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5th Ocular Diseases & Drug Development

  December 20, 2012  
GTC Conferences, San Francisco, CA
2013-3-21 to 2013-3-22

Register by January 21, 2013 for a 20% Discount. Or Register 2the 3rd goes free with the coupon code rcdvb!

Day 1Day 2
Day 1 - Thurday, March 21, 2013
7:00Continental Breakfast & Registration
7:55Welcome & Opening Remarks
8:00A Phase 2b Study of FovistaTM, a Platelet Derived Growth Factor (PDGF) Inhibitor in Combination with a Vascular Endothelial Growth Factor (VEGF) Inhibitor for Neovascular Age-Related Macular Degeneration (AMD)


Samir Patel

President, CEO

 Purpose/Methods: To assess the safety and efficacy of FovistaTM in combination with ranibizumab compared to ranibizumab monotherapy, 449 patients with neovascular AMD were randomized in a prospective, controlled, superiority trial to receive one of the following treatment regimens administered every 4 weeks for 24 weeks: FovistaTM 0.3 mg in combination with ranibizumab 0.5 mg; FovistaTM 1.5 mg in combination with ranibizumab 0.5 mg; or sham in combination with ranibizumab 0.5 mg.

Results: The combination of FovistaTM (1.5 mg) with ranibizumab met the pre-specified primary endpoint of superiority in mean visual acuity gain compared to ranibizumab monotherapy (10.6 ETDRS letters at week 24, compared to 6.5 letters, p=0.019). An additional 62% benefit from baseline was noted in the FovistaTM (1.5 mg) combination therapy arm over ranibizumab monotherapy. A classic dose-response curve was observed. Enhanced visual outcomes for FovistaTM 1.5 mg combination therapy compared to ranibizumab monotherapy were present at every monthly timepoint. The relative magnitude of visual benefit increased over time, implying a benefit to continued combination therapy. The superiority of FovistaTM 1.5 mg combination therapy over ranibizumab monotherapy was consistent across all subgroups including those analyzing baseline vision, lesion size, and central retinal thickness. FovistaTM 1.5 mg combination was superior to ranibizumab monotherapy across multiple treatment endpoints including 3, 4 and 5 lines of vision gain (ETDRS chart). OCT and fluorescein angiography analysis showed patients receiving FovistaTM 1.5 mg combination therapy had greater reduction in neovascular size compared to those receiving ranibizumab monotherapy. No significant safety issues were observed for either treatment group in the trial.
Session: Novel Targets, Developments and Technologies
8:35Lipoprotein-associated Phospholipase A2 Inhibition Regulates Retinal Vasopermeability During Experimental Diabetes

Peter Adamson
Vice President and Head of Research, GSK Ophthalmology

 Diabetic macular edema is recognized to have an inflammation-linked etiology. It is hypothesized that inhibition of lipoprotein-associated phospholipase A2 (Lp-PLA2) is protective against hyperglycemia-related compromise of the blood retinal barrier (BRB). Lp-PLA2 was localized to the vascular endothelium of human retinal capillaries,and in parallel, brown Norwegian rats had diabetes induced and maintained for 4 weeks with treatment using vehicle or SB435495 (a specific inhibitor of Lp-PLA2). A different group of hyperglycemic animals were maintained treatment free for 4 weeks prior to initiating the 4 wk treatment regimen with SB435495. A group of non-diabetic BN rats were used as controls. BRB function was determined by retinal fluorescein angiography, Evan’s blue (EB) leakage and immunohistochemical detection of intravascular and extravasated rat albumin in the retina.

SB435495-treatment during initiation of diabetes resulted in less vascular leak when compared to the vehicle-treated diabetic controls. EB leakage was elevated in the vehicle-treated diabetic group when compared to non-diabetic counterparts. 4 weeks treatment with SB435495 significantly prevented this response after either 4 or 8 weeks of prior diabetes. In vehicle-treated diabetic rats, albumin immunoreactivity was apparent in the retina from both superficial and deep capillary plexi. In SB435495-treated diabetic rats, albumin was co-localized with blood vessels with a pattern similar to non-diabetic controls.

