retrospective chart review of 19 patients with clinically significant edema who were poor candidates for focal/grid photocoagulation, mean logMAR VA of subjects receiving 0.3 mg of pegaptanib improved by 0.29 from baseline to final visit, an average time span of 6.5 months. These results suggest that pegaptanib may provide an effective alternative treatment for patients for whom laser treatment is contraindicated. (Beck CJ, et al. IOVS 2010;51:ARVO E-abstract 4228) In separate studies, pegaptanib treatment also led to VA gains in patients with branch retinal vein occlusion (Rosen BS, et al. IOVS 2010;51:ARVO E-abstract 4739) as well as among a small group of patients with Stage 3A Coats' disease. (Gupta AP, et. al. IOVS 2010;51:ARVO E-abstract 5116)
Further down the pipeline, another potential VEGF-inhibitor, erythropoietin, showed efficacy in a rat model of early diabetes. Eyes treated with intravitreal EPO had downregulated expression of VEGF and HIF-1alpha (a transcription factor involved in the cellular response to hypoxia) and exhibited total retinal thickness and cell numbers similar to those of the non-diabetic controls. (Zhang J, et. al. IOVS 2010;51:ARVO E-abstract 5601)
Several presentations at the ARVO meeting represented the continuing endeavor to better understand the risk factors and pathophysiology of dry eye. Japan's Murat Dogru, MD, and colleagues demonstrated the role of dehydration in dry eye by comparing subjects drinking a controlled amount of alcohol (n: 20) to those drinking green tea (n: 7). Twelve hours after alcohol intake, substantial detrimental changes were observed in tear-function metrics (e.g., tear-film breakup time, Schirmer's test, staining) when compared to baseline, while no significant tear function changes were observed in the green tea group. These results suggest substantial effects of alcohol on tear function. (Dogru M, et al. IOVS 2010;51:ARVO E-abstract 6257)
Research efforts to enhance the understanding of the intricate relationship between visual function, blinking and dry eye were present in abundance across different groups of scientists and clinicians. Researchers from SUNY College of Optometry demonstrated increased symptomatology following computer use compared to that reported after hard-copy fixation in a study of 24 participants. While these findings correlated to ocular surface disease severity, there was no apparent correlation to decreased blink rate. (
Clinical research models and results of clinical trials of developing therapies were also presented. Our group presented exciting data using the Enhanced Controlled Adverse Environment system, which has been used in a number of clinical trials in recent years, and represents the precision possible when using honed diagnostics and clinical trial design features. (Ousler GW, et al. IOVS 2010;51:ARVO E-abstract 3362) Researchers and statisticians from Eyegate Pharmaceuticals and Statistics and Data Corp. presented a poster detailing strategic selection of Phase III endpoints, based on the results of a bootstrapping method using Phase II study findings. (Hsu H-C, et al. IOVS 2010;51:ARVO E-abstract 6270) Researchers from
In addition, a few intriguing examples of preclinical research with potential clinical application in the future emerged. Lubricin—a glycoprotein found in the cartilage of the knee—demonstrated reduced friction and tissue wear when tested using biomechanical machinery and human corneas and eyelids, which may suggest an advantage as an ocular surface lubricant. (Schmidt TA, et al. IOVS 2010;51:ARVO E-abstract 3399) One group of researchers presented intriguing results of a mouse study demonstrating the potential of both vitamin D and its active metabolite (1,25-(OH)2D) to improve corneal epithelial barrier function, which may suggest clinical applications with further research. (Watsky MA, et al. IOVS 2010;51:ARVO E-abstract 1945)
Finally, prior to ARVO, expert clinical researchers, scientists, regulators, pharmaceutical executives, and venture capitalists interested in dry eye convened at the Dry Eye Summit, an event co-sponsored by our pharmaceutical consulting firm, Ora. Topics presented ranged from the history of dry eye, to defining dry eye, to clinical regulatory and exit strategies. The summit imparted a business and regulatory spin to the discussion of innovations in dry-eye therapy.
