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Forward-looking research in drug delivery and therapies filled the sessions at this year’s meeting of the Association for Research in Vision and Ophthalmology.
Take-home message: Forward-looking research in drug delivery and therapies filled the sessions at this year’s meeting of the Association for Research in Vision and Ophthalmology.
By James T. McLaughlin, PhD, Special to Ophthlamology Times
Denver-Much like the studies it features, the 2015 meeting of the Association for Research in Vision and Ophthalmology (ARVO)-with this year’s theme of “Powerful Connections”-met its primary objective. Some of the best and most interesting presentations focused on connections between new therapies and innovations in therapeutic delivery schemes.
Here are highlights of some of the many presentations from this year’s meeting.
Development of new methods of ophthalmic drug delivery has taken advantage of an explosion in research into the formulation and manufacture of new biopolymers based upon modified collagens or hyaluronic acids.
For example, drug release from a chemically modified HA was explored in several presentations, including one using a polymer matrix to deliver recombinant human growth hormone (Bowen RC.IOVS. 2015;56:ARVO E-Abstract 1295; Wirostko B. IOVS. 2015;56:ARVO E-Abstract 262). The study found that the HA polymer could deliver rHGH in a controlled, sustained manner-both in vitro and in vivo-over a course of days to months.
Another type of delivery system involved the use of a collagen hydrogel implant (Mondal D.IOVS. 2015;56:ARVO E-Abstract 4135). In this study, the gel was used to deliver vancomycin to be used as a preventive for postoperative ocular infection.
Other presentations described new designs for implant-based drug delivery. In one, difluprednate for treatment of inflammation and pain associated with ocular surgery was delivered by either subconjunctival or intracameral implantation, and it demonstrated a prolonged drug delivery and a reduction in ocular inflammation over 4 weeks in a rabbit model of corneal inflammation (Garcia A.IOVS. 2015;56:ARVO E-Abstract 5897). Such treatments have the potential to bypass the need for topicals requiring multiple daily instillations.
More extensive device engineering was demonstrated in a “nanowafer” drug delivery system, tested in a model of corneal neovascularization (Acharya G.IOVS. 2015;56:ARVO E-Abstract 5032). The nanowafer-composed of a transparent circular disc that contains arrays of drug-loaded nanoreservoirs-is placed on the ocular surface. For this study, the tyrosine kinase inhibitor, axitinib (Inlyta, Pfizer), an FDA-approved treatment for renal cell carcinoma, was used as a test therapy. One-daily nanowafer was significantly more efficacious than twice-daily eye drop treatments of axitinib.
Other studies of drug delivery paradigms focused on slow-release depot forms of vascular endothelial growth factor (VEGF) inhibitors. Initial in vitro pharmacokinetic work is being done on controlled-release polymer reservoirs (Abe T. IOVS. 2015;56:ARVO E-Abstract 4146) and a polymer nanoparticle system was described in which conjugation of bevacizumab (Avastin, Genentech) was shown to reduce leakage of the drug into the bloodstream (Kong L. IOVS. 2015 56:ARVO E-Abstract 5029). This prolonged its retention in the vitreous, making it potentially safer and more effective by reducing systemic exposure and extending ocular residence time.
A number of studies examining properties of bevacizumab-packaged microparticles were also presented, including pharmacokinetic studies of microparticles within sustained-release hydrogel matrices (Tully S. IOVS. 2015;56:ARVO E-Abstract 222; Owens G. IOVS. 2015;56:ARVO E-Abstract 236; Verhoeven RS. IOVS. 2015;56:ARVO E-Abstract 230).
If this year’s presentations are any indication, a major focus of retinal therapies in the near future will be the refinement of these many therapeutic delivery options.
Improving the treatment options and visual outcomes for patients with retinal diseases-including age-related macular degeneration (AMD)-was not just about drug delivery, however. While monoclonal antibody inhibitors of VEGF have provided a valuable treatment option for many patients with AMD, variable responses and the necessity of once- or twice-monthly intravitreal injections provide a continuous pressure to develop new treatment regimes.
One approach involves a system of de novo-designed, cell-penetrating peptide constructs fused to a therapeutic protein transduction domain (DeCogan F.IOVS. 2015;56:ARVO E-Abstract 4147). This system was shown to transport µg quantities of macromolecules, such as very large monoclonal VEGF inhibitors, in a topical eyedrop that enables penetration to the posterior segment.