This data indicates that inhibition of Lp-PLA2 in a preclinical model of hyperglycemia induced retinal vascular leak can prevent breakdown of the inner BRB. Lp-PLA2 may thus be a useful target for treatment of DME.

1. Understanding pre-clinical models of hyperglycemia-induced retinal vascular permeability.
2. Treatment for DME
3. Role of inflammation in DME
4. Blood-brain barrier vs Blood-retinal barriers
9:10Intrinsic Lipid Circuits: Key Regulators of Innate Immunity and Ocular Inflammatory-Reparative Responses
 Karsten Gronert, Associate Professor, Ophthalmology, University of California, Berkeley
 Inflammation, a frequent and self-resolving response, is essential for protection and integrity of tissues and is intimately linked to wound healing. Healthy execution of inflammatory/reparative responses requires activation of conserved resolution programs. Distinct classes of lipoxygenase (LOX)-derived eicosanoids and their w-3 PUFA homologs establish a tone of anti-inflammatory signals, are early response signals to injury or infection and key regulators of resolution and healing. Our research efforts are focused on elucidating function and regulation of these protective lipid circuits in the eye. We have discovered intrinsic lipid circuits in the cornea and retina that control inflammation, leukocyte function, wound healing and angiogenesis. These protective lipid circuits are regulated by dietary w-3 PUFA that amplify the generation of specific docosahexaenoic acid-derived autacoids. Sex-specific differences in ocular inflammatory/reparative responses and estrogen’s role in ocular diseases are not well understood. Our ongoing work has uncovered that estrogen receptors selectively regulate protective lipid circuits, which correlates with estrogen-driven and sex-specific differences in wound healing and inflammation. 

In addition, we recently discovered that eicosanoids are an early and obligatory effector function of inflammasomes, which are critical intracellular sensor for infection/stress and activators of essential cellular innate immune responses. The lecture will present our current understanding of the formation, regulation and mechanism of action of intrinsic lipid circuits and their potential role in the pathogenesis of ocular inflammatory diseases.
9:35Justin Shaka, Chief Operating Officer, REBIScan
10:00Morning Networking Break
10:30Sean Caffey, Chairman, CEO and Co-Founder, Replenish
10:55Polyesteramides: Materials, Formulation and Processes for Ocular Drug Delivery
 Lukasz Koroniak, Senior Scientist Formulation Development, DSM Biomedical
 The incorporation of amino acid-based units into resorbable, biodegradable polymers introduces not only metabolisable building blocks within the polymer, but also one or more functional groups along the polymer chain. This allows modification of the polymer to tailor its physicochemical properties, bio-erosion and performance as drug eluting matrices. DSM is developing a portfolio of polyesteramide polymers (“PEAs”) based on ?-amino acids, aliphatic dicarboxylic acids and aliphatic ?-? diols. A main advantage of PEAs is that by design, they predominantly degrade via an enzymatic mechanism and consequently due to exclusive surface erosion, drug release follows nearly zero-order kinetics.

Recently, significant advances have been made in optimizing the delivery of drugs to target tissues within the eye. Although topical administration remains the most common method, application of injectable, degradable ocular delivery devices provide better control over dosage, reduces amounts of formulated drug required and offers the opportunity to delivery drug more efficiently to the posterior segment of the eye.