In a preclinical study, the combination of dexamethasone and povidone-iodine (0.1%/0.4%; FST100, Foresight Pharmaceuticals) was compared to two other treatments in a rabbit model of adenoviral conjunctivitis. FST100 reduced viral titers significantly more than placebo or Tobradex when all were applied q.i.d. Titer reductions with FST100 were comparable with those seen with twice daily cidofavir (0.5%). Animals were also scored for symptoms such as conjunctival and eyelid inflammation, exudates, excessive tearing and corneal neovascularization. The FST100 group had significantly lower scores (i.e., more symptomatic improvement) when compared to other treatment groups. (Hill JM, et al. IOVS 2010;51:ARVO E-abstract 3878)
A study by scientists from Bausch + Lomb tracked resistance trends among ocular pathogens in the United States, comparing MIC values of besifloxacin, ciprofloxacin, moxifloxacin, azithromycin and tobramycin against both gram-positive and gram-negative isolates. Against methicillin-resistant staph and ciprofloxacin-non-susceptible (NS) isolates, besifloxacin was the most effective agent, with an MIC50/MIC90 (µg/mL) value of 1/4. For the same isolates, moxifloxacin and ciprofloxacin had MIC50/MIC90 values of 4/16 and 64/256 respectively. Besifloxacin was comparable to moxifloxacin and ciprofloxacin against H. influenza, and ciprofloxacin was more potent against P. aeruginosa than either besifloxacin or moxifloxacin. (Haas W, et al. IOVS 2010;51:ARVO E-abstract 2417)
Alcon and NovaBay Pharma-ceuticals presented findings regarding a new product, N, N-dichloro-2, 2-dimethyltaurine (AL-46383A or NVC-422), which is a synthetic analog of N-chloro taurine (NCT). As part of the body's natural defense against infection, granulocytes and monocytes produce NCT, a compound with anti-inflammatory and anti-infective activity. NovaBay scientists examined the chemical stability, anti-microbial and antiviral activity of NVC-422 in the presence of artificial tears. (Najafi KK, et al. IOVS 2010;51:ARVO E-abstract 1992) The Alcon group, in collaboration with scientists from the
Researchers reported interim results from a multicenter, open-label trial examining anti-TNF antibody adalimumab (Humira, Abbott) as a therapy for refractory uveitis. Treatment involved a 40 mg sc injection every two weeks and assessment of safety and efficacy over a 10-week trial. Inclusion in the study required diagnosis of noninfectious uveitis refractory to corticosteroids and at least one immunosuppressive. Endpoints included acuity improvement, de--creased intraocular inflammation and steroid tapering. Seventeen of 26 patients who completed the 10-week trial responded positively to therapy, and 15 of these continued with treatment for 50 weeks. One initial responder discontinued treatment due to a loss of efficacy, and the only significant adverse event was unrelated to adalimumab. (Salom D, et al. IOVS 2010;51:ARVO E-abstract 5270)
Several other trials examined the use of monoclonal antibody (mAb) therapy targeting other immuno-modulators. Most of these agents were originally developed to treat systemic disorders but they have significant therapeutic potential in ocular inflammatory disease. An open-label study tested AIN457, a humanized monoclonal directed against IL-17, for patients with noninfectious uveitis. The drug was supplied intravenously (10 mg/kg) at baseline and three weeks later, and patients were evaluated over a nine-month period. Efficacy variables included acuity, vitreous haze, anterior chamber inflammation and reduction of corticosteroid dosing. Eight of 11 patients (73 percent) with posterior segment uveitis and three of five patients (60 percent) with anterior uveitis met the response criteria in this study. Only one patient showed no response and required prednisone rescue. (Samson CM, et al. IOVS 2010;51:ARVO E-abstract 2917) Another study examined safety and efficacy of rituximab, an anti-CD-20 mAb developed to treat B-cell lymphomas, for refractory scleritis and non-infective orbital inflammation. A total of 15 patients received rituximab infusion (500 or 1,000 mg) on days one and 15 of the study; followed by monthly safety monitoring and efficacy assessment at 24 and 48 weeks. The overall outcome was positive: Four patients were able to taper steroid dosing, and only one patient required increased steroids. Vision was stable or improved in 14 patients, and patient and physician global health assessments also improved. The only significant safety issue involved seven of the first nine patients treated; they experienced inflammatory exacerbations after infusion that required adjunctive corticosteroids. This didn't occur in the remaining six patients, nor has it occurred in the patients that have been re-infused since then. (de Saint Sardos A, et al. IOVS 2010;51:ARVO E-abstract 2919)
Another approach to ocular inflammation is the use of lipid-derived agents. One study reported that the endogenous lipid eicosapentaenoic acid currently in use to treat hyperlipidemias is effective for the treatment of endotoxin-induced uveitis. (Suzuki M, et al. IOVS 2010;51:ARVO E-abstract 1978) A related compound under study at Resolvyx Pharmaceuticals, Resolvin E1, was shown to be effective in treating corneal inflammation due to HSV. (Rajasagi NK, et al. IOVS 2010;51:ARVO E-abstract 3867)