Another area of interest is small-molecule therapies that can avoid the problems of penetration and absorption of the macromolecule monoclonal VEGF inhibitors. Initial in vitro screens included inhibitors of the P13K/Akt/mTOR pathway (Sasore T. IOVS. 2015;56:ARVO E-Abstract 2305) and iso-quinolone sulfonamide derivatives that inhibit protein kinase function (Sugimoto M. IOVS. 2015;56:ARVO E-Abstract 150). Pharmacokinetics and initial vascular leakage models were used to assess the ability of mucus-penetrating particles to deliver drug (in this case, a tyrosine kinase inhibitor) in topical formulations to the back of the eye (Schopf L. IOVS. 2015;56:ARVO E-Abstract 2279).
Another kinase inhibitor, regorafenib (Stivarga, Bayer), showed positive results in two studies as a potential topical therapy for AMD and related disorders (Beottger MK.IOVS. 2015;56:ARVO E-Abstract 2294; Klar J. IOVS. 2015;56:ARVO E-Abstract 246). Oral docosahexaenoic acid supplements protected against neovascularization and retinopathy in rat models of AMD (Ogami S. IOVS. 2015;56:ARVO E-Abstract 2350), and a new RNAi-based agent appears to inhibit both angiogenesis and fibrosis promoted by periostin (Nakama T. IOVS. 2015;56:ARVO E-Abstract 2280).
The variety of new agents showing promise in preclinical studies bodes well for future improvements in retinal proliferative disease.
The 1-year results of a phase I/II combination therapy of low-dose, proton beam irradiation and anti-VEGF therapy were presented (Osmanovic S. IOVS. 2015;56:ARVO E-Abstract 4906). This study was based on observed synergism of VEGF inhibitors and proton beam therapy in patients receiving radiotherapy. Though this was only an interim analysis, results are encouraging, with fewer injections needed in the group receiving radiation treatment.
Dry AMD continues to be one of the main ocular disorders without significant, FDA-approved therapies. In the clinic, BAM114341, a therapy designed to block formation of β-amyloid deposits seen in Alzheimer’s disease, is being tested in a phase II study in geographic atrophy secondary to AMD (Shearn SP. IOVS. 2015;56:ARVO E-Abstract 2840). Though this presentation only covered results from the 4-month run-in period in which endpoint criteria values were established, it will be exciting to see the efficacy results of this study given the emerging link between β-amyloid formation in AMD and other neurodegenerative disorders.
Retinal branch occlusion and diabetic macular edema (DME) were both the focus of important clinical trial results. First-year results from the VIBRANT study-a trial in which monthly intravitreal aflibercept (Eylea, Regeneron) injections were compared with laser therapy for retinal branch occlusion-were presented (BoyerDS. IOVS. 2015;56:ARVO E-Abstract 3749). Using the proportion of patients with a ≥15 letter gain in best-corrected visual acuity (BCVA) as primary endpoint, intravitreal aflibercept injection therapy was superior to control at both 24 weeks (52.7% versus 26.7%, p = 0.0003) and at 52 weeks (57.1% versus41.1%, p = 0.0296).
Another trial involved head-to-head comparison of the VEGF inhibitor, bevacizumab, with a depot form of dexamethasone (Ozurdex, Allergan) for treatment of DME (Gillies MC. IOVS. 2015;56:ARVO E-Abstract 3144). Improvements of 10 or more letters at 24 months were similar in both groups (Avastin 45% versus Ozurdex 43%), but more subjects (5/46 versus 1/42) in the Ozurdex group showed a decline of ≥0 letters in BCVA, and a significant number in the Ozurdex group showed a progression in cataract formation. (43% versus 8).
Progress in gene-based therapy for inherited disease was demonstrated in study of corneal clouding associated with MPS1, a condition known historically as Hurler’s syndrome (Hirsch M. IOVS.2015;56:ARVO E-Abstract 260). The study tested a viral-based expression of a replacement for the affected gene product in patient fibroblasts, mouse cornea, and human cornea. Optimization of the adeno-associated viral vector for corneal expression was demonstrated in all three test tissues, providing hope for therapeutic intervention for corneal clouding in children with MPS 1 and other variants of mucopolysacharride-associated disorders.
Another therapeutic approach gaining favor for corneal disease is stem cell transplantation. One notable study used a mouse model of bacterial inflammation to demonstrate that the local delivery of mesenchymal stem cells is an effective and safe approach for immunomodulation and treatment of ocular inflammation (Zhang R. IOVS. 2015;56:ARVO E-Abstract 942).