In this presentation we will present DSM’s portfolio of PEAs and address various topics on ocular biocompatibility, degradation, processing and utility as a 6+ month sustained release delivery vehicle for latanoprost and dexamethasone.
11:20Utility of a Mouse Model for Evaluation of Potential Therapies for Age-related Macular Degeneration
 Chi-Chao Chan, Chief, Immunopathology Section; Laboratory of Immunology; Head, Histopathology Core, National Eye Institute, National Institutes of Health
 We use the Ccl2-/-/Cx3cr1-/- on rd8 background (DKO/rd8) mouse as a model for age-related macular degeneration (AMD). These mice develop progressive focal retinal degeneration characterized by photoreceptor and RPE atrophy, elevated ocular A2E and immune dysfunction, plus retinal dystrophy from the rd8 background. We examined the effect of feeding AREDS2 formulation to DKO/rd8 mice: one group was fed the AREDS2 diet with lutein, zeaxanthin and DHA/EPA, the other group was fed an isocaloric diet. After three months, 75% of control DKO/rd8 mice had retinal lesion progression, compared to 19% of AREDS2-treated mice. Ocular A2E levels were significantly lower and the mean outer nuclear layer was also significantly thicker in AREDS2-treated mice compared to the controls. Retinal expression of iNos, Tnf-?, Cox-2, and Vegf were lower in AREDS2-treated eyes. The data suggest that oxidative inflammatory damage was counteracted early enough to halt RPE damage and photoreceptor loss, and thus support a beneficial effect of AREDS2 formulation for AMD. While the identification of rd8 and rd8-associated retinal phenotype impacts the power of DKO/rd8 as an AMD model, the use of the model as self-control by treating one eye as the control allows for appropriate experimental interventional studies. In intervention studies on DKO/rd8, treatment is shown to alleviate photoreceptor and RPE lesions that can be attributed to Ccl2 and Cxcr3 null while showing little or no effect on rd8 lesions. Therefore, DKO/rd8 may still serve as a suitable and relevant model for compound screening on focal retinal degenerative diseases including AMD.
11:45Lunch on Your Own
Session: Novel Drug Delivery Methods to the Anterior and Posterior Segments
1:15Gene Therapy for the Treatment of Neovascular AMD
 Abraham Scaria, Senior Scientific Director, Genzyme
 VEGF plays a critical role in neovascular age-related macular degeneration and proliferative diabetic retinopathy. VEGF antagonists are useful for treating such disorders; however current treatments require monthly intravitreal injections. We have designed a soluble anti-VEGF molecule (sFLT01) and delivered it by intravitreal injection of an adeno-associated viral (AAV) vector since AAV vectors are capable of long-term gene expression. AAV2-sFLT01 inhibited retinal neovascularization in the murine oxygen-induced retinopathy model and in the laser-induced choroidal neovascularization (laser-CNV) model in mice. In the eyes of rodents and cynomolgus monkeys, AAV2-sFLT01 gives expression levels persistent for at least one year. We also performed laser-CNV experiments 5 months after vector administration in non-human primates and showed that sFLT01 is effective at inhibiting neovascularization in this model. Results of our 12-month safety study of AAV2-sFLT01 administered intravitreally in cynomolgus monkeys will be discussed. In summary, we have demonstrated long-term efficacy with minimal side effects following intravitreal delivery of AAV-sFLT01 in rodents and non-human primate models. These results suggest an alternate method for the long-term treatment for diseases of ocular neovascularization, without the need for repeated intraocular injections. A Phase I clinical trial is under way at four clinical sites in the USA.
1:40Drug Delivery to the Posterior Segment Using Topical Ocular Drops
 Martin Wax, CMO and EVP R&D, PanOptica
2:05Suprachoroidal Drug Delivery: Clinical and Pre-Clinical Experience
 Samirkumar Patel, Director, Research and New Product Development, Clearside Biomedical
 Treating diseases that affect the posterior segment of the eye is primarily done by direct injection of drugs into the vitreous. Currently doctors have very few viable options to deliver a drug directly to the choroid and retina where the pathology of many posterior segment diseases occurs. Direct injection into the suprachoroidal space with a microneedle can accomplish this and be done in a minimally invasive manner. This talk will focus on how injecting drugs into the suprachoroidal space using Clearside’s proprietary microneedle, has demonstrated efficacy in posterior inflammation (uveitis) in animal models and early human clinical safety experience.