Inotek Pharmaceuticals presented pre-clinical data on its A1 adenosine agonist INO-8875. Single topical doses reduced intraocular pressure in both rabbits and monkeys. Several in vitro studies provided insights into the underlying mechanism of IOP reduction. In cultured trabecular cells, INO-8875 causes a rapid activation of ERK kinase that is blocked by A1 receptor antagonists. In isolated, perfused porcine anterior segments, INO-8875 increased trabecular outflow when compared to the vehicle treatment. (Kim N, et al. IOVS 2010;51:ARVO E-abstract 3238)
A recurring theme at both poster and paper sessions was the importance of the Rho-associated, coiled-coil protein kinases referred to by the acronym ROCK. These kinases regulate a number of cellular processes including those involved in cytoskeletal and extracellular matrix dynamics. They are attractive therapeutic candidates for modulating the trabecular network and thus improving IOP by increasing outflow. A group from Aerie Pharmaceuticals presented results of Phase II study of their ROCK-inhibitor AR-12286 and demonstrated both significant clinical efficacy and a good safety profile. (
Researchers for Lexicon Pharma-ceuticals used a knockout mouse model to demonstrate involvement of a related protein kinase, LIMK2, in regulation of IOP. Mice engineered with a LIMK2 gene knockout had lower IOP compared to wild-type littermates, while knockouts of the related kinases LIMK1 and MLCK did not display an altered IOP phenotype. Their studies went further to show that LIMK2 (but not LIMK1) knockouts were insensitive to the IOP-lowering effects of drugs that act as ROCK inhibitors. This work further defines this IOP regulatory pathway and confirms both LIMK2 and ROCK kinases as potential targets for future glaucoma therapy. (Whitlock A, et al. IOVS 2010;51:ARVO E-abstract 2147) A number of other studies, including posters from Alcon, implicated ROCK activity in control of trabecular outflow as well. (Ramachandran C, et al. IOVS 2010;51:ARVO E-abstract 3234; Srinivas SP, et al. IOVS 2010;51:ARVO E-abstract 3235; Yang C, et al. IOVS 2010;51:ARVO E-abstract 3237)
Building on ocular sign and symptom results reported at last year's ARVO conference, pooled nasal data was presented from two Phase III Conjunctival Allergen Challenge trials using the topical antihistamine bepotastine besilate 1.5% (Bepreve, Ista Pharmaceuticals). The post-hoc analyses show a 77-percent mean reduction of rhinorrhea from baseline at 15 minutes after dosing in the treatment group compared to a 37 percent reduction in the placebo group. Similar results were seen eight hours after dosing, with an average reduction of 81 percent with bepotastine and 27 percent with placebo. These results suggest bepotastine and other drugs of its class may reduce the symptoms of nasal allergies and do so over a prolonged duration. (Gow JA, et al. IOVS 2010;51:ARVO E-abstract 1915)
Besides the standard-of-care topical antihistamines and mast-cell stabilizers, researchers continue to study alternative treatments for ocular allergies including steroids. In a retrospective case review of children with allergic conjunctivitis who underwent supratarsal injections of 1-ml triamcinolone (40 mg/ml) and 1-ml betnesol (4 mg/ml) under general anesthesia, researchers found an improvement in visual acuity in all 10 patients (mean improvement: two lines logMAR) with no cases of an intraocular pressure rise above 21 mmHg. These results support the use of supratarsal steroid injections in children with allergic conjunctivitis and show that steroid injections may reduce a patient's dependence on topical medications. (Afshar MF, et. al. IOVS 2010;51:ARVO E-abstract 1930)
In an effort to more effectively screen new treatments for allergic conjunctivitis in a preclinical setting, researchers from our group have modified a murine short ragweed (SRW) sensitization model to enhance the allergic response and reduce the duration of experiments. In addition to other preclinical allergy models such as the rabbit 48/80 and guinea pig histamine, the modified SRW (using additional sensitization boosters administered via intraperitoneal injection or topical SRW drops) may provide an improved method of studying early- and late-phase allergic reactions and allergic mediators to determine the mechanism of action of prospective allergy medications. (Crawford KS, et. al. IOVS 2010;51:ARVO E-abstract 1933)
The presentations at this year's ARVO meeting were an immense assortment of fascinating research. Pre-ARVO events, poster presentations and special-interest groups prompted stimulating discussion, debate and education. While we're unable to acknowledge all of the research presented at the meeting, we hope we've given you a better understanding of the promising future of eye and vision research, and we look forward to discovering all of the cutting-edge research efforts at future ARVO meetings.
Dr. Abelson, an associate clinical professor of ophthalmology at