Two presentations used continuous monitoring technology to analyze blink behavior under natural conditions (Lane. IOVS. 2015;56:ARVO E-Abstract 4447; Harmeling. IOVS. 2015;56:ARVO E-Abstract 4486). These studies continue to advance clinicians’ understanding of compensatory mechanisms in ocular surface disease. (Photo courtesy of Keith Lane)Chronic keratitis-whether from infection, trauma, or surgical complication-remains a significant therapeutic challenge. As in past years, a wealth of studies from neurotrophic keratitis to dry eye were aimed at improving therapeutic outcomes for those with corneal disease.
One study tested the efficacy of the rho-kinase inhibitor, AMA0076 (Amakem NV, Belgium), in a rabbit model of corneal debridement (Defert O.IOVS. 2015;56:ARVO E-Abstract 5610). Rho kinase inhibitors have been explored as potential therapies for open-angle glaucoma, and more recently, their role in cell inflammation and differentiation has been recognized.
This study followed 4 days of healing for untreated animals (t.i.d., placebo), AMA0076-treated animals (also t.i.d.), and a positive comparator of recombinant growth hormone (q.i.d.). The kinase inhibitor and the GH treatments were comparable for both re-epithelialization and resolution of corneal haze, and both were superior to the control animals.
Reports focusing on advancements in ocular allergy and inflammation included one study demonstrating the therapeutic potential for PI3K inhibitors (Whitlock A.IOVS. 2015;56:ARVO E-Abstract 4886). The study used reduction in ocular redness in a mouse model as a reporter for relief of allergic inflammation.
Another presentation demonstrated how immune cell infiltration can be assessed using confocal microscopy, a new approach that is particularly useful in studies of chronic disease (Gomes P. IOVS. 2015;56:ARVO E-Abstract 4892).
A novel treatment strategy for dry eye was examined with weekly dosing of cyclosporin delivered using mucoadhesive nanoparticles in a mouse model of dry eye (Lui S. IOVS. 2015;56:ARVO E-Abstract 5036). This delivery regime enhanced anti-inflammatory efficacy relative to placebo or to higher topical doses of drug.
It has long been thought that dry eye was a condition most severe in winter months, but no studies have been done to test whether this belief is fact or fiction. Data were pooled from 10 clinical trials and identified 270 patients who had participated in at least one summer study (April to September) and one winter study (November to April), and were randomly assigned to placebo groups for both studies (Ousler et al. IOVS. 2015;56:ARVO E-Abstract 4462). Both ocular discomfort and dryness symptom scores were significantly higher during the winter months, consistent with the prevailing wisdom. It will be interesting to see if clinical signs of dry eye such as corneal staining show similar patterns.
Many presentations this year examined the potential of repurposed compounds for dry eye. One of these tested the immunosuppressant, rapamycin (Rapamune, Pfizer), as a therapy for Sjögren’s syndrome, using a non-obese mouse model as a test platform. (Shah M. IOVS. 2015;56:ARVO E-Abstract 4810). After a 12-week treatment of bi.d. rapamycin, SS markers were all significantly reduced compared with placebo, including lacrimal lymphocytic infiltration (6.4-fold decrease) and tear cathepsin S activity (5.9-fold decrease).
Another preclinical trial tested the integrin antagonist GW559090 in a mouse model of dry eye (Krauss AH. IOVS. 2015;56:ARVO E-Abstract2472). Integrins are key players in lymphocyte activation and chemotaxis. Lifitegrast (Shire), a drug for treatment of dry currently under FDA review, inhibits another member of the integrin family, lymphocyte function antigen 1.
Since ARVO always highlights cutting-edge scientific progress, it was not surprising to see a number of presentations that described the latest in progress toward genetically based therapies. One of these reports combined gene-editing CRISPR technology and genetically modified, induced pluripotent stem cells to generate 3-D retina reporter cell lines for the study of photoreceptors (Wahlin KJ. IOVS. 2015;56:ARVO E-Abstract 3596).
Several studies focused on utilizing gene therapy to target the oxidative stress that accompanies a number of retinal diseases. By utilizing a mouse model of retinal pigment epithelium oxidative stress, it was demonstrated that delivery of genes for antioxidant enzymes can be used as a tool to reverse oxidative stress (Biswal MR. IOVS. 2015;56:ARVO E-Abstract 3189).
In contrast, another study proposed targeting of transcription factors that regulate hundreds of genes that combat oxidative stress would be more effective than the delivery of antioxidant enzymes (Xiong WIOVS 2015; 56: ARVO E-Abstract 3188).
Two presentations used continuous monitoring technology to analyze blink behavior under natural conditions (Lane. IOVS. 2015;56:ARVO E-Abstract 4447; Harmeling. IOVS. 2015;56:ARVO E-Abstract 4486). These studies continue to advance clinicians’ understanding of compensatory mechanisms in ocular surface disease.