Benefits/topic covered: 
- An understanding of the microinjection technology 
- An understanding of the suprachoroidal space anatomy and benefits of drug administration to this space
- Safety and efficacy data on suprachoroidal delivery in animal models
- Early clinical safety experience with Clearside’s suprachoroidal microinjection technology in human subjects
2:30Eugene de Juan, Founder & Vice-Chairman, ForSight Labs
2:55Afternoon Networking Break
3:30Drug-Eluting Contact Lenses
 Joseph B. Ciolino, Assistant Professor, Ophthalmology, Mass. Eye & Ear Infirmary, Harvard Medical School
 Purpose: To the report the in vitro and in vivo results in the development of a latanoprost-eluting contact lens designed for the treatment of glaucoma.

Methods: Drug-eluting therapeutic contact lenses (TCL) were created by encapsulating drug-polymer films in methafilcon A by ultraviolet light polymerization. TCLs were placed in phosphate buffered solution at 37°C with continuous rotation. The release media was sampled and changed daily. Drug concentrations were measured with an enzyme-linked immunosorbent assay (ELISA). TCLs were inserted on the left eye of New Zealand white rabbits for 4 weeks. The eyes were examined under an operating microscope and the anterior chamber (AC) fluid was collected during 28 days of continuous wear. For comparison, latanoprost 0.005% solution (drops) was topically applied and the AC fluid was sampled after drop administration (1, 3, 6, 12, and 24 hrs). Each sample was collected on a different day and the AC drug concentration was measured by ELISA. The 24-hr area under the curve (AUC) for latanoprost drops was calculated and compared to the AC concentration measured during 28 days of TCL wear. 

Results: In vitro, TCLs demonstrated an initial burst and then eluted a sustained and therapeutic daily amount of latanoprost for 4 weeks. In vivo, the TCLs demonstrated no signs of toxicity. Through 28 days of continuous wear, the TCLs delivered a therapeutic level of latanoprost to the anterior chamber without any signs of toxicity.

Conclusions: This contact lens design can potentially be used as a treatment for glaucoma and as a platform for ocular drug delivery with widespread applications.

-Highlight potential future therapeutics
-Discuss the potential of contact lens drug delivery
-Discuss advantages and disadvantages of contact lenses as a means of drug delivery
3:55Oral Presentations from Exemplary Submitted Abstracts
 To be considered for an oral presentation, please submit an abstract here by February 21, 2013. Selected presentations will be based on quality of abstract and availability. Presentation slots fill up fast so please submit your abstract ASAP.
5:30Networking Reception and Poster Session

Day 1Day 2
Day 2 - Friday, March 22, 2013
7:30Continental Breakfast
Panel Discussion: BD, Investments and Potential for Collaborations
8:00Moderator: Emmett Cunningham, Partner, Clarus Ventures
 Panelist: Pharma representative - Baldo Sforzolini, Vice President, Global Drug Development, Bausch & Lomb
 Panelist: Pharma representative
 Panelist: VC representative
 Panelist: VC representative
 Panelist: CEO representative
Session: Clinical Development Advances & Updates 

Barbara Wirostko
Chief Scientific Officer and Co-Founder
Jade Therapeutics
Clinical Adjunct Associate Professor, Ophthalmology 
University of Utah


9:20Kenneth J. Mandell, President and Chief Operating Officer, Xcovery Vision; Research Affiliate, Massachusetts Institute of Technology (MIT)
9:45Morning Networking Break
10:15Casey Kopczynski, Chief Scientific Officer, Aerie Pharmaceuticals
10:40Dark Adaptation: A Functional Clinical Trial Endpoint for Age-related Macular Degeneration
 Gregory Jackson, Associate Professor, Ophthalmology, Penn State University
 Age-related macular degeneration is a progressive chronic retinal disease. AMD causes the deterioration of the Bruch’s membrane/retinal pigment epithelium cell complex which compromises photoreceptor function and health. Disruption of retinal pigment epithelium function alters the retinoid cycle which primarily governs the speed of dark adaptation. Slowed dark adaptation is a prominent deficit of visual function in patients with early AMD. Cone recovery is slower. The rod-cone break and rod intercept are delayed, and the slope of the second component of rod-mediated dark adaptation is shallower. Studies of dark adaptation in AMD patients report increasing impairment of DA with increasing disease severity. This relationship suggests that there is a progressive loss of dark adaptation with disease progression. A significant change in DA parameters within one year might be a useful marker of disease progression which could be modified by therapeutic intervention. To address this possibility, we have conducted a 12-month natural history study of DA in patients with mild to intermediate AMD. We found that nearly 20% of patients with AMD exhibited a significant change in dark adaptation while maintaining stable acuity and AREDS severity grade. This study suggests that dark adaptation may be a suitable functional endpoint for early clinical studies evaluating novel treatments for early to intermediate AMD.

1. A framework for the validation of novel functional clinical trial endpoints will be presented
2. Data will be presented supporting dark adaptation as a clinical trial endpoint for age-related macular degeneration
3. The 12-month natural history of dark adaptation in early to intermediate AMD will be described
11:05Advancing the State of the Art...the True Path for Innovation in Clinical Development
 Philip G. Ralston, Chief Executive Officer, MacuCLEAR
11:30Thrombogenics NV
11:55GTC Sponsored Lunch
Session: Safety Assessment and Regulatory Landscape in Ocular Drug Development
1:00Thirty Years of Developing New Therapeutic Ophthalmic Drugs – Some Simple Principles

Gary Novack
PharmaLogic Development


 The author has been involved in the development of scores of ophthalmic products over the past 30 years. In this talk, he will present a brief list of basic principles of pharmacology, the scientific method, and communication and their application to ophthalmic product development. As well, he will discuss how these product development perspectives align with regulatory laws, regulations and guidances.
1:35Tentative: FDA
Panel Discussion: Safety and Regulatory in Ocular Development
2:10Moderator: TBA
 Panelist:Gary Novack, President, PharmaLogic Development
 Panelist: Judy F. Gordon, Founder and President, ClinReg Consulting Services
 Panelist: Tentative: Michael D. Ackermann, Stanford
 Panelist: Tentative: Susan Orr, Alcon
3:00Conference Concludes
Day 1Day 2
Organized by: GTC Conferences
Invited Speakers:
Samir Patel
President, CEO
Peter Adamson
Vice President and Head of Research, GSK Ophthalmology
Barbara Wirostko
Chief Scientific Officer and Co-Founder
Jade Therapeutics
Clinical Adjunct Associate Professor, Ophthalmology 
University of Utah
Gary Novack
PharmaLogic Development
Sean Caffey
Chairman, CEO and Co-Founder
Chi-Chao Chan
Chief, Immunopathology Section; Laboratory of Immunology; Head, Histopathology Core
National Eye Institute, National Institutes of Health
Joseph B. Ciolino
Assistant Professor, Ophthalmology
Mass. Eye & Ear Infirmary, Harvard Medical School
Emmett Cunningham
Clarus Ventures
Judy F. Gordon
Founder and President
ClinReg Consulting Services
Karsten Gronert
Associate Professor, Ophthalmology
University of California, Berkeley
Gregory Jackson
Associate Professor, Ophthalmology
Penn State University
Eugene de Juan
Founder & Vice-Chairman
ForSight Labs
Casey Kopczynski
Chief Scientific Officer 
Aerie Pharmaceuticals
Lukasz Koroniak
Senior Scientist Formulation Development 
DSM Biomedical
Kenneth J. Mandell
President and Chief Operating Officer
Xcovery Vision
Research Affiliate
 Massachusetts Institute of Technology (MIT)
Samirkumar Patel
Director, Research and New Product Development
Clearside Biomedical
Philip G. Ralston
Chief Executive Officer
Abraham Scaria
Senior Scientific Director
Baldo Sforzolini
Vice President, Global Drug Development
Bausch & Lomb
Justin Shaka
Chief Operating Officer
Martin Wax 
Please check back for updates!
Deadline for Abstracts: 2013-02-21
Registration: https://www.gtcbio.com/index.php?option=com_register&cn=5th%20Ocular%20Diseases%20&cid=23
E-mail: infogtcbio@gtcbio.com
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